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[Changes and the impact on immune function of opioid-dependent subjects by Jitai tabelets during the withdrawal stage].

Fri, 05/05/2017 - 7:10am
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[Changes and the impact on immune function of opioid-dependent subjects by Jitai tabelets during the withdrawal stage].

Zhonghua Liu Xing Bing Xue Za Zhi. 2017 Apr 10;38(4):531-536

Authors: Li XX, Fan HY, Sun L, Liang JC, Deng YP

Abstract
Objective: To detect the changes in the immune function of opioid-dependent subjects during the withdrawal stage through the administration of Jitai tablet. Methods: Subjects were treated as Jitai tablet alone, Jitai tablet plus buprenorphine and placebo, in a randomized,double-blind, placebo-controlled trial. Before and after the 14(th) day of withdrawal, levels of immunoglobulin (IgM, IgA, IgG), T cell subsets (CD(3)(+), CD(4)(+), CD(8)(+), CD(4)(+)/CD(8)(+)) and cytokines (IL-2, IFN-γ, IL-4, IFN-γ/IL-4) were detected. Results: Compared with healthy people, immunity function before withdrawal among the opioid abusers showed higher levels of IgM, IL-2, IFN-γ, IL-4 and lower level of CD(3)(+)T, as (1.67±0.87) g/L, (14.44±13.50)%, (20.23±15.10)%, (1.97±1.59)%, (47.01±13.62)%, respectively, with difference statistically significant (P<0.05). There was no big difference of other immunity indicators between the two groups (P>0.05). At the 14(th) day of withdrawal in placebo group, levels of IL-4 returned to normal while IFN-γ/IL-4 ratio increased by 3.43 times (P<0.05). Levels of IgA, IgG, CD(4)(+) and CD(4)(+)/CD(8)(+) ratio fluctuated within normal range. There were no significant changes in other immunity indicators (P>0.05). Compared with placebo group, fluctuation of IgG and IgM decreased in Jitai group during withdrawal period, together with a normal level of IgM at the 14(th) day. Level of IL-4 abnormally rose up by 0.54 times in Jitai tablet plus buprenorphine group, while IFN-γ/IL-4 ratio been switched back at the 14(th) day of withdrawal. Other immune indicators were not affected by medical interventions. Conclusion: We noticed that certain impairment of the immune function might be restored by Jitai tablet during the withdrawal period.

PMID: 28468077 [PubMed - in process]

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Analgesia and mouse strain influence neuromuscular plasticity in inflamed intestine.

Thu, 05/04/2017 - 8:59am
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Analgesia and mouse strain influence neuromuscular plasticity in inflamed intestine.

Neurogastroenterol Motil. 2017 May 03;:

Authors: Blennerhassett MG, Lourenssen SR, Parlow LRG, Ghasemlou N, Winterborn AN

Abstract
BACKGROUND: Mouse models of inflammatory bowel disease (IBD) identify an impact on the enteric nervous system (ENS) but do not distinguish between Crohn's disease and ulcerative colitis phenotypes. In these models, analgesia is required, but its influence on different strains and disease outcomes is unknown. Therefore, changes to the ENS and intestinal smooth muscle were studied in trinitrobenzene sulfonic acid (TNBS) and dextran sodium sulfate (DSS) induced colitis to identify the effects of analgesia, and compared between two mouse strains.
METHODS: Colitis was induced in CD1 or BALB/c mice receiving analgesia with either buprenorphine or tramadol. Euthanasia was on Day 8 (DSS) or Day 4 (TNBS). Outcomes were Disease Activity Index and cytokine assay, and quantitative histology and immunocytochemistry were used to evaluate effects of inflammation on neurons and smooth muscle.
KEY RESULTS: In BALB/c mice, both models of colitis caused >2-fold increase in smooth muscle cell number. DSS caused axon proliferation without neuron loss while TNBS caused significant neuron loss and axonal damage. Buprenorphine (but not tramadol) was generally anti-inflammatory in both strains, but correlated with lethal outcomes to TNBS in BALB/c mice.
CONCLUSIONS AND INFERENCES: Smooth muscle growth is common to both models of colitis. In contrast, ENS damage in TNBS is correlated with the severe response of a Crohn's disease-like phenotype, while DSS correlates with a milder, ulcerative colitis-like outcome in the deeper tissues. Analgesia with tramadol over buprenorphine is supported for mouse studies of IBD.

