Time-Dependent Neuroendocrine Alterations and Drug Craving during the First Month of Abstinence in Heroin Addicts

Rationale: Heroin use and withdrawal cause abnormality in the endocrine system. However, the time course of neuroendocrine alterations in heroin addicts during pharmacologically unassisted withdrawal is still unclear. Objectives: To investigate alterations in cortisol, adrenocorticotrophic hormone (ACTH), beta-endorphin (beta-EP), leptin, and neuropeptide Y (NPY) during the first month of abstinence in heroin addicts. Methods: Twelve heroin addicts and eight matched healthy control subjects were recruited for this study. The neuroendocrine alterations and self-reported heroin craving, anxiety, and depression in heroin addicts were assessed at different time points (days 3, 10, and 30) of first month of abstinence from heroin use. Results: Self-reported heroin craving, anxiety, and depression in heroin addicts decreased gradually during the first month of abstinence. The cortisol levels increased from abstinence day 3 to 30, while ACTH and beta-EP levels decreased over this period in heroin addicts. The leptin and NPY levels were significantly decreased on days 3 and 10 but had normalized on day 30 of abstinence. A positive correlation between cortisol level and heroin craving, anxiety, and depression was observed, while a negative correlation was observed between beta-EP level and craving and anxiety and between leptin and depression and NPY and anxiety. Conclusions: Abnormal alterations in the neuroendocrine system, including levels of cortisol, ACTH and beta-EP persist throughout the first month of abstinence. These results suggest that neuroendocrine system dysfunctions in heroin abusers is independent of the acute and protracted withdrawal syndromes, and may thus contribute to relapse to heroin use.     

Dysfunction of the Hypothalamic–Pituitary–Adrenal Axis in Opioid Dependent Subjects: Effects of Acute and Protracted Abstinence

Objectives: The function of the Hypothalamic–Pituitary–Adrenal (HPA) axis during opioid dependence has been inconsistent. We compared HPA axis measures between subjects during methadone stabilization and drug-free detoxification with healthy controls. Methods: Sixty heroin dependent patients received either non-opiate treatment (NOT) with benzodiazepines and clonidine (n = 30) or methadone stabilization treatment (MT, n = 30), and their serum levels of corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and cortisol (COR) were measured and compared to those of healthy, nondependent controls. Results: Compared with healthy controls, CRH was significantly lower (p <. 001) while COR was higher (p <. 001) during acute withdrawal in the NOT group. CRH and COR was lower (p <. 001), while ACTH was normal in the MT group compared to healthy controls. Conclusions: Our findings suggest that chronic opioid dependence may cause reduced function of the HPA axis, while opioid withdrawal may decrease the response of the pituitary to CRH and increase the adrenal response to ACTH.     

Efficacy of clonidine, guanfacine and methadone in the rapid detoxification of heroin addicts: a controlled clinical trial

The efficacy of clonidine, methadone, and guanfacine in rapid detoxification of heroin inpatients was assessed in a randomized controlled clinical trial. Signs and symptoms of abstinence and of side effects were analysed in 90 heroin addicts successfully completing a 12–day inpatient trial, all patients fit DSM-III criteria for opioid dependence, the age range being 18 to 36 years. All three drugs were effective in controlling abstinence; however, the course of abstinence was different in the methadone group as compared to the adrenergic agonists, the latter showing limitations in their ability to suppress withdrawal manifestations. While mean number of withdrawal signs and symptoms was significantly tower during days 2 to 5 in the methadone group (p < 0.01), adrenergic agonists were slightly more effective at the end of the trial. Incidence of side effects was closely related to the dose administered. Hypotensive action of adrenergic agonists was more marked in orthostatic position. The present results suggest that methadone is superior to adrenergic agonists. Between these drugs clonidine appears to be less effective than guanfacine in controlling some withdrawal manifestations, and causes more side effects, mainly of cardiovascular nature.     

The dysphoria of heroin addiction.

