Associations Between Buprenorphine\Naloxone and Methadone Treatment and non-Opioid Substance Use in Prescription-Type Opioid Use Disorder: Secondary Analyses From the OPTIMA Study: Associations entre le traitement avec la buprénorphine/naloxone et avec la méthadone et l'utilisation de substances non opioïdes dans le trouble lié à l'usage d'opioïdes de type sur ordonnance : analyses secondaires de l'étude OPTIMA.

OBJECTIVES: There is limited evidence on how opioid agonist treatment (OAT) may affect psychoactive non-opioid substance use in prescription-type opioid use disorder (POUD) and whether this effect might explain OAT outcomes. We aimed to assess the effect of methadone on non-opioid substance use compared to buprenorphine/naloxone (BUP/NX), to explore whether non-opioid substance use is associated with opioid use and retention in treatment, and to test non-opioid use as a moderator of associations between methadone with retention in OAT and opioid use compared to BUP/NX. METHODS: This is a secondary analysis of data from the OPTIMA trial, an open-label, pragmatic, parallel, two-arm, pan-Canadian, multicentre, randomized-controlled trial to compare standard methadone model of care and flexible take-home dosing BUP/NX for POUD treatment. We studied the effect of methadone and BUP/NX on non-opioid substance use evaluated by urine drug screen (UDS) and by classes of non-opioid substances (i.e., tetrahydrocannabinol [THC], benzodiazepines, stimulants) (weeks 2-24) using adjusted generalized estimation equation (GEE). We studied the association between non-opioid substance-positive UDS and opioid-positive UDS and retention in treatment, using adjusted GEE and logistic regressions. RESULTS: Overall, methadone was not associated with non-opioid substance-positive UDS compared to BUP/NX (OR: 0.78; 95%CI, 0.41 to 1.48). When non-opioid substances were studied separately, methadone was associated with lower odds of benzodiazepine-positive UDS (OR: 0.63; 95% CI: 0.40 to 0.98) and THC-positive UDS (OR: 0.47; 95% CI: 0.28 to 0.77), but not with different odds of stimulant-positive UDS (OR: 1.29; 95% CI: 0.78 to 2.16) compared to BUP/NX. Substance-positive UDS, overall and separate classes, were not associated with opioid-positive UDS or retention in treatment. CONCLUSION: Methadone did not show a significant effect on overall non-opioid substance use in POUD compared to BUP/NX treatment but was associated with lower odds of benzodiazepine and THC use in particular. Non-opioid substance use did not predict OAT outcomes. Further research is needed to ascertain whether specific patterns of polysubstance use (quantity and frequency) may affect treatment outcomes.

Impact of Depressive Symptom Severity on Buprenorphine/Naloxone and Methadone Outcomes in People With Prescription-Type Opioid Use Disorder: Results From a Pragmatic Randomized Controlled Trial.

OBJECTIVE: To evaluate the impact of depressive symptom severity on opioid use and treatment retention in individuals with prescription-type opioid use disorder (POUD). METHOD: We analyzed data from a multi-centric, pragmatic, open-label, randomized controlled trial comparing buprenorphine/naloxone to methadone models of care in 272 individuals with POUD. Opioid use was self-reported every two weeks for 24 weeks using the Timeline Followback. Depressive symptom severity was self-reported with the Beck Depression Inventory at baseline, week 12 and week 24. RESULTS: Baseline depressive symptom severity was not associated with opioid use nor treatment retention. At week 12, moderate depressive symptoms were associated with greater opioid use while mild to severe depressive symptoms were associated with lowered treatment retention. At week 24, moderate depressive symptoms were associated with greater opioid use. CONCLUSIONS: Ongoing depressive symptoms lead to poorer outcomes in POUD. Clinicians are encouraged to use integrative approaches to optimize treatment outcomes. This study was registered in ClinicalTrials.gov (NCT03033732) on January 27th, 2017, prior to participants enrollment.

Effects of Buprenorphine/Naloxone and Methadone on Depressive Symptoms in People with Prescription Opioid Use Disorder: A Pragmatic Randomised Controlled Trial.

