Post-marketing surveillance of buprenorphine

pharmacoepidemiology and drug safety 2004; 13: 615–619Published online 14 May 2004 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/pds.975

ORIGINAL REPORT

Post-marketing surveillance of buprenorphine{

Rajat Ray MD*, Hemraj Pal MD, Rajesh Kumar MD, Pallab Maulick MD and R. Mangla DPM

National Drug Dependence Treatment Centre, All India Institute Of Medical Sciences, New Delhi, India

SUMMARY

Purpose This study was undertaken to evaluate the adverse consequences of recently introduced higher strength (0.4 and2.0 mg per tablet) buprenorphine in Indian market. Buprenorphine, a partial opiate agonist and antagonist, is an emergingalternative to methadone as an agent for long-term treatment of opiate dependence.Methods The current investigation was conducted through a multi-centric post-marketing surveillance (PMS)study usinga structured performa from patients receiving buprenorphine as routine therapy from de-addiction centres. Evaluationincluded subjective and objective assessments and recording of adverse events.Results Of the 5551 observations from ten centres, common subjective symptoms were generalised weakness (48.9%),sense of high (euphoria) (44.5%), muscle aches (39.5%) and relief from pain (37.2%). About 5% observations recordedsystolic hypertension. Among 55 subjects where laboratory tests were conducted, 12 showed raised levels of AST ad9 had elevated ALT. Twelve adverse events reported included seizure, epistaxis, panic attacks, constipation and dyspnoea.Significant relation was seen between duration of use and time since last dose, and total number of subjective symptomsreported.Conclusions Majority of the adverse effects could be understood as either effects related to intoxication or withdrawalfrom agonists. Copyright # 2004 John Wiley & Sons, Ltd.

key words— buprenorphine; post-marketing surveillance; adverse effects

INTRODUCTION

Among various agents available to treat opiate depen-dence, buprenorphine has been found to be efficaciousfor both short-term (detoxification) and long-term(maintenance) therapy. In India, till recently, bupre-norphine was available only as 0.2 mg sublingual tab-lets and generally was prescribed in low doses andmostly for detoxification. In April 1999, the DrugsController of India (DCI) permitted introduction of0.4 and 2 mg sublingual tablets and this in turnenabled the clinicians to prescribe in higher doses. It

was perceived that increasing use of enhanced dosemight raise the risk of occurrence of adverse effectsand the DCI, thus requested to record these sideeffects if any, through a post-marketing surveillance(PMS) study of higher strength of tablet buprenor-phine (0.4 and 2 mg).

The objectives of PMS are to study a drug’s efficacyand toxicity under conditions approaching its actualclinical use in order to identify particular conditions ofbenefits or hazards as well as to evaluate the drug’spotential and overall impact on the conditions forwhich it is prescribed. Ideally, both short- and long-term impact should be measured and both beneficialand adverse impact should be identified. The Food andDrug Administration (FDA, U.S.A.) envisages them asthe discovery of unknown risks and benefits as well asmeasurement of known risks and benefits of treatment.Between 1977 and 1982, series of formal studies werecarried out to investigate drug toxicity. These studies

Received 8 April 2003Revised 16 February 2004

Copyright # 2004 John Wiley & Sons, Ltd. Accepted 25 March 2004

* Correspondence to: Dr Rajat Ray, MD, Professor and Chief, Centrefor Behavioural Sciences, All India Institute of Medical Sciences,New Delhi-110029, India. E-mail: [email protected]{No conflict of interest was declared.

Contract Grant Sponsor: RUSAN PHARMA Limited, India.

have tended to be referred to by the collective termPMS studies.1

In general, the term PMS connotes observationalstudies undertaken on a drug following its marketingand lie somewhere between adverse reaction registriesand randomised controlled trials. They are mostlyuncontrolled cohort studies designed without a specifichypothesis and without predetermined statisticalpower. Common to all these studies is the idea of iden-tifying a cohort of recipients of a drug, and followingup these individuals for various lengths of time, whilerecording any new diagnosis (events) that occurs forthe first time after use of the (new) drug.

