Treatment outcome in methadone detoxification: relationship to initial levels of illicit opiate use

Two groups each of 10 patients enrolled in a 90-day outpatient detoxification program were classified on the basis of high (92.5% of tests) and low (7.5% of tests) rates of opiate-positive urine test results during two weeks of dosage stabilization. Pretreatment demographic variables did not differ between the two groups. Relapse to opiate use during the detoxification occurred in patients who were initially opiate free. By the end of the dose reduction period, opiate-positive rates were 60% and 87% of tests for the low and high opiate use groups, respectively. Sedative use and missed clinic days showed similar trends for both groups during the detoxification, although different patterns of drop-out from treatment were noted. Symptomatology increased during dose reduction for the low- but not for the high-frequency opiate group. In general, treatment outcome appeared equally poor for patients who showed low or high levels of illicit opiate drug use early in detoxification treatment.     

Randomised double-blind comparison of lofexidine and clonidine in the out-patient treatment of opiate withdrawal

This study compares the clinical response to lofexidine and clonidine in the out-patient treatment of opiate withdrawal in 50 opiate addicts, using a randomised double-blind study design. Patients were taking 40 mg or less methadone daily, or equivalent amounts of other opiates. Fifty-eight percent of those starting treatment completed detoxification, and were opiate free at 4 weeks: more patients completed withdrawal in the lofexidine group, but the difference was not significant. Clonidine produced more hypotensive effects: more home visits were also required by medical staff. There was no other significant difference in side effects. Both drugs can be used successfully in out-patient detoxification, but lofexidine is more economical in regard to staff time.     

METODO,A Prospective Observational Study to Assess the Efficacy and Tolerability of Methadone in Heroin-Addicted Patients Undergoing a Methadone Maintenance Treatment: Preliminary Results at Baseline Evaluation

METODO (methadone efficacy therapy optimization dosage on-going) is a prospective observational study to assess the efficacy and tolerability of methadone in 500 heroin-addicted patients taking a methadone maintenance treatment, enrolled through 2010 to 2011 in five Italian sites, observed over 2 years. The Opiate Dosage Adequacy Scale has been used for the evaluation of the “adequacy” of the methadone dosage and to stratify patients in adequate and not adequate groups. The treatment efficacy has been evaluated in correlation to the dosage adequacy during the visits. Moreover, patients have been evaluated according to the retention rate and duration of retention in treatment and a series of questionnaires.     

Acupuncture treatment for opiate addiction: a systematic review

A review of the efficacy of acupuncture as treatment for opiate addiction, covering 33 years of reported literature in western scientific journals, was systematically undertaken. Some abstracts from Chinese language journals were also briefly reviewed.

Supportive evidence often came from noncontrolled nonblinded methodologies. When well-designed clinical trials (randomized, controlled, single-blind methodologies) were used, there was no significant evidence for acupuncture being a more effective treatment than controls. Some of the current supportive evidence for efficacy came from Chinese journals that have not been translated into English yet.     

Pharmacokinetics of methadone and its primary metabolite in 20 opiate addicts

In a closed metabolic ward the pharmacokinetics of methadone and its primary metabolite (EDDP) were studied in 20 long-term opiate addicts. After administration of the daily oral dose of methadone HCl (mean 60 mg, range 10–225 mg) blood samples were taken and analysed, using a newly developed high-performance liquid chromatography (HPLC) method. The steady-state plasma concentrations of the 20 subjects varied from 65–630 ng·ml^–1 and from 5 to 55 ng·ml^–1, whereas the peak concentrations were 124–1255 ng·ml^–1 and 10 – 301 ng·ml^–1 for methadone and EDDP, respectively. The calculated ratios between the area under the curve (AUC_{(0–24 h)}) for methadone and the AUC_{(0–24 h)} for EDDP varied from 5.9 to 44.6, indicating interindividual differences in metabolic activity. In 19 out of 20 subjects the pharmacokinetics of methadone are best described using a two-compartment model. The mean body clearance was 1.64 ml·min^–1·kg^–1, whereas the mean elimination rate constant () and plasma half-life (t _1/2) were 0.026·h^–1 (range 0.013–0.053·h^–1) and 31.2 h (range 13–53 h), respectively. Differences of gender were also found. A poor correlation was found between the methadone dose and the steady-state level. A much better correlation was found between the normalized steady-state level and the body clearance.     

