Opiate Dependence Research Articles

A Psychiatric Presentation of Adrenal Insufficiency: A Case Report.

To the Editor: Adrenal insufficiency has been shown to display a wealth of possible psychiatric presentations including psychosis, depression, anxiety, mania, and cognitive impairment, alongside the known vague physical symptoms.1 Adrenal insufficiency is notoriously challenging to diagnose, with up to 60% of patients having been seen by at least 2 clinicians prior to diagnosis and a median duration to diagnosis of up to 2 years.2 These psychiatric symptoms may even present with no physical symptoms.1 There are several known causes of secondary adrenal insufficiency, although it is most commonly associated with an abrupt disruption in prescribed corticosteroid therapy (such as during an emergency hospital admission). Another less-often considered and rarer cause for secondary adrenal insufficiency is use of opiate medication, a commonly prescribed class of painkillers in both hospital and general practice settings. Opiates can cause hypothalamic suppression of corticotrophin-release hormone and, therefore, adrenocorticotropic hormone (ACTH) with resultant adrenal atrophy.3 In fact, while “opiate endocrinopathy” has earned increasing interest in the literature as a potential side effect of long-term or high-dose opiate use,3 only a handful of case reports4,5 describe opiate-induced secondary adrenal insufficiency, and none describe a solely psychiatric presentation. Guidelines for the management of depression from the National Institute for Clinical Excellence6 in the United Kingdom currently only contain information on the recognition and management of low mood symptoms, with no guidance for the screening of their many potential physical causes. With our increasing understanding of the fine interplay between physical disease and mental health, this guidance is potentially outdated. This case highlights the need to rule out physical causes even for patients with long-standing psychiatric diagnoses, as often the line between physical and mental health can be so blurred that careful investigation is important to avoid either potentially life-threatening complications or incorrect and ineffective treatment regimens. Case report. Mr A, a 32-year-old man with a 6-year history of poorly controlled depression and nonspecific anxiety disorder, was admitted in February 2014 to the assessment ward of a busy mental health unit in South Wales, United Kingdom, with a 1-day history of distressing and persecutory auditory hallucinations, paranoid delusions, and polydipsia. A urine drug screen was positive for amphetamines, benzodiazepines, and opiates; the latter 2 were most likely related to prescribed medication. Treatment was commenced accordingly with low-dose quetiapine. The symptomatology improved quickly, and a diagnosis of drug-induced psychosis (DSM-IV criteria) was made. The drug and alcohol services team was familiar with Mr A, as he had a long-standing history of opiate dependence for pain relief after a road traffic accident 8 years prior. He now takes buprenorphine replacement. His long-standing symptoms of low mood, poor concentration, poor sleep, and low energy have affected his education, work, and personal life for several years. For a 6-year period, he has received trials of numerous antidepressants including citalopram, sertraline, fluoxetine, venlafaxine, and mirtazapine with no long-term improvement. Mr A has a strong family history of mental health disorder; his maternal mother and grandmother suffer from depression and his maternal aunt has bipolar affective disorder. During the hospital admission, Mr A’s laboratory test results were reviewed historically and revealed persistent, uninvestigated mild hyponatremia (2–3 mmol/L) of several years’ duration. Results of other laboratory investigations and imaging were normal (Table 1). While polydipsia might account for his serum sodium changes, an undetectable random cortisol level was found, alluding to a potential cause for his psychiatric and laboratory test findings. An intravenously administered short Synacthen test revealed an inappropriate cortisol response with a low-normal ACTH level, confirming secondary adrenal insufficiency (see Table 1), with his opiate-replacement medication identified as the most likely cause. Mr A was transferred to the endocrine team to begin corticosteroid replacement therapy. There were no complaints of weight loss or gain by Mr A prior to or during the admission, and his blood pressure remained stable. Table 1. Mr A’s Laboratory Test Results Following commencement of corticosteroid replacement therapy, Mr A’s biochemical results normalized and his mental state improved. Mr A now reports a sustained improvement in mood and concentration and no further psychotic symptoms. His family states that he is spending more time out of the house with friends and has begun to take steps to seek employment. The plan is to gradually wean Mr A off psychiatric medication with a view to ascertaining whether these markedly positive changes are indeed related to corticosteroid replacement therapy.

