1 Innovations in agonist maintenance treatment of opioid-dependent patients Christian Haasen a and Wim van den Brink b Purpose of review To provide an overview of published studies on agonist maintenance treatment options for opioid-dependent patients. Recent findings The recent publication of controlled trials confirms earlier clinical evidence of the efficacy of diamorphine (heroin) in the treatment of opioid dependence. Findings show not only efficacy with respect to improvement of health, reduction of illicit drug use, reduction of criminality and stabilization of social conditions, but also cost effectiveness in the treatment of chronic treatment-resistant heroin addicts. Summary Agonist maintenance treatment has become the first-line treatment for chronic opioid dependence. High-quality studies demonstrate the effectiveness of a growing number of different agonist maintenance treatments for opioid dependence such as methadone and buprenorphine. In addition, there is new evidence for the effectiveness of other agonists, mainly slow-release morphine, intravenous and inhalable diamorphine and possibly oral diamorphine. Maintenance treatment with intravenous or inhalable diamorphine should be implemented into the healthcare system to treat a group of severely dependent treatmentresistant patients. Furthermore, the opioid-dependent patients not under treatment need to be engaged in maintenance treatments through other harm reduction measures. Agonist maintenance treatment is very effective in stabilizing the health condition and social situation, while also reducing harm, thereby increasing life expectancy and quality of life. Keywords buprenorphine, diamorphine, maintenance treatment, methadone, opioid dependence, slow-release morphine Curr Opin Psychiatry 19: ß 2006 Lippincott Williams & Wilkins. a Department of Psychiatry, University Medical Center Eppendorf, Center for Interdisciplinary Addiction Research, Hamburg, Germany and b Academic Medical Center, University of Amsterdam, Department of Psychiatry, Amsterdam Institute for Addiction Research, Amsterdam, The Netherlands Correspondence to Christian Haasen, Department of Psychiatry, University Medical Center Eppendorf, Martinistr. 52, Hamburg, Germany Tel: ; fax: ; Current Opinion in Psychiatry 2006, 19: Abbreviations HAT heroin-assisted treatment LAAM levo-acethylmethadol SROM slow-release oral morphine TdP Torsade de Pointes ß 2006 Lippincott Williams & Wilkins Introduction Given the chronic, relapsing nature of opioid dependence and the generally disappointing long-term results of detoxification in combination with relapse prevention, agonist maintenance treatment has become the most important treatment modality for opioid dependence in many countries. The primary interest of both professionals and addicts is still in the cure of the disease, defined as long-term stable abstinence from all opioids. Despite considerable progress in the treatment of opioid dependence in the last two decades, outcomes in abstinence-oriented programs remain poor . Considering the high rate of relapse and the increased risk of fatal intoxications after detoxification, agonist maintenance treatment is currently considered to be the first-line treatment for opioid-dependent patients . The aim of agonist maintenance treatment is prevention of withdrawal, reduced craving, reduction of illegal drug use and drug-related criminality, improvement of health and well being and reduction of drug-related harm [3,4]. Although opioid-assisted maintenance programs have been introduced in most countries of the world, the medication of choice differs from one country to the other. Methadone is the most extensively studied and most widely used opioid in maintenance treatment. Other mu-opiate agonists that are used include levoacethylmethadol (LAAM), codeine, slow-release morphine and diamorphine, as well as the partial mu-opioid agonist buprenorphine. According to the most recent Cochrane reviews [5 7], maintenance treatment with methadone, LAAM and buprenorphine are all proven effective interventions, provided that adequate dosages are prescribed. For example, a Cochrane review  found methadone dosages ranging from 60 to 100 mg/day to be more effective than lower dosages in terms of treatment retention and reduction of heroin and cocaine use during treatment. A comparative meta-analysis covering studies 631
2 632 Clinical therapeutics between 1966 and 1999 indicated that high doses of methadone (50 mg/day) were more effective than low doses (<50 mg/day) in reducing illicit opiate use that high doses of methadone were more effective than low doses of buprenorphine (<8 mg/day) and equally effective compared with high doses of buprenorphine (8 mg/day) in terms of treatment retention and reduction of illicit opiate use, and that LAAM was at least as effective as high-dose methadone, but that patients treated with LAAM were more likely to leave treatment prematurely . Similar conclusions were drawn from a randomized controlled trial with four study arms: low-dose methadone, high-dose methadone, high-dose buprenorphine and LAAM . Maintenance treatment with LAAM emerged to be at least as promising, if not better than maintenance treatment with other opioid agonists. In a randomized crossover clinical trial, the