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Buprenorphine in the treatment of opioid dependence
European Neuropsychopharmacology 14 (2004) 209 – 216 www.elsevier.com/locate/euroneuro
Buprenorphine in the treatment of opioid dependence Eugen Davids *, Markus Gastpar Rhine Clinics Essen, Department of Psychiatry and Psychotherapy, University of Duisburg-Essen, Virchowstr. 174, 45147 Essen, Germany Received 7 April 2003; received in revised form 17 July 2003; accepted 17 July 2003
Abstract Buprenorphine has become of increasing interest to be an alternative to methadone in the treatment of heroin addicts. The aim of the paper is to review, from a clinical perspective, the current status of what is known about the pharmacology of buprenorphine, with a particular emphasis on the issues of maintenance therapy in heroin addiction. A systematic review of published follow-up data, from observational and experimental studies was done. Electronic databases Medline and PSYNDEXplus were searched from their earliest entries. Buprenorphine appears to be a well-tolerated drug, with a benign overall side effect. Buprenorphine is an additional treatment option for heroin dependent patients, especially for those who do not wish to start or continue with methadone or for those who do not seem to benefit from adequate dosages of methadone. D 2003 Elsevier B.V./ECNP. All rights reserved. Keywords: Buprenorphine; Opioid dependence; Maintenance therapy
1. Introduction Substitution for opioid addicts has established itself as an effective medical therapy over the past years. Scientific examinations have been able to demonstrate that this form of treatment leads to a reduction in the consumption of opioids and a reduction in the higher rate of mortality and morbidity (Segest et al., 1990; Kreek et al., 2002). Moreover, an improvement in the social situation of the persons affected, a reduction in drug-related crimes and a reduction in the transmission rate of HIV could also be achieved (Senay, 1985; Metzger et al., 1993). Methadone has up to now been the standard substance in the substitution therapy of opioid addicts (O’Connor and Fiellin, 2000). This is a pure A-opioid receptor agonist with the corresponding pharmacological properties. New possibilities have arisen with respect to a differentiated therapy through the availability of new substances such as buprenorphine and levacetylmethadol (LAAM) for the substitution treatment of patients addicted to opioids (Krook et al., 2002; Law and Nutt, 2003; Ling et al., 1994; O’Connor et al., 1996). Buprenorphine was first suggested by Jasinski et al. (1978) as an alternative in the oral substitution therapy of opiate * Corresponding author. Tel.: +49-201-7227-0; fax: +49-201-7227310. E-mail address: [email protected] (E. Davids). 0924-977X/$ - see front matter D 2003 Elsevier B.V./ECNP. All rights reserved. doi:10.1016/S0924-977X(03)00146-9
addicts. This article will discuss the pharmacology and clinical applicability of buprenorphine in both substitution and detoxification of opioid dependence. A systematic review of published follow-up data, from observational and experimental studies was done. Electronic databases Medline and PSYNDEXplus were searched from their earliest entries.
2. Pharmacology of buprenorphine 2.1. Pharmacokinetics When planning therapeutic approaches to opiate addiction it is very important that injectable forms of administration be avoided. This can reduce the spread of infectious diseases such as HIV, hepatitis and other parenterally transferred infections. On account of its intestinal and hepatic metabolism, buprenorphine has a very low oral bioavailability. The successful development of a sublingual pain tablet proves the acceptance of this form of application. In the majority of clinical studies, buprenorphine was used as an aqueous ethanolic solution for sublingual administration. This galenic formulation was the most comfortable method of using corresponding doses in blind studies. However, this formulation has a low stability that made a further galenic development necessary for the daily administration for patients (sublingual tablet).
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In initial tests, it could be shown that the sublingual application form of buprenorphine is absorbed well and develops a sufficient opiate-agonistic effect compared to subcutaneous administration (Jasinski et al., 1989). The maximum plasma level is reached approximately 70 – 90 min after sublingual administration. The absolute bioavailability of sublingually administered buprenorphine is quoted at around 35– 50% (Kuhlman et al., 1996; Mendelson et al., 1997). The relative bioavailability of buprenorphine sublingual tablets compared to the alcoholic solutions used in the majority of studies is around 70%. Plasma levels above 0.7 ng/ml effectively prevent the appearance of withdrawal symptoms (Kuhlman et al., 1998). Plasma levels between 3 and 12 ng/ml are achieved with doses of between 2 and 32 mg (Walsh et al., 1994). Following absorption buprenorphine initially accumulates quickly in various organs such as the liver, kidneys, muscular tissue and finally fatty tissue. It is released from here when the plasma level drops and is thus available at the opioid receptor. Numerous receptor binding studies (primarily on the brains of rats and guinea pigs) demonstrated slow dissociation kinetics for buprenorphine, which would explain the long period of effectiveness (Robinson, 2000, 2002a; Robinson and Wallace, 2001; Tzschentke, 2002). The metabolisation in the liver is carried out by dealkylation and glucuronidation involving the cytochrome P450 CYP3A4 (Kobayashi et al., 1998), leading to possible interactions with other drugs that are metabolised via this system. The terminal elimination phase is quite long with approximately 20 –25 h. This is due on the one hand to the re-absorption of buprenorphine after hydrolysis of the conjugated derivative in the stomach and on the other hand to the distinctively lipophile character of the molecule with redistribution from the tissues. Approximately 80% is excreted through biliary excretion of the glucuronidased metabolites and around 20% via urine (Jasinski et al., 1978; Mendelson and Mello, 1992). 2.2. Pharmacodynamics Opioids are classified according to their affinity for certain receptor subtypes. The analgesic effects and some of the familiar side effects (euphoria, respiratory depression, sedation, constipation) of the opiates are primarily ascribed to the mediation of the A-opioid receptors. Opioids cause dysphoric and sedative effects via the n-receptor whereas the y-receptor is possibly responsible for the peripheral analgesic effect. j-Receptors convey special nonthermal pain reactions (Su, 1985; Takemori et al., 1986; Nutt, 1996). Buprenorphine is a semi-synthetic opiate derivative made from thebaine. Thebaine is one of the numerous alkaloids that occurs naturally in opium. Whereas opium poppies contain only small amounts (approximately 0.2– 0.8%), the milky exudate of papaver bracteatum contains up to 90% thebaine. Buprenorphine acts as a partial agonist on the A-
