Clonidine and opiate receptor antagonists in the treatment of heroin addiction. The effectiveness of combined naloxone/lofexidine in opiate detoxification: results from a double-blind randomized and placebo-controlled trial. Three methods of opioid detoxification in a primary care setting. A randomized trial. Primary care-based ambulatory opioid detoxification: the results of a clinical trial. A comparison of rapid (opioid) detoxification with clonidine-assisted detoxification for heroin-dependent persons. The impact of naloxone/lofexidine combination treatment on the opiate withdrawal syndrome. Rapid opiate detoxication in outpatient treatment: relationship with naltrexone compliance. Naltrexone and lofexidine combination treatment compared with conventional lofexidine treatment for in-patient opiate detoxification. Naltrexone shortened opioid detoxification with buprenorphine.
Good results in detoxification methods have been reached using both together clonidine and opiate receptors antagonists. One hundred fifty-two heroin-abusing patients were studied evaluating withdrawal symptoms after therapy with (a) clonidine only, (b) clonidine and naltrexone, (c) clonidine and naloxone, and (d) placebos. Treatment results, emotional and behavioral changes, and involvement in psychosocial programs were evaluated after a 6-month follow-up. Although opiate antagonists were able to induce slight and transient withdrawal signs and symptoms, there was, in the group of patients treated with clonidine and naltrexone together, a low percentage of catabolites in urine and an improvement in mood and family relationships. Furthermore, the patients that underwent longer naltrexone treatment showed a stronger involvement in psychosocial programs, and even their relatives demonstrated more interest in the recovery program. A decrease in the difficulties of accepting an opiate antagonists treatment and a different evaluation of withdrawal syndrome were the results of an early use of naltrexone. The efficacy of lofexidine/naloxone was compared with lofexidine/placebo in a double-blind, randomized, placebo-controlled trial in 89 opiate-dependent patients. There were no significant differences between the two groups in the proportion of patients completing detoxification or in the length of stay. Patients in the active naloxone group demonstrated gradual reductions in levels of withdrawal and craving over the detoxification period. At completion of detoxification, patients who received naloxone maintained a level of withdrawal consistently lower than that in the placebo group; however, naloxone did not substantially accelerate the resolution of the withdrawal syndrome. Implications for future research are discussed. Opioid detoxification in a primary care setting followed by ongoing substance abuse treatment may be appropriate for selected opioid-dependent patients.
                To compare three pharmacologic protocols for opioid detoxification in a primary care setting.
                Randomized, double-blind clinical trial with random assignment to treatment protocols.
                A free-standing primary care clinic affiliated with drug treatment programs.
                162 heroin-dependent patients.
                Three detoxification protocols: donidine, combined donidine and naltrexone, and buprenorphine.
                Successful detoxification (that is, when study participants received a full opioid-blocking dose [50 mg] of naltrexone), treatment retention (8 days), and withdrawal symptoms.
                Overall, 65% of participants (36 of 55) who received clonidine, 81% (44 of 54) who received combined clonidine and naltrexone, and 81% (43 of 53) who received buprenorphine were successfully detoxified. Retention did not differ significantly across the groups: 65% of participants (36 of 55) who received clonidine, 54% (29 of 54) who received combined clonidine and naltrexone, and 60% (32 of 53) who received buprenorphine. Participants who received buprenorphine had a significantly lower mean withdrawal symptom score than those who received clonidine or combined clonidine and naltrexone.
                Participants in the combined clonidine and naltrexone group and those in the buprenorphine group were more likely to complete detoxification, although retention at 8 days did not differ among the groups. Participants who were assigned to the buprenorphine group experienced less severe withdrawal symptoms than those assigned to the other two groups. To determine the feasibility of primary care-based ambulatory opioid detoxification (AOD) using two protocols: clonidine and clonidine plus naltrexone.
                The Central Medical Unit (CMU)--a freestanding primary care medical clinic staffed by physicians and nurse practitioners.
