Treatment in England of Canadian Patients Addicted to Narcotic Drugs

The method of treatment and the results obtained from the treatment of 50 Canadian patients addicted to narcotic drugs who went to England are recorded. These patients were first stabilized on the minimal dose of narcotic drug which permitted them to work, and to acquire security and self-respect. Then, after psychiatric treatment dealing with the basic problem of their personality disorder, complete withdrawal treatment of the narcotic drug was undertaken.Nine of 10 patients aged between 20 and 30, of good social and cultural background, have been relieved of dependence on drugs for over two years.The other 40 patients came from a different background. Nearly all had been imprisoned for drug offences and they had come to England to obtain treatment and to avoid further prison sentences in Canada.The 31 patients whose prison sentences had been directly connected with drug offences are working steadily and leading an apparently normal life.The remaining nine patients had been convicted of criminal acts before becoming addicted to narcotic drugs and, with two exceptions, the results of their treatment compare unfavourably with the other patients, seven having been convicted and imprisoned in London.     

Can the Chronic Administration of the Combination of Buprenorphine and Naloxone Block Dopaminergic Activity Causing Anti-reward and Relapse Potential?

Opiate addiction is associated with many adverse health and social harms, fatal overdose, infectious disease transmission, elevated health care costs, public disorder, and crime. Although community-based addiction treatment programs continue to reduce the harms of opiate addiction with narcotic substitution therapy such as methadone maintenance, there remains a need to find a substance that not only blocks opiate-type receptors (mu, delta, etc.) but also provides agonistic activity; hence, the impetus arose for the development of a combination of narcotic antagonism and mu receptor agonist therapy. After three decades of extensive research, the federal Drug Abuse Treatment Act 2000 (DATA) opened a window of opportunity for patients with addiction disorders by providing increased access to options for treatment. DATA allows physicians who complete a brief specialty-training course to become certified to prescribe buprenorphine and buprenorphine/naloxone (Subutex, Suboxone) for treatment of patients with opioid dependence. Clinical studies indicate that buprenorphine maintenance is as effective as methadone maintenance in retaining patients in substance abuse treatment and in reducing illicit opioid use. With that stated, we must consider the long-term benefits or potential toxicity attributed to Subutex or Suboxone. We describe a mechanism whereby chronic blockade of opiate receptors, in spite of only partial opiate agonist action, may ultimately block dopaminergic activity causing anti-reward and relapse potential. While the direct comparison is not as yet available, toxicity to buprenorphine can be found in the scientific literature. In considering our cautionary note in this commentary, we are cognizant that, to date, this is what we have available, and until such a time when the real magic bullet is discovered, we will have to endure. However, more than anything else this commentary should at least encourage the development of thoughtful new strategies to target the specific brain regions responsible for relapse prevention.     

Chronic morphine administration decreases 5-hydroxytryptamine and 2-hydroxyindoleacetic acid content in the brain of rats

To study the effects of chronic morphine treatment on cerebral 5-hydroxytryptamine (5HT) metabolism morphine was administered twice daily for 5 or 8 weeks to male Wistar rats. Control rats were treated with 0.9% NaCl solution for the same period. In rats treated chronically with morphine for 8 weeks the cerebral concentrations of 5HT and 5HIAA were reduced by 12--15% (P less than 0.05) at 26--28 h after the last morphine injection (50 mg/kg s.c.). No such decrease was found in the brain of rats treated with morphine for 5 weeks. A test dose of morphine (30 mg/kg s.c. 2h) increased the cerebral concentration and probenecid-induced accumulation of 5HIAA in the rats treated with morphine for 8 weeks almost as much as in the brain of the control rats. Naloxone (10 mg/kg s.c. 2h) did not cause clear changes in the cerebral 5HT or 5HIAA concentration. These experiments suggest that endogenous opioid mechanisms are concerned in the regulation of 5HT neurons and that prolonged morphine treatment weakens these mechanisms. This weakening of endogenous regulation of 5HT neurons, which, however, still respond to acute morphine administration, might be part of the mechanism of compulsive drug use in narcotic addiction. It is possible that these neurons in dependent individuals do not function optimally without exogenous morphine. A similar phenomenon--weakening of endogenous regulation combined with clear responsivity to exogenous opiates--occurs in the cerebral dopamine neurons of rats treated chronically with narcotic analgesics.     