Levels of dysphoria and opioid dependence were assessed in 54 male patients with heroin addiction applying for drug treatment. During a period of naturalistic heroin use, symptom measures of dysphoria and of spontaneous opioid withdrawal reported by these patients were highly correlated. Upon admission to treatment, levels of dysphoria and opioid withdrawal were assessed before and after a pharmacological challenge with either 0.4 mg naloxone or placebo. Signs and symptoms of opioid withdrawal and symptoms of dysphoria increased in patients following naloxone, but not placebo administration. Naloxone-induced changes in symptoms of dysphoria were correlated with changes in opioid withdrawal as assessed by both subjective and objective measures. These findings suggest that dysphoric mood states in heroin addicts may be, in part, pharmacological sequelae of their drug dependence. Dysphoria due to opioid withdrawal may contribute to the initiation and maintenance of heroin use, and to the high rates of syndromal affective disorders reported in this population.     

Clinical Pharmacokinetics of Lofexidine,the α 2-Adrenergic Receptor Agonist,in Opiate Addicts Plasma Using a Highly Sensitive Liquid Chromatography Tandem Mass Spectrometric Analysis

Objectives: The objective of this investigation was to characterize the pharmacokinetic profile of lofexidine. Lofexidine is an orally bioavailable α 2-adrenergic receptor agonist analogue of clonidine that acts centrally to suppress opiate withdrawal symptoms. Methods: During the detoxification period of a phase 3 placebo-controlled, randomized, double-blind trial, six subjects were entered in this preliminary pharmacokinetic study. Results: Pharmacokinetic analysis of plasma samples collected during study day 7 indicated that C_max was 3242 ± 917 ng/L. The mean trough levels between the study days were not significantly different (p >. 05), suggesting that the subjects were at steady-state. Conclusions: Although preliminary due to the limited number of subjects, these findings are the first to document lofexidine clinical pharmacokinetics in opiate addicts using a highly sensitive liquid chromatography tandem mass spectrometric analysis.     

The Combination Very Low-Dose Naltrexone–Clonidine in the Management of Opioid Withdrawal

Background: The management of withdrawal absorbs substantial clinical efforts in opioid dependence (OD). The real challenge lies in improving current pharmacotherapies. Although widely used, clonidine causes problematic adverse effects and does not alleviate important symptoms of opioid withdrawal, alone or in combination with the opioid antagonist naltrexone. Very low-dose naltrexone (VLNTX) has been shown to attenuate withdrawal intensity and noradrenaline release following opioid agonist taper, suggesting a combination with clonidine may result in improved safety and efficacy. Objectives: We investigated the effects of a VLNTX–clonidine combination in a secondary analysis of data from a double-blind, randomized opioid detoxification trial. Methods: Withdrawal symptoms and treatment completion were compared following VLNTX (.125 or .25 mg/day) and clonidine (.1–.2 mg q6h) in 127 individuals with OD undergoing 6-day methadone inpatient taper at a community program. Results: VLNTX was more effective than placebo or clonidine in reducing symptoms and signs of withdrawal. The use of VLNTX in combination with clonidine was associated with attenuated subjective withdrawal compared with each medication alone, favoring detoxification completion in comparison with clonidine or naltrexone placebo. VLNTX/clonidine was effective in reducing symptoms that are both undertreated and well controlled with clonidine treatment and was not associated with significant adverse events compared with other treatments. Conclusions and Scientific Significance: Preliminary results elucidate neurobiological mechanisms of OD and support the utility of controlled studies on a novel VLNTX + low-dose clonidine combination for the management of opioid withdrawal.     

海洛因成瘾者唾液表皮生长因子含量及相关舌苔的观察

目的测定海洛因成瘾者脱瘾后唾液表皮生长因子(EGF)含量,观察相应的舌苔变化,探讨成瘾者EGF与舌苔的关系及脾虚的本质.方法92例海洛因成瘾者脱毒后15～30d,对照组85例,测定唾液EGF并同时观察舌苔.结果成瘾者唾液EGF含量比对照组显著低下(P＜0.01).成瘾者舌苔厚腻者明显多于对照组.结论海洛因成瘾者脱瘾后EGF低下是其舌苔厚腻和脾虚的原因之一.     

