Respiratory effects of oral mitragynine and oxycodone in a rodent model.

RATIONALE: Kratom derives from Mitragyna speciosa (Korth.), a tropical tree in the genus Mitragyna (Rubiaceae) that also includes the coffee tree. Kratom leaf powders, tea-like decoctions, and commercial extracts are taken orally, primarily for health and well-being by millions of people globally. Others take kratom to eliminate opioid use for analgesia and manage opioid withdrawal and use disorder. There is debate over the possible respiratory depressant overdose risk of the primary active alkaloid, mitragynine, a partial µ-opioid receptor agonist, that does not signal through ß-arrestin, the primary opioid respiratory depressant pathway. OBJECTIVES: Compare the respiratory effects of oral mitragynine to oral oxycodone in rats with the study design previously published by US Food and Drug Administration (FDA) scientists for evaluating the respiratory effects of opioids (Xu et al., Toxicol Rep 7:188-197, 2020). METHODS: Blood gases, observable signs, and mitragynine pharmacokinetics were assessed for 12 h after 20, 40, 80, 240, and 400 mg/kg oral mitragynine isolate and 6.75, 60, and 150 mg/kg oral oxycodone hydrochloride. FINDINGS: Oxycodone administration produced significant dose-related respiratory depressant effects and pronounced sedation with one death each at 60 and 150 mg/kg. Mitragynine did not yield significant dose-related respiratory depressant or life-threatening effects. Sedative-like effects, milder than produced by oxycodone, were evident at the highest mitragynine dose. Maximum oxycodone and mitragynine plasma concentrations were dose related. CONCLUSIONS: Consistent with mitragynine's pharmacology that includes partial µ-opioid receptor agonism with little recruitment of the respiratory depressant activating ß-arrestin pathway, mitragynine produced no evidence of respiratory depression at doses many times higher than known to be taken by humans.

Relationship between receptor occupancy and the antinociceptive effect of mu opioid receptor agonists in male rats.

The analgesic mechanisms of mu opioid receptor (MOR) agonists, including receptor occupancy at the site of action, are not completely understood. The aims of the present study were to evaluate: (i) receptor occupancy in the rat brain after administration of MOR agonists; (ii) the relationship between occupancy and the antinociceptive effect. Morphine (2 or 4 mg/kg) or oxycodone (1 or 3 mg/kg) was subcutaneously administered to rats. The antinociceptive effect of these drugs was measured by the hot-plate test. MOR occupancy in the thalamus was assessed by conducting an ex vivo receptor binding assay using [3H] [D-Ala2, N-MePhe4, Gly-ol]-enkephalin, followed by autoradiographic analysis. Both drugs produced antinociception in a dose-dependent manner, and these effects disappeared after the time point at which the maximal effect was elicited. Thalamic MOR occupancy was observed in a dose-dependent manner at the time point at which maximal antinociception was elicited, and relatively low occupancy was observed when the antinociceptive effect was decreasing. Good correlation between thalamic MOR occupancy and the antinociceptive effect was observed. These findings provide direct evidence for the receptor occupancy of MOR agonists at the site of action and its relationship with the analgesic effect.

Grip strength in mice with joint inflammation: A rheumatology function test sensitive to pain and analgesia.

Grip strength deficit is a measure of pain-induced functional disability in rheumatic disease. We tested whether this parameter and tactile allodynia, the standard pain measure in preclinical studies, show parallels in their response to analgesics and basic mechanisms. Mice with periarticular injections of complete Freund's adjuvant (CFA) in the ankles showed periarticular immune infiltration and synovial membrane alterations, together with pronounced grip strength deficits and tactile allodynia measured with von Frey hairs. However, inflammation-induced tactile allodynia lasted longer than grip strength alterations, and therefore did not drive the functional deficits. Oral administration of the opioid drugs oxycodone (1-8 mg/kg) and tramadol (10-80 mg/kg) induced a better recovery of grip strength than acetaminophen (40-320 mg/kg) or the nonsteroidal antiinflammatory drugs ibuprofen (10-80 mg/kg) or celecoxib (40-160 mg/kg); these results are consistent with their analgesic efficacy in humans. Functional impairment was generally a more sensitive indicator of drug-induced analgesia than tactile allodynia, as drug doses that attenuated grip strength deficits showed little or no effect on von Frey thresholds. Finally, ruthenium red (a nonselective TRP antagonist) or the in vivo ablation of TRPV1-expressing neurons with resiniferatoxin abolished tactile allodynia without altering grip strength deficits, indicating that the neurobiology of tactile allodynia and grip strength deficits differ. In conclusion, grip strength deficits are due to a distinct type of pain that reflects an important aspect of the human pain experience, and therefore merits further exploration in preclinical studies to improve the translation of new analgesics from bench to bedside.