majority (69%) of 62 stable patients treated with methadone preferred LAAM to methadone because of its less withdrawal symptoms, fewer side effects, less craving for heroin and fewer pick-up days . LAAM maintenance treatment had also been shown to be feasible and potentially effective in heroindependent detainees in prison: 61% of the prisoners who were initiated on LAAM during imprisonment entered maintenance treatment after release , a success rate very similar to the findings of a methadone prison program . In March 2001, the Committee of Proprietary Medicinal Products (CPMP), however, recommended the European Commission the suspension of LAAM after noting seven cases of treatment-related Torsade de Pointes (TdP), a potentially fatal ventricular arrhythmia, during LAAM treatment, and the marketing authorization was recommended to be suspended in Europe in 2001 . In the USA, the Food and Drug Administration (FDA) changed the labeling for LAAM for the same reason to emphasize that the drug should be used only to treat opioid-dependent patients who do not respond to other adequate treatments . So far, the best studied and the most effective opioid agonist for maintenance treatment is methadone [16,17]. Treatment outcome in methadone maintenance has been shown to improve substantially with increased dosages of methadone [18 21,22 ] and the provision of adequate psychosocial support [18,23,24]. Methadone maintenance treatment even without the provision of adequate psychosocial care as an interim solution until entry into a comprehensive methadone maintenance treatment program, however, has shown to increase the likelihood of entry into comprehensive treatment and reduce heroin use and criminality [25 ]. Adequate daily dosing has an important effect on retention in methadone maintenance treatment . In the USA, low dosages of methadone have, to a large extent, been replaced by higher dosages: in 1988, almost 80% of the patients received dosages less than 60 mg/day, whereas this was the case in 36% of the patients in 2000 . Low dosage of methadone has been described to be one of the main problems for methadone treatment in other countries also, such as Italy , Israel  and The Netherlands . Recent studies [21,31] further indicate that methadone dosages between 30 and 60 mg/day may be effective in suppressing withdrawal symptoms, but dosages of 120 mg/day or more are needed to eliminate heroin use when in methadone maintenance treatment. Nonetheless, as very high dosages of methadone have also been associated with the occurrence of TdP, high dosages need to be monitored carefully . Sporadic cases of TdP, however, have also been reported in patients receiving a recommended dose between 60 and 100 mg methadone per day . Although adequate psychosocial care is likely to increase the effectiveness of methadone maintenance treatment, excessive supplementary services, such as day care programs, show little added benefit and are not cost-effective [34,35]. Methadone is at present the first-choice agonist maintenance treatment in most countries. Buprenorphine has become the main alternate as a first-choice agonist treatment, but it is also used for those heroin-dependent patients not benefiting from methadone maintenance (although no empirical data are available for this second-line indication). Several studies have shown the efficacy of buprenorphine in maintenance treatment of opioid dependence (for a review of trials, refer to Sung and Conry [36 ]). In addition, the partial opioid agonist effect has been hypothesized to lead to a lower risk of overdose: observational data from France, indeed, suggest lower mortality in buprenorphine maintenance treatment than in the methadone maintenance treatment . The lower overdose risk is one of the reasons why buprenorphine might be a safe and feasible alternate for office-based opioid-assisted treatments in primary care. In two small-scale US studies [38,39], buprenorphine prescription in primary care was associated with good retention (70 80%) and reasonable rates of opiatefree urines (43 64% achieving three or more consecutive weeks of opiate-free urines). These positive effects were confirmed in a larger trial, showing a reduction in craving for and the use of illegal opioids under buprenorphine . Similar results were obtained in France some years ago . A consensus statement on office-based treatment of opioid dependence using buprenorphine has been developed for the US . Buprenorphine, however, is generally administered as a sublingual tablet, and therefore it must be water-soluble. As a consequence, buprenorphine tablets can be
