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Successful management of opioid withdrawal improves long-term treatment outcomes and reduces opioid use-related morbidity and mortality. Mechanistically supported pharmacotherapeutic approaches are needed to effectively manage acute and protracted opioid withdrawal. Buspirone is a D2 antagonist and 5-HT1a agonist that may decrease opioid withdrawal. Individuals (

Initial experiences with drugs may influence an individual’s motivations for continued use. This study evaluated the relationship between subjective effects elicited by an individual’s first use of alcohol or cannabis, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) alcohol use disorder (AUD) or cannabis use disorder (CUD) severity, and behavioral economic demand for alcohol or cannabis. Self-reports of initial subjective effects associated with drugs were analyzed for N = 463 participants whose first substance use was either alcohol or cannabis. The likelihood that a particular subjective effect at the time of first use was associated with current AUD/CUD was assessed using ordinal logistic regression with subjective effects as predictors of DSM-5 severity. Behavioral economic demand was assessed using a hypothetical purchase task in which participants indicated their hypothetical consumption of alcohol or cannabis as a function of price. Significant associations were observed for initial subjective effects elicited by alcohol or cannabis and increased DSM-5 severity: (alcohol) relief (OR = 2.52 [95% CI 1.51–4.25], p = .0005) and (cannabis) energetic (OR = 2.31 [95% CI 3.27–55.5], p = .0004). The mean (±SEM) P(max) value for the alcohol subgroup endorsing relief ($96.22 ± $26.48) was significantly greater than the P(max) value for the alcohol subgroup not endorsing relief ($33.81 ± $12.93), t(237) = 2.276, p = .0237. These results suggest that the initial subjective effects associated with a given substance may predict the development and/or severity of substance misuse and substance use disorders (SUDs). These findings are consistent with anecdotal reports that persons with SUD feel energized by the use of substances whereas persons without SUD do not report experiencing such subjective effects upon first use.

Sleep impairment is a common comorbid and debilitating symptom for persons with opioid use disorder (OUD). Research into underlying mechanisms and efficacious treatment interventions for OUD-related sleep problems requires both precise and physiologic measurements of sleep-related outcomes and impairment. This pilot examined the feasibility of a wireless sleep electroencephalography (EEG) monitor (Sleep Profiler™) to measure sleep outcomes and architecture among participants undergoing supervised opioid withdrawal. Sleep outcomes were compared to a self-reported sleep diary and opioid withdrawal ratings. Participants (n = 8, 100% male) wore the wireless EEG 85.6% of scheduled nights. Wireless EEG detected measures of sleep architecture including changes in total, NREM and REM sleep time during study phases, whereas the diary detected changes in wakefulness only. Direct comparisons of five overlapping outcomes revealed lower sleep efficiency and sleep onset latency and higher awakenings and time spent awake from the wireless EEG versus sleep diary. Associations were evident between wireless EEG and increased withdrawal severity, lower sleep efficiency, less time in REM and non-REM stages 1 and 2, and more hydroxyzine treatment; sleep diary was associated with total sleep time and withdrawal only. Data provide initial evidence that a wireless EEG is a feasible and useful tool for objective monitoring of sleep in persons experiencing acute opioid withdrawal. Data are limited by the small and exclusively male sample, but provide a foundation for using wireless EEG sleep monitors for objective evaluation of sleep-related impairment in persons with OUD in support of mechanistic and treatment intervention research. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The potential synergistic effects of combining cannabinoids and opioids for analgesia has received considerable attention. No studies to date have evaluated this combination in patients with chronic pain. The present study aimed to evaluate the combined analgesic and drug effects of oral opioid (hydromorphone) and delta-9-tetrahydrocannabinol (dronabinol), as well as their effects on physical and cognitive functioning, and human abuse potential (HAP) outcomes among individuals with knee osteoarthritis (KOA). This was a within-subject, double-blind, randomized, placebo-controlled study. Participants (N = 37; 65% women; mean age = 62) diagnosed with knee osteoarthritis of ≥3/10 average pain intensity were included. Participants received (1) placebo-placebo, (2) hydromorphone (4 mg)-placebo; (3) dronabinol (10 mg)-placebo, and (4) hydromorphone (4 mg)-dronabinol (10 mg). Clinical and experimentally-induced pain, physical and cognitive function, subjective drug effects, HAP, adverse events, and pharmacokinetics were evaluated. No significant analgesic effects were observed for clinical pain severity or physical functioning across all drug conditions. Little enhancement of hydromorphone analgesia by dronabinol was observed on evoked pain indices. While subjective drug effects and some HAP ratings were increased in the combined drug condition, these were not significantly increased over the dronabinol alone condition. No serious adverse events were reported; hydromorphone produced more mild adverse events than placebo, but hydromorphone + dronabinol produced more moderate adverse events than both placebo and hydromorphone alone. Only hydromorphone impaired cognitive performance. Consistent with laboratory studies on healthy adults, the present study shows minimal benefit of combining dronabinol (10 mg) and hydromorphone (4 mg) for analgesia and improving physical functioning in adults with KOA.