OBJECTIVE: This study aimed to evaluate the effectiveness of flexible take-home dosing of buprenorphine/naloxone (BUP/NX) and methadone standard model of care in reducing depressive symptoms in people with prescription-type opioid use disorder (POUD). This trial also evaluated whether improvements in depressive symptoms were mediated by opioid use. METHODS: Analyzed data came from the OPTIMA study (clinicaltrials.gov identifier: NCT03033732), a pragmatic randomised controlled trial comparing flexible take-home dosing of BUP/NX and methadone standard model of care for reducing opioid use in people with POUD. A total of 272 participants were recruited in four Canadian provinces. Participants were randomised 1:1 to BUP/NX or methadone. After treatment induction, past two-week opioid use was measured using the Timeline Followback every two weeks for a total of 24 weeks. Depressive symptoms were measured with the Beck Depression Inventory at baseline, weeks 12 and 24. RESULTS: Both BUP/NX and methadone significantly reduced depressive symptoms at week 12 (aß ± SE = -3.167 ± 1.233; P < 0.001) and week 24 (aß ± SE = -7.280 ± 1.285; P < 0.001), with no interaction between type of treatment and time (P = 0.284). Improvements in depressive symptoms were only partially mediated by a reduction in opioid use (proportion mediated = 36.8%; 95% confidence interval = -1.158 to -0.070; P = 0.015). CONCLUSIONS: BUP/NX and methadone showed similar effectiveness in decreasing comorbid depressive symptoms in people with POUD. This effect was partially explained by a reduction in opioid use. As both treatments seem equally effective, clinicians are encouraged to tailor the selection of OAT to patients' needs and characteristics.

[Opioid use disorder in patients with chronic non-cancer pain]. / Les troubles liés à l'utilisation des opioïdes prescrits médicalement.

Epidemiology Canada now has the second highest number of opioid prescriptions per capita in the world. The rate of prescriptions has increased over the last decade, most notably in adults over 55 years of age. A recognition of the importance of treating pain has influenced this increase, but higher rates of opioid prescribing have produced undesirable outcomes including the misuse of medication as well as an increased number of deaths and emergency department visits attributable to opioids. Diverse psychiatric disorders, such as major depression, now also occur in 40% of those with an opioid use disorder (OUD). Neuroscience We now understand that addictive behaviors are caused by both environmental and genetic factors. Although OUD has historically been perceived as a weakness of character, it is now clear that it is a chronic disease, which results from a complex interaction between a substance, such as opioid, environmental factors, and an individual's genotype. Unfortunately, this evidence has yet to be successfully translated into clinical practice and most physicians are unable to diagnose and manage OUD patients appropriately.Clinical guidelines Many clinical guidelines for the management of chronic, non-cancer pain are available. All guidelines identify the need to assess the patient appropriately and screen for factors associated with misuse before prescribing opioids. Guidelines generally acknowledge that patients should not be denied appropriate pain management, but that some patients will require close supervision and frequent follow-up to prevent the misuse of prescription opioids.

Absence of Evidence for Sustained Effects of Daily Cannabidiol Administration on Anandamide Plasma Concentration in Individuals with Cocaine Use Disorder: Exploratory Findings from a Randomized Controlled Trial.

Background: Cannabidiol (CBD) has been proposed to have a therapeutic potential over a wide range of neuropsychiatric disorders, including substance use disorders. Pre-clinical evidence suggests that CBD can increase anandamide (AEA) plasma concentration, possibly mediating some of its therapeutic properties. Whether CBD exerts such an effect on AEA in individuals with cocaine use disorder (CUD) remains unknown. Aims: To explore the sustained effects of daily CBD administration on AEA plasma concentrations compared with placebo in CUD. Methods: We used data from a randomized, double-blind, placebo-controlled trial evaluating CBD's efficacy in CUD. Seventy-eight individuals were randomized to receive a daily oral dose of 800 mg CBD (n = 40) or a placebo (n = 38). Participants stayed in an inpatient detoxification setting for 10 days, after which they were followed in an outpatient setting for 12 weeks. AEA plasma concentration was measured at baseline and at 23-h post CBD ingestion on day 8 and week 4. A generalized estimating equation model was used to assess CBD's effects on AEA, and sensitivity analyses were computed using Bayesian linear regressions. Results: Sixty-four participants were included in the analysis. Similar mean AEA plasma concentrations in both treatment groups (p = 0.357) were observed. At day 8, mean AEA plasma concentrations (± standard deviation) were 0.26 (± 0.07) ng/mL in the CBD group and 0.29 (± 0.08) ng/mL in the placebo group (p = 0.832; Bayes factor [BF] = 0.190). At week 4, they were 0.27 (± 0.09) ng/mL in the CBD group and 0.30 (± 0.09) ng/mL in the placebo group (p = 0.181; BF = 0.194). Conclusion: While not excluding any potential acute and short-term effect, daily CBD administration did not exert a sustained impact on AEA plasma concentrations in individuals with CUD compared with placebo. Registration: clinicaltrials.gov (NCT02559167).

Differential effect of cannabis use on opioid agonist treatment outcomes: Exploratory analyses from the OPTIMA study.

