Naltrexone and buprenorphine combination in the treatment of opioid dependence

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1 Original Papers Naltrexone and buprenorphine combination in the treatment of opioid dependence G. Gerra National Department on Drug Policy, Rome, Italy. A. Fantoma National Department on Drug Policy, Rome, Italy. A. Zaimovic Addiction Research Centre, Ser.T., AUSL, Parma, Italy. JPsychopharm Journal of Psychopharmacology 2(6) (26) British Association for Psychopharmacology ISSN SAGE Publications Ltd, London, Thousand Oaks, CA and New Delhi / Abstract Naltrexone treatment has demonstrated some advantages for special populations of heroin addicted individuals, but patients compliance seems to be very poor, with a low adherence and low retention rate. Kappa-opioid system overdrive seems to contribute to opioid protracted abstinence syndrome, with dysphoria and psychosomatic symptoms during naltrexone treatment. The objective of this observational study was to determine the effectiveness of a functional k antagonist in improving naltrexone treatment outcome. A partial mu agonist/kappa antagonist (buprenorphine) and a mu antagonist (naltrexone) were combined during a 12 weeks protocol, theoretically leaving k antagonism as the major medication effect. Sixty patients were submitted to outpatient rapid detoxification utilizing buprenorphine and opioid antagonists. Starting on the fifth day, 3 patients (group A) received naltrexone alone. Alternatively, 3 patients (group B) received naltrexone (5mg oral dose) plus buprenorphine (4mg sublingual) for the 12 weeks of the observational study. The endpoints of the study were: retention in treatment, negative urinalyses, changes in psychological symptoms (Symptom Checklist-9 Revised: SCL-9) and craving scores (visual analysis scale (VAS)). Thirty-four subjects (56.67%) completed the 12 weeks study. Twenty-one patients (35.%) had all urine samples negative for opiates and cocaine. nine subjects (15.%) had urine samples negative for cocaine and opiates for the last 4 weeks of the study. five subjects (8.3%) continued to use cocaine during the 12 weeks of the study. No significant change in pupillary diameter after buprenorphine administration was evidenced during clinical observations from baseline across the weekly measurements. Retention rates in group A (naltrexone) and group B (naltrexone buprenorphine) at week 12 were respectively 4% (12 patients) and 73.33% (22 patients), with a significant difference in favour of group B (p.18). Patients treated with naltrexone in combination with buprenorphine (B patients) showed a significantly lower rate of positive urines for morphine (4.45%) and cocaine metabolites (9.9%) than those treated with naltrexone alone (A) (25%, morphine; 33.33% cocaine) (p.5; p.5). Irritability, depression, tiredness, psychosomatic symptoms and craving scores decreased significantly less in patients than in group B patients. The dysfunction of opioid system with kappa receptors hyper-activation provoked by heroin exposure, probably underlying dysphoric and psychosomatic symptoms during naltrexone treatment, seems to be counteracted, at least in part, by buprenorphine. The combination of buprenorphine and naltrexone may significantly improve the outcome of opioid antagonists treatment in terms of retention, negative urinalyses, and reduced dysphoria, mood symptoms and craving. Keywords naltrexone, buprenorphine, heroin, craving, opioid dependence, opioid receptors Introduction Naltrexone maintenance has been reported effective in the treatment of heroin dependence in previous studies (Callahan et al., 198; O Brien et al., 1986; Gerra et al., 2; Kleber, 23), but patients compliance seems to be very poor, with low adherence to rehabilitation programmes and low retention rates (van Brussel, 21; Kirchmayer et al., 22; Rothenberg et al., 22; Armadi et al., 23; Bachs and Waal, 23). Opioid-receptor antagonists have demonstrated some advantages for special populations of heroin addicted individuals (Wodak, 1994), reducing drug craving intensity particularly in motivated patients attending psychotherapy and counselling, who were characterized by low incidence of side effects and strong family support (Gonzalez and Brogden, 1988). Accordingly, a trend in favour of naltrexone treatment was observed more recently for certain target groups, again including highly motivated patients (Kirchmayer et al., 22; Madoz-Gurpide et al., Corresponding author: Gilberto Gerra, MD, National Department on Drug Policy, Via Quintino Sella, 69, 187 Roma, Italy. g.gerra@palazzochigi.it

