Naltrexone implants after in-patient treatment for opioid dependence: randomised controlled trial.

In the first randomised trial, implants which block opiate-type drugs for months helped heroin addicts in Norway avoid relapse after detoxification. If these or allied products gain a UK licence, they could help pave the way to abstinence for the minority of suitable addicts.
Abstract Naltrexone is a medication which blocks the effects of heroin and other opiate-type drugs. Its considerable potential in helping to prevent post-detoxification relapse has not been realised because patients generally refuse to take it or quickly discontinue. However, these limitations apply to the oral formulation which has be taken daily. Longer-lasting formulations in the form of a depot injection or an implant inserted under the skin avoid the need to take the medication daily. This is the first randomised trial of an implant whose opiate-blocking effects last for about six months.
Over 18 months from January 2006, staff at inpatient drug clinics in south-eastern Norway invited opiate-dependent patients on abstinence–oriented programmes to participate in the study. Patients who agreed were contacted by researchers at the end of their detoxification or residential treatment. The 56 who joined the study were told that for the first six months they would be randomly allocated to the implant or to usual aftercare arrangements, but that then all would be offered (re)implantation. Typically they were male injectors in their 30s who had used heroin for on average seven years; nearly all also used other drugs.

Three of the implant group left the clinic before they could be implanted and another three had the implants removed. All but three of the surviving (there were two deaths) patients were reassessed six months later. The main analysis included all the patients whether or not they had received or retained their implants. Over the six months of the follow-up, usual-care patients recalled using opiate-type drugs on average on 97 days, the implant group on just 37 days chart. This differential remained in the last month of the follow-up, when the corresponding figures were 17 and six days, a statistically significant difference. Average frequency of use was also significantly higher among the usual-care patients. At the six-month follow-up assessment, 18 out of 27 usual-care patients but just 9 of the 29 implant patients continued to meet criteria for opioid dependence. In line with this, implant patients were much less likely to experience craving. Nevertheless, during the study over half (18 of 29) tried opioids at least once.
In the last month of the follow-up, implant patients scored significantly lower on an index of multiple drug use and injected less often, but there were no significant differences in drinking or use of non-opioid drugs. Over the follow-up, usual-care patients averaged significantly more repeat detoxifications (0.71 versus 0.21); there were no significant differences in outpatient treatment attendance or use of aftercare services. By the end of the follow-up, implant patients expressed greater satisfaction with their lives but there were no significant differences in levels of depression, work, or criminal activity.
One patient in the implant group reported three non-fatal overdoses (there were four in the usual-care group) while using combinations of opioids, amphetamines and benzodiazepines. Three had implants removed due to infection, discomfort or side-effects. In another two, wound-opening required antibiotic treatment, and three had allergic reactions treated with antihistamines. The single death among patients allocated to implants was an overdose prior to implantation. There was also one overdose death among the usual-care patients.
The authors concluded that naltrexone implants safely and significantly reduced opioid use in a motivated population of patients.
As with oral naltrexone, the main limitation of the treatment is its acceptability to patients. In Norway acceptability will have been heightened by restricted access to substitute prescribing programmes, particularly for people unwilling to contract to forgo not just heroin, but persistent substance use of any kind. Nevertheless, recruitment to the study seems to have been slow. The 56 out of 667 patients who joined the study were probably unusually highly motivated to sustain abstinence from opiates, yet over half the implant patients tried resuming opiate use, and those who did used for on average 60 days. This degree of persistence seems incompatible with the implant having totally eliminated opiate-type effects. The reduction in multiple drug use seems to have been mainly due to the effect on opiate use, since drinking and use of other drugs were not significantly affected. As this study shows, implants and depot injections do not guarantee abstinence. Implants can be removed and both these and depot injections can be sidestepped by turning to non-opiate drugs (as may have happened in Australia) or overridden by very high doses of opiate-type drugs, attempts which risk overdose.
