Naloxone and nalmefene are μ opioid receptor (MOR) antagonist medications for reversing opioid overdose and naltrexone is a MOR antagonist medication for treating opioid use disorder (preventing relapse). MOR agonist medications for treating opioid use disorder include methadone and buprenorphine. The magnitude of effect of buprenorphine can be less than the effect of higher efficacy MOR agonists with some effects of buprenorphine (eg, ventilatory depression) resistant to reversal by naloxone, compared with reversal of the effects of other MOR agonists. Drug discrimination was used to compare the ability of naloxone, naltrexone, nalmefene, and methocinnamox (MCAM) to prevent and reverse the effects of buprenorphine and the ultrapotent fentanyl analog carfentanil in male and female rats discriminating fentanyl from saline. Naloxone, naltrexone, nalmefene, and MCAM (0.01-0.1 mg/kg) were equipotent at preventing the discriminative stimulus effects of 0.01 mg/kg buprenorphine and 0.0001 mg/kg carfentanil. Compared with their potencies to prevent discriminative stimulus effects, naloxone, naltrexone, and nalmefene were ≥92-fold less potent in reversing the discriminative stimulus effects of buprenorphine and ≥31-fold less potent in reversing the discriminative stimulus effects of carfentanil. In contrast, MCAM was equipotent in preventing and reversing the discriminative stimulus effects of buprenorphine and carfentanil. There was no significant difference in the onset of action of naloxone, naltrexone, nalmefene, or MCAM. The greater potency of MCAM, compared with naloxone, naltrexone, and nalmefene for reversing the effects of buprenorphine and carfentanil might translate to MCAM reversing adverse effects of a wide range of MOR agonists in patients. SIGNIFICANCE STATEMENT: Buprenorphine, a μ opioid receptor (MOR) agonist used to treat opioid use disorder, can produce adverse effects that are reportedly more difficult to reverse with naloxone, compared with reversal of the effects of other MOR agonists. This study provides evidence for the potential utility of the MOR antagonist methocinnamox to reverse the adverse effects of buprenorphine by demonstrating the relatively greater potency of methocinnamox, compared with currently available MOR antagonists, to reverse the discriminative stimulus effects of buprenorphine and carfentanil.

Nav1.7 has emerged as a promising target for developing novel analgesics that avoid central side effects, yet clinical trials involving systemically administered Nav1.7 inhibitors have thus far yielded disappointing outcomes. In this study, we explored whether delivering PF-05089771-a highly selective Nav1.7 inhibitor previously tested in clinical settings-directly into the intrathecal space could elicit potent analgesic effects. We assessed pain responses using a range of behavioral assays, including the Hargreaves, hot plate, von Frey hair, and Randall-Selitto tests, while evaluating motor coordination and gastrointestinal transit through the rotarod test and a charcoal meal gavage method, respectively. Intrathecal administration of PF-05089771 produced rapid (within 15 minutes) and long-lasting (>4 hours) analgesia across multiple pain models, including nociceptive, inflammatory, neuropathic, and morphine-tolerant pain, as well as both acute and chronic itch. However, no significant effect was observed in a visceral pain model. The analgesic effects were abolished by naloxone pretreatment, implicating endogenous opioid signaling in the mechanism of action. Importantly, repeated intrathecal injections did not lead to analgesic tolerance, and no adverse effects on motor function or gastrointestinal motility were detected. These results indicate that changing the delivery route of Nav1.7 inhibitors may overcome limitations seen with systemic administration and highlight the potential of intrathecal PF-05089771 as a powerful and well-tolerated analgesic.

Objective: Intrathecal morphine (ITM) has been administered in recent years to provide postoperative pain control in non-obstetric surgery; however, current research has limited consideration of the recommendations for regular, basic analgesia from clinical guidelines when exploring its efficacy. This systematic review and meta-analysis aimed to compare ITM against alternative methods of analgesia in the presence of multimodal analgesia, for reducing pain scores within the first 24 h postoperatively. Secondary outcomes included postoperative opioid consumption, incidence of opioid-related effects, and time to mobilisation. Methods: Database searches and screening identified 11 trials for inclusion in this review. Pain scores were compared by meta-analysis at 6, 12, and 24 h postoperatively at rest and on movement, with sub-analysis of systemic versus regional techniques. Results: The data found no significant difference between ITM and active comparators for reducing pain scores at rest or on movement at any of the time intervals explored. Sub-analysis demonstrated that regional techniques may provide superior analgesia at 24 h at rest (MD = -1.19; 95% CI [-1.73, -0.66], p < 0.001, I[2] = 0%) and on movement (MD = 1.27 [0.44, 2.10], p = 0.003, I[2] = 0%). Cumulative opioid consumption was reduced in ITM groups (MD = -11.61 [-18.73, -4.50], p = 0.001, I[2] = 95%), with significantly increased risk of pruritus (p < 0.001) but not nausea and vomiting (p = 0.93). There was no evidence of respiratory depression. Conclusions: This meta-analysis was unable to demonstrate any significant benefit to postoperative pain relief with the use of ITM but may suggest that it is as a viable option compared to other active modalities. However, this meta-analysis was limited by a low quantity and quality of data from which to draw conclusions and demonstrated high statistical fragility. We believe this highlights a significant gap in the current literature on ITM.

