The role of opioid transmission in music-induced pleasure.

Studies conducted in rodents indicate a crucial role of the opioid circuit in mediating objective hedonic reactions to primary rewards. However, it remains unclear whether opioid transmission is also essential to experience pleasure with more abstract rewards, such as music. We addressed this question using a double-blind within-subject pharmacological design in which opioid levels were up- and downregulated by administering an opioid agonist (oxycodone) and antagonist (naltrexone), respectively, before healthy participants (n = 21) listened to music. Participants also performed a monetary incentive delay (MID) task to control for the effectiveness of the treatment and the specificity of the effects. Our results revealed that the pharmacological intervention did not modulate subjective reports of pleasure, nor the occurrence of chills. On the contrary, psychophysiological (objective) measures of emotional arousal, such as skin conductance responses (SCRs), were bidirectionally modulated in both the music and MID tasks. This modulation specifically occurred during reward consumption, with greater pleasure-related SCR following oxycodone than naltrexone. These findings indicate that opioid transmission does not modulate subjective evaluations but rather affects objective reward-related psychophysiological responses. These findings raise new caveats about the role of the opioidergic system in the modulation of pleasure for more abstract or cognitive forms of rewarding experiences, such as music.

Pain management & opioid dose reduction with topical sevoflurane instillations in intractable venous ulcers: a case report

Abstract Vascular ulcers (VU) constitute a major cause of pain and disability, and significantly compromise quality of life. VU have a natural tendency to become chronic and in many cases exhibit anunsatisfactoryresponse to many of the standard therapeutic options.The case of a 73 year-old Caucasian female with severe pain and poorly-controlled pain (Visual Analogic Scale-VAS- of 8-9) due to three lower leg long-standing VUs is reported and discussed herein. The patient was treated with topical instillations of undiluted sevoflurane as per institutional off-label protocol (starting doses of 1mL/cm2 twice a day, and up-titrated according to response to a maximum of 7 mL twice daily). The VAS score dropped to 0-1 shortly after initiation of therapy and remained stable throughout treatment up until the closure of the observations. Subsequently, opioid therapy was gradually tapered down and ultimately abandoned.Sevoflurane application resulted on adequate and sustained pain management of refractory VU, with no significant side effects. On account of its beneficial effectivity and safety profiles, topical sevoflurane emerges as an add-on alternative for the long-term management of VU, and potentially other painful conditions.

Biphalin-A Potent Opioid Agonist-As a Panacea for Opioid System-Dependent Pathophysiological Diseases?

Biphalin, one of the opioid agonists, is a dimeric analog of enkephalin with a high affinity for opioid receptors. Opioid receptors are widespread in the central nervous system and in peripheral neuronal and non-neuronal tissues. Hence, these receptors and their agonists, which play an important role in pain blocking, may also be involved in the regulation of other physiological functions. Biphalin was designed and synthesized in 1982 by Lipkowski as an analgesic peptide. Extensive further research in various laboratories on the antinociceptive effects of biphalin has shown its excellent properties. It has been demonstrated that biphalin exhibits an analgesic effect in acute, neuropathic, and chronic animal pain models, and is 1000 times more potent than morphine when administered intrathecally. In the course of the broad conducted research devoted primarily to the antinociceptive effect of this compound, it has been found that biphalin may also potentially participate in the regulation of other opioid system-dependent functions. Nearly 40 years of research on the properties of biphalin have shown that it may play a beneficial role as an antiviral, antiproliferative, anti-inflammatory, and neuroprotective agent, and may also affect many physiological functions. This integral review analyzes the literature on the multidirectional biological effects of biphalin and its potential in the treatment of many opioid system-dependent pathophysiological diseases.

Can Treatment for Substance Use Disorder Prescribe the same Substance as that Used? The Case of Injectable Opioid Agonist Treatment.

