Experimentally induced aggressiveness in heroin-dependent patients treated with buprenorphine: comparison of patients receiving methadone and healthy subjects

Objective measures of experimentally induced aggressiveness were evaluated in heroin-dependent patients (HDP), 15 receiving buprenorphine (BUP) and 15 receiving methadone (METH) treatment. HDP were randomly assigned to BUP and METH groups. Fifteen healthy subjects (CONT) were included in the study as controls. During a laboratory task, the Point Subtraction Aggression Paradigm, subjects earned monetary reinforcement and could respond by ostensibly subtracting money from a fictitious subject (the aggressive response). Money-earning (points maintained) responses did not differ in BUP patients and in controls. In contrast, point-maintained responses were significantly lower in the group of HDP treated with METH than in both the BUP and CONT groups. Aggressive responses were significantly higher in the HDP group than in the CONT group. No significant differences in aggressive responses were found between the BUP and METH groups. Baseline concentrations of plasma adrenocorticotropic hormone (ACTH) and cortisol (CORT) were higher in HDP than in CONT. During the experimental task, ACTH and CORT increased significantly less in METH patients than in BUP patients and CONT. Norepinephrine (NE) and epinephrine (EPI) levels increased significantly more in HDP than in CONT, without any difference between the METH and BUP patients. PSAP aggressive responses positively correlated with NE and EPI changes, as well as with Buss-Durkee Hostility Inventory (BDHI) scores in both METH and BUP patients and also in CONT subjects. No correlation was found between the extent of heroin exposure, drug doses and aggressiveness levels. BUP, similarly to METH, does not seem to affect outward-directed aggressiveness, as aggressive responses related more to monoamine levels and personality traits than to the action of opioid agonists. Money-earning responses seemed to be unimpaired in BUP patients.     

Differential effects of gestational buprenorphine, naloxone, and methadone on mesolimbic mu opioid and ORL1 receptor G protein coupling

In addition to its use for heroin addiction pharmacotherapy in general, buprenorphine has advantages in treating maternal heroin abuse. To examine the gestational effects of buprenorphine on opioid receptor signaling, the [(35)S]-GTP gamma S in situ binding induced by the mu agonist [D-Ala(2),MePhe(4),Gly(5)-ol] enkephalin (DAMGO) or the nociceptin/orphanin FQ (N/OFQ) agonist was measured in mesolimbic structures of pup brains from pregnant rats administered with buprenorphine +/- naloxone, naloxone, or methadone by osmotic minipump. Drug- and gender-based changes in DAMGO- and N/OFQ-induced GTP gamma S binding were discovered in mesolimbic regions of dam, P2, and P7 brains. Buprenorphine and/or methadone gestational treatment attenuated DAMGO-induced GTP gamma S binding in some dam and male P2 mesolimbic regions. Methadone diminished DAMGO-induced GTP gamma S binding in almost all monitored brain regions of the dam but had few effects on their N/OFQ-induced GTP gamma S binding. Naloxone used in combination with buprenorphine blocked the inhibition by buprenorphine alone on DAMGO-induced GTP gamma S binding. In contrast to its inhibitory effects on DAMGO-induced GTP gamma S binding, buprenorphine stimulated N/OFQ-induced GTP gamma S binding in male P2 nucleus accumbens and lateral septum. Brain region-dependent gender differences in DAMGO-induced GTP gamma S binding were seen in P2 pups, and males showed greater sensitivity to buprenorphine and methadone than females. Our findings on mu opioid receptor (MOR) GTP-binding regulatory protein (G protein) coupling and its gender dependency are consistent with our earlier studies on mu receptor binding adaptation induced by buprenorphine in dams and neonatal rats after in utero treatment regimens, and they extend the gestational effects of this opiate to mu and N/OFQ receptor functionality.     