French Experience with Buprenorphine : Do Physicians Follow the Guidelines?

Opiate dependence affects about 15,479,000 people worldwide. The effectiveness of opiate substitution treatments (OST) has been widely demonstrated. Buprenorphine plays a particular role in opiate dependence care provision in France. It is widely prescribed by physicians and national opiate substitution treatment guidelines have been available since 2004. In order to study the prescribing of buprenorphine, we used a questionnaire sent by email, to a large sample of physicians. These physicians were either in practice, or belonged to an addiction treatment network or a hospital. The main objective of this work was to measure the extent to which the theoretical, clinical attitude of physicians towards prescribing buprenorphine (BHD) complied with the statutory guidelines. We showed that the physicians we interviewed rarely took into account the guidelines regarding buprenorphine prescription. The actual prescribing of Buprenorphine differed from the guidelines. Only 42% of independent Family Physicians (FPs), working outside the national health care system, had prescribed buprenorphine as a first-time prescription and 40% of FPs do not follow up patients on buprenorphine. In terms of compliance with the guidelines, 55% of FPs gave theoretical answers that only partially complied with the guidelines. The variations in compliance with the guidelines was noted according to different variables and took into particular account whether the physician were affiliated to a network or in training.

Retention in medication-assisted treatment for opiate dependence: A systematic review

ABSTRACTRetention in medication-assisted treatment among opiate-dependent patients is associated with better outcomes. This systematic review (55 articles, 2010–2014) found wide variability in retention rates (i.e., 19%–94% at 3-month, 46%–92% at 4-month, 3%–88% at 6-month, and 37%–91% at 12-month follow-ups in randomized controlled trials), and identified medication and behavioral therapy factors associated with retention. As expected, patients who received naltrexone or buprenorphine had better retention rates than patients who received a placebo or no medication. Consistent with prior research, methadone was associated with better retention than buprenorphine/naloxone. And, heroin-assisted treatment was associated with better retention than methadone among treatment-refractory patients. Only a single study examined retention in medication-assisted treatment for longer than 1 year, and studies of behavioral therapies may have lacked statistical power; thus, studies with longer-term follow-ups and larger samples are needed. Contingency management showed promise to increase retention, but other behavioral therapies to increase retention, such as supervision of medication consumption, or additional counseling, education, or support, failed to find differences between intervention and control conditions. Promising behavioral therapies to increase retention have yet to be identified.

Morphine Regulated Synaptic Networks Revealed by Integrated Proteomics and Network Analysis

Despite its efficacy, the use of morphine for the treatment of chronic pain remains limited because of the rapid development of tolerance, dependence and ultimately addiction. These undesired effects are thought to be because of alterations in synaptic transmission and neuroplasticity within the reward circuitry including the striatum. In this study we used subcellular fractionation and quantitative proteomics combined with computational approaches to investigate the morphine-induced protein profile changes at the striatal postsynaptic density. Over 2,600 proteins were identified by mass spectrometry analysis of subcellular fractions enriched in postsynaptic density associated proteins from saline or morphine-treated striata. Among these, the levels of 34 proteins were differentially altered in response to morphine. These include proteins involved in G-protein coupled receptor signaling, regulation of transcription and translation, chaperones, and protein degradation pathways. The altered expression levels of several of these proteins was validated by Western blotting analysis. Using Genes2Fans software suite we connected the differentially expressed proteins with proteins identified within the known background protein-protein interaction network. This led to the generation of a network consisting of 116 proteins with 40 significant intermediates. To validate this, we confirmed the presence of three proteins predicted to be significant intermediates: caspase-3, receptor-interacting serine/threonine protein kinase 3 and NEDD4 (an E3-ubiquitin ligase identified as a neural precursor cell expressed developmentally down-regulated protein 4). Because this morphine-regulated network predicted alterations in proteasomal degradation, we examined the global ubiquitination state of postsynaptic density proteins and found it to be substantially altered. Together, these findings suggest a role for protein degradation and for the ubiquitin/proteasomal system in the etiology of opiate dependence and addiction.