This article examines injectable Opioid Agonist Treatment (iOAT), in which patients suffering from long-term, treatment refractory opioid use disorder (OUD) are prescribed injectable diacetylmorphine, the active ingredient of heroin. While iOAT is part of the continuum of care for OUD in some European countries and in some parts of Canada, it is not an available treatment in the United States. We suggest that one reason for this situation is the belief that a genuine treatment for substance use disorder cannot prescribe the same substance as that used. We examine possible rationales for this belief by considering four combinations of views on the constitutive causal basis of substance use disorders and the definition of effective treatment. We show that all but one combination counts iOAT as a genuine treatment and that there are good reasons to reject the one that does not. Specifically, we claim that medical interventions, such as iOAT, that significantly reduce the severity of a disorder deserve to be categorized as effective treatments and regarded as such in practice.

Opioid Use Disorder and Perinatal Outcomes.

OBJECTIVES: Evidence on the perinatal health of mother-infant dyads affected by opioids is limited. Elevated risks of opioid-related harms for people with opioid use disorder (OUD) increase the urgency to identify protective factors for mothers and infants. Our objectives were to determine perinatal outcomes after an OUD diagnosis and associations between opioid agonist treatment and birth outcomes. METHODS: We conducted a population-based retrospective study among all women with diagnosed OUD before delivery and within the puerperium period in British Columbia, Canada, between 2000 and 2019 from provincial health administrative data. Controlling for demographic and clinical characteristics, we determined associations of opioid agonist treatment on birth weight, gestational age, infant disorders related to gestational age and birth weight, and neonatal abstinence syndrome via logistic regression. RESULTS: The population included 4574 women and 6720 live births. Incidence of perinatal OUD increased from 166 in 2000 to 513 in 2019. Compared with discontinuing opioid agonist treatment during pregnancy, continuous opioid agonist treatment reduced odds of preterm birth (adjusted odds ratio: 0.6; 95% confidence interval: 0.4-0.8) and low birth weight (adjusted odds ratio: 0.4; 95% confidence interval: 0.2-0.7). Treatment with buprenorphine-naloxone (compared with methadone) reduced odds of each outcome including neonatal abstinence syndrome (adjusted odds ratio: 0.6; 95% confidence interval: 0.4-0.9). CONCLUSIONS: Perinatal OUD in British Columbia tripled in incidence over a 20-year period. Sustained opioid agonist treatment during pregnancy reduced the risk of adverse birth outcomes, highlighting the need for expanded services, including opioid agonist treatment to support mothers and infants.

Medications Development for Treatment of Opioid Use Disorder.

This review describes methods for preclinical evaluation of candidate medications to treat opioid use disorder (OUD). The review is founded on the propositions that (1) drug self-administration procedures provide the most direct method for assessment of medication effectiveness, (2) procedures that assess choice between opioid and nondrug reinforcers are especially useful, and (3) states of opioid dependence and withdrawal profoundly influence both opioid reinforcement and effects of candidate medications. Effects of opioid medications and vaccines on opioid choice in nondependent and opioid-dependent subjects are reviewed. Various nonopioid medications have also been examined, but none yet have been identified that safely and reliably reduce opioid choice. Future research will focus on (1) strategies for increasing safety and/or effectiveness of opioid medications (e.g., G-protein-biased µ-opioid agonists), and (2) continued development of nonopioid medications (e.g., clonidine) that might serve as adjunctive agents to current opioid medications.

In Vivo, In Vitro and In Silico Studies of the Hybrid Compound AA3266, an Opioid Agonist/NK1R Antagonist with Selective Cytotoxicity.

AA3266 is a hybrid compound consisting of opioid receptor agonist and neurokinin-1 receptor (NK1R) antagonist pharmacophores. It was designed with the desire to have an analgesic molecule with improved properties and auxiliary anticancer activity. Previously, the compound was found to exhibit high affinity for µ- and δ-opioid receptors, while moderate binding to NK1R. In the presented contribution, we report on a deeper investigation of this hybrid. In vivo, we have established that AA3266 has potent antinociceptive activity in acute pain model, comparable to that of morphine. Desirably, with prolonged administration, our hybrid induces less tolerance than morphine does. AA3266, contrary to morphine, does not cause development of constipation, which is one of the main undesirable effects of opioid use. In vitro, we have confirmed relatively strong cytotoxic activity on a few selected cancer cell lines, similar to or greater than that of a reference NK1R antagonist, aprepitant. Importantly, our compound affects normal cells to smaller extent what makes our compound more selective against cancer cells. In silico methods, including molecular docking, molecular dynamics simulations and fragment molecular orbital calculations, have been used to investigate the interactions of AA3266 with MOR and NK1R. Insights from these will guide structural optimization of opioid/antitachykinin hybrid compounds.

