Glial modulators as novel therapeutics for comorbid pain and opioid use disorder.

Chronic pain and opioid use disorder (OUD) are major public health problems, with rising opioid-related overdose deaths linked to increased opioid prescriptions for pain management. Novel treatment approaches for these commonly comorbid disorders are needed. Growing evidence supports a role for glial activation for both chronic pain and substance use disorders, including OUD. This review provides an overview of glial modulators as a novel treatment approach for comorbid pain and OUD. We aim to synthesize clinical studies investigating the efficacy of glial modulators in treating these comorbid disorders. We conducted a literature search of PubMed and Google Scholar databases in October 2023 to identify relevant clinical trials. The included studies varied in terms of patient population, study methodology and outcomes assessed, and were often limited by small sample sizes and other methodological issues. Additionally, several glial modulators have yet to be studied for chronic pain and OUD. Despite these limitations, these studies yielded positive signals that merit further investigation. Both chronic pain and OUD remain significant public health problems, with many treatment challenges. Glial modulators continue to hold promise as novel therapeutics for comorbid pain and OUD, given positive indications that they can improve pain measures, and reduce addiction-related outcomes. As our understanding of the mechanisms underlying the contributions of glial modulators to pain and addiction behaviours deepens, we will be better equipped to identify more specific therapeutic targets for chronic pain and OUD.

From taboo to treatment: The emergence of psychedelics in the management of pain and opioid use disorder.

The rise of psychedelics in contemporary medicine has sparked interest in their potential therapeutic applications. While traditionally associated with countercultural movements and recreational use, recent research has shed light on the potential benefits of psychedelics in various mental health conditions. In this review, we explore the possible role of psychedelics in the management of chronic pain and opioid use disorder (OUD), 2 critical areas in need of innovative treatment options. Pain control remains a significant clinical challenge, particularly for individuals with OUD and those who receive long-term opioid therapy who develop marked tolerance to opioid-induced analgesia. Despite the magnitude of this problem, there is a scarcity of controlled studies investigating pain management alternatives for these populations. Drawing from preclinical and human evidence, we highlight the potential of psychedelics to act on shared neurobiological substrates of chronic pain and OUD, potentially reversing pain- and opioid-induced neuroadaptations, such as central sensitization. We elaborate on the multifaceted dimensions of the pain experience (sensory, affective and cognitive) and their intersections that overlap with opioid-related phenomena (opioid craving and withdrawal), hypothesizing how these processes can be modulated by psychedelics. After summarizing the available clinical research, we propose mechanistic insights and methodological considerations for the design of future translational studies and clinical trials, building on a shared clinical and neurobiological understanding of chronic pain and OUD. Our intention is to provide timely perspectives that accelerate the development and exploration of novel therapeutics for chronic pain and OUD amidst the escalating opioid crisis.

The relationship of pain intensity and opioid craving with delayed methadone dose: A preliminary study of individuals with opioid use disorder.

AIMS: Despite a strong theoretical link between opioid craving and pain, little is known about the temporal relationship between pain and craving and the acute experience of pain in the context of methadone treatment. Using a cross-over design, the current study evaluated the time course of pain and craving and objective experience of pain as a function of the last methadone dose. METHODS: Participants (n = 20) presented for the study in the morning and either received methadone dose as scheduled or delayed dose until the afternoon. During the 4-h study visit, participants completed a series of tasks, including repeated assessment of pain and craving at 0, +40, +70, +130, +160 and +240 min and a cold pressor test (CPT) at +15 and +220 min. RESULTS: Separate mixed model results demonstrated no effect of dosing condition on craving; however, there was a significant dosing condition by time interaction (F(5,209) = 3.38, P = .006) such that pain increased over time in the delayed methadone condition but decreased in time in the scheduled methadone condition. A mixed model predicting self-reported pain revealed a three-way interaction between dosing condition, craving and time (F(5,197) = 2.39, P = .039) explained by a positive association between craving and pain at each time point (except 240 min) in delayed condition (P-range = .004-.0001). A separate mixed model on CPT data indicated a significant condition by time interaction such that pain threshold decreased in the delayed, but not scheduled, condition (F(1,57) = 4.01, P = .050). CONCLUSIONS: These preliminary findings highlight the potential for increased risks after even a short delay in receiving a methadone dose.