Basal opioid receptor activity, neutral antagonists, and therapeutic opportunities

The mu opioid receptor (MOR, OPRM)--the principal receptor involved in narcotic addiction--has been shown to display basal (spontaneous, constitutive) signaling activity. Interaction with other signaling proteins, such as calmodulin, regulates basal MOR activity. Providing a mechanism for long-lasting regulation, basal MOR activity potentially plays a key role in addiction, in combination with gene regulation and synaptic remodeling. Recent results support a link to physical dependence--one of the main manifestations of addiction to drugs of abuse. The prototypical opioid antagonists, naloxone and naltrexone, were shown to act as inverse agonists in the morphine-dependent state (i.e., they suppress basal MOR signaling) and thereby appear to elicit or contribute to precipitated withdrawal. This affords the opportunity to explore therapeutic applications for neutral antagonists (blocking agonists at MOR without affecting basal activity) with reduced adverse effects. Neutral antagonists are promising drug candidates in the treatment of addiction and overdose, and of peripheral adverse effects of narcotic analgesics.     

Violence and psychosis. I. Risk of violence among psychotic men.

A survey of the records of 1241 men remanded in prison on criminal charges over four months yielded a high prevalence of psychiatric disorder. Of the total prison intake of 2743 men over the same period, 246 (9.0%) showed major symptoms of psychiatric illness and a further 237 (8.6%) symptoms of withdrawal from drugs or alcohol. Symptoms of neurotic disorders were underrecorded, so in terms of diagnosis 237 men (8.7%) were considered to be psychotic. Of these, 166 (70%) were schizophrenic. The influence of affective psychosis was small. The risk of violence among men with schizophrenia was high. Twenty five (9%) non-fatal personal assaults and 24 (21%) offences of damage to property were committed by men with schizophrenia. The presence of mental illness probably influences the decision to remand in custody for some of these offences, but this is unlikely to explain the substantially higher prevalence of schizophrenia among men convicted of homicide (five (11%) ) and arson (six (30%) ) than would be expected in the general population of Greater London (0.1-0.4%). The prevalence of schizophrenia among men convicted of homicide may even be an underestimate, as may the prevalence of affective psychosis and possibly of other psychiatric abnormalities, given the substantial incidence of concurrent suicide in such men.     

Single‐nucleotide polymorphism (A118G) in exon 1 of OPRM1 gene causes alteration in downstream signaling by mu‐opioid receptor and may contribute to the genetic risk for addiction

The opioid receptor mu1 (OPRM1) mediates the action of morphine. Although genetic background plays an important role in the susceptibility toward abuse of drugs as evident from familial, adoption and twin studies, association of specific single‐nucleotide polymorphisms of OPRM1 gene with narcotic addiction is to be established. Here, we demonstrate the involvement of A118G polymorphism of exon1 of human OPRM1 gene (hOPRM1), with heroin and alcohol addiction, in a population in eastern India. Statistical analysis exhibited a significant association of G allele with both heroin and alcohol addiction with a risk factor of P_trend < 0.05. The functional significance of G allele in A118G single‐nucleotide polymorphisms was evaluated by studying the regulation of protein kinase A (PKA), pCREB, and pERK1/2 by morphine in Neuro 2A cells, stably transfected with either wild type or A118G mutant hOPRM1. Unlike acute morphine treatment, both chronic morphine exposure and withdrawal precipitated by naloxone were differentially regulated by A118 and G118 receptor isoforms when both PKA and pERK1/2 activities were compared. Results suggest that the association of A118G polymorphism to heroin and alcohol addiction may be because of the altered regulation of PKA and pERK1/2 during opioid and alcohol exposures.     