PMID: 28466581 [PubMed - as supplied by publisher]

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Current Progress in Opioid Treatment.

Tue, 05/02/2017 - 6:30am
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Current Progress in Opioid Treatment.

Am J Psychiatry. 2017 May 01;174(5):414-416

Authors: Woody GE

PMID: 28457152 [PubMed - in process]

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Canadian harm reduction policies: A comparative content analysis of provincial and territorial documents, 2000-2015.

Sun, 04/30/2017 - 6:03am
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Canadian harm reduction policies: A comparative content analysis of provincial and territorial documents, 2000-2015.

Int J Drug Policy. 2017 Apr 25;45:9-17

Authors: Wild TC, Pauly B, Belle-Isle L, Cavalieri W, Elliott R, Strike C, Tupper K, Hathaway A, Dell C, MacPherson D, Sinclair C, Karekezi K, Tan B, Hyshka E

Abstract
BACKGROUND: Access to harm reduction interventions among substance users across Canada is highly variable, and largely within the policy jurisdiction of the provinces and territories. This study systematically described variation in policy frameworks guiding harm reduction services among Canadian provinces and territories as part of the first national multimethod case study of harm reduction policy.
METHODS: Systematic and purposive searches identified publicly-accessible policy texts guiding planning and organization of one or more of seven targeted harm reduction services: needle distribution, naloxone, supervised injection/consumption, low-threshold opioid substitution (or maintenance) treatment, buprenorphine/naloxone (suboxone), drug checking, and safer inhalation kits. A corpus of 101 documents written or commissioned by provincial/territorial governments or their regional health authorities from 2000 to 2015 were identified and verified for relevance by a National Reference Committee. Texts were content analyzed using an a priori governance framework assessing managerial roles and functions, structures, interventions endorsed, client characteristics, and environmental variables.
RESULTS: Nationally, few (12%) of the documents were written to expressly guide harm reduction services or resources as their primary named purpose; most documents included harm reduction as a component of broader addiction and/or mental health strategies (43%) or blood-borne pathogen strategies (43%). Most documents (72%) identified roles and responsibilities of health service providers, but fewer declared how services would be funded (56%), specified a policy timeline (38%), referenced supporting legislation (26%), or received endorsement from elected members of government (16%). Nonspecific references to 'harm reduction' appeared an average of 12.8 times per document-far more frequently than references to specific harm reduction interventions (needle distribution=4.6 times/document; supervised injection service=1.4 times/document). Low-threshold opioid substitution, safer inhalation kits, drug checking, and buprenorphine/naloxone were virtually unmentioned. Two cases (Quebec and BC) produced about half of all policy documents, while 6 cases - covering parts of Atlantic and Northern Canada - each produced three or fewer.
CONCLUSION: Canada exhibited wide regional variation in policies guiding the planning and organization of Canadian harm reduction services, with some areas of the country producing few or no policies. Despite a wealth of effectiveness and health economic research demonstrating the value of specific harm reduction interventions, policies guiding Canada from 2000 to 2015 did not stake out harm reduction interventions as a distinct, legitimate health service domain.

PMID: 28454045 [PubMed - as supplied by publisher]

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Supervised dosing with a long-acting opioid medication in the management of opioid dependence.

Fri, 04/28/2017 - 6:54am

Supervised dosing with a long-acting opioid medication in the management of opioid dependence.