Modelling integrated antiretroviral treatment and harm reduction services on HIV and overdose among people who inject drugs in Tijuana, Mexico.

INTRODUCTION: The HIV epidemic in Tijuana, Mexico is concentrated in key populations, including people who inject drugs (PWID). However, HIV interventions among PWID are minimal, and federal funding was provided for compulsory abstinence programmes associated with HIV and overdose. Alternatively, opioid agonist therapy reduces overdose, reincarceration, HIV, while improving antiretroviral therapy (ART) outcomes. We assessed potential impact and synergies of scaled-up integrated ART and opioid agonist therapy, compared to scale-up of each separately, and potential harms of compulsory abstinence programmes on HIV and fatal overdose among PWID in Tijuana. METHODS: We developed a dynamic model of HIV transmission and overdose among PWID in Tijuana. We simulated scale-up of opioid agonist therapy from zero to 40% coverage among PWID. We evaluated synergistic benefits of an integrated harm reduction and ART scale-up strategy (40% opioid agonist therapy coverage and 10-fold ART recruitment), compared to scale-up of each intervention alone or no scale-up of low coverage ART and no harm reduction). We additionally simulated compulsory abstinence programmes (associated with 14% higher risk of receptive syringe sharing and 76% higher odds of overdose) among PWID. RESULTS: Without intervention, HIV incidence among PWID could increase from 0.72 per 100 person-years (PY) in 2020 to 0.92 per 100 PY in 2030. Over ten years, opioid agonist therapy scale-up could avert 31% (95% uncertainty interval (UI): 18%, 46%) and 22% (95% UI: 10%, 28%) new HIV infections and fatal overdoses, respectively, with the majority of HIV impact from the direct effect on HIV transmission due to low ART coverage. Integrating opioid agonist therapy and ART scale-up provided synergistic benefits, with opioid agonist therapy effects on ART recruitment/retention averting 9% more new infections compared to ART scale-up alone. The intervention strategy could avert 48% (95% UI: 26%, 68%) of new HIV infections and one-fifth of fatal overdoses over ten years. Conversely, compulsory abstinence programmes could increase HIV and overdoses. CONCLUSIONS: Integrating ART with opioid agonist therapy could provide synergistic benefits and prevent HIV and overdoses among PWID in Tijuana, whereas compulsory abstinence programmes could cause harm. Policymakers should consider the benefits of integrating harm reduction and HIV services for PWID.

Pregnant Smokers Receiving Opioid Agonist Therapy Have an Elevated Nicotine Metabolite Ratio: A Replication Study.

INTRODUCTION: Pregnant women exposed chronically to opioids smoked more cigarettes per day (CPD) and had a higher nicotine metabolite ratio (NMR), 3-hydroxycotinine/cotinine, a biomarker of nicotine metabolism and clearance, than those not receiving opioids. We examined CPD and NMR in a group of pregnant smokers, a quarter of whom were receiving opioid agonist therapy (OAT). AIMS AND METHODS: Pregnant smokers recruited to participate in a placebo-controlled trial of bupropion for smoking cessation provided a blood sample for measurement of NMR. RESULTS: Half (52.4%) of the 124 women with NMR data were African American. OAT-treated women (n = 34, 27.4%; 27 receiving methadone and 7 buprenorphine) were more likely to be white (79% vs. 30%, p < .001) and to have a lower mean PHQ-9 total score (2.91 [SD = 2.83] vs. 4.83 [SD = 3.82], p = .007). OAT-treated women reported smoking more CPD (9.50 [SD = 5.26] vs. 7.20 [SD = 3.65], p = .005) and had higher NMR (0.78 [SD = 0.36] vs. 0.56 [SD = 0.25], p = .001) than the non-OAT-treated group. In a linear regression analysis adjusting for race, depression severity, and CPD, NMR was greater in the OAT group (p = .025), among whom the daily methadone-equivalent dosage correlated with NMR (Spearman's ρ = 0.49, p = .003). CONCLUSIONS: Consistent with the findings of Oncken et al. (2019), we found that OAT smokers smoked more and had higher NMR than non-OAT smokers. As higher NMR is associated with a reduced likelihood of smoking cessation, the effects on NMR of both pregnancy and OAT could contribute to a lower smoking cessation rate in pregnant smokers receiving chronic opioid therapy. IMPLICATIONS: We replicated the finding that the NMR is significantly greater among pregnant smokers receiving OAT than those not receiving this treatment for opioid use disorder. Furthermore, we found that the dosage of the OAT was significantly associated with the NMR level. These findings may contribute to a poorer response to smoking cessation treatment in pregnant women treated with OAT, particularly those receiving high-dose therapy, and raise the question of whether novel approaches are needed to treat smoking in this subgroup of pregnant smokers.

