Co-administration of nalbuphine attenuates the morphine-induced anxiety and dopaminergic alterations in morphine-withdrawn rats.

INTRODUCTION: The classical effects of exogenous opioids, such as morphine, are predominantly mediated through µ-opioid receptors. The chronic use of morphine induces anxiety-like behavior causing functional changes in the mesolimbic dopaminergic system. The mixed µ/κ-agonist, nalbuphine, used either as an analgesic or as an adjuvant with morphine, produces different and opposite effects. However, whether nalbuphine can be used to antagonize morphine-induced anxiety and dopaminergic alterations is not fully known. OBJECTIVE: This study aimed to compare acute and chronic effects of nalbuphine on morphine-induced anxiety and dopaminergic alterations in rats. METHODS: Male adult Wistar albino rats were made opioid-dependent by administering increasing doses of morphine (5-25 mg/kg; i.p.; b.i.d.). Withdrawal was induced by naloxone (1 mg/kg, i.p.), 4 h after the last morphine injection. Anxiety-like behavior was measured using Activity Monitor (Coulbourn Instruments, Inc. USA). Thereafter, the animals were sacrificed and the brain dissected out and the level of cAMP and the transcriptional and translational expression of TH was measured. Nalbuphine was co-administered with morphine, acutely and chronically, at various doses (0.1, 0.3, 1.0, 3.0 mg/kg, i.p.). RESULTS: Morphine-dependent rats showed a significant higher anxiety and cAMP levels and a significant decrease in the expression of TH. Co-administration of chronic doses of nalbuphine attenuates the higher anxiety, cAMP levels, and upregulates the TH expressions; however, the acute nalbuphine treatment does not attenuate the morphine-induced side effects. CONCLUSION: Therefore, nalbuphine might have an important role in attenuating the anxiety and the effects of the dopaminergic pathway and may have potential in the treatment of opioid addiction.

ERK-Directed Phosphorylation of mGlu5 Gates Methamphetamine Reward and Reinforcement in Mouse.

Methamphetamine (MA) is a highly addictive psychomotor stimulant drug. In recent years, MA use has increased exponentially on a global scale, with the number of MA-involved deaths reaching epidemic proportions. There is no approved pharmacotherapy for treating MA use disorder, and we know relatively little regarding the neurobiological determinants of vulnerability to this disease. Extracellular signal-regulated kinase (ERK) is an important signaling molecule implicated in the long-lasting neuroadaptations purported to underlie the development of substance use disorders, but the role for this kinase in the propensity to develop addiction, particularly MA use disorder, is uncharacterized. In a previous MA-induced place-conditioning study of C57BL/6J mice, we characterized mice as MA-preferring, -neutral, or -avoiding and collected tissue from the medial prefrontal cortex (mPFC). Using immunoblotting, we determined that elevated phosphorylated ERK expression within the medial prefrontal cortex (mPFC) is a biochemical correlate of the affective valence of MA in a population of C57BL/6J mice. We confirmed the functional relevance for mPFC ERK activation for MA-induced place-preference via site-directed infusion of the MEK inhibitor U0126. By contrast, ERK inhibition did not have any effect upon MA-induced locomotion or its sensitization upon repeated MA treatment. Through studies of transgenic mice with alanine point mutations on T1123/S1126 of mGlu5 that disrupt ERK-dependent phosphorylation of the receptor, we discovered that ERK-dependent mGlu5 phosphorylation normally suppresses MA-induced conditioned place-preference (MA-CPP), but is necessary for this drug's reinforcing properties. If relevant to humans, the present results implicate individual differences in the capacity of MA-associated cues/contexts to hyper-activate ERK signaling within mPFC in MA Use Disorder vulnerability and pose mGlu5 as one ERK-directed target contributing to the propensity to seek out and take MA.

Opioid use patterns and risk characteristics among injured patients.

Background: Injured patients are at risk for prolonged opioid use after discharge from care. Limited evidence exists regarding how continued opioid use may be related to opioid medication misuse and opioid use disorder (OUD) following injury. This pilot study characterized opioid consumption patterns, health characteristics, and substance use among patients with active prescriptions for opioid medications following injury care. Methods: This study was a cross-sectional screening survey combined with medical record review from February 2017 to March 2018 conducted among outpatient trauma and orthopedic surgery clinic patients. Eligible patients were 18-64 years of age, admitted/discharged for an injury or trauma-related orthopedic surgery, returning for clinic follow-up ≤6 months post hospital discharge after the index injury, prescribed opioid pain medication at discharge, and currently taking an opioid medication (from discharge or a separate prescription post discharge). Data collected included demographic, substance use, mental health, and physical health information. Descriptive and univariate statistics were calculated to characterize the population and opioid-related risks. Results: Seventy-one participants completed the survey (92% response). Most individuals (≥75%) who screened positive for misuse or OUD reported no nonmedical/illicit opioid use in the year before the index injury. A positive depression screen was associated with a 3.88 times increased likelihood for misuse or OUD (95% confidence interval [CI] = 1.1-13.5). Nonopioid illicit drug use (odds ratio [OR] = 1.89, 95% CI = 1.1-3.4) and opioid craving (OR = 1.29, 95% CI = 1.1-1.5) were also associated with increased likelihood for misuse or OUD. Number of emergency department visits in the 3 years previous to the index injury was associated with a 22% likelihood of being misuse or OUD positive (95% CI = 1.0-1.5). Conclusions: Patients with behavioral health concerns and greater emergency department utilization may have heightened risk for experiencing adverse opioid-related outcomes. Future research must further establish these findings and possibly develop protocols to identify patients at risk prior to pain management planning.