3 Agonist maintenance treatment options Haasen and van den Brink 633 dissolved and injected, and its abuse has already been reported in several countries, especially in countries with office-based prescription . Owing to this abuse potential, interest has shifted to the development of a tablet that contains both buprenorphine (good sublingual bioavailability) and naloxone (poor sublingual bioavailability). Thus, a combined buprenorphine/naloxone tablet taken sublingually should produce a buprenorphine effect, whereas a tablet dissolved and injected will produce an opioid withdrawal syndrome. These assumptions were confirmed in several experimental studies indicating that a 4 : 1 buprenorphine/naloxone combination indeed has a low abuse potential  but equal efficacy with regard to reduction of illicit opiate use and craving . It should, however, be noted that the additional value of the (more expensive) combination strategy has not been proven in a routine clinical setting. Another recent development is the availability of an injectable depot formulation of buprenorphine. This formulation may offer effective treatment of opioid dependence and enhance treatment delivery when minimizing risks of patient nonadherence or illicit diversion of the medication . Finally, a study on the cost-effectiveness  of adding buprenorphine maintenance treatment to an existing treatment system that already includes methadone maintenance showed that buprenorphine maintenance would be cost-effective if the price is less than $5 per daily dose, whereas at $15 per day (or higher), buprenorphine would be cost-effective only in optimistic models. A more recent study  shows methadone after buprenorphine introduction to be slightly more effective, cheaper and thus more cost-effective than buprenorphine as a first-line treatment. An important issue in agonist maintenance treatment is the prescription of methadone or buprenorphine in prisons. A number of studies [48,49,50,51] in Europe, Australia, Puerto Rico and Canada have now shown that methadone maintenance treatment in prison leads to a reduction in drug use, drug injection and needle sharing, produces improvements in institutional behavior and gives a positive effect on release outcomes. A rather new development is the medical prescription of heroin or diamorphine to chronic, treatment refractory heroin-dependent patients, an intervention that has been and will be tested in a variety of countries in Europe and North America . In two recent reports [53,54] about the Swiss experience, it was concluded that supervised medical prescription of heroin was associated with good retention (70% over 12 months) and resulted in reduced illicit drug use (both opiates and cocaine), reduced criminality and improved health outcomes and social functioning. Owing to design restrictions, however, no final conclusion could be drawn with respect to the causal role of heroin in the observed benefits [55 57]. In a recent report  on two randomized controlled trials that were conducted in the Netherlands, the effect of a combined treatment with methadone and injectable or inhalable heroin was compared with a treatment with methadone alone, while keeping the psychosocial treatment offer constant between the treatment conditions. The results of these trials were very similar to those of the Swiss trials, but for the first time, the observed improvements could be attributed to the medical prescription of heroin [59,60,61 ]. Moreover, from a societal perspective, the coprescription of heroin in this specific population was found to be cost-effective as compared with treatment with methadone alone [62 ]. Recently, similar results were reported from a small, randomized controlled trial from Spain, where patients treated with heroin and methadone showed better improvement of health, reduction of street heroin use, HIV-risk behavior and days involved in crime . In Germany, initial results from a large, randomized controlled trial showed that patients treated with heroin have a greater improvement of health and reduction of illicit drug use than those treated with methadone . In 2005, two other randomized control trials that compared the effectiveness of heroin-assisted treatment (HAT) with methadone maintenance treatment, one in the UK and one in Canada, were started . A Cochrane review  found currently available results (not including the Spanish and German data) not allowing a definitive conclusion about the overall effectiveness of heroin prescription because of the noncomparability of the experimental studies. Some authors have warned against unintended consequences of heroin prescription, such as lowering the motivation of opioid-dependent patients to enter the methadone maintenance treatment and lowering the threshold of sharing heroin use because an easy treatment will be available in case of addiction. So far, none of these risks has been substantiated . In addition, the Swiss experience with the heroin prescription has been related to the decreasing incidence of heroin use: the emphasis on the medicalization of the heroin problem seems to have contributed to the image of heroin as unattractive for young people . Diamorphine as an oral medication for maintenance treatment of opioid dependence has been studied recently in an open-label, prospective cohort study , comparing efficacy and safety for a group of patients treated with oral diamorphine only, a group treated with a combination of oral diamorphine and other agonist substances and a third group of historical controls mainly consisting of patients treated with injectable diamorphine only. Twelve-month retention rates were significantly higher in the groups treated with oral diamorphine