An international systematic review of smoking prevalence in addiction treatment.

Smoking prevalence is higher among people enrolled in addiction treatment compared with the general population, and very high rates of smoking are associated with opiate drug use and receipt of opiate replacement therapy (ORT). We assessed whether these findings are observed internationally. PubMed, PsycINFO and the Alcohol and Alcohol Problems Science Database were searched for papers reporting smoking prevalence among addiction treatment samples, published in English, from 1987 to 2013. Search terms included tobacco use, cessation and substance use disorders using and/or Boolean connectors. For 4549 papers identified, abstracts were reviewed by multiple raters; 239 abstracts met inclusion criteria and these full papers were reviewed for exclusion. Fifty-four studies, collectively comprising 37,364 participants, were included. For each paper we extracted country, author, year, sample size and gender, treatment modality, primary drug treated and smoking prevalence. The random-effect pooled estimate of smoking across people in addiction treatment was 84% [confidence interval (CI) = 79, 88%], while the pooled estimate of smoking prevalence across matched population samples was 31% (CI = 29, 33%). The difference in the pooled estimates was 52% (CI = 48%, 57%, P < .0001). Smoking rates were higher in programs treating opiate use compared with alcohol use [odds ratio (OR) = 2.52, CI = 2.00, 3.17], and higher in ORT compared to out-patient programs (OR = 1.42, CI = 1.19, 1.68). Smoking rates among people in addiction treatment are more than double those of people with similar demographic characteristics. Smoking rates are also higher in people being treated for opiate dependence compared with people being treated for alcohol use disorder.

Expression of BDNF and TrkB Phosphorylation in the Rat Frontal Cortex During Morphine Withdrawal are NO Dependent.

Nitric oxide (NO) mediates pharmacological effects of opiates including dependence and abstinence. Modulation of NO synthesis during the induction phase of morphine dependence affects manifestations of morphine withdrawal syndrome, though little is known about mechanisms underlying this phenomenon. Neurotrophic and growth factors are involved in neuronal adaptation during opiate dependence. NO-dependent modulation of morphine dependence may be mediated by changes in expression and activity of neurotrophic and/or growth factors in the brain. Here, we studied the effects of NO synthesis inhibition during the induction phase of morphine dependence on the expression of brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and insulin-like growth factor 1 (IGF1) as well as their receptors in rat brain regions after spontaneous morphine withdrawal in dependent animals. Morphine dependence in rats was induced within 6days by 12 injections of morphine in increasing doses (10-100mg/kg), and NO synthase inhibitor L-N(G)-nitroarginine methyl ester (L-NAME) (10mg/kg) was given 1h before each morphine injection. The expression of the BDNF, GDNF, NGF, IGF1, and their receptors in the frontal cortex, striatum, hippocampus, and midbrain was assessed 40h after morphine withdrawal. L-NAME treatment during morphine intoxication resulted in an aggravation of the spontaneous morphine withdrawal severity. Morphine withdrawal was accompanied by upregulation of BDNF, IGF1, and their receptors TrkB and IGF1R, respectively, on the mRNA level in the frontal cortex, and only BDNF in hippocampus and midbrain. L-NAME administration during morphine intoxication decreased abstinence-induced upregulation of these mRNAs in the frontal cortex, hippocampus and midbrain. L-NAME prevented from abstinence-induced elevation of mature but not pro-form of BDNF polypeptide in the frontal cortex. While morphine abstinence did not affect TrkB protein levels as well as its phosphorylation status, inhibition of NO synthesis decreased levels of phosphorylated TrkB after withdrawal. Thus, NO signaling during induction of dependence may be involved in the mechanisms of BDNF expression and processing at abstinence, thereby affecting signaling through TrkB in the frontal cortex.

