Clinical profile of responders to buprenorphine as a substitution treatment in heroin addicts: results of a multicenter study of 73 patients

Abstract

In France, high-dosage buprenorphine (HDB) is the main substitution treatment for narcotic addiction. Few data have been published concerning clinical factors predicting a good response to this treatment in a daily practice. A hospital-based multicenter clinical research program (PHRC) was undertaken in heroin-addicted patients, diagnosed according to DSM-III-R, to detect clinical criteria susceptible of predicting a good response to HDB administered during a 3-month treatment period. At the inclusion time in the study, a diagnostic structured interview (DIGS) was performed, and the Addiction Severity Index (ASI), Zuckerman scale, depression scale from Jouvent, and CGI were scored. MMPI was also administered. Good response was defined as an ongoing participation in the study, with absence of opiate detected in 75% of urine collected during the last month of treatment. Only subjects treated for at least 1 month were eligible for analyses. One hundred fifteen patients were recruited and 73 were analyzed. Patients received 8.5±2.6 mg (m±S.D.) of buprenorphine for 1 to 3 months. A forward stepwise logistic regression showed that six clinical parameters may predict a good response to treatment: probability to respond to buprenorphine was higher in subjects having a high psychopathology (ASI) subscore, low disinhibition and boredom susceptibility factor scores (Zuckerman scale), no alcohol dependence, no family history of addiction or mood disorder, and duration of opiate dependence less than 10 years. Only the MMPI D subscale was a psychological pattern correlated to a good response to substitution treatment. These findings are important to consider when making the decision to prescribe HDB substitution treatment in opiate addiction.

Introduction

Buprenorphine is a partial agonist of μ-opioid receptor that has been intended as an alternative to traditional full agonist maintenance therapy for the treatment of opioid addiction. As a partial agonist, the effects of buprenorphine on nontolerant individuals are dose-dependent within a limited therapeutic interval, above which increasing dosages do not produce dose effect. Therefore, for certain pharmacological consequences (e.g. respiratory depression and sedation), buprenorphine may present an enhanced safety profile compared with full opioid agonists.

The potential utility of buprenorphine for the treatment of opioid addiction was demonstrated in the definitive work of Jasinski et al. (1978): daily sublingually dosages of 8 mg blocked the effects of subsequently administrated morphine and did not appear to induce a physical dependence. Different dose-ranging studies and short-term clinical trials have shown that buprenorphine suppresses heroin use in addict drug-dependent individuals in a research ward. This substitution heroin replacement treatment also blocks the effects of experimentally administrated opiates (Bickel et al. 1988).

The study carried out by Johnson et al. (1992) suggested that 8 mg of buprenorphine showed an efficacy superior to 20 mg of methadone and equivalent to 60 mg of methadone. This suggestion was drawn up according to three criteria: retention in treatment throughout the 17-week study, illicit opioids use as determined by urinalysis and the Addiction Severity Index (ASI) score.

Kosten et al. (1993) compared buprenorphine (2 and 6 mg) versus methadone (35 and 65 mg) based on efficacy criteria: treatment continuation during the 6 months of study, absence of opioids in urinalysis in at least in 70% of urine samples, number of sequences of three consecutive weeks of drug abstinence, substance use reported by patients, signs of withdrawal symptoms, and scores in the ASI. This study seemed to suggest that administering buprenorphine in 2 and 6 mg daily doses was less effective than 35 or 65 mg of methadone given daily.

Ling et al. (1996), in a double-blind control study covering 225 patients with a mean age of 41 years, compared 80 and 30 mg of methadone versus 8 mg of buprenorphine. The mean duration of substance abuse was 18 years. It seemed that 80 mg of methadone was superior to 30 mg of methadone and to 8 mg of buprenorphine after 6 and 12 months, but with marked improvement in all three groups from the first week.

