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Aims: Persons with opioid-use disorder (OUD) often experience opioid withdrawal and opioid craving, which can drive continued opioid use and treatment discontinuation. In addition, hyperalgesia is common among persons with OUD, yet few studies have examined the role of pain impact during OUD treatment. The purpose of the present study was to test whether opioid withdrawal and craving were elevated in the context of greater pain impact (i.e. greater pain intensity and interference), and whether these associations changed throughout treatment., Methods: Participants in residential OUD treatment (n = 24) wore wrist actigraphy to measure sleep and completed daily measures of pain impact, opioid withdrawal and opioid craving for up to 28 days. Mixed effects models were used to examine whether daily elevations in pain impact and sleep continuity were associated with withdrawal severity and opioid craving., Results: Elevations in withdrawal, but not craving, occurred on days when individuals reported higher scores on the pain impact scale. Associations between pain impact and withdrawal were present throughout treatment, but stronger during early treatment. In contrast, both withdrawal and opioid craving were elevated following nights of greater wake after sleep onset and awakenings, but these findings were often more pronounced in early treatment., Conclusions: Pain impact and sleep disturbance are 2 factors associated with opioid withdrawal and opioid craving. Novel pharmacotherapies and scalable adjunctive interventions targeting sleep and pain impact should be tested in future work to improve OUD treatment outcomes., (© 2024 British Pharmacological Society.)

Objectives: Persons with chronic pain and women tend to enter treatment for opioid use disorder with greater opioid withdrawal severity than persons without chronic pain and men, respectively. This study examined characteristics of facilities with opioid withdrawal treatment, including gender-based services, as a function of whether they reported having a tailored pain management program., Methods: The National Survey of Substance Abuse Treatment Services 2020 was used to examine 3942 facilities with opioid withdrawal treatment in the United States. Using a multivariable binary logistic regression model, facilities were examined for the presence of a tailored program for individuals with co-occurring pain. Regional location of the facility, ownership status, and availability of tailored gender programs, nonhospital residential services, and outpatient services served as independent variables in the analysis., Results: A slight majority of the sample had a program for both adult men and adult women ( n = 2010, 51.0%). Most facilities had outpatient services ( n = 3289, 83.4%) and did not have a tailored program for addressing co-occurring pain ( n = 2756, 69.9%). Binary logistic regression analysis showed that among opioid withdrawal facilities, programs with nonhospital residential services, government or private nonprofit funding, or tailored gender programming had higher odds of reporting having a tailored program for pain and substance use disorder. Facilities in the Western United States were most likely to have tailored programs for pain and substance use disorder., Conclusions: Future research should investigate what support patients may receive and how to better scale access to pain management during opioid withdrawal treatment., (Copyright © 2024 American Society of Addiction Medicine.)

Tweet: The authors discuss harm reduction strategies and associated outcome metrics in relation to the ongoing opioid crisis., Competing Interests: Dr. Dunn has served as consultant for Cessation Therapeutics, DemeRx, Indivior, and Mind Med and has received research funding from Cure Addiction Now and NIDA. Dr. Huhn has served as consultant for Gilgamesh and has received research funding from Ashley Addiction Treatment, Indivior, and NIH. Dr. Ellis reports no financial relationships with commercial interests.

The twin opioid-stimulant epidemics have led to increased overdose deaths and present unique challenges for individuals entering treatment with opioid-stimulant polysubstance use. This study examined tonic and cue-induced craving as a primary outcome among persons in substance use treatment who reported primary substances of opioids, methamphetamine, or cocaine. The sample consisted of 1974 individuals in 55 residential substance-use treatment centers in the United States in 2021. Weekly surveys were delivered via a third-party outcomes tracking system, including measures of tonic and cue-induced craving. Initial comparisons on tonic and cue-induced craving were made among those who primarily used opioids, cocaine, or methamphetamine. Further, the effect of opioid/stimulant polysubstance use on tonic and cue-induced craving was evaluated using marginal effect regression models. Primary methamphetamine use was associated with decreased tonic craving compared to primary opioid use (β = -5.63, p < 0.001) and primary cocaine use was also associate with decreased tonic craving compared to primary opioid use (β = -6.14, p < 0.001). Primary cocaine use was also associated with lower cue-induced cravings compared to primary opioid use (β = -0.53, p = 0.037). Opioid-methamphetamine polysubstance use was associated with higher tonic craving (β = 3.81, p = <0.001) and higher cue-induced craving (β = 1.55, p = 0.001); however, this was not the case for opioid-cocaine polysubstance use. The results of this study indicate that individuals who primarily use opioids and have secondary methamphetamine use experience higher cue-induced and tonic-induced craving, suggesting that these individuals may benefit from additional interventions that target craving and mitigate relapse risk and other negative sequelae., Competing Interests: Declaration of competing interest None of the authors have any conflicts of interest to declare., (Copyright © 2023. Published by Elsevier Ltd.)

