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    Method of Providing Sustained Analgesia with Buprenorphine Abstract A method of effectively treating pain in humans is achieved by administering buprenorphine in accordance with first order kinetics over an initial thee-day dosing interval, such that a maximum 5 plasma concentration from about 20pg/mL to about 1052pg/mL is attained, and thereafter maintaining the administration of buprenorphine for at least an additional two-day dosing interval in accordance with substantially zero order kinetics, such that the patients experience analgesia thoughout the at least two-day additional dosing interval.
    公开号:AU2013204227A1
    申请号:U2013204227
    申请日:2013-04-12
    公开日:2013-05-09
    发明作者:Paul D. Goldenhelm；Robert F. Kaiko；Robert F. Reder
    申请人:Euro Celtique SA；
    IPC主号:A61K31-00
    专利说明:
    1 Method of Providing Sustained Analgesia with Buprenorphine Field of the Invention The invention is related to the use of a pharmaceutical medicament for treating patients in pain with buprenorphine which achieves prolonged and effective pain management. 5 Background of the Invention It is the intent of all sustained-release pharmaceutical preparations to provide a longer period of pharmacological effect after the administration of a drug than is ordinarily experienced after the administration of immediate release preparations of the same drug. Such longer periods of efficacy can provide many inherent therapeutic benefits that are not achieved with corresponding immediate 10 release preparations. The benefits of prolonged analgesia afforded by sustained release oral analgesic preparations have become universally recognised and oral opioid analgesic sustained release preparations are commercially available. Prolonged analgesia is particularly desirable in patients suffering from moderate to severe pain, such as cancer patients. Available oral preparations provide a duration of effect lasting eg., about 1s twelve hours (and sometimes 24h) such that a drug may only have to be administered to a patient one to thee times a day. For example, morphine, which has been considered to be the prototypic opioid analgesic, has been formulated into twice-daily, oral controlled release formulations (eg., MS Contin@ tablets, commercially available from The Purdue Frederick Company). Another approach to sustained delivery of a therapeutically active agent are transdermal 20 delivery systems, such as transdermal patches. Generally, transdermal patches contain a therapeutically active agent (eg., an opioid analgesic), a reservoir or matrix containing the opioid or other active ingredient(s) and an adhesive which allows the transdermal device to adhere to the skin, allowing for the passage of the active agent from the device though the skin of the patient. Once the active agent has penetrated the skin layer, the drug is absorbed into the blood stream where it can 25 exert a desired pharmacotherapeutic effect, such as analgesia. Transdermal delivery systems in which an opioid analgesic is the active ingredient have been contemplated. For example, a commercially available opioid analgesic transdermal formulation is Duragesic@ (commercially available from Janssen Pharmaceutical; active ingredient is fentanyl). The Duragesic@ patch is said to provide adequate analgesia for up to 48 to 72h (2 to 3 days). 30 Buprenorphine, a partially synthetic opiate, has also been contemplated for prolonged analgesia. Although other types of opioid analgesic transdermal formulations have been reported in the literature (such as fentanyl, discussed above), buprenorphine transdermal delivery systems are of particular interest because buprenorphine is a potent, partial agonist opioid analgesic with desirable therapeutic properties. For example, buprenorphine is 50 to 100 times more potent than morphine, but 35 has a much safer therapeutic index than morphine (see Wallenstein S L, et aL, Crossover Trials in Clinical Analgesic Assays: Studies of Buprenorphine and Morphine, Pharmacotherapy, G(5): 225-235, 1986 hereby incorporated by reference). Further, the partial agonist properties of buprenorphine are useful in the treatment of opioid addiction.
    2 There are several types of transdermal formulations of buprenorphine reported in the literature. See, for example, US 5 240 711, 5 225 199, 5 069 909, 4 806 341, and 5 026 556, all of which are hereby incorporated by reference. Buprenorphine has a low oral bioavailability and has been considered by certain of those skilled 5 in the art to be like other narcotics which are habit-forming (see, eg., US 5 240 711) and induce tolerance (see, eg., US 5 613 958). As reported in 5 240 711, experts are of the opinion that the form of administration of a medicinal drug contributes to the risk of addiction, and higher than necessary blood levels created immediately after administration of a drug such as buprenorphine, followed by a drastic decrease (causing in succession euphoria and then ineffective pain treatment), cause the 10 patient to start to long for the next dosage (referred to as an "iatrogenic" addiction). In the case of buprenorphine, 5 240 711 reported that continuous infusion would be considered the most suitable mode to avoid such an iatrogenic addition by providing constant blood levels; however, continuous infusion requires physician control and insertion of a cannula (which may cause inflammation at the site). This problem is considered to be overcome by 5 240 711 by virtue of their use of a transdermal 15 delivery system which includes buprenorphine or one of its pharmaceutically compatible salts and which releases the drug over a period of at least 24h in a controlled manner, and ensures that the buprenorphine does not notably decompose when the transdermal delivery system is stored, and which further ensures that the buprenorphine in-vivo penetrates though the skin at the required amount. 20 5 613 958 describes a transdermal system for the modulated administration of tolerance inducing drugs. Buprenorphine is identified therein as such a drug. The system is designed to deliver the drug though the patient's skin via a thee-phase drug delivery profile. In the first phase, which begins with patch application and ends at 2-10h after patch application, plasma levels of the drug are obtained. This phase is followed by a second phase in which therapeutic plasma levels of the drug are 25 maintained. The second phase begins at about two to ten hours after patch application and ends at about 8-18h after patch application. In a third phase, sub-therapeutic levels of the drug are maintained, via inherent patch design and/or patch removal. The rationale behind the drug delivery profile of 5 613 958 is that initial high blood levels may be more effective when followed by a period of decreasing dosage (down to sub-therapeutic levels), than if the blood levels are maintained either at 30 the higher or lower level (ie., sub-therapeutic levels) throughout the entire administration period. By virtue of this modulated profile, it is said that the onset of tolerance to the drug being administered can be prevented or greatly reduced. Despite these advances in the art, there remains a need for methods of treating patients with buprenorphine that provide effective analgesic levels of buprenorphine for prolonged periods of time 35 while eliminating or minimising dependence, tolerance, and side effects, thus providing a safe and effective method of pain management. Objects and Summary of the Invention It is an object of the present invention to provide a method which allows for reduced plasma concentrations of buprenorphine over a prolonged time period than possible according to prior art 40 methods, while still providing effective pain management.
    3 It is a further object of the present invention to provide a method for treating patients in pain with buprenorphine which achieves prolonged and effective pain management, while at the same time provides the opportunity to reduce side effects, dependence and tolerance which the patients may experience when subjected to prolonged treatment with a narcotic such as buprenorphine. 5 It is yet a further object to provide a method for the treatment of pain in patients by utilising a transdermal delivery system which contains buprenorphine in a manner which maximises the dosage interval, ie., the interval during which the transdermal delivery system is maintained in contact with the skin, and minimises the plasma concentrations in the patients during the dosage interval, while surprisingly maintaining effective pain management. 10 A further object of the invention is to provide a method for treating opioid-addicted patients in a manner which gradually reduces the plasma concentration of opioid in the patients' plasma while at the same time providing effective plasma concentrations for those patients to be detoxified. The invention is directed in part to the surprising result that effective pain management is provided by providing a substantially first order rate of increase of blood plasma concentrations of 15 buprenorphine over about a thee day (eg., 72h) time interval, followed by a prolonged time period of at least about two days (eg., 48h) during which the plasma concentrations of buprenorphine are maintained according to substantially zero order pharmacokinetics. In accordance with the above objects and others, the invention relates in part to a method of effectively treating pain in humans, comprising administering buprenorphine to human patients in a 20 manner such that the following mean plasma concentrations are achieved over a 72h dosing interval: a mean plasma concentration from about 0.3 to about 113pg/mL at about 6h after initiation of the dosing interval; a mean plasma concentration from about 3 to about 296pg/mL at about 12h after initiation of the dosing interval; a mean plasma concentration from about 11 to about 644pg/mL at about 24h after initiation of the dosing interval; a mean plasma concentration from about 13 to about 25 630pg/mL at about 30h after initiation of the dosing interval; a mean plasma concentration from about 15 to about 715pg/mL at about 36h after initiation of the dosing interval; a mean plasma concentration from about 20 to about 984pg/mL at about 48h after initiation of the dosing interval; a mean plasma concentration from about 21 to about 914pg/mL at about 60h after initiation of the dosing interval; a mean plasma concentration from about 24 to about 850pg/mL at about 72h after initiation of the 30 dosing interval; and thereafter administering the buprenorphine in a manner such that the mean plasma concentrations are maintained from about 19 to about 850pg/mL over at least the next 48h. In certain preferred embodiments, the dosing interval is maintained over a seven day period. Any mode of administration may be utilised to attain the above plasma concentrations over time. For example, the buprenorphine may be administered transdermally, parenterally, sublingually, 35 orally, buccally, rectally, etc. Oral bioavailability of buprenorphine is very low (estimated as 15%). In order to better control plasma concentrations of buprenorphine within the concentrations desired in the herein-described inventive methods, it is preferred that the buprenorphine is administered via a transdermal delivery system or via continuous infusion. In a further preferred embodiment of the invention, the method comprises applying a 40 transdermal delivery system containing buprenorphine as the active ingredient onto the skin of 4 patients which provide a release rate of buprenorphine over about a 72h dosing interval such that a maximum plasma concentration from about 20pg/mL to about 850pg/mL is attained (depending upon the dosage levels needed to maintain analgesia in the particular patients), and then maintaining the transdermal delivery systems on the skin of the patients for at least an additional 24h interval during 5 which the plasma concentrations of buprenorphine in the patients are maintained above minimum effective concentrations of the drug and the patients continue to experience effective pain management during this additional dosing interval. The invention is further directed to a method of effectively treating pain in humans, comprising administering buprenorphine transdermally to human patients such that mean relative release rates 10 are achieved as follows: a mean relative release rate of from about 3pg/h to about 86pg/h from initiation of the dosing interval until about 72h thereafter; and a mean relative release rate of about 0.3pg/h to about 9pg/h from about 72h after the initiation of the dosing interval until at least about 120h hours after the initiation of the dosing interval. In certain preferred embodiments, the mean relative release rate of about 0.3pg/h to about 9pg/h is maintained from about 72h after the initiation of 1s the dosing interval until at least about 168h after the initiation of the dosing interval. The present invention is further related to a method of effectively treating pain in humans, comprising administering buprenorphine transdermally to human patients such that a mean relative release rate from about 3pg/h to about 86pg/h of buprenorphine is achieved until about 72h after the application of a transdermal delivery system, and thereafter providing (either with the same 20 transdermal delivery system or upon removal of the system and replacement with a different transdermal delivery system) a mean relative release rate of about 0.3pg/h to about 9pg/h from about 72h after the initiation of the dosing interval until at least about 120h after the initiation of the dosing interval, and preferably until at least about 168h after the initiation of the dosing interval. In preferred embodiments, the method comprises the application of a transdermal delivery 25 system which is designed to be provide analgesia for about 72h, and which provides a release rate of the drug when applied to the skin which generally follows first order pharmacokinetics over that 72h period, and further comprises taking advantage of the fact that such transdermal delivery systems typically provide a dramatic drop-off in the release rate of buprenorphine after the first 72h, but nevertheless provide a relatively small but sufficient release of buprenorphine to maintain analgesia 30 and desirable plasma concentrations in the patients over a further period of time of at least, eg., preferably at least 48h, by leaving the transdermal delivery system in contact with the skin of the patient for such additional desired dosing interval, which may be as long as, eg., an additional 96h or more. Surprisingly, it has been found that such transdermal dosage systems exhibit substantially zero order release after about the initial 72h dosage interval, and therefore are capable of maintaining 35 effective plasma concentrations of buprenorphine for a much longer period than previously reported in the prior art. However, the inventive method also contemplates the possibility of utilising a first transdermal delivery system which provides the desired substantially first order kinetics, and thereafter the removal of the first transdermal delivery system and its replacement with a second system which provides the desired substantially zero order pharmacokinetics for a prolonged period of 40 time (eg., at least about 24h, preferably at least about 48h, and most preferably about 96h). This 5 second system may be a second transdermal delivery system which provides the afore-mentioned mean relative release rate of about 0.3pg/h to about 9pg/h. On the other hand, the second system may even utilise a different mode of administration, for example, continuous infusion. The present invention is also related, in part, to a method of effectively treating pain in patients, 5 comprising applying onto the skin of the patients a transdermal delivery system containing buprenorphine which transdermal delivery system delivers the buprenorphine substantially according to first order kinetics to provide a mean plasma concentration from about 24 to about 850pg/mL about 3 days after application, and then maintaining the transdermal buprenorphine formulation in contact with the skin of the human patient for about 2 to about 6 additional days without removing the 10 transdermal formulation, such that the patient continues to receive effective analgesia from the transdermal buprenorphine formulation. The invention also provides, in certain preferred embodiments, an improvement in a method of treating pain in human patients by applying a 3 day transdermal delivery system containing buprenorphine onto the skin of the patient and maintaining the transdermal delivery system in contact 15 with the skin for a 3 day dosing interval, the transdermal delivery system containing an amount of buprenorphine sufficient to provide effective analgesia in the patient for about 3 days, the improvement comprising maintaining the transdermal dosage form in contact with the patient's skin for at least 2 to about 6 additional days beyond the 3 day dosing interval. The present invention also relates to a method of treating opioid addiction by administering 20 buprenorphine transdermally to human patients which provides a release rate of the drug when applied to the skin which generally follows first order pharmacokinetics over a 72h period, such that the addict attains a buprenorphine plasma concentration from about 1000 to about 10 000pg/mL, and preferably from about 5000 to about 8000pg/mL, about 72h after application of a buprenorphine transdermal delivery system, and thereafter maintaining the transdermal delivery system in contact 25 with the skin of the addict such that a mean relative release rate of buprenorphine approximating zero order kinetics over an additional dosing interval of at least about 48h, to provide the desired therapeutic effect (detoxification). In preferred embodiments the transdermal delivery system is maintained in contact with the addict's skin for about 7 days. The methods of the present invention are described in further detail in the following sections. 30 However, it should be understood that for purposes of the present invention, the following terms have the following meanings: The term "effective analgesia" is defined for purposes of the present invention as a satisfactory reduction in or elimination of pain, along with the process of a tolerable level of side effects, as determined by the human patient. 35 The term "effective pain management" means for purposes of the present invention as the objective evaluation of a human patient's response (pain experienced versus side effects) to analgesic treatment by a physician as well as subjective evaluation of therapeutic treatment by the patient undergoing such treatment. The skilled artisan will understand that effective analgesia will vary according to many factors, including individual patient variations.
    6 The term "breakthrough pain" means pain which the patient experiences despite the fact that the patient is being administered generally effective amounts of, eg., an opioid analgesic such as buprenorphine. The term "rescue" refers to a dose of an analgesic which is administered to a patient 5 experiencing breakthrough pain. The term "first order" pharmacokinetics is defined as plasma concentrations which increase over a specified time period. Drug release from suspension matrices according to first order kinetics may be defined as follows: Amount released per area unit Q De 2.C - C,.C, .t (First order kinetics) 10 Deff apparent diffusion coefficient M / t = 2.C. D Co = initial drug concentration in the transdermal delivery system Cs = saturation concentration t = time Assumptions: perfect sink; diffusion of dissolved drug is rate controlling; therefore 15 Q ~ const.1 Drug release from solution matrices according to first order kinetics may be defined as follows: Amount released per area unit Q = f. D . -j(First order kinetics) Assumptions: perfect sink; diffusion of dissolved drug is rate controlling; M, <; 0.4M therefore Q ~ const.J 20 The term "zero order" pharmacokinetics contemplates an amount of drug released from a buprenorphine formulation which substantially maintains plasma concentrations at a relatively constant level. For purposes of the present invention, a relatively constant plasma concentration is defined as a concentration which does not decrease more than about 30% over a 48h time period. Drug release from membrane-controlled systems may be defined as follows: 25 Amount released per area unit Q = const (zero order kinetics) The term "mean relative release rate" is determined from the amount of drug released per unit time from the transdermal delivery system though the skin and into the bloodstream of a human patient. Mean relative release rate may be expressed, eg, as pg drug/cm 2 /h. For example, a transdermal delivery system that releases 1.2mg of buprenorphine over a time period of 72h is 30 considered to have a relative release rate of 16.67pg/h. For purposes of the invention, it is understood that relative release rates may change between any particular time points within a particular dosing interval, and the term therefore only reflects the overall release rate during the particular dosing interval. For purposes of the present invention, relative release rate should be considered synonymous with the term "flux rate". 35 The term "sustained release" is defined for purposes of the present invention as the release of the drug (opioid analgesic) from the transdermal formulation at such a rate that blood (eg., plasma) concentrations (levels) are maintained within the therapeutic range (above the minimum effective 7 analgesic concentration or "MEAC") but below toxic levels over a period of time of about 3 days or longer. The term "steady state" means that the blood plasma concentration curve for a given drug has been substantially repeated from dose to dose. 5 The term "minimum effective analgesic concentration" is defined for purposes of this invention as the minimum effective therapeutic blood plasma level of the drug at which at least some pain relief is achieved in a given patient. It will be well understood by those skilled in the medical art that pain measurement is highly subjective and great individual variations may occur among patients. For purposes of the present invention, the term "buprenorphine" shall include buprenorphine 10 base, pharmaceutically acceptable salts thereof, stereoisomers thereof, ethers and esters thereof, and mixtures thereof. The term "overage" means for the purposes of the present invention the amount of buprenorphine contained in a transdermal delivery system which is not delivered to the patient. The overage is necessary for creating a concentration gradient by means of which the active agent (eg., 15 buprenorphine) migrates though the layers of the transdermal dosage form to the desired site on a patient's skin. Brief Description of the Drawings The following drawings are illustrative of embodiments of the invention and are not meant to limit the scope of the invention as encompassed by the claims. 20 Figure 1 is a graphical representation of the mean plasma concentration (pg/mL) versus time (days) for Example 1; Figure 2 is a graphical representation of pharmacodynamic variables versus time (days) for Example 1; Figure 3 is a graphical representation of the plasma concentration (pg/mL) over time (hours) for 25 Comparative Example A; Figure 4 is a graphical representation of the plasma concentration (pg/mL) over time (hours) for Comparative Example B (intravenous concentrations divided by 100); Figure 5 is a graphical representation of the plasma concentration (pg/mL) over time (hours) for Comparative Example C; 30 Figure 6 is a graphical representation pharmacodynamic variables versus time (hours) for Comparative Example A; Figure 7 is a graphical representation pharmacodynamic variables versus time (hours) for Comparative Example B; Figure 8 is a graphical representation pharmacodynamic variables versus time (hours) for 35 Comparative Example C; Figure 9 is a graphical representation of the plasma concentration (pg/mL) over time (hours) for Comparative Example D; Figure 10 is a graphical representation of the plasma concentration (pg/mL) over time (hours) for Comparative Example E; 8 Figure 11 is a graphical representation of the plasma concentration (pg/mL) over time (hours) for Comparative Example F; Figure 12 is a graphical representation pharmacodynamic variables versus time (hours) for Comparative Example D; 5 Figure 13 is a graphical representation pharmacodynamic variables versus time (hours) for Comparative Example E; and Figure 14 is a graphical representation pharmacodynamic variables versus time (hours) for Comparative Example F. Detailed Description 10 While chronic pain is often manageable with the use of the combination of 'mild" analgesics, and nonpharmacological interventions, selected patients continue to experience unacceptably intense pain. Some patients with chronic pain cannot tolerate therapeutic doses of 'mild" analgesics, while others develop pain of such severity that 'strong" analgesics should be considered for subacute or chronic use 1s The phase 'strong analgesics" encompasses, inter alia, several classes of opioid analgesics, including the partial agonists. Parenteral buprenorphine (a Schedule V drug under the Controlled Substances Act) is the only example of a partial agonist opioid analgesic currently marketed in the United States. Partial agonists provide several therapeutic advantages in many patients when compared to 20 morphine-like agonists and mixed agonists-antagonists. For example, unlike the mixed agonists antagonists (eg., pentazocine, butorphanol, nalbuphine), buprenorphine is devoid of psychotomimetic adverse reactions; in comparison with agonists (eg., morphine and fentanyl), the dose-responsive relationship for respiratory depression with buprenorphine is relatively low and the abuse liability of buprenorphine is less. 25 The chemical of name of buprenorphine is 21 -cyclopropyl-7o-[(S)-1-hydroxy-1,2,2 tr methylpropyl]-6,14-endo-ethano-6,7,8,14-tetrahIydrooripavine The molecular weight of buprenorphine base is 467.7; the empirical formula is C 2 9HtNO 4 The structural formula of buprenorphine is shown below: HO MN
    H
    3 0 H HO CH 3
    C(CH
    3
    )
    3 Ko Buprenorphine is an opioid partial agonist and shares many of the actions, such as analgesia, of opioid agonists. A 'ceiling effect" to analgesia (ie., no additional analgesia with increasing dose) is well documented with respect to buprenorphine in many animal models. It is highly lipophilic and dissociates slowly from opioid receptors. Buprenorphine is considered in the ad to be a partial agonist at p opioid receptors in the central nervous system ('CNS") and peripheral tissues. It is furtherthought 9 that buprenorphine binds with high affinity to p and Ki receptors, and, with lower affinity, to delta. receptors. The intrinsic agonist activity at the .kappa. receptor seems to be limited and most evidence suggests that buprenorphine has antagonist activity at K receptors. The lack of K agonism accounts for buprenorphine's freedom from the dysphoric and psychotomimetic effects often seen with 5 agonist/antagonist drugs. Other studies suggest that the opioid antagonist effects of buprenorphine may be mediated via an interaction with 6 opioid receptors. It is known in the art that buprenorphine binds slowly with, and dissociates slowly from, the p receptor. The high affinity of buprenorphine for the p receptor and its slow binding to, and dissociation from, the receptor is thought to possibly account for the prolonged duration of analgesia, and in part, 10 for the limited physical dependence potential observed with the drug. The high affinity binding may also account for the fact that buprenorphine can block the p agonist effects of other administered opioids. Like other opioid agonists, buprenorphine produces dose-related analgesia. The exact mechanism has not been fully explained, but analgesia appears to result from a high affinity of 15 buprenorphine for p and possibly K opioid receptors in the CNS. The drug may also alter the pain threshold (threshold of afferent nerve endings to noxious stimuli). On a weight basis, the analgesic potency of parenteral buprenorphine appears to be about 25 to about 50 times that of parenteral morphine, about 200 times that of pentazocine, and about 600 times that of meperidine. Buprenorphine may produce sex-related differences in analgesia, with females requiring substantially 20 less drug than males to produce adequate analgesia. For a study of transdermal delivery of buprenorphine though cadaver skin, see Roy, Samir D. et aL, "Transdermal Delivery of Buprenorphine Though Cadaver Skin", Journal of Pharmaceutical Sciences, Vol. 83, No. 2, pp. 126-130, (1994), hereby incorporated by reference. For a discussion of buprenorphine pharmacokinetics resulting from application of a fillable transdermal therapeutic 25 system, see Wilding, I. R. et aL, "Pharmacokinetic evaluation of transdermal buprenorphine in man," International Journal of Pharmaceutics, 132 (1996) pp. 81-87, hereby incorporated by reference. For a discussion of the permeation of buprenorphine and alkyl esters thereof, see Imoto, et aL, "Transdermal Prodrug Concepts: Permeation of Buprenorphine and its Alkyl Esters Though Hairless Mouse Skin and Influence of Vehicles," Biol. Pharm. Bull., 19(2)263-267 (1996), hereby incorporated 30 by reference. Buprenorphine has a low abuse liability compared to full agonist opioids. Although infrequent, however, buprenorphine may also produce limited physical dependence, and signs and symptoms of mild withdrawal may appear following discontinuance of prolonged therapy with the drug alone. Due to buprenorphine's slow binding with and slow dissociation from the p receptor, elimination of the drug 35 from the CNS is prolonged following abrupt discontinuance; consequently, signs and symptoms of acute withdrawal are less intense than those produced by morphine and are delayed in appearance. In patients physically dependent on opioids, buprenorphine produces many of the subjective and objective effects of opioids; however, the drug may not be a satisfactory substitute for opioid agonists in all patients physically dependent on opioids. Tolerance to the opiod agonist activity of the 40 drug reportedly develops rarely, if at all.
    10 Buprenorphine may produce psychological dependence. Buprenorphine is a partial opioid agonist with behavioural and psychic effects similar to morphine. Unlike pentazocine, however, buprenorphine rarely causes psychotomimetic effects. Like other opioid agonists, buprenorphine may produce increases in cerebrospinal fluid pressure. 5 The pharmacokinetics of buprenorphine administered parenterally and sublingually are known. Intravenous administration of a single dose of about 0.3mg of buprenorphine has been shown to provide mean peak plasma drug concentrations of about 18ng/mL which occur within about 2 minutes; plasma concentrations declined to about 9 and about 0.4ng/mL after about 5 minutes and about 3h, respectively. Following intramuscular administration of a second 0.3mg dose 3h after the initial 10 intravenous dose, mean peak plasma buprenorphine concentrations of about 3.6ng/mL occur within about 2 to about 5 minutes and decline to about 0.4ng/mL after about 3h. Approximately 10 minutes after administration, plasma concentrations of buprenorphine are similar following intravenous or intramuscular injection. A parenteral solution of buprenorphine hydrochloride (0.3mg buprenorphine/mL) is 15 commercially available as Buprenex@ (Reckitt & Colman) for intramuscular and intravenous administration. The usual adult dose (over age 13) is 0.3mg IM or IV every 6 to 8h as needed for moderate to severe pain. The paediatric dose in patients age 2 to 12 is 2-6pg/kg of body weight every 4-6h. The increased frequency of administration in the paediatric population is believed to be caused by increased clearance of buprenorphine compared to the adult population. The mean duration of 20 analgesia generally is six hours following single intramuscular or intravenous doses of 0.2 to 0.3mg or 2 to 4pg/kg; however, in some studies, the mean duration of analgesia reportedly ranged from 4 to 10h following single intramuscular doses of 0.2 to 0.6mg and 2 to 24h following single intravenous doses of 0.3mg or 2 to 15pg/kg. For reference, the mean peak plasma buprenorphine concentration, time to peak concentration, 25 and systemic availability for a 0.4mg and 0.8mg single-dose sublingual dose of buprenorphine has been reported by Cowan, Alan and Lewis John, W., Buprenorphine: Combating Drug Abuse With a Unique Opioids, Wiley-Liss, Inc., New York, pp. 137-147 (1995), hereby incorporated by reference in its entirety. For a 0.4mg sublingual dose, the Cmax was reported as 0.50±0.06ng/mL; the Tmax was reported 210±40 minutes; and a systemic availability of 57.7%±6. For a 0.8mg sublingual dose, the 30 Cmax was reported as 1.04±0.27ng/mL; the Tmax was reported 192±49 minutes; and a systemic availability of 54.1%±12.7. It has previously been reported that a usual sublingual analgesic dose of buprenorphine is 0.2 to 0.4mg every 8h (eg., Kuhlman, J J et al. J Analyt Toxicol 1996; 20(10)). For a transdermal patch which might provide a nominal delivery rate of about 12.5pg/h, the total buprenorphine administered 35 over a 24h period would be about 0.3mg, and the sublingual equivalent dose over the same period would be about 0.6mg. For a transdermal delivery system (eg., a transdermal patch) which might provide a nominal delivery rate of about 25pg/h, the total buprenorphine administered over a 24h period would be about 0.6mg, and the sublingual equivalent dose over the same period would be about 1.2mg. For a transdermal patch which might provide a nominal delivery rate of about 50pg/h, 40 the total buprenorphine administered over a 24h period would be about 1.2mg, and the sublingual 11 equivalent dose over the same period would be about 2.4mg. It is contemplated that one of ordinary skill in the art will appreciate that by simple pharmaceutical calculations, the equivalent doses for achieving the inventive buprenorphine plasma concentration set forth herein can be determined regardless of the mode of administration. In the present discussion, the comparison is made between 5 transdermal dose and sublingual dose. Distribution of buprenorphine into human body tissues and fluids has not been well characterised. Following oral or intramuscular administration in rats, buprenorphine distributes into the liver, brain, placenta, and GI tract; highest concentrations were attained in the liver within 10 or 40 minutes following oral or intramuscular administration, respectively. The hepatic extraction ratio of 10 buprenorphine is approximately 1. The drug and its metabolites are distributed into bile. Following intravenous administration in humans, the drug rapidly distributes into cerebro spinal fluid ("CSF")(within several minutes). CSF buprenorphine concentrations appear to be approximately 15% to 25% of concurrent plasma concentrations. Buprenorphine is approximately 96% bound to plasma proteins, mainly to .varies. and .beta. globulins; the drug does not appear to bind substantially to 15 albumin. Buprenorphine is almost completely metabolised in the liver, principally by N-dealkylation, to form norbuprenorphine (N-dealkylbuprenorphine); buprenorphine and norbuprenorphine also undergo conjugation with glucuronic acid. Like the metabolites of other opioid agonists, norbuprenorphine may have weak analgesic activity; however, studies to determine the analgesic activity of the metabolites 20 of buprenorphine have not been performed. Buprenorphine and its metabolites are excreted principally in faeces via biliary elimination and also in urine. Buprenorphine is excreted in faeces mainly as unchanged drug; small amounts of norbuprenorphine are also excreted in faeces. The drug and its metabolites are believed to undergo enterohepatic circulation. Norbuprenorphine appears to be excreted principally in urine at a slower 25 rate than the parent drug. Total plasma clearance of buprenorphine reportedly is approximately 1.28L/minute in conscious postoperative patients. Limited data indicate that there is considerable interindividual variability in buprenorphine pharmacokinetics in children; however, clearance of the drug appears to be increased in children (eg., those 5 to 7 years of age) compared with that in adults. Optimal dosing interval of buprenorphine may have to be decreased in paediatric patients. 30 Achieving effective analgesic plasma opioid concentrations in patients is very complicated and involves a host of considerations, including the inherent chemical and physical properties of the opioid itself. Further considerations include in-vivo metabolism, individual patient response and tolerance. Generally, however, there is a "minimally effective analgesic concentration" (MEAC) in plasma for a particular opioid below which no analgesia is provided. There is relationship between plasma opioid 35 levels and analgesia. Higher plasma levels are generally associated with greater pain relief, and (possibly) greater incidence and severity of side effects. In preferred embodiments of the present invention where the patient(s) is being treated for moderate to severe pain, the buprenorphine is administered in a manner such that the following mean plasma concentrations are achieved over a 72h dosing interval: a mean plasma concentration from 40 about 0.3 to about 113pg/mL at about 6h after initiation of the dosing interval; a mean plasma 12 concentration from about 3 to about 296pg/mL at about 12h after initiation of the dosing interval; a mean plasma concentration from about 7 to about 644pg/mL at about 24h after initiation of the dosing interval; a mean plasma concentration from about 13 to about 753pg/mL at about 36h after initiation of the dosing interval; a mean plasma concentration from about 16 to about 984pg/mL at about 48h after 5 initiation of the dosing interval; a mean plasma concentration from about 20 to about 984pg/mL at about 60h after initiation of the dosing interval; a mean plasma concentration from about 21 to about 1052pg/mL at about 72h after initiation of the dosing interval. Thereafter, the buprenorphine is administered in a manner such that the mean plasma concentrations are maintained from about 19 to about 1052pg/mL over at least the next 48h. In further preferred embodiments, this method further 10 comprises maintaining the dosing of buprenorphine during the at least next 48h in accordance with zero order kinetics. Preferably, the mean plasma concentrations are maintained after the 72h dosing interval as follows: a mean plasma concentration from about 23 to about 1052pg/mL at about 96h after initiation of the dosing interval; a mean plasma concentration from about 23 to about 1052pg/mL at about 120h after initiation of the dosing interval; a mean plasma concentration from about 22 to 15 about 970pg/mL at about 144h after initiation of the dosing interval; and a mean plasma concentration from about 19 to about 841 pg/mL at about 168h after initiation of the dosing interval (for a seven day dosing interval). In this embodiment where a transdermal delivery system is used, a mean relative release rate from about 3pg/h to about 86pg/h is preferably maintained from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate is 20 preferably maintained from about 0.3pg/h to about 9pg/h from about 72h after the initiation of the dosing interval until the end of the dosing interval. Preferably, the administration of buprenorphine is accomplished via a mode selected from the group consisting of transdermally, continuous infusion, and a mixture of transdermally and continuous infusion. Most preferably, the administration is accomplished by applying a transdermal delivery 25 system to the skin of a patient, and maintaining said transdermal delivery system in contact with the patient's skin for at least 5 days. In a further preferred embodiment of the invention, buprenorphine is administered to human patients in a manner such that the following mean plasma concentrations are achieved over a 72h dosing interval: a mean plasma concentration from about 1 to about 28pg/mL at about 6h after 30 initiation of the dosing interval; a mean plasma concentration from about 14 to about 74pg/mL at about 12h after initiation of the dosing interval; a mean plasma concentration from about 30 to about 161 pg/mL at about 24h after initiation of the dosing interval; a mean plasma concentration from about 51 to about 188pg/mL at about 36h after initiation of the dosing interval; a mean plasma concentration from about 62 to about 246pg/mL at about 48h after initiation of the dosing interval; a mean plasma 35 concentration from about 79 to about 246pg/mL at about 60h after initiation of the dosing interval; a mean plasma concentration from about 85 to about 263pg/mL at about 72h after initiation of the dosing interval. Thereafter, buprenorphine is administered in a manner such that the mean plasma concentrations are maintained from about 77 to about 263pg/mL over at least the next 48h. Preferably, the plasma concentrations are maintained after the 72h dosing interval as follows: a mean 40 plasma concentration from about 92 to about 263pg/mL at about 96h after initiation of the dosing 13 interval; a mean plasma concentration from about 94 to about 263pg/mL at about 120h after initiation of the dosing interval; a mean plasma concentration from about 86 to about 243pg/mL at about 144h after initiation of the dosing interval; and a mean plasma concentration from about 77 to about 21Opg/mL at about 168h after initiation of the dosing interval (for a seven day dosing interval). In this 5 embodiment wherein a transdermal delivery system is used, it is preferred that a mean relative release rate of from about 13pg/h to about 21pg/h is maintained from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and that a mean relative release rate of about 1 pg/h to about 2pg/h from about 72h after the initiation of the dosing interval until the end of the dosing interval is maintained (eg., about 168h after initiation for a seven-day dosing interval). 10 In a further preferred embodiment of the invention, buprenorphine is administered to human patients in a manner such that the following mean plasma concentrations are achieved over a 72h dosing interval: a mean plasma concentration from about 0.3 to about 7pg/mL at about 6h after initiation of the dosing interval; a mean plasma concentration from about 4 to about 19pg/mL at about 12h after initiation of the dosing interval; a mean plasma concentration from about 7 to about 40pg/mL 15 at about 24h after initiation of the dosing interval; a mean plasma concentration from about 13 to about 47pg/mL at about 36h after initiation of the dosing interval; a mean plasma concentration from about 16 to about 62pg/mL at about 48h after initiation of the dosing interval; a mean plasma concentration from about 21 to about 62pg/mL at about 60h after initiation of the dosing interval; a mean plasma concentration from about 20 to about 66pg/mL at about 72h after initiation of the dosing 20 interval. Thereafter, the buprenorphine is administered in a manner such that the mean plasma concentrations are maintained from about 19 to about 66pg/mL over at least the next 48h. Preferably, the buprenorphine is administered in a manner such that the mean plasma concentrations are maintained as follows: a mean plasma concentration from about 23 to about 66pg/mL at about 96h after initiation of the dosing interval; a mean plasma concentration from about 23 to about 66pg/mL at 25 about 120h after initiation of the dosing interval; a mean plasma concentration from about 22 to about 61 pg/mL at about 144h after initiation of the dosing interval; and a mean plasma concentration from about 19 to about 53pg/mL at about 168h after initiation of the dosing interval (for a seven day dosing interval). In embodiments where a transdermal delivery system is used, a mean relative release rate is maintained from about 3pg/h to about 5pg/h from the initiation of the dosing interval until about 72h 30 after the initiation of the dosing interval; and a mean relative release rate of about 0.3pg/h to about 0.6pg/h from about 72h after the initiation of the dosing interval until the end of the dosing interval (eg., about 168h after initiation of a seven-day dosing interval). In a further preferred embodiment of the invention, buprenorphine is administered to human patients in a manner such that the following mean plasma concentrations are achieved over a 72h 35 dosing interval: a mean plasma concentration from about 0.7 to about 14pg/mL at about 6h after initiation of the dosing interval; a mean plasma concentration from about 7 to about 37 pg/m at about 12h after initiation of the dosing interval; a mean plasma concentration from about 15 to about 80pg/mL at about 24h after initiation of the dosing interval; a mean plasma concentration from about 25 to about 94pg/mL at about 36h after initiation of the dosing interval; a mean plasma concentration 40 from about 31 to about 123pg/mL at about 48h after initiation of the dosing interval; a mean plasma 14 concentration from about 40 to about 123pg/mL at about 60h after initiation of the dosing interval; a mean plasma concentration from about 42 to about 132pg/mL at about 72h after initiation of the dosing interval. Thereafter, the buprenorphine is administered in a manner such that the mean plasma concentrations are maintained from about 38 to about 132pg/mL over at least the next 48h. 5 Preferably, the buprenorphine is further administered in a manner such that the mean plasma concentrations are maintained as follows: a mean plasma concentration from about 46 to about 132pg/mL at about 96h after initiation of the dosing interval; a mean plasma concentration from about 47 to about 132pg/mL at about 120h after initiation of the dosing interval; a mean plasma concentration from about 43 to about 121pg/mL at about 144h after initiation of the dosing interval; 10 and a mean plasma concentration from about 38 to about 105pg/mL at about 168h after initiation of the dosing interval (for a seven day dosing interval). In embodiments where a transdermal delivery system is used, a mean relative release rate from about 6pg/h to about 11 pg/h is maintained from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 0.7pg/h to about 1 pg/h is maintained from about 72h after the initiation of 1s the dosing interval until the end of the dosing interval (eg., about 168h after initiation of a seven day dosing interval). In a further preferred embodiment of the invention, buprenorphine is administered to human patients in a manner such that the following mean plasma concentrations are achieved over a 72h dosing interval: a mean plasma concentration from about 3 to about 57pg/mL at about 6h after 20 initiation of the dosing interval; a mean plasma concentration from about 28 to about 148pg/mL at about 12h after initiation of the dosing interval; a mean plasma concentration from about 59 to about 322pg/mL at about 24h after initiation of the dosing interval; a mean plasma concentration from about 102 to about 377pg/mL at about 36h after initiation of the dosing interval; a mean plasma concentration from about 124 to about 492pg/mL at about 48h after initiation of the dosing interval; a 25 mean plasma concentration from about 159 to about 492mL at about 60h; after initiation of the dosing interval; a mean plasma concentration from about 169 to about 526pg/mL at about 72h after initiation of the dosing interval. Thereafter, the buprenorphine is administered in a manner such that the mean plasma concentrations are maintained from about 153 to about 526pg/mL over at least the next 48h. Preferably, the buprenorphine is administered in a manner such that the mean plasma concentrations 30 are maintained as follows: a mean plasma concentration from about 184 to about 526pg/mL at about 96h after initiation of the dosing interval; a mean plasma concentration from about 187 to about 526pg/mL at about 120h after initiation of the dosing interval; a mean plasma concentration from about 173 to about 485pg/mL at about 144h after initiation of the dosing interval; a mean plasma concentration from about 153 to about 420pg/mL at about 168h after initiation of the dosing interval 35 (for a seven day dosing interval). In embodiments where a transdermal delivery system is used, a mean relative release rate from about 26pg/h to about 43pg/h is maintained from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 2pg/h to about 4pg/h is maintained from about 72h after the initiation of the dosing interval until the end of the dosing 40 interval (eg., about 168h after initiation of a seven-day dosing interval).
