Randomized controlled trial of zolpidem as a pharmacotherapy for cannabis use disorder.

BACKGROUND: Sleep disturbance is commonly reported among individuals meeting criteria for cannabis use disorder (CUD), and people who use cannabis frequently report sleep disturbance as a contributor to failed quit attempts. The purpose of this study was to measure sleep in individuals enrolled in treatment for CUD, and to determine whether use of hypnotic medication during treatment increased abstinence rates. METHOD: The study enrolled 127 adults seeking treatment for CUD in a 12-week clinical trial and randomized to receive extended-release zolpidem (zolpidem-XR) or placebo. All participants received computerized behavioral therapy and abstinence-based contingency management. The study conducted in-home ambulatory polysomnography (PSG) assessments at baseline and during treatment to objectively measure sleep. Self-report measures of recent sleep, Insomnia Severity Index (ISI), and drug use (Timeline Follow-Back) were collected at each study visit, and the study confirmed self-reported abstinence via quantitative urine drug testing. RESULT: Participants randomized to placebo, but not zolpidem-XR exhibited significant sleep disturbance during week 1 of treatment. Sleep disturbance emerged in the zolpidem-XR group after study medication was stopped at the end of treatment. Though participants assigned to the zolpidem-XR condition had qualitatively greater rates of abstinence compared with placebo (27 % versus 15 % negative at end of treatment), the difference was not statistically significant. Treatment retention was poor (about 50 % drop out in both groups) and medication adherence was a challenge without the use of contingent incentives. CONCLUSION: Results from this randomized controlled trial suggest that zolpidem-XR can attenuate abstinence-induced sleep disturbance early in treatment for CUD, but that sleep problems are likely to emerge after the medication is stopped. Further research should identify alternative pharmacotherapies and behavioral treatments for CUD and elucidate the role of sleep disturbance in the development and maintenance of CUD.

Substance Use in the Performing Artist with Chronic Pain.

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.

"I got a bunch of weed to help me through the withdrawals": Naturalistic cannabis use reported in online opioid and opioid recovery community discussion forums.

A growing body of research has reported on the potential opioid-sparing effects of cannabis and cannabinoids, but less is known about specific mechanisms. The present research examines cannabis-related posts in two large online communities on the Reddit platform ("subreddits") to compare mentions of naturalistic cannabis use by persons self-identifying as actively using opioids versus persons in recovery. We extracted all posts mentioning cannabis-related keywords (e.g., "weed", "cannabis", "marijuana") from December 2015 through August 2019 from an opioid use subreddit and an opioid recovery subreddit. To investigate how cannabis is discussed at-scale, we identified and compared the most frequent phrases in cannabis-related posts in each subreddit using term-frequency-inverse document frequency (TF-IDF) weighting. To contextualize these findings, we also conducted a qualitative content analysis of 200 random posts (100 from each subreddit). Cannabis-related posts were about twice as prevalent in the recovery subreddit (n = 908; 5.4% of 16,791 posts) than in the active opioid use subreddit (n = 4,224; 2.6% of 159,994 posts, p < .001). The most frequent phrases from the recovery subreddit referred to time without using opioids and the possibility of using cannabis as a "treatment." The most frequent phrases from the opioid subreddit referred to concurrent use of cannabis and opioids. The most common motivations for using cannabis were to manage opioid withdrawal symptoms in the recovery subreddit, often in conjunction with anti-anxiety and GI-distress "comfort meds," and to enhance the "high" when used in combination with opioids in the opioid subreddit. Despite limitations in generalizability from pseudonymous online posts, this examination of reports of naturalistic cannabis use in relation to opioid use identified withdrawal symptom management as a common motivation. Future research is warranted with more structured assessments that examines the role of cannabis and cannabinoids in addressing both somatic and affective symptoms of opioid withdrawal.

National trends in testing for hepatitis C virus in licensed opioid treatment programs: Differences by facility ownership and state medicaid expansion status.