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 ( n = 15) admitted to a residential treatment center for opioid use disorder (OUD) were enrolled into a double-blind randomized clinical trial to assess the efficacy and acceptability of buspirone (45 mg/day) as an adjunctive medication to buprenorphine-assisted, supervised opioid withdrawal. Participants completed daily questionnaires which consisted of the Subjective Opiate Withdrawal Scale (SOWS) and a consensus sleep diary, which assessed total sleep time, time to sleep onset, and sleep quality. Total SOWS scores, individual opioid withdrawal symptoms and sleep outcomes were assessed between treatment groups (Placebo and Buspirone) and over time in a repeated measures linear mixed model. Total SOWS scores significantly decreased across study phases for both groups but decreased to a greater extent among individuals assigned to buspirone during both the first and second week of stable buspirone. Greater decreases in withdrawal were observed during Week 2 of stable buspirone relative to Week 1 of stable buspirone. Participants also reported significant increases in sleep duration and significant decreases in latency to sleep onset. This study provides further support that buspirone can help mitigate opioid withdrawal during a supervised opioid taper. Buspirone may confer unique benefits during protracted withdrawal periods. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Competing Interests: The authors have no relevant conflicts of interest to declare.

Importance: Novel 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., Observations: Consensus 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 Relevance: Applying 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.

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).

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) 2022 APA, all rights reserved).

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/likability 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/likability. 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 likability such that males lower in peer-nominated likability were more likely to misuse opioids relative to males higher in likability., 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.

Background: 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., Methods: 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., Results: 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., Conclusions: 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., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: 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., Methods: 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)., Results: 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., Conclusions: 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., Competing Interests: Declarations of Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

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 ( P s < 0.05). Previous history of treatment and/or withdrawal management were associated with worse self-reported physical and mental health, quality of life, and increased craving ( P s < 0.05). Physical and mental health improved across timepoints and was most pronounced when comparing persons receiving treatment for opioid use disorder versus AUD, wherein persons with opioid use disorder had worse physical health at all time points, and greater sleep disturbance and negative affect at discharge ( P s < 0.05)., Conclusions: It is feasible to embed patient outcome monitoring into routine clinic operations, which could be used in the future to tailor treatment plans., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 American Society of Addiction Medicine.)

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 48hours 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 24hours 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., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 American Society of Addiction Medicine.)

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., Competing Interests: The authors report no conflicts of interest.

Objectives: To evaluate how performing artists (PAs) with chronic pain may differ on measures of substance use compared to non-PA controls., Methods: 157 participants reporting chronic pain (89 PAs, 68 non-PA controls) completed an online cross-sectional survey. Participants were assessed for self-reported current pain severity using the Brief Pain Inventory Short-Form, opioid misuse risk using the Screener and Opioid Assessment for Patients with Pain-Revised, opioid withdrawal using the Subjective Opiate Withdrawal Scale, and symptoms of opioid use disorder (OUD) using a modified version of the DSM-V checklist., Results: PAs had lower pain severity (p <0.05, t=2.196, df=155) and lower pain interference (p <0.05, t=2.194) than non-PA controls. 24% of PAs and 13% of controls reported using opioids within the past month. Among PAs, the number of days using opioids in the past month was positively associated with hours spent practicing per week (r=0.508, p <0.05). PAs (66%) were more likely to endorse current alcohol use than controls (44.1%, t= -2.136, X2=7.72, p <0.01). Importantly, PAs (19%) were more likely than controls (3%) to endorse symptoms of at least mild OUD (X2(3)=11.3, p <0.01) and higher ratings of opioid misuse risk (t=-2.166, p <0.05). Past month opioid withdrawal was also greater in PAs than controls (t=-2.136, p <0.05), and 5.6% of PAs and 1.5% of controls reported at least one prior incidence incident of opioid overdose in their lifetime (X2 =1.80, NS)., Conclusions: Among persons with chronic pain, PAs may have higher risk for opioid-related consequences, including OUD, and should be screened during health care encounters.

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (© 2022 American Academy of Sleep Medicine.)

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. χ 2 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., (© 2021 American Academy of Addiction Psychiatry.)

Objective: Research has demonstrated that hypothalamic-pituitary-adrenal (HPA) axis function and sleep patterns are dysregulated in patients diagnosed with opioid use disorder (OUD). It is unclear whether and/or when cortisol and sleep might re-regulate over time, and, whether re-regulation is associated with abstinence following discharge from residential treatment. The current study evaluated changes in sleep and basal cortisol levels in prescription OUD patients in residential treatment, and the association between these measures and treatment outcome following discharge., Method: As part of a larger study, 55 participants with prescription OUD provided two days of salivary cortisol samples and 12 consecutive nights of sleep actigraphy between days 19-30 of residential treatment (Time Point 1; TP1). Thirteen of the original 55 participants remained in residence and repeated the measures between days 60-72 (Time Point 2; TP2). Thirty-seven healthy controls (HC) provided baseline measures (TP1) of salivary cortisol and sleep. Treatment outcome data, abstinence vs relapse, were established at 120 days following discharge., Results: Prescription OUD patients had higher cortisol levels and lower total sleep time (TST) than HC at TP1. At TP2, TST and cortisol levels no longer differed from HCs in the subgroup of patients who remained abstinent following discharge after TP2. Individuals whose cortisol and TST did not change from TP1 to TP2 were more likely to relapse following discharge from residential treatment., Conclusion: Re-regulation of TST and cortisol levels while in residential treatment was associated with better treatment outcome following discharge for prescription OUD patients., (Copyright © 2021. Published by Elsevier B.V.)