The opioid crisis has devasted individuals, families, and communities in the United States and abroad. Improving opioid use disorder (OUD) treatment requires a nuanced understanding of the risk factors associated with the onset of OUD, and barriers to successful, long-term recovery. Women and men might have several unique risk factors for initiating opioid use, progressing from non-medical opioid use to OUD, and experiencing negative OUD treatment outcomes. These unique risk factors are best understood by examining sex and a biological variable and gender as a social construct in persons with OUD. Toward this end, the research reviewed in this chapter includes sex-based biological factors that affect opioid use, such as neurohormonal interactions with the endogenous opioid system and sex-based differences in neural development, as well as gender-based societal influences that can lead to OUD and potentially stymie attempts at treatment, such as traditional gender roles within the family unit and stigma surrounding OUD treatment. Factors that encompass the intersection of sex and gender are also discussed in the context of OUD treatment, including co-morbid mental health conditions, chronic pain, and response to medications for OUD (MOUD). Building on the preclinical and clinical research on these topics, future studies should aim to optimize pharmacotherapeutic approaches within subpopulations of women and men with OUD, develop strategies to better engage women and men with childcare responsibilities in OUD treatment, and reduce stigma associated with living with OUD and seeking treatment for OUD.

Supervised opioid withdrawal (also referred to as detoxification or detox) is a medical treatment aimed at fully discontinuing opioid use in persons who are physically dependent on opioids. There is a long history of supervised withdrawal treatment programs in the United States, although the approach has varied wildly and to this day there is little guidance regarding best practices. Early approaches to supervised withdrawal favored an abrupt discontinuation of opioids rather than longer opioid tapers, though recent more data support an extended approach. Withdrawal is a highly variable process with many decision points, including residential versus outpatient status, choice of withdrawal treatment and complementary/supportive interventions, duration of treatment, percent change in daily dose, and whether the withdrawal schedule is determined by the patient, provider, or both. Several treatments to help reduce withdrawal severity will be discussed. This chapter reviews the historical basis of withdrawal programs; the data supporting the aforementioned decision points; and the rationale, efficacy, and unique considerations for the different withdrawal methods. Outcomes following withdrawal programs, including resolution of medical comorbidities, overdose risk, and linkage to aftercare are also reviewed. Since the United States now has a formal indication of opioid withdrawal, this chapter also includes a discussion of important considerations for empirical trials of medications and/or other interventions for opioid withdrawal management. Future efforts to maximize the efficacy of withdrawal treatment, and importantly, to link individuals to long-term care (preferably with a medication for OUD) are important directions for future research and practice.

BACKGROUND: Understanding the course of anxiety and depressive symptoms in early opioid use disorder (OUD) treatment may inform efforts to promote positive early treatment response and reduce treatment attrition. METHODS: Persons in treatment for nonmedical opioid use were identified from 86 addiction treatment facilities. Growth mixture modeling was used to identify trajectories of anxiety and depression symptoms during the first month of treatment among individuals who screened positive for depression (N=3016) and/or anxiety (N=2779) at intake. RESULTS: A three-class solution best fit the data for anxiety symptoms and included the following trajectories: 1) persistent moderate-to-severe anxiety symptoms, 2) remitting severe anxiety symptoms, and 3) persistent minimal-to-mild anxiety symptoms. Similarly, a three-class solution best fit the data for depressive symptoms and included trajectories characterized by 1) persistent moderate-to-severe depressive symptoms, 2) persistent moderate depressive symptoms, and 3) mild/remitting depressive symptoms. Persistent moderate-to-severe anxiety and depressive symptoms were predicted by female gender and heavy past-month benzodiazepine co-use. LIMITATIONS: Fine grained-information about substance use was not collected. Results may not be generalizable to individuals receiving treatment outside of specialty addiction clinics. CONCLUSIONS: Analysis of anxiety and depression symptom trajectories in early treatment suggest that a subset of individuals entering treatment for opioid use experienced persistent and significant anxiety and depressive symptoms, whereas others experience a remission of symptoms. Interventions designed to target individuals at the greatest risk, such as women and individuals reporting opioid/benzodiazepine co-use, may help improve mental health symptoms in early OUD treatment.

ImportanceNovel treatments for opioid use disorder (OUD) are needed to address both the ongoing opioid epidemic and long-standing barriers to existing OUD treatments that target the endogenous μ-opioid receptor (MOR) system. The goal of this review is to highlight unique clinical trial design considerations for the study of emerging treatments for OUD that address targets beyond the MOR system. In November 2019, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration sponsored a meeting to discuss the current evidence regarding potential treatments for OUD, including cannabinoids, psychedelics, sedative-hypnotics, and immunotherapeutics, such as vaccines.ObservationsConsensus recommendations are presented regarding the most critical elements of trial design for the evaluation of novel OUD treatments, such as: (1) stage of treatment that will be targeted (eg, seeking treatment, early abstinence/detoxification, long-term recovery); (2) role of treatment (adjunctive with or independent of existing OUD treatments); (3) primary outcomes informed by patient preferences that assess opioid use (including changes in patterns of use), treatment retention, and/or global functioning and quality of life; and (4) adverse events, including the potential for opioid-related relapse or overdose, especially if the patient is not simultaneously taking maintenance MOR agonist or antagonist medications.Conclusions and RelevanceApplying the recommendations provided here as well as considering input from people with lived experience in the design phase will accelerate the development, translation, and uptake of effective and safe therapeutics for individuals struggling with OUD.

