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Private clinics in Australia have performed several hundred episodes of naltrexone-accelerated detoxification in the past 18 months. However, there has been little systematic investigation of accelerated detoxification, and existing studies are limited by variation in methods, poor research design, and lack of data on long-term outcomes.^2,3 Safety is a crucial issue. Greater levels of sedation are assumed to make the procedure more tolerable, but increase the risk of aspiration.⁴ General anaesthesia with intubation presumably reduces this risk,² but makes the procedure expensive.

Our study was undertaken to determine whether naltrexone-accelerated detoxification can be performed with minimal sedation in awake patients. The rationale was to identify a safe, acceptable and affordable procedure for use in formal trials of accelerated detoxification as a treatment for addiction. A secondary aim was to monitor outcomes of detoxified patients treated for three months with naltrexone.

Participants were enrolled in blocks of four or six: the first four people to contact were booked for assessment, and no further bookings taken until these four had undergone detoxification. The process was repeated until 15 heroin and 15 methadone users had been enrolled.

Each patient was allocated a case manager who attended detoxification and conducted follow-up. Case managers comprised a psychologist, a registered nurse and a pharmacist with counselling qualifications.

Patients received oral premedication with flunitrazepam (2 mg) and clonidine (150 µg). Half an hour later, they were given oral naltrexone at a dose of 12.5 mg (first five patients) or 50 mg (subsequent patients). Oral ondansetron (4 mg) was given orally to the first four patients to control vomiting, and then intravenously when vomiting became established. However, it was observed to be ineffective and was replaced by subcutaneous octreotide (100 µg) in subsequent patients. During acute withdrawal, further clonidine (150 µg, four-hourly) and flunitrazepan (1 mg) were given if patients reported feeling agitated. Oral buscopan (200 mg, four-hourly) was given for complaints of abdominal cramps, and oral quinine sulfate (300 mg, eight-hourly) for leg cramps. Additional doses of octreotide (100 µg) were given in the evening of detoxification and the next morning.

Naltrexone was given at a dose of 50 mg/day from Day 2 onwards. Patients were discharged when well enough, with instructions to continue taking this dose of naltrexone.

Key outcomes were acceptability of detoxification to patients, duration of hospitalisation, success of induction onto naltrexone maintenance, retention on naltrexone, and psychoactive drug use over the ensuing three months (the latter measured with the Opiate Treatment Index⁶ and confirmed by urine tests). Patients were deemed to have "dropped out" of the trial if they ceased taking naltrexone for a continuous 28-day period. The last day they were known to have taken naltrexone was considered the day of attrition.

After premedication with flunitrazepam and clonidine, most patients became drowsy or fell into a light sleep. About 40-60 minutes after administration of naltrexone (50 mg), patients woke abruptly and began to complain of agitation and discomfort. All reported that symptoms were quite different from those of spontaneous heroin withdrawal. Symptoms escalated over the next 30 minutes, and most patients were moderately distressed. Thereafter, almost all entered a delirium for about three to four hours; they were often confused but not aggressive, none required restraint, and nursing care was straightforward. Six patients were found to have self-medicated with benzodiazepines while in hospital and were less easily managed, as higher doses of benzodiazepines appeared to increase delirium and disinhibition.

After about four hours, delirium and agitation subsided. Patients felt miserable, often depressed, withdrawn and exhausted. Most had only a vague recollection of the acute phase of withdrawal. Over the ensuing 24 hours, they became increasingly alert but reported feeling "flat", "washed out" and dysphoric, and most ate little. Average dose of clonidine on Day 1 was 415 µg (range, 150-750 µg). Fourteen patients received further clonidine on Day 2.

Subjective withdrawal severity could not be rated during the acute phase. At 24 hours post-naltrexone, scores ranged widely, from 0-42 with a median of 23 (out of a possible maximum of 64, where 42 = quite severe). However, the primary feature of withdrawal -- delirium -- was not assessed by this scale.

The first four patients who received ondansetron but not octeotride during withdrawal (three from heroin and one from methadone) all experienced repeated vomiting for more than 24 hours and required intravenous fluid replacement. All subsequent patients received octreotide. Their gastrointestinal symptoms are shown in Box 2. Vomiting was common and could occur throughout the first 48 hours, but most of those who vomited did so only once, and none required intravenous fluids. Patients withdrawing from methadone had more gastrointestinal symptoms than those withdrawing from heroin.

Duration of hospitalisation varied. Among patients withdrawing from heroin, 11 needed only one night's hospitalisation, while the other four needed two nights. Patients withdrawing from methadone tended to need longer hospitalisation: seven stayed one night, five stayed two, and the other three stayed three, four and five nights, respectively. Patients who did not receive otreotide also tended to need longer hospitalisation.

Detailed outcomes after three months (Day 91) are shown in Figure 2. Although most patients discontinued naltrexone, this did not necessarily indicate relapse to opioid use. Five patients who had discontinued claimed to be abstinent from opioids (defined as a continuous 28-day period free of opioid use). This was confirmed by serial urine tests in four patients. The other moved interstate within a week of detoxification and did not have urine tests, but reported being drug-free during follow-up telephone interviews.