Important insights and consensus remain lacking for risk prediction of opioid-induced respiratory depression (OIRD), reversal of respiratory depression (RD), the pathophysiology of OIRD, and which sites make the most significant contribution to its induction. The ventilatory response to inhaled carbon dioxide is the most sensitive biomarker of OIRD. To accurately predict respiratory depression (RD), a multivariant RD prospective trial using continuous capnography and oximetry examining five independent variables, age ≥60, sex, opioid naivety, sleep disorders, and chronic heart failure (PRODIGY trial), were undertaken. Intermittent oximetry alone substantially underestimates the incidence of RD. Naloxone, with an elimination half-life of ∼33 min (cf. morphine 2-3 h; fentanyl and congeners only 5-15 min), has limitations for the rescue of patients with severe OIRD. Buprenorphine is potentially valuable in patients being treated long term since its high µ-receptor (MOR) affinity makes it difficult for an opioid of lower affinity (e.g., fentanyl) to displace it from the receptor. In the last decade, synthetic opioids, for example, fentanyl, its potent analogs such as carfentanil, and the benzimidazole derivative nitazene "superagonists" have contributed to the exponential growth in opioid deaths due to RD. The MOR, encoded by gene Oprm1, is widely expressed in the central and peripheral nervous systems, including centers that modulate breathing. Opioids bind to the receptors, but consensus is lacking on which site(s) makes the most significant contribution to the induction of OIRD. Both the preBötzinger complex (preBötC), the inspiratory rhythm generator, and the Kölliker-Fuse nucleus (KFN), the respiratory modulator, contribute to RD, but receptor binding is not restricted to a single site. Breathing is composed of three phases, inspiration, postinspiration, and active expiration, each generated by distinct rhythm-generating networks: the preBötC, the postinspiratory complex (PiCo), and the lateral parafacial nucleus (pFL), respectively. Somatostatin-expressing mouse cells involved in breathing regulation are not involved in opioid-induced RD.

Despite a significant decrease in the number of prescriptions for opioids, the opioid crisis continues, fueled in large part by the availability of the phenylpiperidine mu opioid receptor (MOR) agonist fentanyl. In contrast, the number of prescriptions for and the off-label use of gabapentinoids (gabapentin and pregabalin) has increased dramatically, with gabapentinoids commonly detected in opioid overdose victims. Although gabapentinoids can decrease the potency of the opioid receptor antagonist naloxone to reverse heroin-induced hypoventilation in male rats, the specificity and nature of interaction between gabapentinoids and MOR agonists and any potential sex difference in those interactions are not well characterized. Gabapentinoids were studied in female and male rats discriminating fentanyl (0.0032 mg/kg, i.p.) or cocaine (3.2 mg/kg, i.p.). Alone, neither gabapentin nor pregabalin significantly increased fentanyl- or cocaine-appropriate responding. In rats discriminating fentanyl, each gabapentinoid dose-dependently shifted the fentanyl and heroin discrimination dose-effect functions to the left, whereas naloxone dose-dependently shifted the fentanyl and heroin discrimination dose-effect functions to the right. Each gabapentinoid (100 mg/kg) significantly decreased the potency of naloxone to antagonize the discriminative stimulus effect of fentanyl or heroin. In contrast, each gabapentinoid dose-dependently shifted the cocaine and d-methamphetamine discrimination dose-effect functions to the right. There were no significant sex differences in this study. These results suggest that gabapentinoids impact the misuse of opioids, the co-use of opioids and stimulant drugs, and the increasing number of overdose deaths in individuals using opioids, stimulant drugs, and gabapentinoids in mixtures. SIGNIFICANCE STATEMENT: The number of prescriptions for and the off-label use of gabapentinoids (gabapentin and pregabalin) has increased dramatically, with gabapentinoids commonly detected in opioid overdose victims. This study reports that in rats gabapentinoids increase the potency of fentanyl and heroin to produce discriminative stimulus effects while decreasing the potency of naloxone to antagonize those effects of fentanyl and heroin. These results can help guide policies for regulating gabapentinoids and treating opioid misuse and overdose.