This Phase II study evaluated analgesia, abuse liability, and cognitive performance of hydromorphone and oral delta-9-tetrahydrocannabinol (THC; dronabinol) using a within-subject, double-blind, randomized, placebo-controlled, human laboratory trial. Healthy adults (N = 29) with no history of drug use disorder received combinations of placebo, hydromorphone (4 mg; oral), and dronabinol (2.5 mg, 5.0 mg, 10 mg; oral). Primary outcomes were quantitative sensory testing (QST) measures of acute (thermal, pressure pain; thermal, punctate probe temporal summation; cold pressor; conditioned pain modulation) and chronic pain (capsaicin 10% topical cream with thermal rekindling), measures of drug abuse liability, cognitive functioning, and adverse events. Subgroup analyses were conducted within opioid-responders (endorsed >20 on a Drug Effect visual analog scale during the hydromorphone-only condition) and nonresponders. A consistent dose-effect relationship of dronabinol on hydromorphone across all measures was not observed. Analgesia only improved in the hydromorphone + dronabinol 2.5 mg condition. Hydromorphone + dronabinol 2.5 mg showed the lowest and hydromorphone+dronabinol 5 mg showed the highest risk for abuse. Hydromorphone+dronabinol 10 mg produced a high rate of dysphoric effects, and hydromorphone+dronabinol 5 mg and hydromorphone + dronabinol 10 mg produced AEs. Subgroup analyses showed subjective effects and abuse risk was increased among opioid responders and largely absent among nonresponders. Overall, only hydromorphone+dronabinol 2.5 mg modestly enhanced hydromorphone-based analgesia and hydromorphone + dronabinol 5 mg and 10 mg increased risk for abuse and AEs. These data can help inform opioid-sparing efforts in clinical pain populations. Demonstration that potential opioid effects varied as a function of participant opioid sensitivity (e.g., responder status) is a novel finding that warrants additional research.

OBJECTIVE: Opioid misuse has become an epidemic in the United States. In the present study, we examine potential malleable early childhood predictors of opioid misuse including whether childhood achievement, aggressive behavior, attention problems, and peer social preference/likeability in first grade predicted opioid misuse and whether these relationships differed depending on participant sex. METHOD: Data are drawn from three cohorts of participants (N = 1,585; 46.7% male) recruited in first grade as part of a series of elementary school-based, universal preventive interventions conducted in a Mid-Atlantic region of the US. In first grade, participants completed standardized achievement tests, teachers reported on attention problems, and peers nominated their classmates with respect to their aggressive behavior and social preference/likeability. At approximately age 20, participants reported on their misuse of opioids defined as lifetime use of heroin or misuse of prescription opioids. RESULTS: Higher levels of peer nominations for aggressive behavior in first grade predicted a greater likelihood of opioid misuse. An interaction between participant sex and attention problems was observed such that females higher in attention problems were more likely to misuse opioids, particularly prescription opioids, than females lower in attention problems. An interaction was also found between participant sex and peer likeability such that males lower in peer-nominated likeability were more likely to misuse opioids relative to males higher in likeability. CONCLUSION: Given the malleable nature of attention problems, aggression, and social skills in early childhood, prevention programs that target these behaviors during this developmental period may attenuate risk for opioid misuse.

PURPOSE OF REVIEW: Pharmacotherapies are the most effective means of reducing the harms associated with opioid use disorder (OUD). Translational research seeking to develop novel medications to treat OUD has been challenging due to the complex etiology of addiction. Preclinical outcome measures are often behavioral, and it is difficult, if not impossible, to fully mirror the various emotional and cognitive processes that motivate opioid use in humans. The goal of the current narrative review was to summarize the translational progression of three potential medications for OUD, which had varying levels of success. RECENT FINDINGS: Memantine, lorcaserin, and lofexidine all showed promise in preclinical studies; however, only lofexidine was able to consistently replicate these findings in human subjects, and receive FDA approval. It was the authors’ objective to use this review to identify areas of needed improvement in translational research for OUD. SUMMARY: Preclinical studies vary significantly in their ability to forecast effectiveness in clinical trials. Among the various preclinical models, suppression of opioid self-administration appears to have the best predictive validity. As they model a mostly physiological phenomenon, preclinical assessments of opioid withdrawal also appear to have high predictive validity. In our review of the literature, the authors noted numerous examples of clinical trials that were underpowered, lack precision, and proper outcomes. Better-validated preclinical targets and improved design of proof-of-concept human studies should allow investigators to more efficiently develop and test medications for OUD.

OBJECTIVES Efforts to improve buprenorphine access for opioid use disorder have focused on increasing the number of waivered providers. However, it is unknown how efforts to increase initial prescribing result in a sustained pool of prescribers. We examine the prevalence of year-to-year provider-level buprenorphine prescribing, and provider- and state-level factors associated with provider continuity. METHODS Providers prescribing buprenorphine/naloxone within the Medicare Part D claims database were evaluated from 2013 to 2017 with prescriber continuity measured as prescriptions made in consecutive years from the same provider (N = 14,222 unique providers; 6670 in 2013). RESULTS The number of providers prescribing buprenorphine/naloxone within Medicare Part D increased from 2013 to 2017. The majority of providers prescribed buprenorphine/naloxone to 10 or fewer beneficiaries. Approximately 84% of providers prescribing buprenorphine/naloxone in 1 year prescribed it in the following year. Continuous prescribing from 2013 to 2017 was 59.4%, which was 86% the rate of a comparator chronic health medication (ie, lisinopril). Survival analyses indicated that female providers (adjusted hazard ratios [AHR] = 1.30, P

