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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.

BackgroundUnderstanding 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.MethodNinety-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.ResultsBaseline 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.ConclusionsThis 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.

BackgroundOlder 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.MethodsPublicly 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.ResultsThe 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

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.

BackgroundOpioid use disorder (OUD) is a significant public health problem, and opioid maintenance treatment (OMT) on methadone or buprenorphine is a common approach. This study characterized sleep impairment in patients maintained on methadone or buprenorphine, and evaluated its association with psychiatric and medical comorbidities.MethodsParticipants (N=185) maintained on methadone (N=125) or buprenorphine (N=60) for OUD completed the Medical Outcomes Study Sleep Scale (MOS) to provide a point-prevalence assessment of sleep impairment. Measures of lifetime problems and current functioning were also examined and compared as both a function of OMT and level of sleep impairment.ResultsParticipants reported high levels of sleep impairment on the MOS, including not getting the amount of sleep they needed (42.9%), not sleeping enough to feel rested (39.6%) and trouble falling asleep (23.3%) or falling back asleep after waking (25.8%). Few differences were observed between OMT groups, and psychiatric dysfunction emerged as the most robust predictor of sleep impairment ratings. Patients with sleep impairment, independent of OMT medications, also reported current opioid withdrawal, psychiatric impairment, negative affect, and pain.ConclusionsResults demonstrate substantial and clinically-significant impairments in sleep that are associated with a variety of current problems that could impact OMT outcomes and decrease quality of life. Outcomes support the development of methods to improve sleep in OMT patients, and to examine the degree to which sleep improvements may be associated with improvements in mood and other health-related measures.

Background and aimsProbability 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.DesignThis cross-sectional on-line study determined state/trait associations with addiction-related medication decisions in CPP.SettingUS-based CPP participated via Amazon Mechanical Turk; data were collected and analyzed in Baltimore, Maryland.ParticipantsA total of 263 CPP (70.6% female) participated in the study from 12-13 December 2014.MeasurementsCPP 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.FindingsAcross 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 (

BackgroundRelatively 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.MethodsParticipants (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.ResultsParticipants 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

BackgroundOver 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.MethodsThis 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.ConclusionsThe 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.

ObjectivesAlcohol use disorders (AUDs) represent a large public health burden with relatively few efficacious pharmacotherapies. Randomized controlled trials (RCTs) for new AUD therapies can be hampered by ineffective recruitment, leading to increased trial costs. The current analyses examined the effectiveness of recruitment efforts during two consecutive outpatient RCTs of novel AUD pharmacotherapies conducted between 2009 and 2012.MethodsDuring an initial phone screen, participants identified an ad source for learning about the study. Qualified persons were then scheduled for in-person screens. The present analyses examined demographic differences amongst the eight ad sources utilized. Recruitment effectiveness was determined by dividing the number of persons meeting criteria for an in-person screen by the total number of callers from each ad source. Cost-effectiveness was determined by dividing total ad source cost by number of screens, participants randomized, and completers.Results1,813 calls resulted in 1,005 completed phone screens. The most common ad source was TV (34%), followed by print (29%), word-of-mouth (11%), flyer (8%), internet (5%), radio (5%), bus ad (2%), and billboard (1%). Participants reporting bus ads (46%), billboard (44%), or print ads (34%) were significantly more likely than the other sources to meet criteria to be scheduled for in-person screens. The most cost-effective ad source was print ($2,506 per completer), while bus ad was the least cost-effective ($13,376 per completer).ConclusionsRecruitment in AUD RCTs can be successful using diverse advertising methods. The present analyses favored use of print ads as most cost-effective.

BackgroundChronic pain is common among patients receiving opioid maintenance treatment (OMT) for opioid use disorder. To aid development of treatment recommendations for coexisting pain and opioid use disorder, it is necessary to characterize pain treatment needs and assess whether needs differ as a function of OMT medication.MethodsA point-prevalence survey assessing pain and engagement in coping strategies was administered to 179 methadone and buprenorphine-maintained patients.ResultsForty-two percent of participants were categorized as having chronic pain. Methadone patients had greater severity of pain relative to buprenorphine patients, though both groups reported high levels of interference with daily activities, and participants with pain attended the emergency room more frequently relative to participants without pain. Only 2 coping strategies were being utilized by more than 50% of participants (over-the-counter medication, prayer).ConclusionsResults indicate that pain among OMT patients is common, severe, and of significant impairment. Methadone patients reported greater severity pain, particularly worse pain in the past 24h, though interference from pain in daily activities did not vary as a function of OMT. Most participants with pain were utilizing few evidenced-based pain coping strategies. Increasing OMT patient access to additional pain treatment strategies is an opportunity for immediate intervention, and similarities across OMT type suggest interventions do not need to be customized to methadone vs. buprenorphine patients.