BACKGROUND: The recent surge in hepatitis C virus (HCV) prevalence is primarily due to increased injection drug use. Opioid treatment programs (OTPs) are a major source of treatment for people at risk for HCV and are ideal settings for on-site HCV testing. The purpose of this national study was to identify state- and facility-level factors associated with HCV testing availability. METHODS: We used the National Survey of Substance Abuse Treatment Services (2019) to identify OTPs in the US (n = 1679). We used multilevel logistic regression to test for an association between HCV testing and state Medicaid expansion status, and assessed whether the association depended on private or non-profit OTP ownership, adjusted for state racial/ethnic minority populations, poverty, Medicaid access to HCV treatment, and HCV, opioid use disorder, and overdose rates. RESULTS: Two-thirds of OTPs offered HCV testing. Medicaid expansion (versus non-expansion) was associated with a higher odds of HCV testing within OTPs owned by non-profits (adjusted odds ratio=1.99, 95% CI=1.02-3.91, p = 0.04). Nearly all non-profit OTPs that were in expansion states had predicted probabilities that were higher than the national average. CONCLUSION: HCV testing was highest in non-profit OTPs in expansion states. This is concerning given the increasing dominance of private OTPs in the marketplace. Payment structures and reimbursement are likely factors driving the low rate of HCV testing in private facilities and could be addressed with health policies aimed at eliminating HCV. Expanding support for non-profit OTPs also has the potential to strengthen testing rates and improve health.

Methadone maintenance patients lack analgesic response to a cumulative intravenous dose of 32 mg of hydromorphone.

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.

The relationship between pupil diameter and other measures of opioid withdrawal during naloxone precipitated withdrawal.

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.

Individuals with Chronic Pain Who Misuse Prescription Opioids Report Sex-Based Differences in Pain and Opioid Withdrawal.

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 < 0.001), average (P < 0.001), and worst (P = .002) pain in the last 24 hours compared with men. Women also endorsed higher scores on the PCS (P = 0.006) and marginally higher past-30-day SOWS ratings (P = 0.068) compared with men. SOWS ratings moderated the relationship between PCS and BPI Worst Pain in women (ΔR2 < 0.127, ΔF(1, 78) = 12.39, P = 0.001), but not in men (ΔR2 < 0.000, ΔF(1, 98) = 0.003, P = 0.954). Conclusions These data suggest a strong relationship between opioid withdrawal, pain catastrophizing, and the experience of pain in women with chronic pain who misuse opioids.

Prefrontal cortex response to drug cues, craving, and current depressive symptoms are associated with treatment outcomes in methadone-maintained patients.

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 (∆F1, 24 = 13.19, p = 0.001, ∆R2 = 0.30), and correctly classified 86% of MMPs as either using opioids, or abstaining from opioids (χ2(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 (∆F3, 22 = 16.75, p < 0.001, ∆R2 = 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.

Sex differences in measures of central sensitization and pain sensitivity to experimental sleep disruption: implications for sex differences in chronic pain.

Study Objectives: Females demonstrate heightened central sensitization (CS), a risk factor for chronic pain characterized by enhanced responsivity of central nervous system nociceptors to normal or subthreshold input. Sleep disruption increases pain sensitivity, but sex has rarely been evaluated as a moderator and few experiments have measured CS. We evaluated whether two nights of sleep disruption alter CS measures of secondary hyperalgesia and mechanical temporal summation in a sex-dependent manner. We also evaluated differences in measures of pain sensitivity. Methods: Seventy-nine healthy adults (female n = 46) participated in a randomized crossover experiment comparing two consecutive nights of eight pseudorandomly distributed forced awakenings (FA [-200 min sleep time]) against two nights of undisturbed sleep (US). We conducted sensory testing the mornings following Night 2; the heat-capsaicin pain model was used to induce secondary hyperalgesia. Results: FA reduced total sleep time (REM and NREM Stage 3) more profoundly in males. We observed divergent, sex-dependent effects of FA on secondary hyperalgesia and temporal summation. FA significantly increased secondary hyperalgesia in males and significantly increased temporal summation in females. Sex differences were not attributable to differential sleep loss in males. FA also significantly reduced heat-pain threshold and cold pressor pain tolerance, independently of sex. Conclusions: Sleep disruption enhances different pain facilitatory measures of CS in males and females suggesting that sleep disturbance may increase risk for chronic pain in males and females via distinct pathways. Findings have implications for understanding sex differences in chronic pain and investigating sleep in chronic pain prevention efforts.