2 Opioid dependence and treatment 87 24). In particular, a positive outcome of naltrexone treatment was reported in the trials utilizing depot opioid antagonists in subcutaneous implants, that were found more effective than the oral formulation (Carreno et al., 23). A double blind placebo-controlled study demonstrated naltrexone s effectiveness in reducing relapse rate in heroin addicts, though the drug had no valuable effect on anhedonia symptoms, which reduced compliance (Grinenko et al., 23); these symptoms were counteracted by the combination of naltrexone with SSRI antidepressants (Grinenko et al., 23). In attempts to normalize mood, reduce the intensity of dysphoric states, and the subsequent relapse risk during naltrexone maintenance treatment, other authors evaluated the combination of naltrexone and buprenorphine, with a positive response in terms of retention that exceeded that expected from naltrexone alone (Rothman et al., 2). The hypothesis supporting the combination of the mu partial agonist kappa antagonist buprenorphine with the opioid receptors antagonist naltrexone was that a k receptor system overdrive, to compensate for the continued exposure to mu agonists, may underlie the protracted abstinence syndrome with dysphoric mood in opioid-dependent individuals (Rothman et al., 1991; Rothman, 1992), which may be further increased by naltrexone mu opioid receptor blockade. In combining naltrexone treatment with buprenorphine the naltrexone should almost completely block the mu agonist effects of buprenorphine, permitting its k antagonist effects to become unmasked, which should improve mood states and naltrexone compliance itself. Although naltrexone is a relatively non-selective opioid receptor antagonist, its affinity for the kappa receptors is considerably lower than that for mu receptors (Giordano et al., 199) and its ability to counteract kappa opioid system hyper-activity during protracted withdrawal syndrome, after a prolonged exposure to heroin, could be extremely weak, justifying the association of the kappa antagonist buprenorphine. In agreement with this hypothesis, our previous findings demonstrated that buprenorphine may be more effective in heroin dependent patients affected by depression, once again suggesting the possible ability of its kappa receptor antagonist activity to improve mood and control dysphoric states (Gerra et al., 24). Similarly, buprenorphine was reported to induce strong antidepressant effects in patients with endogenous depression (Emrich et al., 1983) and to be effective also in subjects with treatmentrefractory depression, obtaining a significant clinical improvement in both subjective and objective measures (Bodkin et al., 1995). For these reasons it was decided to test the possible advantage of the combination of naltrexone and buprenorphine, in comparison with naltrexone maintenance alone, during the first 3 months of maintenance treatment following heroin discontinuation. The aim of the present study was to replicate and extend the findings of Rothman and co-workers, including in the observational design a control group treated with naltrexone alone which was not utilized in the previous study. The hypothesis of the study is that upon protracted withdrawal following cessation of the mu agonist, the hyperactive k receptor system drives the development of dysphoric states, which in turn leads to the relapse to use mu agonists or cocaine in an attempt to normalize mood. Kappa antagonists such as buprenorphine should prevent relapse in abstinent opioid abusers undertaking naltrexone treatment, counteracting both dysphoric mood states induced by longlasting subtle withdrawal and symptoms of possible comorbid affective disorders emerging after heroin discontinuation. To this purpose, we evaluated the outcome of naltrexone maintenance treatment, in terms of retention at 3 months, in two groups of patients with (3 subjects) and without (3 subjects) additional buprenorphine treatment; both groups attended the same psychosocial programme. The study was performed utilizing an open clinical observational procedure. Material and methods Patient selection Heroin dependent subjects (following the criteria of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders; American Psychiatric