Associations Between Childhood Trauma and Tobacco Use Outcomes in Adults after Overnight Abstinence.

INTRODUCTION: Childhood trauma is known to be associated with nicotine dependence, yet limited smoking outcomes have been examined and few studies have assessed associations between specific trauma subscales and smoking. Additionally, sex differences in trauma-smoking relations are understudied. This study examined associations between childhood trauma and several smoking-related outcomes in adults who smoke after overnight abstinence. AIMS AND METHODS: People who smoke (N = 205) completed self-report and biochemical assessments evaluating childhood trauma, affect, nicotine dependence, smoking urges, withdrawal, and plasma cortisol and cotinine levels. Smoking outcomes were compared between those with and without a history of moderate to severe childhood trauma among the total sample and by sex. RESULTS: Relative to those with no to minimal abuse, those with moderate to severe abuse had higher negative affect, withdrawal severity, and plasma cotinine levels. Exploratory analyses revealed that women were more likely than men to have urges to smoke for negative reinforcement and have higher withdrawal severity, but no interactions between abuse group and sex were observed. Examining specific trauma subscales, the moderate to severe emotional abuse group had more severe nicotine dependence, negative affect, and withdrawal compared to the no to minimal group. The moderate to severe sexual abuse group had more severe nicotine dependence and withdrawal compared to the no to minimal group. CONCLUSIONS: Exposure to childhood trauma is associated with more severe nicotine dependence, negative affect, withdrawal, and higher plasma cotinine levels. Findings also indicate that different types of trauma may differentially affect smoking behaviors. IMPLICATIONS: This study of adults who smoke finds that childhood trauma history may be a marker for smoking susceptibility and suggests that individuals with experiences of emotional and sexual abuse may require targeted forms of smoking cessation interventions. Moreover, findings suggest that smoking risks may differ for men and women. Findings inform public health interventions intended to reduce cigarette use in individuals with exposure to childhood trauma.

Brief report: The influence of childhood trauma on the effects of delta-9-tetrahydrocannabinol in persons with opioid use disorder.

BACKGROUND AND OBJECTIVES: Childhood trauma (CT) increases addiction vulnerability. We examined CT's impact on delta-9-tetrahydrocannabinol (THC) effects. METHODS: This is a post-hoc analysis of a randomized, placebo-controlled, crossover trial investigating the effects of oral THC (10, 20 mg) among 25 persons receiving methadone for opioid use disorder (OUD). RESULTS: Greater CT was associated with lower aversive effects from higher THC doses (20 mg) (p = .006). DISCUSSION AND CONCLUSIONS: CT may reduce the subjective aversive effects of THC, potentially leading to greater cannabis use in individuals with OUD. SCIENTIFIC SIGNIFICANCE: These findings offer insights into THC's risks versus benefits in OUD subgroups and emphasize assessing CT in OUD treatment and research.

Delta-9-tetrahydrocannabinol modulates pain sensitivity among persons receiving opioid agonist therapy for opioid use disorder: A within-subject, randomized, placebo-controlled laboratory study.

The opioid and cannabinoid receptor systems are inextricably linked-overlapping at the anatomical, functional and behavioural levels. Preclinical studies have reported that cannabinoid and opioid agonists produce synergistic antinociceptive effects. Still, there are no experimental data on the effects of cannabinoid agonists among humans who receive opioid agonist therapies for opioid use disorder (OUD). We conducted an experimental study to investigate the acute effects of the delta-9-tetrahydrocannabinol (THC) among persons receiving methadone therapy for OUD. Using a within-subject, crossover, human laboratory design, 25 persons on methadone therapy for OUD (24% women) were randomly assigned to receive single oral doses of THC (10 or 20 mg, administered as dronabinol) or placebo, during three separate 5-h test sessions. Measures of experimental and self-reported pain sensitivity, abuse potential, cognitive performance and physiological effects were collected. Mixed-effects models examined the main effects of THC dose and interactions between THC (10 and 20 mg) and methadone doses (low-dose methadone defined as <90 mg/day; high dose defined as >90 mg/day). Results demonstrated that, for self-reported rather than experimental pain sensitivity measures, 10 mg THC provided greater relief than 20 mg THC, with no substantial evidence of abuse potential, and inconsistent dose-dependent cognitive adverse effects. There was no indication of any interaction between THC and methadone doses. Collectively, these results provide valuable insights for future studies aiming to evaluate the risk-benefit profile of cannabinoids to relieve pain among individuals receiving opioid agonist therapy for OUD, a timely endeavour amidst the opioid crisis.