PMS STUDIES INVOLVING BUPRENORPHINE

The first and the only PMS study was reported byHarcus et al.2 on 17 120 administrations of injectionbuprenorphine as an analgesic, to 9123 patients.Adverse drug reactions (ADRs)were reported on8187 patients. Nausea (8.8%), vomiting (7.4%), drow-siness (4.3%) were the common symptoms. Someother symptoms like sweating, headache, confusion,dry mouth and depression were infrequently reported(below 1%). Although the study confirmed the effi-cacy of the analgesic, it added little to the knowledgeobtained about the drug before marketing, at substan-tial cost, in time and money. However, it demonstratedthe feasibility of such studies to assess drug effects inclinical practice. The current study collected informa-tion on ADRs associated with sublingual administra-tion of higher strength (0.4 and 2 mg) tablets ofbuprenorphine in opiate dependent patients.

MATERIALS AND METHODS

It was a multi-centred study with the National DrugDependence Treatment Centre, (NDDTC), All IndiaInstitute of Medical Sciences (AIIMS) being the co-ordinating centre. The participating centres (govern-ment and non-government centres) were those whoprescribed higher strength buprenorphine (Addnok,0.4 or 2 mg) to their patients for treatment of opiatedependence syndrome.3 Fifteen drug dependencetreatment centres were contacted through post/e-mailand requested to participate in the study and ten cen-tres contributed the data between July 2000 and 2001.The information was collected from the subjectsduring face-to-face interviews through a structuredperforma. The data items, both subjective and objec-tive items were derived from the list as suggestedby Harcus et al.2 and those available in a standardtext book of pharmacology.4 Interviews and physical

examinations were carried out on these patients foradverse effects. Additionally haemoglobin (Hb), totalleucocytes count (TLC), differential count (DLC),erythrocyte sedimentation rate (ESR) and biochemicaltests (serum bilirubin, alkaline phosphatase (ALP),aspartate aminotransferase (AST), alanine aminotrans-ferase (ALT), urea and creatinine) were done at theco-ordinating centre.

DATA ANALYSIS

The data were expressed as descriptive statistics usingmeasures of central tendency for demographic, druguse (prescription and non-prescription), adverse reac-tions (subjective and objective), laboratory para-meters, and dose and duration of buprenorphine.Significant adverse events occurring during the ther-apy were recorded. The relationship between dose,duration, time since last administration and adversereactions was assessed using Pearson’s ‘rho’.

RESULTS

Background information

The mean age of these patients was 35.6 years (SD7.6) and was similar across the centres except in onecentre where the subjects were younger (mean29.4 years). The dose administered in different centresvaried ( p< 0.000) and the mean dose was 2.9 mg (SD3.5) (range 0.4–36 mg) per day and the median dosebeing 2.8 mg. The duration of treatment with buper-norphine was also variable, the mean being 177.5 days(SD 167.7) (range 1–1080 days) and the median being138 days.

Adverse effects

Table 1 shows the common subjective symptomsreported from all the centres. Subjective symptomsmost often reported by the subjects, in order ofdecreasing frequency were: generalised weakness(48.9%), sense of high (44.5%), muscle aches(39.5%), yawning (38.5%), relief from pain (37.2%)and constipation (33.1%). Symptoms like flatulence,cramps, headache, pain abdomen, giddiness, light-headedness, drowsiness, blurred vision, vomiting,pre-mature ejaculation, low libido and poor appetitewere reported less frequently and was less than10%. Some had however, reported better sexual per-formance and increased appetite. Patients from threeagencies namely, Calcutta Samaritans (n¼ 2543),NDDTC, AIIMS (n¼ 1267)) and SHARAN(n¼ 879) reported most of these symptoms.

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Copyright # 2004 John Wiley & Sons, Ltd. Pharmacoepidemiology and Drug Safety, 2004; 13: 615–619

Among the objective signs recorded it was seen thatpupil size was normal in 61.9% of occasions, howeveramong 24.5% it was dilated. The mean systolic bloodpressure was 114.4 and diastolic blood pressure was74 mm Hg, respiratory rate was 18.8/minute andpulse rate was 75.8/minute. Systolic hypertension(BP> 140 mm Hg), diastolic hypertension (BP>95 mm Hg) and tachypnoea (respiratory rate> 30/minute) were seen among 5.2, 0.8 and 2.2% of theobservations respectively.