    15 In a further preferred embodiment of the invention, buprenorphine is administered to human patients in a manner such that the following mean plasma concentrations are achieved over a 72h dosing interval: a mean plasma concentration from about 4 to about 85pg/mL at about 6h after initiation of the dosing interval; a mean plasma concentration from about 42 to about 222pg/mL at 5 about 12h after initiation of the dosing interval; a mean plasma concentration from about 89 to about 483pg/mL at about 24h after initiation of the dosing interval; a mean plasma concentration from about 152 to about 565pg/mL at about 36h after initiation of the dosing interval; a mean plasma concentration from about 186 to about 738pg/mL at about 48h after initiation of the dosing interval; a mean plasma concentration from about 238 to about 738pg/mL at 60h after initiation of the dosing 10 interval; a mean plasma concentration from about 254 to about 789pg/mL at about 72h after initiation of the dosing interval. Thereafter; the buprenorphine is administered in a manner such that the mean plasma concentrations are maintained from about 230 to about 789pg/mL over at least the next 48h. Preferably, the buprenorphine is administered in a manner such that the mean plasma concentrations are maintained as follows: a mean plasma concentration from about 276 to about 789pg/mL at about 15 96h after initiation of the dosing interval; a mean plasma concentration from about 281 to about 789pg/mL at about 120h after initiation of the dosing interval; a mean plasma concentration from about 259 to about 727pg/mL at about 144h after initiation of the dosing interval; a mean plasma concentration from about 230 to about 630pg/mL at about 168h after initiation of the dosing interval (for a seven day dosing interval). 20 In embodiments where a transdermal delivery system is used, a mean relative release rate of from about 38pg/h to about 64pg/h is maintained from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 4pg/h to about 7pg/h is maintained from about 72h after the initiation of the dosing interval until the end of the dosing interval (eg., about 168h after the initiation of a seven-day dosing interval). 25 In a further preferred embodiment of the invention, buprenorphine is administered to human patients in a manner such that the following mean plasma concentrations are achieved over a 72h dosing interval: a mean plasma concentration from about 5 to about 113pg/mL at about 6h after initiation of the dosing interval; a mean plasma concentration from about 55 to about 296pg/mL at about 12h after initiation of the dosing interval; a mean plasma concentration from about 118 to about 30 644pg/mL at about 24h after initiation of the dosing interval; a mean plasma concentration from about 203 to about 753pg/mL at about 36h after initiation of the dosing interval; a mean plasma concentration from about 247 to about 984pg/mL at about 48h after initiation of the dosing interval; a mean plasma concentration from about 317 to about 984pg/mL at about 60h after initiation of the dosing interval; a mean plasma concentration from about 339 to about 1052pg/mL at about 72h after 35 initiation of the dosing interval. Thereafter, the buprenorphine is administered in a manner such that the mean plasma concentrations are maintained from about 306 to about 1052pg/mL over at least the next 48h. Preferably, the buprenorphine is administered in a manner such that the mean plasma concentrations are maintained as follows: a mean plasma concentration from about 369 to about 1052pg/mL at about 96h after initiation of the dosing interval; a mean plasma concentration from 40 about 374 to about 1052pg/mL at about 120h after initiation of the dosing interval; a mean plasma 16 concentration from about 346 to about 970pg/mL at about 144h after initiation of the dosing interval; a mean plasma concentration from about 306 to about 841pg/mL at about 168h after initiation of the dosing interval (for a seven day dosing interval). In embodiments where a transdermal delivery system is used, a mean relative release rate of from about 51 pg/h to about 86pg/h is maintained from the 5 initiation of the dosing interval until about 72h after the initiation of the, eg., dosing interval; and a mean relative release rate of about 5pg/h to about 9pg/h is maintained from about 72h after the initiation of the dosing interval until the end of the dosing interval, eg., about 168h after the initiation of a seven-day dosing interval (eg., about 168h after the initiation of a seven-day dosing internal). In further embodiments of the invention, the method comprises the administration of 10 buprenorphine transdermally to human patients according to very different relative release rates for the first 3 day portion of the dosing interval (indicative of substantially first order release), and the additional at least 2 day long portion of the dosing interval (substantially zero order release) such that mean relative release rates are achieved over the dosing interval as follows: a mean relative release rate of from about 3pg/h to about 86pg/h from the initiation of the dosing interval until about 72h after 1s the initiation of the dosing interval; and a mean relative release rate of about 0.3pg/h to about 9pg/h from about 72h after the initiation of the dosing interval until the end of the dosing interval (eg., about 168h after the initiation of a seven-day dosing interval). In one preferred embodiment, the mean relative release rates achieved over the dosing interval are as follows: a mean relative release rate of from about 3pg/h to about 5pg/h from the initiation of 20 the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 0.3pg/h to about 0.6pg/h from about 72h after the initiation of the dosing interval until the end of the dosing interval (eg., about 168h after initiation of a seven-day dosing interval). In another preferred embodiment, the mean relative release rates achieved over the dosing interval are as follows: a mean relative release rate of from about 6pg/h to about 11 pg/h from the 25 initiation of the dosing interval until about 72h after the initiation of dosing interval; and a mean relative release rate of about 0.7pg/h to about 1 pg/h from about 72h after the initiation of the dosing interval until the end of the dosing interval (eg., about 168h after initiation of a seven-day dosing interval). In another preferred embodiment, the mean relative release rates achieved over the dosing interval are as follows: a mean relative release rate of from about 13pg/h to about 21pg/h from the 30 initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 1pg/h to about 2pg/h from about 72h after the initiation of the dosing interval until the end of the dosing interval (eg., about 168h after initiation of a seven-day dosing interval). In yet another preferred embodiment, the mean relative release rates achieved over the dosing 35 interval are as follows: a mean relative release rate of from about 26pg/h to about 43pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 3pg/h to about 4pg/h from about 72h after the initiation of the dosing interval until the end of the dosing interval (eg., about 168h after the initiation of a seven-day dosing interval).
    17 In yet a further preferred embodiment, the mean relative release rates achieved over the dosing interval are as follows: a mean relative release rate of from about 39pg/h to about 64pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 4pg/h to about 7pg/h from about 72h after the initiation of the dosing 5 interval until the end of the dosing interval (eg., about 168h after the initiation of a seven-day dosing interval). In yet a further preferred embodiment, the mean relative release rates achieved over the dosing interval are as follows: a mean relative release rate of from about 51pg/h to about 86pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean 10 relative release rate of about 5pg/h to about 9pg/h from about 72h after the initiation of the dosing interval until the end of the dosing interval, eg., about 168h after the initiation of the dosing interval. The method of the present invention may be accomplished by any mode of administration useful for buprenorphine known to those skilled in the art. However, certain modes of administration are more practical than others. Preferably, the mode of administration is via continuous infusion, 1s though the oral mucosa, or most preferably, transdermally. In embodiments of the invention where the plasma concentrations described herein are accomplished intravenous infusion, the pattern of plasma concentrations seen though time in this invention can be achieved by using the injectable, parenteral form of, eg., buprenorphine hydrochloride suitably diluted in an intravenous infusion solution. The infusion rate would be controlled 20 by a programmable infusion pump, to provide the desired plasma profile. In preferred embodiments of the invention, the mode of administration of the buprenorphine is transdermal. Transdermal delivery of active agents is measured in terms of "relative release rate" or "flux", ie., the rate of penetration of the active agent though the skin of an individual. Skin flux may be generally determined from the following equation: 25 dM/dt=J=P*C where J is the skin flux, P is the permeability coefficient and C is the concentration gradient across the membrane, assumed to be the same as the donor concentration. M represents the cumulative amount of drug entering the blood stream. The variables dM and dt represent the change in cumulative amount of drug entering the blood stream and change in time, respectively. 30 It is well understood in the art of transdermal delivery systems that in order to maintain a desired flux rate for a desired dosing period, it is necessary to include an overage of active agent in the transdermal delivery system in an amount that is substantially greater than the amount to be delivered to the patient over the desired time period. For example, to maintain the desired flux rate for a thee day time period, it is considered necessary to include much greater than 100% of a thee day 35 dose of an active agent in a transdermal delivery system. This overage is necessary for creating a concentration gradient by means of which the active agent migrates though the layers of the transdermal delivery system to the desired site on a patient's skin. The remainder of the active agent remains in the transdermal delivery system. It is only the portion of active agent that exits the transdermal delivery system that becomes available for absorption into the skin. The total amount of 40 active agent absorbed into the patient's blood stream is less than the total amount available. The 18 amount of overage to be included in a transdermal delivery system is dependent on these and other factors known to the skilled artisan. Surprisingly, it has been found that it is possible to treat pain according to the present invention by providing a transdermal delivery system containing a sufficient amount of opioid, eg. 5 buprenorphine, to provide a desired relative release rate for up to 3 days, and after single administration (application) of the transdermal dosage form, leaving the dosage form on the skin for approximately a 5 to 8 day time period, thereby resulting in the flux being maintained over the prolonged period and effective blood plasma levels and pain management being maintained over the prolonged period. Preferably, the desired flux is maintained at least about 5, preferably at least about 10 8 days after application of the transdermal delivery system. If the transdermal delivery system is removed 3 days after its administration, no analgesia is present a short time after removal. Surprisingly however, if the same transdermal delivery system is maintained in contact with the skin for an about 5 to about 8 day period, analgesia is maintained over the prolonged period of contact, but the patient continues to experience analgesia. In other words, inclusion of the aforementioned 15 overage of buprenorphine provides analgesia for at least about twice the expected 3 day dosing interval. Any type of transdermal delivery system may be used in accordance with the methods of the present invention so long as the desired pharmacokinetic and pharmacodynamic response(s) are attained over at least 3 days, eg., from about 5 to about 8 days. Preferable transdermal delivery 20 systems include eg., transdermal patches, transdermal plasters, transdermal discs, iontophoretic transdermal devices and the like. Transdermal dosage forms used in accordance with the invention preferably include a backing layer made of pharmaceutically acceptable material which is impermeable to the buprenorphine. The backing layer preferably serves as a protective cover for the active agent, eg. buprenorphine and may 25 also provide a support function. Examples of materials suitable for making the backing layer are films of high and low density polyethylene, polypropylene, polyvinylchloride, polyurethane, polyesters such as poly(ethylene phthalate), metal foils, metal foil laminates of such suitable polymer films, textile fabrics, if the components of the reservoir cannot penetrate the fabric due to their physical properties and the like. Preferably, the materials used for the backing layer are laminates of such polymer films 30 with a metal foil such as aluminium foil. The backing layer can be any appropriate thickness which will provide the desired protective and support functions. A suitable thickness will be from about 10 to about 200 microns. Desirable materials and thickness will be apparent to the skilled artisan. In certain preferred embodiments, the transdermal dosage forms used in accordance with the invention contain a polymer matrix layer. Generally, the polymers used to form the biologically 35 acceptable polymer matrix are those capable of forming thin walls or coatings though which pharmaceuticals can pass at a controlled rate. A non-limiting list of exemplary materials for inclusion in the polymer matrix includes polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethylacrylate copolymers, ethylenevinyl acetate copolymers, silicones, rubber, rubber-like synthetic homo-, co- or block polymers, polyacrylic esters and the copolymers thereof, polyurethanes, 40 polyisobutylene, chlorinated polyethylene, polyvinylchloride, vinyl chloride-vinyl acetate copolymer, 19 polymethacrylate polymer (hydrogel), polyvinylidene chloride, poly(ethylene terephthalate), ethylene vinyl alcohol copolymer, ethylene-vinyloxyethanol copolymer, silicones including silicone copolymers such as polysiloxane-polymethacrylate copolymers, cellulose polymers (eg., ethyl cellulose, and cellulose esters), polycarbonates, polytetrafluoroethylene and mixtures thereof 5 Preferred materials for inclusion in the polymer matrix layer are silicone elastomers of the general polydimethylsiloxane structures, (eg., silicone polymers). Preferred silicone polymers cross link and are pharmaceutically acceptable. Other preferred materials for inclusion in the polymer matrix layer include: silicone polymers that are cross-linkable copolymers having dimethyl and/or dimethylvinyl siloxane units which can be crosslinked using a suitable peroxide catalyst. Also 10 preferred are those polymers consisting of block copolymers based on styrene and 1,3-dienes (particularly linear styrene-isoprene-block copolymers of styrene-butadiene-block copolymers), polyisobutylenes, polymers based on acrylate and/or methacrylate. The polymer matrix layer may optionally include a pharmaceutically acceptable crosslinking agent. Suitable crosslinking agents include, eg., tetrapropoxy silane. 15 Preferred transdermal delivery systems used in accordance with the methods of the present invention include an adhesive layer to affix the dosage form to the skin of the patient for a desired period of administration, eg., about 5 to about 8 days. If the adhesive layer of the dosage form fails to provide adhesion for the desired period of time, it is possible to maintain contact between the dosage form with the skin by, for instance, affixing the dosage form to the skin of the patient with an adhesive 20 tape, eg, surgical tape. It is not critical for purposes of the present invention whether adhesion of the dosage form to the skin of the patient is achieved solely by the adhesive layer of the dosage form or in connection with a peripheral adhesive source, such as surgical tape, provided that the dosage form is adhered to the patient's skin for the requisite administration period. The adhesive layer preferably includes using any adhesive known in the art that is 25 pharmaceutically compatible with the dosage form and preferably hypoallergenic, such as polyacrylic adhesive polymers, acrylate copolymers (eg., polyacrylate) and polyisobutylene adhesive polymers. In other preferred embodiments of the invention, the adhesive is a pressure-sensitive contact adhesive, which is preferably hypoallergenic. The transdermal dosage forms which can be used in accordance with the present invention 30 may optionally include a permeation enhancing agent. Permeation enhancing agents are compounds which promote penetration and/or absorption of the buprenorphine into the blood stream of the patient. A non-limiting list of permeation enhancing agents includes polyethylene glycols, surfactants, and the like. Alternatively, permeation of buprenorphine may be enhanced by occlusion of the dosage form 35 after application to the desired site on the patient with, eg. an occlusive bandage. Permeation may also be enhanced by removing hair from the application site by, eg. clipping, shaving or use of a depilatory agent. Another permeation enhancer is heat. It is thought that heat enhancement can be induced by, among other things, using a radiating heat form, such as an infrared lamp, onto the application site after application of the transdermal dosage form.
    20 Other means of enhancing permeation of buprenorphine such as the use of iontophoretic means are also contemplated to be within the scope of the present invention. A preferred transdermal dosage form which may be used in accordance with the present invention includes a non-permeable backing layer made, for example, of polyester; an adhesive layer 5 made, for example of a polyacrylate; and a matrix containing the buprenorphine and other desirable pharmaceutical aids such as softeners, permeability enhancers, viscosity agents and the like. The active agent may be included in the device in a drug reservoir, drug matrix or drug/adhesive layer. Preferably, the active agent is buprenorphine or a pharmaceutically acceptable salt thereof. 10 Certain preferred transdermal delivery systems also include a softening agent. Suitable softening agents include higher alcohols such as dodecanol, undecanol, octanol, esters of carboxylic acids, wherein the alcohol component may also be a polyethoxylated alcohol, diesters of dicarboxylic acids, such as di-n-butyladiapate, and triglycerides particularly medium-chain triglycerides of the caprylic/capric acids or coconut oil, have proved to be particularly suitable. Further examples of 15 suitable softeners are multivalent alcohols, for example, levulinic acid, cocprylic acids glycerol and 1,2-propanediol which can also be etherified by polyethylene glycols. A buprenorphine solvent may also be included in the transdermal delivery systems of the present invention. Preferably, the solvents dissolve the buprenorphine to a sufficient extent thereby avoiding complete salt formation. A non-limiting list of suitable solvents include those with at least one 20 acidic group. Particularly suitable are monoesters of dicarboxylic acids such as monomethylglutarate and monomethyladipate. Other pharmaceutically acceptable compounds which may be included in the reservoir or matrix include: solvents, for example alcohols such as isopropanol; permeation enhancing agents such as those described above; and viscosity agents, such as cellulose derivatives, natural or synthetic gums, 25 such as guar gum, and the like. In preferred embodiments, the transdermal dosage form includes a removable protective layer. The removable protective layer is removed prior to application, and consists of the materials used for the production of the backing layer described above provided that they are rendered removable, for example, by a silicone treatment. Other removable protective layers, for example, are 30 polytetrafluoroethylene, treated paper, allophane, polyvinyl chloride, and the like. Generally, the removable protective layer is in contact with the adhesive layer and provides a convenient means of maintaining the integrity of the adhesive layer until the desired time of application. The composition of the transdermal dosage forms used in accordance with the invention and the type of device used are not considered critical to the method of the invention, provided that the 35 device delivers the active agent, eg. buprenorphine, for the desired time period and at the desired flux rate and/or the desired delivery rate of the transdermal dosage form. Certain preferred transdermal dosage forms for use in accordance with the present invention are described in US. 5 240 711, hereby incorporated by reference. Such buprenorphine transdermal delivery systems may be a laminated composite having an impermeable backing layer containing 40 buprenorphine, and optionally, a permeation enhancer combined with a pressure-sensitive adhesive.
    21 A preferred transdermal dosage form in accordance with 5 240 711 includes: (i) a polyester backing layer which is impermeable to buprenorphine; (ii) a polyacrylate adhesive layer; (iii) a separating polyester layer; and (iv) a matrix containing buprenorphine, a solvent for the buprenorphine, a softener and a polyacrylate adhesive. The buprenorphine solvent may or may not be present in the final 5 formulation. The transdermal delivery device described therein includes a backing layer which is impermeable to the active substance, a pressure-sensitive adhesive reservoir layer and optionally, a removable protective layer. Preferably, the reservoir layer includes about 10 to about 95wt% polymeric material, about 0.1 to about 40wt% softener, about 0.1 to about 30wt% buprenorphine. A solvent for the buprenorphine base or pharmaceutically acceptable salt thereof may be included as 10 about 0.1 to about 30wt%. In a preferred embodiment, the transdermal delivery system is prepared in accordance with Example 1 appended hereto. In this example, the transdermal delivery system was prepared in accordance with the disclosure of W096/19975, hereby incorporated by reference. In this device, the buprenorphine transdermal delivery device contains resorption-promoting 15 auxiliary substances. The resorption-promoting auxiliary substance forms an undercooled mass. The delivery system contains 10% buprenorphine base, 10-15% acid (such as levulinic acid), about 10% softener (such as oleyoleate); 55-70% polyacrylate; and 0-10% polyvinylpyrollidone (PVP). In embodiments of the present invention wherein the buprenorphine plasma concentrations described herein are achieved via the use of a transdermal delivery device prepared in accordance 20 with W096/19975, it is contemplated for example that the nominal delivery rate of buprenorphine from such patches will be, eg., from about 12.5 to about 100pg/h. In certain preferred embodiments, in order to achieve a nominal delivery rate of 12.5pg/h, the total of buprenorphine included in the transdermal patch is about 5mg, the active surface area is about 6.25cm 2 and the patch size may be, eg., about 19.4cm 2 . In certain preferred embodiments, in order to achieve a nominal delivery rate of 25 25pg/h, the total of buprenorphine included in the transdermal patch is about 10mg, the active surface area is about 12.5cm 2 and the patch size may be, eg., about 30.6cm 2 . In certain preferred embodiments, in order to achieve a nominal delivery rate of 50pg/h, the total of buprenorphine included in the transdermal patch is about 20mg, the active surface area is about 25cm 2 and the patch size may be, eg., about 51.8cm 2 . In certain preferred embodiments, in order to achieve a nominal 30 delivery rate of 75pg/h, the total of buprenorphine included in the transdermal patch is about 30mg, the active surface area is about 37.5cm 2 and the patch size may be, eg., about 69.8cm 2 . In certain preferred embodiments, in order to achieve a nominal delivery rate of 100pg/h, the total of buprenorphine included in the transdermal patch is about 40mg, the active surface area is about 50cm 2 and the patch size may be, eg., about 87.8 cm 2 . 35 In accordance with a method of the invention, the above-described transdermal delivery system has been designed to be adhered to the patient for only thee days and is expected to release analgetically effective doses of buprenorphine for only about 3 days. Instead, in accordance with the present invention, the transdermal delivery device is maintained in contact with the skin of the patient for a much longer time period, eg., from about 5 to about 8 days, without any change in the 40 formulation of the transdermal device itself. It has surprisingly been found that analgesia is maintained 22 for this extended period of time (the time beyond the useful life designed for the transdermal formulation). In other embodiments, the buprenorphine transdermal delivery system may be a plaster such as that described in US 5 225 199, hereby incorporated by reference. Such plasters include a film 5 layer including a polyester film of about 0.5 to about 4.9pm thickness, about 8 to about 85g/mm strength, respectively in the two directions intersecting substantially at right angles, about 30 to about 150% elongation, in the two directions intersecting substantially at right angles and an elongation ratio of A to B of about 1.0 to about 5.0, wherein A and B represent data in two directions intersecting at right angles, and A is greater than B and wherein said polyester film includes about 0.01 to about 10 1.0wt%, based on the total weight of the polyester film, of solid fine particles in which the average particle size is about 0.001 to about 3.Opm and an adhesive layer which is composed of an adhesive containing transdermally absorbable drugs; wherein the adhesive layer is laminated on said film layer over the surface in about 2 to about 60pm thickness. The average particle size is substantially not more than 1.5 times the thickness of the polyester film. 1s The transdermal delivery system used in the present invention may also be prepared in accordance with US 5 069 909, hereby incorporated by reference. This patent describes a laminated composite for administering buprenorphine transdermally to treat pain. The composite includes an impermeable backing layer providing a protective covering for the composite which may be made from an elastomeric polymer such as polyurethane, polyether amide, or copolyester and may be about 15 20 250pm in thickness. The composite further includes a reservoir lamina composed of buprenorphine (base or HCI) in n amount of 1-12wt% and a pressure-sensitive adhesive, eg., polyisobutylene, or a silicone adhesive such as silastic, or an acrylate adhesive, and 2-35% permeation enhancer (comprising propylene glycol monolaurate in combination with capric acid or oleic acid). The amounts of buprenorphine and permeation enhancer are sufficient to cause the buprenorphine to pass though 25 the skin at a rate of about 1 to 1 00pg/cm 2 /h. The transdermal delivery system used in the present invention may also be prepared in accordance with US 4 806 341, hereby incorporated by reference. This patent describes a transdermal morphinan narcotic analgesic or antagonist (including buprenorphine) pharmaceutical polymer matrix dosage unit having a backing layer which is substantially impervious to the 30 buprenorphine, and a polymer matrix disc layer which is adhered to the backing layer and which has microdispersed therein effective dosage amounts of the buprenorphine. The polymer matrix may be a silicon polymer or copolymer, such as methyl silicone polymer or copolymer, or methylvinyl silicone polymer or copolymer. The polymer matrix layer preferably has dispersed therein a skin permeation enhancing agent such as isopropyl myristate, azone, or a combination of ethyl caprylate and capryl 35 alcohol. The transdermal delivery system used in the present invention may also be that described in US 5 026 556 , hereby incorporated by reference. Therein, compositions for the transdermal delivery of buprenorphine comprise buprenorphine in a carrier of a polar solvent material selected from the group consisting of C 3
    -C
    4 diols, C 3
    -C
    6 triols, and mixtures thereof, and a polar lipid material selected 40 from the group consisting of fatty alcohol esters, fatty acid esters, and mixtures thereof; wherein the 23 polar solvent material and the lipid material are present in a weight ratio of solvent material:lipid material of from 60:40 to about 99:1. The transdermal delivery system used in the present invention may also be that described in US 4 588 580, hereby incorporated by reference. That system comprises a reservoir for the drug 5 having a skin proximal, material releasing surface area in the range of about 5-100cm 2 and containing between 0.1 and 50wt% of a skin permeable form of the buprenorphine. The reservoir contains an aqueous gel comprising up to about 47-95% ethanol, 1-10% gelling agent, 0.1-10% buprenorphine, and release rate controlling means disposed in the flow path of the drug to the skin which limits the flux of the buprenorphine from the system though the skin. The release rate controlling means is more 10 permeable to the buprenorphine than to the ethanol, and may be for example low density polyethylene (LDPE), ethylene-vinyl acetate (EVA) copolymers, heat sealable polyesters, and elastomeric polyester block copolymers, such as HYTREL@ from DuPont. This system is said to be capable of providing an administration rate of about 10-300pg/h. It is contemplated that each of the transdermal delivery systems described herein (other than the system exemplified in Example 1 appended hereto) would 15 require minor manipulation in order to achieve the methods of the invention. Such modifications are within the abilities of one skilled in the art of formulating such transdermal delivery systems. The present invention may also be accomplished via the use of a sustained oral mucosal delivery system. Such a system is described by McQuinn, R. L. et al., "Sustained Oral Mucosal Delivery in Human Volunteers J. Controlled Release; (34) 1995 (243-250). Therein, oral mucosal 20 patches were prepared by homogeneously mixing buprenorphine free base (8%), Carbopol 934 (52%), polyisobutylene (35%) and polyisoprene (5%, w/w) via a two-roll mill and then compressing the mixture to the appropriate thickness. A membrane backing (ethylcellulose) was applied to one side of the compressed material and then circular disks (0.5cm 2 ) were punched from the material. The backing was included in order to retard drug release from one side of the disk and to prohibit adhesion 25 to opposing side tissues. Each soft, flexible disk was approximately 0.6mm thick and contained 2.9mg buprenorphine. These patches were worn by the subjects for 12h. Gum and lip application was tested, although adhesion at the gum site was considered superior. After the initial appearance of serum buprenorphine (oo25pg/mL), levels generally increased relatively rapidly and persisted until the patch was removed. After the patch was removed, buprenorphine levels fell promptly and were at a 30 relatively low (but measurable) level by 24h post-dose. It was estimated that 0.42±0.18mg were delivered via the gum treatment. From this discussion, it is apparent that an oral mucosal patch can be prepared which will provide plasma concentrations considered desirable according to the present invention. A significantly higher incidence in side effects such as nausea, vomiting or drowsiness would 35 normally be expected when high blood levels of opioid analgesics are administered. The present invention, by maintaining a lower blood level of drug over the 7 day dosing period while maintaining effective pain management, has a lower incidence of side effects. In comparison, a much higher plasma concentration is seen in patients over the same period of time when a new transdermal delivery device of the same strength is put on every thee days, and therefore increased side effects 40 are expected with each new 3 day transdermal application.
    24 In general, upon administration of an opioid analgesic, there is a lag time or "hysteresis", between the pharmacodynamic effects and the time course of opioid plasma concentration levels. Generally, peak plasma level concentrations are often attained prior to exhibition of the maximum pharmacotherapeutic or side effect response. It has been surprisingly discovered that the method 5 according to the present invention provides a "reverse hysteresis", ie. the rise in plasma concentrations follow the appearance and rise of certain of the pharmacodynamic events and side effects. Detailed Description of Preferred Embodiments The following examples illustrate various aspects of the present invention. They are not to be 10 construed to limit the claims in any manner whatsoever. Example 1 A seven day pharmacokinetic/pharmacodynamic study was conducted on 24 healthy human patients. The subjects were comprised of approximately an equal number of male and female subjects. In this study, the buprenorphine was administered via a transdermal patch which is 15 described in W096/19975. The transdermal patch is prepared in accordance with the disclosure of WO 96/19975 for Example 1 therein as follows: 1.1 39g of a 47.83w/% polyacrylate solution with a self netting acrylate copolymers containing 2 ethylhexylacrylates, vinyl acetates, acrylic acid (dissolving agent:ethyl 20 acetate:heptan:isopropanol:toluol:acetylacetonate in the ratio of 37:26:26:4:1), 100g laevulinic acid, 150g oleyloleate, 100g polyvinylpyrollidone, 150g ethanol, 200g ethyl acetate and 100g buprenorphine base are homogenised. The mixture is stirred for about 2h and then examined visually to determine if all solid substances have been dissolved. One has to control the evaporation loss by method of weighing back and makes up for the solvent with the help of ethylacetate, if necessary. 25 Thereafter, the mixture is put onto a 420 mm wide, transparent polyester foil, since the surface weight of the dried layer of paste is 80g/m 2 . The polyester foil which can be dissolved again with treatment of silicone serves as a protective layer. The solvent is removed by drying with heated air which is led over a moist lane. With this treatment of warmth not only do solvents evaporate but the laevulinic acid melts as well. Thereafter, the sealing film is covered with a polyester foil 15pab. A surface of about 30 16cm 2 is cut with the help of the appropriate cutting tool, and the rims that have been left between the individual systems are removed. The formulation utilised for Example 1 is substantially the same as that described in Example 3 of W096/19975, which is prepared in accordance with Example 1 and is stated therein to include 10% buprenorphine, 10% levulinic acid, 10% polyvinylpyrollidone, 10% oleyloeate, and 60% polyacrylate. 35 In order to achieve the nominal delivery rate of 25ug/h expected for the formulation of Example 1, the total of buprenorphine included in the transdermal patch is about 10mg, the active surface area is about 12.5cm 2 and the patch size may be, eg., about 30.6cm 2 . The dosing regimen was one (1) patch containing 10mg buprenorphine base/patch reservoir applied to the subject's skin and maintained in contact with the skin for a time period of seven (7) 40 days.
    25 The adhesive patch with the medication being tested was placed on the right midaxilliary line at the level of the 5th intercostal space at approximately 0800h on day 1. For patch application, the skin was washed with lukewarm soapy water, then rinsed with clear water and left to air dry. The skin was not rubbed while it was being washed. The application site was relatively hairless. Hair was not 5 clipped or shaven. The patches were removed at approximately 0800h on day 8. Following patch removal, the patch site was not washed or rubbed until the last blood collection for that treatment period was over. Each patch was placed unfolded onto its release liner and the patch/release liner unit was placed back in the correct pouch, which was then sent to a bioanalytical laboratory for residual buprenorphine assay. 10 Blood sampling (10mL at each time point) started on day 1, and continued thereafter at the following times: 1 h (pre-dose) and at regular intervals thereafter during the 7 day dosing interval. Patch site skin observations of the patch sites were performed by the investigator/staff rating the quality of the skin at the site of the actual medication reservoir of the patch at Oh (prior to patch placement) and 30 minutes after patch removal. The rating scale was as follows: 15 Erythema: 0 = No visible redness; 1 = Very slight redness (just perceptible); 2 = Slight but well defined redness; 3 = Moderately intense redness; 4 = Severe erythema (dark red discolouration of the skin). Oedema: 0 = No visible reactions; 1 = Very mild oedema (just perceptible); 2 = Mild oedema (corners of the area are well defined due to noticeable swelling); 3 = Moderate oedema (up to 1 mm 20 swelling in diameter); 4 = Severe oedema (more than 1 mm swelling in diameter, protruding over the edges of the patch). The following pharmacokinetic parameters were estimated: AUC(O-last) (pg.h/mL)-the area under the curve from time zero to the time of last non-zero plasma buprenorphine concentration, calculated by the linear trapezoidal method; Cmax (pg/mL)-maximum observed plasma buprenorphine 25 concentration over the dosing interval; if Cmax occurs at more than one time point, Tmax is defined as the time point for the first Cmax ; residual = buprenorphine remaining in used patches (mg/patch). A summary of the plasma buprenorphine concentrations (provided in picograms per millilitre, or pg/mL), is set forth in Table 1 below: Table 1
    HOURS
    1
    MEAN
    2 STD. DEV 3 CV %4 6 1.76 6.20 352.77 12 18.47 26.00 140.78 18 39.45 36.16 91.67 24 58.94 44.66 75.76 30 67.69 48.78 72.06 36 82.44 53.02 64.32 42 107.61 65.43 60.81 48 104.69 60.69 57.97 54 105.81 66.68 63.02 60 112.93 63.02 55.81 66 129.25 64.37 49.80 72 130.55 64.16 49.14 78 122.83 54.97 44.75 84 129.03 51.50 39.92 26
    HOURS
    1
    MEAN
    2 STD. DEV 3 CV%4 90 139.50 68.26 48.93 96 146.70 62.76 42.78 102 130.19 57.68 44.31 108 135.49 67.72 49.98 114 150.24 71.69 47.72 120 136.22 63.62 46.70 126 130.25 57.77 44.35 132 124.78 52.82 42.34 138 138.55 58.34 42.11 144 115.23 48.30 41.92 150 116.30 49.04 42.16 156 120.07 50.88 42.38 162 117.66 52.71 44.80 168 102.00 49.92 48.94 1 h after administration of dose (eg., application of patch) 2 mean blood plasma concentration for the 24 test subjects (pg/mL) 3 standard deviation of mean blood plasma concentrations 4 coefficient of variation (%) 5 The mean plasma concentrations are further depicted in Figure 1 (concentration pg/mL vs. time (days)). It is apparent from the pharmacokinetic results obtained with respect to Example 1 that the mean blood plasma concentrations rose steadily and peaked at about the 3-day time point during the dosing interval (eg., about 72h after application of the patch), and thereafter surprisingly remained relatively steady throughout the remaining portion of the dosing interval (eg. to about the 7-day time 10 point, 168h after initiation of the dosing interval). Further, it is apparent from the buprenorphine plasma concentrations that first order kinetics were present during the first 72h of the dosing interval, and substantially zero order kinetics were present thereafter. A summary of the pharmacokinetic parameters obtained for Example 1 are set forth in Table 2 below: 15 Table 2 Mean Std. Dev. Geometric Mean CV % AUC (0-168h) 17740.68 7503.50 16263.88 42.30 Cmax (pg/mL) 184.80 68.84 171.78 37.25 Tmax (h) 110.50 26.48 23.96 The following pharmacodynamic parameters were assessed 5 minutes prior to each blood collection by having each patient respond to several questions by placing a vertical mark at the appropriate spot on a 100mm visual analog scale ("VAS") anchored on one end by "not at all" and on the other end by "an awful lot". The first question asked to the subjects was "Do you feel any effect of 20 the drug " After the patient marked his/her response on the VAS to this question, responses were obtained via the VAS as to whether the subjects had experienced (i) nausea, (ii) dizziness, and (iii) sleepiness. The results are set forth in Table 3. All pharmacodynamic parameters were summarised and tabulated. Then a mixed (linear or non-linear) effect was used to model the pharmacokinetic and pharmacodynamic relationships. The results concerning pharmacodynamic parameters (VAS) are set 25 forth in Figure 2.
