Buprenorphine and methadone maintenance treatment of heroin addicts preserves immune function

Opiate addiction influences many physiological functions including immune responses. The objective of this study was to investigate the immune system function in heroin addicted patients submitted to methadone or buprenorphine maintenance treatment compared to untreated heroin addicts and healthy controls. Four groups were studied: group A included nine heroin addicted subjects, who were still injecting heroin; groups B and C were composed of 12 patients previously addicted to heroin, being treated with methadone (mean dosage 58+/-12.7 mg/day) or buprenorphine (mean dose 9.3+/-2.3mg/day) since at least 6 months; group D was composed of 15 sex and age matched healthy controls. Lymphoproliferation and peripheral mononuclear cell cultures production of the Th1 cytokines IL-2 and IFN-gamma, the Th2 cytokine IL-4, and of the pro-inflammatory cytokine TNF-alpha were evaluated in all the patients and controls. PHA-lymphoproliferation was lower in untreated heroin addicts than in controls, while it was normal in methadone and buprenorphine treated patients. An altered Th1/Th2 balance, characterized by reduced IL-4, IFN-gamma and TNF-alpha but normal IL-2 levels, was present in untreated heroin addicted subjects, while the Th1/Th2 balance was well conserved in the methadone and buprenorphine groups. These findings suggest that the immune system abnormalities in heroin addicted patients can be restored to almost normal values by controlled treatment with methadone and buprenorphine.     

Buprenorphine reduces alcohol drinking through activation of the nociceptin/orphanin FQ-NOP receptor system.

BACKGROUND: Activation of the NOP receptor by its endogenous ligand nociceptin/orphanin FQ reduces ethanol intake in genetically selected alcohol preferring Marchigian Sardinian alcohol preferring (msP) rats. Here we evaluated whether buprenorphine, a partial agonist at micro-opioid and NOP receptors, would reduce ethanol consumption in msP rats via activation of NOP receptors. METHODS: Marchigian Sardinian alcohol preferring rats trained to drink 10% alcohol 2 hours/day were injected with buprenorphine (.03, .3, 3.0, or 6.0 mg/kg intraperitoneally [IP]) 90 min before access to ethanol. RESULTS: Similar to prototypical micro-agonists, the two lowest doses of buprenorphine significantly increased ethanol consumption (p < .01); in contrast, the two highest doses reduced it (p < .05). Pretreatment with naltrexone (.25 mg/kg IP) prevented the increase of ethanol intake induced by .03 mg/kg of buprenorphine (p < .001) but did not affect the inhibition of ethanol drinking induced by 3.0 mg/kg of buprenorphine. Conversely, pretreatment with the selective NOP receptor antagonist UFP-101 (10.0 or 20.0 microg/rat) abolished the suppression of ethanol drinking by 3.0 mg/kg of buprenorphine. CONCLUSIONS: Buprenorphine has dualistic effects on ethanol drinking; low doses increase alcohol intake via stimulation of classic opioid receptors, whereas higher doses reduce it via activation of NOP receptors. We suggest that NOP agonistic properties of buprenorphine might be useful in the treatment of alcoholism.     

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.     

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.     

Chronic cannabis use does not affect the normalization of hypothalamic-pituitary-adrenal (HPA) axis induced by methadone in heroin addicts

The hypothalamic-pituitary-adrenal (HPA) axis activity is usually altered by heroin use. In the present study we evaluated in one hundred twenty-one heroin addicts the effects of marijuana smoking on the normalization of HPA axis upon methadone treatment. The study showed that in heroin addicts who are chronic cannabis smokers a treatment with methadone lasting 12 months was able to normalize both plasma corticotropin (ACTH) and cortisol levels, as well as to control both heroin withdrawal symptoms and opioid craving. As expected in the same group of patients marijuana smoking and its craving were not reduced by methadone treatment. Our data confirm that methadone treatment outcomes are not modified by cannabis use and they add in the literature the evidence that chronic cannabis use is not able to affect the normalization of HPA axis upon methadone treatment in heroin addicts.     

Inadequate plasma concentrations in some high-dose methadone maintenance patients

The author studied 18 heroin addicts who had been maintained on 80 mg/day of methadone and who abused drugs or alcohol. His findings suggest that in some cases of aberrant methadone metabolism, the dose can be raised to achieve plasma concentrations adequate to eliminate drug and alcohol abuse.     