Comparative effects of Mitragyna speciosa extract, mitragynine, and opioid agonists on thermal nociception in rats.

This study sought to compare the effects of Mitragyna speciosa (Korth.) Havil. extract, alkaloids fraction, and mitragynine, a µ-opioid receptor agonist, to that of morphine and oxycodone in a test of thermal nociception. In Experiment 1, male Sprague-Dawley rats were administered test articles intraperitoneally (IP) 30 min prior to testing to compare the effects of M. speciosa articles to opioid reference compounds on the hotplate assay. Test articles were vehicle, 10 mg/kg morphine, 3 mg/kg oxycodone, 300 mg/kg M. speciosa extract, 75 mg/kg M. speciosa alkaloids fraction, or 30 mg/kg mitragynine. To mirror consumer usage, Experiment 2 sought to determine whether M. speciosa articles retained their biological activity when given orally (PO). Test articles were vehicle, 6 mg/kg oxycodone, 300 mg/kg M. speciosa extract, or 100mg/kg mitragynine with hotplate tests conducted 30 and 60 min after administration. Mitragynine produced antinociceptive effects similar to the reference opioid agonists when administered IP and PO routes. These data suggest that M. speciosa extracts containing significant quantities of mitragynine may warrant consideration for further studies in primate self-administration models to yield insight into the abuse liability of this commercially available product.

Opioid modulation of resting-state anterior cingulate cortex functional connectivity.

Individuals misuse oxycodone, a widely prescribed opioid analgesic, in part to self-medicate physical and emotional pain. Physical and emotional pain is thought to be represented in the brain by a 'pain matrix,' consisting of the insula, thalamus, and somatosensory cortices, with processing of the affective dimension of pain in the dorsal and rostral anterior cingulate cortex (ACC). The current study examined oxycodone's effects on resting-state functional connectivity between the dorsal ACC, rostral ACC, and other regions of the pain matrix using functional magnetic resonance imaging (fMRI). In a within-subjects, randomized, double-blind, placebo-controlled, dose-response design, 14 healthy subjects completed a resting-state scan following ingestion of placebo, 10 mg, or 20 mg of oxycodone. Functional correlations between the dorsal and rostral ACC seed regions and the pain matrix were examined and compared across sessions. Both doses of oxycodone reduced functional coupling between the dorsal ACC and bilateral anterior insula/putamen and the rostral ACC and right insula relative to placebo (no differences between doses). The findings do not withstand correction for multiple comparisons, and thus should be considered preliminary. However, they are consistent with the idea that oxycodone may produce its physical and emotional 'analgesic' effects through disruption of ACC-insula and ACC-putamen connectivity.

Loss of antinociceptive effectiveness of morphine and oxycodone following titration of levothyroxine: case reports and a brief review of published literature.

Chronic pain management is a complex process involving numerous facets of care. Although pharmacotherapy is a part of the treatment plan for these patients, it often represents the most complex of the modalities to manage. Two chronic pain patients with loss of pain control following dosage increase in levothyroxine supplementation are presented. The authors sought to identify relationships among thyroid status, opioid pharmacokinetics, and nociceptive processing. In conclusion, well-designed human studies using pain models and controlling for thyroid status are warranted to better understand the impact this system has on pain control.

Capsaicin instillation for postoperative pain following total knee arthroplasty: a preliminary report of a randomized, double-blind, parallel-group, placebo-controlled, multicentre trial.

