Enantiomeric contributions to methamphetamine's bidirectional effects on basal and fentanyl-depressed respiration in mice.

RATIONALE: Fentanyl remains the primary cause of fatal overdoses, and its co-use with methamphetamine (METH) is a growing concern. We previously demonstrated that racemic METH can either enhance or mitigate opioid-induced respiratory depression (OIRD) dependent upon whether a low or high dose is administered. The optical isomers of METH, dextromethamphetamine (d-METH) and levomethamphetamine (l-METH), differ substantially in their selectivity and potency to activate various monoamine (MA) receptors, and these pharmacological differences may underlie the bidirectional effects of the racemate. Since it is unknown which of METH's MA receptor mechanisms mediate these respiratory effects, examination of METH's pharmacologically distinct enantiomers may provide insight into treatment targets for OIRD. METHODS: The two optical isomers of METH, d-METH and l-METH, were tested in adult male mice to determine their effects on basal and fentanyl-depressed respiratory frequency, tidal volume, and minute ventilation (MVb; i.e., respiratory frequency x tidal volume) using whole-body plethysmography. RESULTS: When tested at dose ranges of 1.0-10 mg/kg, d-METH elevated MVb and l-METH decreased basal MVb. A dose of 30 mg/kg l-METH increased basal MVb. Under fentanyl-depressed conditions, the bidirectional effects of racemic METH were observed with d-METH treatment while l-METH significantly exacerbated OIRD at 1.0 and 3.0 mg/kg. CONCLUSIONS: d-METH and l-METH differentially contribute to the bidirectional respiratory modulation observed by the racemate, with d-METH exhibiting predominantly stimulatory effects and l-METH exhibiting primarily depressant effects depending on dose.

Theophylline reverses oxycodone's but not fentanyl's respiratory depression in mice while caffeine is ineffective against both opioids.

RATIONALE: The opioid epidemic remains a pressing public health crisis in the United States. Most of these overdose deaths are a result of lethal respiratory depression. In recent years the increasing incidence of opioid-involved overdose deaths has been driven by fentanyl, which is more resistant to adequate reversal by naloxone (NARCAN ®) than semi-synthetic or classical morphinan predecessors like oxycodone and heroin. For this and other reasons (e.g., precipitating withdrawal) non-opioidergic pharmacotherapies to reverse opioid-depressed respiration are needed. Methylxanthines are a class of stimulant drugs including caffeine and theophylline which exert their effects primarily via adenosine receptor antagonism. Evidence suggests methylxanthines can stimulate respiration by enhancing neural activity in respiratory nuclei in the pons and medulla independent of opioid receptors. This study aimed to determine whether caffeine and theophylline can stimulate respiration in mice when depressed by fentanyl and oxycodone. METHODS: Whole-body plethysmography was used to characterize fentanyl and oxycodone's effects on respiration and their reversal by naloxone in male Swiss Webster mice. Next, caffeine and theophylline were tested for their effects on basal respiration. Finally, each methylxanthine was evaluated for its ability to reverse similar levels of respiratory depression induced by fentanyl or oxycodone. RESULTS AND CONCLUSIONS: Oxycodone and fentanyl dose-dependently reduced respiratory minute volume (ml/min; MVb) that was reversible by naloxone. Caffeine and theophylline each significantly increased basal MVb. Theophylline, but not caffeine, completely reversed oxycodone-depressed respiration. In contrast, neither methylxanthine elevated fentanyl-depressed respiration at the doses tested. Despite their limited efficacy for reversing opioid-depressed respiration when administered alone, the methylxanthines safety, duration, and mechanism of action supports further evaluation in combination with naloxone to augment its reversal of opioid-depressed respiration.

Amphetamines modulate fentanyl-depressed respiration in a bidirectional manner.

BACKGROUND: The opioid epidemic remains one of the most pressing public health crises facing the United States. Fentanyl and related synthetic opioid agonists have largely driven the rising rates of associated overdose deaths, in part, because of their surreptitious use as substitutes for other opioids and as adulterants in psychostimulants. Deaths involving opioids typically result from lethal respiratory depression, and it is currently unknown how co-use of psychostimulants with opioids affects respiratory toxicity. Considering psychostimulant overdoses have increased over 3-fold since 2013, and half of those co-involved opioids, this is a cardinal question. METHODS: Naloxone, d-amphetamine (AMPH), and (±)-methamphetamine (METH) were evaluated for their effects on basal and fentanyl-depressed respiration. Minute volume (MVb) was measured in awake, freely moving mice via whole-body plethysmography to quantify fentanyl-induced respiratory depression and its modulation by dose ranges of each test drug. RESULTS: Naloxone immediately reversed respiratory depression induced by fentanyl only at the highest dose tested (10 mg/kg). Both AMPH and METH exhibited bidirectional effects on MVb under basal conditions, producing significant (p ≤ 0.05) depressions then elevations of respiration as dose increased. Under depressed conditions the bidirectional effects of AMPH and METH on respiration were exaggerated, exacerbating and then reversing fentanyl-induced depression as dose increased. CONCLUSIONS: These results indicate that co-use of amphetamines with fentanyl may worsen respiratory depression, but conversely, monoaminergic components of the amphetamines may possibly be exploited to mitigate fentanyl overdose.