    27 Table 3 Summary of severity for the most commonly reported (> 10% of subjects) adverse events (related to treatment) (N= 24) MILD MODERATE SEVERE TOTAL N (%) N (%) N (%) N (%) CONSTIPATION 3 12.5 0 0.0 0 0.0 3 12.5 DIZZINESS 8 33.3 0 0.0 0 0.0 8 33.3 HEADACHE 7 29.2 0 0.0 0 0.0 7 29.2 NAUSEA 6 25.0 0 0.0 0 0.0 6 25.0 RASH 20 83.3 0 0.0 0 0.0 20 83.3 SOMNOLENCE 11 45.8 0 0.0 0 0.0 11 45.8 VOMITING 2 8.3 1 4.2 0 0.0 3 12.5 As can be seen from the results set forth in Table 3, there was only one incident of a moderate 5 adverse event, and no incidents of severe adverse events reported by the test subjects during the application interval. Further, turning to Figure 2, it can be seen that the level of dizziness, nausea and sleepiness significantly decreased after day 3 of the dosage interval. Other side effects such as headache, vomiting and constipation were also low in occurrence. Table 4 provides a summary of the amount of drug which was measured as remaining in the 10 patches which were removed from the subjects after 7 days. Table 4 Amount left in patch (mg) MEAN 8.59 SE 0.11 % RELEASED (ASSAY) MEAN 14.02 SE 1.08 Comparative Examples A-C A thee (3) treatment, randomised, crossover study was conducted in normal volunteers. The treatments consisted of Comparative Example A (a single application buprenorphine transdermal 15 delivery system); Comparative Example B (a single dose of buprenorphine administered intravenously) and Comparative Example C (3 sequential applications, every three days, of the buprenorphine transdermal delivery system used in Comparative Example A). A 10-14 day washout period intervened between the first dosing (application) day of each treatment. For the buprenorphine transdermal delivery system, the wash-out started when the third sequential patch was removed. This 20 study was not analytically blinded due to analytical chemistry considerations and different sampling times. The buprenorphine transdermal delivery system (patch) used in Comparative Examples A and C contained 20mg buprenorphine base, and is prepared in accordance with Example 1. It was contemplated that the buprenorphine patch of Comparative Examples A and C would provide 25 approximately double the dose and approximately double the relative release rate as compared to the buprenorphine patch of Example 1. For Comparative Examples A and C, it was contemplated that approximately 1.2mg buprenorphine would be released from the patch per day, which is equivalent to an intravenous dose of 0.3mg every 6h. The reference buprenorphine intravenous injection (Comparative Example B) was 0.3mg (Temgesic@) Injectable 0.3mg/mL, [1 mL/vial]).
    28 In Comparative Example A, the buprenorphine transdermal delivery system (single dose) was adhered to a relatively hairless area of a subject's right thorax at the level of the fifth intercostal space in the midaxilliary line at approximately 8 am on day 1 and removed at approximately 8 am on day 4. For Comparative Example A (buprenorphine transdermal delivery system single dose), blood 5 sampling was conducted as follows: Day 1: 0, (buprenorphine transdermal delivery system adhered) 2, 3, 4, 6, 8, 10, 12, and 16h; Day 2: 0, 6, 12h; Day 3: 0, 12h; Day 4: 0 (prior to removal), 0.25, 0.5, 0.75, 1, 2, 3, 6, 12h post-removal; Day 5: 0, 12h; Day 6: 0, 12h; Day 7: Oh. With respect to Comparative Example B, buprenorphine intravenous (IV) injection, 0.3mg was infused over 2 minutes at approximately 8 am on day 1 though an in-dwelling cannula in the right 10 anticubital vein. The buprenorphine intravenous 0.3mg blood sampling was conducted as follows: Day 1: 0, 1, 2, 3, 5, 10, 15, 20, 25, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 10, 12, 24h; arterial blood sampling (left radial artery) for the first 4h; venous blood sampling from 2h post-dose to 24h post dose. Therefore arterial and venous blood sampling occurred simultaneously 2, 3 and 4h post-dose. With respect to Comparative Example C, the buprenorphine transdermal delivery system (3 15 sequential applications), was adhered to a relatively hairless area of a subject's right thorax at the level of the fifth intercostal space in the midaxilliary line at approximately 8 am on day 1 and removed at approximately 8 am on day 4. The second buprenorphine transdermal delivery system 50pg/h was placed just adjacent to the first patch after the first was removed on day 4 at approximately 8 am and removed on day 7 at approximately 8 am. The third buprenorphine transdermal delivery system 20 50pg/h was placed just adjacent to the second patch but not in the same place as the first patch after the second patch is removed on day 7 at approximately 8 am and removed on day 10 at approximately 8 am. Blood samples for Comparative Example C, buprenorphine transdermal delivery system 3 sequential applications, were obtained as follows: Day 1: 0, (buprenorphine transdermal delivery system adhered), 2, 3, 4, 6, 8, 10, 12, and 16h; Day 2: 0, 6, 12h; Day 3: 0, 12h; Day 4: 0 25 (prior to removal), and 2, 3, 4, 6, 8, 10, 12, 16h (after second buprenorphine transdermal delivery system adhered); Day 5: 0, 6, 12h; Day 6: 0, 12h; Day 7: 0 (prior to removal), and 2, 3, 4, 6, 8, 10, 12, 16h (after third buprenorphine transdermal delivery system adhered); Day 8: 0, 6, 12h; Day 9: 0, 12h; Day 10: 0 (prior to buprenorphine transdermal delivery system removal), and 0.25, 0.5, 0.75, 1, 2, 3, 6, 12h (post-removal); the wash-out period started after patch removal on Day 10; Day 11: 0, 12h; 30 Day 12: 0, 12h; and Day 13: 0. The pharmacokinetic variables determined for Comparative Examples A-C were as follows: AUC(o-ast) : pg-h/mL--The area under the curve, as calculated by the linear trapezoidal method, up to the last observed value; AUCn : pg-h/mL--The area under the curve, calculated using the linear trapezoidal method; 35 Cmax:pg/mL--Maximum measured plasma buprenorphine over the time span specified; Tmax :h--Time of the maximum measured plasma buprenorphine; when the maximum value occurs in more than one time point, Tmax is defined as the first time point with this value; T(1/2)elm : The plasma half life of buprenorphine elimination, defined as ln 2 /Keim, where Keim is the apparent first order elimination constant. The elimination rate constant was obtained from the slope of 29 the terminal portion of the plasma-concentration time curve determined by regression analysis techniques; T(1/2)abs : The absorption half life of transdermal buprenorphine elimination, defined as ln2/Kabs, where Kabs is the apparent first order absorption constant. Absorption rate was calculated only for the 5 transdermal buprenorphine; CI:mL/min or L/h--Total clearance characterises the clearing of the hypothetical plasma volume of drug per unit time; Vd : L or L/kg--Hypothetical volumes in which the drug is distributed in the body; and Absorption Rate:pg/h--The rate at which buprenorphine enters the systemic circulation. 10 Plasma concentration data was analysed using standard noncompartmental and compartmental techniques to derive pharmacokinetic parameters. In addition, various exploratory methods including fitting the intravenous data to pharmacokinetic models to determine which model best describes the data, and deconvolution analysis to determine the absorption rate was employed. Other parameters such as clearance, volumes of distribution, absorption rate, amount absorbed and 15 bioavailability were determined by either standard noncompartmental or compartmental analysis or exploratory methods. The intravenous data was also analysed utilising compartmental modelling techniques. A summary of plasma buprenorphine concentrations for Comparative Example A is provided in Table 5 below: 20 Table 5 Comparative Example A HOUR MEAN PLASMA CONC. (pg/mL) STD. DEV CV % 2 2.04 5.87 287.10 3 7.96 16.28 204.47 4 14.84 18.63 125.51 6 23.49 25.81 109.85 8 42.34 37.91 89.52 10 72.03 71.36 99.07 12 85.96 68.69 79.90 16 133.89 103.43 77.25 24 175.58 120.17 68.44 30 169.15 108.65 64.23 36 200.16 134.45 67.17 48 251.10 156.66 62.39 60 250.11 125.01 49.98 72 286.50 131.58 45.92 78 168.73 61.26 36.30 84 114.68 52.72 45.97 96 90.75 39.12 43.11 108 56.82 25.66 45.17 120 44.85 23.80 53.06 132 30.40 21.87 71.95 144 29.14 20.27 69.58 A summary of plasma buprenorphine concentrations (pg/mL) for Comparative Example C at each sampling time is set forth in Table 6 below: 30 Table 6 Comparative Example C HOUR MEAN PLASMA CONC. (pg/mL) STD. DEV CV % 2 0.54 2.63 489.90 3 5.70 13.18 231.23 4 10.33 14.64 141.71 6 28.84 31.19 108.13 8 54.62 65.83 120.52 10 78.92 81.23 102.93 12 95.14 75.70 79.57 16 162.26 114.80 70.75 24 218.57 153.58 70.27 30 206.10 141.70 68.75 36 205.08 110.76 54.01 48 265.04 123.66 46.66 60 256.18 133.48 52.11 72 306.02 152.77 49.92 74 278.22 135.14 48.57 75 245.91 112.66 45.82 76 237.01 83.41 35.19 78 213.54 94.42 44.22 80 215.45 103.75 48.15 82 216.00 107.68 49.85 84 210.52 107.67 51.14 88 219.77 110.46 50.26 96 269.91 134.61 49.87 102 205.54 102.03 49.64 108 225.11 87.97 39.08 120 310.27 153.57 49.50 132 300.34 157.05 52.29 144 305.99 159.75 52.21 146 301.39 141.37 46.91 147 289.96 132.91 45.84 148 287.68 151.93 52.81 150 260.04 130.19 50.07 152 236.61 119.77 50.62 154 284.15 158.84 55.90 156 271.83 145.11 53.38 160 303.46 182.37 60.10 168 340.71 209.87 61.60 174 302.22 179.74 59.47 180 322.67 183.63 56.91 192 395.95 220.27 55.63 204 344.83 201.90 58.55 216 415.33 229.92 55.36 216.25 388.64 186.67 48.03 216.50 390.97 208.34 53.29 216.75 392.63 188.89 48.11 217 399.51 197.86 49.53 218 312.65 173.12 55.37 219 295.17 148.13 50.18 222 201.37 85.54 42.48 228 173.89 75.96 43.68 240 119.13 48.99 41.13 31 HOUR MEAN PLASMA CONC. (pg/mL) STD. DEV CV % 252 84.21 49.61 58.91 264 72.33 37.86 52.42 276 50.18 25.83 51.47 288 43.06 26.61 61.79 A summary of mean plasma buprenorphine concentrations (pg/mL) at each sampling time for Comparative Example B (buprenorphine intravenous 0.3mg single dose) is provided in Table 7 below: Table 7 Comparative Example B HOUR MEAN PLASMA CONC. (pg/mL) STD. DEV CV % 0.02 14812.04 11319.10 76.42 0.03 31052.04 16156.81 52.03 0.05 24547.00 16461.86 67.06 0.08 6418.80 1976.26 30.79 0.17 3360.76 2457.58 73.13 0.25 1747.96 465.81 26.65 0.33 1210.08 219.28 18.12 0.42 1050.00 242.10 23.06 0.50 931.52 207.25 22.25 0.75 692.92 175.29 25.30 1.00 584.40 148.93 25.48 1.50 457.44 131.44 28.73 2.00 335.12 79.36 23.68 3.00 238.80 63.03 26.39 4.00 170.87 49.84 29.17 5 A summary of the mean maximum concentration (Cmax) for Comparative Examples A-C measured in pg/mL is set forth in Table 8 below: Table 8 Cmax Values for Comparative Examples A-C Comparative Example A Comparative Example B Comparative Example C Mean 318.20 38635.56 477.33 Std. Dev 151.24 14499.55 216.92 Geometric Mean 291.13 35251.92 435.50 CV % 47.53 37.53 45.44 A summary of mean Tmax values obtained for Comparative Examples A-C is set forth in Table 9 10 below: Table 9 Tmax Prior to Patch Removal (h) Comparative Example A Comparative Example B Comparative Example C Mean 61.92 (out of 72h total) 0.04 168.39 (out of 260h total) Std. Dev. 13.27 0.01 42.68 CV % 21.43 26.26 25.35 Table 10 provides a summary of the area under the curve (AUC) (0-t) for Comparative Examples A-C: 15 Table 10 Comparative Example A Comparative Example B Comparative Example C Mean 18,829.13 65,217.25 3,699.91 Std. Dev. 9,136.12 31,124.37 526.64 Geometric Mean 16,760.39 57,794.90 3,666.65 CV % 48.52 47.72 14.23 32 The pharmacodynamics were determined via VAS "drug effect" observations. The subject was asked "do you feel any effect of the drug ". The subject then rated the item by placing a vertical mark along a 100 mm visual analog scale (VAS) anchored on one end by "not at all" and on the other end by "an awful lot". The "drug effect" question was assessed just prior to each blood sample during the 5 study. The following adverse effects were elicited just prior to blood sampling using the VAS: nausea; dizziness; and sleepiness. Asymmetric blood sampling was used in this study due to the number of sampling times. The pharmacokinetic results (concentration in pg/mL vs. hours) for Comparative Examples A-C are depicted in FIGS. 3-5, respectively. Figure 4 depicts the plasma concentration obtained divided by 10 100. The pharmacodynamic results (PD variables (VAS)) for Comparative Examples A-C are depicted in FIGS. 6-8, respectively. Comparative Examples D-F The bioequivalence between a buprenorphine transdermal delivery system in accordance with Example 1 is compared to identically prepared patches having different sizes and therefore different 15 amounts of buprenorphine contained therein. Comparative Example D utilised a patch identical in size and containing the same amount of buprenorphine as Example 1. The total of buprenorphine included in the transdermal patch is 10mg, the active surface area is 12.5cm 2 and the patch size is 30.6 cm 2 . In Comparative Example E, two patches are utilised, each patch including total of buprenorphine of about 5mg, and having an active 20 surface area of 6.25cm 2 and a patch size of 19.4cm 2 . Comparative Example F allows for the determination of the dose proportionality of a buprenorphine transdermal delivery system (patch) having twice the dose as compared to Example 1. In Comparative Example F, the total of buprenorphine included in the transdermal patch is 20mg, the active surface area is 25cm 2 and the patch size is 51.8cm 2 . The study was conducted via a 3-way cross-over design. The patches were left 25 in place for 72h and then removed. Table 11 provides a summary of mean plasma buprenorphine concentrations (pg/mL) at each sampling time for Comparative Example D: Table 11 HOUR MEAN PLASMA CONC. (pg/mL) STD. DEV CV % 3 1.92 8.82 458.26 6 22.69 30.98 136.54 9 38.54 48.79 126.62 12 59.22 62.92 106.24 16 89.85 78.93 87.84 24 128.70 72.79 56.55 30 125.99 84.68 67.21 36 143.07 78.40 54.80 48 196.72 101.50 51.59 60 182.72 82.61 45.21 72 169.95 65.04 38.27 84 122.19 41.69 34.12 96 83.30 35.56 42.69 108 55.09 30.82 55.94 120 41.63 20.74 49.82 33 HOUR MEAN PLASMA CONC. (pg/mL) STD. DEV CV % 132 27.14 25.47 93.84 144 17.54 20.09 114.51 Table 12 provides a summary of the pharmacokinetic parameters for Comparative Example D: Table 12 PARAMETER ARITHMETIC MEAN (SE) GEOMETRIC MEAN (SE) AUC (0-Infinity) 16278.05 (1246.6) 15255.84 (1272.5) AUC (0-Last) 14446.10 (1292.0) 13162.96 (1340.6) Cmax (pg/mL) 229.87 (19.29) 214.47 (17.92) T 1/2 Eiim. (h) 30.53 (2.80) Tmax (h) 67.02 (3.14) Table 13 provides a summary of mean plasma buprenorphine concentrations for Comparative Example E: 5 Table 13 HOUR MEAN PLASMA CONC. (pg/mL) STD. DEV CV % 3 1.63 7.29 447.21 6 19.61 33.28 169.70 9 29.09 44.04 151.40 12 44.43 56.91 128.09 16 59.77 66.25 110.86 24 110.49 98.86 89.48 30 107.58 86.83 80.71 36 116.36 83.01 71.34 48 154.35 83.40 54.03 60 151.22 90.70 59.98 72 145.20 62.84 43.28 84 106.91 38.86 36.35 96 82.61 34.87 42.21 108 44.83 26.74 59.65 120 29.68 24.26 81.73 132 22.52 24.42 108.44 144 9.24 17.28 186.93 Table 14 provides a summary of the pharmacokinetic parameters for Comparative Example E: Table 14 PARAMETER ARITHMETIC MEAN (SE) GEOMETRIC MEAN (SE) AUC (0-Infinity) 13450.96 (1326.8) 12315.56 (1142.0) AUC (0-Last) 12026.65 (1318.7) 10796.23 (1110.3) Cmax (pg/mL) 199.10 (17.50) 186.49 (14.69) T 1/2 Eiim. (h) 25.82 (1.51) Tmax (h) 68.26 (3.18) Table 15 provides a summary of mean plasma buprenorphine concentrations for Comparative Example F: 10 Table 15 HOURS MEAN PLASMA CONC. (pg/mL). STD. DEV CV % 3 5.23 13.21 252.44 6 34.49 55.11 159.80 9 58.67 91.17 155.40 12 94.52 111.07 117.51 16 137.07 118.65 86.56 24 195.58 148.53 75.94 30 201.51 142.24 70.59 34 HOURS MEAN PLASMA CONC. (pg/mL). STD. DEV CV % 36 229.52 154.25 67.20 48 283.35 124.06 43.78 60 314.17 173.81 55.32 72 306.60 124.57 40.63 84 209.66 62.84 29.97 96 143.30 43.88 30.62 108 113.53 70.33 61.95 120 78.71 37.46 47.59 132 75.29 47.92 63.64 144 44.45 32.26 72.57 Table 16 provides a summary of the dose-corrected pharmacokinetic parameters for Comparative Example F. The values are calculated based on a Cmax value which is one-half the actual reported value: Table 16 PARAMETER ARITHMETIC MEAN (SE) GEOMETRIC MEAN (SE) AUC (0-Infinity) 14761.59 (1469.7) 13540.78 (1228.3) AUC (0-Last) 12558.04 (1313.9) 11456.76 (1067.0) Cmax (pg/mL) 191.84 (16.93) 179.60 (14.23) T 1/2 Eiim. (h) 26.59 (1.52) Tmax (h) 72.37 (1.89) 5 Table 17 provides a summary of the buprenorphine patch residuals for each of Comparative Examples D-F: Table 17 Summary of buprenorphine patch residuals Ex.D Ex.F Ex.E AMOUNT LEFT IN PATCH (mg) N 27 27 52 MEAN 8.76 18.31 4.75 SE 0.07 0.15 0.03 % RELEASED (ASSAY) N 27 27 52 MEAN 12.31 10.84 8.43 SE 0.67 0.73 0.53 The pharmacokinetic results (concentration in pg/mL vs. hours) for Comparative Examples D-F 10 are depicted in FIGS. 9-11, respectively. The pharmacodynamic results (PD variables (VAS)) for Comparative Examples A-C are depicted in FIGS. 12-14, respectively. Conclusions In order to readily consider the results obtained comparing the method of the present invention to the Comparative Examples, the following tables are provided. 1s Table 18 provides a direct comparison of the plasma concentrations obtained from Example 1 (a 10mg buprenorphine patch maintained in contact with the subjects' skin for 7 days) to Comparative Example A (20mg buprenorphine patch left on the subjects' skin for only 3 days, then removed) to Comparative Example C (thee sequential applications of a 20mg buprenorphine patch left on the subjects' skin for only 3 days, then removed). In order to compare the plasma concentrations, the 20 plasma concentrations of Comparative Examples A and C are also presented at 50% concentrations for each time interval: 35 Table 18 Comparison of plasma concentrations HOUR/(DAY) Ex. 1 COMPARATIVE EXAMPLE C COMPARATIVE EXAMPLE A MEAN MEAN MEAN (1/2 DOSE) MEAN MEAN (1/2 DOSE) 24(1) 58.94 218.57 109.29 175.58 87.79 48(2) 104.69 265.04 132.52 251.10 125.55 72(3) 130.55 306.02 153.01 286.50 143.25 96(4) 146.70 269.91 134.96 90.75 45.38 120(5) 136.22 310.27 155.14 44.85 22.43 144(6) 115.23 305.99 153.00 29.14 14.57 168(7) 102.00 340.71 170.36 192(8) 395.95 197.98 The data presented in Table 18 shows that, surprisingly, plasma levels effective to provide analgesia were present in Example 1 (patch remained on skin for 7 days) even 7 days after 5 application of the patch; whereas in Comparative Example A (patch removed after 3 days), blood levels fell dramatically once the patch was removed, such that plasma levels which would be indicative of ineffective treatment for the dosage of buprenorphine occurred not long after patch removal. On the other hand, turning to Comparative Example C, it is apparent that the plasma levels obtained from 3-day sequential administration of the buprenorphine patch resulted in significant 10 increases in Cmax levels during each day dosing interval. This fact is confirmed by the graph of plasma concentration over time for Comparative Example C provided in Figure 3. In contrast, the plasma level for Example 1 remained substantially level over the time-frame of 72h-168h after patch application. The results indicate that the method of the present invention has the surprising benefit of reducing total plasma concentrations of buprenorphine required to allow patients to experience effective 15 analgesia. Furthermore, comparing the VAS results graphically depicted for Example 1 to Comparative Example C, it is apparent that side effects were significantly reduced according to the method of Example 1, during the 7-day dosage interval. Further benefits are obtained from the invention with respect to modes of administration other than transdermally where the large plasma concentration peaks obtained in the prior art, eg., though intravenous dosing, can be avoided. For 20 example, in Comparative Example B, a Cmax in excess of about 30 OOOpg/mL was obtained. Table 19 provides a direct comparison of the plasma concentrations of Example 1 (a 10mg buprenorphine patch maintained in contact with the subjects' skin for 7 days) to Comparative Example D (same 10mg buprenorphine patch left on the subjects' skin for only 3 days, then removed) to Comparative Example E (two 5mg buprenorphine patches left on the subject' skin for only 3 days, 25 then removed): Table 19 Comparison of plasma concentrations (pg/mL) Hours (Post- Ex. 1 Ex. D Ex. E Application) MEAN CONC. MEAN CONC. MEAN CONC. 3 1.92 1.63 6 1.76 22.69 19.61 9 38.54 29.09 12 18.47 59.22 44.43 16 1 89.85 59.77 36 Hours (Post- Ex. 1 Ex. D Ex. E Application) MEAN CONC. MEAN CONC. MEAN CONC. 24 58.94 128.70 110.49 30 67.69 125.99 107.58 36 82.44 143.07 116.36 48 104.69 196.72 154.35 60 112.93 182.72 151.22 72 130.55 169.95 145.20 84 129.03 122.19 106.91 96 146.70 83.30 82.61 108 135.49 55.09 44.83 120 136.22 41.63 29.68 132 124.78 27.14 22.52 144 115.23 17.54 9.24 The results depicted in Table 19 confirm that the method according to the present invention provides effective plasma levels over the 7-day period; whereas if the patch (or patches) containing the same dose is removed after 3 days, the buprenorphine plasma levels fall precipitously over the next 24 hour interval to levels which would be indicative of ineffective treatment for the dosage of 5 buprenorphine. This result is surprising in view of the fact that the patches are designed to provide effective analgesic levels of buprenorphine only for a three day period--these patches are not designed to provide effective plasma levels of buprenorphine over a substantially longer period of time. (It must be noted that the absolute mean plasma levels of Example 1 and the Comparative Examples are not directly comparable because these results are taken from different studies involving 10 different subjects, etc.). Further surprising results are apparent from the data provided in Table 20 below, which compares the amount of buprenorphine retained in the transdermal delivery systems in Example 1 to certain Comparative Examples, as well as their relative release rates: Table 20 15 Buprenorphine patch release rates Patch strength Example cum. amt. RR[mg/patch/d RR[mg/patch/d RRorm released [mg] ay] 3 days appl. ay] 7 days appl. [mg/cm 2 /day] 5mg E 0.44mg 0.146 - 0.0234 10mg D 1.23mg 0.410 - 0.0328 20mg F 2.52mg 0.742 - 0.0297 20mg A, C 3.21mg 1.090 - 0.0437 10mg 1 1.40mg - 0.200 0.160 RR = relative release rate The total amount of buprenorphine released for Example 1 (1.40mg) may be expressed as 0.2mg buprenorphine administered per day, when averaged over the seven day dosing interval. In contrast, Comparative Example E (same patch over 3 days) released a total of 1.23mg, which may be 20 expressed as 0.41mg buprenorphine administered per day. Comparing the cumulative amount released for Example 1 as compared to Comparative Example D, it can be seen that the present invention results in one-half the dose (mg/patch/day) which would be administered based on prior art methodology. Further, it is apparent that almost all of the buprenorphine dose for Example 1 is released over the first 72h (3 days)--1.23mg released from the 10mg patch over 3 days is 87.86% of 37 the 1.4mg released from the same patch over 7 days. It is surprising that analgesia can be maintained given the very low amount of buprenorphine released from the 10mg patch over the 72-168 hour dosing interval. Further, the results indicate that over the first 72h the buprenorphine is released substantially 5 according to first order kinetics, whereas during the 72-168 hour time period after administration, the buprenorphine is released substantially according to zero order kinetics. This is confirmed from the plasma concentration curve provided for Example 1 in Figure 1. Thus, during the first 72 hours after administration according to the invention, a relative release rate of 17.1pg/h is obtained (1.23mg divided by 72h); whereas from 72-168h after administration according to the invention, the relative 10 release rate may be lowered to only 1.77pg/h (1.40mg minus 1.23mg = 0.17mg divided by 96h) while maintaining effective analgesic levels of buprenorphine in human patients. Example 2 In Example 2, the method of the present invention is accomplished via a different mode of administration, ie., intravenous infusion. The pattern of plasma concentrations seen though time in this 1s invention can be achieved by using an intravenous infusion using the injectable, parenteral form of, eg., buprenorphine hydrochloride suitably diluted in an intravenous infusion solution. The infusion rate would be controlled by a programmable infusion pump, to provide the desired plasma concentration profile. The rate of infusion though time can be determined and adjusted based upon pharmacodynamic parameters such as pupil size (pupilometry) or pain relief (analgesia) or by the 20 results of a suitable bioassay to determine the plasma buprenorphine concentrations at any particular point in time. In addition, it is possible to model the desired curve using pharmacokinetic modelling techniques; in this way the desired curve can be approximated without need for pharmacokinetic or pharmacodynamic monitoring. However, periodic plasma concentration determinations would make the model more accurate and allow further adjustment of the infusion rate. 25 Following the method set forth above, mean plasma concentrations are obtained as follows: a mean plasma concentration from about 1 to about 28pg/mL at about 6h after initiation of the dosing interval; a mean plasma concentration from about 14 to about 74pg/mL at about 12h after initiation of the dosing interval; a mean plasma concentration from about 30 to about 161 pg/mL at about 24h after initiation of the dosing interval; a mean plasma concentration from about 51 to about 188pg/mL at 30 about 36h after initiation of the dosing interval; a mean plasma concentration from about 62 to about 246pg/mL at about 48h after initiation of the dosing interval; a mean plasma concentration from about 79 to about 246pg/mL at about 60h after initiation of the dosing interval; a mean plasma concentration from about 85 to about 263pg/mL at about 72h after initiation of the dosing interval; a mean plasma concentration from about 92 to about 263pg/mL at about 96h after initiation of the dosing interval; a 35 mean plasma concentration from about 94 to about 263pg/mL at about 120h after initiation of the dosing interval; a mean plasma concentration from about 86 to about 243pg/mL at about 144h after initiation of the dosing interval; and a mean plasma concentration from about 77 to about 21 Opg/mL at about 168h after initiation of the dosing interval (for a seven day dosing interval). It will be readily apparent that various modifications to the invention may be made by those 40 skilled in the art without departing from the scope of this invention. For example, many different 38 transdermal delivery systems may be utilised in order to obtain the relative release rates and plasma levels described herein. Further, it is possible that mean values for plasma concentrations over a particular patient population for a particular described time point along the dosing interval may vary from the plasma concentration ranges described herein for that time point. Such obvious modifications 5 are considered to be within the scope of the appended claims.
    权利要求:
    Claims (245)
    [1] 1. The use of buprenorphine base in the preparation of a transdermal delivery system for treating pain in a human patient for a dosing interval of 7 days, said transdermal delivery system being suitable for administering buprenorphine transdermally to a human patient by applying the 5 transdermal delivery system to the skin of a patient, and having a mean relative release rate of 3 pg/hr to 86 pg/hr until 72 hours after the initiation of the dosing interval and a mean relative release rate of 0.3 pg/hr to 9 pg/hr from 72 hours until 168 hours after the initiation of the dosing interval such that mean plasma concentrations are provided as follows: a mean plasma concentration from 0.3 to 113 pg/ml at 6 hours after initiation of the 10 dosing interval; a mean plasma concentration from 3 to 296 pg/ml at 12 hours after initiation of the dosing interval; a mean plasma concentration from 7 to 644 pg/ml at 24 hours after initiation of the dosing interval; 15 a mean plasma concentration from 13 to 753 pg/ml at 36 hours after initiation of the dosing interval; a mean plasma concentration from 16 to 984 pg/ml at 48 hours after initiation of the dosing interval; a mean plasma concentration from 20 to 984 pg/ml at 60 hours after initiation of the 20 dosing interval; a mean plasma concentration from 20 to 1052 pg/ml at 72 hours after initiation of the dosing interval; a mean plasma concentration from 23 to 1052 pg/ml at 96 hours after initiation of the dosing interval; 25 a mean plasma concentration from 23 to 1052 pg/ml at 120 hours after initiation of the dosing interval; a mean plasma concentration from 22 to 970 pg/ml at 144 hours after initiation of the dosing interval; and a mean plasma concentration from 19 to 841 pg/ml at 168 hours after initiation of the 30 dosing interval, wherein the transdermal delivery system comprises a polymer matrix layer which comprises the buprenorphine base, and wherein the Tmax occurs from 3 to 5 days after application of said transdermal delivery system.
    [2] 2. The use of claim 1, wherein the mean plasma concentrations are provided as follows: 35 a mean plasma concentration from 1 to 28 pg/ml at 6 hours after initiation of the dosing interval; a mean plasma concentration from 14 to 74 pg/ml at 12 hours after initiation of the dosing interval; 40 a mean plasma concentration from 30 to 161 pg/ml at 24 hours after initiation of the dosing interval; a mean plasma concentration from 51 to 188 pg/ml at 36 hours after initiation of the dosing interval; 5 a mean plasma concentration from 62 to 246 pg/ml at 48 hours after initiation of the dosing interval; a mean plasma concentration from 79 to 246 pg/ml at 60 hours after initiation of the dosing interval; a mean plasma concentration from 85 to 263 pg/ml at 72 hours after initiation of the 10 dosing interval; a mean plasma concentration from 92 to 263 pg/ml at 96 hours after initiation of the dosing interval; a mean plasma concentration from 94 to 263 pg/ml at 120 hours after initiation of the dosing interval; 15 a mean plasma concentration from 86 to 243 pg/ml at 144 hours after initiation of the dosing interval; a mean plasma concentration from 77 to 210 pg/ml at 168 hours after initiation of the dosing interval.
    [3] 3. The use of claim 1, wherein the mean plasma concentrations are provided as follows: 20 a mean plasma concentration from 0.3 to 7 pg/ml at 6 hours after initiation of the dosing interval; a mean plasma concentration from 4 to 19 pg/ml at 12 hours after initiation of the dosing interval; a mean plasma concentration from 7 to 40 pg/ml at 24 hours after initiation of the dosing 25 interval; a mean plasma concentration from 13 to 47 pg/ml at 36 hours after initiation of the dosing interval; a mean plasma concentration from 16 to 62 pg/ml at 48 hours after initiation of the dosing interval; 30 a mean plasma concentration from 20 to 62 pg/ml at 60 hours after initiation of the dosing interval; a mean plasma concentration from 21 to 66 pg/ml at 72 hours after initiation of the dosing interval; a mean plasma concentration from 23 to 66 pg/ml at 96 hours after initiation of the dosing 35 interval; a mean plasma concentration from 23 to 66 pg/ml at 120 hours after initiation of the dosing interval; a mean plasma concentration from 22 to 61 pg/ml at 144 hours after initiation of the dosing interval; and 41 a mean plasma concentration from 19 to 53 pg/ml at 168 hours after initiation of the dosing interval.
    [4] 4. The use of claim 1, wherein the mean plasma concentrations are provided as follows: a mean plasma concentration from 0.7 to 14 pg/ml at 6 hours after initiation of the dosing 5 interval; a mean plasma concentration from 7 to 37 pg/ml at 12 hours after initiation of the dosing interval; a mean plasma concentration from 15 to 80 pg/ml at 24 hours after initiation of the dosing interval; 10 a mean plasma concentration from 25 to 94 pg/ml at 36 hours after initiation of the dosing interval; a mean plasma concentration from 31 to 123 pg/ml at 48 hours after initiation of the dosing interval; a mean plasma concentration from 40 to 123 pg/ml at 60 hours after initiation of the 15 dosing interval; a mean plasma concentration from 40 to 132 pg/ml at 72 hours after initiation of the dosing interval; a mean plasma concentration from 46 to 132 pg/ml at 96 hours after initiation of the dosing interval; 20 a mean plasma concentration from 47 to 132 pg/ml at 120 hours after initiation of the dosing interval; a mean plasma concentration from 43 to 121 pg/ml at 144 hours after initiation of the dosing interval; and a mean plasma concentration from 38 to 105 pg/ml at 168 hours after initiation of the 25 dosing interval.
    [5] 5. The use of claim 1, wherein the mean plasma concentrations are provided as follows: a mean plasma concentration from 3 to 57 pg/ml at 6 hours after initiation of the dosing interval; a mean plasma concentration from 28 to 148 pg/ml at 12 hours after initiation of the 30 dosing interval; a mean plasma concentration from 59 to 322 pg/ml at 24 hours after initiation of the dosing interval; a mean plasma concentration from 102 to 377 pg/ml at 36 hours after initiation of the dosing interval; 35 a mean plasma concentration from 124 to 492 pg/ml at 48 hours after initiation of the dosing interval; a mean plasma concentration from 159 to 492 pg/ml at 60 hours after initiation of the dosing interval; 42 a mean plasma concentration from 169 to 526 pg/ml at 72 hours after initiation of the dosing interval; a mean plasma concentration from 184 to 526 pg/ml at 96 hours after initiation of the dosing interval; 5 a mean plasma concentration from 187 to 526 pg/ml at 120 hours after initiation of the dosing interval; a mean plasma concentration from 173 to 485 pg/ml at 144 hours after initiation of the dosing interval; a mean plasma concentration from 153 to 420 pg/ml at 168 hours after initiation of the 10 dosing interval.
    [6] 6. The use of claim 1, wherein the mean plasma concentrations are provided as follows: a mean plasma concentration from 4 to 85 pg/ml at 6 hours after initiation of the dosing interval; a mean plasma concentration from 42 to 222 pg/ml at 12 hours after initiation of the 15 dosing interval; a mean plasma concentration from 89 to 483 pg/ml at 24 hours after initiation of the dosing interval; a mean plasma concentration from 152 to 565 pg/ml at 36 hours after initiation of the dosing interval; 20 a mean plasma concentration from 186 to 738 pg/ml at 48 hours after initiation of the dosing interval; a mean plasma concentration from 238 to 738 pg/ml at 60 hours after initiation of the dosing interval; a mean plasma concentration from 254 to 789 pg/ml at 72 hours after initiation of the 25 dosing interval; a mean plasma concentration from 276 to 789 pg/ml at 96 hours after initiation of the dosing interval; a mean plasma concentration from 281 to 789 pg/ml at 120 hours after initiation of the dosing interval; 30 a mean plasma concentration from 259 to 727 pg/ml at 144 hours after initiation of the dosing interval; a mean plasma concentration from 230 to 630 pg/ml at 168 hours after initiation of the dosing interval.
    [7] 7. The use of claim 1, wherein the mean plasma concentrations are provided as follows: 35 a mean plasma concentration from 5 to 113 pg/ml at 6 hours after initiation of the dosing interval; a mean plasma concentration from 55 to 296 pg/ml at 12 hours after initiation of the dosing interval; 43 a mean plasma concentration from 118 to 644 pg/ml at 24 hours after initiation of the dosing interval; a mean plasma concentration from 203 to 753 pg/ml at 36 hours after initiation of the dosing interval; 5 a mean plasma concentration from 247 to 984 pg/ml at 48 hours after initiation of the dosing interval; a mean plasma concentration from 317 to 984 pg/ml at 60 hours after initiation of the dosing interval; a mean plasma concentration from 339 to 1052 pg/ml at 72 hours after initiation of the 10 dosing interval; a mean plasma concentration from 369 to 1052 pg/ml at 96 hours after initiation of the dosing interval; a mean plasma concentration from 374 to 1052 pg/ml at 120 hours after initiation of the dosing interval; 15 a mean plasma concentration from 346 to 970 pg/ml at 144 hours after initiation of the dosing interval; a mean plasma concentration from 306 to 841 pg/ml at 168 hours after initiation of the dosing interval.