BACKGROUND: Pain following total knee arthroplasty (TKA) interferes with rehabilitation. Capsaicin applied in high concentration to nociceptors can cause relatively selective C-fibre desensitization for a period of weeks to months. Resultant long-lasting analgesia might facilitate rehabilitation. OBJECTIVE: The objective of this study was to determine if direct instillation of a high-concentration capsaicin preparation into the wound following TKA would provide pain relief, improve physical functioning and rehabilitation, and reduce opioid requirements. METHODS: This was a randomized, double-blind, parallel-group, placebo-controlled, multicentre, phase II trial carried out in a teaching hospital system. Non-opioid-tolerant males or females aged 18-85 years with a body mass index (BMI) ≤45 kg/m2, American Society of Anesthesiologists (ASA) physical status 1-3 and end-stage osteoarthritis who were scheduled for primary unilateral TKA were included. Patients received placebo vehicle or capsaicin 15 mg (Anesiva 4975) by instillation immediately prior to wound closure. Surgery was conducted under spinal anaesthesia and femoral nerve block. Postoperative rescue analgesia consisted of intravenous patient-controlled analgesia with morphine for 24 hours; oral oxycodone was provided thereafter as needed. It was hypothesized prior to data collection that capsaicin instillation would reduce postoperative pain scores and result in improved patient satisfaction and ambulation. The primary outcome was the area under the numerical rating scale (NRS) for pain score-time curve from 4 to 24 hours (AUC(4-24)). NRS for pain scores were obtained every 4 hours for 24 hours then daily with ambulation and physical therapy for 3 days. Function and patient satisfaction were assessed at 14, 28 and 42 days. RESULTS: Data from 14 patients (seven per group) from a single centre (data were not available from other sites because of sponsor bankruptcy) were available for this preliminary report. AUC(4-24) was not significantly different clinically (placebo 70.3; capsaicin 65.7) in this sample; however, a significant opioid-sparing effect was seen in the capsaicin group despite the fact that patients in this group had higher BMIs. Pain scores tended to be lower in the capsaicin group, despite the fact that patients in this group received significantly less rescue opioid medication. Morphine use from 12-24 hours was lower (capsaicin group mean 13.4 mg; 95% confidence interval [CI] 7.4, 19.5; range 10-21 mg vs placebo group mean 25.9 mg; 95% CI 19.8, 32.0; range 15-36 mg; p = 0.009). Total intravenous and oral opioid in morphine equivalents over 72 hours was also lower with capsaicin compared with placebo (p = 0.03). Active range of motion (ROM) was also significantly improved at day 14 in the capsaicin group compared with the placebo group (p = 0.0014). A higher percentage of patients in the capsaicin group reported being extremely satisfied with their treatment. The only statistically significant difference in treatment-emergent adverse events was for pruritus, which was more frequent in the placebo group (p = 0.03). CONCLUSION: Despite having higher BMIs, patients in the capsaicin group achieved comparable or better pain scores with significantly less opioid use in the first 3 postoperative days. They also had less pruritus, which may have been a consequence of the opioid-sparing effect. The effects of capsaicin with respect to function, however, appeared to be longer lasting, with improved active ROM reported at 14 days.

Acute oxycodone induces the pro-emetic pica response in rats.

Oxycodone, a semisynthetic opioid analgesic, is frequently prescribed for the management of pain. Side effects of nausea and emesis affect patient compliance and limit its therapeutic use. The present study established that an antinociceptive dose of oxycodone (15 mg/kg; oral) induces the pica response. We found sex differences in the temporal course of pica, with females having a longer duration. Opioid receptors mediated the pica response, as 1.0 mg/kg naloxone transiently attenuated and 2.0 mg/kg naloxone blocked pica. A κ-selective antagonist failed to block the response, suggesting mediation by µ opioid receptor. For further validation, we used the well established kaolin intake model to assess pica with the chemotherapeutic drug cisplatin as a positive control. Oxycodone and cisplatin significantly increased kaolin intake 4- to 7-fold, and the wet weight of stomach was elevated 2- to 3-fold. To examine the underlying neural circuitry, we investigated c-fos activation in the area postrema and nucleus of solitary tract (NTS). Oxycodone treatment significantly increased the number of c-fos-positive neurons in the area postrema and NTS compared with water controls. As expected, cisplatin also increased the number of c-fos-positive cells in these regions. In the area postrema, the oxycodone effect was greater than cisplatin, especially at 2 h. These results indicate that an antinociceptive dose of oxycodone is associated with the expression of pica, a pro-emetic response.

mu-Opioid receptor-independent fashion of the suppression of sodium currents by mu-opioid analgesics in thalamic neurons.