Cochrane Database Syst Rev. 2017 Apr 27;4:CD011983

Authors: Saulle R, Vecchi S, Gowing L

Abstract
BACKGROUND: Opioid dependence (OD) is an increasing clinical and public health problem worldwide. International guidelines recommend opioid substitution treatment (OST), such as methadone and buprenorphine, as first-line medication treatment for OD. A negative aspect of OST is that the medication used can be diverted both through sale on the black market, and the unsanctioned use of medications. Daily supervised administration of medications used in OST has the advantage of reducing the risk of diversion, and may promote therapeutic engagement, potentially enhancing the psychosocial aspect of OST, but costs more and is more restrictive on the client than dispensing for off-site consumption.
OBJECTIVES: The objective of this systematic review is to compare the effectiveness of OST with supervised dosing relative to dispensing of medication for off-site consumption.
SEARCH METHODS: We searched in Cochrane Drugs and Alcohol Group Specialised Register and Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, Web of Science from inception up to April 2016. Ongoing and unpublished studies were searched via ClinicalTrials.gov (www.clinicaltrials.gov) and World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (http://www.who.int/ictrp/en/).All searches included non-English language literature. We handsearched references on topic-related systematic reviews.
SELECTION CRITERIA: Randomised controlled trials (RCTs), controlled clinical trials (CCTs), and prospective controlled cohort studies, involving people who are receiving OST (methadone, buprenorphine) and comparing supervised dosing with dispensing of medication to be consumed away from the dispensing point, usually without supervision.
DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane.
MAIN RESULTS: Six studies (four RCTs and two prospective observational cohort studies), involving 7999 participants comparing supervised OST treatment with unsupervised treatment, met the inclusion criteria. The risk of bias was generally moderate across trials, but the results reported on outcomes that we planned to consider were limited. Overall, we judged the quality of the evidence from very low to low for all the outcomes.We found no difference in retention at any duration with supervised compared to unsupervised dosing (RR 0.99, 95% CI 0.88 to 1.12, 716 participants, four trials, low-quality evidence) or in retention in the shortest follow-up period, three months (RR 0.94; 95% CI 0.84 to 1.05; 472 participants, three trials, low-quality evidence). Additional data at 12 months from one observational study found no difference in retention between groups (RR 0.94, 95% CI 0.77 to 1.14; n = 300).There was no difference in abstinence at the end of treatment (self-reported drug use) (67% versus 60%, P = 0.33, 293 participants, one trial, very low-quality evidence); and in diversion of medication (5% versus 2%, 293 participants, one trial, very low-quality evidence).Regarding our secondary outcomes, we did not found a difference in the incidence of adverse effects in the supervised compared to unsupervised control group (RR 0.63; 96% CI 0.10 to 3.86; 363 participants, two trials, very low-quality evidence). Data on severity of dependence were very limited (244 participants, one trial) and showed no difference between the two approaches. Data on deaths were reported in two studies. One trial reported two deaths in the supervised group (low-quality evidence), while in the cohort study all-cause mortality was found lower in regular supervision group (crude mortality rate 0.60 versus 0.81 per 100 person-years), although after adjustment insufficient evidence existed to suggest that regular supervision was protective (mortality rate ratio = 1.23, 95% CI = 0.67 to 2.27).No studies reported pain symptoms, drug craving, aberrant opioid-related behaviours, days of unsanctioned opioid use and overdose.
AUTHORS' CONCLUSIONS: Take-home medication strategies are attractive to treatment services due to lower costs, and place less restrictions on clients, but it is unknown whether they may be associated with increased risk of diversion and unsanctioned use of medication. There is uncertainty about the effects of supervised dosing compared with unsupervised medication due to the low and very low quality of the evidence for the primary outcomes of interest for this review. Data on defined secondary outcomes were similarly limited. More research comparing supervised and take-home medication strategies is needed to support decisions on the relative effectiveness of these strategies. The trials should be designed and conducted with high quality and over a longer follow-up period to support comparison of strategies at different stages of treatment. In particular, there is a need for studies assessing in more detail the risk of diversion and safety outcomes of using supervised OST to manage opioid dependence.

PMID: 28447766 [PubMed - as supplied by publisher]

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Commentary on Daubresse et al. (2017): An epidemic of outdated data.

Fri, 04/28/2017 - 6:54am
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Commentary on Daubresse et al. (2017): An epidemic of outdated data.