Opium and Heroin Alter Biochemical Parameters of Human's Serum

Background: Iran is a significant consumer of opium, and, generally, of opioids, in the world. Addiction is one of the important issues of the 21st century and is an imperative issue in Iran. Long-term consumption of opioids affects homeostasis. Objective: To determine the effects of opium and heroin consumption on serum biochemical parameters. Methods: In a cross-sectional study, subjects who had consumed heroin (n = 35) or opium (n = 42) for more than two years and 35 nonaddict volunteers as the control group were compared in regard to various biochemical parameters such as fasting blood sugar (FBS), Na⁺, K⁺, Ca²⁺, blood urea nitrogen (BUN), uric acid (UA), triglyceride (TG), cholesterol, creatinine, and total protein. Chromatography was used to confirm opioid consumption, and the concentration of biochemical parameters was determined by laboratory diagnostic tests on serum. Results: No significant differences were found in Na⁺, Ca²⁺, BUN, UA, TG, creatinine, and total protein concentrations among the three groups. FBS, K⁺, and UA levels were significantly lower in opium addicts compared to the control group. Serum Ca²⁺ concentration of heroin addicts showed a significant decrease compared to that of the control group. Both addict groups showed a significant decrease in serum cholesterol levels. Conclusion: Chronic use of opium and heroin can change serum FBS, K⁺, Ca²⁺, UA, and cholesterol. Scientific Significance: This study, one of few on the effects of opium on serum biochemical parameters in human subjects, has the potential to contribute to the investigation of new approaches for further basic studies.     

Meperidine in detoxification of hospitalized heroin addicts

Forty-six heroin abusers were hospitalized and treated with meperidine either alone or in association with clonidine. Meperidine was given orally in rapidly decreasing doses according to three different schedules. The majority of patients (87%) successfully completed the detoxification program. The best meperidine starting posology was 200 mg four times daily, which allowed stoppage of the opioid treatment after gradual reduction of the daily dose in a mean time of 9.5 days. Association with clonidine was not proven to be useful. This study shows that meperidine can be effectively used in rapidly decreasing doses in the pharmacological detoxification treatment of hospitalized heroin addicts.     

THE EFFECT OF HEROIN ADDICTION ON PITUITARY-TESTICULAR FUNCTION

The effect of heroin addiction on pituitary-testicular function was studied in 54 active and 19 abstinent addicts and their results were compared with those of 43 age-matched controls. Abnormal sexual function was frequently found in heroin addicts and this persisted after drug withdrawal. The mean total (mean +/- SE, 18.1 +/- 1.0 nmol/1) and free (0.17 +/- 0.03 nmol/1) testosterone (T) levels in heroin addicts were significantly lower than those in healthy controls (total T 22.8 +/- 1.1 nmol/1), P less than 0.005; free T 0.30 +/- 0.03 nmol/1, P less than 0.005). The mean sex hormone binding globulin binding capacity was higher in heroin addicts (60.1 +/- 5.2 mM) than in healthy controls (35.5 +/- 2.1 mM). These hormonal changes returned promptly to normal after withdrawal. The basal LH and FSH and the responses to LHRH were comparable in the three groups studied. The finding of significantly lower total and free T together with higher SHBG indicates an abnormal testicular function in heroin addiction. Normal basal and LHRH-stimulated LH and FSH levels suggest that chronic heroin abuse depressed testicular function via the hypothalamus or higher centres.     

Alpha2-adrenergic agonists in opioid withdrawal

Objectives This paper presents the main findings of a systematic (Cochrane) review of the effectiveness of α₂‐adrenergic agonists in managing opioid withdrawal. Design The original systematic review included controlled trials that compared α₂‐adrenergic agonists with another form of treatment (or placebo) in participants who were primarily opioid‐dependent. Main findings Ten studies compared a treatment regime based on an α₂‐adrenergic agonist with one based on reducing doses of methadone. Withdrawal intensity is similar to, or marginally greater with α₂‐adrenergic agonists, but signs and symptoms of withdrawal occur and resolve earlier in treatment. Participants stay in treatment longer with methadone. The likelihood of completing withdrawal is similar, or slightly less, with clonidine or lofexidine. Clonidine is associated with more adverse effects than reducing doses of methadone. Three studies compared the α₂‐adrenergic agonists, clonidine and lofexidine. Lofexidine does not reduce blood pressure to the same extent as clonidine, but is otherwise similar to clonidine. Conclusions Participants stay in treatment longer with methadone regimes, which may provide greater opportunity for psychosocial intervention. Methadone regimes may be preferable for withdrawal in outpatient settings where the risk of relapse to heroin use is high. The use of methadone may also facilitate transfer to maintenance treatment should completion of withdrawal become unlikely. For those who are well prepared for withdrawal and seeking earlier resolution of withdrawal symptoms, α₂‐adrenergic agonist treatment may be preferred. Clonidine and lofexidine appear equally effective for inpatient settings, but the lower incidence of hypotension makes lofexidine more suited to use in outpatient settings.     