Increased orexin/hypocretin signaling is implicated in opioid withdrawal, sleep disturbances, and drug-seeking behaviors. This study examined whether a dual-orexin receptor antagonist would improve sleep and withdrawal outcomes when compared with placebo during a buprenorphine/naloxone taper. Thirty-eight participants with opioid use disorder were recruited to a clinical research unit and maintained on 8/2 to 16/4 mg of buprenorphine/naloxone treatment for 3 days before being randomized to 20 mg of suvorexant ( n = 14), 40 mg of suvorexant ( n = 12), or placebo ( n = 12); 26 individuals completed the study. After randomization, participants underwent a 4-day buprenorphine/naloxone taper and 4-day post-taper observation period. Total sleep time (TST) was collected nightly with a wireless electroencephalography device and wrist-worn actigraphy; opioid withdrawal symptoms were assessed via the Subjective Opiate Withdrawal Scale (SOWS); and abuse potential was assessed on a 0- to 100-point visual analog scale of “High” every morning. A priori outcomes included two-group (collapsing suvorexant doses versus placebo) and three-group comparisons of area-under-the-curve (AUC) scores for TST, SOWS, and High. In two-group comparisons, participants receiving suvorexant displayed increased TST during the buprenorphine/naloxone taper and decreased SOWS during the post-taper period. In three-group comparisons, participants receiving 20 mg of suvorexant versus placebo displayed increased AUC for TST during the buprenorphine/naloxone taper, but there was no difference in SOWS among groups. There was no evidence of abuse potential in two- or three-group analyses. The results suggest that suvorexant might be a promising treatment for sleep and opioid withdrawal in individuals undergoing a buprenorphine/naloxone taper.

Higher-dose formulations of naloxone were recently approved by the FDA for the treatment of opioid overdose. These products were developed based on projected saturation of high-potency fentanyl analogues in the illicit marketplace although the evidence base for their necessity is still under scrutiny. Concern has been raised that unintended reductions in patient acceptance of naloxone may occur due to increased precipitated withdrawal risk associated with higher naloxone doses. A well-founded and time-sensitive call for representation of people who use drugs in this decision-making process has been made. This study provides the first data on patient perceptions of higher-dose formulations to inform this scientific debate and distribution efforts.Patients (N=1152) entering treatment for opioid use disorder at one of 49 addiction treatment facilities located across the United States completed a preference assessment of naloxone nasal spray formulations. Patients selected a formulation preference across three scenarios (administration for self, administration to others, community responder administration).A majority of respondents that had been administered naloxone previously reported that their most recent overdose reversal included two or more naloxone administrations (59.9%). Most respondents either had no preference (48.4%) or preferred a higher-dose formulation (35.9%) if personally experiencing an overdose. Similar preference distributions were observed for administration to others and by community responders. Relative to standard-dose preference, respondents preferring higher-dose formulations had a greater odds of recent suspected fentanyl exposure.These data inform patients, advocates, and policy-makers considering distribution and utilization of naloxone formulations by reporting perspectives of patients with opioid use and overdose experience. Limited evidence for widespread avoidance of higher-dose formulations was found. As real-world evidence of acceptability and effectiveness emerges, either supporting or refuting the widespread need for higher-dose naloxone formulations, it is the responsibility of the scientific and public health community to be responsive to those data.

STUDY OBJECTIVES: Individuals with opioid use disorder (OUD) may experience worsening sleep quality over time, and a subset of individuals may have sleep disturbances that precede opioid use and do not resolve following abstinence. The purpose of the present study was to (1) collect retrospective reports of sleep across the lifespan and (2) identify characteristics associated with persistent sleep disturbance and changes in sleep quality in persons with OUD. METHODS: Adults with OUD (n = 154) completed a cross-sectional study assessing current and past sleep disturbance, opioid use history, and chronic pain. Repeated-measures analysis of variance was used to examine changes in retrospectively reported sleep quality, and whether changes varied by screening positive for insomnia and/or chronic pain. Multivariate linear regression analyses were used to identify additional correlates of persistent sleep disturbance. RESULTS: Participants reported that their sleep quality declined over their lifespan. Changes in reported sleep over time varied based on whether the individual screened positive for co-occurring insomnia and/or chronic pain. In regression analyses, female sex (β = 0.16, P = .042), a greater number of treatment episodes (β = 0.20, P = .024), and positive screens for chronic pain (β = 0.19, P = .018) and insomnia (β=0.22, P = .013) were associated with self-reported persistent sleep disturbance. Only a portion of participants who screened positive for sleep disorders had received a formal diagnosis. CONCLUSIONS: OUD treatment providers should routinely screen for co-occurring sleep disturbance and chronic pain. Interventions that treat co-occurring OUD, sleep disturbance, and chronic pain are needed. CITATION: Ellis JD, Mayo JL, Gamaldo CE, Finan PH, Huhn AS. Worsening sleep quality across the lifespan and persistent sleep disturbances in persons with opioid use disorder. J Clin Sleep Med. 2022;18(2):587–595.