BackgroundDual dependence on opiate and cocaine occurs in about 60% of patients admitted to methadone maintenance and negatively impacts prognosis (Kosten et al. 2003. Drug Alcohol Depend. 70, 315). Topiramate (TOP) is an antiepileptic drug that may have utility in the treatment of cocaine dependence because it enhances the GABAergic system, antagonizes the glutamatergic system, and has been identified by NIDA as one of only a few medications providing a "positive signal" warranting further clinical investigation. (Vocci and Ling, 2005. Pharmacol. Ther. 108, 94).MethodIn this double-blind controlled clinical trial, cocaine dependent methadone maintenance patients (N=171) were randomly assigned to one of four groups. Under a factorial design, participants received either TOP or placebo, and monetary voucher incentives that were either contingent (CM) or non-contingent (Non-CM) on drug abstinence. TOP participants were inducted onto TOP over 7 weeks, stabilized for 8 weeks at 300 mg daily then tapered over 3 weeks. Voucher incentives were supplied for 12 weeks, starting during the fourth week of TOP induction. Primary outcome measures were cocaine abstinence (Y/N) as measured by thrice weekly urinalysis and analyzed using Generalized Estimating Equations (GEE) and treatment retention. All analyses were intent to treat and included the 12-week evaluation phase of combined TOP/P treatment and voucher intervention period.ResultsThere was no significant difference in cocaine abstinence between the TOP vs. P conditions nor between the CM vs. Non-CM conditions. There was no significant TOP/CM interaction. Retention was not significantly different between the groups.ConclusionTopiramate is not efficacious for increasing cocaine abstinence in methadone patients.

AimsWe evaluated the immunogenicity, efficacy, and safety of succinylnorcocaine conjugated to cholera toxin B protein as a vaccine for cocaine dependence.MethodsThis 6-site, 24 week Phase III randomized double-blind placebo-controlled trial assessed efficacy during weeks 8 to 16. We measured urine cocaine metabolites thrice weekly as the main outcome.ResultsThe 300 subjects (76% male, 72% African-American, mean age 46 years) had smoked cocaine on average for 13 days monthly at baseline. We hypothesized that retention might be better and positive urines lower for subjects with anti-cocaine IgG levels of ≥42 μg/mL (high IgG), which was attained by 67% of the 130 vaccine subjects receiving five vaccinations. Almost 3-times fewer high than low IgG subjects dropped out (7% vs 20%). Although for the full 16 weeks cocaine positive urine rates showed no significant difference between the three groups (placebo, high, low IgG), after week 8, more vaccinated than placebo subjects attained abstinence for at least two weeks of the trial (24% vs 18%), and the high IgG group had the most cocaine-free urines for the last 2 weeks of treatment (OR=3.02), but neither were significant. Injection site reactions of induration and tenderness differed between placebo and active vaccine, and the 29 serious adverse events did not lead to treatment related withdrawals, or deaths.ConclusionsThe vaccine was safe, but it only partially replicated the efficacy found in the previous study based on retention and attaining abstinence.

BackgroundAbuse liability assessments influence drug development, federal regulation, and clinical care. One suggested procedure to reduce variability of assessments is a qualification phase, which assesses whether study applicants adequately distinguish active drug from placebo; applicants failing to make this distinction are disqualified. The present analyses assessed differences between qualification phase qualifiers and non-qualifiers.MethodsData were collected from 23 completers of the qualification phase of an abuse liability study. Opioid abusing participants received 30 mg oxycodone and placebo orally on separate days, and were characterized as qualifiers (vs. non-qualifiers) if their peak visual analog scale liking rating for oxycodone was at least 20 points higher than placebo's peak rating. Groups were compared on demographic characteristics, drug history, and physiologic, subject and observer ratings.Results61% of participants were qualifiers and 39% were non-qualifiers. Groups had similar demographic characteristics, drug use histories, and pupillary constriction responses. However, unlike qualifiers, non-qualifiers had an exaggerated placebo response for the liking score (p=0.03) and an attenuated oxycodone response for the liking score (p

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Opioid therapy for pain is associated with an increased risk for substance use disorders. This study's purpose was to determine the association between opioid misuse propensity (Screener and Opioid Assessment for Patients in Pain-Revised) and delay discounting (DD), a behavioral process linked to substance use disorders, which quantifies the extent to which outcomes are devalued because of their delay. Participants reporting chronic pain (N = 249) answered pain and opioid use questions and then completed 4 DD tasks. Each of these tasks assessed either money or pain consequences, framed as either rewards or punishments. Each task involved hypothetical choices between immediate smaller vs delayed larger consequences. The extant Monetary Choice Questionnaire assessed DD of money rewards, and a modified version assessed discounting of money losses (immediate smaller loss vs larger delayed loss). Based on the Monetary Choice Questionnaire, the novel Pain Relief Choice Questionnaire assessed choices between an immediate short duration of pain relief vs a longer duration of pain relief. Similarly, the novel Additional Pain Choice Questionnaire assessed choices between an immediate short duration of additional pain vs a longer duration of additional pain. Discounting of both additional pain and money losses were significantly associated with high Screener and Opioid Assessment for Patients in Pain-Revised scores-indicating participants at greatest risk for opioid misuse discount future punishments rather than future rewards compared with those at low risk. Measures of DD may have promise in more accurately identifying individuals at highest risk for opioid misuse during chronic opioid therapy. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. • Sleep disturbance is commonly reported among individuals with cannabis use disorder. • This RCT evaluated extended-release zolpidem for cannabis-related sleep disturbance. • Zolpidem-XR attenuated sleep disturbance but sleep problems re-emerged at EoT. • Zolpidem-XR resulted in non-significant improvement in cannabis abstinence relative to placebo. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]