INVITED REVIEW

Buprenorphine: The Basic Pharmacology Revisited

Alan Cowan, PhD

Abstract: The historical background leading to the current use of buprenorphine as an analgesic and its role in the management of opioid dependence is summarized. The popular description of buprenorphine as a partial agonist is discussed in relation to efcacy in animal models of antinociception and clinical analgesia. The latest information on the respiratory depressant effects of buprenorphine and its N-dealkylated metabolite (norbuprenorphine) is presented. New data on the buprenorphine withdrawal syndrome in rats are described. Key Words: partial agonist, efcacy, respiratory depression, withdrawal syndrome (J Addict Med 2007;1: 6872)

HISTORICAL OVERVIEW
Buprenorphine (Fig. 1) is an oripavine derivative that evolved from a comprehensive analgesic discovery program in the late 1960s at Reckitt and Colman (now Reckitt Benckiser) in Hull, England.1 Etorphine (M-99) and diprenorphine (M-5050) are 2 early successes from the program that have enjoyed widespread use as: 1) reference agonist and antagonist, respectively, in preclinical laboratories; and as 2) immobilizing and reversal agent, respectively, for several species of captive and free-ranging animals.2 The notion of buprenorphine occupying a benecial intermediate position on the pharmacological spectrum between the opioid antagonism displayed by diprenorphine and the potent analgesia associated with etorphine has persisted throughout the years. Buprenorphine may represent the best of both compounds in one molecule. The particular balance of these opioid activities, along with distinctive receptor interactions and high lipid solubility, have prompted the frequent description of buprenorphines pharmacological prole as being unique35 and, perhaps, complex.6 8 An injectable formulation of buprenorphine (Temgesic; Buprenex) was rst marketed in the United Kingdom in 1978 for the treatment of moderate to severe pain. A sublingual tablet form of the analgesic was launched in 1981. The utility of buprenorphine as an effective treatment of opioid addiction was recognized and demonstrated by Jasinski and colleagues
From the Department of Pharmacology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA. Send correspondence and reprint requests to Dr. Alan Cowan, Department of Pharmacology, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, PA 19140. e-mail: acowan@temple.edu Copyright 2007 American Society of Addiction Medicine ISSN: 1921-0629/07/0102-0068

and described in an inuential report published in 1978.9 Despite being labeled as a partial agonist (vide infra), buprenorphine provided sufcient agonism at mu receptors to reduce craving and withdrawal symptoms in human subjects. The nonscientic (but nevertheless helpful) imagery at the time was of a bee without the sting or, again, if heroin turns the light on full blast, buprenorphine merely twiddles the dimmer switch to produce a icker of high sensation. Accumulating evidence emphasized the superior safety prole of buprenorphine over methadone or morphine, particularly with respect to respiratory depression, which is a major toxic effect of these drugs.10 12 Sublingual buprenorphine (Subutex) was introduced into France in 1996 and is available by prescription for therapy for heroin addiction.13 After several combined submissions by Reckitt Benckiser and the U.S. National Institute on Drug Abuse (NIDA), buprenorphine was approved by the U.S. Food and Drug Administration in October 2002 as a Schedule III controlled substance for use in treating opioiddependent individuals. In addition to Subutex, a second sublingual formulation of buprenorphine (Suboxone) was approved. This tablet is available in 2 dosage forms and contains buprenorphine and naloxone, the well-known opioid antagonist, at a ratio of 4:1. The second formulation is intended to discourage diversion of buprenorphine for illicit use by injection. Thus, although naloxone has poor bioavailability by the sublingual route, if it is administered parenterally by an opioid-dependent person, an unpleasant abstinence syndrome is the likely outcome. Legislation in the United States allows buprenorphine tablets to be prescribed from the ofce of specially certied physicians and hence away from traditional methadone clinics. The hope is that private, individualized treatment will remove much of the stigma believed to be associated with the institutional clinic setting and help improve compliance and promote successful therapy. The latest initiative, earmarked for 2007, is a NIDA-sponsored study of Suboxone for the treatment of subjects physically dependent on prescription opioid analgesics rather than heroin. Additional routes (eg, intranasal)14 and modes of administration of buprenorphine are currently being investigated extensively. Elegant transdermal formulations of the drug are now available commercially (Transtec)15 or under development.16 These skin patches provide consistent buprenorphine delivery for 3 or 7 days and hold promise for improved ease of use and patient compliance in a variety of severe and chronic pain-related conditions. Two subcutaneously applied depot forms of buprenorphine are targeted for long-term withdrawal suppression and opioid blockade in
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Basic Pharmacology of Buprenorphine