    [8] 8. The use of claim 1, wherein the transdermal delivery system is an iontophoretic 20 transdermal delivery system.
    [9] 9. The use of any one of claims 1 to 8, wherein the transdermal delivery system comprises 10 to 95 %-wt polymeric material, 0.1 to 40 %-wt softener and 0.1 to 30 %-wt buprenorphine.
    [10] 10. The use of claim 9, wherein said transdermal delivery system comprises an adhesive matrix layer comprising 10 %-wt buprenorphine base, 10 to 15 %-wt levulinic acid, 10 %-wt 25 oleyloleate, 55 to 70 %-wt polyacrylate and 0 to 10 %-wt polyvinylpyrrollidone.
    [11] 11. The use of any one of claims 1 to 10, wherein the transdermal delivery system provides a nominal delivery rate of buprenorphine base of 12.5 pg/hr; the total amount of buprenorphine base contained in the transdermal delivery system is 5 mg; and the active surface area of the transdermal delivery system is 6.25 cm 2 . 30
    [12] 12. The use of any one of claims 1 to 10, wherein the transdermal delivery system provides a nominal delivery rate of buprenorphine base of 25 pg/hr; the total amount of buprenorphine base contained in the transdermal delivery system is 10 mg; and the active surface area of the transdermal delivery system is 12.5 cm 2 .
    [13] 13. The use of any one of claims 1 to 10, wherein the transdermal delivery system provides a 35 nominal delivery rate of buprenorphine base of 50 pg/hr; the total amount of buprenorphine base contained in the transdermal delivery system is 20 mg; and the active surface area of the transdermal delivery system is 25 cm 2 . 44
    [14] 14. The use of any one of claims 1 to 10, wherein the transdermal delivery system provides a nominal delivery rate of buprenorphine base of 75 pg/hr; the total amount of buprenorphine base contained in the transdermal delivery system is 30 mg; and the active surface area of the transdermal delivery system is 37.5 cm 2 . 5
    [15] 15. The use of any one of claims 1 to 10, wherein the transdermal delivery system provides a nominal delivery rate of buprenorphine base of 100 pg/hr; the total amount of buprenorphine base contained in the transdermal delivery system is 40 mg; and the active surface area of the transdermal delivery system is 50 cm 2 .
    [16] 16. The use of buprenorphine in the preparation of a transdermal delivery system for treating 10 pain in a human patient for a dosing interval of 7 days, said transdermal delivery system being suitable for administering buprenorphine transdermally to a human patient by applying the transdermal delivery system to the skin of a patient, and having a mean relative release rate of about 0.3 pg/hr to about 9 pg/hr from 72 hours until 168 hours after the initiation of the dosing interval such that mean plasma concentrations are provided as follows: 15 a mean plasma concentration from about 0.3 to about 113 pg/ml at about 6 hours after initiation of the dosing interval; a mean plasma concentration from about 3 to about 296 pg/ml at about 12 hours after initiation of the dosing interval; a mean plasma concentration from about 7 to about 644 pg/ml at about 24 hours after 20 initiation of the dosing interval; a mean plasma concentration from about 13 to about 753 pg/ml at about 36 hours after initiation of the dosing interval; a mean plasma concentration from about 16 to about 984 pg/ml at about 48 hours after initiation of the dosing interval; 25 a mean plasma concentration from about 20 to about 984 pg/ml at about 60 hours after initiation of the dosing interval; a mean plasma concentration from about 20 to about 1052 pg/ml at about 72 hours after initiation of the dosing interval; a mean plasma concentration from about 23 to about 1052 pg/ml at about 96 hours after 30 initiation of the dosing interval; a mean plasma concentration from about 23 to about 1052 pg/ml at about 120 hours after initiation of the dosing interval; a mean plasma concentration from about 22 to about 970 pg/ml at about 144 hours after initiation of the dosing interval; and 35 a mean plasma concentration from about 19 to about 841 pg/ml at about 168 hours after initiation of the dosing interval.
    [17] 17. The use of claim 16, wherein the mean plasma concentrations are provided as follows: a mean plasma concentration from about 1 to about 28 pg/ml at about 6 hours after initiation of the dosing interval; 45 a mean plasma concentration from about 14 to about 74 pg/ml at about 12 hours after initiation of the dosing interval; a mean plasma concentration from about 30 to about 161 pg/ml at about 24 hours after initiation of the dosing interval; 5 a mean plasma concentration from about 51 to about 188 pg/ml at about 36 hours after initiation of the dosing interval; a mean plasma concentration from about 62 to about 246 pg/ml at about 48 hours after initiation of the dosing interval; a mean plasma concentration from about 79 to about 246 pg/ml at about 60 hours after 10 initiation of the dosing interval; a mean plasma concentration from about 85 to about 263 pg/ml at about 72 hours after initiation of the dosing interval; a mean plasma concentration from about 92 to about 263 pg/ml at about 96 hours after initiation of the dosing interval; 15 a mean plasma concentration from about 94 to about 263 pg/ml at about 120 hours after initiation of the dosing interval; a mean plasma concentration from about 86 to about 243 pg/ml at about 144 hours after initiation of the dosing interval; a mean plasma concentration from about 77 to about 210 pg/ml at about 168 hours after 20 initiation of the dosing interval.
    [18] 18. The use of claim 16, wherein the mean plasma concentrations are provided as follows: a mean plasma concentration from about 0.3 to about 7 pg/ml at about 6 hours after initiation of the dosing interval; a mean plasma concentration from about 4 to about 19 pg/ml at about 12 hours after 25 initiation of the dosing interval; a mean plasma concentration from about 7 to about 40 pg/ml at about 24 hours after initiation of the dosing interval; a mean plasma concentration from about 13 to about 47 pg/ml at about 36 hours after initiation of the dosing interval; 30 a mean plasma concentration from about 16 to about 62 pg/ml at about 48 hours after initiation of the dosing interval; a mean plasma concentration from about 20 to about 62 pg/ml at about 60 hours after initiation of the dosing interval; a mean plasma concentration from about 21 to about 66 pg/ml at about 72 hours after 35 initiation of the dosing interval; a mean plasma concentration from about 23 to about 66 pg/ml at about 96 hours after initiation of the dosing interval; a mean plasma concentration from about 23 to about 66 pg/ml at about 120 hours after initiation of the dosing interval; 46 a mean plasma concentration from about 22 to about 61 pg/ml at about 144 hours after initiation of the dosing interval; and a mean plasma concentration from about 19 to about 53 pg/ml at about 168 hours after initiation of the dosing interval. 5
    [19] 19. The use of claim 16, wherein the mean plasma concentrations are provided as follows: a mean plasma concentration from about 0.7 to about 14 pg/ml at about 6 hours after initiation of the dosing interval; a mean plasma concentration from about 7 to about 37 pg/ml at about 12 hours after initiation of the dosing interval; 10 a mean plasma concentration from about 15 to about 80 pg/ml at about 24 hours after initiation of the dosing interval; a mean plasma concentration from about 25 to about 94 pg/ml at about 36 hours after initiation of the dosing interval; a mean plasma concentration from about 31 to about 123 pg/ml at about 48 hours after 1s initiation of the dosing interval; a mean plasma concentration from about 40 to about 123 pg/ml at about 60 hours after initiation of the dosing interval; a mean plasma concentration from about 40 to about 132 pg/ml at about 72 hours after initiation of the dosing interval; 20 a mean plasma concentration from about 46 to about 132 pg/ml at about 96 hours after initiation of the dosing interval; a mean plasma concentration from about 47 to about 132 pg/ml at about 120 hours after initiation of the dosing interval; a mean plasma concentration from about 43 to about 121 pg/ml at about 144 hours after 25 initiation of the dosing interval; and a mean plasma concentration from about 38 to about 105 pg/ml at about 168 hours after initiation of the dosing interval.
    [20] 20. The use of claim 16, wherein the mean plasma concentrations are provided as follows: a mean plasma concentration from about 3 to about 57 pg/ml at about 6 hours after 30 initiation of the dosing interval; a mean plasma concentration from about 28 to about 148 pg/ml at about 12 hours after initiation of the dosing interval; a mean plasma concentration from about 59 to about 322 pg/ml at about 24 hours after initiation of the dosing interval; 35 a mean plasma concentration from about 102 to about 377 pg/ml at about 36 hours after initiation of the dosing interval; a mean plasma concentration from about 124 to about 492 pg/ml at about 48 hours after initiation of the dosing interval; 47 a mean plasma concentration from about 159 to about 492 pg/ml at about 60 hours after initiation of the dosing interval; a mean plasma concentration from about 169 to about 526 pg/ml at about 72 hours after initiation of the dosing interval; 5 a mean plasma concentration from about 184 to about 526 pg/ml at about 96 hours after initiation of the dosing interval; a mean plasma concentration from about 187 to about 526 pg/ml at about 120 hours after initiation of the dosing interval; a mean plasma concentration from about 173 to about 485 pg/ml at about 144 hours after 10 initiation of the dosing interval; a mean plasma concentration from about 153 to about 420 pg/ml at about 168 hours after initiation of the dosing interval.
    [21] 21. The use of claim 16, wherein the mean plasma concentrations are provided as follows: a mean plasma concentration from about 4 to about 85 pg/ml at about 6 hours after 1s initiation of the dosing interval; a mean plasma concentration from about 42 to about 222 pg/ml at about 12 hours after initiation of the dosing interval; a mean plasma concentration from about 89 to about 483 pg/ml at about 24 hours after initiation of the dosing interval; 20 a mean plasma concentration from about 152 to about 565 pg/ml at about 36 hours after initiation of the dosing interval; a mean plasma concentration from about 186 to about 738 pg/ml at about 48 hours after initiation of the dosing interval; a mean plasma concentration from about 238 to about 738 pg/ml at about 60 hours after 25 initiation of the dosing interval; a mean plasma concentration from about 254 to about 789 pg/ml at about 72 hours after initiation of the dosing interval; a mean plasma concentration from about 276 to about 789 pg/ml at about 96 hours after initiation of the dosing interval; 30 a mean plasma concentration from about 281 to about 789 pg/ml at about 120 hours after initiation of the dosing interval; a mean plasma concentration from about 259 to about 727 pg/ml at about 144 hours after initiation of the dosing interval; a mean plasma concentration from about 230 to about 630 pg/ml at about 168 hours after 35 initiation of the dosing interval.
    [22] 22. The use of claim 16, wherein the mean plasma concentrations are provided as follows: a mean plasma concentration from about 5 to about 113 pg/ml at about 6 hours after initiation of the dosing interval; 48 a mean plasma concentration from about 55 to about 296 pg/ml at about 12 hours after initiation of the dosing interval; a mean plasma concentration from about 118 to about 644 pg/ml at about 24 hours after initiation of the dosing interval; 5 a mean plasma concentration from about 203 to about 753 pg/ml at about 36 hours after initiation of the dosing interval; a mean plasma concentration from about 247 to about 984 pg/ml at about 48 hours after initiation of the dosing interval; a mean plasma concentration from about 317 to about 984 pg/ml at about 60 hours after 10 initiation of the dosing interval; a mean plasma concentration from about 339 to about 1052 pg/ml at about 72 hours after initiation of the dosing interval; a mean plasma concentration from about 369 to about 1052 pg/ml at about 96 hours after initiation of the dosing interval; 15 a mean plasma concentration from about 374 to about 1052 pg/ml at about 120 hours after initiation of the dosing interval; a mean plasma concentration from about 346 to about 970 pg/ml at about 144 hours after initiation of the dosing interval; a mean plasma concentration from about 306 to about 841 pg/ml at about 168 hours after 20 initiation of the dosing interval.
    [23] 23. The use of claim 16, wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system.
    [24] 24. The use of claim 16, wherein the transdermal delivery system comprises a polymer matrix layer which comprises buprenorphine.
    [25] 25 25. The use of claim 16, wherein the transdermal delivery system is an iontophoretic transdermal delivery system.
    [26] 26. The use of any one of claims 16 to 25, wherein the transdermal delivery system comprises 10 to 95 %-wt polymeric material, 0.1 to 40 %-wt softener and 0.1 to 30 %-wt buprenorphine. 30
    [27] 27. The use of claim 26, wherein said transdermal delivery system comprises an adhesive matrix layer comprising 10 %-wt buprenorphine, 10 to 15 %-wt levulinic acid, 10 %-wt oleyoleate, 55 to 70 %-wt polyacrylate and 0 to 10 %-wt polyvinylpyrrollidone.
    [28] 28. The use of any one of claims 16 to 27, wherein the transdermal delivery system provides a nominal delivery rate of buprenorphine of 12.5 pg/hr; the total amount of buprenorphine contained in 35 the transdermal delivery system is 5 mg; and the active surface area of the transdermal delivery system is 6.25 cm 2 . 49
    [29] 29. The use of any one of claims 16 to 27, wherein the transdermal delivery system provides a nominal delivery rate of buprenorphine of 25 pg/hr; the total amount of buprenorphine contained in the transdermal delivery system is 10 mg; and the active surface area of the transdermal delivery system is 12.5 cm 2 . 5
    [30] 30. The use of any one of claims 16 to 27, wherein the transdermal delivery system provides a nominal delivery rate of buprenorphine of 50 pg/hr; the total amount of buprenorphine contained in the transdermal delivery system is 20 mg; and the active surface area of the transdermal delivery system is 25 cm 2 .
    [31] 31. The use of any one of claims 16 to 27, wherein the transdermal delivery system provides 10 a nominal delivery rate of buprenorphine of 75 pg/hr; the total amount of buprenorphine contained in the transdermal delivery system is 30 mg; and the active surface area of the transdermal delivery system is 37.5 cm 2 .
    [32] 32. The use of any one of claims 16 to 27, wherein the transdermal delivery system provides a nominal delivery rate of buprenorphine of 100 pg/hr; the total amount of buprenorphine contained in 1s the transdermal delivery system is 40 mg; and the active surface area of the transdermal delivery system is 50 cm 2 .
    [33] 33. The use of buprenorphine in the preparation of a transdermal delivery system for treating pain in a human patient for a dosing interval of 7 days, said transdermal delivery system being suitable for administering buprenorphine transdermally to a human patient by applying the 20 transdermal delivery system to the skin of a patient, and having a mean relative release rate of 3 pg/hr to 86 pg/hr until 72 hours after the initiation of the dosing interval and a mean relative release rate of 0.3 pg/hr to 9 pg/hr from 72 hours until 168 hours after the initiation of the dosing interval such that mean plasma concentrations are provided as follows: a mean plasma concentration from 0.3 to 113 pg/ml at 6 hours after initiation of the 25 dosing interval; a mean plasma concentration from 3 to 296 pg/ml at 12 hours after initiation of the dosing interval; a mean plasma concentration from 7 to 644 pg/ml at 24 hours after initiation of the dosing interval; 30 a mean plasma concentration from 13 to 753 pg/ml at 36 hours after initiation of the dosing interval; a mean plasma concentration from 16 to 984 pg/ml at 48 hours after initiation of the dosing interval; a mean plasma concentration from 20 to 984 pg/ml at 60 hours after initiation of the 35 dosing interval; a mean plasma concentration from 20 to 1052 pg/ml at 72 hours after initiation of the dosing interval; a mean plasma concentration from 23 to 1052 pg/ml at 96 hours after initiation of the dosing interval; 50 a mean plasma concentration from 23 to 1052 pg/ml at 120 hours after initiation of the dosing interval; a mean plasma concentration from 22 to 970 pg/ml at 144 hours after initiation of the dosing interval; and 5 a mean plasma concentration from 19 to 841 pg/ml at 168 hours after initiation of the dosing interval.
    [34] 34. The use of claim 33, wherein the mean plasma concentrations are provided as follows: a mean plasma concentration from 1 to 28 pg/ml at 6 hours after initiation of the dosing interval; 10 a mean plasma concentration from 14 to 74 pg/ml at 12 hours after initiation of the dosing interval; a mean plasma concentration from 30 to 161 pg/ml at 24 hours after initiation of the dosing interval; a mean plasma concentration from 51 to 188 pg/ml at 36 hours after initiation of the 15 dosing interval; a mean plasma concentration from 62 to 246 pg/ml at 48 hours after initiation of the dosing interval; a mean plasma concentration from 79 to 246 pg/ml at 60 hours after initiation of the dosing interval; 20 a mean plasma concentration from 85 to 263 pg/ml at 72 hours after initiation of the dosing interval; a mean plasma concentration from 92 to 263 pg/ml at 96 hours after initiation of the dosing interval; a mean plasma concentration from 94 to 263 pg/ml at 120 hours after initiation of the 25 dosing interval; a mean plasma concentration from 86 to 243 pg/ml at 144 hours after initiation of the dosing interval; a mean plasma concentration from 77 to 210 pg/ml at 168 hours after initiation of the dosing interval. 30
    [35] 35. The use of claim 33, wherein the mean plasma concentrations are provided as follows: a mean plasma concentration from 0.3 to 7 pg/ml at 6 hours after initiation of the dosing interval; a mean plasma concentration from 4 to 19 pg/ml at 12 hours after initiation of the dosing interval; 35 a mean plasma concentration from 7 to 40 pg/ml at 24 hours after initiation of the dosing interval; a mean plasma concentration from 13 to 47 pg/ml at 36 hours after initiation of the dosing interval; 51 a mean plasma concentration from 16 to 62 pg/ml at 48 hours after initiation of the dosing interval; a mean plasma concentration from 20 to 62 pg/ml at 60 hours after initiation of the dosing interval; 5 a mean plasma concentration from 21 to 66 pg/ml at 72 hours after initiation of the dosing interval; a mean plasma concentration from 23 to 66 pg/ml at 96 hours after initiation of the dosing interval; a mean plasma concentration from 23 to 66 pg/ml at 120 hours after initiation of the 10 dosing interval; a mean plasma concentration from 22 to 61 pg/ml at 144 hours after initiation of the dosing interval; and a mean plasma concentration from 19 to 53 pg/ml at 168 hours after initiation of the dosing interval. 15
    [36] 36. The use of claim 33, wherein the mean plasma concentrations are provided as follows: a mean plasma concentration from 0.7 to 14 pg/ml at 6 hours after initiation of the dosing interval; a mean plasma concentration from 7 to 37 pg/ml at 12 hours after initiation of the dosing interval; 20 a mean plasma concentration from 15 to 80 pg/ml at 24 hours after initiation of the dosing interval; a mean plasma concentration from 25 to 94 pg/ml at 36 hours after initiation of the dosing interval; a mean plasma concentration from 31 to 123 pg/ml at 48 hours after initiation of the 25 dosing interval; a mean plasma concentration from 40 to 123 pg/ml at 60 hours after initiation of the dosing interval; a mean plasma concentration from 40 to 132 pg/ml at 72 hours after initiation of the dosing interval; 30 a mean plasma concentration from 46 to 132 pg/ml at 96 hours after initiation of the dosing interval; a mean plasma concentration from 47 to 132 pg/ml at 120 hours after initiation of the dosing interval; a mean plasma concentration from 43 to 121 pg/ml at 144 hours after initiation of the 35 dosing interval; and a mean plasma concentration from 38 to 105 pg/ml at 168 hours after initiation of the dosing interval.
    [37] 37. The use of claim 33, wherein the mean plasma concentrations are provided as follows: 52 a mean plasma concentration from 3 to 57 pg/ml at 6 hours after initiation of the dosing interval; a mean plasma concentration from 28 to 148 pg/ml at 12 hours after initiation of the dosing interval; 5 a mean plasma concentration from 59 to 322 pg/ml at 24 hours after initiation of the dosing interval; a mean plasma concentration from 102 to 377 pg/ml at 36 hours after initiation of the dosing interval; a mean plasma concentration from 124 to 492 pg/ml at 48 hours after initiation of the 10 dosing interval; a mean plasma concentration from 159 to 492 pg/ml at 60 hours after initiation of the dosing interval; a mean plasma concentration from 169 to 526 pg/ml at 72 hours after initiation of the dosing interval; 15 a mean plasma concentration from 184 to 526 pg/ml at 96 hours after initiation of the dosing interval; a mean plasma concentration from 187 to 526 pg/ml at 120 hours after initiation of the dosing interval; a mean plasma concentration from 173 to 485 pg/ml at 144 hours after initiation of the 20 dosing interval; a mean plasma concentration from 153 to 420 pg/ml at 168 hours after initiation of the dosing interval.
    [38] 38. The use of claim 33, wherein the mean plasma concentrations are provided as follows: a mean plasma concentration from 4 to 85 pg/ml at 6 hours after initiation of the dosing 25 interval; a mean plasma concentration from 42 to 222 pg/ml at 12 hours after initiation of the dosing interval; a mean plasma concentration from 89 to 483 pg/ml at 24 hours after initiation of the dosing interval; 30 a mean plasma concentration from 152 to 565 pg/ml at 36 hours after initiation of the dosing interval; a mean plasma concentration from 186 to 738 pg/ml at 48 hours after initiation of the dosing interval; a mean plasma concentration from 238 to 738 pg/ml at 60 hours after initiation of the 35 dosing interval; a mean plasma concentration from 254 to 789 pg/ml at 72 hours after initiation of the dosing interval; a mean plasma concentration from 276 to 789 pg/ml at 96 hours after initiation of the dosing interval; 53 a mean plasma concentration from 281 to 789 pg/ml at 120 hours after initiation of the dosing interval; a mean plasma concentration from 259 to 727 pg/ml at 144 hours after initiation of the dosing interval; 5 a mean plasma concentration from 230 to 630 pg/ml at 168 hours after initiation of the dosing interval.
    [39] 39. The use of claim 33, wherein the mean plasma concentrations are provided as follows: a mean plasma concentration from 5 to 113 pg/ml at 6 hours after initiation of the dosing interval; 10 a mean plasma concentration from 55 to 296 pg/ml at 12 hours after initiation of the dosing interval; a mean plasma concentration from 118 to 644 pg/ml at 24 hours after initiation of the dosing interval; a mean plasma concentration from 203 to 753 pg/ml at 36 hours after initiation of the 15 dosing interval; a mean plasma concentration from 247 to 984 pg/ml at 48 hours after initiation of the dosing interval; a mean plasma concentration from 317 to 984 pg/ml at 60 hours after initiation of the dosing interval; 20 a mean plasma concentration from 339 to 1052 pg/ml at 72 hours after initiation of the dosing interval; a mean plasma concentration from 369 to 1052 pg/ml at 96 hours after initiation of the dosing interval; a mean plasma concentration from 374 to 1052 pg/ml at 120 hours after initiation of the 25 dosing interval; a mean plasma concentration from 346 to 970 pg/ml at 144 hours after initiation of the dosing interval; a mean plasma concentration from 306 to 841 pg/ml at 168 hours after initiation of the dosing interval. 30
    [40] 40. The use of claim 33, wherein the Tmax occurs from 3 to 5 days after application of said transdermal delivery system.
    [41] 41. The use of claim 33, wherein the transdermal delivery system comprises a polymer matrix layer which comprises buprenorphine.
    [42] 42. The use of claim 33, wherein the transdermal delivery system is an iontophoretic 35 transdermal delivery system.
    [43] 43. The use of any one of claims 33 to 42, wherein the transdermal delivery system comprises 10 to 95 %-wt polymeric material, 0.1 to 40 %-wt softener and 0.1 to 30 %-wt buprenorphine. 54
    [44] 44. The use of claim 43, wherein said transdermal delivery system comprises an adhesive matrix layer comprising 10 %-wt buprenorphine, 10 to 15 %-wt levulinic acid, 10 %-wt oleyloleate, 55 to 70 %-wt polyacrylate and 0 to 10 %-wt polyvinylpyrrollidone.
    [45] 45. The use of any one of claims 33 to 44, wherein the transdermal delivery system provides 5 a nominal delivery rate of buprenorphine of 12.5 pg/hr; the total amount of buprenorphine contained in the transdermal delivery system is 5 mg; and the active surface area of the transdermal delivery system is 6.25 cm 2 .
    [46] 46. The use of any one of claims 33 to 44, wherein the transdermal delivery system provides a nominal delivery rate of buprenorphine of 25 pg/hr; the total amount of buprenorphine contained in 10 the transdermal delivery system is 10 mg; and the active surface area of the transdermal delivery system is 12.5 cm 2 .
    [47] 47. The use of any one of claims 33 to 44, wherein the transdermal delivery system provides a nominal delivery rate of buprenorphine of 50 pg/hr; the total amount of buprenorphine contained in the transdermal delivery system is 20 mg; and the active surface area of the transdermal delivery 15 system is 25 cm 2 .
    [48] 48. The use of any one of claims 33 to 44, wherein the transdermal delivery system provides a nominal delivery rate of buprenorphine of 75 pg/hr; the total amount of buprenorphine contained in the transdermal delivery system is 30 mg; and the active surface area of the transdermal delivery system is 37.5 cm 2 . 20
    [49] 49. The use of any one of claims 33 to 44, wherein the transdermal delivery system provides a nominal delivery rate of buprenorphine of 100 pg/hr; the total amount of buprenorphine contained in the transdermal delivery system is 40 mg; and the active surface area of the transdermal delivery system is 50 cm 2 .
    [50] 50. The use of buprenorphine base in the preparation of a transdermal delivery system for 25 treating pain in a human patient for a dosing interval of 7 days, said transdermal delivery system being suitable for administering buprenorphine transdermally to a human patient by applying the transdermal delivery system to the skin of a patient, and having a mean relative release rate of 3 pg/hr to 86 pg/hr until 72 hours after the initiation of the dosing interval and a mean relative release rate of 0.3 pg/hr to 9 pg/hr from 72 hours until 168 hours after the initiation of the dosing interval such 30 that mean plasma concentrations are provided as follows: a mean plasma concentration from 0.3 to 113 pg/ml at 6 hours after initiation of the dosing interval; a mean plasma concentration from 3 to 296 pg/ml at 12 hours after initiation of the dosing interval; 35 a mean plasma concentration from 7 to 644 pg/ml at 24 hours after initiation of the dosing interval; a mean plasma concentration from 13 to 753 pg/ml at 36 hours after initiation of the dosing interval; 55 a mean plasma concentration from 16 to 984 pg/ml at 48 hours after initiation of the dosing interval; a mean plasma concentration from 20 to 984 pg/ml at 60 hours after initiation of the dosing interval; 5 a mean plasma concentration from 20 to 1052 pg/ml at 72 hours after initiation of the dosing interval; a mean plasma concentration from 23 to 1052 pg/ml at 96 hours after initiation of the dosing interval; a mean plasma concentration from 23 to 1052 pg/ml at 120 hours after initiation of the 10 dosing interval; a mean plasma concentration from 22 to 970 pg/ml at 144 hours after initiation of the dosing interval; and a mean plasma concentration from 19 to 841 pg/ml at 168 hours after initiation of the dosing interval. 15
    [51] 51. The use of claim 50, wherein the mean plasma concentrations are provided as follows: a mean plasma concentration from 1 to 28 pg/ml at 6 hours after initiation of the dosing interval; a mean plasma concentration from 14 to 74 pg/ml at 12 hours after initiation of the dosing interval; 20 a mean plasma concentration from 30 to 161 pg/ml at 24 hours after initiation of the dosing interval; a mean plasma concentration from 51 to 188 pg/ml at 36 hours after initiation of the dosing interval; a mean plasma concentration from 62 to 246 pg/ml at 48 hours after initiation of the 25 dosing interval; a mean plasma concentration from 79 to 246 pg/ml at 60 hours after initiation of the dosing interval; a mean plasma concentration from 85 to 263 pg/ml at 72 hours after initiation of the dosing interval; 30 a mean plasma concentration from 92 to 263 pg/ml at 96 hours after initiation of the dosing interval; a mean plasma concentration from 94 to 263 pg/ml at 120 hours after initiation of the dosing interval; a mean plasma concentration from 86 to 243 pg/ml at 144 hours after initiation of the 35 dosing interval; a mean plasma concentration from 77 to 210 pg/ml at 168 hours after initiation of the dosing interval.
    [52] 52. The use of claim 50, wherein the mean plasma concentrations are provided as follows: 56 a mean plasma concentration from 0.3 to 7 pg/ml at 6 hours after initiation of the dosing interval; a mean plasma concentration from 4 to 19 pg/ml at 12 hours after initiation of the dosing interval; 5 a mean plasma concentration from 7 to 40 pg/ml at 24 hours after initiation of the dosing interval; a mean plasma concentration from 13 to 47 pg/ml at 36 hours after initiation of the dosing interval; a mean plasma concentration from 16 to 62 pg/ml at 48 hours after initiation of the dosing 10 interval; a mean plasma concentration from 20 to 62 pg/ml at 60 hours after initiation of the dosing interval; a mean plasma concentration from 21 to 66 pg/ml at 72 hours after initiation of the dosing interval; 15 a mean plasma concentration from 23 to 66 pg/ml at 96 hours after initiation of the dosing interval; a mean plasma concentration from 23 to 66 pg/ml at 120 hours after initiation of the dosing interval; a mean plasma concentration from 22 to 61 pg/ml at 144 hours after initiation of the 20 dosing interval; and a mean plasma concentration from 19 to 53 pg/ml at 168 hours after initiation of the dosing interval.
    [53] 53. The use of claim 50, wherein the mean plasma concentrations are provided as follows: a mean plasma concentration from 0.7 to 14 pg/ml at 6 hours after initiation of the dosing 25 interval; a mean plasma concentration from 7 to 37 pg/ml at 12 hours after initiation of the dosing interval; a mean plasma concentration from 15 to 80 pg/ml at 24 hours after initiation of the dosing interval; 30 a mean plasma concentration from 25 to 94 pg/ml at 36 hours after initiation of the dosing interval; a mean plasma concentration from 31 to 123 pg/ml at 48 hours after initiation of the dosing interval; a mean plasma concentration from 40 to 123 pg/ml at 60 hours after initiation of the 35 dosing interval; a mean plasma concentration from 40 to 132 pg/ml at 72 hours after initiation of the dosing interval; a mean plasma concentration from 46 to 132 pg/ml at 96 hours after initiation of the dosing interval; 57 a mean plasma concentration from 47 to 132 pg/ml at 120 hours after initiation of the dosing interval; a mean plasma concentration from 43 to 121 pg/ml at 144 hours after initiation of the dosing interval; and 5 a mean plasma concentration from 38 to 105 pg/ml at 168 hours after initiation of the dosing interval.
    [54] 54. The use of claim 50, wherein the mean plasma concentrations are provided as follows: a mean plasma concentration from 3 to 57 pg/ml at 6 hours after initiation of the dosing interval; 10 a mean plasma concentration from 28 to 148 pg/ml at 12 hours after initiation of the dosing interval; a mean plasma concentration from 59 to 322 pg/ml at 24 hours after initiation of the dosing interval; a mean plasma concentration from 102 to 377 pg/ml at 36 hours after initiation of the 15 dosing interval; a mean plasma concentration from 124 to 492 pg/ml at 48 hours after initiation of the dosing interval; a mean plasma concentration from 159 to 492 pg/ml at 60 hours after initiation of the dosing interval; 20 a mean plasma concentration from 169 to 526 pg/ml at 72 hours after initiation of the dosing interval; a mean plasma concentration from 184 to 526 pg/ml at 96 hours after initiation of the dosing interval; a mean plasma concentration from 187 to 526 pg/ml at 120 hours after initiation of the 25 dosing interval; a mean plasma concentration from 173 to 485 pg/ml at 144 hours after initiation of the dosing interval; a mean plasma concentration from 153 to 420 pg/ml at 168 hours after initiation of the dosing interval. 30
    [55] 55. The use of claim 50, wherein the mean plasma concentrations are provided as follows: a mean plasma concentration from 4 to 85 pg/ml at 6 hours after initiation of the dosing interval; a mean plasma concentration from 42 to 222 pg/ml at 12 hours after initiation of the dosing interval; 35 a mean plasma concentration from 89 to 483 pg/ml at 24 hours after initiation of the dosing interval; a mean plasma concentration from 152 to 565 pg/ml at 36 hours after initiation of the dosing interval; 58 a mean plasma concentration from 186 to 738 pg/ml at 48 hours after initiation of the dosing interval; a mean plasma concentration from 238 to 738 pg/ml at 60 hours after initiation of the dosing interval; 5 a mean plasma concentration from 254 to 789 pg/ml at 72 hours after initiation of the dosing interval; a mean plasma concentration from 276 to 789 pg/ml at 96 hours after initiation of the dosing interval; a mean plasma concentration from 281 to 789 pg/ml at 120 hours after initiation of the 10 dosing interval; a mean plasma concentration from 259 to 727 pg/ml at 144 hours after initiation of the dosing interval; a mean plasma concentration from 230 to 630 pg/ml at 168 hours after initiation of the dosing interval. 15
    [56] 56. The use of claim 50, wherein the mean plasma concentrations are provided as follows: a mean plasma concentration from 5 to 113 pg/ml at 6 hours after initiation of the dosing interval; a mean plasma concentration from 55 to 296 pg/ml at 12 hours after initiation of the dosing interval; 20 a mean plasma concentration from 118 to 644 pg/ml at 24 hours after initiation of the dosing interval; a mean plasma concentration from 203 to 753 pg/ml at 36 hours after initiation of the dosing interval; a mean plasma concentration from 247 to 984 pg/ml at 48 hours after initiation of the 25 dosing interval; a mean plasma concentration from 317 to 984 pg/ml at 60 hours after initiation of the dosing interval; a mean plasma concentration from 339 to 1052 pg/ml at 72 hours after initiation of the dosing interval; 30 a mean plasma concentration from 369 to 1052 pg/ml at 96 hours after initiation of the dosing interval; a mean plasma concentration from 374 to 1052 pg/ml at 120 hours after initiation of the dosing interval; a mean plasma concentration from 346 to 970 pg/ml at 144 hours after initiation of the 35 dosing interval; a mean plasma concentration from 306 to 841 pg/ml at 168 hours after initiation of the dosing interval.
    [57] 57. The use of claim 50, wherein the Tmax occurs from 3 to 5 days after application of said transdermal delivery system. 59
    [58] 58. The use of claim 50, wherein the transdermal delivery system comprises a polymer matrix layer which comprises the buprenorphine base.
    [59] 59. The use of claim 50, wherein the transdermal delivery system is an iontophoretic transdermal delivery system. 5
    [60] 60. The use of any one of claims 50 to 59, wherein the transdermal delivery system comprises 10 to 95 %-wt polymeric material, 0.1 to 40 %-wt softener and 0.1 to 30 %-wt buprenorphine.
    [61] 61. The use of claim 60, wherein said transdermal delivery system comprises an adhesive matrix layer comprising 10 %-wt buprenorphine base, 10 to 15 %-wt levulinic acid, 10 %-wt 10 oleyloleate, 55 to 70 %-wt polyacrylate and 0 to 10 %-wt polyvinylpyrrollidone.
    [62] 62. The use of any one of claims 50 to 61, wherein the transdermal delivery system provides a nominal delivery rate of buprenorphine base of 12.5 pg/hr; the total amount of buprenorphine base contained in the transdermal delivery system is 5 mg; and the active surface area of the transdermal delivery system is 6.25 cm 2 . 15
    [63] 63. The use of any one of claims 50 to 61, wherein the transdermal delivery system provides a nominal delivery rate of buprenorphine base of 25 pg/hr; the total amount of buprenorphine base contained in the transdermal delivery system is 10 mg; and the active surface area of the transdermal delivery system is 12.5 cm 2 .
    [64] 64. The use of any one of claims 50 to 61, wherein the transdermal delivery system provides 20 a nominal delivery rate of buprenorphine base of 50 pg/hr; the total amount of buprenorphine base contained in the transdermal delivery system is 20 mg; and the active surface area of the transdermal delivery system is 25 cm 2 .
    [65] 65. The use of any one of claims 50 to 61, wherein the transdermal delivery system provides a nominal delivery rate of buprenorphine base of 75 pg/hr; the total amount of buprenorphine base 25 contained in the transdermal delivery system is 30 mg; and the active surface area of the transdermal delivery system is 37.5 cm 2 .
    [66] 66. The use of any one of claims 50 to 61, wherein the transdermal delivery system provides a nominal delivery rate of buprenorphine base of 100 pg/hr; the total amount of buprenorphine base contained in the transdermal delivery system is 40 mg; and the active surface area of the transdermal 30 delivery system is 50 cm 2 .