Objectives: Acute pain management in patients with opioid use disorder who are maintained on methadone presents unique challenges due to high levels of opioid tolerance in this population. This randomized controlled study assessed the analgesic and abuse liability effects of escalating doses of acute intravenous (IV) hydromorphone versus placebo utilizing a validated experimental pain paradigm, quantitative sensory testing (QST)., Methods: Individuals (N = 8) without chronic pain were maintained on 80-100 mg/day of oral methadone. Participants received four IV, escalating/incremental doses of hydromorphone over 270 min (32 mg total) or four placebo doses within a session test day. Test sessions were scheduled at least one week apart. QST and abuse liability measures were administered at baseline and after each injection., Results: No significant differences between the hydromorphone and placebo control conditions on analgesic indices for any QST outcomes were detected. Similarly, no differences on safety or abuse liability indices were detected despite the high doses of hydromorphone utilized. Few adverse events were detected, and those reported were mild in severity., Conclusions: The findings demonstrate that methadone-maintained individuals are highly insensitive to the analgesic effects of high-dose IV hydromorphone and may require very high doses of opioids, more efficacious opioids, or combined non-opioid analgesic strategies to achieve adequate analgesia., (Copyright © 2021. Published by Elsevier B.V.)

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 < 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., Conclusions: 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., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2020 American Society of Addiction Medicine.)

Background: Despite effective, evidence-based medications for opioid use disorder (MOUD), these treatments remain underutilized. This may be due to multiple reasons. Family members may impact patient decision-making when choosing an opioid use disorder (OUD) treatment. While there has been work on patient preferences and attitudes towards opioid use disorder (OUD) treatment, to date, there has been minimal work assessing the attitudes of family member towards OUD treatment and recovery., Methods: Participants were ≥ 18 years of age and endorsed having a first-degree family member with past-year treatment for OUD. Participants were recruited via online crowdsourcing and were asked a number of questions regarding their desired outcomes for OUD treatment, and their familiarity, approval, and perceived effectiveness of various OUD treatment options., Results: The most commonly reported desired treatment outcome (50 %) was for family members to never use any kind of opioid, including maintenance therapies or opioid analgesics. Mean familiarity ratings for MOUD (rated 0-100) were relatively low, with naltrexone being the least familiar (32.3). Among those who endorsed a familiarity rating of at least 30 for a given treatment, mean approval and effectiveness ratings were relatively low-buprenorphine (approve 55.1; effective 54.1), methadone (approve 51.9; effective 49.3), naltrexone (approve 61.6; effective 55.9). These were lower than approval and effectiveness ratings for all non-MOUD treatments queried., Conclusions: These findings highlight a need for clinicians and researchers to engage with family members' regarding their preferences and understanding of treatment, and to better understand how this might impact patient engagement with treatment., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Although craving is a formal DSM-5 criterion and a commonly reported feature of opioid use disorder (OUD), there is no universally accepted assessment of opioid craving for treatment outcome studies or clinical trials. This mixed-methods study characterized dimensions of opioid craving identified in qualitative responses collected via Amazon Mechanical Turk (AMT)., Method: Thirty-nine participants completed an online screener on AMT and met inclusion criteria (e.g., > = 18 years old and past 30-day illicit opioid use). These participants completed a series of closed- and open-ended questions about their opioid use and craving, including several commonly-used craving measures. They also rated their preference for how different questions described craving. Responses to the open-ended question "What do you mean when you say you are craving opioids?" were coded according to dimensions in existing opioid craving assessments and other common themes identified in the data., Results: Among the 39 participants, 8 different dimensions were identified and coded. Descriptions of craving were most frequently categorized as "Anticipation of Negative Reinforcement" (n = 17/39) and "Interfering Thoughts" (N = 14/39). Individuals with drug use characteristics reflecting greater severity of use were more likely to describe craving as "Interfering Thoughts". Participants may prefer opioid craving questions that included Visual Analog Scale response formats relative to Likert scales., Conclusions: There is a wide range of dimensions that were used to describe opioid craving and no single unifying dimension was identified. These data suggest opioid craving is a multidimensional construct including dimensions currently not included in common craving assessments., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Objectives: Individuals exposed to fentanyl are at risk of precipitated withdrawal using typical buprenorphine/naloxone induction procedures., Methods: This case series describes buprenorphine/naloxone inductions of four individuals who tested positive for fentanyl., Results: Buprenorphine-precipitated withdrawal was observed in two individuals who completed a conventional buprenorphine/naloxone induction strategy. Two more individuals completed a revised buprenorphine/naloxone induction strategy that did not precipitate withdrawal., Discussion and Conclusion: Using multiple 2 mg doses of buprenorphine/naloxone in patients already in mild/moderate withdrawal improved outcomes., Scientific Significance: Persons who use illicit fentanyl might be less likely to experience precipitated withdrawal from this revised buprenorphine/naloxone induction strategy. (Am J Addict 2021;30:83-87)., (© 2020 American Academy of Addiction Psychiatry.)