ANIMAL PHARMACOLOGY Buprenorphine and Partial Agonism

Buprenorphine has been variously described during the years as a narcotic antagonist analgesic, mixed opioid receptor agonist-antagonist, high afnity mu agonist/kappa antagonist, mu receptor partial agonist, and even a partial mu opioid agonist. A partial agonist, dened in the most general sense, is a compound that is only partly as effective as full agonists for a particular end point no matter the amount used.22 For drug development, the following bold and encouraging statement serves as a timely catalyst and refers to clinically useful partial agonists as exemplied by buspirone, aripiprazole, and buprenorphine: they seem to provide a way to ne tune the treatment of psychiatric disorders (including opioid dependence, in the case of buprenorphine) by maximizing the treatment effect while minimizing undesirable adverse effects.23 Might this, indeed, be true for buprenorphine? Martin and colleagues24 are usually credited with being rst to describe buprenorphine as a partial agonist at mu opioid receptors, based on inuential ndings using the chronic spinal dog preparation. Early studies21,25 revealed incomplete efcacy for buprenorphine in mouse and rat tail dip tests using a standard noxious stimulus (ie, water temperature of 55C)26 Indeed, not only was antinociception submaximal at this temperature (and even at the less noxious stimulus of 45C), higher doses of buprenorphine (10 and 30 mg/kg) were less effective than lower doses such that an inverted U-shaped dose-response curve was obtained (Fig. 2). Possible reasons for the phenomenon of buprenorphine curvilinear dose-response curves have been discussed elsewhere.27 For present purposes, it is sufcient to point out that a low ceiling effect also could be demonstrated for buprenorphine in the rat standard 55C hot plate test;28 in contrast, full antinociception was obtained in mouse abdominal constriction25 and rat tail/paw pressure tests.25,28 Given the vast body of antinociceptive data on buprenorphine now available, it is clear that the agonist efcacy of the compound is dependent on the choice of test and nature of the noxious stimulus.29 Use, and perhaps overuse, of the word unique in describing the pharmacological prole of buprenorphine has undoubtedly piqued the interest of basic and academic scientists but may have led to misconceptions (at least initially) by pain and addiction physicians in predicting clinical efcacy and applications for the compound.27 It may be that general physicians, not following the scientic literature too closely, have placed undue emphasis on the ambiguous word partial and been confused by talk of the aforementioned pharmacological oddity: a preclinical bell-shaped dose-response curve. The situation could have been different if the rst published results for buprenorphine were obtained from the rat formalin test30 rather than the tail ick test. In the former model (of persistent pain), groups of 5 to 10 rats were pretreated s.c. with buprenorphine (0.0110 mg/kg), morphine (0.30 3 mg/ kg), or nalbuphine (0.0110 mg/kg) immediately before receiving 50 L of 5% formalin or saline s.c. into the dorsal surface of the right hind paw. The incidence of inching/ shaking of this paw and/or hindquarters was taken as a

FIGURE 1. Chemical structure of buprenorphine [N-cyclopropylmethyl-7-(1-[S]-hydroxy-1,2,2-trimethylpropyl)-6,14endo-ethano-6,7,8,14-tetrahydronororipavine].

opioid-dependent individuals. Probuphine is an implantable rod consisting of buprenorphine in a polymer matrix that is designed to release the drug continuously for up to 6 months after a single visit to the doctors ofce.17 Norvex, consisting of buprenorphine suspended in biodegradable polymer microcapsules, also affords sustained release of the opioid.18 With both depot forms, the possibility of illicit diversion and misuse is likely reduced relative to the take-home (sublingual) tablets of buprenorphine. Buprenorphine is a popular analgesic in the veterinary eld and has been licensed for this purpose in dogs and cats in the United Kingdom.19 Fentanyl patches have provided satisfactory postsurgical analgesia in dogs;20 buprenorphine patches have yet to be fully evaluated in this species. Buprenorphine is arguably the most frequently used analgesic for postoperative care of experimental animals, especially rats. Buprenorphines interesting odyssey began more than 3 decades ago with a few laboratory rats, their tails immersed in warm water, amid disbelief at the curvilinear shape of the ensuing dose-response relationship (Fig. 2).21 The arc of progress from rat to man to rat is therefore complete.