Effects of the 5-HT2A receptor antagonist volinanserin on head-twitch response and intracranial self-stimulation depression induced by different structural classes of psychedelics in rodents.

BACKGROUND: Clinical studies suggest that psychedelics exert robust therapeutic benefits in a number of psychiatric conditions including substance use disorder. Preclinical studies focused on safety and efficacy of these compounds are necessary to determine the full range of psychedelics' effects. OBJECTIVES: The present study explores the behavioral pharmacology of structurally distinct psychedelics in paradigms associated with serotonin 2A receptor (5-HT2AR) activation and behavioral disruption in two rodent models. Utilizing the selective 5-HT2AR antagonist volinanserin, we aimed to provide further pharmacological assessment of psychedelic effects in rodents. METHODS: We compared volinanserin (0.0001-0.1 mg/kg) antagonism of the phenethylamine 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 1.0 mg/kg) and the ergoline lysergic acid diethylamide (LSD, 0.32 mg/kg) in preclinical assays predictive of hallucinations (head-twitch response or HTR in mice) and behavioral disruption (intracranial self-stimulation or ICSS in rats). Volinanserin antagonism of the phenethylamine mescaline, the tryptamine psilocybin, and the k-opioid receptor agonist salvinorin A was also evaluated in the rat ICSS assay. RESULTS: Volinanserin had similar potency, effectiveness, and time-course to attenuate DOI-induced HTR in mice and ICSS depression in rats. Volinanserin completely blocked LSD-induced HTR in mice, but not LSD-induced ICSS depression in rats. Volinanserin also reversed ICSS depression by mescaline, but it was only partially effective to reduce the effects of psilocybin, and it exacerbated ICSS depression by salvinorin A. CONCLUSION: Although hallucination-related HTR behavior induced by phenethylamine, ergoline, and tryptamine psychedelics appears to be 5-HT2AR-mediated, the receptor(s) responsible for behavioral disruptive effects may differ among these three structural classes.

Placebo Response Reduction and Accurate Pain Reporting Training Reduces Placebo Responses in a Clinical Trial on Chronic Low Back Pain: Results From a Comparison to the Literature.

OBJECTIVE: A literature review was conducted to compare placebo responses in a recent trial-which implemented an accurate pain reporting (APR) and placebo response reduction (PRR) training program-with placebo responses in similar previous trials in chronic lower back pain (CLBP) that did not use such training. METHODS: A literature search was performed to find parallel design, randomized, controlled trials of pharmacological treatments administered orally or through intravenous injection for CLBP. Studies were assessed for the proportion of placebo responders, defined as the proportion of patients in the placebo group with ≥30% reduction in pain intensity. A χ analysis was performed on the proportion of responders from the SPRINT trial and from other similar studies. RESULTS: Of 844 studies identified in the initial screening process, 16 studies were included for comparison. The percentage of placebo responders was statistically significantly lower in the SPRINT study (19.1%) compared with other CLBP trials (38.0%) (P=0.003). Our results show that the placebo response was lower in the SPRINT trial than other comparable studies on CLBP. DISCUSSION: These findings are consistent with results from other studies showing that neutralizing subject and study staff expectations of therapeutic benefit can decrease the placebo response in clinical trials. The results of this study suggest training participants and staff to improve pain reporting accuracy, neutralize expectations, and decrease external cues that may bias participants' pain ratings in clinical trials may effectively decrease the placebo response leading to increased assay sensitivity.

Assessment of potentially abuse-related events in two phase 3 studies of NKTR-181, a novel opioid analgesic, using the MADDERS® system (Misuse, Abuse, and Diversion Drug Event Reporting System).

Objective: To prospectively evaluate the abuse potential of NKTR-181, a novel opioid analgesic, in two phase 3 clinical trials using a newly developed reporting system: the Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS®).Methods: SUMMIT-07 was an enriched enrollment randomized withdrawal study that examined the safety and efficacy of NKTR-181 across 12 weeks in opioid-naïve subjects with chronic low back pain. SUMMIT-LTS was a 52 week open-label study in opioid-naïve and experienced subjects with chronic low back pain or noncancer pain rolled over from SUMMIT-07 or enrolled de novo. System evaluations were triggered by adverse events of interest and drug accountability discrepancies signaling potentially abuse-related events. Each event was assigned a primary classification and supplementary classification(s) by investigators and by a blinded, independent committee of substance abuse experts (adjudicators). At the final study visit, investigators administered a survey to subjects to identify overlooked events of interest.Results: Seventy-nine (6.6%) of 1189 subjects were associated with 86 events in SUMMIT-07 and 51 (8.0%) of 638 subjects were associated with 59 events in SUMMIT-LTS. Most events were attributed to "Withdrawal" and, primarily in SUMMIT-07, "Therapeutic Error" (unintentional overuse) or "Misuse" (intentional overuse for a therapeutic purpose) of study medication. Adjudicators identified five possible "Abuse" events (three NKTR-181, two placebo) in SUMMIT-07 and four possible "Abuse" events (all NKTR-181) in SUMMIT-LTS.Conclusions: The MADDERS® system discerns potentially abuse-related events and identified low rates of withdrawal and a low risk of abuse potential, diversion or addiction associated with NKTR-181 in phase 3 trials.