Purpose of Review: 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., Recent Findings: 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.

Although opioid withdrawal ratings are frequently used as primary outcomes for therapeutic trials, there has been limited empirical examination of opioid withdrawal symptom onset or etiology as an outcome, and also little examination of differences in outcomes between patient-reported and observer-ratings of withdrawal. Patient-reported (Subjective Opiate Withdrawal Scale, SOWS) and observer ratings (Clinical Opiate Withdrawal Scale, COWS) of opioid withdrawal collected as part of a randomized controlled residential clonidine, tramadol-extended release, and buprenorphine/naloxone 7-day taper for opioid withdrawal management were analyzed. Withdrawal ratings were collected seven times daily and primary outcomes were percent of participants (N = 103) endorsing symptoms, time of symptom onset, and relationship of scales to taper completion. Participants had variable endorsement of specific symptoms, ranging from 37 % ("feel like vomiting") to 97 % ("change in resting pulse"). Symptoms were more likely to be reported on the SOWS than COWS. Most symptoms began around 8 h after last dose, though comparison of like symptoms across the scales revealed patients reported symptoms on the SOWS > 10 h before they were observed on the COWS. SOWS peak severity score was more closely associated with taper completion than the COWS. Data suggest the patient-reported SOWS demonstrated a higher level of symptom endorsement, earlier detection of symptom onset, and better association with taper completion relative to the observer rated COWS. These data provide insight into the etiology of opioid withdrawal symptom expression and time course that can be used to inform treatment intervention timing and provide a baseline for other withdrawal evaluations., (Copyright © 2020. Published by Elsevier B.V.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing interest. ASH receives research funding from Ashley Addiction Treatment through his university. ECS has served on advisory boards, received grant funding from, and/or consulted for Alkermes, Analgesic Solutions, Caron, Indivior Pharmaceuticals, Innocoll Pharmaceuticals, The Oak Group/VitalHub, UpToDate, Otsuka Pharmaceutical Development and Commercialization, and Pinney Associates. He has received honoraria from the World Health Organization, and is currently collaborating with Innovative Health Solutions. All other authors report no financial disclosures., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Importance: While many individuals with opioid use disorder seek treatment at residential facilities to initiate long-term recovery, the availability and use of medications for opioid use disorder (MOUDs) in these facilities is unclear., Objective: To examine differences in MOUD availability and use in residential facilities as a function of Medicaid policy, facility-level factors associated with MOUD availability, and admissions-level factors associated with MOUD use., Design, Setting, and Participants: This cross-sectional study used deidentified facility-level and admissions-level data from 2863 residential treatment facilities and 232 414 admissions in the United States in 2017. Facility-level data were extracted from the 2017 National Survey of Substance Abuse Treatment Services, and admissions-level data were extracted from the 2017 Treatment Episode Data Set-Admissions. Statistical analyses were conducted from June to November 2019., Exposures: Admissions for opioid use disorder at residential treatment facilities in the United States that identified opioids as the patient's primary drug of choice., Main Outcomes and Measures: Availability and use of 3 MOUDs (ie, extended-release naltrexone, buprenorphine, and methadone)., Results: Of 232 414 admissions, 205 612 (88.5%) contained complete demographic data (166 213 [80.8%] aged 25-54 years; 136 854 [66.6%] men; 151 867 [73.9%] white). Among all admissions, MOUDs were used in only 34 058 of 192 336 (17.7%) in states that expanded Medicaid and 775 of 40 078 (1.9%) in states that did not expand Medicaid (P < .001). A relatively low percentage of the 2863 residential treatment facilities in this study offered extended-release naltrexone (854 [29.8%]), buprenorphine (953 [33.3%]), or methadone (60 [2.1%]). Compared with residential facilities that offered at least 1 MOUD, those that offered no MOUDs had lower odds of also offering psychiatric medications (odds ratio [OR], 0.06; 95% CI, 0.05-0.08; Wald χ21 = 542.09; P < .001), being licensed by a state or hospital authority (OR, 0.39; 95% CI, 0.27-0.57; Wald χ21 = 24.28; P < .001), or being accredited by a health organization (OR, 0.28; 95% CI, 0.23-0.33; Wald χ21 = 180.91; P < .001). Residential facilities that did not offer any MOUDs had higher odds of accepting cash-only payments than those that offered at least 1 MOUD (OR, 4.80; 95% CI, 3.47-6.64; Wald χ21 = 89.65; P < .001)., Conclusions and Relevance: In this cross-sectional study of residential addiction treatment facilities in the United States, MOUD availability and use were sparse. Public health and policy efforts to improve access to and use of MOUDs in residential treatment facilities could improve treatment outcomes for individuals with opioid use disorder who are initiating recovery.