Addiction. 2017 Jun;112(6):1054-1055

Authors: Gellad WF

PMID: 28447431 [PubMed - in process]

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Opioid substitution treatment is linked to reduced risk of death in opioid use disorder.

Fri, 04/28/2017 - 6:54am
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Opioid substitution treatment is linked to reduced risk of death in opioid use disorder.

BMJ. 2017 Apr 26;357:j1947

Authors: Manhapra A, Rosenheck R, Fiellin DA

PMID: 28446438 [PubMed - in process]

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Mortality risk during and after opioid substitution treatment: systematic review and meta-analysis of cohort studies.

Fri, 04/28/2017 - 6:54am
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Mortality risk during and after opioid substitution treatment: systematic review and meta-analysis of cohort studies.

BMJ. 2017 Apr 26;357:j1550

Authors: Sordo L, Barrio G, Bravo MJ, Indave BI, Degenhardt L, Wiessing L, Ferri M, Pastor-Barriuso R

Abstract
Objective To compare the risk for all cause and overdose mortality in people with opioid dependence during and after substitution treatment with methadone or buprenorphine and to characterise trends in risk of mortality after initiation and cessation of treatment.Design Systematic review and meta-analysis.Data sources Medline, Embase, PsycINFO, and LILACS to September 2016.Study selection Prospective or retrospective cohort studies in people with opioid dependence that reported deaths from all causes or overdose during follow-up periods in and out of opioid substitution treatment with methadone or buprenorphine.Data extraction and synthesis Two independent reviewers performed data extraction and assessed study quality. Mortality rates in and out of treatment were jointly combined across methadone or buprenorphine cohorts by using multivariate random effects meta-analysis.Results There were 19 eligible cohorts, following 122 885 people treated with methadone over 1.3-13.9 years and 15 831 people treated with buprenorphine over 1.1-4.5 years. Pooled all cause mortality rates were 11.3 and 36.1 per 1000 person years in and out of methadone treatment (unadjusted out-to-in rate ratio 3.20, 95% confidence interval 2.65 to 3.86) and reduced to 4.3 and 9.5 in and out of buprenorphine treatment (2.20, 1.34 to 3.61). In pooled trend analysis, all cause mortality dropped sharply over the first four weeks of methadone treatment and decreased gradually two weeks after leaving treatment. All cause mortality remained stable during induction and remaining time on buprenorphine treatment. Overdose mortality evolved similarly, with pooled overdose mortality rates of 2.6 and 12.7 per 1000 person years in and out of methadone treatment (unadjusted out-to-in rate ratio 4.80, 2.90 to 7.96) and 1.4 and 4.6 in and out of buprenorphine treatment.Conclusions Retention in methadone and buprenorphine treatment is associated with substantial reductions in the risk for all cause and overdose mortality in people dependent on opioids. The induction phase onto methadone treatment and the time immediately after leaving treatment with both drugs are periods of particularly increased mortality risk, which should be dealt with by both public health and clinical strategies to mitigate such risk. These findings are potentially important, but further research must be conducted to properly account for potential confounding and selection bias in comparisons of mortality risk between opioid substitution treatments, as well as throughout periods in and out of each treatment.

PMID: 28446428 [PubMed - in process]

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Pharmacokinetic and pharmacodynamic modelling after subcutaneous, intravenous and buccal administration of a high-concentration formulation of buprenorphine in conscious cats.

Thu, 04/27/2017 - 6:20am

Pharmacokinetic and pharmacodynamic modelling after subcutaneous, intravenous and buccal administration of a high-concentration formulation of buprenorphine in conscious cats.