The prevalence of hepatitis B and C markers among narcotic users

611 patients with acute parenteral virus hepatitis (VH) were studied with a view to find out markers indicating the presence of hepatitis B and hepatitis C virus infection (HB, HC, HB + C, HC + HBsAg). Of these, 166 patients (27.2%) systematically used narcotic drugs intravenously. Essential differences between drug users and VH patients without drug addiction were established regarding the distribution of patients by age and sex, the etiological structure and severity of the disease. Thus, in the group of drug users the prevalence of males, young people (15-29 years of age) and the mixed form of hepatitis B + C was noted. In VH patients using drug the disease took a more severe course than in such patients without drug addiction. The highest proportion of intravenously drug users with a severe and moderate course of the disease was found among patients with HB + C and HB.     

Profiles of brain functional asymmetry in patients with alcoholism and drug addiction

Profiles of motor, sensory, and cognitive asymmetries in patients with drug addiction and alcoholism and in people of relevant control group were studied. To reveal the profiles of interhemispheric asymmetry, a set of tests for determination of lateralization of motor (the dominant hand and leg), sensory (eye and ear) and cognitive (right- and left-hemispheric mode of solution of verbal and/or spatial tasks) was used. In patients with drug addiction and alcoholism as compared with the control group, a statistically significant domination of the left-sided lateralization of motor and sensory indexes was found. The right-hemispheric mode was essentially prevailing in solving the verbal and spatial tasks. No differences in motor asymmetry were observed in narcotic addicts and alcoholics. The dominant left eye and ear were statistically significantly more frequent in patients with alcoholism than in patients with drug addiction. The right-hemispheric mode in solution of cognitive tasks was used more often statistically significantly by narcotic addicts than by alcoholics. The obtained data indicate an essential impairment of profiles of the motor, sensory, and cognitive asymmetries in patients with the chemical addiction.Translated from Zhurnal Evolyutsionnoi Biokhimii i Fiziologii, Vol. 40, No. 5, 2004, pp. 450–454.Original Russian Text Copyright © 2004 by Egorov, Tikhomirov.To the 100-Anniversary of N. N. Traugott     

A systems and control theory approach to dynamic neurotransmitter balance in narcotic addiction and narcotic antagonism.

We have formulated a pharmacological-physiological systems analysis and control theory based on interactive neuronal feedback loops (the effects of endogenous neurochemical diseases and exogenous CNS drugs on neurotransmitter synthesis and release, reuptake and metabolism) for normal, abnormal and catastrophic situations.We set up the systems diagrams for neurotransmitter systems and in that single framework were able to describe endogenous neurochemical disorders, the effect that their drug treatment modalities had on the dynamic neurochemical balance and the effect other CNS drugs such as narcotics and narcotic antagonists had on neurochemical balance. This led to a hypothesis that narcotic addiction is caused by negative feedback induced increase in synthesis and release of certain neurotransmitters, tolerance arises in a related manner, narcotic withdrawal symptoms are caused by out-of-phase feedback and a major mechanism of antagonist action of narcotic antagonists is not merely competitive displacement of a narcotic from its “receptor site” but rather is due to an increase in the concentration of catecholamines in the synaptic cleft.     

Indigenous and expatriate addicts in Laos: A Comparison

Opium addiction has been reported among virtually all large ethnic groups in Asia. Conspicuous by its absence has been any mention of addiction among the Lao, a people surrounded by poppy-growing tribal groups. A sample of Lao patient-addicts are here compared to expatriate Asian addicts in Laos.Lao and expatriate addicts show marked similarity in their sociodemographic profiles and patterns of narcotic use. Some differences in their recent use of narcotic drugs appear related to the greater cash income of the expatriate Asians and their greater access to heroin. No specifically cultural factors for explaining ethnic differences in addiction have yet been identified.Acknowledgement is expressed to Dr. Charles Weldon, Dr. Chomchan Soudaly, Mr. Larry Berger, and Mr. Boun Ke for their support and assistance in this study. Ms. Grace Peng and Ms. Beth Stone assisted in the tabulation and analysis of the data. The project was supported by the Minnesota Medical Foundation, the International Programs Office at the University of Minnesota, and the National Institute of Drug Abuse (grant no. 5 T01 DA 00023-02 and grant no. 1 R01 DA 01599-01).     