Opioid use disorder (OUD) is a public health crisis. Differences in opioid withdrawal severity that predict treatment outcome could facilitate the process of matching patients to treatments. This is a secondary analysis of a randomized controlled trial (RCT) that enrolled treatment seeking heroin-users (N = 89, males = 78) into a residential study. Participants maintained on morphine (30 mg, subcutaneous, four-times daily) underwent a naloxone (0.4 mg, IM = intramuscular) challenge session to precipitate withdrawal. Area-under-the-curve (AUC) values from self-reported withdrawal ratings during the challenge session were analyzed using K-means clustering, revealing two phenotype groups. Withdrawal and retention from the subsequent 14-day double-blind, double-dummy RCT comparing three study medications (clonidine, tramadol-ER, and buprenorphine) were evaluated as a function of phenotype. Cluster analyses suggested HIGH (N = 37; mean [SD] subjective opiate withdrawal scale [SOWS]-AUC 123.7 [65.8]) and LOW (N = 52; SOWS-AUC 68.0 [47.7]) withdrawal phenotype groups. HIGH participants were significantly more female and had lower body mass indices than LOW participants; no drug-use variables were significant. Regarding RCT outcomes, HIGH phenotype participants were less likely to be retained in the study (P = 0.02) and had higher mean self-reported withdrawal (P = 0.05) than LOW phenotype participants. A significant interaction in RCT retention was observed between phenotype (P = 0.02) and study medication (P < 0.01). Self-reported withdrawal was significant for phenotype (P = 0.02); study medication trended towards significance (P = 0.07). Results suggest patients have meaningfully different experiences of opioid withdrawal that may predict differential response to opioid pharmacotherapies during supervised withdrawal. Additional prospective research to replicate and more thoroughly evaluate withdrawal phenotype correlates and sex differences is warranted., (© 2018 Society for the Study of Addiction.)

Introduction: The subjective experience of drug craving is a prominent and common clinical phenomenon for many individuals diagnosed with opioid use disorder (OUD), and could be a valuable clinical endpoint in medication development studies. The purpose of this scoping review is to provide an overview and critical analysis of opioid craving assessments located in the published literature examining OUD., Method: Studies were identified through a search of PubMed, Embase, and PsychInfo databases and included for review if opioid craving was the focus and participants were diagnosed with or in treatment for OUD., Results: Fifteen opioid craving assessment instruments were identified across the 87 studies included for review. The most common were the Visual Analog Scale (VAS, 41 studies), Desires for Drug Questionnaire (DDQ, 12 studies), Heroin Craving Questionnaire (HCQ, 10 studies), and Obsessive-Compulsive Drug Use Scale (OCDUS, 10 studies). Craving assessments varied considerably in their format, content, time frame, and underlying subscales, and only 6 of 15 had been psychometrically evaluated., Discussion: This review identified a variety of opioid craving assessments, but few had been evaluated for their psychometric properties making it difficult to ascertain whether craving is being assessed optimally in studies of OUD. Thus, the development of a reliable and valid opioid craving assessment would be worthwhile and could be guided by recently published Food and Drug Administration Clinical Outcome Assessment (COA) guidelines. Importantly, a COA focused on opioid craving could be a valuable addition to research studies designed to evaluate novel treatments for OUD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Methadone maintenance is an effective treatment for opioid use disorder (OUD), yet many methadone-maintained patients (MMPs) struggle with cocaine use during OUD recovery. The current study aimed to identify whether prefrontal cortex (PFC) activity during a risky decision-making task was associated with cocaine use during a 90-day follow-up in MMPs., Methods: MMPs (N = 28) attended a single neuroimaging session wherein PFC activity was measured using functional near-infrared spectroscopy (fNIRS) during the Balloon Analogue Risk Task (BART). Trait impulsivity was assessed via the Barratt Impulsiveness Scale version 11 (BIS-11). Following the neuroimaging session, MMPs were tracked via electronic health records for 90 days to determine treatment outcomes including cocaine use verified by urine drug screens., Results: During the BART, MMPs who used cocaine displayed increased neural activity in the right PFC during active decision-making (F 1, 22  = 14.75, p = 0.001) and the right dorsolateral PFC during active minus passive decision-making (F 1, 22  = 5.56, p = 0.028) compared to participants who did not use cocaine. Receiver operating characteristic curves confirmed that neural activity in the right PFC during active decision-making (AUC = 0.841, 95% CI, 0.697-0.985, p = 002), and in the right dorsolateral PFC during active minus passive decision-making (AUC = 0.805, 95% CI, 0.643-0.968, p = 0.006) was associated with continued cocaine use. MMPs who used cocaine versus those who did not reported increased trait impulsivity on the BIS-11 Total Score (t=-2.28, p = 0.031)., Conclusions: The fNIRS device is portable, relatively easy to use, and potentially feasible for use in methadone outpatient programs to assess propensity for negative treatment outcomes such as continued cocaine use., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: In response to the opioid overdose epidemic, scalable interventions that instruct at-risk populations how to prevent and respond to overdose scenarios are needed., Method: The following groups of at-risk individuals were recruited online: (1) Acute Pain patients with an opioid prescription, (2) Chronic Pain patients with an opioid prescription, and (3) persons without pain who use Illicit Opioids. Participants were tested on their opioid overdose knowledge using the Brief Opioid Overdose Knowledge (BOOK) questionnaire and randomized to one of two web-based interventions that contained 25 educational content slides. One intervention consisted of embedded questions with corrective feedback (Presentation + Mastery, n = 58), the other did not (Presentation, n = 61). Participants completed the BOOK again at the end of the intervention and 30 days later. Overdose risk behaviors were assessed at baseline and 30-days., Results: Relative to baseline, both Presentation and Presentation + Mastery interventions increased total BOOK scores immediately and 30 days later. There was a significant effect of Group on BOOK Knowledge, whereby those with Acute Pain had lower scores across time, regardless of intervention, relative to those with Chronic Pain and Illicit Opioid Use. Compared to baseline, all three groups reported fewer instances of using opioids alone or concurrently with alcohol at the 30-day follow-up., Conclusions: A web-based intervention increased opioid overdose knowledge and decreased overdose risk behavior immediately and at a one-month follow-up, suggesting that this brief, practical, and scalable program could have utility in several populations who are at-risk of opioid overdose., (Copyright © 2019. Published by Elsevier Inc.)

