Drug and Alcohol Dependence 59 (2000) 287–294 www.elsevier.com/locate/drugalcdep Combined use of trazodone-naltrexone versus clonidine-naltrexone in rapid withdrawal from methadone treatment. A comparative inpatient study Gino Pozzi *, Gianluigi Conte, Sergio De Risio Clinical Psychiatry and Substance Dependence Unit, Institute of Psychiatry and Psychology, Faculty of Medicine ‘Agostino Gemelli’, Catholic Uni6ersity of the Sacred Heart, 00168 Rome, Italy Received 11 June 1999; received in revised form 8 October 1999; accepted 12 October 1999 Abstract Trazodone is a non-tricyclic antidepressant drug with specific antagonistic activities at 5-HT2 and alpha-1 adrenoceptors. We test the efficacy of trazodone (T) compared with clonidine (C) in rapid opiate detoxification (ROD) from methadone after reduction to a daily maintenance dose 520 mg. Forty five inpatients were consecutively assigned either to T (n=30) or to C (n=15) treatment in a 7-day ROD protocol with naltrexone administration starting at day 4. The maximum daily dosage was 800 mg for T and 1.2 mg for C. The retention rate was similar in both groups (93.3%). Overall, T was as effective as C in the ROD protocol. T was slightly superior in controlling some subjective and psychological symptoms, but not under naltexone challenge. No severe adverse effects were observed. We conclude that T is effective, safe and well-tolerated in acute withdrawal from methadone. Further investigation is needed to test the effectiveness and safety of T in ultra-rapid protocols and its usefulness in long-term administration to detoxified addicts. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Opiate withdrawal; Naltrexone; Trazodone; Clonidine 1. Introduction Gossop and Strang, 1991; Kanof et al., 1993). Apart from subjective distress, such symptoms may provoke Long-term methadone maintenance is a treatment of resumption of street drug use in a high percentage of choice for large groups of opiate addicts aimed at clients. Shortening the so-called protracted or sec- stopping the use of illicit drugs, which dramatically ondary abstinence is made possible by adding opioid improves physical health and social adjustment (Coun- antagonists, with the advantage that clients directly cil on Addiction Psychiatry, 1994). Still, the discontinu- begin a maintenance program with naltrexone. Tech- ation of methadone medication may constitute a niques that precipitate opioid withdrawal by naloxone further stage of treatment to comply with other types of or naltrexone administration without anesthesia or drug-free therapeutic intervention and/or to complete heavy sedation are currently named rapid opioid detox- rehabilitation. Clinical studies demonstrate that metha- ification (ROD). On the whole, ROD techniques are done withdrawal may cause severe symptomatology, suitable for selected clients who have failed standard including classical opioid withdrawal symptoms and a detoxification treatment or desire an expedited detoxifi- true organic mood syndrome, starting when the daily cation for psychological or social reasons (O’Connor methadone dose is decreased below 20 mg and reaching and Kosten, 1988). a maximal levels a few weeks after the methadone dose The role of presynaptic 2-adrenoceptors in reducing tapering has been completed (Gossop et al., 1987; morphine withdrawal response at the locus coeruleus is a well-established (Aghajanian, 1978) and the 2-stimu- lant drug clonidine is commonly used as an effective * Corresponding author. Tel.: +39-6-30154573; fax: +39-6- 30154163. anti-withdrawal medication in the management of E-mail address: [email protected] (G. Pozzi) heroin addiction (Gold et al., 1978) and methadone 0376-8716/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0376-8716(99)00125-8 288 G. Pozzi et al. / Drug and Alcohol Dependence 59 (2000) 287–294 withdrawal (Charney et al., 1981). Subsequently, other withdrawal signs and may be further potentiated by a 2-agonists have been tested in preclinical studies of m-CPP exerting its agonistic activity on 5-HT1 recep- a morphine dependence, such as lofexidine (Shearman et tors and on 2-adrenoceptors. Anyhow, the metabolite al., 1980), guanfacine (Boccafusco et al., 1984), ti- seems to be only partially involved in the anti-with- zanidine (Pinelli et al., 1998). Lofexidine was also ad- drawal action of the parent compound and both ministered to humans for the management of molecules act at both spinal and supra-spinal levels non-precipitated opioid withdrawal in open and con- (Silvestrini and Valeri, 1986; Valeri et al., 1988, 1989, trolled studies (Schubert et al., 1984; Bearn et al., 1988; 1991b). Furthermore, 5-HT reuptake inhibition may Kahn et al., 1997), but clonidine remains the drug of play a role in