PLoS One. 2017;12(4):e0176443

Authors: Doodnaught GM, Monteiro BP, Benito J, Edge D, Beaudry F, Pelligand L, Steagall P

Abstract
BACKGROUND: The aim of this study was to describe the joint pharmacokinetic-pharmacodynamic model and evaluate thermal antinociception of a high-concentration formulation of buprenorphine (Simbadol™) in cats.
METHODS: Six healthy cats (4.9 ± 0.7 kg) were included in a prospective, randomized, blinded, crossover study. Simbadol™ (1.8 mg mL-1) was administered by the subcutaneous (SC; 0.24 mg kg-1), intravenous (IV; 0.12 mg kg-1) or buccal (OTM; 0.12 mg kg-1) route of administration and thermal thresholds (TT) were compared with a saline group (SAL). Thermal threshold testing and blood sampling were performed at predetermined time points up to 72 hours including a placebo group. Plasma buprenorphine and norbuprenorphine concentrations were measured using liquid chromatography mass spectrometry. A bespoke bicompartmental pharmacokinetic model simultaneously fitted data from two analytes/three routes of administration. Temporal changes in TT were analyzed using one-way ANOVA followed by Dunnett's test and treatment comparisons using two-way ANOVA with Bonferroni's correction (P < 0.05).
RESULTS: Thermal thresholds were significantly increased after SC, IV and OTM from 1-24 hours (except 2 hours), 0.5-8 hours (except 6 hours), and 1-8 hours (except 6 hours), respectively, when compared with baseline. Thermal thresholds were significantly increased after SC (1-30 hours), IV (1-8 hours) and OTM (1-12 hours) when compared with SAL, but not different among buprenorphine-treated cats. The absolute buprenorphine clearance was 0.98 L kg-1 hour-1, volume of distribution at steady state was 7.9 L kg-1 and the elimination-half-life was 12.3 hours. Bioavailability for SC and OTM was 94% and 24%, respectively. Subcutaneous absorption was biphasic. An initial peak (0.08 hours) was followed by a slow (half-life 11.2 hours) and progressive (peak acceleration at 2.8 hours) uptake.
CONCLUSION: The SC administration of Simbadol™ was characterized by prolonged absorption half-life and sustained plasma concentrations yielding long-lasting antinociception (≥ 24 hours) when compared with the IV and OTM routes.

PMID: 28445495 [PubMed - in process]

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Modulation of drug choice by extended drug access and withdrawal in Rhesus monkeys: Implications for negative reinforcement as a driver of addiction and target for medications development.

Thu, 04/27/2017 - 6:20am
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Modulation of drug choice by extended drug access and withdrawal in Rhesus monkeys: Implications for negative reinforcement as a driver of addiction and target for medications development.

Pharmacol Biochem Behav. 2017 Apr 22;:

Authors: Stevens Negus S, Banks ML

Abstract
Chronic drug exposure is hypothesized to recruit negative reinforcement processes that increase the magnitude and alter the mechanisms of drug reinforcement. Candidate substrates of negative reinforcement include increased signaling via stress-related neurotransmitters such as corticotropin releasing factor (CRF, acting at CRF receptors) or dynorphin (acting at kappa opioid receptors) and/or decreased signaling via reward-related neurotransmitters such as dopamine. Determinants of drug reinforcement can be examined with choice procedures, in which subjects choose between a drug of interest (e.g. heroin or cocaine) and a non-drug alternative reinforcer (e.g. food). This review summarizes evidence collected from studies of drug choice in rhesus monkeys to address the negative reinforcement hypothesis. In monkeys choosing between heroin and food, chronic heroin exposure and subsequent withdrawal produces a robust increase in heroin choice. This withdrawal-associated increase in heroin choice is blocked by morphine and by other mu opioid agonists used to treat opioid use disorder (methadone, buprenorphine); however, withdrawal-associated increases in heroin choice are not reliably blocked by antagonists of CRF or kappa opioid receptors or by an indirect dopamine agonist. In monkeys choosing between cocaine and food, chronic cocaine exposure and withdrawal fail to increase cocaine choice or alter sensitivity of cocaine choice to treatment with candidate therapeutics including an indirect dopamine agonist and a kappa opioid receptor antagonist. These results support a role for negative reinforcement in self-administration of heroin but not cocaine. The constellation of neurobiological changes that constitutes the negative reinforcing stimulus in opioid-dependent rhesus monkeys remains to be determined.