Some (22%) had received additional prescriptionmedication and about 36% were using illicit drugsalong with the prescribed buprenorphine. The subjectsin both these groups reported higher subjectivesymptoms, and the subjects using non-prescription(illicit drugs) many more symptoms.

Significant adverse events

Significant adverse event was defined as any effectthat was not in keeping with available literature onpharmacological effects of buprenorphine (Type BADR). Altogether, 12 such events were reported.

These include seizure, epistaxis, dyspnoea, fever withchills, constipation, premature ejaculation and angeroutbursts. One patient had panic attacks after initia-tion of the drug and finally, one patient reportedimprovement in pre-mature ejaculation after startingof bupernorphine. No major events like cardio-vascular ailments, jaundice or death were reported.

Correlation analysis revealed significant correla-tions between duration, time since administration andthe total subjective symptoms reported. There washowever, no relationship between dose and subjectivesymptoms (Table 2).

Laboratory parameters available among 55 subjectsfollowing 1–12 months of consumption of buprenor-phine revealed that the mean values of haemoglobin,TLC, DLC, ESR and bilirubin were within normalrange. In total, 12 and 9 subjects had elevated AST andALT values respectively. Creatinine was elevated in sixpatients and urea in one.

DISCUSSION

Buprenorphine, a partial �-agonist, is a semi-synthetichighly lipophilic opiate derived from thebaine is25–50 times more potent than morphine as an analge-sic. The dose recommended for maintenance usingbuprenorphine is between 4 and 8 mg a day.5 In India,till recently only 0.2 mg tablet was available. Higherstrength of buprenorphine has now been introduced inIndia in two preparations namely 0.4 and 2.0 mg pertablet. This study looked into the adverse effects onpatients receiving these higher strengths of buprenor-phine (Addnok).

The data consisted of 5551 observations from ten de-addiction centres across the country. The subjects inthis study were mostly young adults. The prescribeddose of bupernorphine was variable and the medianwas about 3 mg. The median dose prescribed amongthese subjects was less than those reported in the worldliterature, i.e. around 4–8 mg a day for maintenance.5

Table 1. Common subjective symptoms reported

Symptom n (5551) %

Generalised weakness 2711 48.9Sense of high 2469 44.5Muscle ache 2192 39.5Yawning 2137 38.5Relief from pain 2063 37.2Constipation 1833 33.1Lacrimation 1476 26.6Craving 1442 26.1Anxiety 1053 18.9Sleeplessness 1052 18.9Sadness 1039 18.7Dry Mouth 1010 18.2

Table 2. Relationship of dose of buprenorphine, duration of treatment, time since last dose of buprenorphine and adverse effects(subjective symptoms)

Duration Dose Time since last administration Subjective symptoms

Duration 1.000Dose �0.04{ (0.008)* 1.000Time �0.17{ (0.000)* �0.019{ (0.168)* 1.000Subjective symptoms 0.29{ (0.000)* �0.007{ (0.589)* �0.13{ (0.000)* 1.000

Time: Time since last administration.{Correlation coefficient.*Significant at p< 0.05.

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Concurrent use of additional prescribed medicationand illicit drugs used influenced the subjectivesymptoms reported.

Generalised weakness, reported by about half ofthe sample is non-specific and can be related to druguse, recovery or the medication consumed. Some ofthe symptoms like muscle ache and yawning (around40%) and lacrimation (26%) could be interpreted asopiate (buprenorphine as well) withdrawal symp-toms. The others like sense of high and relief frompain are akin to those resembling agonist actions ofopiates (bupernorphine) along with use of benzodia-zepines and heroin. It would be very difficult toattribute these effects solely to the administration ofbupernorphine.

Among the objectiveparameters, majority of the sub-jects showed normal pupils (61.9%) and some (24.5%)showed dilated pupils. This could be due to the fact thatthe observations were recorded after a long timeinterval (mean, 6 hours) since last dose of bupernor-phine. This was unlike what had been found in otherstudies,6,7 which showed miosis following buprenor-phine administration.

Between 16 and 21% had elevated serum levels oftwo (ASTand ALT) of the parameters of liver functionsfollowing intake of bupernorphine. Ling et al.8 hadreported deranged liver functions in some subjects onhigher doses of buprenorphine in a multi-centredrandomised clinical trial.