INTRODUCTION: Conflictual evidence exists regarding the effects of cannabis use on the outcomes of opioid agonist therapy (OAT). In this exploratory analysis, we examined the effect of recent cannabis use on opioid use, craving, and withdrawal symptoms, in individuals participating in a trial comparing flexible buprenorphine/naloxone (BUP/NX) take-home dosing model to witnessed ingestion of methadone. METHODS: We analyzed data from a multi-centric, pragmatic, 24-week, open label, randomized controlled trial in individuals with prescription-type opioid use disorder (n = 272), randomly assigned to BUP/NX (n = 138) or methadone (n = 134). The study measured last week cannabis and opioid use via timeline-follow back, recorded at baseline and every two weeks during the study. Craving symptoms were measured using the Brief Substance Craving Scale at baseline, and weeks 2, 6, 10, 14, 18 and 22. The study measured opioid withdrawal symptoms via Clinical Opiate Withdrawal Scale at treatment initiation and weeks 2, 4, and 6. RESULTS: The mean maximum dose taken during the study was 17.3 mg/day (range = 0.5-32 mg/day) for BUP/NX group and 67.7 mg/day (range = 10-170 mg/day) in the methadone group. Repeated measures generalized linear mixed models demonstrated that cannabis use in the last week (mean of 2.3 days) was not significantly associated with last week opioid use (aß ± standard error (SE) = -0.06 ± 0.04; p = 0.15), craving (aß ± SE = -0.05 ± 0.08, p = 0.49), or withdrawal symptoms (aß ± SE = 0.09 ± 0.1, p = 0.36). Bayes factor (BF) for each of the tested models supported the null hypothesis (BF < 0.3). CONCLUSIONS: The current study did not demonstrate a statistically significant effect of cannabis use on outcomes of interest in the context of a pragmatic randomized-controlled trial. These findings replicated previous results reporting no effect of cannabis use on opioid-related outcomes.

Diacetylmorphine versus methadone for the treatment of opioid addiction.

BACKGROUND: Studies in Europe have suggested that injectable diacetylmorphine, the active ingredient in heroin, can be an effective adjunctive treatment for chronic, relapsing opioid dependence. METHODS: In an open-label, phase 3, randomized, controlled trial in Canada, we compared injectable diacetylmorphine with oral methadone maintenance therapy in patients with opioid dependence that was refractory to treatment. Long-term users of injectable heroin who had not benefited from at least two previous attempts at treatment for addiction (including at least one methadone treatment) were randomly assigned to receive methadone (111 patients) or diacetylmorphine (115 patients). The primary outcomes, assessed at 12 months, were retention in addiction treatment or drug-free status and a reduction in illicit-drug use or other illegal activity according to the European Addiction Severity Index. RESULTS: The primary outcomes were determined in 95.2% of the participants. On the basis of an intention-to-treat analysis, the rate of retention in addiction treatment in the diacetylmorphine group was 87.8%, as compared with 54.1% in the methadone group (rate ratio for retention, 1.62; 95% confidence interval [CI], 1.35 to 1.95; P<0.001). The reduction in rates of illicit-drug use or other illegal activity was 67.0% in the diacetylmorphine group and 47.7% in the methadone group (rate ratio, 1.40; 95% CI, 1.11 to 1.77; P=0.004). The most common serious adverse events associated with diacetylmorphine injections were overdoses (in 10 patients) and seizures (in 6 patients). CONCLUSIONS: Injectable diacetylmorphine was more effective than oral methadone. Because of a risk of overdoses and seizures, diacetylmorphine maintenance therapy should be delivered in settings where prompt medical intervention is available. (ClinicalTrials.gov number, NCT00175357.)

Cost-effectiveness of diacetylmorphine versus methadone for chronic opioid dependence refractory to treatment.