Reduced ACTH/cortisol responses to naloxone in men with Parkinson's disease

Summary In order to establish whether the inhibitory control exerted by endogenous opioid peptides on ACTH/cortisol secretion changes in patients affected by Parkinson's disease, ten parkinsonian male subjects and eight age matched normal controls were tested with naloxone (4 mg an i.v. bolus plus 10 mg infused in two hours). In a different occasion all subjects were tested with normal saline. Experiments started at 09.00 h. Plasma ACTH and cortisol concentrations showed a slight physiological decline during saline test in both groups. In the normal controls and in the parkinsonian patients both ACTH and cortisol levels were significantly higher after naloxone administration than during saline test. However, both naloxone induced ACTH and cortisol responses were significantly higher in normal than in parkinsonian subjects. In agreement with the well-known opioid deficiency characterizing the parkinsonian brain, these data show a reduced opioid inhibitory control of ACTH/cortisol secretion in patients with Parkinson's disease.     

Metyrapone effects on beta-endorphin, ACTH and cortisol levels after chronic opiate receptor stimulation in man

The aim of this study was to evaluate beta-endorphin, ACTH, and cortisol plasma levels during metyrapone administration in man after chronic opioid receptor stimulation. Metyrapone (750 mg every 4 hr for 6 doses) was administered to ten male heroin addicts, who had been on a maintenance therapy with methadone for at least 6 months and to ten healthy sex- and age-matched volunteers. Before metyrapone administration the basal levels of cortisol and ACTH were significantly decreased in addicts as compared to normal controls, while plasma beta-endorphin was not different. The response of beta-endorphin and ACTH to metyrapone administration was significantly blunted in addicts (p less than 0.01). These results suggest that the chronic stimulation of opiate receptors can impair the function of the anterior pituitary gland.     

Buprenorphine responders: a diagnostic subgroup of heroin addicts?

1. A 26-32 month follow-up of 16 heroin-dependent subjects who entered a pilot trial of treatment with buprenorphine (a mixed agonist/antagonist) suggests that positive response to treatment may identify a subgroup of untreated addicts whose levels of psychosocial functioning are intermediate between those for whom methadone (a pure agonist) or naltrexone (a pure antagonist) would be indicated. 2. Buprenorphine's pharmacologic profile provides a missing link in available modalities for opiate dependence treatment, making it acceptable for many addicts who will not accept methadone maintenance treatment, join a residential therapeutic community, or be successful on naltrexone treatment. 3. Eight of the 16 ss were abstinent from heroin while receiving 0.6-3.9 mg/day buprenorphine and counseling. Responders (mean age 34 yrs) had been heroin dependent for a mean of 9.5 years (range 6-17 yrs), all were self-supporting, 4 lived with a non-addicted spouse, 5 had no prior treatment for addiction and 3 had prior naltrexone treatment, but had discontinued it and relapsed. Non-responders (mean age 30 yrs) had been heroin dependent for a mean of 7.4 yrs (range 2-19 yrs), 7 had no regular employment, all were single and 7 had no prior treatment for addiction. 4. Levels of psychosocial functioning (work, home, leisure) and global assessments of functioning were significantly higher for buprenorphine responders than non-responders (p less than .001 and p less than .01 respectively). 5. A new formulation of buprenorphine needs to be developed for addiction treatment, ideally consisting of 0.5 mg and 2.0 mg sublingual tablets.     

Facilitation of avoidance behaviour in mice chronically treated with heroin or methadone

Although the repercussion of chronic treatment with large amounts of opioids on cognitive performance is a matter of concern, the effects of opioid drugs on passive avoidance learning have been scarcely studied. Here, we analyzed the effects of prolonged administration of heroin and methadone, as well as the impact of suffering repeated episodes of withdrawal on fear-motivated learning using the passive avoidance test. Mice received chronic treatment (39 days) with methadone (10 mg/kg/24 h), associated or not with repeated withdrawal episodes, or with heroin (5 mg/kg/12 h). Our results show that, regardless of the type of treatment received, all mice displayed similar basal thermal nociceptive thresholds during 25 days of treatment. In the hot plate test, both methadone and heroin induced antinociception 30 min after drug administration. The analgesic effect was absent when measured 4 h after heroin and 12 h after methadone. Pain behavioural responses elicited by growing intensities of electric shock, applied on day 28th of treatment, were similar in all groups of mice. Our results indicate that chronic opioid treatment had promnesic effects on passive avoidance behaviour in mice, unrelated to changes in the nociceptive state.     