Background This study examined whether polygenic risk scores (PRS) for lifetime cannabis and alcohol use were associated with misusing opioids, and whether sex differences existed in these relations in an urban, African-American sample. Methods Data were drawn from three cohorts of participants (N = 1,103; 45% male) who were recruited in first grade as part of a series of elementary school-based, universal preventive intervention trials conducted in a Mid-Atlantic region of the U.S. In young adulthood, participants provided a DNA sample and reported on whether they had used heroin or misused prescription opioids in their lifetime. Three substance use PRS were computed based on prior GWAS: lifetime cannabis use from Pasman et al. (2018), heavy drinking indexed via maximum number of drinks from Gelernter et al. (2019), and alcohol consumption from Kranzler et al. (2019). Results Higher PRS for lifetime cannabis use, greater heavy drinking, and greater alcohol consumption were associated with heightened risk for misusing opioids among the whole sample. Significant sex by PRS interactions were also observed such that higher PRS for heavy drinking and alcohol consumption were associated with a greater likelihood of opioid misuse among males, but not females. Conclusion Our findings further elucidate the genetic contributions to misusing opioids by showing that the genetics of cannabis and alcohol consumption are associated with lifetime opioid misuse among young adults, though replication of our findings is needed.

OBJECTIVES Buprenorphine can precipitate withdrawal in opioid-dependent persons with recent fentanyl use. However, the prevalence of this phenomenon is not clinically established. We sought to evaluate the incidence of buprenorphine-precipitated withdrawal in persons who use fentanyl. METHODS We collected self-report data on opioid withdrawal symptoms after buprenorphine use, and, as a comparator, after methadone use, in 1679 individuals seeking treatment for opioid use disorder across 49 addiction treatment centers in the United States. RESULTS The odds of developing severe withdrawal symptoms significantly increased when taking buprenorphine within 24 hours after fentanyl use (OR = 5.202, 95% CI = 1.979-13.675, P = 0.001), and within 24 to 48 hours after fentanyl use (OR = 3.352, 95% CI = 1.237-9.089, P = 0.017). As expected, patients did not report significantly higher rates of withdrawal when taking methadone after fentanyl use. Of those who waited less than 24 hours after fentanyl before using buprenorphine or methadone, 22.19% (n = 152 of 685) and 11.56% (n = 23 of 199), respectively, reported severe opioid withdrawal. CONCLUSIONS This study supports previous anecdotal reports of buprenorphine-precipitated withdrawal from fentanyl. The odds of withdrawal symptoms significantly increased when taking buprenorphine after recent (within 48 hours) fentanyl use, however, this relationship was not observed in persons taking methadone, suggesting that this effect is specific to buprenorphine. Further research is urgently needed to describe the pharmacokinetics of non-medical fentanyl use to improve buprenorphine inductions strategies.

BACKGROUND More than 3 million individuals receive treatment for alcohol use disorder (AUD) and/or substance use disorder each year, yet there exists no standardized method for measuring patient success in treatment. Quantifying a more comprehensive assessment of treatment outcomes could identify the relative efficacy of different treatment strategies for individuals with AUD/substance use disorders, and help patients to identify, in advance, appropriate treatment options. METHODS This study developed and embedded patient-reported outcome measures into the routine clinical operations of a residential treatment program. Surveys assessed demographics, drug use history, physical and mental health, and quality of life. Outcomes were assessed among participants at admission (n = 961) and in patients who completed the survey at time of discharge (n = 633). RESULTS Past 30-day alcohol and/or opioid use at admission were correlated with worse self-reported physical and mental health, sleep, and quality of life, and greater negative affect and craving (Ps

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

Opioid misuse and abuse is a major international public health issue. Opioid use disorder (OUD) is largely maintained by a desire to suppress aversive opioid withdrawal symptoms. Opioid withdrawal in patients seeking abstinence from illicit or prescribed opioids is often managed by provision of a μ-opioid agonist/partial agonist in combination with concomitant medications. Concomitant medications are administered based on their ability to treat specific symptoms rather than a mechanistic understanding of the opioid withdrawal syndrome; however, their use has not been statistically associated with improved treatment outcomes. Understanding the central and/or peripheral mechanisms that underlie individual withdrawal symptom expression in humans will help promote medication development for opioid withdrawal management. To support focused examination of mechanistically supported concomitant medications, this review summarizes evidence from preclinical (N = 68) and human (N = 30) studies that administered drugs acting on the dopamine, serotonin, cannabinoid, orexin/hypocretin, and glutamate systems and reported outcomes related to opioid withdrawal. These studies provide evidence that each of these systems contribute to opioid withdrawal severity. The Food and Drug Administration has approved medications acting on these respective systems for other indications and research in this area could support the repurposing of these medications to enhance opioid withdrawal treatment. These data support a focused examination of mechanistically informed concomitant medications to help reduce opioid withdrawal severity and enhance the continuum of care available for persons with OUD.

Approximately 2.7 million individuals in the United States had an opioid use disorder (OUD) in 2020. Chronic pain may exacerbate opioid withdrawal severity, yet most research on opioid withdrawal has not collected data on chronic pain status. Moreover, there is limited evidence that women tend to experience greater opioid withdrawal severity than men, but large, confirmatory studies on this topic have not been published. The goal of this study was to examine the roles of chronic pain and gender on opioid withdrawal severity using a large, multi-site database.Data were collected from N = 1252 individuals with OUD entering eight residential addiction treatment facilities. Demographic, drug use behaviors, and chronic pain status were collected at treatment intake, and self-reported opioid withdrawal and craving were measured at intake and 1-3 days, 4-6 days, and 7-9 days after intake. Regression analyses were used to predict withdrawal and craving severity at intake and across the four timepoints.At intake, withdrawal was higher in persons who were older, had greater SUD severity, women, had chronic pain, and used 1 substance (p-values ≤.007) and craving was higher in persons with greater SUD severity (p .001) and women (p = .033). Withdrawal remained higher in women and persons with chronic pain across timepoints but decreased at a similar rate relative to comparators.Women and persons with chronic pain would benefit from earlier engagement in treatment and may require a more intensive strategy to mitigate opioid withdrawal in early treatment.

