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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 bu-

prenorphine as a partial agonist is discussed in relation to efficacy

in animal models of antinociception and clinical analgesia. The

latest information on the respiratory depressant effects of buprenor-

phine and its N-dealkylated metabolite (norbuprenorphine) is pre-

sented. New data on the buprenorphine withdrawal syndrome in rats

are described.

Key Words: partial agonist, efficacy, respiratory depression, with-

drawal syndrome

(J Addict Med 2007;1: 6872)

HISTORICAL OVERVIEWBuprenorphine (Fig. 1) is an oripavine derivative that

evolved from a comprehensive analgesic discovery programin the late 1960s at Reckitt and Colman (now Reckitt Benck-iser) in Hull, England.1 Etorphine (M-99) and diprenorphine(M-5050) are 2 early successes from the program that haveenjoyed widespread use as: 1) reference agonist and antago-

nist, respectively, in preclinical laboratories; and as 2) immo-bilizing and reversal agent, respectively, for several speciesof captive and free-ranging animals.2

The notion of buprenorphine occupying a beneficialintermediate position on the pharmacological spectrum be-tween the opioid antagonism displayed by diprenorphine andthe potent analgesia associated with etorphine has persistedthroughout the years. Buprenorphine may represent the bestof both compounds in one molecule. The particular balanceof these opioid activities, along with distinctive receptorinteractions and high lipid solubility, have prompted thefrequent description of buprenorphines pharmacological pro-file as being unique35 and, perhaps, complex.68

An injectable formulation of buprenorphine (Temgesic;Buprenex) was first marketed in the United Kingdom in 1978for the treatment of moderate to severe pain. A sublingualtablet form of the analgesic was launched in 1981. The utilityof buprenorphine as an effective treatment of opioid addictionwas recognized and demonstrated by Jasinski and colleagues

and described in an influential report published in 1978.9

Despite being labeled as a partial agonist (vide infra), bu-prenorphine provided sufficient agonism at mu receptors toreduce craving and withdrawal symptoms in human subjects.The nonscientific (but nevertheless helpful) imagery at thetime was of a bee without the sting or, again, if herointurns the light on full blast, buprenorphine merely twiddlesthe dimmer switch to produce a flicker of high sensation.Accumulating evidence emphasized the superior safety pro-file of buprenorphine over methadone or morphine, particu-larly with respect to respiratory depression, which is a majortoxic effect of these drugs.1012

Sublingual buprenorphine (Subutex) was introducedinto France in 1996 and is available by prescription fortherapy for heroin addiction.13 After several combined sub-missions by Reckitt Benckiser and the U.S. National Instituteon Drug Abuse (NIDA), buprenorphine was approved by theU.S. Food and Drug Administration in October 2002 as aSchedule III controlled substance for use in treating opioid-dependent individuals. In addition to Subutex, a secondsublingual formulation of buprenorphine (Suboxone) wasapproved. This tablet is available in 2 dosage forms andcontains buprenorphine and naloxone, the well-known opioid

antagonist, at a ratio of 4:1. The second formulation isintended to discourage diversion of buprenorphine for illicituse by injection. Thus, although naloxone has poor bioavail-ability by the sublingual route, if it is administered parenter-ally by an opioid-dependent person, an unpleasant abstinencesyndrome is the likely outcome. Legislation in the UnitedStates allows buprenorphine tablets to be prescribed from theoffice of specially certified physicians and hence away fromtraditional methadone clinics. The hope is that private, indi-vidualized treatment will remove much of the stigma believedto be associated with the institutional clinic setting and helpimprove compliance and promote successful therapy. Thelatest initiative, earmarked for 2007, is a NIDA-sponsored

study of Suboxone for the treatment of subjects physicallydependent on prescription opioid analgesics rather than her-oin.

Additional routes (eg, intranasal)14 and modes of ad-ministration of buprenorphine are currently being investi-gated extensively. Elegant transdermal formulations of thedrug are now available commercially (Transtec)15 or underdevelopment.16 These skin patches provide consistent bu-prenorphine delivery for 3 or 7 days and hold promise forimproved ease of use and patient compliance in a variety ofsevere and chronic pain-related conditions. Two subcutane-ously applied depot forms of buprenorphine are targeted forlong-term withdrawal suppression and opioid blockade in

From the Department of Pharmacology and Center for Substance AbuseResearch, Temple University School of Medicine, Philadelphia, PA.

