Rolley E. Johnson

A clinical trial of buprenorphine: Comparison with methadone in the detoxification of heroin addicts

The efficacy of buprenorphine and methadone was compared in the outpatient detoxification of heroin addicts. Forty‐five patients were randomized to receive either sublingual buprenorphine or oral methadone under double‐dummy and double‐blind conditions to study the pharmacology of buprenorphine in a 90‐day detoxification protocol. The patients were administered either 2 mg buprenorphine or 30 mg methadone for 3 weeks followed by 4 weeks of dose reductions and 6 weeks of placebo medication. No significant between‐group differences were seen on measures of treatment retention, drug use, or symptom report. During the hydromorphone challenge, methadone attenuated opioid effects to a greater extent than did buprenorphine on both physiologic (pupil constriction) and self‐report measures. However, this did not result in greater abuse of illicit opioid drugs by subjects taking buprenorphine. The results of this clinical trial indicated that buprenorphine was acceptable to patients and as effective as methadone in the detoxification treatment of heroin addicts.

Buprenorphine: how to use it right

The unique pharmacology of buprenorphine at the mu-opioid receptor (i.e. high affinity, low intrinsic activity and slow dissociation) results in buprenorphine having: (1) a good safety profile, (2) low physical dependence, and (3) flexibility in dose scheduling. Early studies assessed the effectiveness of buprenorphine for the treatment of opioid dependence using a sublingual solution formulation. More recently, a combination tablet (buprenorphine/naloxone in a 4:1 ratio) has been assessed with the goal of decreasing diversion and abuse. Controlled studies with buprenorphine solution, buprenorphine mono-tablet, and buprenorphine/naloxone combination tablet have uniformly demonstrated the effectiveness of buprenorphine for opioid dependence treatment and the combination tablet appears to decrease (but not eliminate) abuse potential. There is general agreement across studies regarding buprenorphine induction and maintenance dose schedules. The clinical effects of buprenorphine and buprenorphine/naloxone are similar and most patients can be treated initially with and maintained on a daily buprenorphine/naloxone dose of 4:1-24:6 mg. Dosing is possible on a less-than-daily schedule; however, multiples of the daily-dose should be administered to cover the increased interval between doses. If buprenorphine withdrawal is indicated, gradual dose reduction is recommended over a rapid dose reduction or abrupt cessation. Both tablet formulations are approved by the US FDA for opioid dependence treatment as Schedule III narcotics and are, therefore, available for use in office-based practice. The buprenorphine plus naloxone combination product should provide additional safeguards for use in office-based practice by decreasing risk of diversion, and office-based treatment should expand the availability of services to opioid dependent patients.

A placebo controlled clinical trial of buprenorphine as a treatment for opioid dependence

Large-scale placebo controlled clinical trials assessing the efficacy of medications for the treatment of drug dependence have generally been limited to alcohol, cocaine and nicotine dependent populations. The purpose of the present study was to assess the early (1-2 week) clinical effectiveness of buprenorphine versus placebo in an opioid dependent population. The study used a parallel-group design with a behavioral choice component to compare buprenorphine (a mu-opioid partial agonist) to placebo for the treatment of opioid dependence. Opioid dependent volunteer patients participated in a 14-day study to assess the effectiveness and patient acceptance of this new pharmacotherapy for the treatment of opioid dependence. Patients were randomly assigned to placebo (n = 60) or 2 mg (n = 60) or 8 mg (n = 30) daily sublingual buprenorphine. All doses were administered double-blind. On days 6-13 all patients could request a dose change, knowing that their new dose would be randomly chosen from the remaining 2 alternatives. Compared to placebo, patients given buprenorphine (independent of dose) showed greater time on initial dose, requested fewer dose changes, used less illicit opioids (assessed by urinalysis), and rated dose adequacy higher. These results demonstrate that a placebo controlled study with a behavioral choice component is an effective means of assessing the potential efficacy and acceptability of new pharmacotherapies for opioid dependence.