Alternative induction and crossover schedules for methadyl acetate

Various schedules exist for inducting heroin addicts newly admitted to treatment into methadyl acetate maintenance and crossover schedules for the transition from methadone maintenance to methadyl acetate maintenance. A sample of 255 street addicts was randomized to three induction schedules: methadyl acetate three times a week (tiw) with placebos on alternate days; methadyl acetate tiw supplemented with decreasing doses of methadone on alternate days; methadyl acetate six days a week with diminishing doses on three days. Treatment was double-blind for four weeks and single-blind for six. All schedules were considered feasible, but supplementation with methadyl acetate or methadone had no advantage. A sample of 310 patients receiving methadone maintenance was randomized to comparable supplementation groups, except that the group receiving supplementary methadyl acetate received it along with the regular dose. This schedule was not successful. Supplementing with methadone had no advantage.     

Acute effect of methadone maintenance dose on brain FMRI response to heroin-related cues

OBJECTIVE: Environmental drug-related cues have been implicated as a cause of illicit heroin use during methadone maintenance treatment of heroin dependence. The authors sought to identify the functional neuroanatomy of the brain response to visual heroin-related stimuli in methadone maintenance patients. METHOD: Event-related functional magnetic resonance imaging was used to compare brain responses to heroin-related stimuli and matched neutral stimuli in 25 patients in methadone maintenance treatment. Patients were studied before and after administration of their regular daily methadone dose. RESULTS: The heightened responses to heroin-related stimuli in the insula, amygdala, and hippocampal complex, but not the orbitofrontal and ventral anterior cingulate cortices, were acutely reduced after administration of the daily methadone dose. CONCLUSIONS: The medial prefrontal cortex and the extended limbic system in methadone maintenance patients with a history of heroin dependence remains responsive to salient drug cues, which suggests a continued vulnerability to relapse. Vulnerability may be highest at the end of the 24-hour interdose interval.     

Methadone is substantially less effective than morphine in modifying locomotor and brain Fos responses to subsequent methadone challenge in rats

Heroin addicts can benefit from methadone substitution therapy. However, little is known about the significance of pre-exposure to opioids for psychoactive effects of methadone. We modeled some behavioral and neurobiological aspects of the opioid abuse-related phenomena in Sprague-Dawley rats, using morphine (10 mg/kg/day) or methadone (1 or 2 mg/kg/day) treatment (14 doses over a 16-day period) followed by 2-week withdrawal and methadone challenge; control rats were given 0.9% NaCl treatment and methadone challenge by the same schedule. Locomotor response to the challenge showed substantial enhancement only after the morphine treatment. Fos immunohistochemistry in selected brain regions including cortex, nucleus accumbens, striatum and some parts of the hippocampus, thalamus and amygdala also revealed marked differences between the effects of the tested treatments. Sensitization of Fos response was found in a few regions of the morphine-treated rats. The rats given the higher methadone dose treatment showed a fairly weak tendency for sensitization that reached significance only in somatosensory cortex layer IV. The rats given the lower methadone dose treatment showed a weak while widespread tendency for an opposite change, which reached significance in cingulate cortex layer II/III and resulted in significant differences in Fos response between these rats and the morphine-treated rats in most regions studied. These results indicate that lasting neuroplastic changes associated with the sensitization caused by (sub)chronic exposure to opioids are relatively mild for methadone as compared to those caused by morphine, and suggest that psychoactive effects of methadone can be notably enhanced by past opiate use.     

Heroin vs alcohol addiction--quantifiable psychosocial similarities and differences

A pilot study of 50 heroin addicts and 66 alcohol addicts utilizing the recently developed quantitative methods for measuring life change and seriousness of illness. Alcohol addicts were found to have significant attenuation of perception of life change and seriousness of illness as compared to heroin addicts and current “normative” data. The heroin addicts were found to have a mild but significant augmentation of perception of life change and seriousness of illness as compared to the “normative” data. In addition both the heroin addicts and alcohol addicts were found to maintain very high levels of life change. The documented differences in perception and the maintenance of high levels of life change were felt to have potential significance in the treatment and evaluation of both groups of addicts.     