Efficacy of opioids versus placebo in chronic pain: a systematic review and meta-analysis of enriched enrollment randomized withdrawal trials.

INTRODUCTION: Opioids have been used for millennia for the treatment of pain. However, the long-term efficacy of opioids to treat chronic non-cancer pain continues to be debated. To evaluate opioids' efficacy in chronic non-cancer pain, we performed a meta-analysis of published clinical trials for µ-opioid receptor agonists performed for US Food and Drug Administration approval. METHODS: MEDLINE and Cochrane trial register were searched for enriched enrollment randomized withdrawal studies (before June 2016). Selection criteria included: adults, ≥10 subjects per arm, any chronic pain condition, double-blind treatment period lasting ≥12 weeks, and all µ-agonist opioids approved in the USA. RESULTS: Fifteen studies met criteria. Opioid efficacy was statistically significant (p<0.001) versus placebo for pain intensity (standardized mean difference: -0.416), ≥30% and ≥50% improvement in pain (risk difference: 0.166 and 0.137), patient global impression of change (0.163), and patient global assessment of study medication (0.194). There were minor benefits on physical function and no effect on mental function. CONCLUSION: Opioids are efficacious in the treatment of chronic non-cancer pain for up to 3 months in randomized controlled trials. This should be considered, alongside data on opioid safety, in the use of opioids for the treatment of chronic pain.

The nature, magnitude, and reporting compliance of device-related events for intravenous patient-controlled analgesia in the FDA Manufacturer and User Facility Device Experience (MAUDE) database.

BACKGROUND: The aim of this study is to determine the characteristics, magnitude, and the quality of reporting of mandated events involving intravenous patient-controlled analgesia (IV-PCA) devices in the Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database; a postmarket surveillance system. METHODS: We utilized a mixed-methods approach to systematically characterize structured data and text narratives associated with IV-PCA events submitted to MAUDE between 1 January 2011 and 12 September 2016. RESULTS: Of 1,430 IV-PCA events reported during the study period, 6.4% were adverse events (AEs) as identified via structured data fields in the MEDWATCH forms. Upon qualitative review of the narrative texts, 11.0% of events were associated with an unfavorable clinical outcome, which was 71% higher than the incidence of the adverse outcomes reported using the structured data fields. Device-related issues, which were mostly preventable, accounted for 86.9% of events. Of 65 reportable events submitted by manufacturers, 18.5% did not comply with reporting requirements as mandated by law. CONCLUSION: Patients on IV-PCA continue to experience serious complications as a result of preventable errors. Multi-modal interventions including educational training and the development and adoption of PCA devices with improved safety features are needed to improve safety.

Development and preliminary validation of the focused analgesia selection test to identify accurate pain reporters.

Clinical trials of analgesics have been plagued with poor assay sensitivity due, in part, to variability in subjects' pain reporting. Herein, we develop and evaluate the focused analgesia selection test (FAST), a method to measure patients' pain reporting skills. Subjects with osteoarthritis of the hip, knee, and/or ankle with pain intensity of ≥3/10 on a 0-10 numerical rating scale were enrolled. Subjects underwent the FAST procedure, which consists of recording subjects' pain reports in response to repeated administration of thermal noxious stimuli of various intensities applied on the arm with the Medoc® Thermal Sensory Analyzer II. Subjects also rated non-noxious stimuli consisting of visual contrast rating. After performing an exercise task, subjects also rated clinical pain and were asked to report whether their pain had increased, decreased, or stayed the same. Overall, 88 subjects were enrolled, and 83 were included in the analyses. FAST's outcomes including the R2, intraclass correlation coefficient (ICC), and coefficient of variation (CoV) indicated that subjects' pain reporting skills were widely distributed. Higher FAST ICC significantly predicted greater changes in clinical pain following exercise (p=0.017), whereas the visual contrast test did not predict postexercise pain. FAST is the first method that measures subjects' pain reporting skills. Using FAST to enrich clinical trials with "good" pain reporters (with high FAST ICC) could increase assay sensitivity. Further evaluation of FAST is ongoing.