The number of opioid overdose deaths has increased significantly over the past decade. The life-threatening effect of opioids is hypoventilation, which can be reversed by the μ-opioid receptor (MOR) antagonist naloxone; however, because of the very short duration of action of naloxone, reemergence of MOR agonist-induced hypoventilation can occur, requiring additional doses of naloxone. The MOR antagonist methocinnamox (MCAM) antagonizes hypoventilation by the nonmorphinan fentanyl and the morphinan heroin in laboratory animals with an unusually long duration of action. Whole-body plethysmography was used to compare the potency and effectiveness of MCAM and naloxone for preventing and reversing hypoventilation by fentanyl, heroin, and the ultrapotent and longer-acting fentanyl analogs carfentanil and 3-methylfentanyl in male rats breathing normal air. Sessions comprised a 45-minute habituation period followed by intravenous administration of saline or an acute dose of MOR agonist. The rank order of potency to decrease ventilation was 3-methylfentanyl > carfentanil > fentanyl > heroin. MCAM (0.0001-0.1 mg/kg) and naloxone (0.0001-0.01 mg/kg) dose dependently reversed hypoventilation by 3-methylfentanyl (0.01 mg/kg), carfentanil (0.01 mg/kg), fentanyl (0.1 mg/kg), or heroin (3.2 mg/kg). For prevention studies, MCAM, naloxone, or vehicle was administered intravenously 22, 46, or 70 hours prior to a MOR agonist. When administered 22 hours earlier, MCAM (0.1-1.0 mg/kg) but not naloxone (1.0 mg/kg) prevented hypoventilation by each MOR agonist. This study demonstrates the effectiveness of MCAM at reversing and preventing hypoventilation by MOR agonists including ultrapotent fentanyl analogs that have a long duration of action. SIGNIFICANCE STATEMENT: The number of opioid overdose deaths increased over the past decade despite the availability of antagonists that can prevent and reverse the effects of opioids. This study demonstrates the effectiveness and long duration of action of the μ-opioid receptor (MOR) antagonist methocinnamox (MCAM) for reversing and preventing hypoventilation by MOR agonists including ultrapotent fentanyl analogs. These results provide support for the notion that MCAM has the potential to positively impact the ongoing opioid crisis by reversing and preventing opioid overdose.

The number of drug overdoses and deaths has increased significantly over the past decade and co-use of opioids and stimulants is associated with greater likelihood of overdose and decreased likelihood of accessing treatment, compared with use of opioids alone. Potential adverse effects of opioid/stimulant mixtures, particularly methamphetamine, are not well characterized. Two structurally different drugs with agonist properties at µ-opioid receptors (MOR), fentanyl and heroin, and d-methamphetamine, alone and in mixtures, were assessed for their effects on ventilation in rats breathing normal air. Whole-body phethysmography chambers were equipped with a tower and swivel allowing infusions to indwelling intravenous catheters. After a 45-minute habituation period, saline, fentanyl, heroin, or d-methamphetamine, alone and in mixtures, was administered. Five minutes later, the opioid receptor antagonist naloxone or vehicle was injected. Fentanyl (0.0032-0.1 mg/kg) and heroin (0.32-3.2 mg/kg) decreased ventilation [frequency (f) and tidal volume (VT)] in a dose-related manner whereas d-methamphetamine (0.1-3.2 mg/kg) increased f to >400% of control and decreased VT to <60% of control, overall increasing minute volume (product of f and VT) to >240% of control. When combined, d-methamphetamine (0.1-3.2 mg/kg) attenuated the ventilatory depressant effects of fentanyl (0.1 mg/kg) and heroin (3.2 mg/kg). d-Methamphetamine did not alter the potency of naloxone to reverse the ventilatory depressant effects of fentanyl or heroin. These studies demonstrate that d-methamphetamine can attenuate the ventilatory depressant effects of moderate doses of opioid receptor agonists while not altering the potency of naloxone to reverse opioid hypoventilation. SIGNIFICANCE STATEMENT: Co-use of opioids and stimulants is associated with greater likelihood of overdose and decreased likelihood of accessing treatment, compared with use of opioids alone. Potential adverse effects of opioid/stimulant mixtures are not well characterized. This study reports that 1) d-methamphetamine attenuates the ventilatory depressant effects of moderate doses of two structurally different opioid receptor agonists, fentanyl and heroin, and 2) d-methamphetamine does not alter potency or effectiveness of naloxone to reverse the ventilatory depressant effects of these opioid receptor agonists.