FIGURE 2. Dose-response curves obtained with buprenorphine in the rat tail dip test using water at 45C or 55C as the noxious stimulus. Readings were taken with groups of 10 rats per dose at 30 minutes. 2007 American Society of Addiction Medicine

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spontaneous behavior indicative of pain and counted 20 to 35 minutes after the injection of formalin or saline. Flinching was antagonized in a dose-related manner by both buprenorphine and morphine with buprenorphine being approximately 20 times more potent than, and (critically for the present discussion) fully equi-efcacious with, morphine (Fig. 3). In this pain model nalbuphine, the clinically effective analgesic happens to be considerably less efcacious than buprenorphine or morphine. That need not necessarily be the case in other rodent tests for antinociception. The differing efcacies of buprenorphine in animal pain models notwithstanding, the current consensus is as follows: this historical partial agonist is not associated with an analgesic ceiling dose in humans where it acts as a full agonist for analgesia and full analgesic efcacy is achieved.31

Buprenorphine and Respiratory Depression

Unlike the situation with analgesia, the partial agonist action of buprenorphine at mu opioid receptors has been viewed positively because of the associated ceiling on certain respiratory depressant measures in animals32 and humans.33 It is well known that agonists at mu opioid receptors depress respiration, which is reected in an increased arterial pressure of carbon dioxide (PaCO2), reduced PaO2 and hypoxia. Studies with rats have demonstrated a ceiling effect for buprenorphine but not for morphine or fentanyl, the full agonists.34 36 In 1994, Walsh and colleagues10 published a key article on the clinical pharmacology of buprenorphine in which nondependent volunteers received sublingual buprenorphine or oral methadone. The much quoted conclusion focused on the plateau effect of buprenorphine, even after doses as large as 16 and 32 mg, with respect to respiratory depression (and subjective measures). This result has denitely helped to reinforce the belief that buprenorphines ceiling effect is not just a laboratory curiosity of heuristic value but will be of real, practical signicance in limiting

FIGURE 3. Dose-response lines for morphine, buprenorphine, and nalbuphine for antagonism of late phase flinching induced by formalin in rats (N 510; unpublished results).

abuse potential and providing a wider safety margin in clinical use. One consequence of buprenorphines high afnity for mu opioid receptors, and slow dissociation kinetics, is the resultant resistance to reversal by naloxone, in both animals and humans. In cases where buprenorphine has provoked respiratory depression (perhaps in elderly patients or individuals coadministering benzodiazepines) an enduring question has been what to do? Injecting relatively large bolus doses of naloxone often has been ineffective. Recent work conducted by investigators at Leiden University has afforded the answer: continuous infusion of naloxone, rather than bolus administration, is necessary to overcome established, buprenorphine-induced respiratory depression.37 The Leiden group also has investigated the extent to which norbuprenorphine contributes to the respiratory depressant action of buprenorphine in rats by performing elegant pharmacokinetic-pharmacodynamic modeling.38 Norbuprenorphine is the N-dealkylated metabolite of buprenorphine, which, being more polar than buprenorphine, penetrates the blood brain barrier less readily. Ohtani and colleagues35 were rst to study norbuprenorphine in this context and reported that it was approximately 10 times more potent than the parent drug as a respiratory depressant, probably acting via the mu opioid receptor. A decade later, in 2006, Megarbane et al39 described how norbuprenorphine, given at 3 mg/kg i.v. to rats, elicited a rapid increase in PaCO2, decrease in arterial pH, hypoxia, and overt sedation/muscle rigidity/seizures. Finally, Yassen et al38 concluded that because only 10% of i.v. buprenorphine was probably transformed to norbuprenorphine in rats in their study, this small amount of metabolite is unlikely to contribute to buprenorphine-induced respiratory depression to any great extent. It should be emphasized at this point that norbuprenorphine is surprisingly active after s.c. administration to rodents. Experiments conducted in the authors laboratory40 have shown that norbuprenorphine is equi-efcacious with buprenorphine: 1) as an antinociceptive agent in the mouse (acetic acid) abdominal constriction test; and 2) as an antipruritic in the mouse (compound 48/80) scratch test. Norbuprenorphine was only 3 times and 9 times, respectively, less potent than buprenorphine in these assays. Additionally, in the rat charcoal meal test,41 norbuprenorphine and buprenorphine were equipotent (at 0.3 mg/kg s.c.) and equi-efcacious in essentially arresting gastrointestinal transit. The beginning of a bell-shaped doseresponse curve was associated with buprenorphine (as expected) but not with norbuprenorphine. Pretreating rats with naloxone (1 mg/kg s.c.) 5 minutes before norbuprenorphine (0.30 mg/kg) reversed the slowing effect. Collectively, these results in mice and rats represent a start in expanding the in vivo pharmacological prole of norbuprenorphine (for so long a neglected metabolite) in its own right. The conclusion (mentioned earlier) that norbuprenorphine does not contribute greatly to the overall respiratory depressant effect of buprenorphine need not apply to
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other buprenorphine actions mediated by mu opioid receptors.