Background: Understanding mechanisms of physiological opioid withdrawal symptoms can inform treatment strategies. This secondary analysis evaluated the association between mydriasis (dilated pupils), a commonly-assessed opioid withdrawal metric, with self- and observer-rated opioid withdrawal severity., Method: Ninety-five participants with opioid physical dependence were stabilized with morphine before receiving an injection of the opioid antagonist naloxone to precipitate withdrawal. Pupil diameter, the Subjective Opiate Withdrawal Scale (SOWS), and the Clinical Opiate Withdrawal Scale (COWS) were collected at baseline and in 15-minute intervals for 120 min following naloxone administration. Pearson product-moment correlations and linear regressions characterized the relationships between pupil measurements (baseline and peak naloxone-induced) and self- and observer-rated measures of withdrawal. Repeated-measures ANOVAs tested whether self and observer-rated withdrawal severity corresponded to unique patterns in pupil changes., Results: Baseline pupil diameter significantly correlated with SOWS and COWS peak scores. Peak naloxone-induced pupil diameter significantly correlated with SOWS scores only. Peak changes in pupil from baseline did not correspond to peak changes in self- and observer-rated withdrawal scales., Conclusions: This study suggests that pupil diameter measurements were more closely associated with acute opioid withdrawal severity than changes in pupil diameter. Prospective research examining the mechanisms underlying the relationship between pupil diameter and opioid withdrawal severity are warranted., (Copyright © 2019. Published by Elsevier B.V.)

Background and Objectives: In order to address the current opioid crisis, research on treatment outcomes for persons with opioid use disorder (OUD) should account for biological factors that could influence individual treatment response. Women and men might have clinically meaningful differences in their experience in OUD treatment and might also have unique challenges in achieving successful, long-term recovery. This review summarizes and synthesizes the current literature on sex-based differences in OUD treatment outcomes., Methods: Relevant literature was identified via automated and manual searches using the terms "opioid treatment outcome sex [or gender] differences" and "opiate treatment outcome sex [or gender] differences." Search methodology was consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), and were conducted within the PubMed electronic database during March and April of 2018., Results: The initial PubMed search yielded 241 manuscripts and 31 original research articles that met inclusion/exclusion criteria were synthesized in this review. Several important trends emerged, including findings that women are more likely than men to present to treatment with co-occurring mental health conditions such as depression, and that women might respond particularly well to buprenorphine maintenance., Discussion and Conclusions: While much of the literature on this topic is subject to potential cohort effects, interventions that address co-occurring mental health conditions and psychosocial stress might improve treatment outcomes for women with OUD., Scientific Significance: Funding agencies and researchers should focus attention toward human laboratory studies and clinical trials that are prospectively designed to assess sex-based differences in OUD recovery. (Am J Addict 2019;28:246-261)., (© 2019 American Academy of Addiction Psychiatry.)

Background: While most opioid use disorder (OUD) treatment providers consider opioid abstinence to be the preferred outcome, little is known about the treatment preferences of the larger population of individuals who engage in nonmedical opioid use and have not yet sought treatment. This study sought to descriptively quantify the proportion of out-of-treatment individuals with nonmedical opioid use that have abstinent and nonabstinent recovery goals., Methods: Participants (N = 235) who engage in nonmedical opioid use and met self-reported criteria for OUD were recruited online and participated in a cross-sectional survey on recovery goals and treatment perceptions. Participants were dichotomized as having either abstinent (70.6%) or nonabstinent (29.4%) recovery goals. Participants were presented with 13 treatment options and asked which treatment they would "try first" and which treatment they thought would be the best option for long-term recovery., Results: Persons in the nonabstinent group were more likely to want to continue use of prescription opioids as prescribed by a physician compared with the abstinent group (χ[1] = 9.71, P = 0.002). There were no group differences regarding preference for individual OUD treatments. The most frequently endorsed treatments that participants would "try first" were physician visits (23.4%), one-on-one counseling (18.7%), and 12-step groups (13.2%), whereas the most frequently endorsed treatments for long-term recovery were one-on-one counseling (17.4%), residential treatment (16.7%), and buprenorphine (15.3%)., Conclusion: Public health initiatives to engage out-of-treatment individuals should take into account recovery goals and treatment preferences to maximize treatment initiation and retention.