Auricular acupuncture as an adjunct to opiate detoxification treatment: Effects on withdrawal symptoms

It was hypothesized that auricular acupuncture would lead to reduced severity of opiate withdrawal symptoms and craving when provided as an adjunct to methadone detoxification. The study used a randomized, placebo-controlled study design. The sample consisted of 83 drug misusers who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for opiate dependence. Daily measures of withdrawal severity and craving were taken using the Short Opiate Withdrawal Scale and an eight-item craving questionnaire. Urine screening was used as an objective assessment of treatment adherence. The study hypothesis was not confirmed. Auricular acupuncture had no effect upon withdrawal severity or craving when provided as an adjunct to a standard methadone detoxification treatment. The results are consistent with the findings of other studies that failed to find any effect of acupuncture in the treatment of drug dependence. The failure to find any clinical gains from the adjunctive use of auricular acupuncture during detoxification from opiates raises concerns about the widespread acceptance of this intervention.     

Postwithdrawal Exposure Treatment to Prevent Relapse in Opiate Addicts: A Pilot Study

A major problem in treating opiate addiction is relapse within a few months after withdrawal. Learning models of relapse offer some promise toward understanding this problem. The present pilot study examines whether cue-exposure treatment to drug-related cues, in hospital and real life, might reduce relapse. Fourteen opiate addicts were withdrawn on clonidine over 6 days, and 10 of those were exposed to drug-related cues in hospital for 1 week and in real life for another. There were then followed as outpatients up to 6 months. Craving was elicited in half of the 10 patients exposed to drug cues who showed within- and between-session habituation. Four cases were opiate-free at 6 months follow up and 1 at 3 months. Half of the cases had relapsed to heroin at various times up to 6 months. Habituation to craving responses was not obviously related to outcome whereas vocational factors were. The operational use of craving in research is discussed.     

Coca and Cocaine: A Bibliography

Abstract

Using signs, symptoms and serum methadone levels to guide evaluation, the authors treated 164 patients in a methadone maintenance program with doses of methadone exceeding 100 mg/d. The mean dose of these higher dose (HD) patients was 211 mg/d (range 110–780 mg/d). A comparison group (C) of 101 patients was randomly selected from the general clinic population mean dose 65 mg/d). At intake the HD group reponed $153/day of heroin use versus $87/day in the C group. The HD group had more patients whose opiate of choice was an oral pharmaceutical (30% versus 2% of the C group). Sixty-three percent of the HD group had comorbid Axis I psychiatric diagnoses compared to 32% of the C group. Response to psychopharmacologic treatment was enhanced by increased methadone dose in HD patients with “refractory” psychiatric disorders. Urine toxicologies described as “before” were collected prior to increase over 100 mg/d in the HD group or at the first routine urine toxicology collection of the calendar year for the C group. These results were compared to the most recent urine toxicologies for both groups (“after”). The percentage of toxicologies positive for illicit drugs in the HD group dropped from 87% “before” to 3% “after”. The C group were 54% positive “before” and 37% positive “after”. We conclude that doses of methadone in excess of 100 mg/d (range 110—780 mg/d in our sample of 164 patients) are not only safe but necessary to prevent illicit opiate use, stabilize psychiatric symptoms, and diminish abuse of alcohol and benzodiazepines in many patients.     