Send correspondence and reprint requests to Dr. Alan Cowan, Department ofPharmacology, Temple University School of Medicine, 3420 NorthBroad Street, Philadelphia, PA 19140. e-mail: [email protected]

Copyright 2007 American Society of Addiction MedicineISSN: 1921-0629/07/0102-0068

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opioid-dependent individuals. Probuphine is an implantablerod consisting of buprenorphine in a polymer matrix that is

designed to release the drug continuously for up to 6 monthsafter a single visit to the doctors office.17 Norvex, consistingof buprenorphine suspended in biodegradable polymer mi-crocapsules, also affords sustained release of the opioid.18

With both depot forms, the possibility of illicit diversion andmisuse is likely reduced relative to the take-home (sublin-gual) tablets of buprenorphine.

Buprenorphine is a popular analgesic in the veterinaryfield and has been licensed for this purpose in dogs and catsin the United Kingdom.19 Fentanyl patches have providedsatisfactory postsurgical analgesia in dogs;20 buprenorphinepatches have yet to be fully evaluated in this species. Bu-prenorphine is arguably the most frequently used analgesicfor postoperative care of experimental animals, especiallyrats. Buprenorphines interesting odyssey began more than 3decades ago with a few laboratory rats, their tails immersed inwarm water, amid disbelief at the curvilinear shape of theensuing dose-response relationship (Fig. 2).21 The arc ofprogress from rat to man to rat is therefore complete.

ANIMAL PHARMACOLOGY

Buprenorphine and Partial AgonismBuprenorphine has been variously described during the

years as a narcotic antagonist analgesic, mixed opioidreceptor agonist-antagonist, high affinity mu agonist/kappa

antagonist, mu receptor partial agonist, and even a partialmu opioid agonist. A partial agonist, defined in the mostgeneral sense, is a compound that is only partly as effectiveas full agonists for a particular end point no matter theamount used.22 For drug development, the following bold andencouraging statement serves as a timely catalyst and refersto clinically useful partial agonists as exemplified by buspi-rone, aripiprazole, and buprenorphine: they seem to providea way to fine tune the treatment of psychiatric disorders(including opioid dependence, in the case of buprenorphine)by maximizing the treatment effect while minimizing unde-sirable adverse effects.23 Might this, indeed, be true forbuprenorphine?

Martin and colleagues24 are usually credited with beingfirst to describe buprenorphine as a partial agonist at muopioid receptors, based on influential findings using thechronic spinal dog preparation. Early studies21,25 revealedincomplete efficacy for buprenorphine in mouse and rat taildip tests using a standard noxious stimulus (ie, water tem-perature of 55C)26 Indeed, not only was antinociceptionsubmaximal at this temperature (and even at the less noxiousstimulus of 45C), higher doses of buprenorphine (10 and 30mg/kg) were less effective than lower doses such that aninverted U-shaped dose-response curve was obtained (Fig. 2).Possible reasons for the phenomenon of buprenorphine cur-vilinear dose-response curves have been discussed else-where.27 For present purposes, it is sufficient to point out that

a low ceiling effect also could be demonstrated for buprenor-phine in the rat standard 55C hot plate test;28 in contrast, fullantinociception was obtained in mouse abdominal constric-tion25 and rat tail/paw pressure tests.25,28 Given the vast bodyof antinociceptive data on buprenorphine now available, it isclear that the agonist efficacy of the compound is dependenton the choice of test and nature of the noxious stimulus.29

Use, and perhaps overuse, of the word unique in describingthe pharmacological profile of buprenorphine has undoubt-edly piqued the interest of basic and academic scientists butmay have led to misconceptions (at least initially) by pain andaddiction physicians in predicting clinical efficacy and appli-cations for the compound.27 It may be that general physicians,

not following the scientific literature too closely, have placedundue emphasis on the ambiguous word partial and beenconfused by talk of the aforementioned pharmacologicaloddity: a preclinical bell-shaped dose-response curve. Thesituation could have been different if the first publishedresults for buprenorphine were obtained from the rat formalintest30 rather than the tail flick test. In the former model (ofpersistent pain), groups of 5 to 10 rats were pretreated s.c.with buprenorphine (0.0110 mg/kg), morphine (0.303 mg/kg), or nalbuphine (0.0110 mg/kg) immediately before re-ceiving 50 L of 5% formalin or saline s.c. into the dorsalsurface of the right hind paw. The incidence of flinching/shaking of this paw and/or hindquarters was taken as a

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

FIGURE 2. Dose-response curves obtained with buprenor-phine in the rat tail dip test using water at 45C or 55C asthe noxious stimulus. Readings were taken with groups of10 rats per dose at 30 minutes.

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spontaneous behavior indicative of pain and counted 20 to 35minutes after the injection of formalin or saline.