Continuing to take naltrexone was not always associated with abstinence from opioids. Of the six patients still taking naltrexone at three months, four reported sporadically omitting one or two doses, using heroin, and then resuming naltrexone. However, their level of heroin use was clearly less than before detoxification. Another patient from the heroin group who continued taking naltrexone remained abstinent from heroin but took up cannabis smoking. Cannabis use increased from nil before detoxification to 10 "cones" per day at three months. There was no increase in self-reported use of non-opioid drugs among other patients.

The patient who died had discontinued naltrexone use after five weeks. Three weeks after last attending the clinic and receiving a week's supply of naltrexone, this patient died of a heroin overdose. Two other patients who relapsed to heroin use reported overdosing and being revived with naloxone after misjudging their level of tolerance.

Recent literature on opioid withdrawal has focused on controlling withdrawal symptoms with medications, at the expense of psychological treatment.⁷ However, use of multiple medications, including sedatives and anaesthetics, increases the risk.⁸ For example, a recent Spanish study of accelerated detoxification performed under sedation in an intensive care unit reported a complication rate of 4.3%, with six of 300 patients requiring intubation, and one developing aspiration pneumonia.⁴ In contrast, no acute life-threatening complications occurred in our study, but it was too small to establish safety definitively. The main risk we identified was self-medication with benzodiazepines, which led to greater agitation and disinhibition. Although the procedure was performed with no problems in a hospital ward, it could not be performed safely without close professional supervision.

Our technique of detoxification was "ultra-rapid" -- acute detoxification was complete within hours. The acute phase was not as difficult for patients as the 48 hours post-detoxification, when they experienced gastrointestinal distress and feelings of exhaustion. Withdrawal from methadone appeared more severe, with more gastrointestinal side effects, higher ratings of severity, and longer inpatient stays. There are few published, systematic studies of withdrawal under sedation for comparison with our study. After detoxification under anaesthesia, symptoms can occasionally be severe,⁹ and a recent study reported that significant withdrawal symptoms persisted at least a week later.¹⁰

Our rate of induction onto naltrexone (80%) was comparable with rates reported by most others for accelerated detoxification. The only randomised trial to date to compare accelerated and conventional detoxification found rates of induction (defined as taking naltrexone at Day 8) of 65% after clonidine alone, 60% after buprenorphine, and 54% after combined naltrexone-clonidine.¹¹ These differences were not statistically significant. In our study, hospitalisation for at least one night was probably crucial to our higher rate of induction onto naltrexone.

Most studies of naltrexone maintenance have shown high dropout rates and high relapse rates to heroin use,¹² similar to our findings. For example, a recent review calculated that, for people who took a first dose of naltrexone after conventional induction, average reported attrition was 39% in the first two weeks.¹³ Although claims have been made that mean retention on naltrexone is one to six months, depending on patient selection and quality of adjunctive services,¹⁴ this value is skewed by the small proportion of patients who take naltrexone long term, for whom the treatment is highly successful. In our study, which involved unselected patients with poor prognostic indicators, retention (defined as continuing to take naltrexone) was 58% at one month, 23% at two months, and 17% at three months (or 20% including the patient who resumed naltrexone use after repeat detoxification). Most of those who relapsed entered methadone treatment. A report on 781 heroin users in Western Australia estimated that 87% of those who underwent detoxification continued with naltrexone, with subsequent retention rates of 60% at one month, 44% at two months and 33% at three months.¹⁵ However, as these figures were based on monthly prescriptions dispensed, they may slightly overestimate retention. Another Australian study of naltrexone reported that only two of 43 patients (5%) took naltrexone for six months.¹⁶

Some studies have reported much higher rates of heroin abstinence after naltrexone treatment than ours. For example, a recent study of patients undergoing accelerated detoxification under anaesthesia reported 60% of patients were free of heroin use six months later.⁹ However, this was based on a telephone survey of patients who could be contacted, and would require confirmation in more rigorous trials. A Spanish study reported that 93% of 300 patients were abstinent from opioids a month after accelerated detoxification under sedation (confirmed by urine testing).⁴ This is in stark contrast with most previous results.^12,13

Naltrexone maintenance carries risk, with a report of suicides and fatal overdoses.¹⁷ In our study, despite repeated warnings about diminished opioid tolerance when taking naltrexone, one patient died of a heroin overdose and two others reported overdosing after misjudging their tolerance. Others may have had similar experiences but not reported them. This problem needs special monitoring, as post-naltrexone deaths may be hard to identify; naltrexone is almost never found at postmortem toxicological analysis as overdose occurs when the drug is stopped. Therefore, any major study of naltrexone risk needs to monitor death records.

From our data, accelerated detoxification with light sedation resulted in induction and retention rates similar to those found in most published studies of naltrexone. Randomised trials are required to compare techniques of detoxification, and our study has identified a low-cost, low-risk approach for use in such trials. However, results will not be available for years. In the meantime, as uptake of accelerated detoxification has far outstripped research, results of this pilot study may help consumers and health professionals judge the claims made for naltrexone treatment.

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National Drug and Alcohol Research Centre, Sydney, NSW.
Richard P Mattick, PhD, Director of Research.

National Centre for Epidemiology and Population Health, Australian National University, ACT.
Gabriele Bammer, PhD, Senior Fellow.

Reprints will not be available from the authors.
Correspondence: Dr J R Bell, The Langton Centre, 591 South Dowling Street, Surry Hills, NSW 2010.
Email: jamesb@sesahs.nsw.gov.au

©MJA 1999
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