A cannabinoid receptor 1 polymorphism is protective against major depressive disorder in methadone-maintained outpatients.

The burden of opiate dependence not only relies on somatic complications such as infectious diseases or acute intoxication but also on frequent psychiatric events such as major depressive disorder (MDD) and suicidal behavior (SB). Given the preclinical and clinical evidence regarding the associations between cannabinoid systems and both opiate dependence and psychiatric disorders, we chose to address whether one single nucleotide polymorphism (SNP) of the cannabinoid receptor type 1 gene (CNR1) named rs2023239 would be associated with lifetime MDD and SB in a population of opiate-dependent outpatients remitted under stable methadone treatment. Sociodemographic and clinical data were included as independent factors in two logistic regression models aimed at predicting SB and MDD, respectively, performed with 85 Caucasian individuals. The minor C allele of rs2023239 showed an independent protective effect against lifetime MDD after adjustment for potential confounders. It was not associated with variables related to suicidal behavior. Despite limitations due to the modest sample size, our results are consistent with previous research on the endocannabinoid system and suggest new leads for detecting subjects at risk of MDD, which remains insufficiently diagnosed and treated in patients suffering from severe addictive disorders.

Prescription Opioids in Pregnancy and Birth Outcomes: A Review of the Literature.

Prescription opioids are used prenatally for the management of pain, as well as for opiate dependency. Opioids are known to cross the placenta and despite the evidence of possible adverse effects on fetal development, studies have consistently shown prescription opioids are among the most commonly prescribed medications and the prevalence of use is increasing among pregnant women. This article summarizes the available literature documenting potential harms associated with prescription opioid use during pregnancy, including poor fetal growth, preterm birth, birth defects, and neonatal abstinence syndrome.

Regulation of Pleiotrophin, Midkine, Receptor Protein Tyrosine Phosphatase β/ζ, and Their Intracellular Signaling Cascades in the Nucleus Accumbens During Opiate Administration.

Background:Most classes of addictive substances alter the function and structural plasticity of the brain reward circuitry. Midkine (MK) and pleiotrophin (PTN) are growth/differentiation cytokines which, similarly to neurotrophins, play an important role in repair, neurite outgrowth, and cell differentiation. PTN or MK signaling through receptor protein tyrosine phosphatase β/ζ (RPTPβ/ζ), leads to the activation of extracellular signal-regulated kinases and thymoma viral proto-oncogene. This activation induces morphological changes and modulates addictive behaviors. Besides, there is increasing evidence that during the development of drug addiction, astrocytes contribute to the synaptic plasticity by synthesizing and releasing substances such as cytokines.Methods:In the present work we studied the effect of acute morphine administration, chronic morphine administration, and morphine withdrawal on PTN, MK, and RPTPβ/ζ expression and on their signaling pathways in the nucleus accumbens.Results:Present results indicated that PTN, MK, and RPTPβ/ζ levels increased after acute morphine injection, returned to basal levels during chronic opioid treatment, and were up-regulated again during morphine withdrawal. We also observed an activation of astrocytes after acute morphine injection and during opiate dependence and withdrawal. In addition, immunofluorescence analysis revealed that PTN, but not MK, was overexpressed in astrocytes and that dopaminoceptive neurons expressed RPTPβ/ζ.Conclusions:All these observations suggest that the neurotrophic and behavioral adaptations that occur during opiate addiction could be, at least partly, mediated by cytokines.

Quantitative EEG and Low-Resolution Electromagnetic Tomography (LORETA) Imaging of Patients Undergoing Methadone Treatment for Opiate Addiction.