Association, 1994) were selected from patients participating in the Parma Addiction Service Program (Servizio Tossicodipendenze) of the public health system. Addiction Services in Italy provide outpatient treatment programmes, with different therapeutic and rehabilitative strategies: methadone, buprenorphine and naltrexone are administered in association with possible psycho-social intervention, such as psychotherapy, family therapy, group therapy, social support and medication for dually diagnosed patients. Sixty naltrexone treatment-seeking patients (45 males and 15 females; mean age years) who had a urine sample positive for opiates (3 ng/ml cut-off) were enrolled in the study. Eligible patients provided written informed consent and were not paid for their participation. The observational study was approved by the ethical committee of the Local Public Health System. Most of the patients who were likely to see themselves suitable for naltrexone showed high levels of social integration, maintained good interpersonal relationships with relatives and friends, high rates of employment and strong motivation to drug-free treatment. Eighty per cent of the patients were strongly supported by their families during the rehabilitation programme. No exclusion criteria are applied to select patients in the public health system. All the patients were evaluated using a self-report and observer-rated questionnaire, a psychometric test, and a psychiatric diagnostic screening. Data describing a detailed history of the patients were also obtained from the drug addiction centre records. The 12 weeks clinical evaluation was conducted as an observational, non-randomized, study that did not influence treatment choice decision, dosage, psycho-social intervention and diagnostic assessment. Participants were heroin dependent for at least 3 years (mean ) prior to entering the study. Study design The patients were admitted to the day-hospital for detoxification procedures, 24 h after heroin discontinuation. Baseline evaluations

3 88 Opioid dependence and treatment included a medical history, laboratory studies, electrocardiogram, urinalyses for metabolites of psychotropic drugs metabolites. The 4 days protocol for buprenorphine rapid opioid detoxification (BROD) consisted of: day 1 buprenorphine (Subutex) 2 mg orally four times; day 2 buprenorphine 2 mg orally three times in combination with repeated doses of naloxone.4 mg intravenously (ten doses.4 mg); day 3 buprenorphine 2 mg orally twice in combination with naloxone.4 mg intravenously; day 4 buprenorphine 4 mg orally in combination with naltrexone 1 mg. Patients who had no significant withdrawal signs were allowed to continue with the naltrexone maintenance programme (5mg daily oral dose); no patients were excluded on this basis. Sixty patients were recruited during 23 and 24. From day 5 through the remainder of the 12 weeks observational study, 3 patients () received 5mg oral naltrexone daily (Nalorex), and the other 3 patients (group B) received 5mg oral naltrexone plus buprenorphine (4mg sublingual). The patients were enrolled into or utilizing a mixed methodology: buprenorphine treatment in combination with naltrexone was offered to the patients utilizing a random schedule, but the subjects allocated in group B might refuse buprenorphine administration. Seven patients, out of 3, did not accept the combination of buprenorphine and naltrexone and were substituted in the sample of the study with another seven subjects recruited in the following months. This procedure reflected the observational nature of the study and respected the decision of the patients, who were not conditioned by the study. At the end of 12 weeks the patients of group B continued buprenorphine treatment, in combination with naltrexone. All 6 patients ( and B) received the same psycho-social treatment routinely offered to Public Health Unit drug-free patients, including counselling, group therapy and social support. Patients were administered the medication at the outpatient centre Monday through to Saturday. All the patients were submitted to twice weekly urinalyses for morphine, cocaine, cannabis, amphetamines, benzodiazepines, barbiturates and alcohol metabolites, weekly clinical evaluation of pupil diameter (including a weekly pre-medication baseline), to demonstrate the blockade of buprenorphine s mu receptor effects, and weekly evaluation of side effects. Pupil diameter