Autoanalgesia: acquisition, blockade and relationship to opiate binding

Acquisition of autoanalgesia (behaviorally activated antinociception) was assessed across 7 consecutive days by shocking rats 10 sec after the determination of their tail-flick latencies. Thus the effect of conditioned fear on antinociception was being investigated, since each shock preceded the subsequent tail-flick test by 24 h. Autoanalgesia was acquired by the second fear-conditioning trial. Although pretreatment with naltrexone or diazepam had no effect, spinal cord transection at the thoracic level effectively obviated autoanalgesia. Investigations of opiate and opioid binding indicated significantly less binding in the fear-conditioned rats as well as an inverse relationship between binding and antinociception. These changes in binding are suggestive of partial mediation of autoanalgesia by an endogenous opiate peptide that is released by the fear-conditioning procedure.     

Binding of 3H-beta-endorphin to rat brain membranes: characterization of opiate properties and interaction with ACTH

The binding of tritiated beta-endorphin (3H-beta-EP) to brain homogenates is described. This has been difficult to achieve due to the lack of availability of 3H-beta-EP and to technical difficulties associated with high non-specific binding of beta-EP. We now report that 3H-beta-EP binding is saturable, stereospecific, has high affinity and is inhibited by sodium. Its dissociation rate is ten-fold longer than that of naloxone. Its regional distribution exhibits interesting differences from naloxone and enkephalin binding. ACTH1-24 appears to displace it more effectively than it displaces 3H-naloxone. The results are discussed in terms of multiple transmitter systems and the multiple opiate receptor hypothesis.     

Modulation of Fas receptor proteins and dynamin during opiate addiction and induction of opiate withdrawal in rat brain

The Fas receptor is involved in the regulation of apoptosis but also can function as a non-apoptotic signal transducer. This study was mainly designed to quantitate Fas proteins in rat brain during heroin addiction and opiate withdrawal. In rat, mouse and human brains, and in SH-SY5Y cells, similar forms of Fas were immunodetected with different antibodies (i.e., 35 kDa native Fas and 48- and 51-kDa glycosylated Fas). Acute (2 h) treatments with the -opioid receptor agonists heroin (10 mg/kg) and morphine (30 mg/kg) increased the immunodensity of native Fas (124% and 36%) but not that of glycosylated Fas in the cerebral cortex. Chronic (5 days) heroin (5–30 mg/kg) and morphine (10–100 mg/kg) were also associated with increased native Fas (76% and 45%) and with different expressions of glycosylated Fas. In heroin-dependent rats, opiate withdrawal (48 h) resulted in a sustained increase in native Fas (107%) and in up-regulation of 51 kDa glycosylated Fas (51%). Acute treatments with selective -receptor (SNC-80, 10 mg/kg) or -receptor (U 50488-H, 10 mg/kg) agonists did not alter the content of native or glycosylated Fas. Chronic pentazocine (10–80 mg/kg, 5 days), a mixed opiate drug and ₁ receptor agonist, decreased native (48%) and glycosylated (38–82%) Fas proteins. Similarly, the selective ₁ agonist (+)-SKF 10047 also decreased native Fas (37%) and the effect was blocked by the ₁ antagonist BD 1063. Brain dynamin was up-regulated by acute and/or chronic heroin (30–39%), morphine (47–85%), pentazocine (51%) and heroin withdrawal (74%). The main results indicate that chronic heroin/morphine treatment and heroin withdrawal are associated with up-regulation of 35 kDa native Fas (and with different expressions of glycosylated Fas), and also with concomitant increases of dynamin in rat brain.     

No evidence for a protracted change in endogenous opioid activity following chronic opiate treatment in mice: parallel recovery of cross tolerance to stress and morphine antinociception

The involvement of central endogenous opioids in swim-induced antinociception in mice is well documented. The response is attenuated by central or systemic naloxone, displays two-way cross tolerance with morphine and is correlated with apparent occupation of central opiate receptors by endogenous ligands. Swim-induced antinociception was utilised as an in vivo model of endogenous opioid function to investigate a possible protracted functional change in endogenous opioid release or inactivation following chronic opiate treatment. Antinociceptive responses (tailflick latency) to morphine (4.4 mg/kg, SC) and swimming were determined at various times following chronic methadone (24 days treatment, 102 mg/kg day in drinking water for the last 20 days) and chronic morphine (1 g/kg sustained release) treatment. In both experiments, parallel recovery from cross tolerance was observed for morphine-and swim-induced antinociception. These results were consistent with the view that no protracted functional change in the release or inactivation of endogenous opioids had occurred following chronic opiate treatment.     