The adverse effects noted in the study are wellknown side effects of opiates4 and have beendocumented in other studies as well.3,6,7,9,10 However,the frequency of occurrence of symptoms in one ofthe studies2 was less compared to the present study.Between 1 and 9% of patients reported these symptomsfollowing single administration of injection of 0.3 mgbuprenorphine.2

The occurrence of 12 significant adverse events(Type B events) like seizure, fever, constipation, abdo-minal pain etc. not hitherto associated with buprenor-phine use would cause some concern. It wouldseem that there is a definite increase in such eventsalthough these results are best replicated in case-control studies.

To conclude, administration of higher strengthpreparation of buprenorphine (S/L) is associated withcertain side effects. Most of these effects are mild anddo not necessitate discontinuation of medication. Someof the effects, which are of concern, are liver functionabnormalities, which may need to be monitored in thecourse of therapy. Additionally some of the adverseevents (Type B events) may need to be monitored infuture studies.

REFERENCES

1. Lawson DH. Post marketing surveillance in the UK (1984).Br J Clin Pharmacol 1986; 22: 71S–75S.

2. Harcus AW, Ward AE, Smith DW. Methodology of monitoredrelease of a new preparation: buprenorphine. Br Med J 1979;2: 163–165.

3. World Health Organization. The ICD-10 Classification ofMental and Behavioural Disorders: Clinical Descriptionsand Diagnostic Guidelines. World Health Organization:Geneva, 1992.

4. Reisine T, Pasternak G. Opioid analgesics and antagonists.In Goodman and Gillman’s The Pharmacological Basisof Therapeutics, Goodman LS, Gilman A (eds). Health Profes-sion Division, McGraw Hill: New York, 1996; 521–556.

5. Bickel WK, Stitzer ML, Bigelow GE, Liebson IA, JasinskiDR, Johnson RE. Buprenorphine: dose related blockade ofopioid challenge effects in opioid dependent humans. J Phar-macol Exp Ther 1988; 247: 47–53.

6. Jasinski DR, Fudala PJ, Johnson RE. Sublingual versus subcu-taneous buprenorphine in opiate abusers. Clin Pharmacol Ther1989; 45: 513–519.

KEY POINTS

� Higher strength sub-lingual formulations wererecently introduced in the Indian market and theDrugs Controller of India (DCI) required study onthe post-marketing survey on adverse reactionswith this new preparation.

� The study was conducted through 11 participat-ing centers across the country on 5551 observa-tions using a structured Performa for collectingthe information relating to the overdose effects,withdrawal effects, any other significant effectsand death reported during use of the newpreparation.

� The results indicated subjective symptoms notedwere generalised weakness (48.9%), sense ofhigh (44.5%), muscle aches (39.5%) and relieffrom pain (37.2%). The objective signs noted viz.pupil size, blood pressure, respiratory rate andpulse were mostly normal. Twelve significantadverse events reported included seizure, epis-taxis, panic attacks, constipation and dyspnoea.

� Significant relation was seen between duration ofuse and time since last dose, and total number ofsubjective symptoms reported.

� The adverse reactions seen upon administrationof higher strength buprenorphine were relatedmostly either to the toxic effects or withdrawaleffects and that no mortality was reported in thestudy during the observation period.

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7. Walsh SL, Preston KL, Stitzer ML, Cone EJ, Bigelow GE.Clinical pharmacology of buprenorphine: ceiling effects athigh doses. Clin Pharmacol Ther 1994; 55: 569–580.

8. Ling W, Charuvastra C, Collins JF, et al. Buprenorphinemaintenance treatment of opiate dependence: a multi-centre randomised clinical trial. Addiction 1998; 93: 475–486.

9. Mello NK, Mendelson JH, Kuehnle JC. Buprenorphine effectson human heroin self-administration: an operant analysis.J Pharmacol Exp Ther 1982; 223: 30–39.

10. Eissenberg T, Greenwald MK, Johnson RE, Liebson IA,Bigelow GE, Stitzer ML. Buprenorphine’s physical depen-dence potential: antagonist precipitated withdrawal in humans.J Pharmacol Exp Ther 1996; 276: 449–459.

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Post-marketing surveillance of buprenorphine