changes were evidenced only by clinical observations, and not via photographic techniques, because of the observational nature of the study: the pupillary effects were detected pre-dosing and post-dosing at peak effect, at least once a week during the study period. Symptom Checklist-9 Revised (SCL 9) (Derogatis, 1977) was administered on week 1, following detoxification, and week 12, at the end of the study. Serum liver enzymes were evaluated every 4 weeks. Following the criteria of the programme of Parma, no patient was discharged because of consecutive positive urine test results. Urinalyses were performed with immunoenzymatic methodology (polyclonal antibodies with glucose-6-phosphate dehydrogenase: EMIT, Syva, Italy) and positive results were confirmed by thin layer chromatography, using commercial kits (Toxi-lab; ANSYS Technologies, Lake Forest, CA). A total of 27 urine samples (one before admission, four during detoxification week and 22 during the other 11 weeks) were collected for each patient: missing urinalyses were counted as positive. Symptom Check List 9 scale (SCL-9) was used for the evaluation of a broad range of psychological problems and symptoms of psychopathology. Primary symptom dimensions measured by SCL-9 included somatization, obsessive compulsive interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation and psychoticism. Craving intensity self-reported measures were obtained utilizing a 1 mm Visual Analog Scale (VAS), every 2 weeks. The major endpoints of the study were: retention in treatment, negative urine toxicology, changes in Symptom Checklist-9 scores and VAS craving scores. Characteristics of treatment subgroups No significant differences in previous heroin exposure (years and dosage), or other psychotropic drug use (16.67% (five) and 1% (three) for cocaine; 6.67% (two) and 6.67% (two) for ecstasy and 26.67% (eight) and 2% (six) for benzodiazepines, respectively for A and B groups), was evidenced between (naltrexone alone) and (naltrexone plus buprenorphine) patients. Among the patients selected for the study, (11) 18.33% had previously been receiving methadone maintenance treatment; six (2%) in group A and five (16.67%) in group B. Other patients characteristics are included in Table 1: there were no significant baseline differences between the A (naltrexone alone) and B (naltrexone plus buprenorphine) groups. Previous residential treatment was reported in 8 (13.33%) of the sample prior to their enrolment into the study (16.67% (five) and 1% (three) for groups A and B respectively). Benzodiazepines were prescribed to 26.67% (eight) and 3% (nine) of the A and B group patients respectively; 2% (six) of the A patients and 26.67% (eight) of the B patients were prescribed antidepressant agents in association with naltrexone treatment or naltrexone buprenorphine treatment. Statistical analysis The variables were compared between treatment arms utilizing standard Chi-square-tests. A survival analysis, on an intention-to-treat Table 1 Characteristics of A and B patients in terms of age, years of heroin use, number of previous drug treatment programmes, legal problems, employment and prescribed medications Age mean SE Years of dependence Heroin exposure dosage 1.7.2g Previous methadone treatment 2% (6) 16.67% (5) Previous residential treatment 16.67% (5) 1% (3) Benzodiazepines prescribed 26.67% (8) 3% (9) Prescribed antidepressant agents 2% (6) 26.67% (8) Legal problems rate % 2% (6) 26.67% (8) Unemployment rate % 3% (9) 4% (12)

4 Opioid dependence and treatment 89 basis (Kaplan-Meier), was used to measure the efficacy of naltrexone (group A) and naltrexone combined with buprenorphine (group B) in terms of retention. Positive urine samples for heroin were analysed with a Chi-square-test and ANOVA for repeated measures to evaluate the changes over time. SCL 9 psychometric measures and VAS Craving scores were compared utilizing multiple ANOVA and t test. Missing urine specimens were counted positive. The Intention-to-treat sample (ITT-Analysis) was 3 in group A and 3 in group B (6 patients). Results Thirty-four subjects (34) (56.67%) completed the 12 weeks study. Twenty one patients (21) (35%) had all urine samples negative for opiates and cocaine. Nine subjects (9) (15%) had urine samples negative for cocaine and opiates for the last 4 weeks of the study. Five subjects (5) (8.3%) continued to use cocaine during the 12 weeks of the study. No significant