Analgesic Effects of Hydromorphone versus Buprenorphine in Buprenorphine-maintained Individuals.

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.

A hidden aspect of the U.S. opioid crisis: Rise in first-time treatment admissions for older adults with opioid use disorder.

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.

Outpatient transition to extended-release injectable naltrexone for patients with opioid use disorder: A phase 3 randomized trial.

BACKGROUND: Injectable extended-release naltrexone (XR-NTX), approved to prevent relapse to opioid dependence, requires initial abstinence. This multisite outpatient clinical trial examined the efficacy and safety of low-dose oral naltrexone (NTX), combined with a brief buprenorphine (BUP) taper and standing ancillary medications, for detoxification and induction onto XR-NTX. METHODS: Patients (N = 378) were randomized, stratified by primary short-acting opioid-of-use, to one of three regimens: NTX + BUP; NTX + placebo BUP (PBO-B); placebo NTX (PBO-N) + PBO-B. Patients received 7 days of ascending NTX or placebo, concurrent with a 3-day BUP or placebo taper, and ancillary medications in an outpatient setting. Daily psychoeducational counseling was provided. On Day 8, patients passing a naloxone challenge received XR-NTX. RESULTS: Rates of transition to XR-NTX were comparable across groups: NTX/BUP (46.0%) vs. NTX/PBO-B (40.5%) vs. PBO-N/PBO-B (46.0%). Thus, the study did not meet its primary endpoint. Adverse events, reported by 32.5% of all patients, were mild to moderate in severity and consistent with opioid withdrawal. A first, second, and third XR-NTX injection was received by 44.4%, 29.9%, and 22.5% of patients, respectively. Compared with the PBO-N/PBO-B group, the NTX/BUP group demonstrated higher opioid abstinence during the transition and lower post-XR-NTX subjective opioid withdrawal scores. CONCLUSIONS: A 7-day detoxification protocol with NTX alone or NTX + BUP provided similar rates of induction to XR-NTX as placebo. For those inducted onto XR-NTX, management of opioid withdrawal symptoms prior to induction was achieved in a structured outpatient setting using a well-tolerated, fixed-dose ancillary medication regimen common to all three groups.

Extended-release injectable naltrexone for opioid use disorder: a systematic review.

AIMS: To review systematically the published literature on extended-release naltrexone (XR-NTX, Vivitrol® ), marketed as a once-per-month injection product to treat opioid use disorder. We addressed the following questions: (1) how successful is induction on XR-NTX; (2) what are adherence rates to XR-NTX; and (3) does XR-NTX decrease opioid use? Factors associated with these outcomes as well as overdose rates were examined. METHODS: We searched PubMed and used Google Scholar for forward citation searches of peer-reviewed papers from January 2006 to June 2017. Studies that included individuals seeking treatment for opioid use disorder who were offered XR-NTX were included. RESULTS: We identified and included 34 studies. Pooled estimates showed that XR-NTX induction success was lower in studies that included individuals that required opioid detoxification [62.6%, 95% confidence interval (CI) = 54.5-70.0%] compared with studies that included individuals already detoxified from opioids (85.0%, 95% CI = 78.0-90.1%); 44.2% (95% CI = 33.1-55.9%) of individuals took all scheduled injections of XR-NTX, which were usually six or fewer. Adherence was higher in prospective investigational studies (i.e. studies conducted in a research context according to a study protocol) compared to retrospective studies of medical records taken from routine care (6-month rates: 46.7%, 95% CI = 34.5-59.2% versus 10.5%, 95% CI = 4.6-22.4%, respectively). Compared with referral to treatment, XR-NTX reduced opioid use in adults under criminal justice supervision and when administered to inmates before release. XR-NTX reduced opioid use compared with placebo in Russian adults, but this effect was confounded by differential retention between study groups. XR-NTX showed similar efficacy to buprenorphine when randomization occurred after detoxification, but was inferior to buprenorphine when randomization occurred prior to detoxification. CONCLUSIONS: Many individuals intending to start extended-release naltrexone (XR-NTX) do not and most who do start XR-NTX discontinue treatment prematurely, two factors that limit its clinical utility significantly. XR-NTX appears to decrease opioid use but there are few experimental demonstrations of this effect.