Methadone maintenance is an effective treatment for opioid use disorder, yet many methadone-maintained patients (MMPs) continue to struggle with chronic relapse. The current study evaluated whether functional near-infrared spectroscopy (fNIRS) could identify prefrontal cortex (PFC) markers of ongoing opioid use in MMPs, and whether clinical measures of depression and self-report measures of craving would also be associated with opioid use. MMPs (n = 29) underwent a drug cue reactivity paradigm during fNIRS measurements of PFC reactivity. Self-reported opioid craving (measured by a visual analog scale; 0-100) was collected before and after drug cue reactivity, and depressive symptoms were assessed via the 17-item Hamilton Depression Rating Scale (HAM-D). Hierarchical regression and partial correlations were used to evaluate associations between weekly urine drug screens over a 90-day follow-up period and fNIRS, craving, and HAM-D assessments. Neural response to drug cues in the left lateral PFC, controlling for age, sex, and days in treatment was significantly associated with percent opioid-negative urine screens during follow-up (∆F 1, 24  = 13.19, p = 0.001, ∆R 2  = 0.30), and correctly classified 86% of MMPs as either using opioids, or abstaining from opioids (χ 2 (4) = 16.28, p = 0.003). Baseline craving (p < 0.001) and HAM-D assessment (p < 0.01) were also associated with percent opioid-negative urine screens. Combining fNIRS results, baseline craving scores, and HAM-D scores created a robust predictive model (∆F 3, 22  = 16.75, p < 0.001, ∆R 2  = 0.59). These data provide preliminary evidence that the fNIRS technology may have value as an objective measure of treatment outcomes within outpatient methadone clinics. Depressive symptoms and drug craving were also correlated with opioid use in MMPs.

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.

Background: Older adults with opioid use disorder (OUD) are a medically complex population. The current study evaluated trends in older adults seeking treatment for OUD, with a focus on primary heroin versus prescription opioid use. This study also compared older adults with OUD to the younger OUD population on demographics and drug use behaviors., Methods: Publicly available data from state-certified addiction treatment centers were collected via the Treatment Episode Data Set - Admissions (TEDS-A) between 2004-2015. This study utilized Joinpoint Regression to conduct a cross-sectional, longitudinal analysis of trends in first-time treatment admissions for OUD in adults 55 and older (older adults; n = 400,421) versus adults under the age of 55 (n = 7,795,839). Given the rapid increase in older adults seeking treatment for OUD between 2013-2015, secondary outcomes include changes in demographics and drug use between 2012 (as a baseline year) and 2015., Results: The proportion of older adults seeking treatment for OUD rose steadily between 2004-2013 (41.2% increase; p-trend = 0.046), then rapidly between 2013-2015 (53.5% increase; p-trend = 0.009). The proportion of older adults with primary heroin use more than doubled between 2012-2015 (p < 0.001); these individuals were increasingly male (p < 0.001), African American (p < 0.001), and using via the intranasal route of administration (p < 0.001)., Conclusions: There has been a recent surge in older adults seeking treatment for OUD, particularly those with primary heroin use. Specialized treatment options for this population are critically needed, and capacity for tailored elder care OUD treatments will need to increase if these trends continue., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Methadone maintenance treatment (MMT) is an important treatment tool for the opioid epidemic. One challenge is that many persons who present for MMT also have co-occurring psychiatric disorders. Individually, both methadone and psychiatric medications carry risk of weight gain. Therefore, concurrent prescribing of methadone and psychiatric medications places dual diagnosis patients at even greater risk. As a parallel obesity epidemic grows, results from clinical trials assessing weight gain and weight management strategies among MMT and psychiatric patients can both inform and guide clinical practice. This study reviews findings from a literature search for recent clinical trials that focused on weight gain and weight management strategies during MMT with concurrent psychotropic medication use. While several studies have documented weight gain during MMT and psychotropic medication treatment, this study failed to identify recent work that explored concurrent prescribing. Most weight management strategies involved the use of additional medications and available data suggests that MMT and concurrent use of psychotropic medications increases the risk for obesity. More robust research is needed on weight gain and potential mitigation strategies when these treatment modalities are jointly utilized. Clarification of underlying biological mechanisms and development of non-pharmacological interventions merit further consideration.