Most reports in the literature have shown that the effects of opioid analgesics are primarily mediated by mu-opioid receptor (MOR), whereas other potential targets of opioid analgesics have not been thoroughly characterized. In this study, we found that extracellular application of morphine, fentanyl or oxycodone, which are all considered to be MOR agonists, at relatively high concentrations, but not endogenous mu-opioid peptides, produced a concentration-dependent suppression of sodium currents in cultured thalamic neurons. These effects of opioids were not affected by either a MOR antagonist naloxone or a deletion of MOR gene. Among these opioids, fentanyl strongly suppressed sodium currents to the same degree as lidocaine, and both morphine and oxycodone slightly but significantly reduced sodium currents when they were present extracellularly. In contrast, the intracellular application of morphine, but not oxycodone, fentanyl or lidocaine, reduced sodium currents. These results suggest that morphine, fentanyl and oxycodone each produce the MOR-independent suppression of sodium currents by distinct mechanisms in thalamic neurons.

Levo-tetrahydropalmatine attenuates oxycodone-induced conditioned place preference in rats.

Levo-tetrahydropalmatine (l-THP) is an alkaloid purified from the Chinese herb corydalis and stephania and is contained in many traditional Chinese herbal preparations. Our previous studies demonstrated the ability of l-THP to inhibit locomotor stimulation and physical dependence induced by oxycodone in mice and rats. The present study was designed to evaluate effects of l-THP on reward of oxycodone using conditioned place preference assay. Oxycodone (0.32-5.0 mg/kg) induced the development of conditioned place preference in rats. Furthermore, oxycodone (2.5 mg/kg) induced the increased phosphorylation of CREB and ERK in nucleus accumbens and hippocampus, but not in prefrontal cortex. l-THP (6.25-18.50 mg/kg) per se was not able to induce conditioned place preference or conditioned place aversion. l-THP co-administered with oxycodone during the conditioning sessions partly abolished the development of oxycodone-induced conditioned place preference in rats. Furthermore, l-THP inhibited the increased phosphorylation of ERK and CREB in nucleus accumbens and hippocampus of rats. All these results suggest that l-THP can inhibit oxycodone-induced psychological dependence by affecting phosphorylation of CREB and ERK in nucleus accumbens and hippocampus of rats. Together, the present data, combined with previous finding, support the potential use of l-THP for treatment of oxycodone addiction.

Lumiracoxib.

Lumiracoxib is a highly selective and potent cyclo-oxygenase (COX)-2 inhibitor, with a novel structure that conveys weakly acidic properties and a unique pharmacological profile. It is rapidly absorbed, with a relatively short plasma half-life. In well designed clinical trials of 1-52 weeks' duration in patients with osteoarthritis (OA) or rheumatoid arthritis, the efficacy of oral lumiracoxib 100-400 mg/day in decreasing pain intensity and improving functional status was greater than that with placebo and similar to those with nonselective NSAIDs or celecoxib 200mg once daily. In single- and multiple-dose well designed trials in patients with acute pain associated with primary dysmenorrhoea, dental or orthopaedic surgery or tension-type headache, lumiracoxib 100-800 mg once daily was more effective in relieving acute pain than placebo or controlled-release oxycodone 20 mg, and was at least as effective as selective COX-2 inhibitors or nonselective NSAIDs. Lumiracoxib was generally well tolerated in clinical trials, with a similar overall tolerability profile to those of placebo and other COX-2-selective inhibitors. In a large 52-week safety trial in patients with OA, lumiracoxib 400mg once daily had a rate of gastrointestinal ulcer complications that was approximately one-third to one-quarter of that of ibuprofen 800 mg three times daily or naproxen 500 mg twice daily. Lumiracoxib was not associated with an increase in cardiovascular events.