Background and objectives Drug-related dreams are commonly reported by individuals in treatment for substance use disorders, which may be distressing. Existing evidence suggests that dream recollection may be influenced by clinically relevant phenomena, such as opioid use and withdrawal, general sleep disturbance, affective symptoms, and chronic pain. However, very few studies have explored drug-related dreams among individuals who screened positive for opioid use disorder (OUD). Methods Adults recruited from Amazon Mechanical Turk (MTurk) who screened positive for OUD (N = 154) completed a questionnaire about drug-related dreams, as well as measures assessing sleep, opioid use history, stress, anxiety, and chronic pain. χ2 analyses, one-way analysis of variance, and bivariate correlations, correcting for the false discovery rate, were used as appropriate to explore correlates of (1) recollecting a drug-related dream, and (2) experiencing post-dream craving and distress. Results Individuals who recollected a past-week drug-related dream were more likely to report other recent sleep disturbances, including poorer sleep quality, greater insomnia symptoms, and a higher risk for sleep apnea. Post-dream craving and distress were both associated with greater insomnia symptoms, poor sleep hygiene behaviors, and greater anxiety symptoms. Individuals who had ever experienced a drug-related dream (recently, or in their lifetime) were more likely to report a history of severe withdrawal, overdose, and intravenous opioid use. Conclusion and scientific significance Drug-related dreams were common among individuals in the present sample and were related to other clinically relevant phenomena. Interventions that treat co-occurring OUD, pain, sleep symptoms, and affective symptoms may improve overall well-being in this population.

As fatal overdoses from synthetic opioids continue to rise, we need to understand decision-making processes underlying heroin and synthetic opioid use. This study evaluated the influence of sample impurity and fatal overdose risk on hypothetical heroin use. Individuals who currently use heroin (n = 69) were recruited online. Participants completed two probability-discounting tasks evaluating the likelihood of using a sample of heroin based on the likelihood of sample impurity and likelihood of fatal overdose, where greater discounting represented reduced use likelihood. Prior to completing the probability-discounting tasks, participants were randomized to read one of four prompts varying by the presence of information on heroin effects and active (e.g., fentanyl) or inert impurities. Influence of prompts on discounting processes and associations among probability-discounting measures, opioid use behaviors, and dependence severity were evaluated. Heroin use likelihood decreased with increased impurity or overdose risk and in a generally orderly fashion. Discounting was greater (i.e., reduced heroin use likelihood) when overdose risk, compared to sample impurity, was manipulated. Less discounting was associated with more severe opioid dependence. Discounting did not differ among prompts for either task. Individuals might adjust their heroin-use behavior to reduce harm with risk-related information. Greater discounting elicited by overdose relative to impurity risk suggests that equating adulteration and overdose risk is essential for harm reduction. Expanded access to drug checking services, which inform impurity and overdose risk, can reduce fatal overdoses. Due to fear of legal sanctions for these services, legislation and judicial decisions should explicitly protect these services. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Sleep health is an important factor across several physical and mental health disorders, and a growing scientific consensus has identified sleep as a critical component of opioid use disorder (OUD), both in the active disease state and during OUD recovery. The goal of this narrative review is to collate the literature on sleep, opioid use, and OUD as a means of identifying therapeutic targets to improve OUD treatment outcomes. Sleep disturbance is common and often severe in persons with OUD, especially during opioid withdrawal, but also in persons on opioid maintenance therapies. There is ample evidence that sleep disturbances including reduced total sleep time, disrupted sleep continuity, and poor sleep quality often accompany negative OUD treatment outcomes. Sleep disturbances are bidirectionally associated with several other factors related to negative treatment outcomes, including chronic stress, stress reactivity, low positive affect, high negative affect, chronic pain, and drug craving. This constellation of outcome variables represents a more comprehensive appraisal of the quality of life and quality of recovery than is typically assessed in OUD clinical trials. To date, there are very few clinical trials or experimental studies aimed at improving sleep health in OUD patients, either as a means of improving stress, affect, and craving outcomes, or as a potential mechanistic target to reduce opioid withdrawal and drug use behaviors. As such, the direct impact of sleep improvement in OUD patients is largely unknown, yet mechanistic and clinical research suggests that therapeutic interventions that target sleep are a promising avenue to improve OUD treatment. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background: Increases in opioid-related overdose and death have led to increases in the number of organs available for donation and transplant, however persons who have a substance use disorder (SUD) may be disadvantaged relative to other health conditions with regard to receiving an organ for transplant.Objective: This study aimed to evaluate perceptions regarding acceptability and priority for organ donation vs. a control condition (resuscitation) for hypothetical persons with nine target health conditions including a substance use disorder, among persons recruited as part of an online survey.Methods: Respondents (N = 285; male = 172, female = 113) recruited from Amazon Mechanical Turk rated acceptability and priority that hypothetical persons representing nine target health conditions expected to influence transplant success (including a SUD) receive an organ transplant and resuscitation via a survey hosted by Qualtrics. Primary outcomes of stigma ratings and priority ranking of persons as a function of the hypothetical target health condition were analyzed using Repeated Measures Analyses of Variance and Bonferroni-corrected t-tests. Demographic information was presented descriptively for all respondents.Results: Ratings for acceptability and priority for persons who had a SUD were generally lower than ratings for other conditions for both organ for transplant and resuscitation, though respondents reported less stigma toward resuscitation, F(8) = 22.35, p p's < 0.001. Priority rankings favored persons who were young or had a history of heart disease. Multivariable models determined that target health condition, F(8) = 33.64, p < 0.001, was a better and more consistent predictor of response than demographic variables that were examined.Conclusions: Data suggest that general perception of acceptability and priority ranking for receipt of life-saving interventions was lower for persons who have a SUD relative to other clinically-relevant health conditions. Research to examine this effect among persons working in the donation system are warranted and efforts to reduce stigma toward persons who have a SUD should be continued.