BACKGROUND: Although diacetylmorphine has been proven to be more effective than methadone maintenance treatment for opioid dependence, its direct costs are higher. We compared the cost-effectiveness of diacetylmorphine and methadone maintenance treatment for chronic opioid dependence refractory to treatment. METHODS: We constructed a semi-Markov cohort model using data from the North American Opiate Medication Initiative trial, supplemented with administrative data for the province of British Columbia and other published data, to capture the chronic, recurrent nature of opioid dependence. We calculated incremental cost-effectiveness ratios to compare diacetylmorphine and methadone over 1-, 5-, 10-year and lifetime horizons. RESULTS: Diacetylmorphine was found to be a dominant strategy over methadone maintenance treatment in each of the time horizons. Over a lifetime horizon, our model showed that people receiving methadone gained 7.46 discounted quality-adjusted life-years (QALYs) on average (95% credibility interval [CI] 6.91-8.01) and generated a societal cost of $1.14 million (95% CI $736,800-$1.78 million). Those who received diacetylmorphine gained 7.92 discounted QALYs on average (95% CI 7.32-8.53) and generated a societal cost of $1.10 million (95% CI $724,100-$1.71 million). Cost savings in the diacetylmorphine cohort were realized primarily because of reductions in the costs related to criminal activity. Probabilistic sensitivity analysis showed that the probability of diacetylmorphine being cost-effective at a willingness-to-pay threshold of $0 per QALY gained was 76%; the probability was 95% at a threshold of $100,000 per QALY gained. Results were confirmed over a range of sensitivity analyses. INTERPRETATION: Using mathematical modelling to extrapolate results from the North American Opiate Medication Initiative, we found that diacetylmorphine may be more effective and less costly than methadone among people with chronic opioid dependence refractory to treatment.

Sex work involvement among women with long-term opioid injection drug dependence who enter opioid agonist treatment.

BACKGROUND: Substitution with opioid-agonists (e.g., methadone) has shown to be an effective treatment for chronic long-term opioid dependency. Survival sex work, very common among injection drug users, has been associated with poor Opioid Agonist Treatment (OAT) engagement, retention and response. Therefore, this study was undertaken to determine factors associated with engaging in sex work among long-term opioid dependent women receiving OAT. METHODS: Data from a randomized controlled trial, the North American Opiate Medication Initiative (NAOMI), conducted in Vancouver and Montreal (Canada) between 2005-2008, was analyzed. The NAOMI study compared the effectiveness of oral methadone to injectable diacetylmorphine or injectable hydromorphone, the last two on a double blind basis, over 12 months. A research team, independent of the clinic services, obtained outcome evaluations at baseline and follow-up (3, 6, 9, 12, 18 and 24 months). RESULTS: A total 53.6% of women reported engaging in sex work in at least one of the research visits. At treatment initiation, women who were younger and had fewer years of education were more likely to be engaged in sex work. The multivariate logistic generalized estimating equation regression analysis determined that psychological symptoms, and high illicit heroin and cocaine use correlated with women's involvement in sex work during the study period. CONCLUSIONS: After entering OAT, women using injection drugs and engaging in sex work represent a particularly vulnerable group showing poorer psychological health and a higher use of heroin and cocaine compared to women not engaging in sex work. These factors must be taken into consideration in the planning and provision of OAT in order to improve treatment outcomes. TRIAL REGISTRATION: NCT00175357.

Cannabidiol Effect on Anxiety Symptoms and Stress Response in Individuals With Cocaine Use Disorder: Exploratory Results From a Randomized Controlled Trial.

OBJECTIVES: Individuals with a cocaine use disorder (CUD) are more likely to present anxiety, which in turn negatively impacts substance use outcomes. Some evidence suggests that cannabidiol (CBD) presents anxiolytic properties and could be a treatment for substance use disorders. This study explores CBD's effect on stress biomarker (cortisol) and anxiety symptoms in people with CUD. METHODS: Exploratory analyses were conducted using data from a randomized, double-blind, placebo-controlled trial evaluating CBD's efficacy to treat CUD. We randomized 78 individuals with CUD into receiving a daily oral dose up to 800 mg CBD (n = 40) or placebo (n = 38). The trial was divided into 2 phases: an inpatient detoxification lasting 10 days and an outpatient follow-up lasting 12 weeks. Anxiety symptoms and stress response were assessed using a visual analog scale, the Beck Anxiety Inventory, and cortisol levels at multiple time points throughout the study. We also measured anxiety after a stressful and a cocaine-cue scenarios. We used generalized estimating equations models and multiple linear regression to assess CBD's effects on anxiety and cortisol levels. RESULTS: Both treatment groups had similar mean anxiety scores according to the Beck Anxiety Inventory ( P = 0.27) and the visual analog scale ( P = 0.18). CBD did not decrease anxiety after a stressful ( P = 0.14) and a cocaine ( P = 0.885) scenarios compared with placebo. No statistically significant group difference was found in cortisol levels ( P = 0.76). CONCLUSIONS: We found no evidence for 800 mg of CBD to be more efficacious than placebo for modulating anxiety symptoms and cortisol levels in individuals with CUD.

A multi-methods and longitudinal study of patients' perceptions in injectable opioid agonist treatment: Implications for advancing patient-centered methodologies in substance use research.