Developing non-opioid therapeutics to alleviate pain among persons with opioid use disorder: a review of the human evidence.

The opioid crisis remains a major public health concern, causing significant morbidity and mortality worldwide. Pain is frequently observed among individuals with opioid use disorder (OUD), and the current opioid agonist therapies (OAT) have limited efficacy in addressing the pain needs of this population. We reviewed the most promising non-opioid analgesic therapies for opioid-dependent individuals synthesising data from randomised controlled trials in the Medline database from December 2022 to March 2023. Ketamine, gabapentin, serotoninergic antidepressants, and GABAergic drugs were found to be the most extensively studied non-opioid analgesics with positive results. Additionally, we explored the potential of cannabinoids, glial activation inhibitors, psychedelics, cholecystokinin antagonists, alpha-2 adrenergic agonists, and cholinergic drugs. Methodological improvements are required to advance the development of novel analgesic strategies and establish their safety profile for opioid-dependent populations. We highlight the need for greater integration of experimental pain methods and abuse liability assessments, more granular assessments of prior opioid exposure, greater uniformity of pain types within study samples, and a particular focus on individuals with OUD receiving OAT. Finally, future research should investigate pharmacokinetic interactions between OAT and various non-opioid analgesics and perform reverse translation basic experiments, particularly with methadone and buprenorphine, which remain the standard OUD treatment.

Progesterone Increases Nicotine Withdrawal and Anxiety in Male but Not Female Smokers During Brief Abstinence.

INTRODUCTION: Although exogenous progesterone may hold promise as a treatment for nicotine use disorders, it is unclear whether it is similarly effective in males and females. This study examined the effects of progesterone on nicotine use disorder comprehensively using behavioral, psychological, and neural measures in male and female smokers exposed to brief abstinence. AIMS AND METHODS: Thirty-three male and 33 female non-treatment-seeking smokers participated in a double-blind, randomized, placebo-controlled crossover study of 200 mg of progesterone or placebo daily over a four-day abstinence period. Smoking behavior and subjective effects of nicotine were assessed at baseline and after final drug administration. Nicotine withdrawal, smoking urges, mood states, and neural response to smoking cues were measured at baseline, after the first drug administration, and after the final drug administration. RESULTS: No main effect of drug (progesterone vs. placebo) emerged for any outcome. Significant sex by drug interactions emerged for nicotine withdrawal (p = .020), perceived strength of nicotine (p = .040), and perceived bad effects of nicotine (p = .029). Males receiving progesterone reported worse nicotine withdrawal (p = .046) and a trend towards decreased bad effects of nicotine (p = .070). Males on progesterone also reported greater tension and anxiety relative to placebo (p = .021). Females on progesterone perceived nicotine's effects as being stronger relative to placebo (p = .046). CONCLUSIONS: Progesterone causes sex-dependent effects on smoking-related outcomes during brief abstinence. Specifically, progesterone in males may increase rather than decrease nicotine withdrawal and negative affect during abstinence, potentially hindering efforts to quit smoking. IMPLICATIONS: In male and female smokers undergoing a brief period of abstinence, we examined the effects of progesterone on smoking outcomes. While progesterone had limited effects in female smokers, in males, it worsened nicotine withdrawal and negative affect. Our findings emphasize the importance of analyzing sex differences in future studies examining progesterone as a potential treatment and suggest that progesterone in males could potentially exacerbate aspects of nicotine dependence. CLINICALTRIALS.GOV REGISTRATION: NCT01954966. https://clinicaltrials.gov/ct2/show/NCT01954966.