Dispensation of attention deficit hyperactivity disorder (ADHD) medications in patients receiving opioid agonist therapy; a national prospective cohort study in Norway from 2015 to 2017.

BACKGROUND: It is estimated that up to a third of patients on opioid agonist therapy (OAT) have attention deficit hyperactivity disorder (ADHD). Treatment by ADHD medication, including a centrally acting stimulant (CAS) or atomoxetine is one of the essential approaches. This study evaluates the use of dispensed ADHD medications in the Norwegian OAT population in the period from 2015 to 2017. Types and doses of ADHD medications, co-dispensations of other potentially addictive drugs like benzodiazepines, z-hypnotics, gabapentinoids, and non-OAT opioids, as well as direct-acting antivirals (DAA) against hepatitis C infection, are investigated. METHODS: Information about all dispensed ADHD medication, OAT opioids, and the defined potentially addictive drugs were recorded from the Norwegian Prescription Database. Dispensation rates, the types, and the doses of dispensed ADHD medications were estimated by summarizing the number of dispensations, and the dispensed doses. Logistic regression analyses were employed to assess the associations between ADHD medication, and OAT opioid use, and dispensations of other potentially addictive drugs and DAAs against hepatitis C infection. RESULTS: A total of 9235 OAT patients were included. The proportion of patients who were dispensed ADHD medication increased from 3.5 to 4.6% throughout the study period. The three most dispensed CAS were short- and intermediate-acting methylphenidate (55%), lisdexamphetamine (24%), and dexamphetamine (17%) in 2017. Buprenorphine, rather than methadone, as OAT opioid (adjusted odds ratio: 1.6, CI: 1.2-2.1) was associated with being dispensed ADHD medication. Among patients who received CAS and OAT opioids each calendar year, the dispensed doses of methylphenidate increased from 63 mg/day in 2015 to 76 mg/day in 2017 (p = 0.01). Sixty percent of patients receiving ADHD medications were also dispensed other addictive drugs concomitantly in 2017. Similar results were found in 2015 and 2016. CONCLUSION: Co-prescription of ADHD medications was low among patients on OAT in Norway, considering a high prevalence of ADHD in this patient group. On the other hand, concurrent dispensations of multiple addictive drugs were common in this population. Understanding the underlying reasons for such prescribing is essential, and research on how to optimize ADHD medication of patients with ADHD receiving OAT is needed.

Differences in receipt of opioid agonist treatment and time to enter treatment for opioid use disorder among specialty addiction programs in the United States, 2014-17.

BACKGROUND: Access to adequate treatment for opioid use disorder (OUD) has been a high priority among American policymakers. Elucidation of the sociodemographic and institutional differences associated with the use, or lack thereof, of opioid agonist therapy (OAT) provides greater clarity on who receives OAT. Timely access to care is a further consideration and bears scrutiny as well. METHODS: We draw upon data from the Treatment Episode Data Set-Admissions (TEDS-A) to analyse the relationship between sociodemographic and institutional characteristics and the receipt of opioid agonist treatments and time waiting to enter treatment. RESULTS: Estimates from logistic regression models highlight certain groups which show lower odds of receipt of OAT, including those in precarious housing arrangements, those unemployed or not otherwise in the labor force, and those referred by drug abuse care providers, educational institutions, employers, and the criminal justice system. Groups which showed higher odds of waiting over a week to enter treatment included those who were separated, divorced, or widowed, those working part-time, and those referred by drug abuse care providers, employers, and the criminal justice system. CONCLUSION: Given the efficacy of OAT and the adverse outcomes associated with long waiting times, coordinated effort is needed to understand why these differences persist and how they may be addressed through appropriate policy responses.