changes in pupillary diameter after buprenorphine administration was evidenced during the clinical observations from baseline across the weekly measurements. No significant elevations was found in the level of serum liver enzymes. There were no significant differences between completers and non-completers in age, years of heroin use, baseline SCL 9 score, number of previous drug treatment programmes, legal problems and employment rate and prescribed medications (Table 2). Retention Survival analysis showed that the drop out rate during the 12 weeks in the naltrexone maintained group (A) was significantly higher, with respect to the intention to treat sample, than in the Table 2 Characteristics of completers and non-completers in terms of age, years of heroin use, number of previous drug treatment programmes, legal problems, employment and prescribed medications Completers Non-completers (34) (26) Age mean SE Years of dependence Heroin exposure dosage 2.1.5g Previous methadone treatment 2.58% (7) 15,38% (4) Previous residential treatment 11.76% (4) 15.38% (4) Benzodiazepines prescribed 29.41% (1) 26.92% (7) Prescribed antidepressant agents 23.5% (8) 23.7% (6) Legal problems rate % 23.5% (8) 19.23% (6) Unemployment rate % 35.29% (12) 34.55% (9) group (B) maintained on naltrexone in combination with buprenorphine (Fig. 1). The risk of retention failure was higher for naltrexone patients at week 12. Retention rates in group A (naltrexone) and group B (naltrexone buprenorphine) at week 12 were respectively 4% (12 patients) and 73.33% (22 patients), with a significant difference in favour of group B ( 5.49 p.19) (Fig. 1). Non-completers (26 subjects) dropped out for various reasons: 14 (53.8%) because of side effects (abdominal pain, nausea vomiting, chest tightness, anxiety, irritability) and 12 (46.2%) for noncompliance reasons. Positive urinalyses For those patients remaining in treatment at 12 weeks the group treated with naltrexone in combination with buprenorphine (B) Proportion surviving Figure 1 Retention rates measured at the survival analysis, on an intention-to-treat basis (Kaplan-Meier), during the 12 weeks of the study, in the naltrexone maintained group (A) and in the group (B) maintained on naltrexone in combination with buprenorphine.2.1 Initial 2 weeks 4 weeks 6 weeks 8 weeks 1 weeks 12 weeks Weeks

5 81 Opioid dependence and treatment showed a significantly lower rate of positive urines for morphine (4.45%) (one) and cocaine metabolites (9.9%) (two), than those treated with naltrexone alone (group A) (25%) (three) morphine and 33.33% (four) cocaine. ANOVA for repeated measures showed a significant effect of time (p.5), group (p.1) and group per time (p.5) in opioid positive urine changes. ANOVA for repeated measures showed a significant effect of time (p.5), group (p.5) and group per time (p.5) in cocaine positive urine changes. A significant difference in reduction of cocaine was found between A and B groups across the whole study from baseline to end (Fig. 2). SCL 9 and VAS craving scores When evaluated on the whole sample, SCL 9 subscale scores for irritability, depression, tiredness and psychosomatic symptoms had decreased significantly at week 12 (p.1, t 3.23; p.5, t 2.93; p.5, t 2.14; p.5, t 2.17), in comparison with baseline values at week 1. Similarly, VAS craving scores were significantly reduced at week 12, in comparison with week 1 (p.5, t 2.89). Irritability, depression, tiredness and psychosomatic symptoms scores decreased significantly less in the naltrexone group (A) compared to the group (B) treated with naltrexone and buprenorphine. ANOVA for repeated measures showed a significant decrease in SCL 9 irritability, depression, tiredness, psychosomatic symptoms scores over time, in both A and B patients who completed the study (A patients, respectively: F 1.3, df 1 p.1; F 9.7, df 1 p.5; F 9.5, df 1 p.5; F 9.7, df 1. p.5) (B patients, respectively: F 2.5, df 1, p.1; F 16.9, df 1, p.1; F 1.5, df 1 p.1; F 12.5, df 1 p.5), with a significantly more consistent decrease in group B completers, compared to group A completers. ANOVA for repeated measures showed for irritability a significant effect of time (p.1), group (p.5) and group per time (F 12.3, df 5, p.1); for depression a significant % Week 1 Week 4 Week 12 Weeks Figure 2a Rates (%) of positive urines for morphine metabolites in group A (naltrexone alone) and group B (naltrexone plus buprenorphine) patients at week 1, 4 and % Week 1 Week 4 Week 12 Weeks Figure 2b Rates (%) of positive urines for cocaine metabolites in group A (naltrexone alone) and group B (naltrexone plus buprenorphine) patients at week 1, 4 and 12