Reappraising Choice in Addiction: Novel Conceptualizations and Treatments for Tobacco Use Disorder.

The introduction of alternative nicotine and tobacco products (such as e-cigarettes, heat-not-burn devices, nicotine pouches) warrants an updated framework from which to conceptualize tobacco use disorder (TUD). The following review provides considerations for TUD within the context of novel products. Historically, the tobacco industry falsely claimed that cigarettes were not addictive or harmful and that those who smoked simply chose to do so. This generated an inaccurate lay perception that smoking is a free or informed choice. Research on nicotine pharmacology demonstrates the powerful addictive potential of nicotine, which is shaped by dose, speed of delivery, and other constituents generated. In addition, non-pharmacologic reinforcers motivate and maintain tobacco use behaviors for both traditional cigarettes and novel products. The negative consequences of combustible tobacco use are well known; however, these outcomes may differ for alternative products. Strategies used for combustible product cessation may be adapted for novel products, and treatment recommendations for TUD should be made within the context of a harm reduction framework wherein alternative product use may be the desired outcome. Providers must therefore be willing to modify their perceptions of products and treatment recommendations accordingly. Better public health outcomes are accomplished through promotion of abstinence from combustible smoking. For those who cannot wean from nicotine entirely, switching to less risky modes of delivery might be a secondary goal, with an eventual aim of stopping use of the alternative product. Implications: Given the advent of novel, alternative tobacco products, tobacco use disorder (TUD) must be conceptualized within a contemporary framework that includes harm reduction and alternative outcomes. The unique contributions of nicotine pharmacology, non-pharmacologic reinforcers, and consequences of use can be used to inform treatments for TUD with the ultimate goal of improving the health of individuals who use tobacco.

Impact of delivery rate on the acute response to intravenous nicotine: A human laboratory study with implications for regulatory science.

Faster delivery rate enhances the abuse potential of drugs of abuse, yet systematic studies on the impact of delivery rate on the acute effects of nicotine in humans are lacking. Using an intravenous (IV) nicotine infusion procedure that allows precise control of rate of delivery, we examined the impact of nicotine delivery rate on the positive subjective drug effects, smoking urges, withdrawal, heart rate, blood pressure and attention function in smokers. Twenty-four male and female (ages 21-35) dependent smokers attended five experimental sessions, following overnight abstinence from smoking. Using a crossover design, participants attended five sessions, where they were assigned to a random sequence of saline infusion or 1 mg nicotine delivered over 1, 2.5, 5 or 10 min at rates of 1, 0.4, 0.2 or 0.1 mg/min, respectively. The positive subjective effects of nicotine were most robust under the two faster delivery rate conditions, 1- and 0.4-mg nicotine/min. In contrast, all nicotine delivery rates were equally more effective than saline in alleviating urges to smoke. Likewise, nicotine-induced heart rate increases did not vary with the rate of nicotine delivery. Lastly, the cognitive enhancing effects of nicotine were observed only under the two slowest delivery rate conditions-0.1- and 0.2-mg nicotine/min. Collectively, these findings support the critical role of delivery rate in optimizing nicotine's abuse potential versus potential therapeutic effects and have timely implications for developing novel therapeutics for nicotine dependence, as well as for tobacco regulatory science.

Pharmacological treatment of pain among persons with opioid addiction: A systematic review and meta-analysis with implications for drug development.