The implants were compared against relatively weak aftercare arrangements; more active and structured aftercare (for example, regular monitoring, continued well organised care from the initial service, or active referral) might have narrowed the differences between the groups. However, highly motivated patients and imperfect aftercare arrangements probably reflect the conditions in which implants would be deployed in normal practice, as does the fact that patients knew whether they had an active implant; unlike some other studies, there was no placebo comparison group.
Of the 26 patients who were implanted, eight (nearly 1 in 3) experienced complications which led three to have the implant removed. One other potential problem is that implants impede opiate-based pain relief. To cater for this, participants were given a card to carry which specified the presence of a naltrexone implant, its expected duration, possible pain relief options, and contact details for study staff. Without this (as reported in Australia) hospital staff sometimes make futile attempts to relieve pain using opiate-type medications. The same report of hospital admissions after implantation identified severe withdrawal symptoms after rapid detoxification to the point where hospitalisation was required. Long-acting naltrexone means the most effective way of relieving these symptoms (using opiate-type drugs) is denied to the patient.
Other occasionally severe reactions to implants and injections have been observed, but generally these are mild and/or short-lived and treatable. As with any abstinence-based treatment, overdose due to lost tolerance to opiate-type drugs is a serious concern. However, the few studies to date suggest these products protect against overdose while they are active, and that in caseloads prepared to undertake these procedures, opiate overdose reductions can outlast the active period of the implants. These findings are consistent with findings from Britain (1) and elsewhere (1 2 3 4 5) tentatively suggesting that long-acting naltrexone can be used to create an opiate-free period which extends beyond the initial blockade, sometimes aided by further administrations (1 2). In the UK, neither implants nor depot injections of naltrexone have been licensed for medical use; they can still be (and have been; 1 2 3 4) used, but patient and doctor have to accept the added responsibility of a product which has not yet been shown to meet the safety and efficacy requirements involved in licensing. See background notes for more on these important issues of adverse effects and overdose protection.
Among the studies is another randomised trial of a different long-acting form of naltrexone conducted in the USA. Compared to placebo, this injection lasting four weeks nearly doubled the time heroin dependent patients were retained in aftercare following inpatient detoxification. On the credible assumption that drop-outs relapsed, there was a similar impact on heroin use. At the four-week choice point when the naltrexone patients could have refused the second set of injections, few did so, most committing themselves to another period without (or with reduced) opiate effects. Though encouraging, multiple exclusions (such as psychiatric conditions or dependence on other drugs) and the recruitment procedures (partly through newspaper ads) meant the patients may not have been typical of usual caseloads.
A criticism of trials to date is that they included highly selected patients. However, in this they may have reflected normal practice. Patients will only opt for such procedures if they are prepared (irreversibly in the case of depot injections) to commit to weeks or months without the effects of heroin or other opiate-type drugs, or with severely attenuated effects requiring higher than usual doses. From the control groups in naltrexone implant/depot studies, we know that even in these caseloads, treatment drop-out and relapse are common. Long-acting naltrexone helps these highly motivated patients sustain their resolve. The clearest candidates for the treatment are patients who are motivated to return to a life without opiate-type drugs (including prescribed substitutes), have the resources, stability and support to sustain this, are unlikely to simply use other drugs instead, but who when free to experience heroin and allied drugs cannot resist using them, possibly reflected in their poor compliance with oral naltrexone regimens. The treatment may also be considered for unstable patients at very high risk of overdose, but who will not accept or do poorly in substitute prescribing programmes.
Thanks for their comments on this entry in draft to Nikolaj Kunøe of the Norwegian Centre for Addiction Research, Liv Langberg of the Drammen Council Drug Addiction Prevention Centre in Norway, and Duncan Raistrick of the Leeds Addiction Unit. Commentators bear no responsibility for the text including the interpretations and any remaining errors.
Source: Drug and Alcohol Findings July 2009 British Journal of Psychiatry: 2009, 194, p. 541–546.