A stepped care strategy using buprenorphine and methadone versus conventional methadone maintenance in heroin dependence: a randomized controlled trial

OBJECTIVE: Both methadone and buprenorphine are effective therapy for heroin dependence. Efficacy is best documented for methadone maintenance therapy, but safety concerns limit its use. Buprenorphine offers lower overdose risk and improved access, but efficacy may be lower. The authors compared adaptive, buprenorphine-based stepped care to optimal methadone maintenance treatment. METHOD: This randomized controlled trial was undertaken 2004-2006. It consisted of a 24-day uniform double-blind induction phase followed by single-blind flexible dosing based on structured clinical criteria, for a total of 6 months. Ninety-six self-referred subjects with heroin dependence were randomly assigned to methadone or to stepped treatment initiated with buprenorphine/naloxone and escalated to methadone if needed. All subjects received intensive behavioral treatment. Primary outcome was retention in treatment. Secondary outcomes were completer analyses of problem severity (Addiction Severity Index) and proportion of urine samples free of illicit drugs. RESULTS: Overall, 6-month retention was 78%. Stepped treatment and methadone maintenance therapy outcomes were virtually identical. Among completers of stepped therapy, 46% remained on buprenorphine/naloxone. Proportion of urine samples free of illicit opiates increased over time and ultimately reached approximately 80% in both arms. Problem severity decreased significantly and uniformly in both arms. CONCLUSIONS: A stepped treatment of heroin dependence as described here appears equally efficacious compared to optimally delivered methadone maintenance therapy. Together with prior data on the advantageous safety of buprenorphine, this suggests that broad implementation of strategies using buprenorphine as first-line treatment should be considered.     

Cardiac autonomic modulation during methadone therapy among heroin users: A pilot study

Background

Methadone therapy benefits heroin users in both the medical and psychosocial dimensions. However, both heroin and methadone have cardiac toxicity. Only limited information is available describing the changes in cardiac autonomic function of heroin users and effects of methadone therapy. We conduct the current study to explore the cardiac vagal function in heroin users as well as the impact of lapse and methadone therapy.

Methods

80 heroin users from a methadone therapy clinic were distributed into 31 compliant and 49 incompliant patients according to whether they lapsed into heroin use within 10 days. 40 healthy control subjects were recruited from the community. Participants underwent electrocardiographic recordings and the heroin users were further investigated before and after methadone therapy. Spectral analysis of heart rate variability (HRV) was computed for cardiac parasympathetic modulation (high-frequency power, HF) and cardiac sympathetic modulation (normalized low-frequency power, LF%).

Results

The baseline HRV parameters found lower HF values for heroin users and lower RR interval values for patients with a recent lapse compared with the healthy control subjects. After 1 h of methadone administration, heroin users who had lapsed showed a significant increase in HF but the heroin users who had not lapsed did not.

Conclusion

Our findings suggest that heroin users show decreased cardiac vagal activity and that methadone therapy immediately facilitates vagal regulation in patients with a recent lapse. The differential patterns of autonomic alteration under methadone between those with and without lapse might offer an objective measure of lapse.     

Regulation of nonphosphorylated and phosphorylated forms of neurofilament proteins in the prefrontal cortex of human opioid addicts

