Methadone detoxification is safe and efficacious; however, as occurs with methadone maintenance, federal regulations restrict its use to specially licensed programs [4, 7]. Detoxification with clonidine or rapid detoxification with combined clonidine and naltrexone [8-10] may be suitable for primary care settings [6]. In a previous study of detoxification in a primary care setting [6], combined clonidine and naltrexone was more successful than clonidine alone; however, methodologic limitations (nonrandom assignment and nonblinded assessment) make it difficult to draw definitive conclusions about the efficacy of the protocols [6]. Rapid detoxification has the advantage of bringing patients through withdrawal more quickly, although patients require close observation on day 1 because of severe withdrawal symptoms [6, 9]. Buprenorphine (a partial micro-opioid receptor agonist with mixed agonist-antagonist properties) may be more effective in alleviating withdrawal symptoms than is clonidine [11] and, when combined with rapid detoxification [12], may reduce the severity of withdrawal symptoms observed in patients who receive clonidine and naltrexone.

Our objective was to compare three protocols for opioid detoxification in a primary care setting: clonidine, combined clonidine and naltrexone, and buprenorphine. We hypothesized that combined clonidine and naltrexone would result in more successful detoxification than clonidine alone and that buprenorphine would be as effective as and have fewer withdrawal symptoms than the combined agents alone.

Methods

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The site of the study was the Central Medical Unit, a free-standing primary care clinic staffed by internists and nurse practitioners who provide medical care for substance abusers enrolled in programs affiliated with the Yale Substance Abuse Treatment Unit (SATU) [13]. The Central Medical Unit offers a full range of adult primary care services, including preventive care, chronic disease management, and urgent care.

Trial participants were recruited by word of mouth and referral from intake coordinators of SATU-affiliated programs (for example, methadone waiting lists). Participants had to be opioid dependent and 18 to 50 years of age; participants could not be enrolled in a drug treatment program and must have had sufficient social support (such as safe transportation and a residence) for outpatient detoxification. Exclusion criteria were pregnancy, reactions to study medications, medical conditions potentially exacerbated by detoxification (for example, uncontrolled hypertension), contraindications to naltrexone (for example, severe chronic hepatitis or pain that required narcotic treatment), and psychiatric conditions that indicated the need for intensive services (for example, depression with suicidal ideation). All participants had medical and substance use evaluation at baseline, including standardized rating of withdrawal symptoms (24 symptoms were rated on a scale of 0 to 3) [14].

Detoxification started on a Monday (day 1). Participants had daily visits with primary care providers except on the weekend (days 6 and 7), and medications were dispensed at each visit to manage withdrawal symptoms until the next visit [6].

In the clonidine protocol, participants received 0.1 to 0.2 mg of clonidine every 4 hours as needed to control withdrawal symptoms from days 1 through 7 [6]. Detoxified participants were given a full opioid-blocking dose of naltrexone (50 mg) on day 8. In the combined clonidine and naltrexone protocol, participants received clonidine on a similar schedule and 12.5 mg of naltrexone on day 1, 25 mg on day 2, and 50 mg on day 3 [6]. In the buprenorphine protocol, participants received 3 mg of buprenorphine sublingually on days 1 through 3 and then clonidine as described plus 25 mg of naltrexone on day 4 and 50 mg on day 5. The following adjuvant medications were available for participants in all three treatment groups on an as-needed basis: oxazepam for insomnia and cramps, ibuprofen or ketorolac for muscle cramps, and prochlorperazine for nausea [6]. No other drug-treatment services were provided during detoxification.

Participants were randomly assigned to a treatment group, and staff and patients were blinded to the protocols. Study medications were prepared so that participants received either active or placebo preparations of all medications.

The primary outcome of our trial was successful detoxification, which was achieved when a participant received an opioid-blocking dose (50 mg) of naltrexone. Secondary outcomes were treatment retention for 8 days and daily scores of withdrawal symptoms.

All participants who completed detoxification were referred for naltrexone maintenance. Participants who did not complete detoxification and those who had opioid relapse were referred to community treatment programs for opioid dependence (for example, methadone maintenance programs).

Differences in the means of continuous variables were calculated by using the Student t-test. Chi-square statistics were used to evaluate differences in proportions.

Results

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We screened 202 patients, 25 of whom were ineligible because of insufficient social support, comorbid medical or psychiatric conditions, or other reasons. Of the remaining 177 participants, 15 (5 per group) did not show on day 1 (all 15 were lost to follow-up); thus, 162 patients participated in the trial.

Fifty-five patients were randomly assigned to receive clonidine, 54 to receive combined clonidine and naltrexone, and 53 to receive buprenorphine. The groups had no substantial differences in sociodemographic and clinical features (Table 1).

Sixty-five percent of participants in the group receiving clonidine (36 of 55) successfully completed detoxification compared with 81% (44 of 54) in the group receiving clonidine and naltrexone (P = 0.06) and 81% (43 of 53) in the group receiving buprenorphine (P = 0.07). Because the day of protocol completion varied among the groups, we compared retention at day 8, which represented a uniform time point (that is, the first day on which participants in all three protocols had completed detoxification). Retention did not differ significantly among the groups: 65% of participants (36 of 55) who received clonidine, 54% (29 of 54) who received clonidine and naltrexone, and 60% (32 of 53) who received buprenorphine.