opioid receptor, i.e. it combines both agonistic and antagonistic properties and is characterised by a reduced intrinsic activity compared to the pure agonists (Cowan et al., 1977; Jasinski et al., 1978; Bickel et al., 1988). Buprenorphine also has the properties of a n-receptor antagonist, i.e. it does not develop any intrinsic activity on this receptor but can block agonistic effects through a high affinity (Neguss et al., 1989). The n-receptor is also responsible for the dysphoric effects of the opioids (Cowan et al., 1977; Su, 1985). As an antagonist on this receptor buprenorphine is not only neutral but might have an antidepressant effect (Emrich et al., 1982; Bodkin et al., 1995). Contrary to the high affinity for the A- and n-binding sites, buprenorphine has only a very low affinity for the yreceptor and no measurable affinity to the j-receptor (Jasinski et al., 1978; Su, 1985; Takemori et al., 1986). Furthermore, it could be shown in various animal models that buprenorphine produces a so-called ceiling effect with an increasing dose (Cowan et al., 1977; Tzschentke, 2002). This means that with an increasing dose the agonistic effect reaches a maximum and then levels out at this plateau. In a further study, different buprenorphine doses up to 32 mg were compared in parallel groups with methadone (Walsh et al., 1994). This study discovered the aforementioned ceiling effect for the effects of buprenorphine compared to methadone. The ceiling effect appeared in a range between 8 and 32 mg buprenorphine, whereby the desired effects in each case were comparable with those with 60 mg of methadone. Higher doses of buprenorphine (32 mg) result less in an increase in the effect but more in an extension of the effect that can last for up to 48 h after administration. These effects may contribute to the fact that the physical addiction potential that has been systematically investigated in rodents, dogs and monkeys should be rated lower than that of a pure A-opioid receptor agonist (Martin et al., 1976; Dum et al., 1981; Mello et al., 1981, 1983, 1993; Neguss et al., 1989; Tzschentke, 2002). However, the statement that buprenorphine has a rather low addiction potential is almost exclusively based on animal data and not in agreement with anecdotal stories of buprenorphine abuse (through intravenous injection) in countries with officebased prescriptions regimens, such as France (Obadia et al., 2001; Kintz, 2002).
3. Dose finding studies and safety profile In initial studies with buprenorphine, it could be shown that taking into account the different target parameters, buprenorphine is suitable for substitution therapy (Jasinski et al., 1982, 1984; Johnson et al., 1989). The buprenorphine dose needed to suppress the opiate consumption is above 4 mg/day according to the results of the studies. The ratio of the dose to the extent of the bioavailability (AUC) is proportionate to the dose in the dosage range between 2 and 16 mg buprenorphine sublingual tablets and dependent
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on but not proportionate to the dose in the dosage range 16 to 24 mg. In an extensive dose finding study with dosages of up to 16 mg/day buprenorphine was administered to patients who were addicted simultaneously to opiates and cocaine. It could be shown that increasing the dose clearly reduces the forbidden accessory consumption of other opiates, but has hardly any reducing effect on the simultaneous consumption of cocaine (Schottenfeld et al., 1993). Buprenorphine has a unique safety profile, in particular with respect to the respiratory depression that can be observed with opioids. Animal experiments on rhesus monkeys proved that buprenorphine does not cause any respiratory depression that requires intervention, even at very high doses (10 mg/kg) (Kishioka et al., 2000). Case studies using buprenorphine did not show respiratory depression as well (Walsh et al., 1994; Cone and Preston, 2002).
4. Studies for maintenance treatment 4.1. Controlled studies of buprenorphine versus placebo in maintenance treatment In a random, double-blind study with a comparison of parallel groups, sublingual buprenorphine was compared with a placebo (Johnson et al., 1995). Randomisation was carried out at the ratio 2:2:1 for placebo, buprenorphine 2 or 8 mg. This test was based on the assumption that a higher dose of buprenorphine causes a greater effect if all participants in the test take their allocated dose up to and including day 6. Between days 6 and 13, the test persons were then given the option of receiving an altered dose. A randomisation was then carried out to one of the other two treatment groups to which the patient did not currently belong. The new dose then had to be taken up to and including day 14. Compared to the placebo group, the buprenorphine patients asked for fewer changes to the dosage, irrespective of their dose, and had a lower accessory consumption (urine analysis). In a multicentre, double-blind comparative study on the efficacy, 1, 4, 8 and 16 mg/day of buprenorphine was administered sublingually over a period of 16 weeks in 12 out-patient therapy centres (Ling et al., 1998). Since the administration of placebo to patients who are addicted to drugs is regarded as unethical, a dose of 1 mg/day of buprenorphine was regarded as an ‘‘active’’ placebo. Patients (n = 736) addicted to opiates were investigated in this study. The results showed that patients with 1 mg/day of buprenorphine displayed significantly lower maintenance rates than those treated with a dose of 8 mg/day ( p = 0.019) or 16 mg/ day ( p < 0.001). With respect to the secondary efficacy parameters ( = forbidden accessory consumption), the 8 mg dose was much better than the 1 mg dose as regards the mean percentage freedom from drugs in the urine samples ( p < 0.02).