The neurofilament (NF) proteins (NF-H, NF-M, and NF-L for high, medium, and low molecular weights) play a crucial role in the organization of neuronal shape and function. In a preliminary study, the abundance of total NF-L was shown to be decreased in brains of opioid addicts. Because of the potential relevance of NF abnormalities in opioid addiction, we quantitated nonphosphorylated and phosphorylated NF in postmortem brains from 12 well-defined opioid abusers who had died of an opiate overdose (heroin or methadone). Levels of NF were assessed by immunoblotting techniques using phospho-independent and phospho-dependent antibodies, and the relative (% changes in immunoreactivity) and absolute (changes in ng NF/microg total protein) amounts of NF were calculated. Decreased levels of nonphosphorylated NF-H (42-32%), NF-M (14-9%) and NF-L (30-29%) were found in the prefrontal cortex of opioid addicts compared with sex, age, and postmortem delay-matched controls. In contrast, increased levels of phosphorylated NF-H (58-41%) and NF-M (56-28%) were found in the same brains of opioid addicts. The ratio of phosphorylated to nonphosphorylated NF-H in opioid addicts (3.4) was greater than that in control subjects (1.6). In the same brains of opioid addicts, the levels of protein phosphatase of the type 2A were found unchanged, which indicated that the hyperphosphorylation of NF-H is not the result of a reduced dephosphorylation process. The immunodensities of GFAP (the specific glial cytoskeletol protein), alpha-internexin (a neuronal filament related to NF-L) and synaptophysin (a synapse-specific protein) were found unchanged, suggesting a lack of gross changes in glial reaction, other intermediate filaments of the neuronal cytoskeletol, and synaptic density in the prefrontal cortex of opioid addicts. These marked reductions in total NF proteins and the aberrant hyperphosphorylation of NF-H in brains of opioid addicts may play a significant role in the cellular mechanisms of opioid addiction.     

Thrice-weekly versus daily buprenorphine maintenance.

BACKGROUND: Buprenorphine is a promising alternative to methadone or levo-acetyl alpha methadol for opioid agonist maintenance treatment, and thrice-weekly dosing would facilitate its use for this purpose. METHODS: After a 3-day induction, opioid-dependent patients (n = 92) were randomly assigned to daily clinic attendance and 12-weeks maintenance treatment with sublingual buprenorphine administered double blind either daily (n = 45; 16 mg/70 kg) or thrice weekly (n = 47; 34 mg/70 kg on Fridays and Sundays and 44 mg/70 kg on Tuesdays). Outcome measures include retention, results of 3x/week urine toxicology tests, and weekly self-reported illicit drug use. RESULTS: There were no significant differences at baseline in important social, demographic, and drug-use features. Retention was 71% in the daily and 77% in the 3x/week conditions. The proportion of opioid-positive urine tests decreased significantly from baseline in both groups and averaged 57% (daily) and 58% in 3x/week. There were no significant differences between groups in self-reported number of bags of heroin used for any day of the week, including Thursdays (48-72 hours following the last buprenorphine dose for subjects in the 3x/week condition), or in medication compliance (92%, 91%) and counseling attendance (82%, 82%). CONCLUSIONS: At an equivalent weekly dose of 112 mg/70 kg, thrice-weekly and daily sublingual buprenorphine appear comparable in efficacy with regard to retention and reductions in illicit opioid and other drug use. These findings support the potential for utilizing thrice-weekly buprenorphine dosing in novel settings.     

Buprenorphine in pregnancy

The treatment of opioid dependence during pregnancy is a major challenge for doctors, social workers and gynaecologists. Continuous drug abuse during pregnancy can lead to a variety of complications in the mother, fetus and neonate. lt is recommended practice to maintain pregnant opioid-dependent women with synthetic opioids and according to international guidelines, methadone is the recommended substance so far. However, a neonatal abstinence syndrome (NAS) of varying severity is observed in 60 - 80 % of the neonates with even a longer course of duration in comparison to the NAS after heroin consumption during pregnancy. NAS is characterised by tremor, irritability, hypertonicity, vomiting, sneezing, fever, poor suckling, and sometimes convulsions. Recent studies have investigated the safety and efficacy of other synthetic opioids like sublingual buprenorphine for the treatment of pregnant patients. We present a 22 year old opioid-dependent woman, who has been maintained continuously on buprenorphine for 3 years. During the treatment episode she delivered two healthy newborns and both did not show any symptoms of NAS. The maintenance therapy with buprenorphine proved safety and efficacy during pregnancy, the mother was free of continuous heroin abuse, verified through supervised urine-toxicology. The quantitative and qualitative difference in NAS may be explained by the partial mu-receptor agonist and kappa-antagonist receptor profile of buprenorphine compared to pure mu-agonist action of methadone or heroin.     