                Injection drug users (IDUs) seeking substance abuse treatment between the ages of 18 and 50 years who were addicted to opioids (e.g., heroin) and not currently in drug treatment.
                In the clonidine protocol, clonidine was administered every 4 hours "as needed" for up to 12 days. In the clonidine plus naltrexone protocol, clonidine was administered and naltrexone was administered in increasing doses over five days. Both protocols included "adjuvant" medications for muscle cramps, insomnia, and vomiting. Successfully detoxified patients were referred to ongoing drug treatment.
                A prospective nonrandomized clinical trial.
                One hundred forty opioid-addicted IDUs were referred to the medical clinic for AOD. Among the 125 patients who enrolled in the study, 57 selected clonidine and 68 selected clonidine/naltrexone. The treatment groups (clonidine vs clonidine/naltrexone) were similar at baseline with respect to: age at first heroin use (21 years vs 23 years), mean admission opioid craving score (45/100 vs 49/100), and withdrawal symptom score (19/72 vs 18/72). Overall, 70% (88/125) of the AODs were successful, including 42% (24/57) for clonidine and 94% (64/68) for clonidine/naltrexone (p < 0.001).
                This study suggests that primary care-based AOD can be safely and effectively carried out by primary care providers and that clonidine/naltrexone may be more effective in this setting than is clonidine alone. Ambulatory opioid detoxification can give internists a larger role in initiating drug treatment for IDUs who are addicted to opioids. This study compares two methods of detoxification available to heroin users in Western Australia: clonidine-assisted detoxification (CD) or clonidine-naloxone precipitated withdrawal under sedation (rapid opioid detoxification [ROD]). Oral naltrexone was made available to all participants following detoxification. Eighty heroin-dependent persons were randomly assigned to either ROD or CD. Most undertaking ROD commenced and completed this treatment. Less than one-third undertaking CD completed this treatment. There was no significant difference in those treated by CD or ROD in subjective assessment of degree or duration of pain, severity of withdrawal and craving, nor was there an increase in the withdrawal sequelae after treatment. Induction of oral naltrexone following ROD was greater, but oral naltrexone compliance levels and abstinence from heroin four weeks following detoxification were similar between ROD and CD groups. The level of patient satisfaction between the two treatments was also similar. The authors discuss why ROD is considered more effective than CD. Clinical studies in opiate-dependent patients suggest that detoxification treatment with opiate antagonists may accelerate the resolution of the opiate withdrawal syndrome, permitting early induction onto naltrexone maintenance treatment. The present open study compared the clinical efficacy of daily naloxone injections in conjunction with lofexidine, with conventional lofexidine monotherapy, in 49 polysubstance-misusing opiate-dependent patients. Overall, the addition of naloxone did not confer substantial benefit over lofexidine monotherapy, although area-under-the-curve analysis showed that withdrawal severity in the naloxone/lofexidine combination group was significantly less than in the lofexidine monotherapy group, who experienced more severe withdrawal symptoms on days 4, 7, 9 and 13 of treatment. There were no significant differences in rates of completion of detoxification. Blood pressure remained within normal limits in both groups. Naltrexone maintenance treatment acceptability was low; only four patients continued with treatment for 5 or more days. The modest benefit of adding naloxone to lofexidine compared to the findings of previous opiate antagonist detoxification treatment studies is discussed in the context of the hypothesis that a critical level of opiate receptor occupancy is required to accelerate resolution of opiate withdrawal; the neurochemical mechanisms which may promote this are discussed. A variety of detoxification methods have been utilized for the treatment of heroin withdrawal before individuals begin long-term opiate-free and naltrexone programs. While methadone in decreasing doses is still widely used for detoxication procedures, rapid and ultrarapid protocols including clonidine and opiate receptors antagonists have been proposed. This study compares the efficacy of different detoxification methods and investigates