The opiate quasiwithdrawal syndrome in rhesus monkeys: Comparison of naloxone-precipitated withdrawal to effects of cholinergic agents

The effects of the cholinergic agents UM-1046 (3-cyclopropyl-methyl-1,2,3,4,5,6-hexahydro-8-hydroxy-6-methyl-3-benzazocine hydrochloride) and physostigmine in normal rhesus monkeys were compared to naloxone-precipitated withdrawal in morphine-dependent subjects. The two cholinergic drugs produced effects that resembled one another, as well as some of the effects of naloxone in morphine-dependent subjects. The constellation of signs produced by the cholinergic drugs, while overlapping, was not identical to that produced by naloxone in opiate-dependent subjects. Although cholinergic agents produce many of the signs of opiate withdrawal, the withdrawal syndrome in its complete manifestation involves many different neurotransmitter systems.     

Drug-using mothers: social, psychological and substance use problems of women opiate users with children

The present study looks at patterns of drug use and alcohol use, social and economic circumstances, criminal involvement and health problems among a sample of 66 women opiate users with children. Data were collected using a structured interview. The women reported a wide range of substance use and other problems including depression. Many were heavy and regular drinkers. Most of the women were in a relationship with an opiate user: one-third reported that their partner had been physically violent towards them. Almost all of these women were living in a state of poverty. Many of the mothers were in conflict regarding their dependence upon drugs and their fears about their children being taken into care. The women who were most severely dependent upon both heroin and alcohol felt that if they sought treatment this might help them to avoid having their children taken into care. At the same time they were afraid that, by approaching treatment, this might increase the risk of their children being taken from them. Services should seek to reduce the barrier to treatment presented by the anxieties of women with children as well as improving facilities for the care of women with children.     

Pathways through opiate use and offending: A systematic review

BackgroundAlthough evidence points to a strong link between illicit drug use and crime, robust evidence for temporal order in the relationship is scant. We carried out a systematic review to assess the evidence for pathways through opiate/crack cocaine use and offending to determine temporal order.MethodsA systematic review sourced five databases, three online sources, bibliographies and citation mapping. Inclusion criteria were: focus on opiate/crack use, and offending; pre-drug use information; longitudinal design; corroborative official crime records. Rate ratios (RR) of post-drug use initiation to pre-drug use initiation were pooled using random effects meta-analysis.Results20 studies were included; UK (9) and US (11). All were of opiate use. Mean age at (recorded) offending onset (16.7 yrs) preceded mean age at opiate-use onset (19.6 yrs). Substantial heterogeneity (over 80%: unexplained by meta-regression) meant that RRs were not pooled. The RR for total (recorded) offending ranged from 0.71 to 25.7 (10 studies; 22 subsamples: positive association, 4: equivocal, 1: negative association). Positive associations were observed in 14/15 independent samples; unlikely to be a chance finding (sign test p = 0.001).Individual offence types were examined: theft (RR 0.63–8.3, 13 subsamples: positive, 9: equivocal, 1 negative); burglary (RR 0.74–50.0, 9 subsamples: positive, 13: equivocal); violence (RR 0.39–16.0, 6 subsamples: positive, 15: equivocal); and robbery (RR 0.50–5.0, 5 subsamples: positive, 15: equivocal).ConclusionsAvailable evidence suggests that onset-opiate use accelerates already-existing offending, particularly for theft. However, evidence is out of date, with studies characterised by heterogeneity and failure to use a matched non-opiate-user comparison group to better-establish whether onset-opiate use is associated with additional crime.     

