Predictors of outcome for short-term medically supervised opioid withdrawal during a randomized, multicenter trial of buprenorphine–naloxone and clonidine in the NIDA clinical trials network drug and alcohol dependence

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Abstract

Few studies in community settings have evaluated predictors, mediators, and moderators of treatment success for medically supervised opioid withdrawal treatment. This report presents new findings about these factors from a study of 344 opioid-dependent men and women prospectively randomized to either buprenorphine–naloxone or clonidine in an open-label 13-day medically supervised withdrawal study. Subjects were either inpatient or outpatient in community treatment settings; however not randomized by treatment setting. Medication type (buprenorphine–naloxone versus clonidine) was the single best predictor of treatment retention and treatment success, regardless of treatment setting. Compared to the outpatient setting, the inpatient setting was associated with higher abstinence rates but similar retention rates when adjusting for medication type. Early opioid withdrawal severity mediated the relationship between medication type and treatment outcome with buprenorphine–naloxone being superior to clonidine at relieving early withdrawal symptoms. Inpatient subjects on clonidine with lower withdrawal scores at baseline did better than those with higher withdrawal scores; inpatient subjects receiving buprenorphine–naloxone did better with higher withdrawal scores at baseline than those with lower withdrawal scores. No relationship was found between treatment outcome and age, gender, race, education, employment, marital status, legal problems, baseline depression, or length/severity of drug use. Tobacco use was associated with worse opioid treatment outcomes. Severe baseline anxiety symptoms doubled treatment success. Medication type (buprenorphine–naloxone) was the most important predictor of positive outcome; however the paper also considers other clinical and policy implications of other results, including that inpatient setting predicted better outcomes and moderated medication outcomes.

Introduction

Heroin dependence continues to be a serious public health issue throughout many parts of the world, and there is a need for better access to effective treatments (SAMHSA NSDUH, 2004; SAMHSA, TEDS, 2004). Buprenorphine–naloxone (Suboxone®) has been found to be effective in many diverse treatment settings (Bickel et al., 1988, Bickel and Amass, 1995, Boatwright, 2002, Johnson et al., 2003, Amass et al., 2004, Ling et al., 2005). However, there have been few studies of predictors, mediators, and moderators of outcome for medication treatment for opioid dependence (Morral et al., 1997), and these studies have focused on the inpatient setting and clonidine medication. In the inpatient setting, factors such as gender, age, duration of drug use, education, psychopathology, and employment did not predict better or worse treatment outcome in some studies (San et al., 1989, Armenian et al., 1999); however other reports have found worse outcomes for younger age (Jeremiah et al., 1995, Armenian et al., 1999, Gossling et al., 2001, Backmund et al., 2001, Ghodse et al., 2002) being single (Armenian et al., 1999; Perez de los Cobos et al., 1997) and having more severe drug and medical problems (Franken and Hendriks, 1999). One study found worse outcomes amongst those with less education, less regular contact with a counselor, no aftercare plans, history of imprisonment, and not being on probation (Backmund et al., 2001). Another inpatient study found that the intensity of withdrawal symptoms and craving was not related to premature termination from treatment (Scherbaum et al., 2004). In the outpatient setting, worse clonidine treatment outcomes have been found for heroin addicts versus other opioids (Strobbe et al., 2003, McCann et al., 1997), higher levels of subjective withdrawal symptoms (Strobbe et al., 2003, Rounsaville et al., 1985), intravenous users (McCann et al., 1997), benzodiazepine use pre-detoxification (McCann et al., 1997), and depression (Ziedonis and Kosten, 1991).

This report focuses on predictors, moderators, and mediators for buprenorphine–naloxone and clonidine medication treatment and expands on an earlier report of the primary finding that buprenorphine–naloxone had better clinical outcomes compared to clonidine (Ling et al., 2005). This report presents new findings about how predictors, mediators, and moderators are the same (or different) for the two medications. Two prior reports provide more detail about the field experience of using these medications in community-based addiction treatment settings and more details regarding the study design, procedures, medications and settings (Amass et al., 2004, Ling et al., 2005). This study evaluates new variables and the nature of these variables (predictors, moderators, and mediators).

Section snippets

Overview

Study subjects were treatment seeking opioid-dependent men and women who were at least 15 years of age and in general good health. They were randomly assigned in a 2:1 ratio to either buprenorphine–naloxone or clonidine for 13 days. Ancillary medications were available as needed. Doses of study medication were lowered gradually over 13 days. The treatment setting was self-selected or clinically selected, and not randomized (six inpatient; six outpatient sites). “Setting” was categorized at the

Primary hypotheses

Three primary hypotheses were tested: (1) subjects receiving buprenorphine–naloxone will have better outcomes than those receiving clonidine; (2) subjects treated in the inpatient setting would have better outcomes than in the outpatient; and (3) subjects with more severe withdrawal symptoms, regardless of which medication they received, would drop out of treatment earlier and have worse outcomes than subjects with lower levels of withdrawal. Hypothesis 1 was also a primary hypothesis of the

Sample

Of the 344 opioid-dependent men and women, 234 (68%) were randomized to buprenorphine–naloxone and 110 (32%) were randomized to clonidine. The median age was 39.5 years (range 19–65), and subjects were mostly male (68%), white (48.5%) or African-American (31.4%) and unemployed (50.8%). On the average, patients attended two prior drug treatments with 19.3% having no prior treatment and 36.8% having three or more. Patients used heroin a mean of 25.2 (9.7) of 30 days prior to enrollment and 66.5%

Socio-demographic predictors

Logistic regression adjusting for medication type suggested that none of the socio-demographic factors predicted better treatment success: age, gender, race, years of education, employment status (employed versus not employed), and legal status (being on probation or having a history of imprisonment).

Heroin use, severity, and route of administration

As compared to daily heroin users, non-daily heroin users were three times more likely to have treatment success (OR = 3.091, 95% CI: 1.709–5.590, p < .001) after adjusting for medication type,

Discussion

This paper reports predictors, mediators and moderators of treatment success for buprenorphine–naloxone versus clonidine for medically supervised opioid withdrawal in either the inpatient or outpatient setting. Identification of factors that predict relapse and treatment success during acute withdrawal illuminates the early recovery process and may help inform clinical recommendations for a difficult to treat population.

As expected, medication type (buprenorphine–naloxone versus clonidine) was

Conflict of interest

The following is a list of potential conflicts of interest within three years of beginning the work submitted.

D.M.Z. has consulted for Pfizer, Bristol-Myers Squibb, Janssen, Eli Lilly, and Alkermes/Cephalon. D.M.Z. has received grant support from Bristol-Myers Squibb, Janssen, and Eli Lilly. L.A. is currently employed by Schering-Plough, a distributor of buprenorphine. G.W. has consulted for Denver Health. S.M.S. has received grant support from Purdue Pharma, US WorldMeds LLC, and Titan

Acknowledgements

The contents of the manuscript are solely the responsibility of the authors and do not necessarily represent the official views of NIDA.

Role of funding source: This publication was supported by a series of grants from NIDA as part of the Cooperative Agreement on CTN: University of California, Los Angeles: U10 DA13045; Oregon Health & Science University: U10 DA13036; New York University School of Medicine: U10 DA13046; University of Pennsylvania: U10 DA13043, K05-DA17009 and the Department of

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    Present address: University of Alaska Anchorage, Anchorage, AK 99508-4614, USA.

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