6 Opioid dependence and treatment 811 Figure 3 SCL 9 scores at baseline and week 12 in group A (naltrexone alone) and group B (naltrexone plus buprenorphine) patients 3. Irritability Depression Tiredness Psychosomatic symptoms Baseline 12 week Baseline 12 week Figure 4 VAS craving scores in group A (naltrexone alone) and group B (naltrexone plus buprenorphine) patients at baseline and week 12 1 Baseline 12 week effect of time (p.1), group (p.5) and group per time (p.1); for tiredness a significant effect of time (p.5), group (p.5) and group per time (p.5); for psychosomatic symptoms a significant effect of time (p.1), group (p.5) and group per time (p.5) (Fig. 3). Accordingly, VAS craving scores showed a more consistent decrease in patients treated with naltrexone in combination with buprenorphine (group B) than those treated with naltrexone alone (group A). ANOVA for repeated measures showed for VAS craving scores a significant effect of time (p.1), group (p.1) and group per time (p.1) (Fig. 4). Discussion The overall retention rate at 3 months in the present study (56.6%) was greater than the 33% obtained by Rothman et al. (2) and higher than retention rates generally reported for the treatment with naltrexone alone (Crabtree, 1984; Fram et al., 1989). The better naltrexone treatment outcome, as demonstrated in our previous studies in terms of retention (Gerra et al., 1995; Gerra et al., 2), could be attributable not only to the combination of antagonist administration and intensive psycho-social intervention, that seems to consistently improve naltrexone compliance (Roozen et al., 23), but also to the prevailing socio-cultural situation of our patients, who were highly motivated and socially integrated.

7 812 Opioid dependence and treatment The present findings showed a significantly more positive outcome, both in terms of retention and negative urinalyses, in the patients treated with the combination of naltrexone plus buprenorphine, in comparison with the patients who received naltrexone alone. Moreover, the rate of psychiatric symptoms and craving, that may contribute to reduced naltrexone compliance and increased risk of relapse, was found to be lower in the patients treated with buprenorphine and naltrexone, than that observed in the naltrexone alone treated patients. The hypothesis of Rothman and co-workers (2) appears to be, at least in part, confirmed by our findings: the combination of naltrexone and buprenorphine is more effective than naltrexone alone. This is possibly due to a synergetic ability of buprenorphine and naltrexone to counteract kappa receptor overdrive and the associated dysphoric mood observed in the protracted abstinence syndrome. Although obtained in an observational study, with a number of limitations (for example the possible individual variability in the response to antagonist treatment, lack of complete randomization and a placebo buprenorphine control) our findings suggest that the kappa receptor antagonist buprenorphine may improve the outcome measures during treatment with naltrexone. Naltrexone buprenorphine patients in the present study were compared with a control group treated with naltrexone alone with both groups receiving the same psycho-social intervention, which differentiates this study from the previously reported preliminary evaluation (Rothman et al., 2), that did not include a control group. The improved outcome of naltrexone treatment in combination with buprenorphine, demonstrated in the present study seems to indicate that buprenorphine, a kappa receptor antagonist, may contribute to restore the balance between mu and kappa receptors, after a prolonged exposure to opioid drugs. In fact, the drugs with positive reinforcing properties, including morphine, increase brain dynorphin levels (Sivam, 1989; Trujillo and Akil, 1989; Smiley et al., 199; Trujillo et al., 199), suggesting that dynorphin, an endogenous k agonist (Chavkin et al., 1982; Corbett et al., 1982), might function as part of a homeostatic system to oppose the mood-enhancing and reinforcing effects of morphine (Spanagel et al., 1992; Spanagel and Shippenberg, 1993). Accordingly, kappa receptor agonist, such as butorphanol and enadoline have been reported