The clinical features and neurobiology of pain and opioid use disorder (OUD) are inextricably linked. Despite emerging evidence supporting the negative impact of ongoing pain in the treatment of OUD, the pharmacological management of pain in the presence of OUD has received limited attention. We sought to systematically review the studies investigating pharmacotherapies for pain among persons with OUD. Eligible studies had participants with OUD and outcomes including evoked or spontaneous pain. We searched Scopus, Cochrane Database of Systematic Reviews, Medline, and Embase. Out of 1,097 studies that met the search criteria, 12 studies provided data relevant to the research question-five laboratory studies and seven clinical trials. Random effects pooled estimates suggested no significant difference between groups at baseline but a response favoring the active treatment group over placebo, with nonsignificant heterogeneity between studies. Findings from these studies provide preliminary evidence for analgesic and antihyperalgesic effects of gabapentin, GABA agonists, and NMDA antagonists among persons with OUD. To establish the tradeoffs between the analgesic effects and abuse liability of these compounds, further well-controlled clinical trials are required among persons with OUD. This review also underscores the need for methodological enhancement in drug development for pain in OUD. Future research should address the clinical and neurobiological overlap between pain- and addiction-related phenomena. Transdisciplinary approaches may identify biomarkers of these shared phenomena and their neural substrates. The development of novel therapeutics for pain in OUD may be accelerated by such integration of pain and addiction research.

Sex Differences in Opioid Use Disorder Prevalence and Multimorbidity Nationally in the Veterans Health Administration.

OBJECTIVE: Opioid use disorder (OUD) is a significant problem among US veterans with increasing rates of OUD and overdose, and thus has substantial importance for service delivery within the Veterans Health Administration (VHA). Among individuals with OUD, several sex- specific differences have begun to emerge regarding co-occurring medical, psychiatric and pain-related diagnoses. The rates of such multimorbidities are likely to vary between men and women with OUD and may have important implications for treatment within the VHA but have not yet been studied. Methods: The present study utilized a data set that included all veterans receiving VHA health care during Fiscal Year (FY) 2012 (October 1, 2011 through September 30, 2012), who were diagnosed during the year with opioid dependence or abuse. VHA patients diagnosed with OUD nationwide in FY 2012 were compared by sex on proportions with OUD, and among those with OUD, on sociodemographic characteristics, medical, psychiatric and pain-related diagnoses, as well as on service use, and psychotropic and opioid agonist prescription fills. Results: During FY 2012, 48,408 veterans were diagnosed with OUD, 5.77% of whom were women. Among those veterans with OUD, few sociodemographic differences were observed between sexes. Female veterans had a higher rate of psychiatric diagnoses, notably mood, anxiety and personality disorders, as well as higher rates of pain-related diagnoses, such as headaches and fibromyalgia, while male veterans were more likely to have concurrent, severe medical co-morbidities, including hepatic disease, HIV, cancers, peripheral vascular disease, diabetes and related complications, and renal disease. There were few differences in health service utilization, with women reporting greater receipt of prescriptions for anxiolytic/sedative/hypnotics, stimulants and lithium. Men and women did not differ in receipt of opioid agonist medications or mental health/substance use treatments. Conclusions: There are substantial sex-specific differences in patterns of multimorbidity among veterans with OUD, spanning medical, psychiatric and pain-related diagnoses. These results illustrate the need to view OUD as a multimorbid condition and design interventions to target such multimorbidities. The present study highlights the potential benefits of sex-specific treatment and prevention efforts among female veterans with OUD and related co-occurring disorders.

Modulation of "Protective" Nicotine Perception and Use Profile by Flavorants: Preliminary Findings in E-cigarettes.