To take or not to take: the association between perceived addiction risk, expected analgesic response and likelihood of trying novel pain relievers in self-identified chronic pain patients.

BACKGROUND AND AIMS: Probability discounting refers to the effect of outcome uncertainty on decision making. Using probability discounting, we examined the degree to which self-identified chronic pain patients (CPP) were likely to try a novel analgesic medication given increasing addiction risk. We postulated that propensity for opioid misuse, trait impulsivity and previous opioid experience would be associated positively with likelihood of risky medication use. DESIGN: This cross-sectional on-line study determined state/trait associations with addiction-related medication decisions in CPP. SETTING: US-based CPP participated via Amazon Mechanical Turk; data were collected and analyzed in Baltimore, Maryland. PARTICIPANTS: A total of 263 CPP (70.6% female) participated in the study from 12-13 December 2014. MEASUREMENTS: CPP responded to the Benefit versus Addiction Risk Questionnaire (BARQ) assessing likelihood of taking a hypothetical once-daily oral analgesic medication as a function of two factors: risk of addiction (0-50%) and duration of expected complete pain relief (3, 30 or 365 days). The primary outcome was the BARQ, quantified as area under the curve (AUC). Grouping of CPP at high or low risk for opioid misuse was based on the Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R). Predictors included previous experience with opioids, as well as various measures of chronic pain and mental health. FINDINGS: Across hypothetical addiction risk assessed in the BARQ, the likelihood of taking a novel analgesic medication was elevated significantly in patients with high (≥18; n = 137) versus low (<18; n = 126) SOAPP-R scores [P < 0.001; 3-day: Cohen's d = 0.66, 95% confidence interval (CI) = 0.63, 0.69; 30-day: d = 0.74, 95% CI = 0.71, 0.78; 365-day: d = 0.75, 95% CI = 0.72, 0.79]. CONCLUSIONS: In the United States, self-identified chronic pain patients (CPP) at higher risk for opioid misuse were more likely to report willingness to try a novel analgesic despite increasing addiction risk than CPP with low risk of opioid misuse.

The relationship between treatment accessibility and preference amongst out-of-treatment individuals who engage in non-medical prescription opioid use.

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.

Efficacy of Tramadol Extended-Release for Opioid Withdrawal: A Randomized Clinical Trial.