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Kakko et al. (2003) aimed to assess the 1-year efficacy of buprenorphine in combination with intensive psychosocial therapy for treatment of heroin dependence. One-year retention was 75% and 0% in the buprenorphine and placebo groups, respectively. Urine screens were about 75% negative for illicit opiates, central stimulants, cannabinoids, and benzodiazepines in the patients remaining in treatment. According to the authors the combination of buprenorphine and intensive psychosocial treatment is safe and highly efficacious, and should be added to the treatment options available for individuals who are dependent on heroin. 4.2. Controlled studies of buprenorphine versus methadone in maintenance treatment Methadone is generally regarded as the standard drug for the substitution treatment of patients addicted to heroin (Gold, 1993; Gonzalez et al., 2002; Kreek et al., 2002). The developmental of the addiction and tolerances because of a methadone treatment can be problematic for individual patients (Best et al., 1997; Cone and Preston, 2002). The results of several studies are now available that have compared the use of methadone and buprenorphine in the maintenance therapy of opiate addicts (Ling and Wesson, 2003; Mattick et al., 2003a,b). One study that investigated the sublingual administration of 8 mg of buprenorphine per day with the effect of orally administered methadone (20 or 60 mg/day) showed a significant superiority for buprenorphine as regards the maintenance rates ( p < 0.04) compared to a 20 mg methadone dose and an equivalence compared to 60 mg of methadone per day. The percentage share of opiate-free urine proved that both buprenorphine 8 mg/day and methadone 60 mg/day were superior to the lower methadone dose (Johnson et al., 1992). These results were confirmed in a further study in which the patients could chose their own dose as regards an optimisation following an initial stabilisation at buprenorphine 8 mg/day or methadone 50 mg/day. The average dose taken by the patients was 8.9 mg/day buprenorphine or 54 mg/day methadone. Both doses were equally effective (Strain et al., 1994a). A further study that compared the sublingual administration of buprenorphine (2 or 6 mg/day) and orally administered methadone (35 or 65 mg/day) over 24 weeks did show a lower efficacy of the buprenorphine dose as regards both the maintenance rate and accessory consumption (Kosten et al., 1993). This could, however, be due to the relatively low buprenorphine dose of 6 mg/day and the slow increase in the dosage (over 2 weeks). In another study (Ling et al., 1996), 225 treatmentseeking opioid addicts were randomly assigned to receive either 8 mg/day of buprenorphine, 30 mg/day of methadone, or 80 mg/day of methadone maintenance over a 1-year period. Patients assigned to high-dose methadone mainte-
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nance performed significantly better on measures of retention, opioid use, and opioid craving than either the low-dose methadone or the buprenorphine group at both 26- and 52week time points. A recently published study compared the efficacy of buprenorphine, LAAM and methadone over 17 weeks (Johnson et al., 2000). With a four-armed, randomised, double-blind, controlled design, 16 to 32 mg buprenorphine (corresponding to a daily dose of 7 to 14 mg) versus 60 to 100 mg/day methadone versus 20 mg/day methadone was administered three times a week versus three times weekly 75 to 115 mg LAAM. In this case, buprenorphine and highly dosed methadone were equally effective as regards the reduction of illegal accessory consumption, opioidpositive urine samples and the maintenance rate. Only low-dosed methadone was significantly inferior to the three other regimens. Further studies were carried out with patients addicted to both opiates and cocaine (Compton et al., 1995; Schottenfeld et al., 1997). The results of the studies showed that doses of 12 mg/day buprenorphine and 65 mg/day methadone were superior to the lower doses (buprenorphine 4 mg/ day and methadone 20 mg/day) as regards the maintenance rate and the share of opiate and cocaine-free urine. A superiority of buprenorphine as regards the reduction of cocaine consumption compared to methadone could not be determined. In a further study, the initial doses of buprenorphine (8 mg/day) and methadone (50 mg/day) were increased if urine tests proved positive (Strain et al., 1994b). Significant results with regard to cocaine-negative urine ( p < 0.001) and a reduction in the share of opiate-positive urine samples could be achieved over the course of the study with an average buprenorphine dose of 11.2 and 66.6 mg/day methadone. A total of 49% of the patients received the maximum possible dose, 16 mg/day buprenorphine (46%) and 90 mg/day methadone (52%). More recent investigations in Europe also demonstrate a good therapeutic efficacy of buprenorphine compared to methadone (Fischer et al., 1999; Petitjean et al., 2001). Altogether, the results presented here allow the conclusion that buprenorphine in a dosage range of 8 – 16 mg/day guarantees an effective maintenance therapy of opiate-addicted patients.
5. Studies of managed withdrawal Whereas the maintenance therapy is an important stabilising factor in the treatment of drug addiction, a withdrawal treatment should be seen as the ultimate goal as regards the abstinence and drug-free life of patients (Gowing et al., 2002; Lintzeris et al., 2002). Sublingually administered buprenorphine was compared with clonidine within the scope of a temporary withdrawal of patients addicted to heroin (Cheskin et al., 1994). In these studies that ran for 10 days buprenorphine was administered
in a total dose of 17 mg over the first 3 days or clonidine in a total dose of 2.7 mg over the first 5 days. The patients were given a placebo for the remaining period. Although no significant differences as regards various physiological reactions and subjectively measurable parameters were discovered, buprenorphine displayed much less distinctive withdrawal scores than clonidine, in particular during the first 3 days of treatment. In a further study that compared three different methods of detoxification (clonidine versus clonidine plus naltrexone versus buprenorphine) there were significantly less serious withdrawal symptoms during treatment with buprenorphine ( p < 0.02 for both comparisons) (O’Connor et al., 1997). Significantly better results with buprenorphine with respect to the Short Opiate Withdrawal Scale-Scores (SOWS) during the first 7 days of the detoxification treatment were achieved in a study within the scope of a 10-day, in-patient detoxification treatment of 27 opiate-addicted patients that compared the combinations buprenorphine/carbamazepine with oxazepame/carbamazepine. In the oxazepame group, 5 out of 12 patients (42%) broke off the treatment whereas in the buprenorphine group the figure was only 4 out of 15 patients (27%). Four patients who were treated with oxazepame broke off the treatment due to inadequate efficacy whereas only one buprenorphine patient broke off treatment for this reason (Paetzold et al., 2000). Over the last years, there has been a growing tendency for opioid addicts to abuse multiple drugs, although many patients are in substitution therapy with methadone. Abuse of multiple drugs leads to a more complicated withdrawal syndrome. It is therefore necessary to investigate new drug strategies as a treatment for detoxification. A recent study supported the hypothesis that buprenorphine/carbamazepine might be more effective than methadone/carbamazepine in detoxification strategies for opioid addicts with additional multiple drug abuse. However, only 26 inpatients were included in the study and therefore the result have to be interpreted as preliminary (Seifert et al., 2002). In a more recent investigation much better results were achieved as regards the withdrawal symptoms through a gradual reduction in the buprenorphine dose—compared to an acute withdrawal—and this resulted in particular in a better compliance (Amass et al., 1994; Diamant et al., 1998). However, a study by Kutz and Reznik (2002) used a single high dosage (32 mg) of buprenorphine to detoxify heroin addicts. Buprenorphine was given following heroin abstinence of 24 h; all 20 subjects completed the trial with negligible withdrawal symptoms. The results of these studies suggest that the use of buprenorphine is an important addition to detoxification treatment. In an out-patient setting preference should be given to a gradual over an abrupt reduction in the dose. A recent study proved the favourable effects of a supportive behavioural therapy within the scope of psychosocial support during an out-patient detoxification with regard to the duration of the opioid abstinence (Bickel et al., 1997).
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6. Switch from methadone to buprenorphine A few studies investigated the possibility of switching from methadone to buprenorphine. One study is worth mentioning in this context in which it proved easy to adjust to buprenorphine (4 mg/day) 24 – 26 h after the last dose following an abrupt discontinuation of methadone (which was titrated down before the abrupt switching to 20 –30 mg/ day) (Law et al., 1997). These results correspond with other studies (Levin et al., 1997) and confirm that a rapid change in therapy from methadone to buprenorphine is well accepted. The fewer problems are encountered the lower the last methadone dose (ideally V 30 mg/day).