    [67] 67. The use of buprenorphine base in the preparation of a transdermal delivery system for treating pain in a human patient for a dosing interval of 7 days, said transdermal delivery system being suitable for administering buprenorphine transdermally to a human patient by applying the transdermal delivery system to the skin of a patient, and having a mean relative release rate of 35 3 pg/hr to 86 pg/hr until 72 hours after the initiation of the dosing interval and a mean relative release rate of 0.3 pg/hr to 9 pg/hr from 72 hours until 168 hours after the initiation of the dosing interval such that mean plasma concentrations are provided as follows: 60 a mean plasma concentration from 0.3 to 113 pg/ml at 6 hours after initiation of the dosing interval; a mean plasma concentration from 3 to 296 pg/ml at 12 hours after initiation of the dosing interval; 5 a mean plasma concentration from 7 to 644 pg/ml at 24 hours after initiation of the dosing interval; a mean plasma concentration from 13 to 753 pg/ml at 36 hours after initiation of the dosing interval; a mean plasma concentration from 16 to 984 pg/ml at 48 hours after initiation of the 10 dosing interval; a mean plasma concentration from 20 to 984 pg/ml at 60 hours after initiation of the dosing interval; a mean plasma concentration from 20 to 1052 pg/ml at 72 hours after initiation of the dosing interval; 15 a mean plasma concentration from 23 to 1052 pg/ml at 96 hours after initiation of the dosing interval; a mean plasma concentration from 23 to 1052 pg/ml at 120 hours after initiation of the dosing interval; a mean plasma concentration from 22 to 970 pg/ml at 144 hours after initiation of the 20 dosing interval; and a mean plasma concentration from 19 to 841 pg/ml at 168 hours after initiation of the dosing interval, wherein the transdermal delivery system comprises a polymer matrix layer which comprises the buprenorphine base. 25
    [68] 68. The use of claim 67, wherein the mean plasma concentrations are provided as follows: a mean plasma concentration from 1 to 28 pg/ml at 6 hours after initiation of the dosing interval; a mean plasma concentration from 14 to 74 pg/ml at 12 hours after initiation of the dosing interval; 30 a mean plasma concentration from 30 to 161 pg/ml at 24 hours after initiation of the dosing interval; a mean plasma concentration from 51 to 188 pg/ml at 36 hours after initiation of the dosing interval; a mean plasma concentration from 62 to 246 pg/ml at 48 hours after initiation of the 35 dosing interval; a mean plasma concentration from 79 to 246 pg/ml at 60 hours after initiation of the dosing interval; a mean plasma concentration from 85 to 263 pg/ml at 72 hours after initiation of the dosing interval; 61 a mean plasma concentration from 92 to 263 pg/ml at 96 hours after initiation of the dosing interval; a mean plasma concentration from 94 to 263 pg/ml at 120 hours after initiation of the dosing interval; 5 a mean plasma concentration from 86 to 243 pg/ml at 144 hours after initiation of the dosing interval; a mean plasma concentration from 77 to 210 pg/ml at 168 hours after initiation of the dosing interval.
    [69] 69. The use of claim 67, wherein the mean plasma concentrations are provided as follows: 10 a mean plasma concentration from 0.3 to 7 pg/ml at 6 hours after initiation of the dosing interval; a mean plasma concentration from 4 to 19 pg/ml at 12 hours after initiation of the dosing interval; a mean plasma concentration from 7 to 40 pg/ml at 24 hours after initiation of the dosing 1s interval; a mean plasma concentration from 13 to 47 pg/ml at 36 hours after initiation of the dosing interval; a mean plasma concentration from 16 to 62 pg/ml at 48 hours after initiation of the dosing interval; 20 a mean plasma concentration from 20 to 62 pg/ml at 60 hours after initiation of the dosing interval; a mean plasma concentration from 21 to 66 pg/ml at 72 hours after initiation of the dosing interval; a mean plasma concentration from 23 to 66 pg/ml at 96 hours after initiation of the dosing 25 interval; a mean plasma concentration from 23 to 66 pg/ml at 120 hours after initiation of the dosing interval; a mean plasma concentration from 22 to 61 pg/ml at 144 hours after initiation of the dosing interval; and 30 a mean plasma concentration from 19 to 53 pg/ml at 168 hours after initiation of the dosing interval.
    [70] 70. The use of claim 67, wherein the mean plasma concentrations are provided as follows: a mean plasma concentration from 0.7 to 14 pg/ml at 6 hours after initiation of the dosing interval; 35 a mean plasma concentration from 7 to 37 pg/ml at 12 hours after initiation of the dosing interval; a mean plasma concentration from 15 to 80 pg/ml at 24 hours after initiation of the dosing interval; 62 a mean plasma concentration from 25 to 94 pg/ml at 36 hours after initiation of the dosing interval; a mean plasma concentration from 31 to 123 pg/ml at 48 hours after initiation of the dosing interval; 5 a mean plasma concentration from 40 to 123 pg/ml at 60 hours after initiation of the dosing interval; a mean plasma concentration from 40 to 132 pg/ml at 72 hours after initiation of the dosing interval; a mean plasma concentration from 46 to 132 pg/ml at 96 hours after initiation of the 10 dosing interval; a mean plasma concentration from 47 to 132 pg/ml at 120 hours after initiation of the dosing interval; a mean plasma concentration from 43 to 121 pg/ml at 144 hours after initiation of the dosing interval; and 15 a mean plasma concentration from 38 to 105 pg/ml at 168 hours after initiation of the dosing interval.
    [71] 71. The use of claim 67, wherein the mean plasma concentrations are provided as follows: a mean plasma concentration from 3 to 57 pg/ml at 6 hours after initiation of the dosing interval; 20 a mean plasma concentration from 28 to 148 pg/ml at 12 hours after initiation of the dosing interval; a mean plasma concentration from 59 to 322 pg/ml at 24 hours after initiation of the dosing interval; a mean plasma concentration from 102 to 377 pg/ml at 36 hours after initiation of the 25 dosing interval; a mean plasma concentration from 124 to 492 pg/ml at 48 hours after initiation of the dosing interval; a mean plasma concentration from 159 to 492 pg/ml at 60 hours after initiation of the dosing interval; 30 a mean plasma concentration from 169 to 526 pg/ml at 72 hours after initiation of the dosing interval; a mean plasma concentration from 184 to 526 pg/ml at 96 hours after initiation of the dosing interval; a mean plasma concentration from 187 to 526 pg/ml at 120 hours after initiation of the 35 dosing interval; a mean plasma concentration from 173 to 485 pg/ml at 144 hours after initiation of the dosing interval; a mean plasma concentration from 153 to 420 pg/ml at 168 hours after initiation of the dosing interval. 63
    [72] 72. The use of claim 67, wherein the mean plasma concentrations are provided as follows: a mean plasma concentration from 4 to 85 pg/ml at 6 hours after initiation of the dosing interval; a mean plasma concentration from 42 to 222 pg/ml at 12 hours after initiation of the 5 dosing interval; a mean plasma concentration from 89 to 483 pg/ml at 24 hours after initiation of the dosing interval; a mean plasma concentration from 152 to 565 pg/ml at 36 hours after initiation of the dosing interval; 10 a mean plasma concentration from 186 to 738 pg/ml at 48 hours after initiation of the dosing interval; a mean plasma concentration from 238 to 738 pg/ml at 60 hours after initiation of the dosing interval; a mean plasma concentration from 254 to 789 pg/ml at 72 hours after initiation of the 15 dosing interval; a mean plasma concentration from 276 to 789 pg/ml at 96 hours after initiation of the dosing interval; a mean plasma concentration from 281 to 789 pg/ml at 120 hours after initiation of the dosing interval; 20 a mean plasma concentration from 259 to 727 pg/ml at 144 hours after initiation of the dosing interval; a mean plasma concentration from 230 to 630 pg/ml at 168 hours after initiation of the dosing interval.
    [73] 73. The use of claim 67, wherein the mean plasma concentrations are provided as follows: 25 a mean plasma concentration from 5 to 113 pg/ml at 6 hours after initiation of the dosing interval; a mean plasma concentration from 55 to 296 pg/ml at 12 hours after initiation of the dosing interval; a mean plasma concentration from 118 to 644 pg/ml at 24 hours after initiation of the 30 dosing interval; a mean plasma concentration from 203 to 753 pg/ml at 36 hours after initiation of the dosing interval; a mean plasma concentration from 247 to 984 pg/ml at 48 hours after initiation of the dosing interval; 35 a mean plasma concentration from 317 to 984 pg/ml at 60 hours after initiation of the dosing interval; a mean plasma concentration from 339 to 1052 pg/ml at 72 hours after initiation of the dosing interval; 64 a mean plasma concentration from 369 to 1052 pg/ml at 96 hours after initiation of the dosing interval; a mean plasma concentration from 374 to 1052 pg/ml at 120 hours after initiation of the dosing interval; 5 a mean plasma concentration from 346 to 970 pg/ml at 144 hours after initiation of the dosing interval; a mean plasma concentration from 306 to 841 pg/ml at 168 hours after initiation of the dosing interval.
    [74] 74. The use of claim 67, wherein the Tmax occurs from 3 to 5 days after application of said 10 transdermal delivery system.
    [75] 75. The use of claim 67, wherein the transdermal delivery system is an iontophoretic transdermal delivery system.
    [76] 76. The use of any one of claims 67 to 75, wherein the transdermal delivery system comprises 10 to 95 %-wt polymeric material, 0.1 to 40 %-wt softener and 0.1 to 30 %-wt 15 buprenorphine.
    [77] 77. The use of claim 76, wherein said transdermal delivery system comprises an adhesive matrix layer comprising 10 %-wt buprenorphine base, 10 to 15 %-wt levulinic acid, 10 %-wt oleyloleate, 55 to 70 %-wt polyacrylate and 0 to 10 %-wt polyvinylpyrrollidone.
    [78] 78. The use of any one of claims 67 to 77, wherein the transdermal delivery system provides 20 a nominal delivery rate of buprenorphine base of 12.5 pg/hr; the total amount of buprenorphine base contained in the transdermal delivery system is 5 mg; and the active surface area of the transdermal delivery system is 6.25 cm 2 .
    [79] 79. The use of any one of claims 67 to 77, wherein the transdermal delivery system provides a nominal delivery rate of buprenorphine base of 25 pg/hr; the total amount of buprenorphine base 25 contained in the transdermal delivery system is 10 mg; and the active surface area of the transdermal delivery system is 12.5 cm 2 .
    [80] 80. The use of any one of claims 67 to 77, wherein the transdermal delivery system provides a nominal delivery rate of buprenorphine base of 50 pg/hr; the total amount of buprenorphine base contained in the transdermal delivery system is 20 mg; and the active surface area of the transdermal 30 delivery system is 25 cm 2 .
    [81] 81. The use of any one of claims 67 to 77, wherein the transdermal delivery system provides a nominal delivery rate of buprenorphine base of 75 pg/hr; the total amount of buprenorphine base contained in the transdermal delivery system is 30 mg; and the active surface area of the transdermal delivery system is 37.5 cm 2 . 35
    [82] 82. The use of any one of claims 67 to 77, wherein the transdermal delivery system provides a nominal delivery rate of buprenorphine base of 100 pg/hr; the total amount of buprenorphine base 65 contained in the transdermal delivery system is 40 mg; and the active surface area of the transdermal delivery system is 50 cm 2 .
    [83] 83. Use of buprenorphine in the preparation of a transdermal delivery system for treating pain in a human patient for a dosing interval of at least 4 days, said delivery system comprising a 5 polymer matrix layer including buprenorphine or a pharmaceutically acceptable salt thereof and a backing layer made of a pharmaceutically acceptable material which is impermeable to buprenorphine, wherein the transdermal delivery system comprises 10 to 95 %-wt polymeric material, 0.1 to 40 %-wt softener and 0.1 to 30 %-wt buprenorphine, wherein said transdermal delivery system provides over the dosing interval of about 72 hours a release rate of buprenorphine such that a 10 maximum plasma concentration of from 20 pg/ml to 850 pg/ml is attained and the transdermal delivery system when maintained on the skin of the patient for the dosing interval of at least additional 24 hours provides plasma concentrations of buprenorphine in the patients above the minimum effective concentrations of the buprenorphine, such that the patients continue to experience effective pain management during this additional dosing interval. 1s
    [84] 84. The use according to claim 83, wherein the mean relative release rates achieved over the dosing interval are as follows: a mean relative release rate of from 3 pg/hr to 5 pg/hr from initiation of the dosing interval until 72 hours after the initiation of the dosing interval, and a mean relative release rate of from 0.3 pg/hr to 0.6 pg/hr from 72 hours after initiation of 20 the dosing interval until the end of the dosing interval.
    [85] 85. The use according to claim 83, wherein the mean relative release rates achieved over the dosing interval are as follows: a mean relative release rate of from 6 pg/hr to 11 pg/hr from initiation of the dosing interval until 72 hours after the initiation of the dosing interval, and 25 a mean relative release rate of from 0.7 pg/hr to 1 pg/hr from 72 hours after initiation of the dosing interval until the end of the dosing interval.
    [86] 86. The use according to claim 83, wherein the mean relative release rates achieved over the dosing interval are as follows: a mean relative release rate of from 13 pg/hr to 21 pg/hr from initiation of the dosing 30 interval until 72 hours after the initiation of the dosing interval, and a mean relative release rate of from 1 pg/hr to 2 pg/hr from 72 hours after initiation of the dosing interval until the end of the dosing interval.
    [87] 87. The use according to claim 83, wherein the mean relative release rates achieved over the dosing interval are as follows: 35 a mean relative release rate of from 26 pg/hr to 43 pg/hr from initiation of the dosing interval until 72 hours after the initiation of the dosing interval, and a mean relative release rate of from 3 pg/hr to 4 pg/hr from 72 hours after initiation of the dosing interval until the end of the dosing interval. 66
    [88] 88. The use according to claim 83, wherein the mean relative release rates achieved over the dosing interval are as follows: a mean relative release rate of from 39 pg/hr to 64 pg/hr from initiation of the dosing interval until 72 hours after the initiation of the dosing interval, and 5 a mean relative release rate of from 4 pg/hr to 7 pg/hr from 72 hours after initiation of the dosing interval until the end of the dosing interval.
    [89] 89. The use according to claim 83, wherein the mean relative release rates achieved over the dosing interval are as follows: a mean relative release rate of from 51 pg/hr to 86 pg/hr from initiation of the dosing 10 interval until 72 hours after the initiation of the dosing interval, and a mean relative release rate of from 5 pg/hr to 9 pg/hr from 72 hours after initiation of the dosing interval until the end of the dosing interval.
    [90] 90. The use according to claim 83, wherein the Tmax occurs from 3 to 5 days after application of said transdermal delivery system. 15
    [91] 91. The use according to claim 83, wherein at the end of the dosing interval from 68 % to 95 % of the buprenorphine is left in the transdermal delivery system.
    [92] 92. The use of claim 83, wherein the transdermal delivery system comprises 10 %-wt buprenorphine base, 10 to 15 %-wt levulinic acid, about 10 %-wt oleyloleate, 55 to 70 %-wt polyacrylate and 0 to 10 %-wt polyvinylpyrrolidone. 20
    [93] 93. Use of buprenorphine in the preparation of a transdermal delivery device for treating pain in a patient for a dosing interval of at least 5 days, said device comprising a polymer matrix layer containing buprenorphine or a pharmaceutically acceptable salt thereof, wherein the transdermal delivery device comprises 10 to 95 %-wt polymeric material, 0.1 to 40 %-wt softener and 0.1 to 30 % wt buprenorphine. 25
    [94] 94. The use of claim 93, wherein the transdermal delivery system comprises 10 %-wt buprenorphine base, 10 to 15 %-wt levulinic acid, about 10 %-wt oleyloleate, 55 to 70 %-wt polyacrylate and 0 to 10 %-wt polyvinylpyrrolidone.
    [95] 95. The use according to claim 93, wherein said device delivers the buprenorphine to provide a mean plasma concentration from 24 to 850 pg/ml about 3 days after application. 30
    [96] 96. The use according to claim 93, wherein said device provides mean plasma concentrations as follows: a mean plasma concentration from 1 to 28 pg/ml at about 6 hours after initiation of the dosing interval; a mean plasma concentration from 14 to 74 pg/ml at about 12 hours after initiation of the 35 dosing interval; a mean plasma concentration from 30 to 161 pg/ml at about 24 hours after initiation of the dosing interval; 67 a mean plasma concentration from 51 to 188 pg/ml at about 36 hours after initiation of the dosing interval; a mean plasma concentration from 62 to 246 pg/ml at about 48 hours after initiation of the dosing interval; 5 a mean plasma concentration from 79 to 246 pg/ml at about 60 hours after initiation of the dosing interval; a mean plasma concentration from 85 to 263 pg/ml at about 72 hours after initiation of the dosing interval; and thereafter mean plasma concentrations from 77 to 263 pg/ml over at least the next 48 10 hours.
    [97] 97. The use according to claim 96, wherein the mean plasma concentrations are provided as follows: a mean plasma concentration from 92 to 263 pg/ml at about 96 hours after initiation of the dosing interval; 15 a mean plasma concentration from 94 to 263 pg/ml at about 120 hours after initiation of the dosing interval; a mean plasma concentration from 86 to 243 pg/ml at about 144 hours after initiation of the dosing interval; and a mean plasma concentration from 77 to 210 pg/ml at about 168 hours after initiation of 20 the dosing interval.
    [98] 98. The use according to claim 93, wherein said device provides mean plasma concentrations as follows: a mean plasma concentration from 0.7 to 14 pg/ml at about 6 hours after initiation of the dosing interval; 25 a mean plasma concentration from 7 to 37 pg/ml at about 12 hours after initiation of the dosing interval; a mean plasma concentration from 15 to 80 pg/ml at about 24 hours after initiation of the dosing interval; a mean plasma concentration from 25 to 94 pg/ml at about 36 hours after initiation of the 30 dosing interval; a mean plasma concentration from 31 to 123 pg/ml at about 48 hours after initiation of the dosing interval; a mean plasma concentration from 40 to 123 pg/ml at about 60 hours after initiation of the dosing interval; 35 a mean plasma concentration from 42 to 132 pg/ml at about 72 hours after initiation of the dosing interval; and thereafter mean plasma concentrations from 38 to 132 pg/ml over at least the next 48 hours. 68
    [99] 99. The use according to claim 98, wherein the mean plasma concentrations are provided as follows: a mean plasma concentration from 46 to 132 pg/ml at about 96 hours after initiation of the dosing interval; 5 a mean plasma concentration from 47 to 132 pg/ml at about 120 hours after initiation of the dosing interval; a mean plasma concentration from 43 to 121 pg/ml at about 144 hours after initiation of the dosing interval; and a mean plasma concentration from 38 to 105 pg/ml at about 168 hours after initiation of the 10 dosing interval.
    [100] 100. The use according to claim 93, wherein said device provides mean plasma concentrations as follows: a mean plasma concentration from 3 to 57 pg/ml at about 6 hours after initiation of the dosing interval; 15 a mean plasma concentration from 28 to 148 pg/ml at about 12 hours after initiation of the dosing interval; a mean plasma concentration from 59 to 322 pg/ml at about 24 hours after initiation of the dosing interval; a mean plasma concentration from 102 to 377 pg/ml at about 36 hours after initiation of the 20 dosing interval; a mean plasma concentration from 124 to 492 pg/ml at about 48 hours after initiation of the dosing interval; a mean plasma concentration from 159 to 492 pg/ml at about 60 hours after initiation of the dosing interval; 25 a mean plasma concentration from 169 to 526 pg/ml at about 72 hours after initiation of the dosing interval; thereafter mean plasma concentrations from 153 to 526 pg/ml over at least the next 48 hours.
    [101] 101. The use according to claim 100, wherein the mean plasma concentrations are provided as follows: 30 a mean plasma concentration from 184 to 526 pg/ml at about 96 hours after initiation of the dosing interval; a mean plasma concentration from 187 to 526 pg/ml at about 120 hours after initiation of the dosing interval; a mean plasma concentration from 173 to 485 pg/ml at about 144 hours after initiation of the 35 dosing interval; a mean plasma concentration from 153 to 420 pg/ml at about 168 hours after initiation of the dosing interval.
    [102] 102. The use according to claim 93, wherein said device provides mean plasma concentrations as follows: 69 a mean plasma concentration from 4 to 85 pg/ml at about 6 hours after initiation of the dosing interval; a mean plasma concentration from 42 to 222 pg/ml at about 12 hours after initiation of the dosing interval; 5 a mean plasma concentration from 89 to 483 pg/ml at about 24 hours after initiation of the dosing interval; a mean plasma concentration from 152 to 565 pg/ml at about 36 hours after initiation of the dosing interval; a mean plasma concentration from 186 to 738 pg/ml at about 48 hours after initiation of the 10 dosing interval; a mean plasma concentration from 238 to 738 pg/ml at about 60 hours after initiation of the dosing interval; a mean plasma concentration from 254 to 789 pg/ml at about 72 hours after initiation of the dosing interval; 15 thereafter mean plasma concentrations from 230 to 789 pg/ml over at least the next 48 hours.
    [103] 103. The use according to claim 102, wherein the mean plasma concentrations are provided as follows: a mean plasma concentration from 276 to 789 pg/ml at about 96 hours after initiation of the dosing interval; 20 a mean plasma concentration from 281 to 789 pg/ml at about 120 hours after initiation of the dosing interval; a mean plasma concentration from 259 to 727 pg/ml at about 144 hours after initiation of the dosing interval; a mean plasma concentration from 230 to 630 pg/ml at about 168 hours after initiation of the 25 dosing interval.
    [104] 104. The use according to claim 93, wherein the Tmax occurs from 3 to 5 days after application of said transdermal delivery device.
    [105] 105. The use according to claim 93, wherein at the end of the dosing interval from 68 % to 95 % of the buprenorphine is left in the transdermal delivery device. 30
    [106] 106. Use of buprenorphine in the preparation of a transdermal delivery device for treating pain in a patient for a dosing interval of 7 days, said device having a mean relative release rate of buprenorphine of 3 pg/hr to 5 pg/hr until 72 hours after the initiation of the dosing interval and a mean relative release rate of 0.3 pg/hr to 0.6 pg/hr from 72 hours until 168 hours after the initiation of the dosing interval, or 35 having a mean relative release rate of 6 pg/hr to 11 pg/hr until 72 hours after the initiation of the dosing interval and a mean relative release rate of 0.7 pg/hr to 1 pg/hr from 72 hours until 168 hours after the initiation of the dosing interval, or 70 having a mean relative release rate of 13 pg/hr to 21 pg/hr until 72 hours after the initiation of the dosing interval and a mean relative release rate of 1 pg/hr to 2 pg/hr from 72 hours until 168 hours after the initiation of the dosing interval, or having a mean relative release rate of 26 pg/hr to 43 pg/hr until 72 hours after the initiation of 5 the dosing interval and a mean relative release rate of 3 pg/hr to 4 pg/hr from 72 hours until 168 hours after the initiation of the dosing interval, or having a mean relative release rate of 39 pg/hr to 64 pg/hr until 72 hours after the initiation of the dosing interval and a mean relative release rate of 4 pg/hr to 7 pg/hr from 72 hours until 168 hours after the initiation of the dosing interval, or 10 having a mean relative release rate of 51 pg/hr to 86 pg/hr until 72 hours after the initiation of the dosing interval and a mean relative release rate of 5 pg/hr to 9 pg/hr from 72 hours until 168 hours after the initiation of the dosing interval.
    [107] 107. The use of claim 106, wherein the buprenorphine is buprenorphine base.
    [108] 108. The use of claim 106, wherein the transdermal delivery device is selected from 1s transdermal patches, transdermal plasters, transdermal discs or iontophoretic transdermal devices.
    [109] 109. The use of claim 106, wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery device.
    [110] 110. The use of claim 106, wherein at the end of the dosing interval from 68 % to 95 % of the buprenorphine is left in the transdermal delivery device. 20
    [111] 111. Use of buprenorphine in the preparation of a transdermal delivery device for treating pain in a patient for a dosing interval of at least 7 days, wherein the transdermal delivery device comprises a pressure sensitive adhesive layer, wherein the pressure sensitive adhesive layer comprises 10 to 95 %-wt polymeric material, 0.1 to 40 %-wt softener, and 0.1 to 30 %-wt buprenorphine.
    [112] 112. The use of claim 111, wherein the softener is oleyloleate. 25
    [113] 113. The use of claim 112, wherein the pressure sensitive adhesive layer comprises 10 %-wt buprenorphine base, 10 to 15 %-wt levulinic acid, about 10 %-wt oleyloleate, 55 to 70 %-wt polyacrylate and 0 to 10 %-wt polyvinylpyrrolidone.
    [114] 114. The use of any one of claims 111 to 113, wherein the treatment of pain in a patient comprises 30 applying onto the skin of the patient the transdermal delivery device comprising buprenorphine, and maintaining the transdermal buprenorphine delivery device in contact with the skin of the human patient for at least 7 days, such that the patient continues to receive effective analgesia from the transdermal buprenorphine delivery device. 35
    [115] 115. The use of claim 111, wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery device. 71
    [116] 116. The use of claim 111, wherein at the end of the dosing interval from 68 % to 95 % of the buprenorphine is left in the transdermal delivery device.
    [117] 117. Use of buprenorphine in the preparation of a transdermal delivery system comprising buprenorphine for treating pain in a human patient for a dosing interval of at least 4 days, wherein said 5 transdermal delivery system after applying the transdermal delivery system to the skin of a patient provides a release rate of buprenorphine over about a 72 hour dosing interval such that a maximum plasma concentration of from 20 pg/ml to 850 pg/ml is attained and the transdermal delivery device when maintained on the skin of the patient for at least an additional 24 hour interval provides plasma concentrations of buprenorphine in the patients above the minimum effective concentrations of the 10 buprenorphine, such that the patients continue to experience effective pain management during this additional dosing interval.
    [118] 118. The use of claim 117, wherein the buprenorphine is buprenorphine base.
    [119] 119. The use of claim 117 or claim 118, wherein the transdermal delivery system comprises a polymer matrix layer which comprises the buprenorphine. 15
    [120] 120. The use of claim 119, wherein the polymer matrix layer comprises 10 to 95 %-wt polymeric material, 0.1 to 40 %-wt softener and 0.1 to 30 %-wt buprenorphine.
    [121] 121. The use of claim 120, wherein the polymer matrix layer comprises 10 %-wt buprenorphine base, 10 to 15 %-wt levulinic acid, about 10 %-wt oleyloleate, 55 to 70 %-wt polyacrylate and 0 to 10 %-wt polyvinylpyrrolidone. 20
    [122] 122. The use of any one of claims 117 to 121, wherein the treatment of pain in a patient comprises maintaining the transdermal buprenorphine delivery device in contact with the skin of the human patient for at least 7 days, such that the patient continues to receive effective analgesia from the transdermal buprenorphine delivery device.
    [123] 123. The use of claim 117, wherein the Tmax occurs from 3 to 5 days after application of said 25 transdermal delivery system.
    [124] 124. The use of claim 117, wherein at the end of the dosing interval from 68 % to 95 % of the buprenorphine is left in the transdermal delivery device.
    [125] 125. Use of buprenorphine in the preparation of a transdermal delivery device comprising buprenorphine for treating pain in a patient for a dosing interval of 5 to 9 days by 30 applying onto the skin of the patient the transdermal delivery device comprising a polymer matrix layer comprising an amount of buprenorphine expected to be sufficient for about 3 days, and maintaining the transdermal buprenorphine delivery device in contact with the skin of the human patient from 2 to 6 additional days.
    [126] 126. The use of claim 125, wherein said device has a mean relative release rate of 3 pg/hr to 35 86 pg/hr until 72 hours after the initiation of the dosing interval and a mean relative release rate of 0.3 pg/hr to 9 pg/hr from 72 hours until 168 hours after the initiation of the dosing interval. 72
    [127] 127. The use of claim 125 or 126, wherein the buprenorphine is buprenorphine base.
    [128] 128. Use of buprenorphine in the preparation of a transdermal delivery device comprising buprenorphine for treating pain in a patient for a dosing interval of 5 to 9 days by applying onto the skin of the patient the transdermal delivery device comprising a pressure 5 sensitive adhesive layer comprising an amount of buprenorphine expected to be sufficient for about 3 days, and maintaining the transdermal buprenorphine delivery device in contact with the skin of the human patient from 2 to 6 additional days.
    [129] 129. The use of claim 128, wherein the pressure sensitive adhesive layer comprises 10 to 95 10 %-wt polymeric material, 0.1 to 40 %-wt softener and 0.1 to 30 %-wt buprenorphine.
    [130] 130. The use of claim 125, wherein the pressure sensitive adhesive layer comprises 10 %-wt buprenorphine base, 10 to 15 %-wt levulinic acid, about 10 %-wt oleyloleate, 55 to 70 %-wt polyacrylate and 0 to 10 %-wt polyvinylpyrrolidone.
    [131] 131. The use of claim 125 or claim 128, wherein said device provides mean plasma 15 concentrations as follows: a mean plasma concentration from 0.3 to 113 pg/ml at 6 hours after initiation of the dosing interval; a mean plasma concentration from 3 to 296 pg/ml at 12 hours after initiation of the dosing interval; 20 a mean plasma concentration from 11 to 644 pg/ml at 24 hours after initiation of the dosing interval; a mean plasma concentration from 13 to 630 pg/ml at 30 hours after initiation of the dosing interval; a mean plasma concentration from 15 to 715 pg/ml at 36 hours after initiation of the dosing 25 interval; a mean plasma concentration from 20 to 984 pg/ml at 48 hours after initiation of the dosing interval; a mean plasma concentration from 21 to 914 pg/ml at 60 hours after initiation of the dosing interval; and 30 a mean plasma concentration from 24 to 850 pg/ml at 72 hours after initiation of the dosing interval; and thereafter mean plasma concentrations from 19 to 1052 pg/ml over at least the next 48 hours.
    [132] 132. The use of claim 131, wherein the dosing interval is maintained for 7 days.
    [133] 133. The use of claim 125 or claim 128 which delivers the buprenorphine substantially 35 according to first order kinetics to provide a mean plasma concentration from 24 to 850 pg/ml about 3 days after application. 73
    [134] 134. The use of claim 125 or claim 128, wherein the transdermal delivery device is selected from transdermal patches, transdermal plasters, transdermal discs or iontophoretic transdermal devices.
    [135] 135. The use of claim 125 or claim 128, wherein the Tmax occurs from about 3 to about 5 days 5 after application of said transdermal delivery device.
    [136] 136. The use of claim 125 or claim 128, wherein at the end of the dosing interval from 68 % to 95 % of the buprenorphine is left in the transdermal delivery device.
    [137] 137. Use of buprenorphine in the preparation of a buprenorphine transdermal delivery device for use in treating pain in humans for a dosing interval of at least 7 days, said device comprising a 10 polymer matrix layer containing buprenorphine or a pharmaceutically acceptable salt thereof, wherein the transdermal delivery device comprises 10 to 95 %-wt polymeric material, 0.1 to 40 %-wt softener and 0.1 to 30 %-wt buprenorphine.
    [138] 138. The use of claim 137, wherein said device provides the following mean plasma concentrations: 15 a mean plasma concentration from 0.3 to 113 pg/ml at about 6 hours after initiation of the dosing interval; a mean plasma concentration from 3 to 296 pg/ml at about 12 hours after initiation of the dosing interval; a mean plasma concentration from 7 to 644 pg/ml at about 24 hours after initiation of the dosing 20 interval; a mean plasma concentration from 13 to 753 pg/ml at about 36 hours after initiation of the dosing interval; a mean plasma concentration from 16 to 984 pg/ml at about 48 hours after initiation of the dosing interval; 25 a mean plasma concentration from 20 to 984 pg/ml at about 60 hours after initiation of the dosing interval; a mean plasma concentration from 20 to 1052 pg/ml at about 72 hours after initiation of the dosing interval; and thereafter a mean plasma concentration from 19 to 1052 pg/ml over at least the next 48 hours. 30
    [139] 139. The use of claim 138, wherein further the mean plasma concentrations are as follows: a mean plasma concentration from 23 to 1052 pg/ml at about 96 hours after initiation of the dosing interval; a mean plasma concentration from 23 to 1052 pg/ml at about 120 hours after initiation of the dosing interval; 35 a mean plasma concentration from 22 to 970 pg/ml at about 144 hours after initiation of the dosing interval; and a mean plasma concentration from 19 to 841 pg/ml at about 168 hours after initiation of the dosing interval. 74
    [140] 140. The use of claim 137, wherein said device provides the following mean relative release rates over the dosing interval: a mean relative release rate of from 3 ug/hr to 5 ug/hr from the initiation of the dosing interval until about 72 hours after the initiation of the dosing interval; and 5 a mean relative release rate of 0.3 ug/hr to 0.6 ug/hr from about 72 hours after the initiation of the dosing interval until the end of the dosing interval.
    [141] 141. The use of claim 137, wherein from 68% to 95% of the buprenorphine is contained in the transdermal delivery device at the end of the dosing interval.
    [142] 142. The use of claim 137, wherein the Tmax occurs from about 3 to about 5 days after 10 application of said transdermal delivery system.
    [143] 143. The use of claim 137, wherein the transdermal delivery device comprises 10 %-wt buprenorphine base, 10 to 15 %-wt levulinic acid, about 10 %-wt oleyloleate, 55 to 70 %-wt polyacrylate and 0 to 10 %-wt polyvinylpyrrolidone.
    [144] 144. Use of buprenorphine in the preparation of a transdermal delivery device containing 15 buprenorphine for the treatment of human patients suffering from opioid addiction by applying onto the skin of the patient and maintaining the transdermal delivery device in contact with the skin for a 3 day dosing interval, the transdermal delivery device containing about 10 to 95 %-wt polymeric material, 0.1 to 40 %-wt softener and 0.1 to 30 %-wt buprenorphine, the plasma concentration being of from about 1000 pg/ml to about 10,000 pg/ml at the end of said 3 day dosing interval, and the transdermal 20 delivery device being maintained in contact with the skin of the patient for at least 2 to about 5 additional days beyond said 3 day dosing interval, such that the patient continues to receive effective treatment for opioid addiction from said transdermal buprenorphine delivery device over said dosing interval.
    [145] 145. The use of claim 144, wherein the plasma concentration attained at the end of said 3 day 25 dosing interval is from about 5000 pg/ml to about 8000 pg/ml.
    [146] 146. The use of claim 144 or 145, wherein the buprenorphine is buprenorphine base.
    [147] 147. The use of any one of claims 144 to 146, wherein the treatment comprises maintaining the transdermal buprenorphine delivery device in contact with the skin of the addict for at least 7 days in total. 30
    [148] 148. The use of claim 144, wherein the transdermal delivery device is selected from transdermal patches, transdermal plasters, transdermal discs or iontophoretic transdermal devices.
    [149] 149. The use of claim 144, wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery device.
    [150] 150. The use of claim 144, wherein at the end of the dosing interval from 68 % to 95 % of the 35 buprenorphine is left in the transdermal delivery device. 75
    [151] 151. The use of claim 144, wherein the transdermal delivery device comprises 10 %-wt buprenorphine base, 10 to 15 %-wt levulinic acid, about 10 %-wt oleyloleate, 55 to 70 %-wt polyacrylate and 0 to 10 %-wt polyvinylpyrrolidone.
    [152] 152. A method of treating pain in a human patient for a dosing interval of 7 days, comprising 5 administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, said transdermal delivery system being suitable for administering buprenorphine transdermally to a human patient and having a mean relative release rate of 3 pg/hr to 86 pg/hr until 72 hours after the initiation of the dosing interval and a mean relative release rate of 0.3 pg/hr to 9 pg/hr from 72 hours until 168 hours after the initiation of the dosing interval such that 10 mean plasma concentrations are provided as follows: a mean plasma concentration from 0.3 to 113 pg/ml at 6 hours after initiation of the dosing interval; a mean plasma concentration from 3 to 296 pg/ml at 12 hours after initiation of the dosing interval; 15 a mean plasma concentration from 7 to 644 pg/ml at 24 hours after initiation of the dosing interval; a mean plasma concentration from 13 to 753 pg/ml at 36 hours after initiation of the dosing interval; a mean plasma concentration from 16 to 984 pg/ml at 48 hours after initiation of the 20 dosing interval; a mean plasma concentration from 20 to 984 pg/ml at 60 hours after initiation of the dosing interval; a mean plasma concentration from 20 to 1052 pg/ml at 72 hours after initiation of the dosing interval; 25 a mean plasma concentration from 23 to 1052 pg/ml at 96 hours after initiation of the dosing interval; a mean plasma concentration from 23 to 1052 pg/ml at 120 hours after initiation of the dosing interval; a mean plasma concentration from 22 to 970 pg/ml at 144 hours after initiation of the 30 dosing interval; and a mean plasma concentration from 19 to 841 pg/ml at 168 hours after initiation of the dosing interval, wherein the transdermal delivery system comprises a polymer matrix layer which comprises the buprenorphine base, and wherein the Tmax occurs from 3 to 5 days after application of said 35 transdermal delivery system.
