Richard S. Schottenfeld

Buprenorphine versus methadone maintenance for opioid dependence

Buprenorphine at 2 mg and 6 mg daily was compared with methadone at 35 mg and 65 mg during 24 weeks of maintenance among 125 opioid-dependent patients. As hypothesized, 6 mg of buprenorphine were superior to 2 mg of buprenorphine in reducing illicit opioid use, but higher dosage did not improve treatment retention. Self-reported illicit opioid use declined substantially in all groups, but by the third month, significantly more heroin abuse was reported at 2 mg than at 6 mg of buprenorphine or of methadone. From an initial average of

Three Methods of Opioid Detoxification in a Primary Care Setting: A Randomized Trial

1860/month, month 3 usage dropped to

Regulation of Arousal and Attention in Preschool Children Exposed to Cocaine Prenatally

41 (methadone 65 mg),

Disulfiram versus placebo for cocaine dependence in buprenorphine-maintained subjects: a preliminary trial

73 (methadone 35 mg),

Buprenorphine: dose-related effects on cocaine and opioid use in cocaine-abusing opioid-dependent humans

118 (buprenorphine 6 mg), and

Long-Term Treatment with Buprenorphine/Naloxone in Primary Care: Results at 2-5 Years

35I/month (buprenorphine 2 mg). Days of use also dropped from 29 days to 1.7 (methadone 65 mg), 2.8 (methadone 35 mg), 4.0 (buprenorphine 6 mg), and 6.6 days/month (buprenorphine 2 mg). This relatively low efficacy for 2 mg of buprenorphine persisted through month 6 of the trial, with 7.2 days/month and

TREATMENT OF HEROIN DEPENDENCE WITH BUPRENORPHINE IN PRIMARY CARE

235/month of use for buprenorphine at 2 mg versus 1.9 days/month and

Human immunodeficiency virus infection in intravenous drug users: A model for primary care

65/month for the other three groups. Increased opioid abuse also was associated with significantly greater and persistent opioid withdrawal symptoms. Our secondary hypothesis, that buprenorphine would be equivalent to methadone in efficacy, was not supported. Treatment retention was significantly better on methadone (20 us. 16 weeks), and methadone patients had significantly more opioid-free urines (51% vs. 26%). Abstinence for at least 3 weeks was also more common on methadone than buprenorphine (65% vs. 27%). Thus, methadone was clearly superior to these two buprenorphine doses, but illicit opioid use was reduced more by higher than lower buprenorphine dosage. Future studies need to examine higher sublingual buprenorphine doses of 12 mg to 20 mg daily for potential efficacy.

Primary care-based ambulatory opioid detoxification: the results of a clinical trial.

Opioid-dependent persons (for example, those who take heroin) may seek treatment for substance abuse from their primary care physicians [1]. Treatment options include counseling and such pharmacologic therapies as 1) maintenance with opioid agonists [for example, methadone or LAAM] or 2) detoxification followed by maintenance with an opioid antagonist (naltrexone) or by psycho-therapy alone [2]. Opioid maintenance has been demonstrated to effectively decrease drug use [3]. However, maintenance with opioids is highly restricted by federal regulations and may be difficult to access for many patients [4, 5]. Although approaches other than opioid maintenance may be less effective, detoxification followed by ongoing treatment may be a reasonable alternative for patients ineligible for or unable to access maintenance treatment. The extent to which primary care physicians can initiate treatment may improve access to treatment for opioid dependence [5, 6]. 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 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 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). Table 1. Baseline Characteristics of Study Participants 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). Figure 1. Mean scores for withdrawal symptoms by detoxification day. asterisk Discussion 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 s

Prognostic Factors in Buprenorphine- versus Methadone-Maintained Patients

ABSTRACT: Four lines of evidence suggest a plausible link between prenatal cocaine exposure (CE) and specific effects on the mechanisms subserving arousal and attention regulation in infants and preschool‐aged children. These are (1) the association of prenatal CE with alterations in monoaminergic system ontogeny; (2) neurobehavioral effects of prenatal CE in animals consistent with an enduring increased level of activity in response to novelty and inhibited exploration and altered responses to stress, suggesting overarousal in the face of novel/stressful situations and disrupted attention and exploration; (3) altered norepinephrine system function in cocaine‐exposed human infants; and (4) neurobehavioral findings in infants and preschool‐aged children suggestive of disrupted arousal regulation in the face of novelty, increased distractibility, and consequent impaired attention to novel, structured tasks. This paper summarizes findings on response to novel challenges from a cohort of prenatally cocaine‐exposed infants and preschool‐aged children followed longitudinally since birth. Arousal regulation in the face of novel challenges is operationalized behaviorally as state and emotional reactivity and neurophysiologically as the startle response and heart rate variability. Across different ages and tasks, behavioral and neurophysiological findings suggest that prenatally cocaine‐exposed children are more likely to exhibit disrupted arousal regulation. Because the regulation of arousal serves as a gating mechanism to optimize orientation and attention, arousal regulation has important implications for ongoing information processing, learning, and memory. Furthermore, impaired arousal regulation predisposes children to a lower threshold for activation of “stress circuits” and may increase their vulnerability to the developmentally detrimental effects of stressful conditions particularly when such children are also exposed to the chaotic environmental conditions often characterizing substance‐abusing families.