Genome-wide association studies (GWAS) have identified genetic variants associated with brain morphology and substance use behaviors (SUB). However, the genetic overlap between brain structure and SUB has not been well characterized. We leveraged GWAS summary data of 71 brain imaging measures and alcohol, tobacco, and cannabis use to investigate their genetic overlap using linkage disequilibrium score regression. We used genomic structural equation modeling to model a “common SUB genetic factor” and investigated its genetic overlap with brain structure. Furthermore, we estimated SUB polygenic risk scores (PRS) and examined whether they predicted brain imaging traits using the Adolescent Behavior and Cognitive Development (ABCD) study. We identified 8 significant negative genetic correlations, including between (1) alcoholic drinks per week and average cortical thickness, and (2) intracranial volume with age of smoking initiation. We observed 5 positive genetic correlations, including those between (1) insula surface area and lifetime cannabis use, and (2) the common SUB genetic factor and pericalcarine surface area. SUB PRS were associated with brain structure variation in ABCD. Our findings highlight a shared genetic etiology between cortical brain morphology and SUB and suggest that genetic variants associated with SUB may be causally related to brain structure differences.

Sleep disturbances and disorders are a common and sometimes recalcitrant problem in persons recovering from substance use disorders (SUDs). As such, several randomized-controlled trials (RCTs) have been conducted to address sleep disturbances in a variety of SUD subpopulations and clinical scenarios. The goal of this systematic review was to collate patient-reported sleep outcomes used in past SUD-related RCTs to provide guidance for future sleep research in persons with SUDs.This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) on May 7th, 2020 (CRD42020182004). Studies were included if they were peer-reviewed manuscripts describing RCTs in an SUD population.The initial search yielded 13,403 candidate articles, and 76 met a priori criteria and were included in this review. Thirty-five (46.1%) assessed sleep as a primary outcome (i.e., sleep improvement was the primary goal of the research) and 41 (53.9%) assessed sleep as a secondary outcome (i.e., sleep improvement was an important outcome, but not the primary outcome). The most commonly used measures included the Pittsburgh Sleep Quality Index, the Insomnia Severity Index, and sleep diaries. However, multiple additional sleep assessments were also used, including visual analogue and Likert scales.The field of addiction medicine would benefit from a streamlined approach in assessing patient-reported sleep in RCTs, including commonly used and validated assessments of sleep quality, inserting daily or repeated measures into RCTs, and including questionnaires that assess clinically relevant insomnia or other sleep disorders.

Improving sleep health is an important target for substance use disorder (SUD) research. However, there is little guidance for SUD researchers regarding the use of technologies to objectively assess sleep outcomes in randomized-controlled trials (RCTs). This systematic review aimed to describe the use of technologies to objectively measure sleep outcomes in RCTs conducted in persons with SUDs, in order to inform future sleep intervention studies in SUD populations.This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) on May 7th, 2020 (CRD42020182004). RCTs were reviewed here if they were peer-reviewed manuscripts that included objective measures of sleep in RCTs that sought to improve sleep in persons with SUDs.The initial search yielded 13,403 potential articles, with 27 meeting a priori criteria to be included in this review. The most common SUD was alcohol use disorder (59%). The most common technology used to assess sleep was polysomnography (41%), followed by actigraphy (37%), ambulatory polysomnography or components of polysomnography (e.g., electroencephalography; 19%), and at-home sleep apnea testing (7%). The most common sleep outcome reported was total sleep time (96%).There are a range of options to assess objective sleep outcomes. Polysomnography or ambulatory devices that directly measure brain activity are critical to advance medications through the regulatory process for the indication of improving sleep duration, continuity, and/or sleep onset latency outcomes. Actigraphy is also useful in preliminary investigations and in detecting the relationship between diurnal and SUD-related behaviors.

Efforts to improve buprenorphine access for opioid use disorder have focused on increasing the number of waivered providers. However, it is unknown how efforts to increase initial prescribing result in a sustained pool of prescribers. We examine the prevalence of year-to-year provider-level buprenorphine prescribing, and provider- and state-level factors associated with provider continuity.Providers prescribing buprenorphine/naloxone within the Medicare Part D claims database were evaluated from 2013 to 2017 with prescriber continuity measured as prescriptions made in consecutive years from the same provider (N = 14,222 unique providers; 6670 in 2013).The number of providers prescribing buprenorphine/naloxone within Medicare Part D increased from 2013 to 2017. The majority of providers prescribed buprenorphine/naloxone to 10 or fewer beneficiaries. Approximately 84% of providers prescribing buprenorphine/naloxone in 1 year prescribed it in the following year. Continuous prescribing from 2013 to 2017 was 59.4%, which was 86% the rate of a comparator chronic health medication (ie, lisinopril). Survival analyses indicated that female providers (adjusted hazard ratios [AHR] = 1.30, P 0.001) and clinical neuroscience specialties such as psychiatry (AHR = 1.21, P 0.001) exhibited greater discontinuation rates, whereas those with higher buprenorphine/naloxone beneficiary loads (AHR = 0.50, P 0.001) and in states with a greater increase in overdose mortality rates (AHR = 0.88, P 0.05) showed lower discontinuation rates.These data support evidence that providers who begin prescribing buprenorphine continue prescribing, although short of maximum capacity. Efforts to help providers become waivered, understand the impact of overdose fatalities in their area, and prescribe to multiple patients are likely to generate an enduring positive contribution to the number of treated patients.