Impaired circadian rhythmicity of beta-lipotrophin, beta-endorphin and ACTH in heroin addicts

The circadian rhythm of plasma proopiocortin-related peptides was studied in 15 heroin addicts and in 6 sex- and age-matched controls. ACTH, beta-lipotrophin, (beta-LPH), beta-endorphin (beta-EP) and cortisol were measured by RIA either directly (cortisol), or after plasma extraction (ACTH) and Sephadex G-75 gel chromatography (beta-LPH and beta-EP) every 4 h from 8 a.m. to 8 p.m. and again at 8 a.m. the next morning. The means of the two 8 a.m. measurements of beta-LPH (2.67 +/- 0.34 fmol/ml, mean +/- SE), ACTH (2.74 +/- 0.71) and cortisol (218 +/- 31 pmol/ml) levels in heroin addicts were significantly lower than those in controls (6.28 +/- 0.61, 10.1 +/- 0.74 and 364 +/- 27, respectively, P less than 0.01) while beta-EP concentrations in heroin addicts (5.1 +/- 0.6) were similar to those of healthy volunteers (6.44 +/- 0.56). In controls, all three peptides and cortisol show a circadian rhythm of secretion, the lowest values being in the evening and the highest ones in the morning. Heroin addicts partially lack this phenomenon showing constant levels of the three proopiocortin-related peptides throughout the day, with a slight but significant decrease of plasma cortisol. In the 7 subjects who took heroin throughout the study, no systematic changes were observed in the three proopiocortin-related peptides, while it seems that this group of addicts shows a cortisol decrease in the evening to a lesser extent than subjects receiving methadone maintenance only.(ABSTRACT TRUNCATED AT 250 WORDS)     

EFFECTS OF HEROIN ADDICTION ON THYROTROPHIN, THYROID HORMONES AND PROLACTIN SECRETION IN MEN

Pituitary-thyroid function in male heroin addicts and addicts after abstinence (ex-addicts) was studied and compared with that of healthy euthyroid men. In heroin addicts the increases in circulating total thyroxine and triiodothyronine levels were accompanied by an increase in the thyroid hormone uptake test. These changes may reflect a quantitative increase in thyroxine binding globulin. Reverse triiodothyronine concentrations in heroin addicts were normal. The thyrotrophin-releasing hormone elicited a diminished thyrotrophin response in heroin addicts which was significantly different from that in control subjects and ex-addicts. An elevation of serum prolactin was noted in heroin addicts, while ex-addicts had normal levels. Gradual recovery of pituitary-thyroid function occurred after heroin withdrawal.     

Alcohol consumption in heroin users,methadone-substituted and codeine-substituted patients--frequency and correlates of use

This retrospective study aims to determine whether there is a difference in the additional consumption of alcohol between addicts treated with methadone or dihydrocodeine (DHC) and untreated addicts injecting heroin. 1685 patients admitted for opioid withdrawal between 1991 and 1997 were reviewed. Cross-reference tables and multiple logistic regression analyses were carried out. 28% of patients take more than 40 g of alcohol daily (on average 176 g). We found that patients who are treated with methadone or DHC drink alcohol significantly more often daily than the heroin-dependent patients (p < 0.01). Using multiple regression analyses, the results were confirmed. Additionally, we found that co-abuse of alcohol was predicted by male gender, longer duration of drug use, additional daily consumption of tetrahydrocannabinol and daily consumption of benzodiazepines. Alcohol consumption by opioid-addicted patients treated with methadone or DHC presents a serious medical problem. Co-abuse of alcohol will receive more attention.     