    [153] 153. A method of treating pain in a human patient for a dosing interval of 7 days, comprising administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, said transdermal delivery system being suitable for administering buprenorphine transdermally to a human patient and having a mean relative release rate of about 76 0.3 pg/hr to about 9 pg/hr from 72 hours until 168 hours after the initiation of the dosing interval such that mean plasma concentrations are provided as follows: a mean plasma concentration from about 0.3 to about 113 pg/ml at about 6 hours after initiation of the dosing interval; 5 a mean plasma concentration from about 3 to about 296 pg/ml at about 12 hours after initiation of the dosing interval; a mean plasma concentration from about 7 to about 644 pg/ml at about 24 hours after initiation of the dosing interval; a mean plasma concentration from about 13 to about 753 pg/ml at about 36 hours after 10 initiation of the dosing interval; a mean plasma concentration from about 16 to about 984 pg/ml at about 48 hours after initiation of the dosing interval; a mean plasma concentration from about 20 to about 984 pg/ml at about 60 hours after initiation of the dosing interval; 15 a mean plasma concentration from about 20 to about 1052 pg/ml at about 72 hours after initiation of the dosing interval; a mean plasma concentration from about 23 to about 1052 pg/ml at about 96 hours after initiation of the dosing interval; a mean plasma concentration from about 23 to about 1052 pg/ml at about 120 hours after 20 initiation of the dosing interval; a mean plasma concentration from about 22 to about 970 pg/ml at about 144 hours after initiation of the dosing interval; and a mean plasma concentration from about 19 to about 841 pg/ml at about 168 hours after initiation of the dosing interval. 25
    [154] 154. A method of treating pain in a human patient for a dosing interval of 7 days, comprising administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, said transdermal delivery system being suitable for administering buprenorphine transdermally to a human patient and having a mean relative release rate of 3 pg/hr to 86 pg/hr until 72 hours after the initiation of the dosing interval and a mean relative release rate of 30 0.3 pg/hr to 9 pg/hr from 72 hours until 168 hours after the initiation of the dosing interval such that mean plasma concentrations are provided as follows: a mean plasma concentration from 0.3 to 113 pg/ml at 6 hours after initiation of the dosing interval; a mean plasma concentration from 3 to 296 pg/ml at 12 hours after initiation of the dosing 35 interval; a mean plasma concentration from 7 to 644 pg/ml at 24 hours after initiation of the dosing interval; a mean plasma concentration from 13 to 753 pg/ml at 36 hours after initiation of the dosing interval; 77 a mean plasma concentration from 16 to 984 pg/ml at 48 hours after initiation of the dosing interval; a mean plasma concentration from 20 to 984 pg/ml at 60 hours after initiation of the dosing interval; 5 a mean plasma concentration from 20 to 1052 pg/ml at 72 hours after initiation of the dosing interval; a mean plasma concentration from 23 to 1052 pg/ml at 96 hours after initiation of the dosing interval; a mean plasma concentration from 23 to 1052 pg/ml at 120 hours after initiation of the 10 dosing interval; a mean plasma concentration from 22 to 970 pg/ml at 144 hours after initiation of the dosing interval; and a mean plasma concentration from 19 to 841 pg/ml at 168 hours after initiation of the dosing interval. 15
    [155] 155. A method of treating pain in a human patient for a dosing interval of 7 days, comprising administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, said transdermal delivery system being suitable for administering buprenorphine transdermally to a human patient and having a mean relative release rate of 3 pg/hr to 86 pg/hr until 72 hours after the initiation of the dosing interval and a mean relative release rate of 20 0.3 pg/hr to 9 pg/hr from 72 hours until 168 hours after the initiation of the dosing interval such that mean plasma concentrations are provided as follows: a mean plasma concentration from 0.3 to 113 pg/ml at 6 hours after initiation of the dosing interval; a mean plasma concentration from 3 to 296 pg/ml at 12 hours after initiation of the dosing 25 interval; a mean plasma concentration from 7 to 644 pg/ml at 24 hours after initiation of the dosing interval; a mean plasma concentration from 13 to 753 pg/ml at 36 hours after initiation of the dosing interval; 30 a mean plasma concentration from 16 to 984 pg/ml at 48 hours after initiation of the dosing interval; a mean plasma concentration from 20 to 984 pg/ml at 60 hours after initiation of the dosing interval; a mean plasma concentration from 20 to 1052 pg/ml at 72 hours after initiation of the 35 dosing interval; a mean plasma concentration from 23 to 1052 pg/ml at 96 hours after initiation of the dosing interval; a mean plasma concentration from 23 to 1052 pg/ml at 120 hours after initiation of the dosing interval; 78 a mean plasma concentration from 22 to 970 pg/ml at 144 hours after initiation of the dosing interval; and a mean plasma concentration from 19 to 841 pg/ml at 168 hours after initiation of the dosing interval. 5
    [156] 156. A method of treating pain in a human patient for a dosing interval of 7 days, comprising administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, said transdermal delivery system being suitable for administering buprenorphine transdermally to a human patient and having a mean relative release rate of 3 pg/hr to 86 pg/hr until 72 hours after the initiation of the dosing interval and a mean relative release rate of 10 0.3 pg/hr to 9 pg/hr from 72 hours until 168 hours after the initiation of the dosing interval such that mean plasma concentrations are provided as follows: a mean plasma concentration from 0.3 to 113 pg/ml at 6 hours after initiation of the dosing interval; a mean plasma concentration from 3 to 296 pg/ml at 12 hours after initiation of the dosing 1s interval; a mean plasma concentration from 7 to 644 pg/ml at 24 hours after initiation of the dosing interval; a mean plasma concentration from 13 to 753 pg/ml at 36 hours after initiation of the dosing interval; 20 a mean plasma concentration from 16 to 984 pg/ml at 48 hours after initiation of the dosing interval; a mean plasma concentration from 20 to 984 pg/ml at 60 hours after initiation of the dosing interval; a mean plasma concentration from 20 to 1052 pg/ml at 72 hours after initiation of the 25 dosing interval; a mean plasma concentration from 23 to 1052 pg/ml at 96 hours after initiation of the dosing interval; a mean plasma concentration from 23 to 1052 pg/ml at 120 hours after initiation of the dosing interval; 30 a mean plasma concentration from 22 to 970 pg/ml at 144 hours after initiation of the dosing interval; and a mean plasma concentration from 19 to 841 pg/ml at 168 hours after initiation of the dosing interval, wherein the transdermal delivery system comprises a polymer matrix layer which comprises the 35 buprenorphine base.
    [157] 157. A method of treating pain in a human patient for a dosing interval of at least 4 days, comprising administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of said patient, said delivery system comprising a polymer matrix layer including buprenorphine or a pharmaceutically acceptable salt thereof and a backing layer 79 made of a pharmaceutically acceptable material which is impermeable to buprenorphine, wherein the transdermal delivery system comprises 10 to 95 %-wt polymeric material, 0.1 to 40 %-wt softener and 0.1 to 30 %-wt buprenorphine, wherein said transdermal delivery system provides over the dosing interval of about 72 hours a release rate of buprenorphine such that a maximum plasma concentration 5 of from 20 pg/ml to 850 pg/ml is attained and the transdermal delivery system when maintained on the skin of the patient for the dosing interval of at least additional 24 hours provides plasma concentrations of buprenorphine in the patients above the minimum effective concentrations of the buprenorphine, such that the patients continue to experience effective pain management during this additional dosing interval. 10
    [158] 158. A method of treating pain in a human patient for a dosing interval of at least 5 days, comprising administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, said device comprising a polymer matrix layer containing buprenorphine or a pharmaceutically acceptable salt thereof, wherein the transdermal delivery device comprises 10 to 95 %-wt polymeric material, 0.1 to 40 %-wt softener and 0.1 to 30 % 15 wt buprenorphine.
    [159] 159. A method of treating pain in a human patient for a dosing interval of 7 days, comprising administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, said device having a mean relative release rate of buprenorphine of 3 pg/hr to 5 pg/hr until 72 hours after the initiation of the dosing interval and a mean relative release 20 rate of 0.3 pg/hr to 0.6 pg/hr from 72 hours until 168 hours after the initiation of the dosing interval, or having a mean relative release rate of 6 pg/hr to 11 pg/hr until 72 hours after the initiation of the dosing interval and a mean relative release rate of 0.7 pg/hr to 1 pg/hr from 72 hours until 168 hours after the initiation of the dosing interval, or having a mean relative release rate of 13 pg/hr to 21 pg/hr until 72 hours after the initiation of 25 the dosing interval and a mean relative release rate of 1 pg/hr to 2 pg/hr from 72 hours until 168 hours after the initiation of the dosing interval, or having a mean relative release rate of 26 pg/hr to 43 pg/hr until 72 hours after the initiation of the dosing interval and a mean relative release rate of 3 pg/hr to 4 pg/hr from 72 hours until 168 hours after the initiation of the dosing interval, or 30 having a mean relative release rate of 39 pg/hr to 64 pg/hr until 72 hours after the initiation of the dosing interval and a mean relative release rate of 4 pg/hr to 7 pg/hr from 72 hours until 168 hours after the initiation of the dosing interval, or having a mean relative release rate of 51 pg/hr to 86 pg/hr until 72 hours after the initiation of the dosing interval and a mean relative release rate of 5 pg/hr to 9 pg/hr from 72 hours until 35 168 hours after the initiation of the dosing interval.
    [160] 160. A method of treating pain in a human patient for a dosing interval of at least 7 days, comprising administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, wherein the transdermal delivery device comprises a pressure sensitive adhesive layer, wherein the pressure sensitive adhesive layer 80 comprises 10 to 95 %-wt polymeric material, 0.1 to 40 %-wt softener, and 0.1 to 30 %-wt buprenorphine.
    [161] 161. A method of treating pain in a human patient for a dosing interval of at least 4 days, comprising administering buprenorphine transdermally to said human patient by applying a 5 transdermal delivery system to the skin of a patient, wherein said transdermal delivery system after applying the transdermal delivery system to the skin of a patient provides a release rate of buprenorphine over about a 72 hour dosing interval such that a maximum plasma concentration of from 20 pg/ml to 850 pg/ml is attained and the transdermal delivery device when maintained on the skin of the patient for at least an additional 24 hour interval provides plasma concentrations of 10 buprenorphine in the patients above the minimum effective concentrations of the buprenorphine, such that the patients continue to experience effective pain management during this additional dosing interval.
    [162] 162. A method of treating pain in a human patient for a dosing interval of 5 to 9 days, said method comprising 15 applying onto the skin of the patient the transdermal delivery device comprising a polymer matrix layer comprising an amount of buprenorphine expected to be sufficient for about 3 days, and maintaining the transdermal buprenorphine delivery device in contact with the skin of the human patient from 2 to 6 additional days.
    [163] 163. A method of treating pain in a human patient for a dosing interval of 5 to 9 days, said 20 method comprising applying onto the skin of the patient the transdermal delivery device comprising a pressure sensitive adhesive layer comprising an amount of buprenorphine expected to be sufficient for about 3 days, and maintaining the transdermal buprenorphine delivery device in contact with the skin of the 25 human patient from 2 to 6 additional days.
    [164] 164. A method of treating pain in a human patient for a dosing interval of at least 7 days, comprising administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, said device comprising a polymer matrix layer containing buprenorphine or a pharmaceutically acceptable salt thereof, wherein the transdermal 30 delivery device comprises 10 to 95 %-wt polymeric material, 0.1 to 40 %-wt softener and 0.1 to 30 % wt buprenorphine.
    [165] 165. A method for the treatment of human patients suffering from opioid addiction by applying onto the skin of the patient a transdermal delivery device containing buprenorphine and maintaining the transdermal delivery device in contact with the skin for a 3 day dosing interval, the transdermal 35 delivery device containing about 10 to 95 %-wt polymeric material, 0.1 to 40 %-wt softener and 0.1 to 30 %-wt buprenorphine, the plasma concentration being of from about 1000 pg/ml to about 10,000 pg/ml at the end of said 3 day dosing interval, and the transdermal delivery device being maintained in contact with the skin of the patient for at least 2 to about 5 additional days beyond said 3 day dosing 81 interval, such that the patient continues to receive effective treatment for opioid addiction from said transdermal buprenorphine delivery device over said dosing interval. 1. A method of treating pain in a human patient, comprising administering buprenorphine 5 transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, and maintaining said transdermal delivery system in contact with the patient's skin for at least 5 days, said transdermal delivery system maintaining a mean relative release rate of from about 3pg/h to about 86pg/h and providing a substantially first order plasma level increase of buprenorphine from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean 10 relative release rate of about 0.3pg/h to about 9pg/h and providing a substantially zero order plasma level fluctuation of buprenorphine from about 72h after the initiation of the dosing interval until the end of at least the five-day dosing interval, such that the following mean plasma concentrations are achieved: a mean plasma concentration from about 0.3 to about 113pg/mL at about 6h after initiation of the 15 dosing interval; a mean plasma concentration from about 3 to about 296pg/mL at about 12h after initiation of the dosing interval; a mean plasma concentration from about 7 to about 644pg/mL at about 24h after initiation of the dosing interval; 20 a mean plasma concentration from about 13 to about 753pg/mL at about 36h after initiation of the dosing interval; a mean plasma concentration from about 16 to about 984pg/mL at about 48h after initiation of the dosing interval; a mean plasma concentration from about 20 to about 984pg/mL at about 60h after initiation of the 25 dosing interval; a mean plasma concentration from about 21 to about 1052pg/mL at about 72h after initiation of the dosing interval; and a mean plasma concentration from about 19 to about 1052pg/mL over at least the next 48h. 2. The method of claim 1, further comprising maintaining the buprenorphine transdermal 30 delivery system in contact with the patient's skin such that the mean plasma concentrations are maintained as follows: a mean plasma concentration from about 23 to about 1052pg/mL at about 96h after initiation of the dosing interval; a mean plasma concentration from about 23 to about 1052pg/mL at about 120h after initiation of the 35 dosing interval; a mean plasma concentration from about 22 to about 970pg/mL at about 144h after initiation of the dosing interval; and a mean plasma concentration from about 19 to about 841pg/mL at about 168h after initiation of the dosing interval. 82 3. A method of treating pain in a human patient, comprising administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, and maintaining said transdermal delivery system in contact with the patient's skin for at least 5 days, said transdermal delivery system maintaining a mean relative release rate of from about 13pg/h to 5 about 21 pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 1pg/h to about 2pg/h from about 72h after the initiation of the dosing interval until the end of at least the five-day dosing interval, such that the following mean plasma concentrations are achieved: a mean plasma concentration from about 1 to about 28pg/mL at about 6h after initiation of the dosing 10 interval; a mean plasma concentration from about 14 to about 74pg/mL at about 12h after initiation of the dosing interval; a mean plasma concentration from about 30 to about 161pg/mL at about 24h after initiation of the dosing interval; 15 a mean plasma concentration from about 51 to about 188pg/mL at about 36h after initiation of the dosing interval; a mean plasma concentration from about 62 to about 246pg/mL at about 48h after initiation of the dosing interval; a mean plasma concentration from about 79 to about 246pg/mL at about 60h after initiation of the 20 dosing interval; a mean plasma concentration from about 85 to about 263pg/mL at about 72h after initiation of the dosing interval; and a mean plasma concentration from about 77 to about 263pg/mL over at least the next 48h. 4. The method of claim 3, further comprising maintaining the buprenorphine transdermal 25 delivery system in contact with the patient's skin such that the mean plasma concentrations are maintained as follows: a mean plasma concentration from about 92 to about 263pg/mL at about 96h after initiation of the dosing interval; a mean plasma concentration from about 94 to about 263pg/mL at about 120h after initiation of the 30 dosing interval; a mean plasma concentration from about 86 to about 243pg/mL at about 144h after initiation of the dosing interval; and a mean plasma concentration from about 77 to about 210pg/mL at about 168h after initiation of the dosing interval. 35 5. A method of treating pain in a human patient, comprising administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, and maintaining said transdermal delivery system in contact with the patient's skin for at least 5 days, said transdermal delivery system maintaining a mean relative release rate of from about 3pg/h to about 5pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing 40 interval; and a mean relative release rate of about 0.3pg/h to about 0.6pg/h from about 72h after the 83 initiation of the dosing interval until the end of at least the five-day dosing interval, such that the following mean plasma concentrations are achieved: a mean plasma concentration from about 0.3 to about 7pg/mL at about 6h after initiation of the dosing interval; 5 a mean plasma concentration from about 4 to about 19pg/mL at about 12h after initiation of the dosing interval; a mean plasma concentration from about 7 to about 40pg/mL at about 24h after initiation of the dosing interval; a mean plasma concentration from about 13 to about 47pg/mL at about 36h after initiation of the 10 dosing interval; a mean plasma concentration from about 16 to about 62pg/mL at about 48h after initiation of the dosing interval; a mean plasma concentration from about 20 to about 62pg/mL at about 60h after initiation of the dosing interval; 15 a mean plasma concentration from about 21 to about 66pg/mL at about 72h after initiation of the dosing interval; and a mean plasma concentration from about 19 to about 66pg/mL over at least the next 48h. 6. The method of claim 5, further comprising maintaining the buprenorphine transdermal delivery system in contact with the patient's skin such that the mean plasma concentrations are 20 maintained as follows: a mean plasma concentration from about 23 to about 66pg/mL at about 96h after initiation of the dosing interval; a mean plasma concentration from about 23 to about 66pg/mL at about 120h after initiation of the dosing interval; 25 a mean plasma concentration from about 22 to about 61pg/mL at about 144h after initiation of the dosing interval; and a mean plasma concentration from about 19 to about 53pg/mL at about 168h after initiation of the dosing interval. 7. A method of treating pain in a human patient, comprising administering buprenorphine 30 transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, and maintaining said transdermal delivery system in contact with the patient's skin for at least 5 days, said transdermal delivery system maintaining a mean relative release rate of from about 6pg/h to about 11 pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 0.7pg/h to about 1pg/h from about 72h after the 35 initiation of the dosing interval until the end of at least the five-day dosing interval, such that the following mean plasma concentrations are achieved: a mean plasma concentration from about 0.7 to about 14pg/mL at about 6h after initiation of the dosing interval; a mean plasma concentration from about 7 to about 37pg/mL at about 12h after initiation of the dosing 40 interval; 84 a mean plasma concentration from about 15 to about 80pg/mL at about 24h after initiation of the dosing interval; a mean plasma concentration from about 25 to about 94pg/mL at about 36h after initiation of the dosing interval; 5 a mean plasma concentration from about 31 to about 123pg/mL at about 48h after initiation of the dosing interval; a mean plasma concentration from about 40 to about 123pg/mL at about 60h after initiation of the dosing interval; a mean plasma concentration from about 42 to about 132pg/mL at about 72h after initiation of the 10 dosing interval; and a mean plasma concentration from about 38 to about 132pg/mL over at least the next 48h. 8. The method of claim 7, further comprising maintaining the buprenorphine transdermal delivery system in contact with the patient's skin such that the mean plasma concentrations are maintained as follows: 15 a mean plasma concentration from about 46 to about 132pg/mL at about 96h after initiation of the dosing interval; a mean plasma concentration from about 47 to about 132pg/mL at about 120h after initiation of the dosing interval; a mean plasma concentration from about 43 to about 121pg/mL at about 144h after initiation of the 20 dosing interval; and a mean plasma concentration from about 38 to about 105pg/mL at about 168h after initiation of the dosing interval. 9. A method of treating pain in a human patient, comprising administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, 25 and maintaining said transdermal delivery system in contact with the patient's skin for at least 5 days, said transdermal delivery system maintaining a mean relative release rate of from about 26pg/h to about 43pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 2pg/h to about 4pg/h from about 72h after the initiation of the dosing interval until the end of at least the five-day dosing interval, such that the 30 following mean plasma concentrations are achieved: a mean plasma concentration from about 3 to about 57pg/mL at about 6h after initiation of the dosing interval; a mean plasma concentration from about 28 to about 148pg/mL at about 12h after initiation of the dosing interval; 35 a mean plasma concentration from about 59 to about 322pg/mL at about 24h after initiation of the dosing interval; a mean plasma concentration from about 102 to about 377pg/mL at about 36h after initiation of the dosing interval; a mean plasma concentration from about 124 to about 492pg/mL at about 48h after initiation of the 40 dosing interval; 85 a mean plasma concentration from about 159 to about 492pg/mL at about 60h after initiation of the dosing interval; a mean plasma concentration from about 169 to about 526pg/mL at about 60h after initiation of the dosing interval; 5 a mean plasma concentration from about 153 to about 526pg/mL over at least the next 48h. 10. The method of claim 9, further comprising maintaining the buprenorphine transdermal delivery system in contact with the patient's skin such that the mean plasma concentrations are maintained as follows: a mean plasma concentration from about 184 to about 526pg/mL at about 96h after initiation of the 10 dosing interval; a mean plasma concentration from about 187 to about 526pg/mL at about 120h after initiation of the dosing interval; a mean plasma concentration from about 173 to about 485pg/mL at about 144h after initiation of the dosing interval; 15 a mean plasma concentration from about 153 to about 420pg/mL at about 168h after initiation of the dosing interval. 11. A method of treating pain in a human patient, comprising administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, and maintaining said transdermal delivery system in contact with the patient's skin for at least 5 days, 20 said transdermal delivery system maintaining a mean relative release rate of from about 38pg/h to about 64pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 4pg/h to about 7pg/h from about 72h after the initiation of the dosing interval until the end of at least the five-day dosing interval, such that the following mean plasma concentrations are achieved: 25 a mean plasma concentration from about 4 to about 85pg/mL at about 6h after initiation of the dosing interval; a mean plasma concentration from about 42 to about 222pg/mL at about 12h after initiation of the dosing interval; a mean plasma concentration from about 89 to about 483pg/mL at about 24h after initiation of the 30 dosing interval; a mean plasma concentration from about 152 to about 565pg/mL at about 36h after initiation of the dosing interval; a mean plasma concentration from about 186 to about 738pg/mL at about 48h after initiation of the dosing interval; 35 a mean plasma concentration from about 238 to about 738pg/mL at about 48h after initiation of the dosing interval; a mean plasma concentration from about 254 to about 789pg/mL at about 60h after initiation of the dosing interval; a mean plasma concentration from about 230 to about 789pg/mL over at least the next 48h. 86 12. The method of claim 11, further comprising maintaining the buprenorphine transdermal delivery system in contact with the patient's skin such that the mean plasma concentrations are maintained as follows: a mean plasma concentration from about 276 to about 789pg/mL at about 96h after initiation of the 5 dosing interval; a mean plasma concentration from about 281 to about 789pg/mL at about 120h after initiation of the dosing interval; a mean plasma concentration from about 259 to about 727pg/mL at about 144h after initiation of the dosing interval; and 10 a mean plasma concentration from about 230 to about, 630pg/mL at about 168h after initiation of the dosing interval. 13. A method of treating pain in a human patient, comprising administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, and maintaining said transdermal delivery system in contact with the patient's skin for at least 5 days, 15 said transdermal delivery system maintaining a mean relative release rate of from about 51pg/h to about 86pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 5pg/h to about 9pg/h from about 72h after the initiation of the dosing interval until the end of at least the five-day dosing interval, such that the following mean plasma concentrations are achieved: 20 a mean plasma concentration from about 5 to about 113pg/mL at about 6h after initiation of the dosing interval; a mean plasma concentration from about 55 to about 296pg/mL at about 12h after initiation of the dosing interval; a mean plasma concentration from about 118 to about 644pg/mL at about 24h after initiation of the 25 dosing interval; a mean plasma concentration from about 203 to about 753pg/mL at about 36h after initiation of the dosing interval; a mean plasma concentration from about 247 to about 984pg/mL at about 48h after initiation of the dosing interval; 30 a mean plasma concentration from about 317 to about 984pg/mL at about 60h after initiation of the dosing interval; a mean plasma concentration from about 339 to about 1052pg/mL at about 72h after initiation of the dosing interval; and a mean plasma concentration from about 306 to about 1052pg/mL over at least the next 48h. 35 14. The method of claim 13, further comprising maintaining the buprenorphine transdermal delivery system in contact with the patient's skin such that the mean plasma concentrations are maintained as follows: a mean plasma concentration from about 369 to about 1052pg/mL at about 96h after initiation of the dosing interval; 87 a mean plasma concentration from about 374 to about 1052pg/mL at about 120h after initiation of the dosing interval; a mean plasma concentration from about 346 to about 970pg/mL at about 144h after initiation of the dosing interval; 5 a mean plasma concentration from about 306 to about 841pg/mL at about 168h after initiation of the dosing interval. 15. A method of treating pain in a human patient, comprising administering buprenorphine transdermally to said human patient such that mean relative release rates are achieved over a dosing interval as follows: 10 a mean relative release rate of from about 3pg/h to about 86pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 0.3pg/h to about 9pg/h from about 72h after the initiation of the dosing interval until the end of the dosing interval. 16. The method of claim 15, wherein the mean relative release rates achieved over the 15 dosing interval are as follows: a mean relative release rate of from about 3pg/h to about 5pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 0.3pg/h to about 0.6pg/h from about 72h after the initiation of the dosing interval until the end of the dosing interval. 20 17. The method of claim 15, wherein the mean relative release rates achieved over the dosing interval are as follows: a mean relative release rate of from about 6pg/h to about 11pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 0.7pg/h to about 1 pg/h from about 72h after the initiation of the 25 dosing interval until the end of the dosing interval. 18. The method of claim 15, wherein the mean relative release rates achieved over the dosing interval are as follows: a mean relative release rate of from about 13pg/h to about 21pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and 30 a mean relative release rate of about 1pg/h to about 2pg/h from about 72h after the initiation of the dosing interval until the end of the dosing interval. 19. The method of claim 15, wherein the mean relative release rates achieved over the dosing interval are as follows: a mean relative release rate of from about 26pg/h to about 43pg/h from the initiation of the dosing 35 interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 3pg/h to about 4pg/h from about 72h after the initiation of the dosing interval until the end of the dosing interval. 20. The method of claim 15, wherein the mean relative release rates achieved over the dosing interval are as follows: 88 a mean relative release rate of from about 39pg/h to about 64pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 4pg/h to about 7pg/h from about 72h after the initiation of the dosing interval until the end of the dosing interval. 5 21. The method of claim 15, wherein the mean relative release rates achieved over the dosing interval are as follows: a mean relative release rate of from about 51pg/h to about 86pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 5pg/h to about 9pg/h from about 72h after the initiation of the 10 dosing interval until the end of the dosing interval. 22. A method of treating pain in a human patient, comprising applying a transdermal delivery system containing buprenorphine as the active ingredient onto the skin of said human patient to provide a substantially first order plasma level increase of buprenorphine over a first thee-day dosing interval, such that a mean plasma concentration from about 21 to about 1052pg/mL is attained about 15 72h after application of said transdermal delivery system; and maintaining said transdermal delivery system on the skin of said human patient for at least an additional two-day dosing interval, such that a mean relative release rate from about 0.3pg/h to about 9pg/h is maintained over said at least two-day additional dosing interval and said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two-day additional dosing interval. 20 23. The method of claim 22, wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval. 24. The method of claim 23, wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system. 25. The method of claim 22, wherein the mean plasma concentration attained about 72h 25 after application of said transdermal delivery system is from about 85 to about 263pg/mL; and the mean relative release rate maintained over said at least two-day additional dosing interval is from about 13pg/h to about 21pg/h and said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two-day additional dosing interval. 26. The method of claim 25, wherein from about 68% to about 95% of the buprenorphine is 30 contained in the transdermal delivery system at the end of the dosing interval. 27. The method of claim 25, wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system. 28. The method of claim 22, wherein the mean plasma concentration attained about 72h after application of said transdermal delivery system is from about 21 to about 66pg/mL; and the mean 35 relative release rate maintained over said at least two-day additional dosing interval is from about 0.3pg/h to about 0.6pg/h and said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two-day additional dosing interval. 29. The method of claim 28, wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval. 89 30. The method of claim 28, wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system. 31. The method of claim 22, wherein the mean plasma concentration attained about 72h after application of said transdermal delivery system is from about 42 to about 132pg/mL; and the 5 mean relative release rate maintained over said at least two-day additional dosing interval is from about 0.7pg/h to about 1pg/h and said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two-day additional dosing interval. 32. The method of claim 31, wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval. 10 33. The method of claim 31, wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system. 34. The method of claim 22, wherein the mean plasma concentration attained about 72h after application of said transdermal delivery system is from about 169 to about 526pg/mL; and the mean relative release rate maintained over said at least two-day additional dosing interval is from 15 about 3pg/h to about 4pg/h and said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two-day additional dosing interval. 35. The method of claim 34, wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval. 36. The method of claim 34, wherein the Tmax occurs from about 3 to about 5 days after 20 application of said transdermal delivery system. 37. The method of claim 22, wherein the mean plasma concentration attained about 72h after application of said transdermal delivery system is from about 254 to about 789pg/mL; and the mean relative release rate maintained over said at least two-day additional dosing interval is from about 4pg/h to about 7pg/h and said transdermal delivery system provides a therapeutic effect to said 25 human patient throughout the at least two-day additional dosing interval. 38. The method of claim 37, wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval. 39. The method of claim 37, wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system. 30 40. The method of claim 22, wherein the mean plasma concentration attained about 72h after application of said transdermal delivery system is from about 339 to about 1052pg/mL; and the mean relative release rate maintained over said at least two-day additional dosing interval is from about 5pg/h to about 9pg/h and said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two-day additional dosing interval. 35 41. The method of claim 40, wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval. 42. The method of claim 40, wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system. 43. A method of treating pain in a human patient, comprising applying a transdermal delivery 40 system containing buprenorphine as the active ingredient onto the skin of said human patient to 90 provide a first order release rate of buprenorphine over a thee-day dosing interval, such that a maximum plasma concentration from about 20pg/mL to about 1052pg/mL is attained, and maintaining said transdermal delivery systems on the skin of said human patient for at least an additional two-day dosing interval during which said transdermal delivery system provides substantially zero order 5 kinetics, such that said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two-day additional dosing interval. 44. A method of treating a human patient suffering from moderate to severe pain by applying a transdermal delivery system containing buprenorphine onto the skin of the human patient and maintaining the transdermal delivery system in contact with the skin for a 3 day dosing interval, the 10 transdermal delivery system containing an amount of buprenorphine sufficient to maintain an adequate relative release rate to provide a therapeutic effect in the patient for approximately only 3 days, comprising maintaining the transdermal delivery system in contact with the human patient's skin for at least 2 to about 5 additional days beyond said 3 day dosing interval, such that the human patient continues to receive a therapeutic effect from said transdermal buprenorphine delivery system. 15 45. In a method of treating a human patient suffering from moderate to severe pain by applying a transdermal delivery system containing buprenorphine onto the skin of the human patient and maintaining the transdermal delivery system in contact with the skin for a 3 day dosing interval, the transdermal delivery system containing an amount of buprenorphine sufficient to maintain an adequate relative release rate to provide a therapeutic effect in the patient for about 3 days, the 20 improvement comprising maintaining the transdermal delivery system in contact with the human patient's skin for at least 2 to about 5 additional days beyond said 3 day dosing interval. 46. The method of claim 2 wherein the plasma level of buprenorphine at 72h does not decrease by more than 30% over the next 48h. 47. The method of claim 2 wherein the plasma level of buprenorphine at 120h does not 25 decrease by more than 30% over the next 48h. 48. Buprenorphine when used for treating pain in a human patient by administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, and maintaining said transdermal delivery system in contact with the patient's skin for at least 5 days, said transdermal delivery system maintaining a mean relative release rate of from 30 about 3pg/h to about 86pg/h and providing a substantially first order plasma level increase of buprenorphine from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 0.3pg/h to about 9pg/h and providing a substantially zero order plasma level fluctuation of buprenorphine from about 72h after the initiation of the dosing interval until the end of at least the five-day dosing interval, such that the following mean 35 plasma concentrations are achieved: a mean plasma concentration from about 0.3 to about 113pg/mL at about 6h after initiation of the dosing interval; a mean plasma concentration from about 3 to about 296pg/mL at about 12h after initiation of the dosing interval; 91 a mean plasma concentration from about 7 to about 644pg/mL at about 24h after initiation of the dosing interval; a mean plasma concentration from about 13 to about 753pg/mL at about 36h after initiation of the dosing interval; 5 a mean plasma concentration from about 16 to about 984pg/mL at about 48h after initiation of the dosing interval; a mean plasma concentration from about 20 to about 984pg/mL at about 60h after initiation of the dosing interval; a mean plasma concentration from about 21 to about 1052pg/mL at about 72h after initiation of the 10 dosing interval; and a mean plasma concentration from about 19 to about 1052pg/mL over at least the next 48h. 49. The buprenorphine of claim 48, further comprising maintaining the buprenorphine transdermal delivery system in contact with the patient's skin such that the mean plasma concentrations are maintained as follows: 15 a mean plasma concentration from about 23 to about 1052pg/mL at about 96h after initiation of the dosing interval; a mean plasma concentration from about 23 to about 1052pg/mL at about 120h after initiation of the dosing interval; a mean plasma concentration from about 22 to about 970pg/mL at about 144h after initiation of the 20 dosing interval; and a mean plasma concentration from about 19 to about 841pg/mL at about 168h after initiation of the dosing interval. 50. Buprenorphine when used for treating pain in a human patient by administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the 25 skin of a patient, and maintaining said transdermal delivery system in contact with the patient's skin for at least 5 days, said transdermal delivery system maintaining a mean relative release rate of from about 13pg/h to about 21pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 1pg/h to about 2pg/h from about 72h after the initiation of the dosing interval until the end of at least the five-day dosing interval, 30 such that the following mean plasma concentrations are achieved: a mean plasma concentration from about 1 to about 28pg/mL at about 6h after initiation of the dosing interval; a mean plasma concentration from about 14 to about 74pg/mL at about 12h after initiation of the dosing interval; 35 a mean plasma concentration from about 30 to about 161pg/mL at about 24h after initiation of the dosing interval; a mean plasma concentration from about 51 to about 188pg/mL at about 36h after initiation of the dosing interval; a mean plasma concentration from about 62 to about 246pg/mL at about 48h after initiation of the 40 dosing interval; 92 a mean plasma concentration from about 79 to about 246pg/mL at about 60h after initiation of the dosing interval; a mean plasma concentration from about 85 to about 263pg/mL at about 72h after initiation of the dosing interval; and 5 a mean plasma concentration from about 77 to about 263pg/mL over at least the next 48h. 51. The buprenorphine of claim 50, further comprising maintaining the buprenorphine transdermal delivery system in contact with the patient's skin such that the mean plasma concentrations are maintained as follows: a mean plasma concentration from about 92 to about 263pg/mL at about 96h after initiation of the 10 dosing interval; a mean plasma concentration from about 94 to about 263pg/mL at about 120h after initiation of the dosing interval; a mean plasma concentration from about 86 to about 243pg/mL at about 144h after initiation of the dosing interval; and 15 a mean plasma concentration from about 77 to about 210pg/mL at about 168h after initiation of the dosing interval. 52. Buprenorphine when used for treating pain in a human patient by administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, and maintaining said transdermal delivery system in contact with the patient's skin 20 for at least 5 days, said transdermal delivery system maintaining a mean relative release rate of from about 3pg/h to about 5pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 0.3pg/h to about 0.6pg/h from about 72h after the initiation of the dosing interval until the end of at least the five-day dosing interval, such that the following mean plasma concentrations are achieved: 25 a mean plasma concentration from about 0.3 to about 7pg/mL at about 6h after initiation of the dosing interval; a mean plasma concentration from about 4 to about 19pg/mL at about 12h after initiation of the dosing interval; a mean plasma concentration from about 7 to about 40pg/mL at about 24h after initiation of the dosing 30 interval; a mean plasma concentration from about 13 to about 47pg/mL at about 36h after initiation of the dosing interval; a mean plasma concentration from about 16 to about 62pg/mL at about 48h after initiation of the dosing interval; 35 a mean plasma concentration from about 20 to about 62pg/mL at about 60h after initiation of the dosing interval; a mean plasma concentration from about 21 to about 66pg/mL at about 72h after initiation of the dosing interval; and a mean plasma concentration from about 19 to about 66pg/mL over at least the next 48h. 93 53. The buprenorphine of claim 52, further comprising maintaining the buprenorphine transdermal delivery system in contact with the patient's skin such that the mean plasma concentrations are maintained as follows: a mean plasma concentration from about 23 to about 66pg/mL at about 96h after initiation of the 5 dosing interval; a mean plasma concentration from about 23 to about 66pg/mL at about 120h after initiation of the dosing interval; a mean plasma concentration from about 22 to about 61pg/mL at about 144h after initiation of the dosing interval; and 10 a mean plasma concentration from about 19 to about 53pg/mL at about 168h after initiation of the dosing interval. 54. Buprenorphine when used for treating pain in a human patient by administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, and maintaining said transdermal delivery system in contact with the patient's skin 15 for at least 5 days, said transdermal delivery system maintaining a mean relative release rate of from about 6pg/h to about 11 pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 0.7pg/h to about 1pg/h from about 72h after the initiation of the dosing interval until the end of at least the five-day dosing interval, such that the following mean plasma concentrations are achieved: 20 a mean plasma concentration from about 0.7 to about 14pg/mL at about 6h after initiation of the dosing interval; a mean plasma concentration from about 7 to about 37pg/mL at about 12h after initiation of the dosing interval; a mean plasma concentration from about 15 to about 80pg/mL at about 24h after initiation of the 25 dosing interval; a mean plasma concentration from about 25 to about 94pg/mL at about 36h after initiation of the dosing interval; a mean plasma concentration from about 31 to about 123pg/mL at about 48h after initiation of the dosing interval; 30 a mean plasma concentration from about 40 to about 123pg/mL at about 60h after initiation of the dosing interval; a mean plasma concentration from about 42 to about 132pg/mL at about 72h after initiation of the dosing interval; and a mean plasma concentration from about 38 to about 132pg/mL over at least the next 48h. 35 55. The buprenorphine of claim 54, further comprising maintaining the buprenorphine transdermal delivery system in contact with the patient's skin such that the mean plasma concentrations are maintained as follows: a mean plasma concentration from about 46 to about 132pg/mL at about 96h after initiation of the dosing interval; 94 a mean plasma concentration from about 47 to about 132pg/mL at about 120h after initiation of the dosing interval; a mean plasma concentration from about 43 to about 121pg/mL at about 144h after initiation of the dosing interval; and 5 a mean plasma concentration from about 38 to about 105pg/mL at about 168h after initiation of the dosing interval. 56. Buprenorphine when used for treating pain in a human patient by administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, and maintaining said transdermal delivery system in contact with the patient's skin 10 for at least 5 days, said transdermal delivery system maintaining a mean relative release rate of from about 26pg/h to about 43pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 2pg/h to about 4pg/h from about 72h after the initiation of the dosing interval until the end of at least the five-day dosing interval, such that the following mean plasma concentrations are achieved: 15 a mean plasma concentration from about 3 to about 57pg/mL at about 6h after initiation of the dosing interval; a mean plasma concentration from about 28 to about 148pg/mL at about 12h after initiation of the dosing interval; a mean plasma concentration from about 59 to about 322pg/mL at about 24h after initiation of the 20 dosing interval; a mean plasma concentration from about 102 to about 377pg/mL at about 36h after initiation of the dosing interval; a mean plasma concentration from about 124 to about 492pg/mL at about 48h after initiation of the dosing interval; 25 a mean plasma concentration from about 159 to about 492pg/mL at about 60h after initiation of the dosing interval; a mean plasma concentration from about 169 to about 526pg/mL at about 60h after initiation of the dosing interval; a mean plasma concentration from about 153 to about 526pg/mL over at least the next 48h. 30 57. The buprenorphine of claim 56, further comprising maintaining the buprenorphine transdermal delivery system in contact with the patient's skin such that the mean plasma concentrations are maintained as follows: a mean plasma concentration from about 184 to about 526pg/mL at about 96h after initiation of the dosing interval; 35 a mean plasma concentration from about 187 to about 526pg/mL at about 120h after initiation of the dosing interval; a mean plasma concentration from about 173 to about 485pg/mL at about 144h after initiation of the dosing interval; a mean plasma concentration from about 153 to about 420pg/mL at about 168h after initiation of the 40 dosing interval. 