Women with opioid use disorder (OUD) face unique challenges the moment they enter treatment. This narrative review focused on recent literature regarding sex- and gender-based issues that could affect treatment outcomes in women with OUD. Women respond differently to opioids based on hormonal factors, are more likely to present to treatment with mental health conditions, especially depression, and are more likely to have experienced trauma via intimate partner violence compared with men. Women also face stigma when entering OUD treatment, particularly if they have children. Future research to improve OUD treatment outcomes in women should account for sex as a biological variable and gender as a social construct. Women have a fundamentally different experience than men during the course of OUD and upon treatment entry. Programs that address childcare/family support, mental health, and trauma are warranted for women with OUD.

Introduction The illicit opioid supply in the U.S. is increasingly adulterated with fentanyl. As such, persons with opioid use disorder (OUD) may be regularly exposed to fentanyl, however, the pharmacokinetics of repeated fentanyl exposure are not well understood. The current study aimed to quantify renal clearance of fentanyl in OUD patients presenting to residential treatment. Methods Participants (N = 12) who presented to a 28-day residential treatment program were enrolled if they tested positive for fentanyl at intake. Urine samples were collected every 2–3 days and were quantitatively tested for fentanyl, norfentanyl, and creatinine via liquid chromatography mass spectrometry (LC–MS). Fentanyl clearance was defined as the time since last illicit opioid use and the median time between last positive and first negative fentanyl urine screen. Results Participants had a mean and standard deviation (SD) age of 28.9 (11.0), were 67 % male, and 83 % white. The mean (SD) time for fentanyl and norfentanyl clearance was 7.3 (4.9) and 13.3 (6.9) days, respectively. One participant continued to test positive for fentanyl for 19 days and norfentanyl for 26 days following their last use, and left treatment without testing negative for norfentanyl. Conclusion Fentanyl clearance in persons with OUD is considerably longer than the typical 2–4 day clearance of other short-acting opioids. The findings of this study might explain recent reports of difficulty in buprenorphine inductions for persons who use fentanyl, and point to a need to better understand the pharmacokinetics of fentanyl in the context of opioid withdrawal in persons who regularly use fentanyl.

EDITOR’S PERSPECTIVE What We Already Know about This Topic The prevalence of patients prescribed buprenorphine for treatment of opioid use disorder is increasing Managing acute pain in buprenorphine-maintained individuals can be challenging What This Article Tells Us That Is New Large doses of intravenous hydromorphone can provide analgesia in buprenorphine-maintained individuals However, the use of hydromorphone for analgesia in buprenorphine-maintained individuals confers greater abuse liability and side effects than does supplemental intravenous buprenorphine Background Managing acute pain in buprenorphine-maintained individuals in emergency or perioperative settings is a significant challenge. This study compared analgesic and abuse liability effects of adjunct hydromorphone and buprenorphine using quantitative sensory testing, a model of acute clinical pain, in persons maintained on 12 to 16 mg sublingual buprenorphine/naloxone. Methods Participants (N = 13) were enrolled in a randomized within-subject, double-blind, placebo-controlled three-session experiment. Each session used a cumulative dosing design with four IV injections (4, 4, 8, and 16 mg of hydromorphone or 4, 4, 8, and 16 mg of buprenorphine); quantitative sensory testing and abuse liability assessments were measured at baseline and after each injection. The primary analgesia outcome was change from baseline cold pressor testing; secondary outcomes included thermal and pressure pain testing, as well as subjective drug effects and adverse events. Results A significant two-way interaction between study drug condition and dose was exhibited in cold pressor threshold (F10,110 = 2.14, P = 0.027) and tolerance (F10,110 = 2.69, P = 0.006). Compared to after placebo, participants displayed increased cold pressor threshold from baseline after cumulative doses of 32 mg of IV hydromorphone (means ± SD) (10 ± 14 s, P = 0.035) and 32 mg of buprenorphine (3 ± 5 s, P = 0.0.39) and in cold pressor tolerance after cumulative doses of 16 mg (18 ± 24 s, P = 0.018) and 32 mg (48 ± 73 s, P = 0.041) IV hydromorphone; cold pressor tolerance scores were not significant for 16 mg (1 ± 15 s, P = 0.619) or 32 mg (7 ± 16 s, P = 0.066) buprenorphine. Hydromorphone and buprenorphine compared with placebo showed greater ratings on subjective measures of high, any drug effects, good effects, and drug liking. Adverse events were more frequent during the hydromorphone compared with buprenorphine and placebo conditions for nausea, pruritus, sedation, and vomiting. Conclusions In this acute clinical pain model, high doses of IV hydromorphone (16 to 32 mg) were most effective in achieving analgesia but also displayed higher abuse liability and more frequent adverse events. Cold pressor testing was the most consistent measure of opioid-related analgesia.