7. Undesirable effects of buprenorphine The good safety profile of buprenorphine that was indicated in preclinical studies, could be confirmed in the numerous clinical studies that have been carried out. The range of undesirable effects corresponds to the expected side effects under other opiates. In a study that was performed expressly to investigate these criteria the only side effects of a buprenorphine treatment that were listed were a correlation between sedation and constipation (Lange et al., 1990). The evaluation of the 1-year extension period for a largescale study showed that the withdrawal syndrome and insomnia are the most common undesirable effects associated with buprenorphine (Best et al., 1997). The results of experimental studies in which higher buprenorphine doses were only administered every second day reported no additional side effects with the administered dosages (Schottenfeld et al., 2000). On the other hand, buprenorphine may not be used in cases of serious respiratory insufficiency and serious hepatic insufficiency. There are also contraindications with alcohol intoxication, delirium tremens or treatment with monoamino oxidase inhibitors. There should be very careful medical supervision in cases of known or suspected ECG changes or electrolyte imbalance, in particular hypokalaemia. A significant slowing of the heart rate and treatment with antiarrhythmic drugs from classes I and III also require careful monitoring (Johnson and McCagh, 2000; Walsh and Eissenberg, 2003). 7.1. Intoxication Experiences in France have shown that lethal intoxications involving buprenorphine are almost exclusively polyintoxications (Reynaud et al., 1998; Tracqui et al., 1998; Gueye et al., 2002). Lethal monointoxications are exceptionally rare. However, it could be shown in a cross-sectional study in France (Obadia et al., 2001) with 343 intravenous drug addicts that 57% (n = 198) had used buprenorphine at least once during the past 6 months and that of the patients who received buprenorphine as a substitution therapy
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(n = 112), 70.5% had used buprenorphine intravenously during the past 6 months. Kintz (2002) also reported a series of 13 fatalities in France involving buprenorphine where i.v. injection of crushed tablets and a concomitant intake of psychotropics (especially benzodiazepines and neuroleptics) appeared to be major risk factors.
8. Opioid addiction and pregnancy The efficacy of a substitution treatment for pregnant women with an opioid addiction is taken as assured. On the other hand, a Neonatal Abstinence Syndrome (NAS) is often observed under a substitution with methadone (Finnegan, 1991). In principle, there is not enough data on buprenorphine in this context to allow a general recommendation. With respect to an NAS, several studies have provided clues for advantages over a substitution with methadone (Fischer et al., 1998, 2000; Eder et al., 2001; Johnson et al., 2003; Schindler et al., 2003). However, roughly equally good results could be found for methadone and buprenorphine in a prospective investigation of 246 pregnant women (Lejeune et al., 2001). Like methadone, buprenorphine enters the mother’s milk. It is thus strongly advised against a treatment with buprenorphine during the nursing period at present. Nevertheless, some clinicians do not assume a basic contraindication following their own personal positive experiences. Buprenorphine is, however, not approved for use by breast-feeding mothers and there are no controlled clinical studies.
9. Summary The goal of the treatment is to stabilise patients as quickly as possible with an adequate buprenorphine dosage to prevent the occurrence of withdrawal symptoms. As regards the overall success of the treatment, this is very important with regard to the satisfaction of the patients and thus the motivation for the individual to continue the therapy. In any case, it should be clarified if and which co-medication the patient is taking (significant, e.g. with antiviral drugs). The first administration should ideally take place as soon as the first withdrawal symptoms appear (at least 6 h after the last injection). It must be ensured that the patient allows the tablet to dissolve under the tongue and does not swallow it. The observation period after the initial administration should be at least 3 h. If the initial dose is not enough an increase in the dose in 4 – 8 mg stages is recommended (West et al., 2000; Barnett et al., 2001a; Fiellin et al., 2002; Kreek et al., 2002; Robinson, 2002b). Buprenorphine is taken in the form of a sublingual tablet that takes 3 to 5 min to dissolve and be absorbed. In order to reduce the likelihood of individuals abusing buprenorphine via intravenous use, buprenorphine has been combined with naloxone, a narcotic antagonist. Although the naloxone
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component of this combination product is poorly absorbed by mouth and therefore has almost no effect when taken orally, if injected by an opiate-dependent individual, the naloxone will produce very unpleasant precipitated withdrawal reaction. Therefore, to reduce the probability of illicit injection use, the combined buprenorphine/naloxone tablet is likely to be one of the most widely used preparation for addiction treatment (Kreek, 2000; Johnson and McCagh, 2000; Rawson et al., 2000; Stoller et al., 2001; Comer and Collins, 2002; Raisch et al., 2002). There exist only a few studies analyzing the economic and social effects of buprenorphine substitution therapy. The cost-effectiveness of buprenorphine maintenance therapy for opiate addiction were evaluated by incremental costs, including health-care costs, and incremental effectiveness, measured for example as quality-adjusted life years (QALYs) of survival (Barnett et al., 2001b). Because of the convenience of office-based treatment, buprenorphine may increase access to opiate substitution for some addicts. To the extent that treatment is provided to additional high-cost patients who are involved in extensive criminal activity or who undergo multiple detoxifications each year, net cost savings could be substantial. To the extent that treatment is extended to better adjusted addicts who are employed, married and experience fewer adverse effects from their addiction, costs could increase. The total cost impact will depend on which addict subpopulations make greatest use of the treatment opportunity presented by buprenorphine (French, 2001; Reuter, 2001; Rosenheck and Kosten, 2001; Lavignasse et al., 2002). The overall conclusions that can be drawn from the findings summarized in this paper are the following. Buprenorphine is an effective, well-tolerated drug. Due to its partial agonist properties, buprenorphine is a very safe drug since the severe side effects of high doses of other opioids (e.g. respiratory depression) do develop only to an uncritical degree even after extreme over-dosing. The variation between trials comparing buprenorphine to methadone for treatment of opiate dependence may be due to differences in dose levels, patient exclusion criteria and provision of psychosocial treatment. The difference in the effectiveness of buprenorphine and methadone may be statistically significant, but the differences are small compared to the wide variance in outcomes achieved in different methadone treatment programs. Further research is needed to determine if buprenorphine treatment is more effective than methadone in particular settings or in particular subgroups of patients. Therefore, buprenorphine is for now a very worthwhile addition, but not necessary a replacement to methadone.