4 634 Clinical therapeutics (80 and 84%, respectively) than in the group treated with injectable diamorphine (70%), implying that oral diamorphine seems to be at least as effective as injectable diamorphine in maintenance treatment. It should be noted, however, that this study has several methodologic limitations and that no data are currently available regarding the generalizability of these early findings. It also remains to be shown whether there is any difference in the treatment effect of oral diamorphine when compared with oral morphine, as diamorphine is rapidly metabolized to morphine after ingestion. Maintenance treatment has also been described to be effective with two other opiate agonists, mainly codeine and slow-release oral morphine (SROM). Codeine is authorized for maintenance treatment only in Germany, where a comparable effectiveness to methadone maintenance treatment has been described . Owing to the shorter bioavailability, codeine maintenance treatment, however, will probably only play a marginal role in the future treatment of opioid dependence. On the contrary, SROM is a promising compound for maintenance treatment and has been authorized for maintenance treatment of opioid dependence in a few European countries. Several smaller and mostly openlabel studies [71 74] have shown positive results of SROM with respect to retention, reduction of heroin use and/or quality of life. Another open-label study , comparing SROM with methadone and buprenorphine treatment as well as with patients entering the treatments, however, found lower quality-of-life values for patients treated with SROM, despite equal effectivity in the reduction of illicit drug use compared with methadone and buprenorphine treatment. Furthermore, as with buprenorphine, there is criticism concerning the diversion of prescribed SROM toward illicit drug use. Of special concern is the fact that SROM has been found in most fatal intoxications in Austria in 2004 . Further studies will have to confirm these results to be able to evaluate the added value of this substance for the treatment of heroin dependence. Regardless of the substance use, the number of opioiddependent patients receiving agonist maintenance treatment is increasing. This leads to other challenges in the field of medicine, such as the management of acute pain in this subsample, where the risk of inadequate treatment (undertreatment) is even higher than in the general population . Another important issue is the treatment of opioiddependent patients who are pregnant. In their evidence-based guidelines, the British Association for Psychopharmacology recommends that detoxification should be avoided (especially in the first trimester) and that methadone maintenance is the first-choice treatment with buprenorphine probably being a good second choice especially in patients already on buprenorphine . There has been extensive debate about the optimal dose with some studies showing higher methadone or buprenorphine levels associated with positive effects such as higher birth weight and more antenatal care and negative effects such as more severe neonatal abstinence syndrome (NAS). In any case, all pregnant women need close monitoring of their dose. Generally, in opioid-dependent women already maintained on methadone or buprenorphine, the dose can remain the same, but patients may need to increase the dose in the third trimester . Split dosing can be used in the third trimester. Conclusion The chronic relapsing nature of opioid dependence calls for a long-term comprehensive treatment strategy and the disorder should not be viewed as only a brain disease. Treatment goals include motivating the patients to engage in therapy, educating them with respect to the different aspects of the treatment process and making sure that there is continuity of care. These goals can only be achieved by integrating pharmacotherapy and psychosocial services and cooperating with the judicial system. Promoting office-based treatments of opioid-dependent patients will help reduce existing stereotypes and stigmatization . There exist several very effective strategies in the treatment of opioid dependence today that it can be treated effectively through different strategies [16 ]. Owing to the extensive body of scientific evidence, methadone maintenance treatment is considered the single most important first-line treatment for opioid dependence, which reflects the broad experience with its use in clinical practice . Not all opioid-dependent patients, however, fully respond to methadone treatment, so that alternates have become necessary, the main one being buprenorphine . For the small group of patients resistant to these treatments, treatment with diamorphine has been shown to be an effective alternative . Nonetheless, patients not yet motivated for treatment need to be engaged in maintenance treatments through harm reduction measures such as needle exchange programs or even user rooms . As most opioid-dependent patients also abuse other psychoactive substances, agonist maintenance treatment needs to carefully monitor drug and alcohol use patterns. Despite a reduction in illicit opioid use, methadone treatment may lead to an increase in alcohol use requiring treatment. Contingency management programs with vouchers for clean urines can be effectively applied in order to reduce illegal cocaine use in opioid-dependent patients in methadone or buprenorphine maintenance treatment [81,82]. Therefore, the pharmacological
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