The daily mean symptom severity scores for participants in each group are shown in the (Figure 1). Participants assigned to the combined clonidine and naltrexone group had more severe withdrawal symptoms early in detoxification. Participants assigned to the buprenorphine group had a significantly lower mean overall withdrawal symptom score (13.2 ± 8.4) than did those in the clonidine and naltrexone group (17.6 ± 9.3; t = 2.42; P = 0.016) and those in the clonidine group (17.8 ± 10.3; t = 2.56; P = 0.01). The mean peak withdrawal symptom score (the highest score achieved by each patient during detoxification) was also lower for those receiving buprenorphine (22.3 ± 12.3) than for those receiving clonidine and naltrexone (28.0 ± 13.1; t = 2.66; P = 0.03) or clonidine (29.9 ± 14.9; t = 2.96; P = 0.004).

View larger version (16K): [in this window] [in a new window]   Figure 1. Mean scores for withdrawal symptoms by detoxification day. No data were collected on days 6 and 7 (asterisk). Complete data on symptoms are available for 92% of visits (91% in the clonidine group, 90% in the combined clonidine and naltrexone group, and 94% in the buprenorphine group).

Discussion

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Given the high rates of relapse associated with illicit opioid use, new approaches that enhance access to treatment merit investigation. Office-based practices have been advocated as a site for methadone maintenance [5, 15], but methadone is not currently available for use in such settings [4, 5, 7, 16]. Although methadone in tapered doses may be the most effective approach to opioid detoxification, this agent is also unavailable to primary care physicians [7, 16]. Opioid detoxification in a primary carre setting with referral to ongoing drug treatment may be a suitable approach for patients who cannot access, are inappropriate for, or do not want opioid maintenance.

In our study, eligible participants were randomly assigned to treatment groups, with double-blind measures implemented to minimize staff and participant expectations. In a previous study [6], participants were allowed to select their protocol group, thereby raising the possibility of selection bias. In the present study, the differential for success between the group receiving clonidine and the group receiving clonidine and naltrexone (81% compared with 65%) was not as dramatic as previously observed [6]. Although combined clonidine and naltrexone may be modestly superior to clonidine alone for successful detoxification, the effectiveness of the protocols after 8 days of retention was similar. In fact, participants who received clonidine alone were observed to be somewhat more likely than those receiving clonidine and naltrexone to have retention after 8 days. These differences in findings for protocol completion and 8-day retention may be attributable to clinical characteristics of the withdrawal protocols (for example, more severe withdrawal symptoms of participants in the rapid protocol) or other methodologic reasons. This analysis highlights the importance of evaluating both protocol completion and 8-day retention.

This study evaluated buprenorphine as transitional therapy from illicit opioid use to rapid detoxification that is administered to improve patient comfort. In addition to opioid-agonist properties that may lessen withdrawal symptoms, buprenorphine therapy might be particularly appropriate for primary care settings because the partial antagonist properties of buprenorphine make it less toxic, less prone to diversion, and easier to withdraw. This study supported our hypotheses that buprenorphine was as efficacious as combined clonidine and naltrexone for successful completion of detoxification and resulted in fewer withdrawal symptoms than did clonidine and naltrexone.

Study limitations included maintaining the double-blind component, which was not always possible because of the different patterns of symptoms (after patients received naltrexone) associated with each protocol. In addition, buprenorphine is available for detoxification only on an experimental basis in the United States. When the drug is approved, it is likely to be a category II drug because of its potential to be abused [17]. This study also did not provide outcomes on long-term follow-up after detoxification treatment. Such outcomes are needed for drug treatment programs. In our opinion, primary care settings that offer detoxification treatment should be affiliated with drug treatment programs to facilitate follow-up care. Future research should evaluate the long-term outcome of detoxification approaches to more clearly define the optimum approach in the context of other therapies (for example, maintenance therapy) [18].

Because buprenorphine is an experimental drug and the remaining protocols yielded similar rates of retention, clinicians must consider the advantages and disadvantages of all three protocols. Clonidine is initially less labor intensive (especially on day 1) than combined clonidine and naltrexone. The combined drugs may be useful for highly motivated patients who want to complete detoxification rapidly and begin maintenance with naltrexone or return to work quickly; however, patients who receive this therapy require close observation. Until more experience is gained with combined clonidine and naltrexone or with buprenorphine, clonidine therapy may be the protocol of choice for primary care physicians, especially when methadone is unavailable or inappropriate. In addition, although ultrarapid opioid detoxification in which clonidine and naltrexone (or naloxone) are given to patients under general anesthesia has been reported in the literature [19, 20], this approach has not been rigorously evaluated and subjects patients to risk for medical complications associated with general anesthesia [18].

In conclusion, opioid detoxification in a primary care setting with one of the three protocols discussed may be a reasonable approach for some opioid-dependent patients. Although a higher percentage of participants who received combined clonidine and naltrexone or received buprenorphine completed detoxification, this difference did not achieve statistical significance. The statistics for 8-day retention did not differ significantly among the three groups. However, the use of buprenorphine may provide a more comfortable detoxification for patients.

Drs. Carroll, Schottenfeld, and Rounsaville: Connecticut Mental Health Center, Yale University School of Medicine, 34 Park Street, New Haven, CT 06519.

Dr. Shi: Central Medical Unit, 914 1/2 Howard Avenue, New Haven, CT 06519.

Dr. Kosten: Veterans Affairs Connecticut Health Care System, Yale University School of Medicine, Psychiatry 116A, 950 Campbell Avenue, West Haven, CT 06516.