95 58. Buprenorphine when used for treating pain in a human patient by administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, and maintaining said transdermal delivery system in contact with the patient's skin for at least 5 days, said transdermal delivery system maintaining a mean relative release rate of from 5 about 38pg/h to about 64pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 4pg/h to about 7pg/h from about 72h after the initiation of the dosing interval until the end of at least the five-day dosing interval, such that the following mean plasma concentrations are achieved: a mean plasma concentration from about 4 to about 85pg/mL at about 6h after initiation of the dosing 10 interval; a mean plasma concentration from about 42 to about 222pg/mL at about 12h after initiation of the dosing interval; a mean plasma concentration from about 89 to about 483pg/mL at about 24h after initiation of the dosing interval; 15 a mean plasma concentration from about 152 to about 565pg/mL at about 36h after initiation of the dosing interval; a mean plasma concentration from about 186 to about 738pg/mL at about 48h after initiation of the dosing interval; a mean plasma concentration from about 238 to about 738pg/mL at about 48h after initiation of the 20 dosing interval; a mean plasma concentration from about 254 to about 789pg/mL at about 60h after initiation of the dosing interval; a mean plasma concentration from about 230 to about 789pg/mL over at least the next 48h. 59. The buprenorphine of claim 58, further comprising maintaining the buprenorphine 25 transdermal delivery system in contact with the patient's skin such that the mean plasma concentrations are maintained as follows: a mean plasma concentration from about 276 to about 789pg/mL at about 96h after initiation of the dosing interval; a mean plasma concentration from about 281 to about 789pg/mL at about 120h after initiation of the 30 dosing interval; a mean plasma concentration from about 259 to about 727pg/mL at about 144h after initiation of the dosing interval; and a mean plasma concentration from about 230 to about, 630pg/mL at about 168h after initiation of the dosing interval. 35 60. Buprenorphine when used for treating pain in a human patient by administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, and maintaining said transdermal delivery system in contact with the patient's skin for at least 5 days, said transdermal delivery system maintaining a mean relative release rate of from about 51pg/h to about 86pg/h from the initiation of the dosing interval until about 72h after the 40 initiation of the dosing interval; and a mean relative release rate of about 5pg/h to about 9pg/h from 96 about 72h after the initiation of the dosing interval until the end of at least the five-day dosing interval, such that the following mean plasma concentrations are achieved: a mean plasma concentration from about 5 to about 11 3pg/mL at about 6h after initiation of the dosing interval; 5 a mean plasma concentration from about 55 to about 296pg/mL at about 12h after initiation of the dosing interval; a mean plasma concentration from about 118 to about 644pg/mL at about 24h after initiation of the dosing interval; a mean plasma concentration from about 203 to about 753pg/mL at about 36h after initiation of the 10 dosing interval; a mean plasma concentration from about 247 to about 984pg/mL at about 48h after initiation of the dosing interval; a mean plasma concentration from about 317 to about 984pg/mL at about 60h after initiation of the dosing interval; 15 a mean plasma concentration from about 339 to about 1052pg/mL at about 72h after initiation of the dosing interval; and a mean plasma concentration from about 306 to about 1052pg/mL over at least the next 48h. 61. The buprenorphine of claim 60, further comprising maintaining the buprenorphine transdermal delivery system in contact with the patient's skin such that the mean plasma 20 concentrations are maintained as follows: a mean plasma concentration from about 369 to about 1052pg/mL at about 96h after initiation of the dosing interval; a mean plasma concentration from about 374 to about 1052pg/mL at about 120h after initiation of the dosing interval; 25 a mean plasma concentration from about 346 to about 970pg/mL at about 144h after initiation of the dosing interval; a mean plasma concentration from about 306 to about 841pg/mL at about 168h after initiation of the dosing interval. 62. Buprenorphine when used for treating pain in a human patient by administering 30 buprenorphine transdermally to said human patient such that mean relative release rates are achieved over a dosing interval as follows: a mean relative release rate of from about 3pg/h to about 86pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 0.3pg/h to about 9pg/h from about 72h after the initiation of the 35 dosing interval until the end of the dosing interval. 63. The buprenorphine of claim 62, wherein the mean relative release rates achieved over the dosing interval are as follows: a mean relative release rate of from about 3pg/h to about 5pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and 97 a mean relative release rate of about 0.3pg/h to about 0.6pg/h from about 72h after the initiation of the dosing interval until the end of the dosing interval. 64. The buprenorphine of claim 62, wherein the mean relative release rates achieved over the dosing interval are as follows: 5 a mean relative release rate of from about 6pg/h to about 11pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 0.7pg/h to about 1 pg/h from about 72h after the initiation of the dosing interval until the end of the dosing interval. 65. The buprenorphine of claim 62, wherein the mean relative release rates achieved over 10 the dosing interval are as follows: a mean relative release rate of from about 13pg/h to about 21pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 1 pg/h to about 2pg/h from about 72h after the initiation of the dosing interval until the end of the dosing interval. 15 66. The buprenorphine of claim 62, wherein the mean relative release rates achieved over the dosing interval are as follows: a mean relative release rate of from about 26pg/h to about 43pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 3pg/h to about 4pg/h from about 72h after the initiation of the 20 dosing interval until the end of the dosing interval. 67. The buprenorphine of claim 62, wherein the mean relative release rates achieved over the dosing interval are as follows: a mean relative release rate of from about 39pg/h to about 64pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and 25 a mean relative release rate of about 4pg/h to about 7pg/h from about 72h after the initiation of the dosing interval until the end of the dosing interval. 68. The buprenorphine of claim 62, wherein the mean relative release rates achieved over the dosing interval are as follows: a mean relative release rate of from about 51pg/h to about 86pg/h from the initiation of the dosing 30 interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 5pg/h to about 9pg/h from about 72h after the initiation of the dosing interval until the end of the dosing interval. 69. Buprenorphine when used for treating pain in a human patient by applying a transdermal delivery system containing buprenorphine as the active ingredient onto the skin of said human patient 35 to provide a substantially first order plasma level increase of buprenorphine over a first thee-day dosing interval, such that a mean plasma concentration from about 21 to about 1052pg/mL is attained about 72h after application of said transdermal delivery system; and maintaining said transdermal delivery system on the skin of said human patient for at least an additional two-day dosing interval, such that a mean relative release rate from about 0.3pg/h to about 9pg/h is maintained over said at 98 least two-day additional dosing interval and said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two-day additional dosing interval. 70. The buprenorphine of claim 69, wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval. 5 71. The buprenorphine of claim 70, wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system. 72. The buprenorphine of claim 69, wherein the mean plasma concentration attained about 72h after application of said transdermal delivery system is from about 85 to about 263pg/mL; and the mean relative release rate maintained over said at least two-day additional dosing interval is from 10 about 13pg/h to about 21pg/h and said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two-day additional dosing interval. 73. The buprenorphine of claim 72, wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval. 74. The buprenorphine of claim 72, wherein the Tmax occurs from about 3 to about 5 days 15 after application of said transdermal delivery system. 75. The buprenorphine of claim 70, wherein the mean plasma concentration attained about 72h after application of said transdermal delivery system is from about 21 to about 66pg/mL; and the mean relative release rate maintained over said at least two-day additional dosing interval is from about 0.3pg/h to about 0.6pg/h and said transdermal delivery system provides a therapeutic effect to 20 said human patient throughout the at least two-day additional dosing interval. 76. The buprenorphine of claim 75, wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval. 77. The buprenorphine of claim 75, wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system. 25 78. The buprenorphine of claim 70, wherein the mean plasma concentration attained about 72h after application of said transdermal delivery system is from about 42 to about 132pg/mL; and the mean relative release rate maintained over said at least two-day additional dosing interval is from about 0.7pg/h to about 1pg/h and said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two-day additional dosing interval. 30 79. The buprenorphine of claim 78, wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval. 80. The buprenorphine of claim 78, wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system. 81. The buprenorphine of claim 70, wherein the mean plasma concentration attained about 35 72h after application of said transdermal delivery system is from about 169 to about 526pg/mL; and the mean relative release rate maintained over said at least two-day additional dosing interval is from about 3pg/h to about 4pg/h and said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two-day additional dosing interval. 82. The buprenorphine of claim 81, wherein from about 68% to about 95% of the 40 buprenorphine is contained in the transdermal delivery system at the end of the dosing interval. 99 83. The buprenorphine of claim 81, wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system. 84. The buprenorphine of claim 70, wherein the mean plasma concentration attained about 72h after application of said transdermal delivery system is from about 254 to about 789pg/mL; and 5 the mean relative release rate maintained over said at least two-day additional dosing interval is from about 4pg/h to about 7pg/h and said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two-day additional dosing interval. 85. The buprenorphine of claim 84, wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval. 10 86. The buprenorphine of claim 84, wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system. 87. The buprenorphine of claim 70, wherein the mean plasma concentration attained about 72h after application of said transdermal delivery system is from about 339 to about 1052pg/mL; and the mean relative release rate maintained over said at least two-day additional dosing interval is from 15 about 5pg/h to about 9pg/h and said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two-day additional dosing interval. 88. The buprenorphine of claim 87, wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval. 89. The buprenorphine of claim 87, wherein the Tmax occurs from about 3 to about 5 days 20 after application of said transdermal delivery system. 90. Buprenorphine when used for treating pain in a human patient by applying a transdermal delivery system containing buprenorphine as the active ingredient onto the skin of said human patient to provide a first order release rate of buprenorphine over a thee-day dosing interval, such that a maximum plasma concentration from about 20pg/mL to about 1052pg/mL is attained, and maintaining 25 said transdermal delivery systems on the skin of said human patient for at least an additional two-day dosing interval during which said transdermal delivery system provides substantially zero order kinetics, such that said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two-day additional dosing interval. 91. Buprenorphine when used for treating pain in a human patient suffering from moderate 30 to severe pain by applying a transdermal delivery system containing buprenorphine onto the skin of the human patient and maintaining the transdermal delivery system in contact with the skin for a 3 day dosing interval, the transdermal delivery system containing an amount of buprenorphine sufficient to maintain an adequate relative release rate to provide a therapeutic effect in the patient for approximately only 3 days, comprising maintaining the transdermal delivery system in contact with the 35 human patient's skin for at least 2 to about 5 additional days beyond said 3 day dosing interval, such that the human patient continues to receive a therapeutic effect from said transdermal buprenorphine delivery system. 92. Buprenorphine when used for treating pain in a human patient suffering from moderate to severe pain by applying a transdermal delivery system containing buprenorphine onto the skin of 40 the human patient and maintaining the transdermal delivery system in contact with the skin for a 3 day 100 dosing interval, the transdermal delivery system containing an amount of buprenorphine sufficient to maintain an adequate relative release rate to provide a therapeutic effect in the patient for about 3 days, characterised by an improvement comprising maintaining the transdermal delivery system in contact with the human patient's skin for at least 2 to about 5 additional days beyond said 3 day 5 dosing interval. 93. The buprenorphine of claim 50, wherein the plasma level of buprenorphine at 72h does not decrease by more than 30% over the next 48h. 94. The buprenorphine of claim 50, wherein the plasma level of buprenorphine at 120h does not decrease by more than 30% over the next 48h. 10 95. Use of buprenorphine in the manufacture of a medicament for treating pain in a human patient by administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, and maintaining said transdermal delivery system in contact with the patient's skin for at least 5 days, said transdermal delivery system maintaining a mean relative release rate of from about 3pg/h to about 86pg/h and providing a substantially first order 15 plasma level increase of buprenorphine from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 0.3pg/h to about 9pg/h and providing a substantially zero order plasma level fluctuation of buprenorphine from about 72h after the initiation of the dosing interval until the end of at least the five-day dosing interval, such that the following mean plasma concentrations are achieved: 20 a mean plasma concentration from about 0.3 to about 113pg/mL at about 6h after initiation of the dosing interval; a mean plasma concentration from about 3 to about 296pg/mL at about 12h after initiation of the dosing interval; a mean plasma concentration from about 7 to about 644pg/mL at about 24h after initiation of the 25 dosing interval; a mean plasma concentration from about 13 to about 753pg/mL at about 36h after initiation of the dosing interval; a mean plasma concentration from about 16 to about 984pg/mL at about 48h after initiation of the dosing interval; 30 a mean plasma concentration from about 20 to about 984pg/mL at about 60h after initiation of the dosing interval; a mean plasma concentration from about 21 to about 1052pg/mL at about 72h after initiation of the dosing interval; and a mean plasma concentration from about 19 to about 1052pg/mL over at least the next 48h. 35 96. The use of claim 95, further comprising maintaining the buprenorphine transdermal delivery system in contact with the patient's skin such that the mean plasma concentrations are maintained as follows: a mean plasma concentration from about 23 to about 1052pg/mL at about 96h after initiation of the dosing interval; 101 a mean plasma concentration from about 23 to about 1052pg/mL at about 120h after initiation of the dosing interval; a mean plasma concentration from about 22 to about 970pg/mL at about 144h after initiation of the dosing interval; and 5 a mean plasma concentration from about 19 to about 841pg/mL at about 168h after initiation of the dosing interval. 97. Use of buprenorphine in the manufacture of a medicament for treating pain in a human patient by administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, and maintaining said transdermal delivery system in contact 10 with the patient's skin for at least 5 days, said transdermal delivery system maintaining a mean relative release rate of from about 13pg/h to about 21 pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 1 pg/h to about 2pg/h from about 72h after the initiation of the dosing interval until the end of at least the five day dosing interval, such that the following mean plasma concentrations are achieved: 15 a mean plasma concentration from about 1 to about 28pg/mL at about 6h after initiation of the dosing interval; a mean plasma concentration from about 14 to about 74pg/mL at about 12h after initiation of the dosing interval; a mean plasma concentration from about 30 to about 161pg/mL at about 24h after initiation of the 20 dosing interval; a mean plasma concentration from about 51 to about 188pg/mL at about 36h after initiation of the dosing interval; a mean plasma concentration from about 62 to about 246pg/mL at about 48h after initiation of the dosing interval; 25 a mean plasma concentration from about 79 to about 246pg/mL at about 60h after initiation of the dosing interval; a mean plasma concentration from about 85 to about 263pg/mL at about 72h after initiation of the dosing interval; and a mean plasma concentration from about 77 to about 263pg/mL over at least the next 48h. 30 98. The use of claim 97, further comprising maintaining the buprenorphine transdermal delivery system in contact with the patient's skin such that the mean plasma concentrations are maintained as follows: a mean plasma concentration from about 92 to about 263pg/mL at about 96h after initiation of the dosing interval; 35 a mean plasma concentration from about 94 to about 263pg/mL at about 120h after initiation of the dosing interval; a mean plasma concentration from about 86 to about 243pg/mL at about 144h after initiation of the dosing interval; and a mean plasma concentration from about 77 to about 210pg/mL at about 168h after initiation of the 40 dosing interval. 102 99. Use of buprenorphine in the manufacture of a medicament for treating pain in a human patient by administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, and maintaining said transdermal delivery system in contact with the patient's skin for at least 5 days, said transdermal delivery system maintaining a mean 5 relative release rate of from about 3pg/h to about 5pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 0.3pg/h to about 0.6pg/h from about 72h after the initiation of the dosing interval until the end of at least the five-day dosing interval, such that the following mean plasma concentrations are achieved: a mean plasma concentration from about 0.3 to about 7pg/mL at about 6h after initiation of the dosing 10 interval; a mean plasma concentration from about 4 to about 19pg/mL at about 12h after initiation of the dosing interval; a mean plasma concentration from about 7 to about 40pg/mL at about 24h after initiation of the dosing interval; 15 a mean plasma concentration from about 13 to about 47pg/mL at about 36h after initiation of the dosing interval; a mean plasma concentration from about 16 to about 62pg/mL at about 48h after initiation of the dosing interval; a mean plasma concentration from about 20 to about 62pg/mL at about 60h after initiation of the 20 dosing interval; a mean plasma concentration from about 21 to about 66pg/mL at about 72h after initiation of the dosing interval; and a mean plasma concentration from about 19 to about 66pg/mL over at least the next 48h. 100. The use of claim 99, further comprising maintaining the buprenorphine transdermal 25 delivery system in contact with the patient's skin such that the mean plasma concentrations are maintained as follows: a mean plasma concentration from about 23 to about 66pg/mL at about 96h after initiation of the dosing interval; a mean plasma concentration from about 23 to about 66pg/mL at about 120h after initiation of the 30 dosing interval; a mean plasma concentration from about 22 to about 61pg/mL at about 144h after initiation of the dosing interval; and a mean plasma concentration from about 19 to about 53pg/mL at about 168h after initiation of the dosing interval. 35 101. Use of buprenorphine in the manufacture of a medicament for treating pain in a human patient by administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, and maintaining said transdermal delivery system in contact with the patient's skin for at least 5 days, said transdermal delivery system maintaining a mean relative release rate of from about 6pg/h to about 11 pg/h from the initiation of the dosing interval until 40 about 72h after the initiation of the dosing interval; and a mean relative release rate of about 0.7pg/h 103 to about 1 pg/h from about 72h after the initiation of the dosing interval until the end of at least the five day dosing interval, such that the following mean plasma concentrations are achieved: a mean plasma concentration from about 0.7 to about 14pg/mL at about 6h after initiation of the dosing interval; 5 a mean plasma concentration from about 7 to about 37pg/mL at about 12h after initiation of the dosing interval; a mean plasma concentration from about 15 to about 80pg/mL at about 24h after initiation of the dosing interval; a mean plasma concentration from about 25 to about 94pg/mL at about 36h after initiation of the 10 dosing interval; a mean plasma concentration from about 31 to about 123pg/mL at about 48h after initiation of the dosing interval; a mean plasma concentration from about 40 to about 123pg/mL at about 60h after initiation of the dosing interval; 15 a mean plasma concentration from about 42 to about 132pg/mL at about 72h after initiation of the dosing interval; and a mean plasma concentration from about 38 to about 132pg/mL over at least the next 48h. 102. The use of claim 101, further comprising maintaining the buprenorphine transdermal delivery system in contact with the patient's skin such that the mean plasma concentrations are 20 maintained as follows: a mean plasma concentration from about 46 to about 132pg/mL at about 96h after initiation of the dosing interval; a mean plasma concentration from about 47 to about 132pg/mL at about 120h after initiation of the dosing interval; 25 a mean plasma concentration from about 43 to about 121pg/mL at about 144h after initiation of the dosing interval; and a mean plasma concentration from about 38 to about 105pg/mL at about 168h after initiation of the dosing interval. 103. Use of buprenorphine in the manufacture of a medicament for treating pain in a human 30 patient by administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, and maintaining said transdermal delivery system in contact with the patient's skin for at least 5 days, said transdermal delivery system maintaining a mean relative release rate of from about 26pg/h to about 43pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 2pg/h to 35 about 4pg/h from about 72h after the initiation of the dosing interval until the end of at least the five day dosing interval, such that the following mean plasma concentrations are achieved: a mean plasma concentration from about 3 to about 57pg/mL at about 6h after initiation of the dosing interval; a mean plasma concentration from about 28 to about 148pg/mL at about 12h after initiation of the 40 dosing interval; 104 a mean plasma concentration from about 59 to about 322pg/mL at about 24h after initiation of the dosing interval; a mean plasma concentration from about 102 to about 377pg/mL at about 36h after initiation of the dosing interval; 5 a mean plasma concentration from about 124 to about 492pg/mL at about 48h after initiation of the dosing interval; a mean plasma concentration from about 159 to about 492pg/mL at about 60h after initiation of the dosing interval; a mean plasma concentration from about 169 to about 526pg/mL at about 60h after initiation of the 10 dosing interval; a mean plasma concentration from about 153 to about 526pg/mL over at least the next 48h. 104. The use of claim 103, further comprising maintaining the buprenorphine transdermal delivery system in contact with the patient's skin such that the mean plasma concentrations are maintained as follows: 15 a mean plasma concentration from about 184 to about 526pg/mL at about 96h after initiation of the dosing interval; a mean plasma concentration from about 187 to about 526pg/mL at about 120h after initiation of the dosing interval; a mean plasma concentration from about 173 to about 485pg/mL at about 144h after initiation of the 20 dosing interval; a mean plasma concentration from about 153 to about 420pg/mL at about 168h after initiation of the dosing interval. 105. Use of buprenorphine in the manufacture of a medicament for treating pain in a human patient by administering buprenorphine transdermally to said human patient by applying a transdermal 25 delivery system to the skin of a patient, and maintaining said transdermal delivery system in contact with the patient's skin for at least 5 days, said transdermal delivery system maintaining a mean relative release rate of from about 38pg/h to about 64pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 4pg/h to about 7pg/h from about 72h after the initiation of the dosing interval until the end of at least the five 30 day dosing interval, such that the following mean plasma concentrations are achieved: a mean plasma concentration from about 4 to about 85pg/mL at about 6h after initiation of the dosing interval; a mean plasma concentration from about 42 to about 222pg/mL at about 12h after initiation of the dosing interval; 35 a mean plasma concentration from about 89 to about 483pg/mL at about 24h after initiation of the dosing interval; a mean plasma concentration from about 152 to about 565pg/mL at about 36h after initiation of the dosing interval; a mean plasma concentration from about 186 to about 738pg/mL at about 48h after initiation of the 40 dosing interval; 105 a mean plasma concentration from about 238 to about 738pg/mL at about 48h after initiation of the dosing interval; a mean plasma concentration from about 254 to about 789pg/mL at about 60h after initiation of the dosing interval; 5 a mean plasma concentration from about 230 to about 789pg/mL over at least the next 48h. 106. The use of claim 105, further comprising maintaining the buprenorphine transdermal delivery system in contact with the patient's skin such that the mean plasma concentrations are maintained as follows: a mean plasma concentration from about 276 to about 789pg/mL at about 96h after initiation of the 10 dosing interval; a mean plasma concentration from about 281 to about 789pg/mL at about 120h after initiation of the dosing interval; a mean plasma concentration from about 259 to about 727pg/mL at about 144h after initiation of the dosing interval; and 15 a mean plasma concentration from about 230 to about, 630pg/mL at about 168h after initiation of the dosing interval. 107. Use of buprenorphine in the manufacture of a medicament for treating pain in a human patient by administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, and maintaining said transdermal delivery system in contact 20 with the patient's skin for at least 5 days, said transdermal delivery system maintaining a mean relative release rate of from about 51 pg/h to about 86pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 5pg/h to about 9pg/h from about 72h after the initiation of the dosing interval until the end of at least the five day dosing interval, such that the following mean plasma concentrations are achieved: 25 a mean plasma concentration from about 5 to about 11 3pg/mL at about 6h after initiation of the dosing interval; a mean plasma concentration from about 55 to about 296pg/mL at about 12h after initiation of the dosing interval; a mean plasma concentration from about 118 to about 644pg/mL at about 24h after initiation of the 30 dosing interval; a mean plasma concentration from about 203 to about 753pg/mL at about 36h after initiation of the dosing interval; a mean plasma concentration from about 247 to about 984pg/mL at about 48h after initiation of the dosing interval; 35 a mean plasma concentration from about 317 to about 984pg/mL at about 60h after initiation of the dosing interval; a mean plasma concentration from about 339 to about 1052pg/mL at about 72h after initiation of the dosing interval; and a mean plasma concentration from about 306 to about 1052pg/mL over at least the next 48h. 106 108. The use of claim 107, further comprising maintaining the buprenorphine transdermal delivery system in contact with the patient's skin such that the mean plasma concentrations are maintained as follows: a mean plasma concentration from about 369 to about 1052pg/mL at about 96h after initiation of the 5 dosing interval; a mean plasma concentration from about 374 to about 1052pg/mL at about 120h after initiation of the dosing interval; a mean plasma concentration from about 346 to about 970pg/mL at about 144h after initiation of the dosing interval; 10 a mean plasma concentration from about 306 to about 841 pg/mL at about 168h after initiation of the dosing interval. 109. Use of buprenorphine in the manufacture of a medicament for treating pain in a human patient by administering buprenorphine transdermally to said human patient such that mean relative release rates are achieved over a dosing interval as follows: 15 a mean relative release rate of from about 3pg/h to about 86pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 0.3pg/h to about 9pg/h from about 72h after the initiation of the dosing interval until the end of the dosing interval. 110. The use of claim 109, wherein the mean relative release rates achieved over the dosing 20 interval are as follows: a mean relative release rate of from about 3pg/h to about 5pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 0.3pg/h to about 0.6pg/h from about 72h after the initiation of the dosing interval until the end of the dosing interval. 25 111. The use of claim 109, wherein the mean relative release rates achieved over the dosing interval are as follows: a mean relative release rate of from about 6pg/h to about 11pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 0.7pg/h to about 1 pg/h from about 72h after the initiation of the 30 dosing interval until the end of the dosing interval. 112. The use of claim 109, wherein the mean relative release rates achieved over the dosing interval are as follows: a mean relative release rate of from about 13pg/h to about 21pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and 35 a mean relative release rate of about 1pg/h to about 2pg/h from about 72h after the initiation of the dosing interval until the end of the dosing interval. 113. The use of claim 109, wherein the mean relative release rates achieved over the dosing interval are as follows: a mean relative release rate of from about 26pg/h to about 43pg/h from the initiation of the dosing 40 interval until about 72h after the initiation of the dosing interval; and 107 a mean relative release rate of about 3pg/h to about 4pg/h from about 72h after the initiation of the dosing interval until the end of the dosing interval. 114. The use of claim 109, wherein the mean relative release rates achieved over the dosing interval are as follows: 5 a mean relative release rate of from about 39pg/h to about 64pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 4pg/h to about 7pg/h from about 72h after the initiation of the dosing interval until the end of the dosing interval. 115. The use of claim 109, wherein the mean relative release rates achieved over the dosing 10 interval are as follows: a mean relative release rate of from about 51pg/h to about 86pg/h from the initiation of the dosing interval until about 72h after the initiation of the dosing interval; and a mean relative release rate of about 5pg/h to about 9pg/h from about 72h after the initiation of the dosing interval until the end of the dosing interval. 15 116. Use of buprenorphine in the manufacture of a medicament for treating pain in a human patient by applying a transdermal delivery system containing buprenorphine as the active ingredient onto the skin of said human patient to provide a substantially first order plasma level increase of buprenorphine over a first thee-day dosing interval, such that a mean plasma concentration from about 21 to about 1052pg/mL is attained about 72h after application of said transdermal delivery 20 system; and maintaining said transdermal delivery system on the skin of said human patient for at least an additional two-day dosing interval, such that a mean relative release rate from about 0.3pg/h to about 9pg/h is maintained over said at least two-day additional dosing interval and said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two-day additional dosing interval. 25 117. The use of claim 116, wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval. 118. The use of claim 117, wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system. 119. The use of claim 106, wherein the mean plasma concentration attained about 72h after 30 application of said transdermal delivery system is from about 85 to about 263pg/mL; and the mean relative release rate maintained over said at least two-day additional dosing interval is from about 13pg/h to about 21pg/h and said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two-day additional dosing interval. 120. The use of claim 119, wherein from about 68% to about 95% of the buprenorphine is 35 contained in the transdermal delivery system at the end of the dosing interval. 121. The buprenorphine of claim 119, wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system. 122. The use of claim 117, wherein the mean plasma concentration attained about 72h after application of said transdermal delivery system is from about 21 to about 66pg/mL; and the mean 40 relative release rate maintained over said at least two-day additional dosing interval is from about 108 0.3pg/h to about 0.6pg/h and said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two-day additional dosing interval. 123. The use of claim 122, wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval. 5 124. The use of claim 122, wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system. 125. The use of claim 117, wherein the mean plasma concentration attained about 72h after application of said transdermal delivery system is from about 42 to about 132pg/mL; and the mean relative release rate maintained over said at least two-day additional dosing interval is from about 10 0.7pg/h to about 1pg/h and said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two-day additional dosing interval. 126. The use of claim 125, wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval. 127. The use of claim 125, wherein the Tmax occurs from about 3 to about 5 days after 15 application of said transdermal delivery system. 128. The use of claim 117, wherein the mean plasma concentration attained about 72h after application of said transdermal delivery system is from about 169 to about 526pg/mL; and the mean relative release rate maintained over said at least two-day additional dosing interval is from about 3pg/h to about 4pg/h and said transdermal delivery system provides a therapeutic effect to said 20 human patient throughout the at least two-day additional dosing interval. 129. The use of claim 128, wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval. 130. The use of claim 128, wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system. 25 131. The use of claim 117, wherein the mean plasma concentration attained about 72h after application of said transdermal delivery system is from about 254 to about 789pg/mL; and the mean relative release rate maintained over said at least two-day additional dosing interval is from about 4pg/h to about 7pg/h and said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two-day additional dosing interval. 30 132. The use of claim 131, wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval. 133. The use of claim 131, wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system. 134. The use of claim 117, wherein the mean plasma concentration attained about 72h after 35 application of said transdermal delivery system is from about 339 to about 1052pg/mL; and the mean relative release rate maintained over said at least two-day additional dosing interval is from about 5pg/h to about 9pg/h and said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two-day additional dosing interval. 135. The use of claim 134, wherein from about 68% to about 95% of the buprenorphine is 40 contained in the transdermal delivery system at the end of the dosing interval. 109 136. The use of claim 134, wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system. 137. Use of buprenorphine in the manufacture of a medicament for treating pain in a human patient by applying a transdermal delivery system containing buprenorphine as the active ingredient 5 onto the skin of said human patient to provide a first order release rate of buprenorphine over a thee day dosing interval, such that a maximum plasma concentration from about 20pg/mL to about 1052pg/mL is attained, and maintaining said transdermal delivery systems on the skin of said human patient for at least an additional two-day dosing interval during which said transdermal delivery system provides substantially zero order kinetics, such that said transdermal delivery system provides a 10 therapeutic effect to said human patient throughout the at least two-day additional dosing interval. 138. Use of buprenorphine in the manufacture of a medicament for treating pain in a human patient suffering from moderate to severe pain by applying a transdermal delivery system containing buprenorphine onto the skin of the human patient and maintaining the transdermal delivery system in contact with the skin for a 3 day dosing interval, the transdermal delivery system containing an 15 amount of buprenorphine sufficient to maintain an adequate relative release rate to provide a therapeutic effect in the patient for approximately only 3 days, comprising maintaining the transdermal delivery system in contact with the human patient's skin for at least 2 to about 5 additional days beyond said 3 day dosing interval, such that the human patient continues to receive a therapeutic effect from said transdermal buprenorphine delivery system. 20 139. Use of buprenorphine in the manufacture of a medicament for treating pain in a human patient suffering from moderate to severe pain by applying a transdermal delivery system containing buprenorphine onto the skin of the human patient and maintaining the transdermal delivery system in contact with the skin for a 3 day dosing interval, the transdermal delivery system containing an amount of buprenorphine sufficient to maintain an adequate relative release rate to provide a 25 therapeutic effect in the patient for about 3 days, characterised by an improvement comprising maintaining the transdermal delivery system in contact with the human patient's skin for at least 2 to about 5 additional days beyond said 3 day dosing interval. 140. The use of claim 97, wherein the plasma level of buprenorphine at 72h does not decrease by more than 30% over the next 48h. 30 141. The use of claim 97, wherein the plasma level of buprenorphine at 120h does not decrease by more than 30% over the next 48h. 142. A method of treating pain in a human patient, comprising administering buprenorphine transdermally to said human patient by applying a transdermal delivery system comprising buprenorphine, to the skin of a patient, and maintaining said transdermal delivery system in contact 35 with the skin of the patient for at least 5 days, wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval. 143. The method of claim 142, wherein said transdermal delivery system comprises about 5 mg of buprenorphine. 110 144. The method of claim 142, wherein said transdermal delivery system comprises about 10 mg of buprenorphine. 145. The method of claim 142, wherein said transdermal delivery system comprises about 20 mg of buprenorphine. 5 146. The method of claim 142, wherein said transdermal delivery system comprises about 30 mg of buprenorphine. 147. The method of claim 142, wherein said transdermal delivery system comprises about 40 mg of buprenorphine. 148. The method of claim 142, wherein said transdermal delivery system upon first 10 application, maintains a mean relative release rate of about 0.3 pg/hr to about 9 pg/hr from about 72 hours after the initiation of the dosing interval until the end of the dosing interval. 149. The method of claim 142, wherein said transdermal delivery system provides a substantially first order plasma level increase of buprenorphine from the initiation of the dosing interval until about 72 hours after the initiation of the dosing interval; and a substantially zero plasma level 15 fluctuation of buprenorphine from about 72 hours after the initiation of the dosing interval until the end of at least the five-day dosing interval. 150. The method of claim 142, wherein said transdermal delivery system upon first application, maintains a mean relative release rate of about 0.7 pg/hr to about 1 pg/hr from about 72 hours after the initiation of the dosing interval until the end of the dosing interval. 20 151. A method of treating pain in a human patient, comprising administering buprenorphine transdermally to said human patient by applying a transdermal delivery system comprising buprenorphine, to the skin of a patient, and maintaining said transdermal delivery system in contact with the skin of the patient while providing an analgesically effective plasma level for at least 5 days, wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery 25 system at the end of the dosing interval. 152. The method of claim 151, wherein the mean buprenorphine plasma concentration at about 72 hours after the initiation of the dosing interval is from about 20 to about 66 pg/ml; and from about 23 to about 66 pg/ml at about 120 hours after the initiation of the dosing interval. 153. The method of claim 151, wherein the mean buprenorphine plasma concentration at 30 about 72 hours after the initiation of the dosing interval is from about 42 to about 132 pg/ml; and from about 47 to about 132 pg/ml at about 120 hours after the initiation of the dosing interval. 154. The method of claim 151, wherein the mean buprenorphine plasma concentration at about 72 hours after the initiation of the dosing interval is from about 85 to about 263 pg/ml; and from about 94 to about 263 pg/ml at about 120 hours after the initiation of the dosing interval. 111 155. The method of claim 151, wherein the mean buprenorphine plasma concentration at about 72 hours after the initiation of the dosing interval is from about 169 to about 526 pg/ml; and from about 187 to about 526 pg/ml at about 120 hours after the initiation of the dosing interval. 156. The method of claim 151, wherein the mean buprenorphine plasma concentration at 5 about 72 hours after the initiation of the dosing interval is from about 254 to about 789 pg/ml; and from about 281 to about 789 pg/ml at about 120 hours after the initiation of the dosing interval. 157. The method of claim 151, wherein the mean buprenorphine plasma concentration at about 72 hours after the initiation of the dosing interval is from about 339 to about 1052 pg/ml; and from about 374 to about 1052 pg/ml at about 120 hours after the initiation of the dosing interval. 10 158. The method of claim 151, wherein said transdermal delivery system comprises about 5 mg of buprenorphine. 159. The method of claim 151, wherein said transdermal delivery system comprises about 10 mg of buprenorphine. 160. The method of claim 151, wherein said transdermal delivery system comprises about 20 15 mg of buprenorphine. 161. The method of claim 151, wherein said transdermal delivery system comprises about 30 mg of buprenorphine. 162. A method of treating pain in a human patient comprising the steps substantially as hereinbefore described with reference to any one of the examples. 20 163. A pharmaceutical formulation for treating pain in a human patient comprising a pharmaceutically effective amount of buprenorphine in a transdermal delivery system containing buprenorphine as the active ingredient together with instructions for applying said transdermal delivery system onto the skin of a human patient to provide a substantially first order plasma level increase of buprenorphine over a first three-day dosing interval, such that a mean plasma concentration from 25 about 20 pg/ml to about 1052 pg/ml is attained, about 72 hours after application of said transdermal delivery system; and maintaining said transdermal delivery system on the skin of a human patient for at least an additional two-day dosing interval, such that a mean relative release rate from about 0.3 pg/hr to about 9 pg/hr is maintained over said at least two-day additional dosing interval and a human patient experiences analgesia throughout the at least two-day additional dosing interval. 30 164. A pharmaceutical formulation for treating pain in a human patient comprising a pharmaceutically effective amount of buprenorphine in a transdermal delivery system containing buprenorphine as the active ingredient together with instructions for applying said transdermal delivery system in contact with the patient's skin for at least 5 days, said transdermal delivery system maintaining a mean relative release rate of from about 3 pg/hr to about 86 pg/hr and providing a 35 substantially first order plasma level increase of buprenorphine from the initiation of the dosing interval until about 72 hours after the initiation of the dosing interval; and a mean relative release rate of about 112 0.3 pg/hr to about 9 pg/hr and providing a substantially zero order plasma level fluctuation of buprenorphine from about 72 hours after the initiation of the dosing interval until the end of at least the five-day dosing interval, such that the following mean plasma concentrations are achieved: a mean plasma concentration from about 0.3 to about 113 pg/ml at about 6 hours after initiation 5 of the dosing interval; a mean plasma concentration from about 3 to about 296 pg/ml at about 12 hours after initiation of the dosing interval; a mean plasma concentration from about 7 to about 644 pg/ml at about 24 hours after initiation of the dosing interval; 10 a mean plasma concentration from about 13 to about 753 pg/ml at about 36 hours after initiation of the dosing interval; a mean plasma concentration from about 16 to about 984 pg/ml at about 48 hours after initiation of the dosing interval; a mean plasma concentration from about 20 to about 984 pg/ml at about 60 hours after 1s initiation of the dosing interval; a mean plasma concentration from about 20 to about 1052 pg/ml at about 72 hours after initiation of the dosing interval; and thereafter administering the buprenorphine in a manner such that the mean plasma concentrations are maintained from about 19 to about 1052 pg/ml over at least the next 48 hours. 20 165. A pharmaceutical formulation according to claim 164, wherein said instructions further comprise maintaining the buprenorphine transdermal delivery system in contact with the patient's skin such that the mean plasma concentrations are maintained as follows: a mean plasma concentration from about 23 to about 1052 pg/ml at about 96 hours after initiation of the dosing interval; 25 a mean plasma concentration from about 23 to about 1052 pg/ml at about 120 hours after initiation of the dosing interval; a mean plasma concentration from about 22 to about 970 pg/ml at about 144 hours after initiation of the dosing interval; and a mean plasma concentration from about 19 to about 841 pg/ml at about 168 hours after 30 initiation of the dosing interval.