BACKGROUND: Patients' perceptions are vital to the delivery and evaluation of substance use treatment. They are most frequently collected at one time-point and measured using patient satisfaction questionnaires or qualitative methodologies. Interestingly, the findings of these studies often diverge, as satisfaction scores tend to be highly positive, while qualitative findings suggest dissatisfaction and areas for improvement. This divergence limits current understandings of patients' perceptions and their potential change over time in treatment. OBJECTIVE: This study explores the relationship between open-ended positive and negative perceptions of treatment and patient satisfaction scores over time. METHODS: The RUTH (Research on the Utilization of Therapeutic Hydromorphone) prospective cohort study included 131 participants receiving injectable diacetylmorphine or hydromorphone in Canada's first injectable opioid agonist treatment (iOAT) program. The study collected the Client Satisfaction Questionnaire (CSQ-8) at eight time-points over an 18-month period. Following a multi-methods approach, the study complemented the CSQ-8 with open-ended positive and negative comments of iOAT. The research team analyzed these comments thematically at each time-point to develop positive and negative perception themes. We then used growth curve modeling to explore the relationship between positive and negative perception themes and patient satisfaction over time. FINDINGS: Over the eight time-points, six positive and eight negative perception themes emerged, broadly reflecting structural (e.g., expansion of iOAT), process (e.g., schedules), relational (e.g., interactions with providers), and outcome-related (e.g., met/unmet needs) perceptions of iOAT. On average, participants reported high satisfaction (grand mean = 29.2 out of 32), and scores did not significantly change over time. However, we did find significant unexplained variation within participants in their satisfaction trajectories and between participants in their initial satisfaction scores. In conditional growth curve models, the theme "unfavorable interactions with providers" had the strongest independent effect on overall satisfaction trajectories. CONCLUSIONS: This study provides an example of how open-ended comments can be integrated with patient satisfaction questionnaire data to gather a comprehensive and patient-centered evaluation of substance use treatment. Considering the iOAT context specifically, relational dynamics and daily treatment access were significant predictors of patient satisfaction over time and may be attributes of iOAT that require further investigation.

Impact of an Accelerated Pretreatment Evaluation on Linkage-to-Care for Hepatitis C-infected Persons Who Inject Drugs.

Background: Historically, hepatitis C virus (HCV) pretreatment evaluation has required multiple visits, frequently resulting in loss to follow-up and a delayed initiation of treatment. New technologies can accelerate this process. We investigated the feasibility of a single-day evaluation program and its impact on evaluation completion, treatment eligibility awareness, and treatment initiation among people who inject drugs (PWIDs). Methods: HCV-infected PWID who were unaware if they were eligible for treatment were recruited in a prospective evaluation of an accelerated model of care between 2017 and 2019 and compared to a historical cohort. The patients underwent a medical evaluation, rapid HCV viral load testing, and transient elastography during a single visit, at the end of which they were informed whether they were eligible for treatment. A historical cohort of patients fulfilling the same inclusion criteria and evaluated with the usual standard of care spanning several visits who were examined at the addiction medicine clinic from 2014 to 2016 served as the comparison group. Results: The accelerated and historical cohorts included 99 and 76 patients, respectively. The cohorts did not differ significantly by age and gender, but more patients in the historical cohort were undergoing opioid agonist therapy, while more patients in the accelerated cohort injected drugs in the last month. An accelerated evaluation resulted in a higher rate of evaluation completion (100% vs 67.1%; P < .001). Among those eligible for treatment, the proportion of those initiating treatment was similar between the groups (51/64 (79.7%) vs. 26/37 (70.3%); P = .28). The delay in the initiation of treatment was shorter in the accelerated cohort than in the historical cohort (69 (IQR: 49-106) days vs. 219 (IQR: 141-416) days; P < .001). Conclusions: Accelerated evaluation enhanced the awareness of eligibility and reduced the time to initiation among eligible patients. Trial Registration: This study is registered on www.clinicaltrials.gov (NCT02755402).

Flexible Buprenorphine/Naloxone Model of Care for Reducing Opioid Use in Individuals With Prescription-Type Opioid Use Disorder: An Open-Label, Pragmatic, Noninferiority Randomized Controlled Trial.