Background: Relatively little is known regarding the perception of medication-assisted treatments (MATs) and other treatment options amongst individuals that engage in non-medical prescription opioid use. This study surveyed out-of-treatment individuals that misuse opioids to better understand how perceived access to treatment shapes treatment preference., Methods: Participants (n=357) were out-of-treatment adults registered as workers on the Amazon Mechanical Turk platform who reported current non-medical prescription opioid use. Participants were surveyed regarding demographics, insurance status, attitudes toward opioid use disorder (OUD) treatments, and self-reported symptoms of OUD., Results: Participants who were male, did not have health insurance, and knew that counseling-type services were locally available were most likely to first attempt counseling/detox treatments (χ2(6)=30.19, p<0.001). Participants who met criteria for severe OUD, used heroin in the last 30days, knew their insurance covered MAT, and knew of locally available MAT providers were most likely to first attempt MAT (χ2(4)=26.85, p<0.001). Participants with insurance and who knew of locally available physicians were most likely to attempt physician visits without the expressed purpose of MAT (χ2(3)=24.75, p<0.001)., Conclusion: Out-of-treatment opioid users were particularly interested in counseling-based services and medical care that could be attained from a primary-care physician. Results suggest that insurance coverage and perceived access to OUD treatment modalities influences where out-of-treatment opioid users might first seek treatment; understanding the factors that shape treatment preference is critical in designing early interventions to effectively reach this population., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background & Objective: Buprenorphine is an underutilized pharmacotherapy that can play a key role in combating the opioid epidemic. Individuals with opioid use disorder (OUD) often struggle to find physicians that prescribe buprenorphine. Many physicians do not have the waiver to prescribe buprenorphine, and a large proportion of physicians that are waivered do not prescribe to capacity. This study aimed to quantitatively understand why physicians do not utilize buprenorphine for the treatment of OUD more frequently., Methods: Physicians (n=558) with and without the waiver to prescribe buprenorphine were surveyed about perceived drawbacks associated with prescribing buprenorphine. Furthermore, resources were identified that would encourage those without the waiver to obtain it, and those with the waiver to accept more new patients. The survey was distributed online to physicians in the spring/summer of 2016 via the American Society for Addiction Medicine and American Medical Association listservs., Results and Conclusions: A logistic regression analysis was used to identify reasons that respondents indicated no willingness to increase prescribing (χ 2 (4)=73.18, p<0.001); main reasons were lack of belief in agonist treatment (OR 3.98, 95% CI, 1.43 to 11.1, p=0.008), lack of time for additional patients (OR 5.54, 95% CI, 3.5 to 8.7, p<0.001), and belief that reimbursement rates are insufficient (OR 2.50, 95% CI, 1.3 to 4.8, p=0.006). Differences between non-waivered and waivered physicians concerning attitudes toward buprenorphine treatment as well as resources that would increase willingness to prescribe are also discussed. Identifying barriers to buprenorphine utilization is crucial in expanding treatment options for individuals with OUD., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Low positive affect (PA) is likely to contribute to risk of relapse; however, it has received relatively little attention in clinical research. This study examined the associations among positive affect, negative affect (NA), and craving in medically withdrawn patients using ecological momentary assessment (EMA). Participants (n=73) provided reports of their PA, NA, and craving 4 times a day for an average of 10.47 (SD=3.80) days. Person- and day-level associations between PA, NA, and craving were examined using multilevel models. A significant interaction emerged between person- and day-level PA such that PA on the day level was negatively associated with craving for individuals experiencing low mean PA throughout the study. No significant interaction emerged between person- and day-level NA. The main effects for both person- and day-level NA were significant. Individuals experiencing high NA throughout the study experienced higher craving overall and on days when NA was higher than usual, craving was also higher. Results suggest that high person- and day-level NA may directly contribute to the risk for relapse via increased craving, whereas low day- level PA may contribute to risk for relapse among individuals exhibiting low person-level PA via increased craving on days with lower than average levels of PA for those individuals. Given that there is a paucity of research relating low PA to craving, continued investigation into how and when low PA creates risk for relapse is warranted., (Copyright © 2016 Elsevier Inc. All rights reserved.)

ObjectivesAcute pain management in patients with opioid use disorder who are maintained on methadone presents unique challenges due to high levels of opioid tolerance in this population. This randomized controlled study assessed the analgesic and abuse liability effects of escalating doses of acute intravenous (IV) hydromorphone versus placebo utilizing a validated experimental pain paradigm, quantitative sensory testing (QST).MethodsIndividuals (N = 8) without chronic pain were maintained on 80-100 mg/day of oral methadone. Participants received four IV, escalating/incremental doses of hydromorphone over 270 min (32 mg total) or four placebo doses within a session test day. Test sessions were scheduled at least one week apart. QST and abuse liability measures were administered at baseline and after each injection.ResultsNo significant differences between the hydromorphone and placebo control conditions on analgesic indices for any QST outcomes were detected. Similarly, no differences on safety or abuse liability indices were detected despite the high doses of hydromorphone utilized. Few adverse events were detected, and those reported were mild in severity.ConclusionsThe findings demonstrate that methadone-maintained individuals are highly insensitive to the analgesic effects of high-dose IV hydromorphone and may require very high doses of opioids, more efficacious opioids, or combined non-opioid analgesic strategies to achieve adequate analgesia.

Objective Individuals with chronic pain who misuse prescription opioids are at high risk for developing opioid use disorder and/or succumbing to opioid overdose. The current study conducted a survey to evaluate sex-based differences in pain catastrophizing, opioid withdrawal, and current pain in persons with co-occurring chronic pain and opioid misuse. We hypothesized that women with chronic pain who misused prescription opioids would self-report higher pain ratings compared with men and that the relationship between pain catastrophizing and self-reported current pain would be moderated by symptoms of opioid withdrawal in women only. Design Survey assessment of the relationship between pain and opioid misuse. Setting Online via Amazon Mechanical Turk. Participants Persons with ongoing chronic pain who also misused prescription opioids on one or more days in the last 30 days were eligible (N = 181). Methods Participants completed demographic and standardized assessments including the Brief Pain Inventory (BPI), Pain Catastrophizing Scale (PCS), and Subjective Opiate Withdrawal Scale (SOWS). Results Women reported higher levels of current (P