Importance: Opioid use disorder (OUD) is a significant public health problem. Supervised withdrawal (ie, detoxification) from opioids using clonidine or buprenorphine hydrochloride is a widely used treatment. Objective: To evaluate whether tramadol hydrochloride extended-release (ER), an approved analgesic with opioid and nonopioid mechanisms of action and low abuse potential, is effective for use in supervised withdrawal settings. Design, Setting, and Participants: A randomized clinical trial was conducted in a residential research setting with 103 participants with OUD. Participants' treatment was stabilized with morphine, 30 mg, administered subcutaneously 4 times daily. A 7-day taper using clonidine (n = 36), tramadol ER (n = 36), or buprenorphine (n = 31) was then instituted, and patients were crossed-over to double-blind placebo during a post-taper period. The study was conducted from October 25, 2010, to June 23, 2015. Main Outcomes and Measures: Retention, withdrawal symptom management, concomitant medication utilization, and naltrexone induction. Results were analyzed over time and using area under the curve for the intention-to-treat and completer groups. Results: Of the 103 participants, 88 (85.4%) were men and 43 (41.7%) were white; mean (SD) age was 28.9 (10.4) years. Buprenorphine participants (28 [90.3%]) were significantly more likely to be retained at the end of the taper compared with clonidine participants (22 [61.1%]); tramadol ER retention was intermediate and did not differ significantly from that of the other groups (26 [72.2%]; χ2 = 8.5, P = .01). Time-course analyses of withdrawal revealed significant effects of phase (taper, post taper) for the Clinical Opiate Withdrawal Scale (COWS) score (taper mean, 5.19 [SE, .26]; post-taper mean, 3.97 [SE, .23]; F2,170 = 3.6, P = .03) and Subjective Opiate Withdrawal Scale (SOWS) score (taper mean,8.81 [SE, .40]; post-taper mean, 4.14 [SE, .30]; F2,170 = 15.7, P < .001), but no group effects or group × phase interactions. Analyses of area under the curve of SOWS total scores showed significant reductions (F2,159 = 17.7, P < .001) in withdrawal severity between the taper and post-taper periods for clonidine (taper mean, 13.1; post-taper mean, 3.2; P < .001) and tramadol ER (taper mean, 7.4; post-taper mean, 2.8; P = .03), but not buprenorphine (taper mean, 6.4; post-taper mean, 7.4). Use of concomitant medication increased significantly (F2,159 = 30.7, P < .001) from stabilization to taper in the clonidine (stabilization mean, 0.64 [SE, .05]; taper mean, 1.54 [SE, .10]; P < .001) and tramadol ER (stabilization mean, 0.53 [SE, .05]; taper mean, 1.19 [SE, .09]; P = .003) groups and from stabilization to post taper in the buprenorphine group (stabilization mean, 0.46 [SE, .05] post-taper mean, 1.17 [SE, .09]; P = .006), suggesting higher withdrawal for those groups during those periods. Naltrexone initiation was voluntary and the percentage of participants choosing naltrexone therapy within the clonidine (8 [22.2%]), tramadol ER (7 [19.4%]), or buprenorphine (3 [9.7%]) groups did not differ significantly (χ2 = 2.5, P = .29). Conclusions and Relevance: The results of this trial suggest that tramadol ER is more effective than clonidine and comparable to buprenorphine in reducing opioid withdrawal symptoms during a residential tapering program. Data support further examination of tramadol ER as a method to manage opioid withdrawal symptoms. Trial Registration: Clinicaltrials.gov Identifier: NCT01188421.

Providing chronic pain management in the "Fifth Vital Sign" Era: Historical and treatment perspectives on a modern-day medical dilemma.

BACKGROUND: Over 100 million Americans are living with chronic pain, and pain is the most common reason that patients seek medical attention. Despite the prevalence of pain, the practice of pain management and the scientific discipline of pain research are relatively new fields compared to the rest of medicine - contributing to a twenty-first century dilemma for health care providers asked to relieve suffering in the "Fifth Vital Sign" era. METHODS: This manuscript provides a narrative review of the basic mechanisms of chronic pain and history of chronic pain management in the United States - including the various regulatory, health system and provider factors that contributed to the decline of multidisciplinary pain treatment in favor of the predominant opioid treatment strategy seen today. Multiple non-opioid pain treatment strategies are then outlined. The manuscript concludes with three key questions to help guide future research at the intersection of pain and addiction. CONCLUSIONS: The assessment and treatment of chronic pain will continue to be one of the most common functions of a health care provider. To move beyond an over reliance on opioid medications, the addiction and pain research communities must unite with chronic pain patients to increase the evidence base supporting non-opioid analgesic strategies.