Quality of life and well-being from the perspective of patients on opioid agonist maintenance treatment: study protocol for a systematic review of qualitative research and a scoping review of measures.

BACKGROUND: Opioid agonist maintenance treatment (OAMT) is a first-line treatment for heroin dependence, but its effectiveness has been assessed primarily through clinical outcomes with a limited attention to patient perspectives. Despite the increased use of patient reported outcome measures their patient-centeredness is highly questionable. This is the protocol of a systematic review of qualitative research on how OAMT users construct the meaning of their quality of life and well-being and a scoping review of instruments that measure these domains. METHODS: We will conduct a systematic review of qualitative research exploring the views of quality of life of patients on OAMT (registration number CRD42018086490). According pre-specified eligibility criteria, we will include studies from a comprehensive search of bibliographical databases from their inception. We will extract data from included studies and assess their risk of bias with the CASP appraisal criteria, and will implement a thematic analysis to generate a set of interpretative analytical themes ascertaining their confidence using the CERQual approach. We will implement similar methods to conduct a scoping review to assess to what extent the existing measures of these domains were focused on user's views, assessing their validity using the COSMIN methodology, and summarizing their characteristics and level of patient centeredness. CONCLUSION: The findings from the reviews will contribute to obtain a genuine understanding of the perspective from users on OAMT regarding their perception of well-being and quality of life and will likely lead to greater patient centeredness when assessing such variables, which in turn may contribute to a more patient-centered care.

Differential adoption of opioid agonist treatments in detoxification and outpatient settings.

BACKGROUND: Opioid use disorder (OUD) is a significant public health problem for which a substantial amount of treatment exists. The degree to which methadone and buprenorphine are administered in different treatment modalities is not clear but critical to understanding treatment success rates and service development strategies. METHODS: Data from the national Treatment Episode Dataset for Admissions and Discharges (TEDS-A [N = 4,070,264] and TEDS-D [832,731], respectively) were used to determine the likelihood patients initiating detoxification and outpatient OUD treatment between 2006 and 2015 were expected to receive opioid agonist treatment. Joinpoint regression evaluated significant trends and a generalized linear model with logit link function identified characteristics associated with receiving an agonist during detoxification. TEDS-D informed the percent of patients leaving detoxification against medical advice who did/did not receive an opioid agonist. RESULTS: Though agonist use in outpatient settings increased by 60% during 2012-2015, agonist use in detoxification was lower than outpatient treatment, decreased significantly by 26% from 2009 to 2015, and never exceeded 16% of detoxification admissions during 2006-2015. In 2015, persons who were under 25, homeless, had co-occurring psychiatric problems, utilized Medicare, Medicaid, or had no insurance, and had no prior OUD treatment or were high treatment utilizers were the least likely to receive an agonist during detoxification. CONCLUSIONS: Efforts to expand opioid agonist access has been successful for outpatient but not detoxification settings. Improving detoxification outcomes is a potentially high impact way for the US to expand efficacious OUD treatment access in the US.

Opioid agonist therapy during residential treatment of opioid use disorder: Cohort study on access and outcomes.