the modulation of noradrenergic neurons reference in ROD treatments (Charney et al., 1986; hyperactivity at the locus coeruleus (Akaoka and As- Gold, 1993). ton-Jones, 1993). Trazodone is a triazolopyridine derivative that exerts complex effects on the CNS at different levels, partly by 1.1. Aim of the study means of its active metabolite methachlorophenylpiper- azine (m-CPP). As an antidepressant drug, trazodone is Starting from these preclinical evidences and previous devoid of the typical aminergic properties of tricyclics, open clinical studies in the management of non-precipi- showing specific adrenolytic and antiserotonergic ef- tated opiate withdrawal, we decided to test the clinical fects, moderate anti-histaminergic and very little or no efficacy of trazodone in comparison with clonidine anticholinergic and antidopaminergic activities. The under controlled conditions in a 7-day inpatient trial of a parent compound is a strong 1-antagonist with a more rapid detoxification from methadone treatment. a a than 10-fold greater affinity for 1 than for 2-adreno- ceptors; furthermore, it acts as a selective antagonist at 5-HT2 receptors and also as a 5-HT reuptake inhibitor, though over ten times less potent than fluoxetine. The 2. Materials and methods active metabolite m-CPP is a 5-HT1b agonist and a weak 5-HT2 antagonist, and seems unrelated to antide- 2.1. Sampling pressant and sedative–hypnotic effects (Taylor et al., 1980; Riblet and Taylor, 1981; Richelson and Nelson, Patients were enrolled from a waiting list of subjects 1984; Valeri et al., 1988; Richelson, 1990; Marek et al., requiring detoxification from methadone at the Drug 1992; Rotzinger et al., 1998). Trazodone and m-CPP Dependence Unit of the ‘Agostino Gemelli’ University share also antinociceptive properties, which are consid- Hospital in Rome during the period 1995–1997. The ered relevant to the antidepressant activity, exerted treatment costs were covered by the Italian National both through interactions with the opioid system and Health Service. Inpatient ROD was preceded by an through pathways not affected by naloxone (Valeri et outpatient phase of treatment aimed at tapering metha- al., 1991a). done maintenance dosage to 20 mg/day or less. Clinical The use of trazodone in the management of sub- evaluation during the preparation time was performed stance withdrawal syndromes was predicted by some of on a weekly basis, including urinanalysis for opiates its neuropharmacological activities (Riblet and Taylor, and other drugs of abuse. Low-dose psychoactive med- 1981), through different mechanisms from clonidine, ication (excluding clonidine or trazodone) was allowed a since trazodone does not downregulate presynaptic 2 in selected cases for mood and anxiety disorders, or for receptors by direct effect (Price et al., 1986). Open sleeplessness. clinical studies were performed since the late 1970s with Subjects fulfilling inclusion and exclusion criteria encouraging results in detoxification from opiates listed in Table 1 were asked for consent and were (Fedeli et al., 1979) and alcohol (Roccatagliata et al., informed that they could change their mind at any time 1980); trazodone was also proposed for the relief of about the ROD treatment. If so, as well as in case of cocaine withdrawal symptoms (Small and Purcell, failure of the treatment for any reason, they were 1985). More recently, trazodone did well in the man- re-stabilized on 20 mg/day of oral methadone and agement of benzodiazepine dependence in open and referred to outpatient facilities without prejudice for controlled trials (Ansseau and DeRoeck, 1993; Rickels further therapy. et al., 1999). Further preclinical in vivo investigation Patients enrolled in the study were consecutively has amplified our knowledge about the role of tra- assigned either to trazodone or to clonidine treatment zodone in opioid dependence and precipitated with- on a consecutive basis with a 2:1 ratio. All patients drawal at doses similar to those employed in the underwent physical and laboratory examination at the treatment of mood disorders in humans. In particular, beginning of hospitalization. None had abnormal blood a the selective adrenolytic effects of trazodone on 1 chemistry or ECG recording that could counterindicate receptors are responsible for the suppression of opiate the ROD treatment for clinical reasons. G. Pozzi et al. / Drug and Alcohol Dependence 59 (2000) 287–294 289 2.2. Ratings The checklist was completed by a trained medical doctor who was blind to study conditions. The evalua- Withdrawal responses were measured by means of a tion took about 30 min at each rating and was per- 27-item rating scale, specifically devised for the mea- formed daily in the late morning. surement