PMID: 28442370 [PubMed - as supplied by publisher]

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Case Report of Physiologic Phenibut Dependence Treated With a Phenobarbital Taper in a Patient Being Treated With Buprenorphine.

Wed, 04/26/2017 - 8:15am

Case Report of Physiologic Phenibut Dependence Treated With a Phenobarbital Taper in a Patient Being Treated With Buprenorphine.

J Addict Med. 2017 Apr 24;:

Authors: Brunner E, Levy R

Abstract
: This case report describes the development of dependence to phenibut, a gamma-aminobutyric acid-receptor type B agonist, in a patient concurrently being treated with buprenorphine. The patient experienced withdrawal symptoms which were successfully treated with a phenobarbital taper based on a protocol to treat sedative use disorder. This case report provided an example of the development of a phenibut use disorder and also brought up a public health question of whether phenibut should therefore be officially classified and monitored.

PMID: 28441273 [PubMed - as supplied by publisher]

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Another Senseless Death - The Case for Supervised Injection Facilities.

Tue, 04/25/2017 - 7:51am
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Another Senseless Death - The Case for Supervised Injection Facilities.

N Engl J Med. 2017 Mar 16;376(11):1011-1013

Authors: Wakeman SE

PMID: 28296603 [PubMed - indexed for MEDLINE]

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Peripartum Anesthetic Management of the Opioid-tolerant or Buprenorphine/Suboxone-dependent Patient.

Fri, 04/21/2017 - 8:14am
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Peripartum Anesthetic Management of the Opioid-tolerant or Buprenorphine/Suboxone-dependent Patient.

Clin Obstet Gynecol. 2017 Jun;60(2):447-458

Authors: Pan A, Zakowski M

Abstract
Opioid abuse and dependence continues to rise in both the general population and pregnancy, with opioid overdose deaths having quadrupled in the last 15 years. Illicit drug use in last 30 days of pregnancy was over 4% with almost 0.6% documented maternal opiate use at time of birth. The management of the opioid-tolerant, buprenorphine-dependent or methadone-dependent patient in the peripartum period is reviewed. Options for treatment of opioid dependence, acute pain management, and perioperative multimodal analgesia are discussed. The effects of maternal management on neonatal abstinence syndrome are also reviewed.

PMID: 28426507 [PubMed - in process]

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Buprenorphine Treatment and Patient Use of Health Services after the Affordable Care Act in an Integrated Health Care System.

Fri, 04/21/2017 - 8:14am
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Buprenorphine Treatment and Patient Use of Health Services after the Affordable Care Act in an Integrated Health Care System.

J Psychoactive Drugs. 2017 Apr 20;:1-9

Authors: Campbell CI, Parthasarathy S, Young-Wolff KC, Satre DD

Abstract
The Affordable Care Act (ACA) was expected to benefit patients with substance use disorders, including opioid use disorders (OUDs). This study examined buprenorphine use and health services utilization by patients with OUDs pre- and post-ACA in a large health care system. Using electronic health record data, we examined demographic and clinical characteristics (substance use, psychiatric and medical conditions) of two patient cohorts using buprenorphine: those newly enrolled in 2012 ("pre-ACA," N = 204) and in 2014 ("post-ACA," N = 258). Logistic and negative binomial regressions were used to model persistent buprenorphine use, and to examine whether persistent use was related to health services utilization. Buprenorphine patients were largely similar pre- and post-ACA, although more post-ACA patients had a marijuana use disorder (p < .01). Post-ACA patients were more likely to have high-deductible benefit plans (p < .01). Use of psychiatry services was lower post-ACA (IRR: 0.56, p < .01), and high-deductible plans were also related to lower use of psychiatry services (IRR: 0.30, p < .01). The relationship between marijuana use disorder and prescription opioid use is complex, and deserves further study, particularly with increasingly widespread marijuana legalization. Access to psychiatry services may be more challenging for buprenorphine patients post-ACA, especially for patients with deductible plans.

PMID: 28426332 [PubMed - as supplied by publisher]

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