A randomized controlled trial of interim methadone maintenance

CONTEXT: Effective alternatives to long waiting lists for entry into methadone hydrochloride maintenance treatment are needed to reduce the complications of continuing heroin dependence and to increase methadone treatment entry. OBJECTIVE: To compare the effectiveness of interim methadone maintenance with that of the usual waiting list condition in facilitating methadone treatment entry and reducing heroin and cocaine use and criminal behavior. DESIGN: Randomized, controlled, clinical trial using 2 conditions, with treatment assignment on a 3:2 basis to interim maintenance-waiting list control. SETTING: A methadone treatment program in Baltimore. PARTICIPANTS: A total of 319 individuals meeting the criteria for current heroin dependence and methadone maintenance treatment. INTERVENTIONS: Participants were randomly assigned to either interim methadone maintenance, consisting of an individually determined methadone dose and emergency counseling only for up to 120 days, or referral to community-based methadone treatment programs. MAIN OUTCOME MEASURES: Entry into comprehensive methadone maintenance therapy at 4 months from baseline; self-reported days of heroin use, cocaine use, and criminal behavior; and number of urine drug test results positive for heroin and cocaine at the follow-up interview conducted at time of entry into comprehensive methadone treatment (or at 4 months from baseline for participants who did not enter regular treatment). RESULTS: Significantly more participants assigned to the interim methadone maintenance condition entered comprehensive methadone maintenance treatment by the 120th day from baseline (75.9%) than those assigned to the waiting list control condition (20.8%) (P<.001). Overall, in the past 30 days at follow-up, interim participants reported significantly fewer days of heroin use (P<.001), had a significant reduction in heroin-positive drug test results (P<.001), reported spending less money on drugs (P<.001), and received less illegal income (P<.02) than the waiting list participants. CONCLUSION: Interim methadone maintenance results in a substantial increase in the likelihood of entry into comprehensive treatment, and is an effective means of reducing heroin use and criminal behavior among opioid-dependent individuals awaiting entry into a comprehensive methadone treatment program.     

Innovations in agonist maintenance treatment of opioid-dependent patients

PURPOSE OF REVIEW: To provide an overview of published studies on agonist maintenance treatment options for opioid-dependent patients. RECENT FINDINGS: The recent publication of controlled trials confirms earlier clinical evidence of the efficacy of diamorphine (heroin) in the treatment of opioid dependence. Findings show not only efficacy with respect to improvement of health, reduction of illicit drug use, reduction of criminality and stabilization of social conditions, but also cost effectiveness in the treatment of chronic treatment-resistant heroin addicts. SUMMARY: Agonist maintenance treatment has become the first-line treatment for chronic opioid dependence. High-quality studies demonstrate the effectiveness of a growing number of different agonist maintenance treatments for opioid dependence such as methadone and buprenorphine. In addition, there is new evidence for the effectiveness of other agonists, mainly slow-release morphine, intravenous and inhalable diamorphine and possibly oral diamorphine. Maintenance treatment with intravenous or inhalable diamorphine should be implemented into the healthcare system to treat a group of severely dependent treatment-resistant patients. Furthermore, the opioid-dependent patients not under treatment need to be engaged in maintenance treatments through other harm reduction measures. Agonist maintenance treatment is very effective in stabilizing the health condition and social situation, while also reducing harm, thereby increasing life expectancy and quality of life.     

Desipramine in opioid-dependent cocaine abusers maintained on buprenorphine vs methadone

BACKGROUND: Cocaine abuse occurs in 40% to 60% of patients entering opioid maintenance treatment, and effective pharmacotherapies are needed for this combined dependence. METHODS: This 13-week, randomized, double-blind, placebo-controlled trial evaluated the efficacy of desipramine hydrochloride (0 or 150 mg/d) plus buprenorphine hydrochloride (12 mg/d) or methadone hydrochloride (65 mg/d) in 180 opioid-dependent cocaine abusers (124 men, 56 women). Supervised urine samples were obtained thrice weekly, and self-reported cocaine and heroin use was reported once weekly. Desipramine plasma levels were determined at weeks 4 and 10. RESULTS: In men, opioid abstinence was increased more rapidly over time when treated with methadone than with buprenorphine, whereas cocaine abstinence was increased more with buprenorphine than with methadone. In women, opioid abstinence was increased the least rapidly when treated with buprenorphine plus placebo, while cocaine abstinence was increased more rapidly over time when treated with methadone than with buprenorphine. Regardless of sex or opioid medication, desipramine increased opioid and cocaine abstinence more rapidly over time than placebo. Self-reported opioid use confirmed these findings. Desipramine plasma levels were higher in women than in men, particularly those on buprenorphine maintenance. Higher desipramine plasma levels were associated with greater opioid, but not cocaine, abstinence. CONCLUSIONS: Desipramine may be a useful adjunctive medication in facilitating opioid and cocaine abstinence in opioid-maintained patients. The efficacy of opioid medications to treat opioid or cocaine dependence may differ by sex. These findings highlight the importance of including sex as a factor when examining treatment outcome in these types of trials.     

Therapeutic usefulness of propoxyphene napsylate in narcotic addiction.

The maximum doses of propoxyphene napsylate used to treat heroin addicts produce a degree of morphine-like activity equal to that produced by 20 to 25 mg/day of subcutaneously given morphine or 10 mg/day orally given methadone. This degree of activity wound be sufficient to ameliorate abstinence even in patients dependent on large doses of narcotics--an observation that supports the utility of propoxyphene napsylate in detoxification. On the other hand, only patients taking 10 mg/day or less of parenterally administered heroin could be maintained on maximum subtoxic levels of propoxyphene napsylate without abstinence signs or symptoms suggesting that propoxyphene napsylate would be less useful in maintenance therapy.     