OBJECTIVE: To determine access to opioid agonist therapy (OAT) for those entering residential treatment for opioid use disorder; to report on treatment outcomes for those taking OAT and those not taking OAT; and to determine the association between OAT use and residential treatment completion. DESIGN: Retrospective cohort study. SETTING: Ontario. PARTICIPANTS: Patients with opioid use disorder admitted to publicly funded residential treatment programs in the province of Ontario between January 1, 2013, and December 31, 2016. MAIN OUTCOME MEASURES: Access to OAT during residential treatment using descriptive statistics. Treatment outcomes (ie, completed the program, voluntarily left early, involuntary discharged, and other) for the entire cohort and for the OAT and non-OAT groups using descriptive statistics. Association between OAT use at admission and treatment completion (a binary outcome) using bivariate and multivariate models. RESULTS: Among an identified cohort of 1910 patients with opioid use disorder, 52.8% entered programs that permitted access to OAT. Overall, 56.8% of patients completed treatment, 23.3% voluntarily left early (eg, were no-shows, dropped out), 17.0% were involuntarily discharged, and 2.9% were discharged early for other reasons. Those taking OAT were as likely to complete treatment as those not taking OAT (53.9% vs 57.5%, respectively; adjusted odds ratio of 1.07, 95% CI 0.77 to 1.38). CONCLUSION: This study demonstrates 2 large gaps in care for patients with opioid use disorder. First, these patients have poor access to OAT-the first-line treatment of opioid use disorder-while in publicly funded residential treatment programs; and second, many are involuntarily discharged from treatment. Additionally, this study indicates that patients taking OAT have similar likelihood of completing residential treatment as those not taking OAT do. Limitations of this study are that it is based on observational data for patients who self-selected before admission to use OAT or not, and it is likely not all confounders were accounted for.

Reduction in mortality risk with opioid agonist therapy: a systematic review and meta-analysis.

INTRODUCTION: Opioid agonist therapies are effective medications that can greatly improve the quality of life of individuals with opioid use disorder. However, there is significant uncertainty about the risks of cause-specific mortality in and out of treatment. OBJECTIVE: This systematic review and meta-analysis explored the association between methadone and buprenorphine with cause-specific mortality among opioid-dependent persons. METHODS: We searched six online databases to identify relevant cohort studies, calculating all-cause and overdose-specific mortality rates during periods in and out of treatment. We pooled mortality estimates using multivariate random effects meta-analysis of the crude mortality rate per 1000 person-years of follow-up as well as relative risks comparing mortality in vs. out of treatment. RESULTS: A total of 32 cohort studies (representing 150 235 participants, 805 423.6 person-years, and 9112 deaths) met eligibility criteria. Crude mortality rates were substantially higher among methadone cohorts than buprenorphine cohorts. Relative risk reduction was substantially higher with methadone relative to buprenorphine when time in-treatment was compared to time out-of-treatment. Furthermore, the greatest mortality reduction was conferred during the first 4 weeks of treatment. Mortality estimates were substantially heterogeneous and varied significantly by country, region, and by the nature of the treatment provider. CONCLUSION: Precautions are necessary for the safer implementation of opioid agonist therapy, including baseline assessments of opioid tolerance, ongoing monitoring during the induction period, education of patients about the risk of overdose, and coordination within healthcare services.

Efficacy and cost-effectiveness of an adjunctive personalised psychosocial intervention in treatment-resistant maintenance opioid agonist therapy: a pragmatic, open-label, randomised controlled trial.