Vergleichsuntersuchung von Buprenorphin und Methadon im Rahmen der Erhaltungstherapie Opiatkranker

The efficacy of buprenorphine in opioid dependent patients (n = 20) was compared to methadone maintained subjects (n = 20) in a randomized comparison trial. Sublingual application of buprenorphine as an alternative synthetical opioid is being compared to methadone during a 24 week study period. A trend (p = 0.06) could be found in the retention rate of investigated patients being maintained on a mean dosage of 63 mg oral applicable methadone (racemat of L- and D-methadone) in comparison to the group on a mean dosage of 7.3 mg buprenorphine (sublingual tablets). The dropout-rate of 11 subjects at the end of the study in the buprenorphine group was higher when compared to the dropout-rate of 5 in the methadone group. There was no significant difference between the two groups over the treatment period in respect to additional consumption of opiates, benzodiazepines and cocaine as evaluated through urine toxicology. The result in regard to compliance over the study period demonstrates that methadone appears to be the more successful oral opioid (p = 0.04). Nevertheless, efficacy of buprenorphine in maintenance could be demonstrated in the remaining subjects, and further studies with higher daily doses and a higher number of subjects have to be performed.     

An open pilot study of zonisamide augmentation in major depressive patients not responding to a low dose trial with duloxetine: preliminary results on tolerability and clinical effects

Background

The idea that the impact of opioid agonist treatment is influenced by the psychopathological profile of heroin addicts has not yet been investigated, and is based on the concept of a specific therapeutic action displayed by opioid agents on psychopathological symptoms. In the present report we compared the effects of buprenorphine and methadone on the psychopathological symptoms of 213 patients (106 on buprenorphine and 107 on methadone) in a follow-up study lasting 12 months.

Methods

Drug addiction history was collected by means of the Drug Addiction History Rating Scale (DAH-RS) and psychopathological features were collected by means of the Symptom Checklist-90 (SCL-90), using a special five-factor solution. Toxicological urinalyses were carried out for each patient during the treatment period.

Results

No statistically significant differences were detected in psychopathological symptoms, including 'worthlessness-being trapped', 'somatization', and 'panic-anxiety'. Methadone proved to be more effective on patients characterized by 'sensitivity-psychoticism', whereas buprenorphine was more effective on patients displaying a 'violence-suicide' symptomatology.

Conclusions

Heroin-dependent patients with psychiatric comorbidities may benefit from opioid agonist treatment not only because it targets their addictive problem, but also, precisely due to this, because it is effective against their mental disorder too.     

Buprenorphine duration of action: mu-opioid receptor availability and pharmacokinetic and behavioral indices.

BACKGROUND: Buprenorphine (BUP) is effective in the treatment of opioid dependence when given on alternating days, probably as a result of long-lasting occupation of micro opioid receptors (microORs). This study examined the duration of action of BUP at microORs and correlations with pharmacokinetic and pharmacodynamic outcomes in 10 heroin-dependent volunteers. METHODS: Availability of microOR (measured with positron emission tomography and [(11)C]-carfentanil), plasma BUP concentration, opioid withdrawal symptoms, and blockade of hydromorphone (HYD; heroin-like agonist) effects were measured at 4, 28, 52, and 76 hours after omitting the 16 mg/d dose of BUP in a study reported elsewhere. RESULTS: Relative to heroin-dependent volunteers maintained on BUP placebo, whole-brain microOR availability was 30%, 54%, 67%, and 82% at 4, 28, 52, and 76 hours after BUP. Regions of interest showed similar effects. Plasma concentrations of BUP were time dependent, as were withdrawal symptoms, carbon dioxide sensitivity and extent of HYD blockade. Availability of microOR was also correlated with BUP plasma concentration, withdrawal symptoms, and HYD blockade. CONCLUSIONS: Together with our previous findings, it appears that microOR availability predicts changes in pharmacokinetic and pharmacodynamic measures and that about 50%-60% BUP occupancy is required for adequate withdrawal symptom suppression (in the absence of other opioids) and HYD blockade.     