Maintenance treatment of opiate addicts

Maintenance treatment is now the most common treatment of opiate addicts in Germany. The principle of maintenance treatment is the administration of an opioid in order to suppress withdrawal symptoms and heroin craving. In this manner, maintenance treatment successfully reduces heroin abuse and directly associated risk behaviour. Only a minority of maintenance patients became opiate abstinent (including the maintenance drug). Racemic methadone is the most extensively evaluated maintenance drug. A differential indication between medical opioids has not been scientifically established. According to the German regulations psychosocial support is an obligatory part of maintenance treatment. Most opiate addicts suffer from comorbid mental and somatic diseases. Therefore psychiatric and somatic treatment is indicated and of proven value.     

Schedule-induced self-injection of drugs

Studies of acquisition and maintenance patterns of drug intake, including dependence, necessitate voluntary intake of drugs. Voluntary intake in animal studies is difficult to achieve because of aversive taste factors associated with most drugs, and involuntary or forced choice methods obscure the behavior which is the object of study. The schedule-induced polydipsia paradigm has been used to induce oral ingestion of large volumes of alcohol, barbiturate and other drug solutions. We have developed a method of schedule-induced self-injection which allows the study of acquisition and maintenance of drug intake behavior with changing environments free from the interference of taste factors or imbalances due to excessive water intake. In this paper we review our findings on the acquisition and maintenance patterns of amphetamine, methadone, heroin, alcohol, nicotine, cocaine, delta 9-THC and haloperidol. For all drugs except amphetamine, the combination of schedule and nutritional deprivation leads to the highest rates of drug intake as compared to controls. The schedule does not appear to be a potent factor at 90% and free feeding weight, and drug intake is the result of interaction of environmental factors and pharmacological properties of the drugs, rather than the effects of drug or environmental factors separately. The maintenance patterns of nicotine, cocaine, heroin and alcohol are also discussed and the advantages of schedule-induced self-injection over schedule-induced polydipsia methods are presented.     

Patients’ Perceptions of Opioid Replacement Therapy: a Comparison of Diamorphine and Methadone/Levomethadone

Diamorphine was first legalized as a novel treatment option for heroin dependence in Germany in 2009. Today, specialized clinics in ten German cities provide diamorphine to heavily addicted patients. As the medical and societal context of diamorphine-assisted therapy is evolving, continued research into patients’ perceptions of opioid replacement therapy remains important. From February 2018 to June 2018, we conducted a survey study of outpatients on maintenance treatment with either diamorphine (n = 85) or methadone/levomethadone (n = 126). Patients were asked to complete a self-report questionnaire querying, besides socio-demographic information, the study participant’s satisfaction with the substitute drug, relapse with illicit drugs, patterns of craving, and alcohol consumption. Duration of opioid dependence did not differ significantly between groups. Patients on diamorphine were approximately 3 years younger than patients on methadone/levomethadone. They also had a higher frequency of daily intake of their substitute drug and had had their dosage adjusted more often during the preceding 6 months. Still, diamorphine patients reported greater satisfaction with their substitute drug in tandem with significant reductions in relapse-related behaviors and cravings. While the most common relapse reported by patients on methadone replacement was heroin relapse (68%), most instances of illicit drug use in the diamorphine group involved cocaine (48%). Although self-reported alcohol consumption did not differ significantly between groups, a higher percentage of diamorphine patients than methadone patients endorsed decreased alcohol consumption since entering therapy. Taken together, these findings point to meaningful differences between diamorphine and methadone/levomethadone in opioid replacement therapy.

     

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.     

Use of Naltrexone to Treat Opioid Addiction in a Country in Which Methadone and Buprenorphine Are Not Available

Opioid dependence is one of the most severe drug dependencies. Naltrexone is a medication that completely blocks the subjective and other effects of opioids and, when administered to detoxified opioid addicts and taken as directed, prevents relapse and helps maintain abstinence. The major problem with naltrexone is poor compliance, particularly in countries in which there is a treatment alternative based on substitution of illicit opioids such as heroin with orally administered opioid agonists (methadone) or partial agonist/antagonists (buprenorphine). In Russia, substitution therapy is forbidden by law, and naltrexone is the only available pharmacotherapy for heroin dependence. Due to the lack of alternatives to naltrexone and stronger family control of compliance (adherence), naltrexone is more effective for relapse prevention and abstinence stabilization in Russia than in Western countries. Long-acting, sustained-release formulations (injectable and implantable) seem particularly effective compared with oral formulations. This article summarizes the results of studies conducted in Russia during the past 10 years that demonstrate these points.