possible changes in naltrexone compliance. Ninety-eight heroin-addicted individuals were studied to evaluate withdrawal symptoms, craving, mood, urine toxicologic screens, and drop-out rate during therapy with: Group A: clonidine only (5 days); Group B: clonidine, oxazepam, baclofen, and ketoprofene with naloxone and naltrexone (2 days); and Group C: methadone in decreasing doses (10 days). Naltrexone compliance and relapse rates were evaluated during a 6-month follow-up period. Rapid detoxification with opiate antagonists (Group B) induced slight and transient withdrawal symptoms, and resulted in a significantly lower percentage of heroin catabolites in urine controls during the detoxification procedure, lower negative and positive craving, less mood problems, and higher compliance in extended naltrexone treatment. In comparison with clonidine only (Group A) and methadone (Group C), the early use of naltrexone during detoxification in combination with benzodiazepines and clonidine facilitated extended naltrexone acceptance and improved the recovery outcome in outpatients. This study compares a naltrexone/lofexidine combination treatment with a 7-day course of lofexidine alone in the treatment of opiate withdrawal in 22 opiate-dependent patients. Withdrawal symptoms were significantly less severe on days 4-7, and 9-13, in the naltrexone/lofexidine combination group. There were no significant differences in the percentage of patients completing detoxification or in the mean length of stay for the two groups. Both treatments had similar, minimal effects on blood pressure. The naltrexone/lofexidine combination was associated with a more rapid resolution of the opiate withdrawal syndrome than a 7-day lofexidine-only treatment schedule, without substantial increases in withdrawal symptoms or hypotensive side-effects. This double-blind, randomized, placebo-controlled clinical trial evaluated the impact on withdrawal symptoms of (i) combining naltrexone with a 4-day buprenorphine taper for short opioid detoxification (NB Group), compared to (ii) using a 4-day buprenorphine taper alone, followed by naltrexone on day 8 (PB Group). Sublingual buprenorphine was administered on days 1-4 (26 mg total). For the NB Group (n = 32) escalating doses of oral naltrexone were given on days 2-8 (placebo day 1). For the PB Group (n = 28) placebo was given on days 1-7 and naltrexone on day 8. Main outcome measures were Observed Opioid Withdrawal scores (OOW, 0-30) and use of medications to treat opioid withdrawal. Of 32 patients in the NB group, 59% experienced clinically relevant withdrawal (defined as OOW > or = 5) on day 2, but, after day 5, none experienced withdrawal. In the PB group, the number of patients experiencing withdrawal increased over time. The first naltrexone dose induced comparable withdrawal in both groups: peak OOW scores were (mean +/- SD) 5.2 +/- 3.3 on day 2 for the NB group, and 4.0 +/- 3.9 on day 8 for the PB group (NS), though, on day 2, 7 patients dropped out in the NB group and none in the PB group, while only one patient dropped out in the PB group on day 8. Throughout the 8-day study, patients in both groups received similar amount of adjunct medication: 0.64 +/- 0.07 mg (NB group) of clonidine vs 0.73 +/- 0.15 mg (PB group; NS). Only 25% of patients required use of sedatives (up to 20 mg diazepam). Starting naltrexone on day 2 appeared to abolish withdrawal symptoms after day 5 and, thus, to shorten the duration of withdrawal symptoms. Peak withdrawal symptoms after naltrexone were of moderate intensity, suggesting that naltrexone combined with buprenorphine is an acceptable and safe treatment for shortened opioid detoxification and induction of naltrexone maintenance.
The use of opioid antagonists combined with alpha2-adrenergic agonists is a feasible approach to the management of opioid withdrawal. However, it is unclear whether this approach reduces the duration of withdrawal or facilitates transfer to naltrexone treatment to a greater extent than withdrawal managed primarily with an adrenergic agonist.
A high level of monitoring and support is desirable for several hours following administration of opioid antagonists because of the possibility of vomiting, diarrhoea and delirium.
Further research is required to confirm the relative effectiveness of antagonist-induced regimes, as well as variables influencing the severity of withdrawal, adverse effects, the most effective antagonist-based treatment regime, and approaches that might increase retention in subsequent naltrexone maintenance treatment.