Pain catastrophizing and pain acceptance are associated with pain severity and interference among methadone-maintained patients.

OBJECTIVE: The present study examined whether pain catastrophizing and pain acceptance, two important targets of psychosocial interventions for chronic pain, are uniquely associated with pain severity and pain interference among patients on methadone maintenance treatment (MMT). METHOD: A total of 133 MMT patients who reported experiencing some pain during the previous week completed a battery of self-report measures. Multiple regression was used to test whether pain catastrophizing and pain acceptance are related to pain severity and pain interference above and beyond covariates including demographics, emotional distress, and current methadone dose. RESULTS: Both pain acceptance and catastrophizing were significantly associated with pain severity and pain interference while controlling for covariates. CONCLUSIONS: Consistent with previous literature on patients with chronic pain but without opioid use disorder, our findings suggest that both pain catastrophizing and pain acceptance are potentially important intervention targets among MMT patients with co-occurring opioid use disorder and chronic pain.

Patient Patterns and Perspectives on Using Opioid Regimens for Chronic Cancer Pain.

CONTEXT: With increasing attention to the undertreatment of cancer pain in parallel with concerns about opioid misuse, little is known about how patients with advanced cancer adhere to opioid regimens for chronic cancer pain. OBJECTIVES: We explored patient approaches to managing chronic cancer pain with long-acting opioids. METHODS: In a multimethods study at an academic medical center, adult patients with chronic cancer pain (n = 17) used electronic pill caps to record adherence to prescribed long-acting opioid regimens. After eight weeks, patients viewed their adherence records and completed a semistructured interview about their opioid use. With a framework approach, we coded interview data (Kappa >0.95) and identified themes in how patients perceived and used opioids to manage cancer pain. RESULTS: Patients (59% female; 94% non-Hispanic white; median age = 65 years) felt grateful about pain benefit from opioids yet concerned about opioid side effects and addiction/tolerance. Main reasons for nonadherence included both intentional decisions (e.g., skipping doses) and unintentional barriers (e.g., missing doses due to inconsistent sleep schedules). Overall, patients set their own opioid adherence goals and developed routines to achieve them. Residual pain varied and was not consistently linked with opioid adherence. CONCLUSION: Patients commonly felt conflicted about using prescribed long-acting opioids to manage cancer pain due to concurrent perceptions of their risks and benefits, and they set their own parameters for opioid-taking practices. Intentional and unintentional deviations from prescribed opioid schedules highlight the need to enhance adherence communication, education, and counseling, to optimize the use of long-acting opioids as a component of cancer pain management.

Perspectives on rapid fentanyl test strips as a harm reduction practice among young adults who use drugs: a qualitative study.

BACKGROUND: In 2016, drug overdose deaths exceeded 64,000 in the United States, driven by a sixfold increase in deaths attributable to illicitly manufactured fentanyl. Rapid fentanyl test strips (FTS), used to detect fentanyl in illicit drugs, may help inform people who use drugs about their risk of fentanyl exposure prior to consumption. This qualitative study assessed perceptions of FTS among young adults. METHODS: From May to September 2017, we recruited a convenience sample of 93 young adults in Rhode Island (age 18-35 years) with self-reported drug use in the past 30 days to participate in a pilot study aimed at better understanding perspectives of using take-home FTS for personal use. Participants completed a baseline quantitative survey, then completed a training to learn how to use the FTS. Participants then received ten FTS for personal use and were asked to return 2-4 weeks later to complete a brief quantitative and structured qualitative interview. Interviews were transcribed, coded, and double coded in NVivo (Version 11). RESULTS: Of the 81 (87%) participants who returned for follow-up, the majority (n = 62, 77%) used at least one FTS, and of those, a majority found them to be useful and straightforward to use. Positive FTS results led some participants to alter their drug use behaviors, including discarding their drug supply, using with someone else, and keeping naloxone nearby. Participants also reported giving FTS to friends who they felt were at high risk for fentanyl exposure. CONCLUSION: These findings provide important perspectives on the use of FTS among young adults who use drugs. Given the high level of acceptability and behavioral changes reported by study participants, FTS may be a useful harm reduction intervention to reduce fentanyl overdose risk among this population. TRIAL REGISTRATION: The study protocol is registered with the US National Library of Medicine, Identifier NCT03373825, 12/24/2017, registered retrospectively. https://clinicaltrials.gov/ct2/show/NCT03373825?id=NCT03373825&rank=1.