BACKGROUND: Opioid use disorder is a chronic, debilitating, and costly disorder that has increased in prevalence in many countries, with an associated sharp rise in mortality. Maintenance opioid agonist therapy is the first-line treatment, but many patients do not stop using illicit or non-prescribed drugs concomitantly. We aimed to test the efficacy and cost-effectiveness of a personalised psychosocial intervention implemented with a toolkit of behaviour-change techniques as an adjunct to opioid agonist therapy. METHODS: We did a pragmatic, open-label, randomised controlled trial at a specialist UK National Health Service community addictions clinic in London, UK. Eligible patients were aged 18 years or older, met criteria for opioid or cocaine dependence, or both, in the past 12 months, and voluntarily sought continued oral maintenance opioid agonist therapy, which they had been prescribed for at least 6 weeks. All participants were treatment resistant (ie, had used illicit or non-prescribed opioids or cocaine on one or more days in the past 28 days at study screening, which was verified by positive urine drug screen). Participants were allocated (1:1) by a web-accessed randomisation sequence (stratified by opioid agonist medication, current cocaine use, and current rug use) to receive a personalised psychosocial intervention (comprising a flexible toolkit of psychological-change methods, including contingency management to reinforce abstinence, recovery activities, and clinic attendance) in addition to treatment as usual, or treatment as usual only (control group). The primary outcome was treatment response at 18 weeks, which was defined as abstinence from illicit and non-prescribed opioids and cocaine in the past 28 days, as measured with treatment outcomes profiles and urine drug screening. Taking a societal cost perspective, we did an evaluation of cost-effectiveness with a wide range of willingness-to-pay values for a unit improvement in the probability of treatment response. We also calculated quality-adjusted life-years (QALYs). Efficacy was analysed in a modified-intention-to-treat population, including all participants who were randomly allocated but excluding those who had previously completed the intervention. This trial is registered with ISRCTN, number ISRCTN69313751. The trial is completed. FINDINGS: Between June 7, 2013, and Dec 21, 2015, we randomly allocated 136 participants to the psychosocial intervention group and 137 to the control group. The trial database was locked on April 19, 2017. Three patients (one in the psychosocial intervention group and two in the control group) who were re-randomised in error were excluded from the analysis. 22 (16%) of 135 patients in the psychosocial intervention group had a treatment response, compared with nine (7%) of 135 in the control group (adjusted log odds 1·20 [95% CI 0·01-2·37]; p=0·048). The psychosocial intervention had a higher probability of being cost-effective than treatment as usual. There was a probability range of 47-87% for willingness-to-pay thresholds of £0-1000 for a unit improvement in the probability of treatment response. QALYs were higher in the psychosocial intervention group than in the control group (mean difference 0·048 [95% CI 0·016-0·080]; p=0·004) in adjusted analyses, with 60% and 67% probabilities of cost-effectiveness at the UK National Institute for Health and Care Excellence's willingness-to-pay thresholds of £20 000 and £30 000 per QALY, respectively. The number of adverse events was similar between groups, and no severe adverse events in either group were judged to be treatment related. One participant in the control group was hospitalised with drug-injection-related sepsis and died. INTERPRETATION: In maintenance opioid agonist therapy, an adjunctive personalised psychosocial intervention in addition to standard therapy was efficacious and cost-effective compared with standard therapy alone at helping treatment-resistant patients abstain from using illicit and non-prescribed opioids and cocaine. FUNDING: Indivior.

Relative frequency and risk factors for long-term opioid therapy following surgery and trauma among adults: a systematic review protocol.

BACKGROUND: When patients have been on opioid therapy for more than 90 days, more than half of them continue using opioids years later. Knowing that long-term opioid consumption could lead to harmful side effects including misuse, abuse, and addiction, it is important to understand the risks of transitioning to prolonged opioid therapy to reduce its occurrence. Perioperative and trauma contexts are ideal models commonly used to study such transition. Long-term use of opioids might be associated with transformation of acute pain to chronic, which might be an example of a risk factor. The objectives of this knowledge synthesis are to examine the relative frequency and the risk factors for transitioning to long-term opioid therapy among patients who have undergone a surgical procedure or experienced a trauma. METHODS: The proposed study methodology is based on Preferred ReportIng Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) statements on the conduct of systematic review and meta-analysis, the MOOSE Guidelines for Meta-Analyses and Systematic Reviews of Observational Studies, and the Cochrane Handbook for Systematic Review of Interventions. A systematic literature search will include multiple databases: Cochrane Central, EMBASE, MEDLINE, PsycINFO, CINHAL, PubMed, and the grey literature. We will identify studies related to opioid use beyond acute/subacute pain control after surgery or trauma. Two of the reviewers will screen all retrieved articles for eligibility and data extraction then critically appraise all identified studies. We will compile a narrative synthesis of all results and conduct a meta-analysis when feasible. As available data permits, we will perform a subgroup analysis of vulnerable populations. DISCUSSION: This systematic review will contribute to the prevention and harm reduction strategies associated with prescription opioids by identifying risk factors leading to the unwarranted long-term opioid therapy. The identification of common risk factors for long-term opioid therapy will help to orient further research on pain management as well as offer key therapeutic targets for the development of strategies to prevent prolonged opioid use. SYSTEMATIC REVIEW REGISTRATION: This protocol was registered in PROSPERO on March 2, 2018; registration number CRD42012018089907 .