Blood volume pulse biofeedback treatment of chronic cluster headache

Behavioral interventions shown to be clinically effective in the treatment of migraine headache have generally not been employed for cluster headache. Herein, we report on the treatment of a severe case of chronic cluster headache with a common method of migraine treatment, temporal blood volume pulse (BVP) biofeedback. The patient was a 61-year-old male, medically diagnosed as suffering from chronic cluster headaches for over 20 years. Following an 18-day baseline, 14 BVP biofeedback sessions were conducted over a 7-week period. By the last 2 weeks of treatment, there was a 70% reduction in daily headache frequency and a 45% decrease in headache severity. Improvement was maintained at 1, 3, 6, 12, and 21 months follow-up. Large decreases in the consumption of migraine abortives, narcotic analgesics, and antiemetics were also observed. These encouraging results call for further evaluation of the efficacy of BVP biofeedback treatment of chronic cluster headache.This research was supported in part by the Psychological Services Center, Memphis State University. Portions of this article were presented at the meeting of the Society of Behavioral Medicine, Chicago, March 1982.     

Drug Taking in Adolescent Girls: Factors Associated with the Progression to Narcotic Use

A follow-up study of girls in a London remand home during the years 1966-8 showed that 20·6% of those taking non-narcotic drugs on admission, but only 1% of non-drug-taking control admissions, had used narcotics by June 1970. Narcotic use on admission and progression to narcotic use were associated with frequent drug taking, marked involvement in a drug milieu, and a high incidence of personal morbidity. Adolescents who use illicit drugs and have a history of court appearances for any reason are particularly vulnerable to subsequent narcotic usage and other forms of serious drug abuse.     

A COMPARISON OF CERTAIN ACTIONS OF DEMEROL AND METHADONE

Demerol and methadone have advantages over morphine. Demerol requires a higher dosage than methadone, but produces less respiratory depression. Therefore, it can be used more freely in cases where respiratory depression is contraindicated. Demerol does not depress the cough reflex, and methadone is preferred for this purpose. Both drugs have a sufficient tendency to produce addiction that the usual narcotic restrictions should be observed.     

The Journey from Traffic Offender to Severe Road Trauma Victim: Destiny or Preventive Opportunity?

Background

Road trauma is a leading cause of death and injury in young people. Traffic offences are common, but their importance as a risk indicator for subsequent road trauma is unknown. This cohort study assessed whether severe road trauma could be predicted by a history of prior traffic offences.

Methodology and Principal Findings

Clinical data of all adult road trauma patients admitted to the Western Australia (WA) State Trauma Centre between 1998 and 2013 were linked to traffic offences records at the WA Department of Transport. The primary outcomes were alcohol exposure prior to road trauma, severe trauma (defined by Injury Severity Score >15), and intensive care admission (ICU) or death, analyzed by logistic regression. Traffic offences directly leading to the road trauma admissions were excluded. Of the 10,330 patients included (median age 34 years-old, 78% male), 1955 (18.9%) had alcohol-exposure before road trauma, 2415 (23.4%) had severe trauma, 1360 (13.2%) required ICU admission, and 267 (2.6%) died. Prior traffic offences were recorded in 6269 (60.7%) patients. The number of prior traffic offences was significantly associated with alcohol-related road trauma (odds ratio [OR] per offence 1.03, 95% confidence interval [CI] 1.02–1.05), severe trauma (OR 1.13, 95%CI 1.14–1.15), and ICU admission or death (OR 1.10, 95%CI 1.08–1.11). Drink-drinking, seat-belt, and use of handheld electronic device offences were specific offences strongly associated with road trauma leading to ICU admission or death—all in a ‘dose-related’ fashion. For those who recovered from road trauma after an ICU admission, there was a significant reduction in subsequent traffic offences (mean difference 1.8, 95%CI 1.5 to 2.0) and demerit points (mean difference 7.0, 95%CI 6.5 to 7.6) compared to before the trauma event.