Lofexidine in opiate withdrawal: a safety and usage survey

A retrospective, observational survey, conducted under the remit of the Safety Assessment of Marketed Medicines guidelines, collected data on nearly 1100 patients who had attempted an opiate detoxification with lofexidine, to identify current treatment protocols and safety. This approach offered a number of advantages over a prospective, randomized, clinical trial. It captured data on ‘real‐life' patients with a variety of co‐existing illnesses and taking a wide range of concurrent medications. Data on exposure to lofexidine by three pregnant patients were documented and different dosage regimens have been described. The retrospective approach was not, however, without some limitations. The patients' medical notes were found to be incomplete and causality had not been assigned for many of the adverse events. However, providing the limitations of the retrospective approach are acknowledged, useful information has been collected on the current usage and safety of lofexidine, which has enabled the manufacturer to make a number of recommendations. Copyright © 2000 John Wiley & Sons, Ltd.     

The development of addiction to d-amphetamine in an animal model: same principles as for alcohol and opiate

We have established a rat model that reflects the course of development of alcohol and opiate addiction. The present study with d-amphetamine aimed to define general principles in the development of an addiction. Male rats had a continuous free choice between d-amphetamine solutions (100, 200 and 400 mg/l) and water for 47 weeks. An initial intake of high doses of d-amphetamine during the first weeks of drug choice was followed by an individually stable pattern of drug consumption of moderate drug doses. During this period of controlled consumption (from week 10 to week 40), the voluntary intake of d-amphetamine depended on individual factors (dominant rats: 0.37 ± 0.02 mg/kg per day, subordinate rats: 0.57 ± 0.05 mg/kg per day) and environmental variables (group housing: 0.21 ± 0.02 mg/kg per day, single housing: 0.41 ± 0.03 mg/kg per day). Beginning with week 41, voluntary d-amphetamine consumption progressively increased (1.9 ± 0.2 mg/kg per day in week 47), although the experimental conditions remained unchanged. Drug intake during a retest (free choice as before) after 6 months of drug deprivation revealed that the rats had persistently lost their control over drug intake and were no longer able to adjust drug taking to internal and external conditions. These addicted rats took very high drug doses, even when all d-amphetamine solutions but not water were adulterated with bitter tasting quinine (6.6 ± 0.6 mg/kg per day; age-matched controls: 0.37 ± 0.04 mg/kg per day). Forced intake of d-amphetamine for 47 weeks (7.1 ± 0.3 mg/kg per day) via the drinking fluid caused physical dependence (hyperreactivity during withdrawal) but did not lead to drug addiction (voluntary intake in the retest with adulteration: 0.42 ± 0.04 mg/kg per day). Both the temporal development and the prerequisites of psychostimulant addiction were in principle the same as for alcohol and opiates. Received: 3 April 1998/Final version: 26 August 1998     

Methodological investigations for a multisite trial of auricular acupuncture for cocaine addiction: A study of active and control auricular zones

We evaluated objective criteria for defining points for needle insertion prior to conducting a multisite clinical trial of auricular acupuncture for cocaine addiction. Thirty-four cocaine-abusing subjects participated in a study in which the trial's active zones (Shenmen, Liver, Lung, and Sympathetic) and control zones (located on the ear helix) were divided into quadrants and assessed along four dimensions: electrical resistance, skin discoloration, skin topography, and tenderness. Acute effects of needles inserted into points of low electrical resistance in one ear and high electrical resistance in the other were also assessed. Results showed that the active zones had lower overall electrical resistance and more subcutaneous ridges than control zones. Zones did not possess significant variability along any single dimension. Acute effects of needling high and low resistance points were similar, differing only for “fullness.” Based on these findings, and in view of the difficulty of accurately measuring electrical resistance at ear points, we do not recommend the use of electrical devices for point determination in the multisite study. At present, there seems to be little scientific basis for the preselection of specific points for needle insertion within auricular zones. Needle placement should be based upon clinical judgement.