Methadone maintenance treatment (MMT) has been used as a treatment for opiate dependence since the mid-1960s. Evidence suggests that methadone binds to mu opiate receptors as do other opiates and induces changes in neurophysiological function. However, little is known, about how neural activity within the higher frequency gamma band (>30 Hz) while at rest changes in those stabilized on MMT despite its association with the excitation-inhibition balance within pyramidal-interneuron networks. Our study investigated differences in resting gamma power (37-41 Hz) between patients undergoing MMT for opiate dependence, illicit opiate users, and healthy controls subjects. Electroencephalographic data were recorded from 26 sites according to the international 10-20 system. Compared with the healthy controls subjects, people either undergoing MMT (mean difference [MD] = 0.32, 95% CI = 0.09-0.55, P < .01) or currently using illicit opiates (MD = 0.31, 95% CI = 0.06-0.56, P = .01) exhibited significant increased gamma power. The sLORETA (standardized low-resolution electromagnetic tomography) between-group comparison revealed dysfunctional neuronal activity in the occipital, parietal, and frontal lobes in the patients undergoing MMT. A more severe profile of dysfunction was observed in those using illicit opiates. Our findings suggest that long-term exposure to opioids is associated with disrupted resting state network, which may be reduced after MMT.

In the face of threat: neural and endocrine correlates of impaired facial emotion recognition in cocaine dependence.

The ability to recognize facial expressions of emotion in others is a cornerstone of human interaction. Selective impairments in the recognition of facial expressions of fear have frequently been reported in chronic cocaine users, but the nature of these impairments remains poorly understood. We used the multivariate method of partial least squares and structural magnetic resonance imaging to identify gray matter brain networks that underlie facial affect processing in both cocaine-dependent (n=29) and healthy male volunteers (n=29). We hypothesized that disruptions in neuroendocrine function in cocaine-dependent individuals would explain their impairments in fear recognition by modulating the relationship with the underlying gray matter networks. We found that cocaine-dependent individuals not only exhibited significant impairments in the recognition of fear, but also for facial expressions of anger. Although recognition accuracy of threatening expressions co-varied in all participants with distinctive gray matter networks implicated in fear and anger processing, in cocaine users it was less well predicted by these networks than in controls. The weaker brain-behavior relationships for threat processing were also mediated by distinctly different factors. Fear recognition impairments were influenced by variations in intelligence levels, whereas anger recognition impairments were associated with comorbid opiate dependence and related reduction in testosterone levels. We also observed an inverse relationship between testosterone levels and the duration of crack and opiate use. Our data provide novel insight into the neurobiological basis of abnormal threat processing in cocaine dependence, which may shed light on new opportunities facilitating the psychosocial integration of these patients.

Effectiveness of Computer-Assisted Therapy for Substance Dependence Using Breaking Free Online: Subgroup Analyses of a Heterogeneous Sample of Service Users.

BackgroundSubstance misuse services within the United Kingdom have traditionally been oriented to opiate and crack users, and attended predominantly by male service users. Groups who do not fit this demographic, such as women or those whose primary drug of choice is neither heroin nor crack, have tended to be underrepresented in services. In addition, there can be stigma associated with traditional opiate and crack-centric services. Therefore, the computerized treatment and recovery program, Breaking Free Online (BFO), was developed to enable service users to access confidential support for dependence on a wide range of substances. BFO is delivered as computer-assisted therapy (CAT), or, where appropriate, used as self-help.ObjectiveThe aim of this study was to report psychometric outcomes data from 393 service users accessing online support for substance misuse via BFO.MethodsFollowing initial referral to substance misuse services, all participants were supported in setting up a BFO login by a practitioner or peer mentor, and, where required, assisted as they completed an online baseline assessment battery contained within the BFO program. Following a period of engagement with BFO, all participants completed the same battery of assessments, and changes in the scores on these assessments were examined.ResultsSignificant improvements were found across the 393 service users in several areas of psychosocial functioning, including quality of life, severity of alcohol and drug dependence, depression, and anxiety (P=<.001 across all aspects of functioning). Additionally, significant improvements were found within specific subgroups of participants, including females (P=.001-<.001), males (P=.004-<.001), service users reporting alcohol dependence (P=.002-<.001), opiate and crack dependence (P=.014-<.001), and those seeking support for other substances that may be less well represented in the substance misuse sector (P=.001-<.001).ConclusionsData from this study indicates that BFO is an effective clinical treatment for a wide range of individuals requiring support for substance misuse. Further work is currently underway to examine more closely the clinical effectiveness of the program.