Use of buprenorphine in pregnancy: patient management and effects on the neonate

It is estimated that 55-94% of infants born to opioid-dependent mothers in US will show signs of opioid withdrawal. Buprenorphine has been reported to produce little or no autonomic signs or symptoms of opioid withdrawal following abrupt termination in adults. To date, there have been 21 published reports representing approximately 15 evaluable cohorts of infants exposed to buprenorphine in utero. Of approximately 309 infants exposed, a neonatal abstinence syndrome (NAS) has been reported in 62% infants with 48% requiring treatment; apparently greater than 40% of these cases are confounded by illicit drug use. The NAS associated with buprenorphine generally appears within 12-48 h, peaks at approximately 72-96 h, and lasts for 120-168 h. These results appear similar to or less than that observed following in utero exposure to methadone. From a review of the literature, buprenorphine appears to be safe and effective in both mother and infant with an NAS that may differ from methadone both qualitatively and quantitatively.

A controlled comparison of buprenorphine and clonidine for acute detoxification from opioids

We compared the short-term efficacy of a high-dose, 3 day regimen of buprenorphine to a standard 5-day course of clonidine in attenuating the signs and symptoms of the acute opioid abstinence syndrome during rapid detoxification from heroin in 25 men and women admitted to a closed inpatient research ward for this randomized, double-blind, parallel-group trial. Among the 18 completers, there were no significant differences between the buprenorphine and clonidine groups on five subjective and six physiological measures. However, clonidine lowered blood pressure and buprenorphine provided more effective early relief of withdrawal symptoms.

Buprenorphine treatment of opioid dependence: clinical trial of daily versus alternate-day dosing

Buprenorphine, a mu-opioid partial agonist, has demonstrated efficacy for the treatment of opioid dependence comparable to that of methadone. The clinical utility of buprenorphine would be enhanced if it could be dosed on a less than daily basis. The current study is a parallel-group outpatient clinical trial of daily versus alternate-day dosing with 8 mg sublingual (s.l.) buprenorphine. Participants were randomly assigned to daily (n = 51) or alternate-day (n = 48) schedules of active medication administration for an 11-week double-blind trial. Patients assigned to alternate-day buprenorphine received placebo every other day. Primary outcome measures were retention in treatment and urine specimens positive for opiates. Clinic attendance, dose adequacy ratings, withdrawal symptomatology, and urine specimens positive for cocaine were secondary outcome measures. Neither endpoint analysis with the intent-to-treat sample nor time course analysis with treatment completers revealed any statistically significant differences between the dosing schedules on any outcome measure. Examination of 95% confidence intervals suggested a non-significant trend for the daily dosing schedule to have superior clinical efficacy at the dose tested. Nevertheless, these results are generally consistent with previous studies of less than daily dosing with buprenorphine and support the conclusion that an alternate-day dosing schedule can be effective in and acceptable to a substantial portion of patients.

Concurrent Validation of the Clinical Opiate Withdrawal Scale (COWS) and Single-Item Indices against the Clinical Institute Narcotic Assessment (CINA) Opioid Withdrawal Instrument