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Buprenorphine in the treatment of opioid dependence Eugen Davids *, Markus Gastpar Rhine Clinics Essen, Department of Psychiatry and Psychotherapy, University of Duisburg-Essen, Virchowstr. 174, 45147 Essen, Germany Received 7 April 2003; received in revised form 17 July 2003; accepted 17 July 2003
Abstract Buprenorphine has become of increasing interest to be an alternative to methadone in the treatment of heroin addicts. The aim of the paper is to review, from a clinical perspective, the current status of what is known about the pharmacology of buprenorphine, with a particular emphasis on the issues of maintenance therapy in heroin addiction. A systematic review of published follow-up data, from observational and experimental studies was done. Electronic databases Medline and PSYNDEXplus were searched from their earliest entries. Buprenorphine appears to be a well-tolerated drug, with a benign overall side effect. Buprenorphine is an additional treatment option for heroin dependent patients, especially for those who do not wish to start or continue with methadone or for those who do not seem to benefit from adequate dosages of methadone. D 2003 Elsevier B.V./ECNP. All rights reserved. Keywords: Buprenorphine; Opioid dependence; Maintenance therapy
1. Introduction Substitution for opioid addicts has established itself as an effective medical therapy over the past years. Scientific examinations have been able to demonstrate that this form of treatment leads to a reduction in the consumption of opioids and a reduction in the higher rate of mortality and morbidity (Segest et al., 1990; Kreek et al., 2002). Moreover, an improvement in the social situation of the persons affected, a reduction in drug-related crimes and a reduction in the transmission rate of HIV could also be achieved (Senay, 1985; Metzger et al., 1993). Methadone has up to now been the standard substance in the substitution therapy of opioid addicts (O’Connor and Fiellin, 2000). This is a pure A-opioid receptor agonist with the corresponding pharmacological properties. New possibilities have arisen with respect to a differentiated therapy through the availability of new substances such as buprenorphine and levacetylmethadol (LAAM) for the substitution treatment of patients addicted to opioids (Krook et al., 2002; Law and Nutt, 2003; Ling et al., 1994; O’Connor et al., 1996). Buprenorphine was first suggested by Jasinski et al. (1978) as an alternative in the oral substitution therapy of opiate * Corresponding author. Tel.: +49-201-7227-0; fax: +49-201-7227310. E-mail address: [email protected] (E. Davids). 0924-977X/$ - see front matter D 2003 Elsevier B.V./ECNP. All rights reserved. doi:10.1016/S0924-977X(03)00146-9
addicts. This article will discuss the pharmacology and clinical applicability of buprenorphine in both substitution and detoxification of opioid dependence. A systematic review of published follow-up data, from observational and experimental studies was done. Electronic databases Medline and PSYNDEXplus were searched from their earliest entries.
2. Pharmacology of buprenorphine 2.1. Pharmacokinetics When planning therapeutic approaches to opiate addiction it is very important that injectable forms of administration be avoided. This can reduce the spread of infectious diseases such as HIV, hepatitis and other parenterally transferred infections. On account of its intestinal and hepatic metabolism, buprenorphine has a very low oral bioavailability. The successful development of a sublingual pain tablet proves the acceptance of this form of application. In the majority of clinical studies, buprenorphine was used as an aqueous ethanolic solution for sublingual administration. This galenic formulation was the most comfortable method of using corresponding doses in blind studies. However, this formulation has a low stability that made a further galenic development necessary for the daily administration for patients (sublingual tablet).
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In initial tests, it could be shown that the sublingual application form of buprenorphine is absorbed well and develops a sufficient opiate-agonistic effect compared to subcutaneous administration (Jasinski et al., 1989). The maximum plasma level is reached approximately 70 – 90 min after sublingual administration. The absolute bioavailability of sublingually administered buprenorphine is quoted at around 35– 50% (Kuhlman et al., 1996; Mendelson et al., 1997). The relative bioavailability of buprenorphine sublingual tablets compared to the alcoholic solutions used in the majority of studies is around 70%. Plasma levels above 0.7 ng/ml effectively prevent the appearance of withdrawal symptoms (Kuhlman et al., 1998). Plasma levels between 3 and 12 ng/ml are achieved with doses of between 2 and 32 mg (Walsh et al., 1994). Following absorption buprenorphine initially accumulates quickly in various organs such as the liver, kidneys, muscular tissue and finally fatty tissue. It is released from here when the plasma level drops and is thus available at the opioid receptor. Numerous receptor binding studies (primarily on the brains of rats and guinea pigs) demonstrated slow dissociation kinetics for buprenorphine, which would explain the long period of effectiveness (Robinson, 2000, 2002a; Robinson and Wallace, 2001; Tzschentke, 2002). The metabolisation in the liver is carried out by dealkylation and glucuronidation involving the cytochrome P450 CYP3A4 (Kobayashi et al., 1998), leading to possible interactions with other drugs that are metabolised via this system. The terminal elimination phase is quite long with approximately 20 –25 h. This is due on the one hand to the re-absorption of buprenorphine after hydrolysis of the conjugated derivative in the stomach and on the other hand to the distinctively lipophile character of the molecule with redistribution from the tissues. Approximately 80% is excreted through biliary excretion of the glucuronidased metabolites and around 20% via urine (Jasinski et al., 1978; Mendelson and Mello, 1992). 2.2. Pharmacodynamics Opioids are classified according to their affinity for certain receptor subtypes. The analgesic effects and some of the familiar side effects (euphoria, respiratory depression, sedation, constipation) of the opiates are primarily ascribed to the mediation of the A-opioid receptors. Opioids cause dysphoric and sedative effects via the n-receptor whereas the y-receptor is possibly responsible for the peripheral analgesic effect. j-Receptors convey special nonthermal pain reactions (Su, 1985; Takemori et al., 1986; Nutt, 1996). Buprenorphine is a semi-synthetic opiate derivative made from thebaine. Thebaine is one of the numerous alkaloids that occurs naturally in opium. Whereas opium poppies contain only small amounts (approximately 0.2– 0.8%), the milky exudate of papaver bracteatum contains up to 90% thebaine. Buprenorphine acts as a partial agonist on the A-
opioid receptor, i.e. it combines both agonistic and antagonistic properties and is characterised by a reduced intrinsic activity compared to the pure agonists (Cowan et al., 1977; Jasinski et al., 1978; Bickel et al., 1988). Buprenorphine also has the properties of a n-receptor antagonist, i.e. it does not develop any intrinsic activity on this receptor but can block agonistic effects through a high affinity (Neguss et al., 1989). The n-receptor is also responsible for the dysphoric effects of the opioids (Cowan et al., 1977; Su, 1985). As an antagonist on this receptor buprenorphine is not only neutral but might have an antidepressant effect (Emrich et al., 1982; Bodkin et al., 1995). Contrary to the high affinity for the A- and n-binding sites, buprenorphine has only a very low affinity for the yreceptor and no measurable affinity to the j-receptor (Jasinski et al., 1978; Su, 1985; Takemori et al., 1986). Furthermore, it could be shown in various animal models that buprenorphine produces a so-called ceiling effect with an increasing dose (Cowan et al., 1977; Tzschentke, 2002). This means that with an increasing dose the agonistic effect reaches a maximum and then levels out at this plateau. In a further study, different buprenorphine doses up to 32 mg were compared in parallel groups with methadone (Walsh et al., 1994). This study discovered the aforementioned ceiling effect for the effects of buprenorphine compared to methadone. The ceiling effect appeared in a range between 8 and 32 mg buprenorphine, whereby the desired effects in each case were comparable with those with 60 mg of methadone. Higher doses of buprenorphine (32 mg) result less in an increase in the effect but more in an extension of the effect that can last for up to 48 h after administration. These effects may contribute to the fact that the physical addiction potential that has been systematically investigated in rodents, dogs and monkeys should be rated lower than that of a pure A-opioid receptor agonist (Martin et al., 1976; Dum et al., 1981; Mello et al., 1981, 1983, 1993; Neguss et al., 1989; Tzschentke, 2002). However, the statement that buprenorphine has a rather low addiction potential is almost exclusively based on animal data and not in agreement with anecdotal stories of buprenorphine abuse (through intravenous injection) in countries with officebased prescriptions regimens, such as France (Obadia et al., 2001; Kintz, 2002).