Flinching was antagonized in a dose-related manner byboth buprenorphine and morphine with buprenorphine beingapproximately 20 times more potent than, and (critically forthe present discussion) fully equi-efficacious with, morphine

(Fig. 3). In this pain model nalbuphine, the clinically effec-tive analgesic happens to be considerably less efficaciousthan buprenorphine or morphine. That need not necessarilybe the case in other rodent tests for antinociception. Thediffering efficacies of buprenorphine in animal pain modelsnotwithstanding, the current consensus is as follows: thishistorical partial agonist is not associated with an analgesicceiling dose in humans where it acts as a full agonist foranalgesia and full analgesic efficacy is achieved.31

Buprenorphine and Respiratory DepressionUnlike the situation with analgesia, the partial agonist

action of buprenorphine at mu opioid receptors has been

viewed positively because of the associated ceiling on certainrespiratory depressant measures in animals32 and humans.33 Itis well known that agonists at mu opioid receptors depressrespiration, which is reflected in an increased arterial pressureof carbon dioxide (PaCO2), reduced PaO2 and hypoxia.Studies with rats have demonstrated a ceiling effect forbuprenorphine but not for morphine or fentanyl, the fullagonists.3436 In 1994, Walsh and colleagues10 published akey article on the clinical pharmacology of buprenorphine inwhich nondependent volunteers received sublingual bu-prenorphine or oral methadone. The much quoted conclusionfocused on the plateau effect of buprenorphine, even afterdoses as large as 16 and 32 mg, with respect to respiratory

depression (and subjective measures). This result has defi-nitely helped to reinforce the belief that buprenorphinesceiling effect is not just a laboratory curiosity of heuristicvalue but will be of real, practical significance in limiting

abuse potential and providing a wider safety margin inclinical use.

One consequence of buprenorphines high affinity formu opioid receptors, and slow dissociation kinetics, is theresultant resistance to reversal by naloxone, in both animalsand humans. In cases where buprenorphine has provoked

respiratory depression (perhaps in elderly patients or individ-uals coadministering benzodiazepines) an enduring questionhas been what to do? Injecting relatively large bolus dosesof naloxone often has been ineffective.

Recent work conducted by investigators at LeidenUniversity has afforded the answer: continuous infusion ofnaloxone, rather than bolus administration, is necessary toovercome established, buprenorphine-induced respiratorydepression.37

The Leiden group also has investigated the extent towhich norbuprenorphine contributes to the respiratory de-pressant action of buprenorphine in rats by performingelegant pharmacokinetic-pharmacodynamic modeling.38

Norbuprenorphine is the N-dealkylated metabolite of bu-prenorphine, which, being more polar than buprenorphine,penetrates the blood brain barrier less readily. Ohtani andcolleagues35 were first to study norbuprenorphine in thiscontext and reported that it was approximately 10 timesmore potent than the parent drug as a respiratory depres-sant, probably acting via the mu opioid receptor. A decadelater, in 2006, Megarbane et al39 described how norbu-prenorphine, given at 3 mg/kg i.v. to rats, elicited a rapidincrease in PaCO2, decrease in arterial pH, hypoxia, andovert sedation/muscle rigidity/seizures. Finally, Yassen etal38 concluded that because only 10% of i.v. buprenorphinewas probably transformed to norbuprenorphine in rats in

their study, this small amount of metabolite is unlikely tocontribute to buprenorphine-induced respiratory depres-sion to any great extent.

It should be emphasized at this point that norbuprenor-phine is surprisingly active after s.c. administration to ro-dents. Experiments conducted in the authors laboratory40

have shown that norbuprenorphine is equi-efficacious withbuprenorphine: 1) as an antinociceptive agent in the mouse(acetic acid) abdominal constriction test; and 2) as an anti-pruritic in the mouse (compound 48/80) scratch test. Norbu-prenorphine was only 3 times and 9 times, respectively, lesspotent than buprenorphine in these assays.

Additionally, in the rat charcoal meal test,41 norbu-

prenorphine and buprenorphine were equipotent (at 0.3mg/kg s.c.) and equi-efficacious in essentially arresting gas-trointestinal transit. The beginning of a bell-shaped dose-response curve was associated with buprenorphine (as ex-pected) but not with norbuprenorphine. Pretreating rats withnaloxone (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 astart in expanding the in vivo pharmacological profile ofnorbuprenorphine (for so long a neglected metabolite) in itsown right. The conclusion (mentioned earlier) that norbu-prenorphine does not contribute greatly to the overall respi-ratory depressant effect of buprenorphine need not apply to

FIGURE 3. Dose-response lines for morphine, buprenor-phine, and nalbuphine for antagonism of late phase flinch-ing induced by formalin in rats (N 510; unpublished re-sults).

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other buprenorphine actions mediated by mu opioid recep-tors.