Primary care-based ambulatory opioid detoxification

OBJECTIVE: To determine the feasibility of primary care-based ambulatory opioid detoxification (AOD) using two protocols: clonidine and clonidine plus naltrexone. SETTING: The Central Medical Unit (CMU)—a freestanding primary care medical clinic staffed by physicians and nurse practitioners. PATIENTS: Injection drug users (IDUs) seeking substance abuse treatment between the ages of 18 and 50 years who were addicted to opioids (e.g., heroin) and not currently in drug treatment. INTERVENTIONS: In the clonidine protocol, clonidine was administered every 4 hours “as needed” for up to 12 days. In the clonidine plus naltrexone protocol, clonidine was administered and naltrexone was administered in increasing doses over five days. Both protocols included “adjuvant” medications for muscle cramps, insomnia, and vomiting. Successfully detoxified patients were referred to ongoing drug treatment. DESIGN: A prospective nonrandomized clinical trial. MEASUREMENTS AND MAIN RESULTS: One hundred forty opioid-addicted IDUs were referred to the medical clinic for AOD. Among the 125 patients who enrolled in the study, 57 selected clonidine and 68 selected clonidine/naltrexone. The treatment groups (clonidine vs clonidine/naltrexone) were similar at baseline with respect to: age at first heroin use (21 years vs 23 years), mean admission opioid craving score (45/100 vs 49/100), and withdrawal symptom score (19/72 vs 18/72). Overall, 70% (88/125) of the AODs were successful, including 42% (24/57) for clonidine and 94% (64/68) for clonidine/naltrexone (p<0.001). CONCLUSIONS: This study suggests that primary care-based AOD can be safely and effectively carried out by primary care providers and that clonidine/naltrexone may be more effective in this setting than is clonidine alone. Ambulatory opioid detoxification can give internists a larger role in initiating drug treatment for IDUs who are addicted to opioids.     

Treatment of acute opioid withdrawal with ibogaine.

Ibogaine is an alkaloid with putative effect in acute opioid withdrawal. Thirty-three cases of treatments for the indication of opioid detoxification performed in non-medical settings under open label conditions are summarized involving an average daily use of heroin of .64 +/- .50 grams, primarily by the intravenous route. Resolution of the signs of opioid withdrawal without further drug seeking behavior was observed within 24 hours in 25 patients and was sustained throughout the 72-hour period of posttreatment observation. Other outcomes included drug seeking behavior without withdrawal signs (4 patients), drug abstinence with attenuated withdrawal signs (2 patients), drug seeking behavior with continued withdrawal signs (1 patient), and one fatality possibly involving surreptitious heroin use. The reported effectiveness of ibogaine in this series suggests the need for systematic investigation in a conventional clinical research setting.     

Methadone and buprenorphine maintenance therapies for patients with hepatitis C virus infected after intravenous drug use

Heroin addiction is a chronic relapsing disease that is difficult to cure, but stabilisation and harm reduction can importantly increase the life time expectancy and the quality of life of the patient, his immediate vicinity and society in general. Currently, no proven effective pharmacological interventions are available for cocaine addiction, and treatment has to rely on existing cognitive behaviour therapies combined with contingency management strategies. Substitution therapy, however, is effective in caring for heroin addicts. Methadone is a synthetic opioid that counteracts withdrawal symptoms of heroin. Buprenorphine is a derivative of the morphine alkaloid, thebaine, and is a partial opioid agonist at the micro opioid receptor in the nervous system. A substitution treatment program effectively reduces and often eliminates heroin injection behaviour, rendering patients more socially stabilised. Reduction in the number of viral co-infections can be observed. Methadone undergoes oxidative biotransformation in the liver, but is also stored in the liver and released into the blood in unchanged form. The usual dose can be continued in patients with stable chronic liver disease, including advanced cirrhosis. In acute liver disease or acute decompensation of chronic liver disease, close clinical observation for signs of narcotic overdose or withdrawal is necessary. A modest alteration in methadone dose may be appropriate for some patients. Buprenorphine can cause liver dysfunction after sublingual and even more after intravenous administration. It is advised to follow the liver function during buprenorphine treatment and to warn the clients for intravenous use of buprenorphine. Neither methadone nor buprenorphine do influence the effect of interferon and ribavirin during the treatment of chronic hepatitis C patients. It may be necessary to increase the dosage of methadone during interferon treatment.     