The study by Strain et al. (1996) covered 164 patients, ranging from 18 to 50 years of age, with a history of at least one year of opioid dependence. It was the first substitute treatment trial for these patients in which methadone or buprenorphine were used during 16 weeks in a double-blind and double-placebo trial. The evaluation criteria were identical to those used in previous studies. The average daily dose was 54 mg of methadone and 9 mg of buprenorphine. The rates of treatment maintenance for 16 weeks were equivalent in both groups (50%), urine control analysis showed positive results in 40% of individuals in the buprenorphine group and 44% in the methadone group. Subjects staying in the study were slightly older.

Uelhinger et al. (1998) compared the efficacy of methadone and buprenorphine with adequate doses in a double-blind, double-placebo study during 6 weeks. This study showed superior efficiency of methadone with a treatment continuation rate of 90% versus 55%. Twelve milligrams of buprenorphine and 30–80 mg of methadone were the most common doses for the patients with a mean age of 28 years and 4.7 years history of heroin addiction.

The most recent study on the efficacy of buprenorphine, published in 1998 by Ling et al., aimed to define an effective dose for buprenorphine in a comparative protocol with 1, 4, 8, and 16 mg of buprenorphine (alcoholic solution type) carried out in 736 subjects. The patients, with a mean age of 36 years, were followed-up in 12 centers during 6 months and were treated in the usual clinical context. Results suggested that 1 mg of buprenorphine was significantly less effective than other doses in all efficacy domains, while 16 mg of this treatment was a more effective treatment for one variable, namely, the percentage of negative urinalysis during 13 consecutive weeks.

Furthermore, buprenorphine did not appear to be more effective than methadone on the consumption of cocaine in heroin abusers (Schottenfed et al. 1997), or when associated with desipramine (Olivetto et al. 1999).

The definition of opioid substitution treatment response is unclear. In many studies, no effective criteria have been selected. Recently, Ling et al. (1998) used four outcome measures to evaluate efficacy: retention in treatment, illicit opioid use as determined by urinalysis, opioid craving and global ASI scores rated by patients and staff.

Little is known about whether specific subgroups of opioid-dependent patients might respond differentially to methadone or buprenorphine. Early studies suggested that buprenorphine might be superior to methadone for maintenance treatment of patients with concurrent opioid and cocaine dependence Kosten et al., 1989, Mello et al., 1989, but this hypothesis has not been supported in controlled clinical trials Johnson et al., 1992, Ling et al., 1996, Schottenfed et al., 1997, Strain et al., 1994. Various measures of psychopathology (especially depression and sociopathy) have been evaluated as important predictors of substance abuse treatment outcome in general McLellan et al., 1983, Rounsaville et al., 1986, but their prognostic significance has not been systematically evaluated in studies on buprenorphine maintenance. Depression is also of interest because it is a risk factor for escalating cocaine use and continued illicit opioid use after entry into substitution maintenance treatment (Kosten et al., 1987). Moreover, buprenorphine has been used experimentally to treat depression Bodkin et al., 1995, Nutt et al., 1995, and decreased symptoms of depression have been reported in buprenorphine-maintained patients (Kosten et al. 1990).

In France, high-dosage buprenorphine (HDB) is the main replacement therapy for narcotic addiction. Few data have been published concerning clinical factors predicting a good response to this treatment in a daily practice. Gasquet et al. (1999) have tried to define the response factors to buprenorphine from a retrospective follow-up study of 956 patients done by 200 general practitioners.

Subjects were treated with buprenorphine openly with an adjustable dosage and results were evaluated with quantitative socio-behavioral and medical indicators. Some criteria were found to be correlated with a good response: a fixed address and regular income from work, treatment of any associated psychiatric disorder, previous moderated and nonregular use of heroin, and at least one previous attempt at withdrawal. Nevertheless, this study had some limits from a methodological standpoint: absence of validated definition for response criteria, variable duration of treatment, and no standardized psychiatric evaluation.

The present multicenter open hospital clinical research program (PHRC) was carried out to determine clinical criteria predicting a good response to HDB substitution treatment in a prospective study during a 3-month period.