Analysis of connectivity in NeuCube spiking neural network models trained on EEG data for the understanding of functional changes in the brain: A case study on opiate dependence treatment

The paper presents a methodology for the analysis of functional changes in brain activity across different conditions and different groups of subjects. This analysis is based on the recently proposed NeuCube spiking neural network (SNN) framework and more specifically on the analysis of the connectivity of a NeuCube model trained with electroencephalography (EEG) data. The case study data used to illustrate this method is EEG data collected from three groups—subjects with opiate addiction, patients undertaking methadone maintenance treatment, and non-drug users/healthy control group. The proposed method classifies more accurately the EEG data than traditional statistical and artificial intelligence (AI) methods and can be used to predict response to treatment and dose-related drug effect. But more importantly, the method can be used to compare functional brain activities of different subjects and the changes of these activities as a result of treatment, which is a step towards a better understanding of both the EEG data and the brain processes that generated it. The method can also be used for a wide range of applications, such as a better understanding of disease progression or aging.

Resting EEG and ERPs findings in methadone-substituted opiate users: a review.

Methadone has been used to treat opiate dependence since the mid-1960s. Despite its clinical effectiveness there is evidence from neuropsychological studies demonstrating that its long-term use might have negative effects on cognition. Nevertheless, it remains uncertain whether the observed cognitive impairments in patients undertaking methadone maintenance treatment (MMT) are solely attributable to the pharmacological effects of methadone, as suggested by some researchers. Determining the effects of MMT on neuropsychological function using electroencephalography (EEG) combined with event-related potentials (ERP) has been used infrequently. However EEG and ERP provide a means of closely examining information processing to determine whether MMT induces any deficits. The purpose of this review was to investigate whether psychophysiological evidence supports cognitive impairment in association with MMT by focusing on research using EEG and ERPs. The findings of EEG studies to date appear not support the notion that cognitive impairments are attributable to the specific pharmacological effects of methadone suggested by some neuropsychological studies. However, due to the methodological deficits and limited number of the studies, any conclusion based on the findings of the existing EEG studies should be avoided.

Opiate dependence and withdrawal: role of oxidative stress in opiate regulations

Abstract not availableBangladesh Journal of Medical Science Vol.14(2) 2015 p.215

The dopamine theory of addiction: 40 years of highs and lows

For several decades, addiction has come to be viewed as a disorder of the dopamine neurotransmitter system; however, this view has not led to new treatments. In this Opinion article, we review the origins of the dopamine theory of addiction and discuss the ability of addictive drugs to elicit the release of dopamine in the human striatum. There is robust evidence that stimulants increase striatal dopamine levels and some evidence that alcohol may have such an effect, but little evidence, if any, that cannabis and opiates increase dopamine levels. Moreover, there is good evidence that striatal dopamine receptor availability and dopamine release are diminished in individuals with stimulant or alcohol dependence but not in individuals with opiate, nicotine or cannabis dependence. These observations have implications for understanding reward and treatment responses in various addictions.