OBJECTIVE: Extensive exposure to prescription-type opioids has resulted in major harm worldwide, calling for better-adapted approaches to opioid agonist therapy. The authors aimed to determine whether flexible take-home buprenorphine/naloxone is as effective as supervised methadone in reducing opioid use in prescription-type opioid consumers with opioid use disorder. METHODS: This seven-site, pan-Canadian, 24-week, pragmatic, open-label, noninferiority, two-arm parallel randomized controlled trial involved treatment-seeking adults with prescription-type opioid use disorder. Participants were randomized in a 1:1 ratio to treatment with sublingual buprenorphine/naloxone (target dosage, 8 mg/2 mg to 24 mg/6 mg per day; flexible take-home dosing) or oral methadone (≈60-120 mg/day; closely supervised). The primary outcome was the proportion of opioid-free urine drug screens over 24 weeks (noninferiority margin, 15%). All randomized participants were analyzed, excluding one who died shortly after randomization, for the primary analysis (modified intention-to-treat analysis). RESULTS: Of 272 participants recruited (mean age, 39 years [SD=11]; 34.2% female), 138 were randomized to buprenorphine/naloxone and 134 to methadone. The mean proportion of opioid-free urine drug screens was 24.0% (SD=34.4) in the buprenorphine/naloxone group and 18.5% (SD=30.5) in the methadone group, with a 5.6% adjusted mean difference (95% CI=-0.3, +∞). Participants in the buprenorphine/naloxone group had 0.47 times the odds (95% CI=0.24, 0.90) of being retained in the assigned treatment compared with those in the methadone group. Overall, 24 drug-related adverse events were reported (12 in the buprenorphine/naloxone group [N=8/138; 5.7%] and 12 in the methadone group [N=12/134; 9.0%]) and mostly included withdrawal, hypogonadism, and overdose. CONCLUSIONS: The buprenorphine/naloxone flexible model of care was safe and noninferior to methadone in reducing opioid use among people with prescription-type opioid use disorder. This flexibility could help expand access to opioid agonist therapy and reduce harms in the context of the opioid overdose crisis.

Cannabidiol effects on cognition in individuals with cocaine use disorder: Exploratory results from a randomized controlled trial.

BACKGROUND: Cocaine use disorder (CUD) is associated with various cognitive deficits that impede patients' functionality, prognosis and therapeutic outcomes. New pharmacological treatments for CUD that could improve cognition are needed. OBJECTIVE: To explore whether cannabidiol (CBD) is superior to placebo to improve cognitive functioning in individuals with CUD. METHODS: We conducted an exploratory analysis of a single site, randomized, double-blind, placebo-controlled trial evaluating CBD's efficacy in reducing craving, cocaine use and relapse in individuals with CUD. Seventy-eight individuals diagnosed with CUD were randomized to receive either CBD (800 mg) or placebo for 92 days. We used the Cambridge Neuropsychological Test Automated Battery (CANTAB) to assess inhibition (Stop Signal Task; SST), risky decision making (Cambridge Gambling Task; CGT) and visual memory (Pattern Recognition Memory; PRM). This assessment was made on day 1, day 7 and at week 6. We controlled for sex, severity of dependence and baseline cognitive scores in our generalized estimating equation models. RESULTS: Both groups performed similarly on the PRM (correct answers: p = 0.080), SST (stop signal reaction time: p = 0.644) and CGT (quality of decision making: p = 0.994; deliberation time: p = 0.507; delay aversion: p = 0.968; risk taking: p = 0.914) tests. CONCLUSIONS: We found no evidence for 800 mg of CBD to be more efficacious than placebo for improving cognitive outcomes. Clinical trials evaluating pharmacological treatments for CUD should continue to be a research priority.

Buprenorphine/naloxone and methadone effectiveness for reducing craving in individuals with prescription opioid use disorder: Exploratory results from an open-label, pragmatic randomized controlled trial.

BACKGROUND: Craving reduction is an important target in the treatment of prescription-type opioid use disorder (POUD). In this exploratory analysis, we compared the effectiveness of BUP/NX flexible model of care relative to methadone for craving reduction in individuals with POUD. METHODS: We analyzed data from a multicentric, pragmatic, 24-week open-label randomized controlled trial conducted in participants with POUD (N = 272) who were randomly assigned to BUP/NX model of care with flexible take-home dosing (n = 138) or the standard model of care with closely supervised methadone (n = 134). Treatments were prescribed and administered according to local guidelines, in diverse clinical settings. Craving was measured using the Brief Substance Craving Scale at baseline, week 2, 6, 10, 14, 18 and 22. RESULTS: Cravings decreased in both treatment groups over 22 weeks (BUP/NX adjusted mean difference = -5.52, 95% CI = -6.91 to -4.13; methadone adjusted mean difference = -3.95, 95% CI = -5.28 to -2.63; p < 0.001), and were overall lower in the BUP/NX group (adjusted mean = 4.04, 95% CI = 3.43-4.64) than the methadone group (adjusted mean = 5.13, 95% CI = 4.51-5.74; p < 0.001). The time by treatment group interaction (favoring BUP/NX) was statistically significant at week 2 (adjusted mean difference = -1.58, 95% CI = -3.13 to -0.03; p = 0.041). CONCLUSIONS: Compared to the standard methadone model of care, flexible take-home dosing of BUP/NX was associated with lower craving in individuals with POUD. These findings can contribute to guiding shared decision-making regarding OAT treatment in this population.