Decreased immunodensities of micro-opioid receptors, receptor kinases GRK 2/6 and beta-arrestin-2 in postmortem brains of opiate addicts

The homologous regulation of opioid receptors, through G protein-coupled receptor kinases (GRKs) and beta-arrestins, is an initial step in the complex molecular mechanisms leading to opiate tolerance and dependence. This study was designed to evaluate in parallel the contents of immunolabeled micro-opioid receptors (glycosylated proteins), two representative GRKs (GRK 2 and GRK 6) and beta-arrestin-2 in brains of opiate addicts who had died of an opiate overdose (heroin or methadone). The immunodensities of micro-opioid receptors were decreased (66 kDa protein: 24%, n=24, P<0.0001; 85 kDa protein: 16%, n=24, P<0.05) in the prefrontal cortex of opiate addicts compared with sex-, age-, and PMD-matched controls. This down-regulation of brain micro-opioid receptors was more pronounced in opiate addicts dying of a heroin overdose (27-30%, n=13) than in those who died of a methadone overdose (5-16%, n=11). In the same brains, significant decreases in the immunodensities of GRK 2 (19%, n=24, P<0.05), GRK 6 (25%, n=24, P<0.002) and beta-arrestin-2 (22%, n=24, P< 0.0005) were also quantitated. In contrast, the content of alpha-internexin (a neuronal marker used as a negative control) was not changed in brains of opiate addicts. In these subjects, there was a significant correlation between the densities of GRK 6 and beta-arrestin-2 (r=0.63, n=24, P=0.001), suggesting that both proteins are regulated in a coordinated manner by opiate drugs in the brain. The results indicate that opiate addiction in humans (tolerant state) is associated with down-regulation of brain micro-opioid receptors and regulatory GRK 2/6 and beta-arrestin-2 proteins. These molecular adaptations may be relevant mechanisms for the induction of opiate tolerance in brains of opiate addicts.     

Repressive/defensive coping, endogenous opioids and health: how a life so perfect can make you sick

Hyperactivity of endogenous opioid systems has been postulated to mediate the associations between defensive/repressive coping styles, enhanced stress responsivity, and reduced immunocompetence. Study 1 examined whether repressive/defensive coping would be associated with greater sensitivity to opioid antagonism. Judgments of the painfulness of ascending series of electrocutaneous stimulation applied to the forearm were determined before and after the administration of naloxone and placebo in 38 men and 42 women. All subjects were healthy with a mean age of 32.9 years. Naloxone (10 mg i.v.) and placebo were administered in double-blind fashion and counterbalanced. Subjects were classified as High- and Low-defensive and repressive copers on the basis of scores on the Marlowe-Crowne Social Desirability Scale and the Balanced Inventory of Desirable Responding, respectively. High Self-Deception was associated with naloxone-induced hyperalgesia, whereas no effects of naloxone on pain ratings were observed in low-Self-Deceptive subjects. In Study 2, resting plasma beta-endorphin levels were found to be positively correlated with defensiveness in men (n = 26), but not women (n = 44). Study 3 examined 82 healthy subjects (mean age = 28.7 years). Beta-endorphin/defensiveness correlations were found to be greater following, compared to prior to, electrical nociceptive stimulation in men (n = 49), but unrelated in women (n = 33). These findings are consistent with the hypothesized endorphinergic dysregulation associated with repressive/defensive coping styles and are discussed in terms of the immuno-regulatory implications of such a dysregulation.     

Effectiveness of the methadone programme in the treatment of patients on a mephedrone binge and dependent on heroin: a retrospective study, 2010–19

Abstract

Objectives: The purpose of this research was to investigate the effectiveness of the methadone programme in a group of patients taking mephedrone with heroin.

Methods: The research involved 230 people who took part in the methadone programme between 2010 and 2019: 101 people on a mephedrone binge and taking heroin and 129 people addicted to heroin.

Results: Number of re-hospitalisations was higher in a group of patients on a mephedrone binge taking heroin in comparison to heroin dependent patients (91.9 vs 79.8%, p?<?0.01). The interaction of the hepatitis C virus (HCV) infection with the dose of methadone taken explains 67.6% of the variance in the frequency of hospitalisation of the patients on a mephedrone binge (p?<?0.001), and in the case of the dose of methadone alone – only 12% (p?<?0.001). Regression analysis indicated that statistically significant majority of the subjects (p?<?0.001) who received the optimal dose of methadone, namely 100–110?ml, were hospitalised once.