Naloxone-precipitated withdrawal causes an increase in impulsivity in morphine-dependent rats

Opiate dependence is associated with increased impulsivity in both humans and animals. Although the state of withdrawal appears to contribute to this effect, a causal relationship has not been shown. Here, we test whether precipitating withdrawal in morphine-dependent rats through naloxone can cause increased impulsivity. Rats were trained on a delay discounting task and then randomly assigned to either a dependent group that received a nightly 30 mg/kg subcutaneous dose of morphine or a naive group that received nightly saline. Once dependence was established, 2-day test delay discounting curves were determined 1 h after three doses of naloxone (0, 0.25, 0.5 mg/kg). In dependent rats both doses of naloxone caused increased preference for the small reward at short delays. Naloxone had no effect on delay discounting in naive rats. We conclude that precipitating withdrawal in dependent rats can cause increased impulsivity.

Mania following use of ibogaine: A case series

Ibogaine is a naturally occurring hallucinogen with postulated anti-addictive qualities. While illegal domestically, a growing number of individuals have sought it out for treatment of opiate dependence, primarily in poorly regulated overseas clinics. Existing serious adverse events include cardiac and vestibular toxicity, though ours is the first report of mania stemming from its use. To report on a case series of psychiatric emergency room patients whose unregulated use of ibogaine resulted in mania in three patients with no prior diagnosis of bipolar illness. Review and summarize charts of three cases. Relevant literature was also reviewed for discussion. Two cases of reported ibogaine ingestion for self-treatment of addictions, and one for psycho-spiritual experimentation resulted in symptoms consistent with mania. No prior reports of mania were found in the literature, and the literature suggests growing popularity of ibogaine's use. The three cases presented demonstrate a temporal association between ibogaine ingestion and subsequent development of mania. In light of these cases, clinicians faced with a new onset mania may benefit from careful substance use and treatment history, specifically regarding opiates. In the vulnerable and often desperate addiction population, in particular, the number of patients seeking this treatment appears to be growing. We advise clinicians to be prepared for discussing the safety, efficacy, and paucity of good data regarding ibogaine with patients who may be considering its use. (Am J Addict 2015;24:203-205).

Dynamics of the Life Quality Parameters in HIV-Positive Patients With Opiate Dependence

Dynamics of the Life Quality Parameters in HIV-Positive Patients With Opiate Dependence

Mortality among individuals accessing pharmacological treatment for opioid dependence in California, 2006–10

To estimate mortality rates among treated opioid-dependent individuals by cause and in relation to the general population, and to estimate the instantaneous effects of opioid detoxification and maintenance treatment (MMT) on the hazard of all-cause and cause-specific mortality. Population-based treatment cohort study. Linked mortality data on all individuals first enrolled in publicly funded pharmacological treatment for opioid dependence in California, USA from 2006 to 2010. A total of 32 322 individuals, among whom there were 1031 deaths (3.2%) over a median follow-up of 2.6 years (interquartile range = 1.4-3.7). The primary outcome was mortality, indicated by time to death, crude mortality rates (CMR) and standardized mortality ratios (SMR). Individuals being treated for opioid dependence had a more than fourfold increase of mortality risk compared with the general population [SMR = 4.5, 95% confidence interval (CI) = 4.2, 4.8]. Mortality risk was higher (1) when individuals were out-of-treatment (SMR = 6.1, 95% CI = 5.7, 6.5) than in-treatment (SMR = 1.8, 95% CI = 1.6, 2.1) and (2) during detoxification (SMR = 2.4, 95% CI = 1.5, 3.8) than during MMT (SMR = 1.8, 95% CI = 1.5, 2.1), especially in the 2 weeks post-treatment entry (SMR = 5.5, 95% CI = 2.7, 9.8 versus SMR = 2.5, 95% CI = 1.7, 4.9). Detoxification and MMT both independently reduced the instantaneous hazard of all-cause and drug-related mortality. MMT preceded by detoxification was associated with lower all-cause and other cause-specific mortality than MMT alone. In people with opiate dependence, detoxification and methadone maintenance treatment both independently reduce the instantaneous hazard of all-cause and drug-related mortality.