Client satisfaction among participants in a randomized trial comparing oral methadone and injectable diacetylmorphine for long-term opioid-dependency.

BACKGROUND: Substitution with opioid-agonists (e.g., methadone) has shown to be an effective treatment for chronic long-term opioid dependency. Patient satisfaction with treatment has been associated with improved addiction treatment outcomes. However, there is a paucity of studies evaluating patients' satisfaction with Opioid Substitution Treatment (OST). In the present study, participants' satisfaction with OST was evaluated at 3 and 12 months. We sought to test the relationship between satisfaction and patients' characteristics, the treatment modality received and treatment outcomes. METHODS: Data from a randomized controlled trial, the North American Opiate Medication Initiative (NAOMI), conducted in Vancouver and Montreal (Canada) between 2005-2008, was analyzed. The NAOMI study compared the effectiveness of oral methadone vs. injectable diacetylmorphine over 12 months. A small sub-group of patients received injectable hydromorphone on a double blind basis with diacetylmorphine. The Client Satisfaction Questionnaire (CSQ-8) was used to measure satisfaction with treatment. CSQ-8 scores, as well as retention and response to treatment, did not differ between those receiving hydromorphone and diacetylmorphine at 3 or 12 months assessments; therefore, these two groups were analyzed together as the 'injectable' treatment group. RESULTS: A total of 232 (92%) and 237 (94%) participants completed the CSQ-8 at 3 and 12 months, respectively. Participants in both groups were highly satisfied with treatment. Independent of treatment group, participants satisfied with treatment at 3 months were more likely to be retained at 12 months. Multivariate analysis indicated that satisfaction was greater among those randomized to the injection group after controlling for treatment effectiveness. Participants who were retained, responded to treatment, and had fewer psychological symptoms were more satisfied with treatment. Finally, open-ended comments were made by 149 (60.3%) participants; concerns about the randomization process and the study ending were most commonly reported by participants receiving the oral and injectable medications, respectively. CONCLUSIONS: The higher satisfaction among those receiving medically prescribed injectable diacetylmorphine (or hydromorphone) supports current evidence regarding the attractiveness of this treatment for long-term, opioid-dependent individuals not benefiting sufficiently from other treatments. In addition, the measurement of treatment satisfaction provides valuable information about participants at risk of relapse and in need of additional services. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00175357.

Cannabidiol as a treatment for craving and relapse in individuals with cocaine use disorder: a randomized placebo-controlled trial.

BACKGROUND AND AIMS: Cocaine use disorder (CUD) is a significant public health concern for which no efficacious pharmacological interventions are available. Cannabidiol (CBD) has attracted considerable interest as a promising treatment for addiction. This study tested CBD efficacy for reducing craving and preventing relapse in people with CUD. DESIGN: Single-site double-blind randomized controlled superiority trial comparing CBD with placebo. SETTING AND PARTICIPANTS: Centre Hospitalier de l'Université de Montréal, Canada. Seventy-eight adults (14 women) with moderate to severe CUD participated. INTERVENTION: Participants were randomly assigned (1 : 1) by stratified blocks to daily 800 mg CBD (n = 40) or placebo (n = 38). They first underwent an inpatient detoxification phase lasting 10 days. Those who completed this phase entered a 12-week outpatient follow-up. MEASUREMENTS: Primary outcomes were drug-cue-induced craving during detoxication and time-to-cocaine relapse during subsequent outpatient treatment. FINDINGS: During drug-cue exposure, craving scores [mean ± standard deviation (SD)] increased from baseline by 4.69 (2.89) versus 3.21 (2.78) points, respectively, in CBD (n = 36) and placebo (n = 28) participants [confidence interval (CI) = -0.33 to 3.04; P = 0.069; Bayes factor = 0.498]. All but three participants relapsed to cocaine by week 12 with similar risk for CBD (n = 34) and placebo (n = 27) participants (hazard ratio = 1.20, CI = 0.65-2.20, P = 0.51; Bayes factor = 0.152). CBD treatment was well tolerated and associated mainly with diarrhoea. CONCLUSIONS: CBD did not reduce cocaine craving or relapse among people being treated for CUD.

Longitudinal patterns of cocaine use among patients receiving injectable hydromorphone or diacetylmorphine for the treatment of opioid use disorder: A growth curve modeling approach.