INTRODUCTION The Clinical Opiate Withdrawal Scale (COWS) is an 11-item clinician-administered scale assessing opioid withdrawal. Though commonly used in clinical practice, it has not been systematically validated. The present study validated the COWS in comparison to the validated Clinical Institute Narcotic Assessment (CINA) scale. METHOD Opioid-dependent volunteers were enrolled in a residential trial and stabilized on morphine 30 mg given subcutaneously four times daily. Subjects then underwent double-blind, randomized challenges of intramuscularly administered placebo and naloxone (0.4 mg) on separate days, during which the COWS, CINA, and visual analog scale (VAS) assessments were concurrently obtained. Subjects completing both challenges were included (N=46). Correlations between mean peak COWS and CINA scores as well as self-report VAS questions were calculated. RESULTS Mean peak COWS and CINA scores of 7.6 and 24.4, respectively, occurred on average 30 min post-injection of naloxone. Mean COWS and CINA scores 30 min after placebo injection were 1.3 and 18.9, respectively. The Pearsons correlation coefficient for peak COWS and CINA scores during the naloxone challenge session was 0.85 (p<0.001). Peak COWS scores also correlated well with peak VAS self-report scores of bad drug effect (r=0.57, p<0.001) and feeling sick (r=0.57, p<0.001), providing additional evidence of concurrent validity. Placebo was not associated with any significant elevation of COWS, CINA, or VAS scores, indicating discriminant validity. Cronbachs alpha for the COWS was 0.78, indicating good internal consistency (reliability). DISCUSSION COWS, CINA, and certain VAS items are all valid measurement tools for acute opiate withdrawal.

Correlations of maternal buprenorphine dose, buprenorphine, and metabolite concentrations in meconium with neonatal outcomes

For the first time, relationships among maternal buprenorphine dose, meconium buprenorphine and metabolite concentrations, and neonatal outcomes are reported. Free and total buprenorphine and norbuprenorphine, nicotine, opiates, cocaine, benzodiazepines, and metabolites were quantified in meconium from 10 infants born to women who had received buprenorphine during pregnancy. Neither cumulative nor total third‐trimester maternal buprenorphine dose predicted meconium concentrations or neonatal outcomes. Total buprenorphine meconium concentrations and buprenorphine/norbuprenorphine ratios were significantly related to neonatal abstinence syndrome (NAS) scores >4. As free buprenorphine concentration and percentage free buprenorphine increased, head circumference decreased. Thrice‐weekly urine tests for opiates, cocaine, and benzodiazepines and self‐reported smoking data from the mother were compared with data from analysis of the meconium to estimate in utero exposure. Time of last drug use and frequency of use during the third trimester were important factors associated with drug‐positive meconium specimens. The results suggest that buprenorphine and metabolite concentrations in the meconium may predict the onset and frequency of NAS.

Predictors of Outcome in LAAM, Buprenorphine, and Methadone Treatment for Opioid Dependence

This study examined (1) predictors of treatment outcome for opioid-dependent participants in a single-site controlled trial comparing methadone, buprenorphine, and LAAM treatments and (2) the extent to which various subpopulations of patients may have more successful outcomes with each medication. The relationships between patient demographics, drug use history, and psychological status and outcome measures of treatment retention, opiate use, and cocaine use were assessed. We believe this study to be the first to demonstrate that predictors of treatment success appear to be largely similar in LAAM, buprenorphine, and methadone treatment for opioid dependence. We did not find any factors that would strongly guide selection of one medication over others.

Management of Acute Postpartum Pain in Patients Maintained on Methadone or Buprenorphine During Pregnancy

Background: Empirical evidence is needed to guide adequate postpartum pain relief of methadone and buprenorphine stabilized patients. Objectives: To first determine the adequacy of pain control using non-opioid and opioid medication in participants stabilized on buprenorphine or methadone before a vaginal delivery. Second, to compare the amount of non-opioid and opioid medication needed for adequate pain control for buprenorphine-and methadone-maintained patients during the immediate postpartum period. Methods: Pain control adequacy and amount of non-opioid and opioid medication needed in buprenorphine- (n = 8) and methadone-maintained (n = 10) patients over the first five days postpartum were examined. Results: Pain ratings and number of opioid medication doses decreased over time in both medication groups. While the buprenorphine and methadone groups began with similar mean daily ibuprofen (IB) doses, the buprenorphine group decreased its IB use, while the methadone group increased its IB use. Conclusions and Scientific Significance: Patients treated daily with either buprenorphine or methadone can have adequate pain control postpartum with opioid medication and IB. Pain control is dependent on the opioid-agonist medication in use at delivery, and must be individualized.