INTRODUCTION: Characterizing flavors are widely available in e-cigarettes and motivate initiation and continued use. Flavors may enhance appeal and facilitate development of addiction to tobacco products through modulation of tobacco products' reinforcing or aversive actions. Palatable flavors (eg, fruit) may increase appeal through primary reinforcing properties. Menthol's cooling and anesthetic effects may increase appeal by counteracting nicotine's aversive effects. Genetics provide a method for modeling individual differences in sensitivity to nicotine's effects. A common polymorphism, rs16969968, encoded in the α5 nicotinic acetylcholine receptor subunit gene (CHRNA5), is a well-recognized marker for smoking risk and reduces sensitivity to nicotine aversiveness. METHODS: This pilot study tested how flavors impacted e-cigarette appeal and self-administration. In a single testing day, cigarette smokers (N = 32; 94% menthol-smokers) self-administered e-cigarettes containing e-liquids differing in nicotine level (0 mg/mL, 24 mg/mL) and flavor (unflavored, menthol, fruit-flavored) within directed and ad libitum e-cigarette paradigms. Subjective drug effects, number of puffs, rs16969968 genotype, plasma nicotine, and menthol glucuronide levels were collected. RESULTS: Menthol partially ameliorated nicotine aversiveness; fruit did not. In nicotine's absence, fruit flavor increased self-reported preference and ad libitum use relative to menthol-containing or unflavored e-liquids. Individuals with high-smoking-risk rs16969968 genotype (N = 7) reported greater craving alleviation following directed administration of nicotine-containing e-liquids, showed a trend rating nicotine-containing e-liquids as less harsh, and self-administered more nicotine during ad libitum compared to individuals with low-smoking-risk genotype (N = 23). CONCLUSIONS: While menthol countered aversiveness of nicotine-containing e-liquids, fruit flavor increased appeal of nicotine-free e-liquids. These preliminary findings suggest menthol and fruit flavor increase e-cigarettes' appeal through distinct mechanisms. IMPLICATIONS: This study provides a detailed characterization of the effects of flavors (unflavored, menthol, fruit), nicotine (0 mg/mL, 24 mg/mL) and their interactions on the subjective drug effects and ad libitum self-administration of e-cigarettes. Genetics were used to assess these effects in higher-smoking-risk (diminished sensitivity to nicotine aversiveness) and lower-risk groups. Findings could inform impact of regulation of flavors or nicotine in e-cigarettes, and their impacts on vulnerable sub-populations.

Systematic Review of Pain Severity and Opioid Craving in Chronic Pain and Opioid Use Disorder.

OBJECTIVE: To evaluate measurement and associations between pain severity and opioid craving in individuals with chronic pain on long-term opioid therapy and/or with opioid use disorder. STUDY DESIGN: . Systematic review of randomized controlled trials and observational studies. METHODS: . The PubMed, EMBASE, and PsycINFO databases were searched in October 2018. Eligible studies evaluated pain severity and opioid craving in individuals with chronic pain on long-term opioid therapy and/or with opioid use disorder. Two reviewers independently screened eligible studies, assessed risk of bias, and extracted data. RESULTS: Of 625 studies, 16 fulfilled the inclusion/exclusion criteria of this review and were grouped by diagnostic focus (i.e., chronic pain on long-term opioid therapy, opioid use disorder, or both). Methods of assessment varied considerably across studies, especially with respect to opioid craving in chronic pain populations. Mean levels of pain were at what is considered moderate to severe in individuals with chronic pain and/or opioid use disorder. There was a modest positive relationship between pain and opioid craving that was more pronounced in studies of individuals with opioid use disorder compared with those with chronic pain on long-term opioid therapy. CONCLUSIONS: Pain severity and opioid craving are likely related, but inconsistencies in measurement limit confidence. The overall quality of evidence is moderate, and careful consideration of how pain and craving are assessed in both chronic pain and opioid use disorder patients is warranted.

Impact of cannabis on non-medical opioid use and symptoms of posttraumatic stress disorder: a nationwide longitudinal VA study.

BACKGROUND: Multiple states have authorized cannabis as an opioid substitution agent and as a treatment for posttraumatic stress disorder (PTSD). OBJECTIVES: This study sought to investigate the relationship between cannabis use, non-medical opioid use, and PTSD symptoms among U.S. veterans. METHODS: From 1992-2011, veterans admitted to specialized intensive PTSD treatment participated in a national evaluation with assessments at intake and four months after discharge. Participants with non-medical opioid use ≥ 7 days during the 30 days preceding admission were divided into two groups: those with cannabis use ≥ 7 days, and those without cannabis use. These two groups were compared on measures of substance use and PTSD symptoms at baseline and 4-months outpatient follow-up. We hypothesized that, at both assessments, the group with baseline cannabis use would show less non-medical opioid use and less severe PTSD symptoms. RESULTS: Of 1,413 veterans with current non-medical opioid use, 438 (30.3%) also used cannabis, and 985 (69.7%) did not. At baseline, veterans with concurrent non-medical opioid and cannabis use had slightly fewer days of non-medical opioid use (p < .005; d = -0.16), greater use of other substances (p < .0001) and more PTSD symptoms (p = .003; d = 0.16), compared to veterans who used non-medical opioids but not cannabis. At follow-up, substance use or PTSD symptoms did not significantly differ. CONCLUSION: Cannabis use was not associated with a substantial reduction of non-medical opioid use, or either improvement or worsening of PTSD symptoms in this population. Hence, these data do not encourage cannabis use to treat either non-medical opioid use or PTSD.