Treatment of opioid use disorder with ibogaine: detoxification and drug use outcomes

Background: Ibogaine is a monoterpene indole alkaloid used in medical and nonmedical settings for the treatment of opioid use disorder. Its mechanism of action is apparently novel. There are no published prospective studies of drug use outcomes with ibogaine. Objectives: To study outcomes following opioid detoxification with ibogaine. Methods: In this observational study, 30 subjects with DSM-IV Opioid Dependence (25 males, 5 females) received a mean total dose of 1,540 ± 920 mg ibogaine HCl. Subjects used oxycodone (n = 21; 70%) and/or heroin (n = 18; 60%) in respective amounts of 250 ± 180 mg/day and 1.3 ± 0.94 g/day, and averaged 3.1 ± 2.6 previous episodes of treatment for opioid dependence. Detoxification and follow-up outcomes at 1, 3, 6, 9, and 12 months were evaluated utilizing the Subjective Opioid Withdrawal Scale (SOWS) and Addiction Severity Index Composite (ASIC) scores, respectively. Results: SOWS scores decreased from 31.0 ± 11.6 pretreatment to 14.0 ± 9.8 at 76.5 ± 30 hours posttreatment (t = 7.07, df = 26, p < 0.001). At 1-month posttreatment follow-up, 15 subjects (50%) reported no opioid use during the previous 30 days. ASIC Drug Use and Legal and Family/Social Status scores were improved relative to pretreatment baseline at all posttreatment time points (p < .001). Improvement in Drug Use scores was maximal at 1 month, and subsequently sustained from 3 to 12 months at levels that did not reach equivalence to the effect at 1 month. Conclusion: Ibogaine was associated with substantive effects on opioid withdrawal symptoms and drug use in subjects for whom other treatments had been unsuccessful, and may provide a useful prototype for discovery and development of innovative pharmacotherapy of addiction.     

Reduced dopamine D4 receptor mRNA expression in lymphocytes of long-term abstinent alcohol and heroin addicts

Aim It has been repeatedly suggested that dopamine receptor expression in peripheral blood lymphocytes reflects, to some extent, brain status. The aim of the present study was to investigate dopamine receptor expression in peripheral blood lymphocytes of long‐term abstinent alcohol and heroin addicts against the background of the hypothesis, that a persisting dysfunction of the dopaminergic system contributes a biological cause to the chronic character of addiction. Design Dopamine D3 and D4 receptor mRNA expression in peripheral blood lymphocytes was measured by real‐time polymerase chain reaction (PCR) in 19 alcohol addicts, abstinent for 6.2 ± 4.7 months (mean ± SD), and 20 heroin addicts, abstinent for 6.7 ± 3.7 months (mean ± SD), and compared to a control group of 29 age‐ and sex‐matched individuals with no life‐time history of substance abuse. Findings One‐way anova showed significant differences in D4 mRNA expression between the groups (P = 0.005): both groups of addicts showed an approximately 50% reduction in D4 receptor mRNA expression in peripheral blood lymphocytes (PBL) compared to controls. No differences were found for D3 mRNA expression between the groups. Conclusion The results of the present study indicate a withdrawal‐persisting dopaminergic imbalance in abstinent addicts as measured by a suggested peripheral marker.     

Benefits of recurrent, outpatient heroin detoxification

Recurrent heroin detoxification, or the "revolving-door" process, is the treatment of choice for many addicts. Forty-five heroin addicts were detoxified 145 times (mean = 3.2 per patient) on an outpatient basis over a 3-year period and showed significant improvement in arrest and hospitalization rates but not employment or intact marriages. Another group of 74 patients who had detoxified two or more times were compared to a similar group of 61 methadone maintenance (mean maintenance time = 17.9 weeks) patients, and no significant difference was found in a variety of health, employment, and social indicators. These findings indicate that recurrent, outpatient heroin detoxification has some therapeutic benefits and provides an explanation for patient popularity.