3. Dose finding studies and safety profile In initial studies with buprenorphine, it could be shown that taking into account the different target parameters, buprenorphine is suitable for substitution therapy (Jasinski et al., 1982, 1984; Johnson et al., 1989). The buprenorphine dose needed to suppress the opiate consumption is above 4 mg/day according to the results of the studies. The ratio of the dose to the extent of the bioavailability (AUC) is proportionate to the dose in the dosage range between 2 and 16 mg buprenorphine sublingual tablets and dependent
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on but not proportionate to the dose in the dosage range 16 to 24 mg. In an extensive dose finding study with dosages of up to 16 mg/day buprenorphine was administered to patients who were addicted simultaneously to opiates and cocaine. It could be shown that increasing the dose clearly reduces the forbidden accessory consumption of other opiates, but has hardly any reducing effect on the simultaneous consumption of cocaine (Schottenfeld et al., 1993). Buprenorphine has a unique safety profile, in particular with respect to the respiratory depression that can be observed with opioids. Animal experiments on rhesus monkeys proved that buprenorphine does not cause any respiratory depression that requires intervention, even at very high doses (10 mg/kg) (Kishioka et al., 2000). Case studies using buprenorphine did not show respiratory depression as well (Walsh et al., 1994; Cone and Preston, 2002).
4. Studies for maintenance treatment 4.1. Controlled studies of buprenorphine versus placebo in maintenance treatment In a random, double-blind study with a comparison of parallel groups, sublingual buprenorphine was compared with a placebo (Johnson et al., 1995). Randomisation was carried out at the ratio 2:2:1 for placebo, buprenorphine 2 or 8 mg. This test was based on the assumption that a higher dose of buprenorphine causes a greater effect if all participants in the test take their allocated dose up to and including day 6. Between days 6 and 13, the test persons were then given the option of receiving an altered dose. A randomisation was then carried out to one of the other two treatment groups to which the patient did not currently belong. The new dose then had to be taken up to and including day 14. Compared to the placebo group, the buprenorphine patients asked for fewer changes to the dosage, irrespective of their dose, and had a lower accessory consumption (urine analysis). In a multicentre, double-blind comparative study on the efficacy, 1, 4, 8 and 16 mg/day of buprenorphine was administered sublingually over a period of 16 weeks in 12 out-patient therapy centres (Ling et al., 1998). Since the administration of placebo to patients who are addicted to drugs is regarded as unethical, a dose of 1 mg/day of buprenorphine was regarded as an ‘‘active’’ placebo. Patients (n = 736) addicted to opiates were investigated in this study. The results showed that patients with 1 mg/day of buprenorphine displayed significantly lower maintenance rates than those treated with a dose of 8 mg/day ( p = 0.019) or 16 mg/ day ( p < 0.001). With respect to the secondary efficacy parameters ( = forbidden accessory consumption), the 8 mg dose was much better than the 1 mg dose as regards the mean percentage freedom from drugs in the urine samples ( p < 0.02).