Double-Blind Placebo-Controlled Trial of Galantamine for Methadone-Maintained Individuals With Cocaine Use Disorder: Secondary Analysis of Effects on Illicit Opioid Use.

BACKGROUND AND OBJECTIVES: Concurrent use of cocaine and opioids is a persistent and challenging problem, particularly within methadone maintenance settings, and there are no approved pharmacotherapies for this population. Galantamine, a cholinesterase inhibitor, was found in a randomized clinical trial to reduce cocaine use among methadone-maintained individuals who were also cocaine dependent. Because of the potential of galantamine to reduce multiple drugs of abuse, it may also reduce opioid use. METHODS: We conducted a secondary analysis of a randomized, double-blind, placebo-controlled trial of 120 methadone-maintained individuals with concurrent cocaine dependence. Participants were randomized to galantamine or placebo in a 12-week trial with a 6-month follow-up (97% of intention to treat sample reached for final follow-up). RESULTS: There was a significant main effect for galantamine over placebo on percent of urine specimens that were negative for opioids, both within treatment (77% for galantamine vs 62% for placebo, F = 5.0, P = 0.027) and through a 6-month follow-up (81% vs 59%, respectively, F = 10.8, P = 0.001). This effect was seen regardless of whether participants used nonprescribed opioids during the baseline period. Galantamine effects were seen early in treatment, with participants in placebo submitting the first opioid-positive urine specimen significantly sooner than participants in galantamine (median day 15 vs 53, Wilcoxon = 5.7, P = 0.02). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: If these results are supported in future trials, galantamine may hold promise across multiple drugs of abuse, including opioids. (Am J Addict 2019;28:238-245).

Adverse Consequences of Co-Occurring Opioid Use Disorder and Cannabis Use Disorder Compared to Opioid Use Disorder Only.

Background: While there is growing interest in the possibility that cannabis may be a partial substitute for opioids, studies have yet to examine whether individuals with co-occurring opioid and cannabis use disorders (OUD and CUD) have less risk of negative outcomes than those with OUD only. Objective: This study sought to compare the sociodemographic and clinical characteristics of patients diagnosed with co-occurring OUD and CUD to patients with OUD only, CUD only, and patients with any other drug use disorders. We hypothesized that co-occurring OUD and CUD would be associated with lower risk of inpatient admissions and emergency department (ED) visits, lower rates of homelessness, and fewer opioid prescriptions. Methods: Comparisons were based on bivariate analyses, logistic and linear multiple regression models of National Veterans Health Administration (VHA) data from Fiscal Year 2012. Results: Of the 234,181 (94% male) patients diagnosed with drug use disorders, 8.6% were diagnosed with co-occurring OUD and CUD; 33.3% with OUD only; 26.5% with CUD only; and 31.6% with other drug use disorders. Compared to the OUD only group (Mean = 4.8 (SD = 8.84)), the group with co-occurring OUD and CUD was associated with a lower number of opioid prescriptions (Mean = 3.79 (SD = 8.22)) (d = -0.16), but higher likelihood of inpatient psychiatric admission (RR = 1.95) and homelessness (RR = 1.52), and no significant difference in ED visits. Conclusions: These data highlight the need to further investigate whether the complex effects of cannabis use on patients with OUD are counterbalanced by potential benefits of reduced in opioid prescribing.

Cognitive rehabilitation for individuals with opioid use disorder: A randomized controlled trial.