BACKGROUND AND AIMS: Cocaine use is prevalent among people receiving injectable opioid agonist treatment. Investigations of cocaine use in this population have been descriptive and the potential heterogeneity existing in patterns of use have not been characterized. As such, among patients receiving injectable opioid agonist treatment, this study aimed to: 1) quantify intra- and inter-individual variation in cocaine use over 24-months and; 2) determine how predictors of interest explained this variation. METHODS: Participants were patients receiving injectable opioid agonist treatment for opioid use disorder. Study visits were completed at baseline prior to receiving treatment, and 3,6,9,12,18, and 24 months after baseline. A multi-level regression approach to growth curve modeling was employed to estimate and explain intra- (within-person) and inter-individual (between-person) variation in cocaine use. RESULTS: Significant intra and inter-individual variation in cocaine use was identified over 24-months. Treatment engagement was on average associated with reductions in the prior month number of days of cocaine use (range: 0-30)(Estimate (standard error): -0.05(0.02), p = 0.003). On average, men reported less cocaine use compared to women (Estimate (standard error): -5.91(1.57), p=<0.001), and participants reporting ever regularly using cocaine at baseline reported more cocaine use over 24-months compared to participants reporting never regularly using cocaine (Estimate (standard error): 4.72 (1.91), p = 0.013). CONCLUSIONS: Significant reductions in cocaine use were observed and significant heterogeneity in patterns of cocaine use was identified. These heterogeneous cocaine use profiles suggest that an individualized approach to care will be critical in responding to patients' cocaine use in injectable opioid agonist treatment.

Exploring cannabidiol effects on inflammatory markers in individuals with cocaine use disorder: a randomized controlled trial.

Cocaine use disorder (CUD) is a major public health issue associated with physical, social, and psychological problems. Excessive and repeated cocaine use induces oxidative stress leading to a systemic inflammatory response. Cannabidiol (CBD) has gained substantial interest for its anti-inflammatory properties, safety, and tolerability profile. However, CBD anti-inflammatory properties have yet to be confirmed in humans. This exploratory study is based on a single-site randomized controlled trial that enrolled participants with CUD between 18 and 65 years, randomized (1:1) to daily receive either CBD (800 mg) or placebo for 92 days. The trial was divided into a 10-day detoxification (phase I) followed by a 12-week outpatient follow-up (phase II). Blood samples were collected from 48 participants at baseline, day 8, week 4, and week 12 and were analyzed to determine monocytes and lymphocytes phenotypes, and concentrations of various inflammatory markers such as cytokines. We used generalized estimating equations to detect group differences. Participants treated with CBD had lower levels of interleukin-6 (p = 0.017), vascular endothelial growth factor (p = 0.032), intermediate monocytes CD14+CD16+ (p = 0.024), and natural killer CD56negCD16hi (p = 0.000) compared with participants receiving placebo. CD25+CD4+T cells were higher in the CBD group (p = 0.007). No significant group difference was observed for B lymphocytes. This study suggests that CBD may exert anti-inflammatory effects in individuals with CUD.

Preferences for research design and treatment of comorbid depression among patients with an opioid use disorder: A cross-sectional discrete choice experiment.

BACKGROUND: Up to 74 % of people with an opioid use disorder (OUD) will experience depression in their lifetime. Understanding and addressing the concept of preference for depression treatments and clinical trial designs may serve as an important milestone in enhancing treatment and research outcomes. Our goal is to evaluate preferences for depression treatments and clinical trial designs among individuals with an OUD and comorbid depression. METHODS: We evaluated preferences for depression treatments and clinical trial designs using an online cross-sectional survey including a best-best discrete choice experiment. We recruited 165 participants from opioid agonist treatment clinics and community-based services in Calgary, Charlottetown, Edmonton, Halifax, Montreal, Ottawa, Quebec City, St. John's and Trois-Rivières, Canada. RESULTS: Psychotherapy was the most accepted (80.0 %; CI: 73.9-86.1 %) and preferred (31.5 %; CI: 24.4-38.6 %) treatment. However, there was a high variability in acceptability and preferences of depression treatments. Significant predictors of choice for depression treatments were administration mode depending on session duration (p < 0.001), access mode (p < 0.001) and treatment duration (p < 0.001). Significant predictors of choice for clinical trial designs were allocation type (p = 0.008) and monetary compensation (p = 0.033). Participants preferred participating in research compared to non-participation (p < 0.001). CONCLUSIONS: Accessibility and diversity of depression interventions, including psychotherapy, need to be enhanced in addiction services to ensure that all patients can receive their preferred treatment. Ensuring proper monetary compensation and comparing an intervention of interest with an active treatment might increase participation of depressed OUD patients in future clinical research initiative.