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Kakko et al. (2003) aimed to assess the 1-year efficacy of buprenorphine in combination with intensive psychosocial therapy for treatment of heroin dependence. One-year retention was 75% and 0% in the buprenorphine and placebo groups, respectively. Urine screens were about 75% negative for illicit opiates, central stimulants, cannabinoids, and benzodiazepines in the patients remaining in treatment. According to the authors the combination of buprenorphine and intensive psychosocial treatment is safe and highly efficacious, and should be added to the treatment options available for individuals who are dependent on heroin. 4.2. Controlled studies of buprenorphine versus methadone in maintenance treatment Methadone is generally regarded as the standard drug for the substitution treatment of patients addicted to heroin (Gold, 1993; Gonzalez et al., 2002; Kreek et al., 2002). The developmental of the addiction and tolerances because of a methadone treatment can be problematic for individual patients (Best et al., 1997; Cone and Preston, 2002). The results of several studies are now available that have compared the use of methadone and buprenorphine in the maintenance therapy of opiate addicts (Ling and Wesson, 2003; Mattick et al., 2003a,b). One study that investigated the sublingual administration of 8 mg of buprenorphine per day with the effect of orally administered methadone (20 or 60 mg/day) showed a significant superiority for buprenorphine as regards the maintenance rates ( p < 0.04) compared to a 20 mg methadone dose and an equivalence compared to 60 mg of methadone per day. The percentage share of opiate-free urine proved that both buprenorphine 8 mg/day and methadone 60 mg/day were superior to the lower methadone dose (Johnson et al., 1992). These results were confirmed in a further study in which the patients could chose their own dose as regards an optimisation following an initial stabilisation at buprenorphine 8 mg/day or methadone 50 mg/day. The average dose taken by the patients was 8.9 mg/day buprenorphine or 54 mg/day methadone. Both doses were equally effective (Strain et al., 1994a). A further study that compared the sublingual administration of buprenorphine (2 or 6 mg/day) and orally administered methadone (35 or 65 mg/day) over 24 weeks did show a lower efficacy of the buprenorphine dose as regards both the maintenance rate and accessory consumption (Kosten et al., 1993). This could, however, be due to the relatively low buprenorphine dose of 6 mg/day and the slow increase in the dosage (over 2 weeks). In another study (Ling et al., 1996), 225 treatmentseeking opioid addicts were randomly assigned to receive either 8 mg/day of buprenorphine, 30 mg/day of methadone, or 80 mg/day of methadone maintenance over a 1-year period. Patients assigned to high-dose methadone mainte-
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nance performed significantly better on measures of retention, opioid use, and opioid craving than either the low-dose methadone or the buprenorphine group at both 26- and 52week time points. A recently published study compared the efficacy of buprenorphine, LAAM and methadone over 17 weeks (Johnson et al., 2000). With a four-armed, randomised, double-blind, controlled design, 16 to 32 mg buprenorphine (corresponding to a daily dose of 7 to 14 mg) versus 60 to 100 mg/day methadone versus 20 mg/day methadone was administered three times a week versus three times weekly 75 to 115 mg LAAM. In this case, buprenorphine and highly dosed methadone were equally effective as regards the reduction of illegal accessory consumption, opioidpositive urine samples and the maintenance rate. Only low-dosed methadone was significantly inferior to the three other regimens. Further studies were carried out with patients addicted to both opiates and cocaine (Compton et al., 1995; Schottenfeld et al., 1997). The results of the studies showed that doses of 12 mg/day buprenorphine and 65 mg/day methadone were superior to the lower doses (buprenorphine 4 mg/ day and methadone 20 mg/day) as regards the maintenance rate and the share of opiate and cocaine-free urine. A superiority of buprenorphine as regards the reduction of cocaine consumption compared to methadone could not be determined. In a further study, the initial doses of buprenorphine (8 mg/day) and methadone (50 mg/day) were increased if urine tests proved positive (Strain et al., 1994b). Significant results with regard to cocaine-negative urine ( p < 0.001) and a reduction in the share of opiate-positive urine samples could be achieved over the course of the study with an average buprenorphine dose of 11.2 and 66.6 mg/day methadone. A total of 49% of the patients received the maximum possible dose, 16 mg/day buprenorphine (46%) and 90 mg/day methadone (52%). More recent investigations in Europe also demonstrate a good therapeutic efficacy of buprenorphine compared to methadone (Fischer et al., 1999; Petitjean et al., 2001). Altogether, the results presented here allow the conclusion that buprenorphine in a dosage range of 8 – 16 mg/day guarantees an effective maintenance therapy of opiate-addicted patients.
5. Studies of managed withdrawal Whereas the maintenance therapy is an important stabilising factor in the treatment of drug addiction, a withdrawal treatment should be seen as the ultimate goal as regards the abstinence and drug-free life of patients (Gowing et al., 2002; Lintzeris et al., 2002). Sublingually administered buprenorphine was compared with clonidine within the scope of a temporary withdrawal of patients addicted to heroin (Cheskin et al., 1994). In these studies that ran for 10 days buprenorphine was administered
in a total dose of 17 mg over the first 3 days or clonidine in a total dose of 2.7 mg over the first 5 days. The patients were given a placebo for the remaining period. Although no significant differences as regards various physiological reactions and subjectively measurable parameters were discovered, buprenorphine displayed much less distinctive withdrawal scores than clonidine, in particular during the first 3 days of treatment. In a further study that compared three different methods of detoxification (clonidine versus clonidine plus naltrexone versus buprenorphine) there were significantly less serious withdrawal symptoms during treatment with buprenorphine ( p < 0.02 for both comparisons) (O’Connor et al., 1997). Significantly better results with buprenorphine with respect to the Short Opiate Withdrawal Scale-Scores (SOWS) during the first 7 days of the detoxification treatment were achieved in a study within the scope of a 10-day, in-patient detoxification treatment of 27 opiate-addicted patients that compared the combinations buprenorphine/carbamazepine with oxazepame/carbamazepine. In the oxazepame group, 5 out of 12 patients (42%) broke off the treatment whereas in the buprenorphine group the figure was only 4 out of 15 patients (27%). Four patients who were treated with oxazepame broke off the treatment due to inadequate efficacy whereas only one buprenorphine patient broke off treatment for this reason (Paetzold et al., 2000). Over the last years, there has been a growing tendency for opioid addicts to abuse multiple drugs, although many patients are in substitution therapy with methadone. Abuse of multiple drugs leads to a more complicated withdrawal syndrome. It is therefore necessary to investigate new drug strategies as a treatment for detoxification. A recent study supported the hypothesis that buprenorphine/carbamazepine might be more effective than methadone/carbamazepine in detoxification strategies for opioid addicts with additional multiple drug abuse. However, only 26 inpatients were included in the study and therefore the result have to be interpreted as preliminary (Seifert et al., 2002). In a more recent investigation much better results were achieved as regards the withdrawal symptoms through a gradual reduction in the buprenorphine dose—compared to an acute withdrawal—and this resulted in particular in a better compliance (Amass et al., 1994; Diamant et al., 1998). However, a study by Kutz and Reznik (2002) used a single high dosage (32 mg) of buprenorphine to detoxify heroin addicts. Buprenorphine was given following heroin abstinence of 24 h; all 20 subjects completed the trial with negligible withdrawal symptoms. The results of these studies suggest that the use of buprenorphine is an important addition to detoxification treatment. In an out-patient setting preference should be given to a gradual over an abrupt reduction in the dose. A recent study proved the favourable effects of a supportive behavioural therapy within the scope of psychosocial support during an out-patient detoxification with regard to the duration of the opioid abstinence (Bickel et al., 1997).
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6. Switch from methadone to buprenorphine A few studies investigated the possibility of switching from methadone to buprenorphine. One study is worth mentioning in this context in which it proved easy to adjust to buprenorphine (4 mg/day) 24 – 26 h after the last dose following an abrupt discontinuation of methadone (which was titrated down before the abrupt switching to 20 –30 mg/ day) (Law et al., 1997). These results correspond with other studies (Levin et al., 1997) and confirm that a rapid change in therapy from methadone to buprenorphine is well accepted. The fewer problems are encountered the lower the last methadone dose (ideally V 30 mg/day).