Aim: To examine the efficacy of cognitive rehabilitation treatment (CRT) for people with opioid use disorder who were recruited into a methadone maintenance treatment (MMT) programme. Method: 120 male subjects were randomly assigned to (1) MMT plus CRT in two months or (2) MMT plus a control intervention. Subjects were assessed at the beginning, mid-point and post-intervention as well as at 1-, 3- and 6-month follow-up time points. Results: Analysis with repeated measure ANOVA showed that the CRT group performed significantly better in tests of learning, switching, processing speed, working memory and memory span. Moreover, the CRT group had significantly lower opiate use over the control group during 3-months follow-up. Analysis including only those with a history of methamphetamine use showed that the CRT group had significantly lower amphetamine use. No group differences were observed for treatment retention. Conclusions: Our findings provide evidence that adding CRT as an adjunct intervention to MMT can improve cognitive performance as well as abstinence from both opiates and stimulants.

Feasibility and preliminary efficacy of dialectical behaviour therapy skills groups for Veterans with suicidal ideation: pilot.

BACKGROUND: Veterans are at high risk for suicide; emotion dysregulation may confer additional risk. Dialectical behaviour therapy (DBT) is a well-supported intervention for suicide attempt reduction in individuals with emotion dysregulation, but is complex and multi-component. The skills group component of DBT (DBT-SG) has been associated with reduced suicidal ideation and emotion dysregulation. DBT-SG for Veterans at risk for suicide has not been studied. AIMS: This study sought to evaluate the feasibility and acceptability of DBT-SG in Veterans and to gather preliminary evidence for its efficacy in reducing suicidal ideation and emotion dysregulation and increasing coping skills. METHOD: Veterans with suicidal ideation and emotion dysregulation (N = 17) enrolled in an uncontrolled pilot study of a 26-week DBT-SG as an adjunct to mental health care-as-usual. RESULTS: Veterans attended an average 66% of DBT-SG sessions. Both Veterans and their primary mental health providers believed DBT-SG promoted Veterans' use of coping skills to reduce suicide risk, and they were satisfied with the treatment. Paired sample t-tests comparing baseline scores with later scores indicated suicidal ideation and emotion dysregulation decreased at post-treatment (d = 1.88, 2.75, respectively) and stayed reduced at 3-month follow-up (d = 2.08, 2.59, respectively). Likewise, skillful coping increased at post-treatment (d = 0.85) and was maintained at follow-up (d = 0.91). CONCLUSIONS: An uncontrolled pilot study indicated DBT-SG was feasible, acceptable, and demonstrated potential efficacy in reducing suicidal ideation and emotion dysregulation among Veterans. A randomized controlled study of DBT-SG with Veterans at risk for suicide is warranted.

Effects of galantamine on smoking behavior and cognitive performance in treatment-seeking smokers prior to a quit attempt.

OBJECTIVE: Drugs that enhance cholinergic transmission have demonstrated promise treating addictive disorders. Galantamine, an acetylcholinesterase inhibitor, may reduce cigarette smoking in otherwise healthy treatment-seeking smokers. METHODS: The current study is a double-blind, placebo-controlled, study that randomized daily smokers (n = 60) to receive one of two doses of galantamine extended release (8 or 16 mg/day), or a placebo treatment. Participants completed a smoking choice task as well as study measures and cognitive tasks in the laboratory and daily life using ecological momentary assessment. Analysis focused on smoking behavior and satisfaction, cognitive performance, and decision to smoke prior to a quit attempt. RESULTS: Linear mixed models demonstrated that, compared with placebo, both doses of galantamine reduced smoking in a laboratory choice task (p = 0.006) and decreased urine cotinine levels, but not self-reported cigarettes, during the pre-quit period (p = 0.007). Treatment had minimal effect on smoking satisfaction or cognitive performance. CONCLUSIONS: The results suggest that galantamine reduces nicotine intake but it is unlikely that galantamine improves cognitive performance in otherwise healthy, treatment-seeking smokers. Larger randomized clinical trials can determine if galantamine adjunctive to addiction treatment can improve smoking treatment outcomes.