Unusual Physical Dependence onBuprenorphine in Rats

It is typically not possible to demonstrate physical

dependence in rats receiving multiple injections of buprenor-phine after naloxone challenge or abrupt withdrawal of bu-prenorphine. Overt behaviors indicative of withdrawal areessentially absent and the overall syndrome is classified asmild, at best. Animals injected daily with 3 mg/kg s.c. ofbuprenorphine for 28 days (and with saline thereafter)showed only 1 sign of withdrawalweight loss, which onlybecame apparent on day 6 of withdrawal.42 Dum and col-leagues43 were able to elicit an enhanced abstinence syn-drome in buprenorphine-injected rats only if the animalsreceived a single dose of morphine 1 hour before naloxonechallenge. This innovative maneuver uncovered an underly-ing neuroadaptation of rats to buprenorphine, with the pre-sumed involvement of mu opioid receptors. The experimentalstrategy has been repeated in the authors laboratory wherethe kappa agonists, U50,488H and tifluadom, were used aspriming agents instead of morphine to reveal possible ago-nism by buprenorphine at kappa opioid receptors.

METHODSGroups of 8 to 11 male, Sprague Dawley albino rats

(225250 g) were injected s.c. with buprenorphine (0.50mg/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), tifluadom (10 mg/kg), morphine (20 mg/kg), orvehicle (s.c.) and placed in individual observation boxes. At1 hour, the rats were weighed, challenged with naloxone

(10 mg/kg) or saline (i.p.), observed for 1 hour, and thenreweighed. Severity of abstinence was assessed as previouslydescribed.44 Mean abstinence scores were examined statisti-cally by analysis of variance and Dunnetts test.

Results and CommentUse of morphine (10 mg/kg) as a priming agent in-

creased naloxone-induced abstinence in rats pretreated withbuprenorphine (Table 1). This finding is in agreement withthe original report by Dum et al.43 Use of U50,488H (20mg/kg) or tifluadom (10 mg/kg) also enhanced abstinence;

however, with these kappa agonists, the following signjumpingwas the main contributor to the scores. This dom-inant (as opposed to recessive) sign45 has been regardedhistorically as a key indicator of physical dependence onopioids. It is important to note that the jumping associatedwith these rats on buprenorphine differed from the familiar

jumping displayed by morphine-dependent rats challengedwith naloxone. First, the latency to first jump was muchlonger in rats primed with U50,488H and tifluadom, andsecond, the behavior took the form of a sudden and unex-pected jumping frenzy, which continued as long as the ratwas removed from the top of the observation box and re-turned to the bottom. Delayed, compulsive jumping mayreflect critical interactions between buprenorphine,U50,488H/tifluadom and naloxone at kappa (rather than mu)receptors. If this is the case, then the study implicates kappareceptors in the neuroadaptation of rats to buprenorphine andadds a component of kappa agonism to the established mureceptor partial agonist-kappa antagonist profile of the oripa-

vine.

Clinical ImplicationsAfter reading this short survey about buprenorphine,

the interested clinician may ask, Is buprenorphines ceilingeffect of real, practical significance? The answer is anunequivocal yesno. Yes, based on reports46 of a loweredplateau for cardiorespiratory effects and the resultant im-proved safety margin. No, in terms of analgesic efficacy.Three prominent and experienced scientists have made thefollowing statement: There are no published data indicatingan analgesic ceiling dose in humans.31 No equivocationthere.

The particular abstinence syndrome displayed by ratsreceiving buprenorphine, primed with a kappa agonist ofdiverse chemical structure, then challenged with naloxoneis yet another behavioral event to be added to buprenor-phines already extensive repertoire. Clinicians have beenpleased to associate buprenorphine with kappa receptorantagonism, rather than kappa agonism (and the possibilityof dysphoric side effects). In this context, buprenorphinesin vitro binding profile may be summarized as follows47:binds at nanomolar concentrations to mu, kappa and deltareceptors, and at micromolar concentration to ORL 1receptors. At a functional level, buprenorphine acts as apartial agonist at mu, kappa and ORL 1 receptors, and asan antagonist at delta receptors.

EpilogueAdd enigmatic to the list of descriptions for bu-

prenorphine. Whereas such analgesics as butorphanol, nalbu-phine, and pentazocine were once competitors for the atten-tion of research scientists, only buprenorphine has stayed thecourse to widespread clinical utility andretained the ability tostill fascinate the academic community.

ACKNOWLEDGMENTThe author thanks Dr. Saadet Inan for constructive

discussions and help with the figures.

TABLE 1. Abstinence Scores Associated with NaloxoneChallenge in Rats Pretreated with Buprenorphine thenPrimed with Test Agent

Drug Treatment

Mean 1-hr

Abstinence Score SEM

Buprenorphine-vehicle-naloxone 15.6 3.3

Buprenorphine-morphine-naloxone 28.4 2.2*

Buprenorphine-U50,488H-naloxone 42 5.4*

Buprenorphine-vehicle-naloxone 11 2.9

Buprenorphine-tifluadom-naloxone 37.5 6.8*

*P 0.05.

SEM, standard error of the mean.

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