7. Undesirable effects of buprenorphine The good safety profile of buprenorphine that was indicated in preclinical studies, could be confirmed in the numerous clinical studies that have been carried out. The range of undesirable effects corresponds to the expected side effects under other opiates. In a study that was performed expressly to investigate these criteria the only side effects of a buprenorphine treatment that were listed were a correlation between sedation and constipation (Lange et al., 1990). The evaluation of the 1-year extension period for a largescale study showed that the withdrawal syndrome and insomnia are the most common undesirable effects associated with buprenorphine (Best et al., 1997). The results of experimental studies in which higher buprenorphine doses were only administered every second day reported no additional side effects with the administered dosages (Schottenfeld et al., 2000). On the other hand, buprenorphine may not be used in cases of serious respiratory insufficiency and serious hepatic insufficiency. There are also contraindications with alcohol intoxication, delirium tremens or treatment with monoamino oxidase inhibitors. There should be very careful medical supervision in cases of known or suspected ECG changes or electrolyte imbalance, in particular hypokalaemia. A significant slowing of the heart rate and treatment with antiarrhythmic drugs from classes I and III also require careful monitoring (Johnson and McCagh, 2000; Walsh and Eissenberg, 2003). 7.1. Intoxication Experiences in France have shown that lethal intoxications involving buprenorphine are almost exclusively polyintoxications (Reynaud et al., 1998; Tracqui et al., 1998; Gueye et al., 2002). Lethal monointoxications are exceptionally rare. However, it could be shown in a cross-sectional study in France (Obadia et al., 2001) with 343 intravenous drug addicts that 57% (n = 198) had used buprenorphine at least once during the past 6 months and that of the patients who received buprenorphine as a substitution therapy
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(n = 112), 70.5% had used buprenorphine intravenously during the past 6 months. Kintz (2002) also reported a series of 13 fatalities in France involving buprenorphine where i.v. injection of crushed tablets and a concomitant intake of psychotropics (especially benzodiazepines and neuroleptics) appeared to be major risk factors.
8. Opioid addiction and pregnancy The efficacy of a substitution treatment for pregnant women with an opioid addiction is taken as assured. On the other hand, a Neonatal Abstinence Syndrome (NAS) is often observed under a substitution with methadone (Finnegan, 1991). In principle, there is not enough data on buprenorphine in this context to allow a general recommendation. With respect to an NAS, several studies have provided clues for advantages over a substitution with methadone (Fischer et al., 1998, 2000; Eder et al., 2001; Johnson et al., 2003; Schindler et al., 2003). However, roughly equally good results could be found for methadone and buprenorphine in a prospective investigation of 246 pregnant women (Lejeune et al., 2001). Like methadone, buprenorphine enters the mother’s milk. It is thus strongly advised against a treatment with buprenorphine during the nursing period at present. Nevertheless, some clinicians do not assume a basic contraindication following their own personal positive experiences. Buprenorphine is, however, not approved for use by breast-feeding mothers and there are no controlled clinical studies.
9. Summary The goal of the treatment is to stabilise patients as quickly as possible with an adequate buprenorphine dosage to prevent the occurrence of withdrawal symptoms. As regards the overall success of the treatment, this is very important with regard to the satisfaction of the patients and thus the motivation for the individual to continue the therapy. In any case, it should be clarified if and which co-medication the patient is taking (significant, e.g. with antiviral drugs). The first administration should ideally take place as soon as the first withdrawal symptoms appear (at least 6 h after the last injection). It must be ensured that the patient allows the tablet to dissolve under the tongue and does not swallow it. The observation period after the initial administration should be at least 3 h. If the initial dose is not enough an increase in the dose in 4 – 8 mg stages is recommended (West et al., 2000; Barnett et al., 2001a; Fiellin et al., 2002; Kreek et al., 2002; Robinson, 2002b). Buprenorphine is taken in the form of a sublingual tablet that takes 3 to 5 min to dissolve and be absorbed. In order to reduce the likelihood of individuals abusing buprenorphine via intravenous use, buprenorphine has been combined with naloxone, a narcotic antagonist. Although the naloxone
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component of this combination product is poorly absorbed by mouth and therefore has almost no effect when taken orally, if injected by an opiate-dependent individual, the naloxone will produce very unpleasant precipitated withdrawal reaction. Therefore, to reduce the probability of illicit injection use, the combined buprenorphine/naloxone tablet is likely to be one of the most widely used preparation for addiction treatment (Kreek, 2000; Johnson and McCagh, 2000; Rawson et al., 2000; Stoller et al., 2001; Comer and Collins, 2002; Raisch et al., 2002). There exist only a few studies analyzing the economic and social effects of buprenorphine substitution therapy. The cost-effectiveness of buprenorphine maintenance therapy for opiate addiction were evaluated by incremental costs, including health-care costs, and incremental effectiveness, measured for example as quality-adjusted life years (QALYs) of survival (Barnett et al., 2001b). Because of the convenience of office-based treatment, buprenorphine may increase access to opiate substitution for some addicts. To the extent that treatment is provided to additional high-cost patients who are involved in extensive criminal activity or who undergo multiple detoxifications each year, net cost savings could be substantial. To the extent that treatment is extended to better adjusted addicts who are employed, married and experience fewer adverse effects from their addiction, costs could increase. The total cost impact will depend on which addict subpopulations make greatest use of the treatment opportunity presented by buprenorphine (French, 2001; Reuter, 2001; Rosenheck and Kosten, 2001; Lavignasse et al., 2002). The overall conclusions that can be drawn from the findings summarized in this paper are the following. Buprenorphine is an effective, well-tolerated drug. Due to its partial agonist properties, buprenorphine is a very safe drug since the severe side effects of high doses of other opioids (e.g. respiratory depression) do develop only to an uncritical degree even after extreme over-dosing. The variation between trials comparing buprenorphine to methadone for treatment of opiate dependence may be due to differences in dose levels, patient exclusion criteria and provision of psychosocial treatment. The difference in the effectiveness of buprenorphine and methadone may be statistically significant, but the differences are small compared to the wide variance in outcomes achieved in different methadone treatment programs. Further research is needed to determine if buprenorphine treatment is more effective than methadone in particular settings or in particular subgroups of patients. Therefore, buprenorphine is for now a very worthwhile addition, but not necessary a replacement to methadone.
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