to increase dysphoria, confusion, sedation and to produce feelings of depersonalization in humans (Greenwald and Stitzer, 1998; Walsh et al., 21), increasing the evidence for a possible role of the kappa opioid system in counteracting the positive mood effects of mu agonists. The long lasting exposure to heroin in these patients could have induced a persisting dysfunction in the opioid receptor system, with kappa receptor over-stimulation, underlying dysphoric and psychosomatic symptoms that were commonly observed in naltrexone patients (Renault, 1981; Malcolm et al., 1987), and which were partly counteracted by buprenorphine. Previous evidence concerning the involvement of corticoreleasing-hormone (CRH) release and hypothalamus pituitary adrenal axis hyperactivity in withdrawal symptoms (Koob, 1992; Schluger et al., 23) may further support the role of kappa opioid overdrive in this clinical condition. In fact, endogenous kappaopioid peptides have been reported to increase adrenocorticotropic hormone (ACTH) output at the pituitary level and also CRH release at the hypothalamic level through an autocrine and/or ultra-short positive feedback mechanism (Calogero et al., 1996). Similarly, kappa agonists have been found to stimulate HPA axis in man (Walsh et al., 21). To this purpose, the ability of buprenorphines to counteract the activation of HPA axis reducing ACTH secretion in response to cocaine has previously been demonstrated (Mendelson et al., 1992), suggesting that the kappa antagonist action may also exert an inhibitory role on HPA axis hyperactivity underlying protracted withdrawal symptoms during naltrexone treatment. In addition, buprenorphine could have improved outcome measures in naltrexone patients because of its possible effects on depressive symptoms, unmasked by heroin discontinuation, as demonstrated by SCL measures in our patients. In fact, increased positive responses on scales of liking, good effects and euphoria have been reported during acute drug administration in an experimental setting (Pickworth et al., 1993) and depressive symptoms were found to decrease significantly in heroin addicted patients who were depressed at intake to buprenorphine treatment (Kosten et al., 199). In agreement with these findings, a recent study has indicated that buprenorphine produces positive mood effects, although with substantial variability among participants (Umbricht et al., 24), probably in relationship to personality traits and underlying biological correlates. The absence of pupil diameter changes or very small changes, difficult to detect at the clinical observations, not associated with photographic techniques, makes it unlikely that the positive response to treatment in buprenorphine naltrexone patients can be attributed to agonist activity at mu receptors. In this respect, pupil diameter would be expected to decrease after buprenorphine administration at this dose (Walsh et al., 1995); however it is apparent that at a dose of 5 mg naltrexone almost completely blocked the mu receptor effects of buprenorphine. A weak agonist action of buprenorphine on mu receptors cannot be definitely excluded in the interpretation of our findings: both buprenorphine and naltrexone have very high affinity for mu opioid receptors, and may coexist in mu opioid competitive binding (Mello et al., 1993). Some mu opioid receptor agonism of buprenorphine, although significantly less than that provided without any competition from naltrexone, should provide a possible alternative explanation of our clinical results. In addition, the present findings could have been affected by the use of other prescribed drugs, such as benzodiazepines and antidepressants, but the non-significant difference between completers and non-completers in the rates of use of these drugs seems to exclude this further interpretation. Finally, the more consistent reduction of cocaine use across the study observed in the patients treated with buprenorphine, in comparison with those who received naltrexone alone, may be attributable to a decreased need to self-medicate dysphoria and normalize mood. To this purpose, buprenorphine has been previously reported to obtain some positive effects in the treatment of cocaine addiction (Montoya et al., 24). Although our data need to be interpreted with caution because of the small sample of patients and the lack of full randomized

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