Unusual Physical Dependence on Buprenorphine in Rats

It is typically not possible to demonstrate physical dependence in rats receiving multiple injections of buprenorphine after naloxone challenge or abrupt withdrawal of buprenorphine. Overt behaviors indicative of withdrawal are essentially absent and the overall syndrome is classied as mild, at best. Animals injected daily with 3 mg/kg s.c. of buprenorphine for 28 days (and with saline thereafter) showed only 1 sign of withdrawalweight loss, which only became apparent on day 6 of withdrawal.42 Dum and colleagues43 were able to elicit an enhanced abstinence syndrome in buprenorphine-injected rats only if the animals received a single dose of morphine 1 hour before naloxone challenge. This innovative maneuver uncovered an underlying neuroadaptation of rats to buprenorphine, with the presumed involvement of mu opioid receptors. The experimental strategy has been repeated in the authors laboratory where the kappa agonists, U50,488H and tiuadom, were used as priming agents instead of morphine to reveal possible agonism by buprenorphine at kappa opioid receptors.

however, with these kappa agonists, the following sign jumpingwas the main contributor to the scores. This dominant (as opposed to recessive) sign45 has been regarded historically as a key indicator of physical dependence on opioids. It is important to note that the jumping associated with these rats on buprenorphine differed from the familiar jumping displayed by morphine-dependent rats challenged with naloxone. First, the latency to rst jump was much longer in rats primed with U50,488H and tiuadom, and second, the behavior took the form of a sudden and unexpected jumping frenzy, which continued as long as the rat was removed from the top of the observation box and returned to the bottom. Delayed, compulsive jumping may reect critical interactions between buprenorphine, U50,488H/tiuadom and naloxone at kappa (rather than mu) receptors. If this is the case, then the study implicates kappa receptors in the neuroadaptation of rats to buprenorphine and adds a component of kappa agonism to the established mu receptor partial agonist-kappa antagonist prole of the oripavine.

Clinical Implications
After reading this short survey about buprenorphine, the interested clinician may ask, Is buprenorphines ceiling effect of real, practical signicance? The answer is an unequivocal yesno. Yes, based on reports46 of a lowered plateau for cardiorespiratory effects and the resultant improved safety margin. No, in terms of analgesic efcacy. Three prominent and experienced scientists have made the following statement: There are no published data indicating an analgesic ceiling dose in humans.31 No equivocation there. The particular abstinence syndrome displayed by rats receiving buprenorphine, primed with a kappa agonist of diverse chemical structure, then challenged with naloxone is yet another behavioral event to be added to buprenorphines already extensive repertoire. Clinicians have been pleased to associate buprenorphine with kappa receptor antagonism, rather than kappa agonism (and the possibility of dysphoric side effects). In this context, buprenorphines in vitro binding prole may be summarized as follows47: binds at nanomolar concentrations to mu, kappa and delta receptors, and at micromolar concentration to ORL 1 receptors. At a functional level, buprenorphine acts as a partial agonist at mu, kappa and ORL 1 receptors, and as an antagonist at delta receptors.

METHODS
Groups of 8 to 11 male, Sprague Dawley albino rats (225250 g) were injected s.c. with buprenorphine (0.50 mg/kg) or saline at noon and midnight for 4 consecutive days. At noon on day 5, the animals were primed with U50,488H (20 mg/kg), tiuadom (10 mg/kg), morphine (20 mg/kg), or vehicle (s.c.) and placed in individual observation boxes. At 1 hour, the rats were weighed, challenged with naloxone (10 mg/kg) or saline (i.p.), observed for 1 hour, and then reweighed. Severity of abstinence was assessed as previously described.44 Mean abstinence scores were examined statistically by analysis of variance and Dunnetts test.

Results and Comment

Use of morphine (10 mg/kg) as a priming agent increased naloxone-induced abstinence in rats pretreated with buprenorphine (Table 1). This nding is in agreement with the original report by Dum et al.43 Use of U50,488H (20 mg/kg) or tiuadom (10 mg/kg) also enhanced abstinence;

TABLE 1. Abstinence Scores Associated with Naloxone Challenge in Rats Pretreated with Buprenorphine then Primed with Test Agent
Drug Treatment Buprenorphine-vehicle-naloxone Buprenorphine-morphine-naloxone Buprenorphine-U50,488H-naloxone Buprenorphine-vehicle-naloxone Buprenorphine-tiuadom-naloxone
*P 0.05. SEM, standard error of the mean.

Epilogue
Add enigmatic to the list of descriptions for buprenorphine. Whereas such analgesics as butorphanol, nalbuphine, and pentazocine were once competitors for the attention of research scientists, only buprenorphine has stayed the course to widespread clinical utility and retained the ability to still fascinate the academic community.

Mean 1-hr Abstinence Score SEM 15.6 3.3 28.4 2.2* 42 5.4* 11 2.9 37.5 6.8*

ACKNOWLEDGMENT
The author thanks Dr. Saadet Inan for constructive discussions and help with the gures.

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