Conclusions: The interaction of the methadone dose with HCV infection plays a very important role in the frequency of hospitalisation of patients taking mephedrone with heroin on a regular basis.

• KEY POINTS

• The number of hospitalisations was higher in a group of patients on a mephedrone binge taking heroin in comparison to heroin dependent patients

• The interaction of the sex of the subjects and HCV infection with the dose of methadone taken explains 80.3 and 67.6% of variance in the frequency of hospitalisations, respectively

• The most optimal dose of methadone in the group of people taking mephedrone with heroin ranges between 100 and 110?ml

     

The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Substance Use and Related Disorders. Part 2: Opioid dependence

Abstract

Objectives. To develop evidence-based practice guidelines for the pharmacological treatment of opioid abuse and dependence. Methods. An international task force of the World Federation of Societies of Biological Psychiatry (WFSBP) developed these practice guidelines after a systematic review of the available evidence pertaining to the treatment of opioid dependence. On the basis of the evidence, the Task Force reached a consensus on practice recommendations, which are intended to be clinically and scientifically meaningful for physicians who treat adults with opioid dependence. The data used to develop these guidelines were extracted primarily from national treatment guidelines for opioid use disorders, as well as from meta-analyses, reviews, and publications of randomized clinical trials on the efficacy of pharmacological and other biological treatments for these disorders. Publications were identified by searching the MEDLINE database and the Cochrane Library. The literature was evaluated with respect to the strength of evidence for efficacy, which was categorized into one of six levels (A–F). Results. There is an excellent evidence base supporting the efficacy of methadone and buprenorphine or the combination of buprenorphine and naloxone for the treatment of opioid withdrawal, with clonidine and lofexidine as secondary or adjunctive medications. Opioid maintenance with methadone and buprenorphine is the best-studied and most effective treatment for opioid dependence, with heroin and naltrexone as second-line medications. Conclusions. There is enough high quality data to formulate evidence-based guidelines for the treatment of opioid abuse and dependence. This task force report provides evidence for the efficacy of a number of medications to treat opioid abuse and dependence, particularly the opioid agonists methadone or buprenorphine. These medications have great relevance for clinical practice.     

Methadone dose increase and abstinence reinforcement for treatment of continued heroin use during methadone maintenance

BACKGROUND: Although methadone maintenance is an effective therapy for heroin dependence, some patients continue to use heroin and may benefit from therapeutic modifications. This study evaluated a behavioral intervention, a pharmacological intervention, and a combination of both interventions. METHODS: Throughout the study all patients received daily methadone hydrochloride maintenance (initially 50 mg/d orally) and weekly counseling. Following baseline treatment patients who continued to use heroin were randomly assigned to 1 of 4 interventions: (1) contingent vouchers for opiate-negative urine specimens (n = 29 patients); (2) methadone hydrochloride dose increase to 70 mg/d (n = 31 patients); (3) combined contingent vouchers and methadone dose increase (n = 32 patients); and (4) neither intervention (comparison standard; n = 28 patients). Methadone dose increases were double blind. Vouchers had monetary value and were exchangeable for goods and services. Groups not receiving contingent vouchers received matching vouchers independent of urine test results. Primary outcome measure was opiate-negative urine specimens (thrice weekly urinalysis). RESULTS: Contingent vouchers and a methadone dose increase each significantly increased the percentage of opiate-negative urine specimens during intervention. Contingent vouchers, with or without a methadone dose increase, increased the duration of sustained abstinence as assessed by urine screenings. Methadone dose increase, with or without contingent vouchers, reduced self-reported frequency of use and self-reported craving. CONCLUSIONS: In patients enrolled in a methadone-maintainence program who continued to use heroin, abstinence reinforcement and a methadone dose increase were each effective in reducing use. When combined, they did not dramatically enhance each other's effects on any 1 outcome measure, but they did seem to have complementary benefits.