Significance

Previous traffic offences were a significant risk factor for alcohol-related road trauma and severe road trauma leading to ICU admission or death.     

Tuberculosis surveillance in immigrants to Manitoba.

Despite a decrease in the incidence of tuberculosis in Canada over the last decade, the proportion of cases in people not born in Canada has increased. To determine the prevalence of active tuberculosis at the first surveillance clinic visit and the incidence of the disease over a 2-year to 6-year follow-up period, we reviewed the records of all 523 immigrants admitted to Manitoba between 1981 and 1985 who were placed under surveillance. Of the 523, 429 (82%) were seen at least once in the clinic. Among the 429, active tuberculosis was diagnosed at the first visit in 12 (3%) and during the follow-up period in 7 (2%). The relative risk of tuberculosis was 4.5 times higher for immigrants under surveillance than for those not under surveillance. Of the 483 immigrants who were to be seen in Winnipeg 232 (48%) were noncompliant: 94 were not seen at any time, and 138 did not attend for the full follow-up period. Active disease was not reported to have developed in any of the noncompliant subjects. Noncompliers were significantly older than compliers (p less than 0.005), and variations in compliance were noted according to region of origin. Further attempts to improve compliance with surveillance without resorting to punitive measures are indicated.     

Long-term maintenance of improvements achieved with (abortive) pharmacological and nonpharmacological treatments for migraine: Preliminary findings

This report presents the first prospective comparison of the long-term maintenance of reductions in recurrent migraine headaches achieved with (abortive) pharmacological and nonpharmacological (combined relaxation training and thermal biofeedback training) treatments. Nineteen of 21 (90%) successfully treated patients (50% or greater reduction in headache activity) were contacted for follow-up evaluation 3 years later. Migraine sufferers who had been treated with ergotamine were less likely to still be relying on the treatment they had received and more likely to have additional medical treatment for their headaches and to be using prophylactic or narcotic medication than were migraine sufferers who had been treated with relaxation/biofeedback training. However, daily headache recordings revealed that patients in both treatment groups continued to show lower headache activity at 3-year follow-up than prior to treatment. Although preliminary, these findings raise the possibility that improvements achieved with nonpharmacological treatment are more likely to be maintained without additional treatment than are similar improvements achieved with abortive pharmacological treatment.A Baker Award from Ohio University provided support for the original outcome study.Abgelo Theofanous with R. L. Associates (Ann Arbor).     

Long-term maintenance of improvements achieved with (abortive) pharmacological and nonpharmacological treatments for migraine: preliminary findings

This report presents the first prospective comparison of the long-term maintenance of reductions in recurrent migraine headaches achieved with (abortive) pharmacological and nonpharmacological (combined relaxation training and thermal biofeedback training) treatments. Nineteen of 21 (90%) successfully treated patients (50% or greater reduction in headache activity) were contacted for follow-up evaluation 3 years later. Migraine sufferers who had been treated with ergotamine were less likely to still be relying on the treatment they had received and more likely to have additional medical treatment for their headaches and to be using prophylactic or narcotic medication than were migraine sufferers who had been treated with relaxation/biofeedback training. However, daily headache recordings revealed that patients in both treatment groups continued to show lower headache activity at 3-year follow-up than prior to treatment. Although preliminary, these findings raise the possibility that improvements achieved with nonpharmacological treatment are more likely to be maintained without additional treatment than are similar improvements achieved with abortive pharmacological treatment.     

Opiate receptors

The main goal of pharmacology is to establish the complete chain of causality between the combination of a drug with its specific receptor and the manifest effects of that drug in the organism. The central concern of modern molecular pharmacology is to understand the first step in that chain -- the drug-receptor interaction (1). Unusual interest attaches to opiate receptors because of the role they may play in analgesia, the euphorigenic effects of narcotics, and other aspects of narcotic addiction such as tolerance and physical dependence.