    [166] 166. A pharmaceutical formulation according to claim 164, wherein said instructions further comprise maintaining the buprenorphine transdermal delivery system in contact with the patient's skin such that the following mean plasma concentrations are achieved: a mean plasma concentration from about 1 to about 28 pg/ml at about 6 hours after initiation of 35 the dosing interval; 113 a mean plasma concentration from about 14 to about 74 pg/ml at about 12 hours after initiation of the dosing interval; a mean plasma concentration from about 30 to about 161 pg/ml at about 24 hours after initiation of the dosing interval; 5 a mean plasma concentration from about 51 to about 188 pg/ml at about 36 hours after initiation of the dosing interval; a mean plasma concentration from about 62 to about 246 pg/ml at about 48 hours after initiation of the dosing interval; a mean plasma concentration from about 79 to about 246 pg/ml at about 60 hours after 10 initiation of the dosing interval; a mean plasma concentration from about 85 to about 263 pg/ml at about 72 hours after initiation of the dosing interval; and thereafter administering the buprenorphine in a manner such that the mean plasma concentrations are maintained from about 77 to about 263 pg/ml over at least the next 48 hours. 15
    [167] 167. A pharmaceutical formulation according to claim 164, wherein said instructions further comprise maintaining the buprenorphine transdermal delivery system in contact with the patient's skin such that the mean plasma concentrations are maintained as follows: a mean plasma concentration from about 92 to about 263 pg/ml at about 96 hours after initiation of the dosing interval; 20 a mean plasma concentration from about 94 to about 263 pg/ml at about 120 hours after initiation of the dosing interval; a mean plasma concentration from about 86 to about 243 pg/ml at about 144 hours after initiation of the dosing interval; and a mean plasma concentration from about 77 to about 210 pg/ml at about 168 hours after 25 initiation of the dosing interval.
    [168] 168. A pharmaceutical formulation according to claim 164, wherein said instructions further comprise maintaining the buprenorphine transdermal delivery system in contact with the patient's skin such that the following mean plasma concentrations are achieved: a mean plasma concentration from about 0.3 to about 7 pg/ml at about 6 hours after initiation of 30 the dosing interval; a mean plasma concentration from about 4 to about 19 pg/ml at about 12 hours after initiation of the dosing interval; a mean plasma concentration from about 7 to about 40 pg/ml at about 24 hours after initiation of the dosing interval; 35 a mean plasma concentration from about 13 to about 47 pg/ml at about 36 hours after initiation of the dosing interval; 114 a mean plasma concentration from about 16 to about 62 pg/ml at about 48 hours after initiation of the dosing interval; a mean plasma concentration from about 20 to about 62 pg/ml at about 60 hours after initiation of the dosing interval; 5 a mean plasma concentration from about 21 to about 66 pg/ml at about 72 hours after initiation of the dosing interval; and thereafter administering the buprenorphine in a manner such that the mean plasma concentrations are maintained from about 19 to about 66 pg/ml over at least the next 48 hours.
    [169] 169. A pharmaceutical formulation according to claim 168, wherein said instructions further 10 comprise maintaining the buprenorphine transdermal delivery system in contact with the patient's skin such that the mean plasma concentrations are maintained as follows: a mean plasma concentration from about 23 to about 66 pg/ml at about 96 hours after initiation of the dosing interval; a mean plasma concentration from about 23 to about 66 pg/ml at about 120 hours after 1s initiation of the dosing interval; a mean plasma concentration from about 22 to about 61 pg/ml at about 144 hours after initiation of the dosing interval; and a mean plasma concentration from about 19 to about 53 pg/ml at about 168 hours after initiation of the dosing interval. 20
    [170] 170. A pharmaceutical formulation according to claim 164, wherein said instructions further comprise maintaining the buprenorphine transdermal delivery system in contact with the patient's skin such that the following mean plasma concentrations are achieved: a mean plasma concentration from about 0.7 to about 14 pg/ml at about 6 hours after initiation of the dosing interval; 25 a mean plasma concentration from about 7 to about 37 pg/ml at about 12 hours after initiation of the dosing interval; a mean plasma concentration from about 15 to about 80 pg/ml at about 24 hours after initiation of the dosing interval; a mean plasma concentration from about 25 to about 94 pg/ml at about 36 hours after initiation 30 of the dosing interval; a mean plasma concentration from about 31 to about 123 pg/ml at about 48 hours after initiation of the dosing interval; a mean plasma concentration from about 40 to about 123 pg/ml at about 60 hours after initiation of the dosing interval; 35 a mean plasma concentration from about 42 to about 132 pg/ml at about 72 hours after initiation of the dosing interval; and 115 thereafter administering the buprenorphine in a manner such that the mean plasma concentrations are maintained from about 38 to about 132 pg/ml over at least the next 48 hours.
    [171] 171. A pharmaceutical formulation according to claim 170, wherein said instructions further comprise maintaining the buprenorphine transdermal delivery system in contact with the patient's skin 5 such that the mean plasma concentrations are maintained as follows: a mean plasma concentration from about 46 to about 132 pg/ml at about 96 hours after initiation of the dosing interval; a mean plasma concentration from about 47 to about 132 pg/ml at about 120 hours after initiation of the dosing interval; 10 a mean plasma concentration from about 43 to about 121 pg/ml at about 144 hours after initiation of the dosing interval; and a mean plasma concentration from about 38 to about 105 pg/ml at about 168 hours after initiation of the dosing interval.
    [172] 172. A pharmaceutical formulation according to claim 164, wherein said instructions further 15 comprise maintaining the buprenorphine transdermal delivery system in contact with the patient's skin such that the following mean plasma concentrations are achieved: a mean plasma concentration from about 3 to about 57 pg/ml at about 6 hours after initiation of the dosing interval; a mean plasma concentration from about 28 to about 148 pg/ml at about 12 hours after 20 initiation of the dosing interval; a mean plasma concentration from about 59 to about 322 pg/ml at about 24 hours after initiation of the dosing interval; a mean plasma concentration from about 102 to about 377 pg/ml at about 36 hours after initiation of the dosing interval; 25 a mean plasma concentration from about 124 to about 492 pg/ml at about 48 hours after initiation of the dosing interval; a mean plasma concentration from about 159 to about 492 pg/ml at about 60 hours after initiation of the dosing interval; a mean plasma concentration from about 169 to about 526 pg/ml at about 72 hours after 30 initiation of the dosing interval; and thereafter administering the buprenorphine in a manner such that the mean plasma concentrations are maintained from about 153 to about 526 pg/ml over at least the next 48 hours.
    [173] 173. A pharmaceutical formulation according to claim 172, wherein said instructions further comprise maintaining the buprenorphine transdermal delivery system in contact with the patient's skin 35 such that the mean plasma concentrations are maintained as follows: 116 a mean plasma concentration from about 184 to about 526 pg/ml at about 96 hours after initiation of the dosing interval; a mean plasma concentration from about 187 to about 526 pg/ml at about 120 hours after initiation of the dosing interval; 5 a mean plasma concentration from about 173 to about 485 pg/ml at about 144 hours after initiation of the dosing interval; and a mean plasma concentration from about 153 to about 420 pg/ml at about 168 hours after initiation of the dosing interval.
    [174] 174. A pharmaceutical formulation according to claim 164, wherein said instructions further 10 comprise maintaining the buprenorphine transdermal delivery system in contact with the patient's skin such that the following mean plasma concentrations are achieved: a mean plasma concentration from about 4 to about 85 pg/ml at about 6 hours after initiation of the dosing interval; a mean plasma concentration from about 42 to about 222 pg/ml at about 12 hours after 1s initiation of the dosing interval; a mean plasma concentration from about 89 to about 483 pg/ml at about 24 hours after initiation of the dosing interval; a mean plasma concentration from about 152 to about 565 pg/ml at about 36 hours after initiation of the dosing interval; 20 a mean plasma concentration from about 186 to about 738 pg/ml at about 48 hours after initiation of the dosing interval; a mean plasma concentration from about 238 to about 738 pg/ml at about 60 hours after initiation of the dosing interval; a mean plasma concentration from about 254 to about 789 pg/ml at about 72 hours after 25 initiation of the dosing interval; and thereafter administering the buprenorphine in a manner such that the mean plasma concentrations are maintained from about 230 to about 789 pg/ml over at least the next 48 hours.
    [175] 175. A pharmaceutical formulation according to claim 174, wherein said instructions further comprise maintaining the buprenorphine transdermal delivery system in contact with the patient's skin 30 such that the mean plasma concentrations are maintained as follows: a mean plasma concentration from about 276 to about 789 pg/ml at about 96 hours after initiation of the dosing interval; a mean plasma concentration from about 281 to about 789 pg/ml at about 120 hours after initiation of the dosing interval; 35 a mean plasma concentration from about 259 to about 727 pg/ml at about 144 hours after initiation of the dosing interval; and 117 a mean plasma concentration from about 230 to about 630 pg/ml at about 168 hours after initiation of the dosing interval.
    [176] 176. A pharmaceutical formulation according to claim 164, wherein said instructions further comprise maintaining the buprenorphine transdermal delivery system in contact with the patient's skin 5 such that the following mean plasma concentrations are achieved: a mean plasma concentration from about 5 to about 113 pg/ml at about 6 hours after initiation of the dosing interval; a mean plasma concentration from about 55 to about 296 pg/ml at about 12 hours after initiation of the dosing interval; 10 a mean plasma concentration from about 118 to about 644 pg/ml at about 24 hours after initiation of the dosing interval; a mean plasma concentration from about 203 to about 753 pg/ml at about 36 hours after initiation of the dosing interval; a mean plasma concentration from about 247 to about 984 pg/ml at about 48 hours after 1s initiation of the dosing interval; a mean plasma concentration from about 317 to about 984 pg/ml at about 60 hours after initiation of the dosing interval; a mean plasma concentration from about 339 to about 1052 pg/ml at about 72 hours after initiation of the dosing interval; and 20 thereafter administering the buprenorphine in a manner such that the mean plasma concentrations are maintained from about 306 to about 1052 pg/ml over at least the next 48 hours.
    [177] 177. A pharmaceutical formulation according to claim 176, wherein said instructions further comprise maintaining the buprenorphine transdermal delivery system in contact with the patient's skin such that the mean plasma concentrations are maintained as follows: 25 a mean plasma concentration from about 369 to about 1052 pg/ml at about 96 hours after initiation of the dosing interval; a mean plasma concentration from about 374 to about 1052 pg/ml at about 120 hours after initiation of the dosing interval; a mean plasma concentration from about 346 to about 970 pg/ml at about 144 hours after 30 initiation of the dosing interval; and a mean plasma concentration from about 306 to about 841 pg/ml at about 168 hours after initiation of the dosing interval.
    [178] 178. A pharmaceutical formulation comprising a pharmaceutically effective amount of buprenorphine for treating pain in a human patient together with instructions for administering 35 buprenorphine transdermally to a human patient such that mean relative release rates are achieved over a dosing interval as follows: 118 a mean relative release rate of from about 3 pg/hr to about 86 pg/hr from the initiation of the dosing interval until about 72 hours after the initiation of the dosing interval; and a mean relative release rate of about 0.3 pg/hr to about 9 pg/hr from about 72 hours after the initiation of the dosing interval until the end of the dosing interval. 5
    [179] 179. A pharmaceutical formulation according to claim 178, wherein said instructions indicate that the mean relative release rates achieved over the dosing interval are as follows: a mean relative release rate of from about 3 pg/hr to about 5 pg/hr from the initiation of the dosing interval until about 72 hours after the initiation of the dosing interval; and a mean relative rate of about 0.3 pg/hr to about 0.6 pg/hr from about 72 hours after the initiation 10 of the dosing interval until the end of the dosing interval.
    [180] 180. A pharmaceutical formulation according to claim 178, wherein said instructions indicate that the mean relative release rates achieved over the dosing interval are as follows: a mean relative release rate of from about 6 pg/hr to about 11 pg/hr from the initiation of the dosing interval until about 72 hours after the initiation of the dosing interval; and 15 a mean relative release rate of about 0.7 pg/hr to about 1 pg/hr from about 72 hours after the initiation of the dosing interval until the end of the dosing interval.
    [181] 181. A pharmaceutical formulation according to claim 178, wherein said instructions indicate that the mean relative release rates achieved over the dosing interval are as follows: a mean relative release rate of from about 13 pg/hr to about 21 pg/hr from the initiation of the 20 dosing interval until about 72 hours after the initiation of the dosing interval; and a mean relative release rate of about 1 pg/hr to about 2 pg/hr from about 72 hours after the initiation of the dosing interval until the end of the dosing interval.
    [182] 182. A pharmaceutical formulation according to claim 178, wherein said instructions indicate that the mean relative release rates achieved over the dosing interval are as follows: 25 a mean relative release rate of from about 26 pg/hr to about 43 pg/hr from the initiation of the dosing interval until about 72 hours after the initiation of the dosing interval; and a mean relative release rate of about 3 pg/hr to about 4 pg/hr from about 72 hours after the initiation of the dosing interval until the end of the dosing interval.
    [183] 183. A pharmaceutical formulation according to claim 178, wherein said instructions indicate 30 that the mean relative release rates achieved over the dosing interval are as follows: a mean relative release rate of from about 39 pg/hr to about 64 pg/hr from the initiation of the dosing interval until about 72 hours after the initiation of the dosing interval; and a mean relative release rate of about 4 pg/hr to about 7 pg/hr from about 72 hours after the initiation of the dosing interval until the end of the dosing interval. 35
    [184] 184. A pharmaceutical formulation according to claim 178, wherein said instructions indicate that the mean relative release rates achieved over the dosing interval are as follows: 119 a mean relative release rate of from about 51 pg/hr to about 86 pg/hr from the initiation of the dosing interval until about 72 hours after the initiation of the dosing interval; and a mean relative release rate of about 5 pg/hr to about 9 pg/hr from about 72 hours after the initiation of the dosing interval until the end of the dosing interval. 5
    [185] 185. A pharmaceutical formulation for treating pain in a human patient comprising a pharmaceutically effective amount of buprenorphine in a transdermal delivery system containing buprenorphine as the active ingredient together with instructions for applying said transdermal delivery system onto the skin of a human patient to provide a substantially first order plasma level increase of buprenorphine over a first three-day dosing interval, such that a mean plasma concentration from 10 about 21 to about 1052 pg/ml is attained about 72 hours after application of said transdermal delivery system; and maintaining said transdermal delivery system on the skin of a human patient for at least an additional two-day dosing interval, such that a mean relative release rate from about 0.3 pg/hr to about 9 pg/hr is maintained over said at least two-day additional dosing interval and a human patient experiences analgesia throughout the at least two-day additional dosing interval. 15
    [186] 186. A pharmaceutical formulation according to claim 185, wherein said instructions indicate that a mean plasma concentration attained about 72 hours after application of said transdermal delivery system is from about 85 to about 263 pg/ml; and the mean relative release rate maintained over said at least two-day additional dosing interval is from about 13 pg/hr to about 21 pg/hr.
    [187] 187. A pharmaceutical formulation according to claim 185, wherein said instructions indicate 20 that the mean plasma concentration attained about 72 hours after application of said transdermal delivery system is from about 20 to about 66 pg/ml; and the mean relative release rate maintained over said at least two-day additional dosing interval is from about 0.3 pg/hr to about 0.6 pg/hr.
    [188] 188. A pharmaceutical formulation according to claim 185, wherein said instructions indicate that the mean plasma concentration attained about 72 hours after application of said transdermal 25 delivery system is from about 42 to about 132 pg/ml; and the mean relative release rate maintained over said at least two-day additional dosing interval is from about 0.7 pg/hr to about 1 pg/hr.
    [189] 189. A pharmaceutical formulation according to claim 185, wherein said instructions indicate that the mean plasma concentration attained about 72 hours after application of said transdermal delivery system is from about 169 to about 526 pg/ml; and the mean relative release rate maintained 30 over said at least two-day additional dosing interval is from about 2 pg/hr to about 4 pg/hr.
    [190] 190. A pharmaceutical formulation according to claim 185, wherein said instructions indicate that the mean plasma concentration attained about 72 hours after application of said transdermal delivery system is from about 254 to about 789 pg/ml; and the mean relative release rate maintained over said at least two-day additional dosing interval is from about 4 pg/hr to about 7 pg/hr. 35
    [191] 191. A pharmaceutical formulation according to claim 185, wherein said instructions indicate that the mean plasma concentration attained about 72 hours after application of said transdermal 120 delivery system is from about 339 to about 1052 pg/ml; and the mean relative release rate maintained over said at least two-day additional dosing interval is from about 5 pg/hr to about 9 pg/hr.
    [192] 192. A pharmaceutical formulation according to any one of claims 163 to 191, wherein said instructions indicate that the transdermal delivery system is to be maintained in contact with skin of a 5 patient for at least 5 days.
    [193] 193. A pharmaceutical formulation according to claim 192, wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval.
    [194] 194. A pharmaceutical formulation according to claim 192, wherein the instructions indicate 10 that Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system.
    [195] 195. A pharmaceutical formulation for treating opioid addiction in a human patient comprising a pharmaceutically effective amount of buprenorphine in a transdermal delivery system containing buprenorphine together with instructions for applying said transdermal delivery system onto the skin of the human patient and maintaining the transdermal delivery system in contact with the skin for a 3-day 15 dosing interval, the transdermal delivery system to provide a plasma concentration of from about 1000 pg/ml to about 10,000 pg/ml at the end of said 3-day dosing interval, and the transdermal delivery system being maintained in contact with the skin of the patient for an additional dosing interval of at least 2 to about 5 additional days beyond said 3-day dosing interval, such that the human patient continues to receive effective treatment for opioid addiction from said transdermal buprenorphine 20 delivery matrix over said additional dosing interval.
    [196] 196. A pharmaceutical formulation according to claim 195, wherein the instructions indicate that the plasma concentration attained at the end of said 3 first day dosing interval is from about 5000 pg/ml to about 8000 pg/ml.
    [197] 197. A pharmaceutical formulation for treating a human patient suffering from moderate to 25 severe pain comprising a pharmaceutically effective amount of buprenorphine in a transdermal delivery system containing buprenorphine together with instructions for applying said transdermal delivery system onto the skin of the human patient and maintaining the transdermal delivery system in contact with the skin for a 3-day dosing interval, the transdermal delivery system containing an amount of buprenorphine sufficient to maintain an adequate relative release rate to provide effective 30 analgesia in the human patient for approximately only 3 days, wherein the transdermal delivery system is maintained in contact with the human patient's skin for an additional dosing interval of at least 2 to about 6 additional days beyond said 3-day dosing interval, such that the human patient continues to experience effective analgesia.
    [198] 198. A pharmaceutical formulation for treating a human patient suffering from moderate to 35 severe pain comprising a pharmaceutically effective amount of an opioid in a transdermal delivery system containing said opioid together with instructions for applying said transdermal delivery system 121 onto the skin of the human patient and maintaining the transdermal delivery system in contact with the skin for a 3-day dosing interval, the transdermal delivery system containing an amount of said opioid sufficient to maintain an adequate relative release rate to provide effective analgesia in the human patient for approximately only 3 days, wherein the transdermal delivery system is maintained in 5 contact with the human patient's skin for an additional dosing interval of at least 2 to about 6 additional days beyond said 3 day dosing interval, such that the human patient continues to experience effective analgesia during said additional dosing interval.
    [199] 199. A pharmaceutical formulation for treating a human patient suffering from moderate to severe pain comprising a pharmaceutically effective amount of an opioid in a transdermal delivery 10 system containing said opioid together with instructions for applying said transdermal delivery system onto the skin of the human patient and maintaining the transdermal delivery system in contact with the skin for a 3-day dosing interval, the transdermal delivery system containing an amount of said opioid such that the human patient receives effective treatment for opioid addiction from said transdermal opioid delivery matrix during said 3-day dosing interval, and the transdermal delivery system being 15 maintained in contact with the skin of the patient for an additional dosing interval of at least 2 to about 5 additional days beyond said 3-day dosing interval, such that the human patient continues to receive effective treatment for opioid addiction from said transdermal opioid delivery matrix over said additional dosing interval.
    [200] 200. A pharmaceutical formulation for treating pain in a human patient substantially as 20 hereinbefore described with reference to any one of the examples.
    [201] 201. Use of buprenorphine in the manufacture of a medicament for treating pain in a human patient comprising administering buprenorphine transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, and maintaining said transdermal delivery system in contact with the skin of the patient for at least 5 days, wherein from about 68% to about 95% of the 25 buprenorphine is contained in the transdermal delivery system at the end of the dosing interval.
    [202] 202. Use of claim 201, wherein said transdermal delivery system comprises about 5 mg of buprenorphine.
    [203] 203. Use of claim 201, wherein said transdermal delivery system comprises about 10 mg of buprenorphine. 30
    [204] 204. Use of claim 201, wherein said transdermal delivery system comprises about 20 mg of buprenorphine.
    [205] 205. Use of claim 201, wherein said transdermal delivery system comprises about 30 mg of buprenorphine.
    [206] 206. Use of claim 201, wherein said transdermal delivery system comprises about 40 mg of 35 buprenorphine. 122
    [207] 207. Use of claim 201, wherein said transdermal delivery system upon first application, maintains a mean relative release rate of about 0.3 pg/hr to about 9 pg/hr from about 72 hours after the initiation of the dosing interval until the end of the dosing interval.
    [208] 208. Use of claim 201, wherein said transdermal delivery system provides a substantially first 5 order plasma level increase of buprenorphine from the initiation of the dosing interval until about 72 hours after the initiation of the dosing interval; and a substantially zero plasma level fluctuation of buprenorphine from about 72 hours after the initiation of the dosing interval until the end of at least the five-day dosing interval.
    [209] 209. Use of claim 201, wherein said transdermal delivery system upon first application, 10 maintains a mean relative release rate of about 0.7 pg/hr to about 1 pg/hr from about 72 hours after the initiation of the dosing interval until the end of the dosing interval.
    [210] 210. Use of buprenorphine in the manufacture of a medicament for treating pain in a human patient comprising administering buprenorphine transdermally to said human patient by applying a transdermal delivery system in contact with the skin of a patient while providing an analgesically 15 effective plasma level for at least 5 days, wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval.
    [211] 211. Use of claim 210, wherein the mean buprenorphine plasma concentration at about 72 hours after the initiation of the dosing interval is from about 20 to about 66 pg/ml; and from about 23 to about 66 pg/ml at about 120 hours after the initiation of the dosing interval. 20
    [212] 212. Use of claim 210, wherein the mean buprenorphine plasma concentration at about 72 hours after the initiation of the dosing interval is from about 42 to about 132 pg/ml; and from about 47 to about 132 pg/ml at about 120 hours after the initiation of the dosing interval.
    [213] 213. Use of claim 210, wherein the mean buprenorphine plasma concentration at about 72 hours after the initiation of the dosing interval is from about 85 to about 263 pg/ml; and from about 94 25 to about 263 pg/ml at about 120 hours after the initiation of the dosing interval.
    [214] 214. Use of claim 210, wherein the mean buprenorphine plasma concentration at about 72 hours after the initiation of the dosing interval is from about 169 to about 526 pg/ml; and from about 187 to about 526 pg/ml at about 120 hours after the initiation of the dosing interval.
    [215] 215. Use of claim 210, wherein the mean buprenorphine plasma concentration at about 72 30 hours after the initiation of the dosing interval is from about 254 to about 789 pg/ml; and from about 281 to about 789 pg/ml at about 120 hours after the initiation of the dosing interval.
    [216] 216. Use of claim 210, wherein the mean buprenorphine plasma concentration at about 72 hours after the initiation of the dosing interval is from about 339 to about 1052 pg/ml; and from about 374 to about 1052 pg/ml at about 120 hours after the initiation of the dosing interval. 35
    [217] 217. Use of claim 210, wherein said transdermal delivery system comprises about 5 mg of buprenorphine. 123
    [218] 218. Use of claim 210, wherein said transdermal delivery system comprises about 10 mg of buprenorphine.
    [219] 219. Use of claim 210, wherein said transdermal delivery system comprises about 20 mg of buprenorphine. 5
    [220] 220. Use of claim 210, wherein said transdermal delivery system comprises about 30 mg of buprenorphine.
    [221] 221. Use of buprenorphine in the manufacture of a medicament for treating pain in a human patient substantially as hereinbefore described with reference to any one of the examples.
    [222] 222. The use of buprenorphine in the preparation of a medicament for treating pain in a 10 human patient, comprising applying a transdermal delivery system containing buprenorphine as the active ingredient onto the skin of a human patient for a dosing interval of at least about 7 days, wherein during the period of from about 72 hours to at least about 168 hours after initiation of the dosing interval a mean relative release rate from about 0.3 pg/hr to about 9 pg/hr is maintained, and a human patient 15 experiences analgesia throughout the dosing interval.
    [223] 223. The use of buprenorphine in the preparation of a medicament for treating pain in a human patient, comprising administering buprenorphine transdermally to a human patient by applying a transdermal delivery system to the skin of a patient, and maintaining said transdermal delivery system in contact with the patient's skin for a dosing interval of at least about 7 days, said transdermal 20 delivery system maintaining a mean relative release rate of about 0.3 pg/hr to about 9 pg/hr and providing a substantially zero order plasma level fluctuation of buprenorphine from about 72 hours until at least about 168 hours after the initiation of the dosing interval such that mean plasma concentrations are maintained as follows: a mean plasma concentration from about 23 to about 1052 pg/ml at about 96 hours after 25 initiation of the dosing interval; a mean plasma concentration from about 23 to about 1052 pg/ml at about 120 hours after initiation of the dosing interval; a mean plasma concentration from about 22 to about 970 pg/ml at about 144 hours after initiation of the dosing interval; and 30 a mean plasma concentration from about 1.9 to about 841 pg/ml at about 168 hours after initiation of the dosing interval.
    [224] 224. The use of claim 223, further comprising maintaining the buprenorphine transdermal delivery device system in contact with the patient's skin such that the mean plasma concentrations are maintained as follows: 35 a mean plasma concentration from about 92 to about 263 pg/ml at about 96 hours after initiation of the dosing interval; 124 a mean plasma concentration from about 94 to about 263 pg/ml at about 120 hours after initiation of the dosing interval; a mean plasma concentration from about 86 to about 243 pg/ml at about 144 hours after initiation of the dosing interval; and 5 a mean plasma concentration from about 77 to about 2W pg/ml at about 168 hours after initiation of the dosing interval.
    [225] 225. The use of claim 223, further comprising maintaining the buprenorphine transdermal delivery device system in contact with the patient's skin such that the mean plasma concentrations are maintained as follows: 10 a mean plasma concentration from about 23 to about 66 pg/ml at about 96 hours after initiation of the dosing interval; a mean plasma concentration from about 23 to about 66 pg/ml at about 120 hours alter initiation of the dosing interval; a mean plasma concentration from about 22 to about 61 pg/ml at about 144 hours after 1s initiation of the dosing interval; and a mean plasma concentration from about 19 to 53 pg/ml at about 168 hours after initiation of the dosing interval.
    [226] 226. The use of claim 223, further comprising maintaining the buprenorphine transdermal delivery device system in contact with the patient's skin such that the mean plasma 20 concentrations are maintained as follows: a mean plasma concentration from about 46 to about 132 pg/ml at about 96 hours after initiation of the dosing interval; a mean plasma concentration from about 47 to about 132 pg/ml at about 120 hours after initiation of the dosing interval; 25 a mean plasma concentration from about 43 to about 121 pg/ml at about 144 hours after initiation of the dosing interval; and a mean plasma concentration from about 38 to about 105 pg/ml at about 168 hours after initiation of the dosing interval.
    [227] 227. The use of claim 223, further comprising maintaining the buprenorphine transdermal 30 delivery device system in contact with the patient's skin such that the mean plasma concentrations are maintained as follows: a mean plasma concentration from about 184 to about 526 pg/ml at about 96 hours after initiation of the dosing interval; a mean plasma concentration from about 187 to about 526 pg/ml at about 120 hours 35 after initiation of the dosing interval; 125 a mean plasma concentration from about 173 to about 485 pg/ml at about 144 hours after initiation of the dosing interval; a mean plasma concentration from about 153 to about 420 pg/ml at about 168 hours after initiation of the dosing interval. 5
    [228] 228. The use of claim 223, further comprising maintaining the buprenorphine transdermal delivery device system in contact with the patient's skin such that the mean plasma concentrations are maintained as follows: a mean plasma concentration from about 276 to about 789 pg/ml at about 96 hours after initiation of the dosing interval; 10 a mean plasma concentration from about 281 to about 789 pg/ml at about 120 hours after initiation of the dosing interval; a mean plasma concentration from about 259 to about 727 pg/ml at about 144 hours after initiation of the dosing interval; and a mean plasma concentration from about 230 to about 630 pg/ml at 168 hours after 1s initiation of the dosing interval.
    [229] 229. The use of claim 223, further comprising maintaining the buprenorphine transdermal delivery device system in contact with the patient's skin such that the mean plasma concentrations are maintained as follows: a mean plasma concentration from about 369 to about 1052 pg/ml at about 96 hours 20 after initiation of the dosing interval; a mean plasma concentration from about 374 to about 1052 pg/ml at about 120 hours after initiation of the dosing interval; a mean plasma concentration from about 346 to about 970 pg/ml at about 144 hours after initiation of the dosing interval; 25 a mean plasma concentration from about 306 to about 841 pg/ml at about 168 hours after initiation of the dosing interval.
    [230] 230. The use of buprenorphine in the preparation of a medicament for treating pain in a human patient, comprising administering buprenorphine transdermally to a human patient for a dosing period of at least 7 days, such that a mean relative release rate of about 0.3 pg/hr to about 9 pg/hr is 30 achieved from about 72 hours after the initiation of the dosing interval until the end of the dosing interval.
    [231] 231. The use of claim 230, wherein a mean relative release rate of about 0.3 pg/hr to about 0.6 pg/hr is achieved from about 72 hours after the initiation of the dosing interval until the end of the dosing interval. 126
    [232] 232. The use of claim 230, wherein a mean relative release rate of 0.7 pg/hr to 1 pg/hr is achieved from about 72 hours after the initiation of the dosing interval until the end of the dosing interval.
    [233] 233. The use of claim 230, wherein a mean relative release rate of about 1 pg/hr to about 2 5 pg/hr is achieved from about 72 hours after the initiation of the dosing interval until the end of the dosing interval.
    [234] 234. The use of claim 230, wherein a mean relative release rate of about 3 pg/hr to about 4 pg/hr is achieved from about 72 hours after the initiation of the dosing interval until the end of the dosing interval. 10
    [235] 235. The use of claim 230, wherein a mean relative release rate of about 4 pg/hr to about 7 pg/hr is achieved from about 72 hours after the initiation of the dosing interval until the end of the dosing interval.
    [236] 236. The use of claim 230, wherein a mean relative release rate of about 5 pg/hr to about 9 pg/hr is achieved from about 72 hours after the initiation of the dosing interval until the end of the 15 dosing interval.
    [237] 237. The use of buprenorphine in the preparation of a medicament for treating pain in a human patient, comprising applying a transdermal delivery system containing buprenorphine as the active ingredient onto the skin of a human patient for a dosing interval of at least about 7 days such that a mean relative release rate from about 0.3 pg/hr to about 9 pg/hr is maintained over the period 20 from about 72 hours until at least about 168 hours after the initiation of the dosing interval, and a human patient experiences analgesia throughout the period from about 72 hours until at least about 168 hours after the initiation of the dosing interval.
    [238] 238. The use of claim 237, wherein the mean relative release rate maintained over the period from about 72 hours until at least about 168 hours after the initiation of the dosing interval is from 25 about 0.3 pg/hr to about 0.6 pg/hr.
    [239] 239. The use of claim 237, wherein the mean relative release rate maintained over the period from about 72 hours until at least about 168 hours after the initiation of the dosing interval is from about 0.7 pg/hr to about 1 pg/hr.
    [240] 240. The use of claim 237, wherein the mean relative release rate maintained over the period 30 from about 72 hours until at least about 168 hours after the initiation of the dosing interval is from about 2 pg/hr to about 4 pg/hr.
    [241] 241. The use of claim 237, wherein the mean relative release rate maintained over the period from about 72 hours until at least about 168 hours after the initiation of the dosing interval is from about 4 pg/hr to about 7 pg/hr. 127
    [242] 242. The use of claim 237, wherein the mean relative release rate maintained over the period from about 72 hours until at least about 168 hours after the initiation of the dosing interval is from about 5 pg/hr to about 9 pg/hr.
    [243] 243. The use of claim 222, wherein from about 68% to about 95% of the buprenorphine is 5 contained in the transdermal delivery system at the end of the dosing interval.
    [244] 244. The use of claim 222, wherein the Tmax occurs from about 3 to about 5 days after application of transdermal delivery system.
    [245] 245. The use of claim 222, wherein the transdermal delivery system comprises a polymer matrix layer which comprises buprenorphine. 10 Dated 10 April, 2013 EURO-CELTIQUE, S.A. Patent Attorneys for the Applicant/Nominated Person SPRUSON&FERGUSON
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    同族专利:
    公开号 | 公开日
    AU2013204227B2|2017-06-15|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2017-10-12| FGA| Letters patent sealed or granted (standard patent)|
    2017-10-26| PC| Assignment registered|Owner name: MUNDIPHARMA PTY LIMITED Free format text: FORMER OWNER(S): EURO-CELTIQUE, S.A. |
    2018-01-04| PC| Assignment registered|Owner name: MUNDIPHARMA PTY LIMITED Free format text: FORMER OWNER(S): MUNDIPHARMA PTY LIMITED |
    2018-03-15| MK14| Patent ceased section 143(a) (annual fees not paid) or expired|
    优先权:
    申请号 | 申请日 | 专利标题
    US60/038919||1997-02-24||
    US08/939068||1997-09-29||
    AU2008261134A|AU2008261134B2|1997-02-24|2008-12-19|Method of providing sustained analgesia with buprenorphine|
    AU2012244363A|AU2012244363B2|1997-02-24|2012-11-02|Method of providing sustained analgesia with buprenorphine|
    AU2013204227A|AU2013204227B2|1997-02-24|2013-04-12|Method of providing sustained analgesia with buprenorphine|AU2013204227A| AU2013204227B2|1997-02-24|2013-04-12|Method of providing sustained analgesia with buprenorphine|
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