RECENT FINDINGS: Recent studies have been focused on the interactions of mitragynine, the most abundant alkaloid, and opioid-like effects. This has been driven by the harm that kratom products have produced in the Western world, in stark contrast to the lack of harm in Southeast Asian traditional use over centuries. Many users in the Western world ingest kratom for mood enhancement and/or to ween themselves from prescription or illicit opioids. Highly concentrated products and recreational use and misuse have resulted in individuals pushing doses to levels that have not been imagined or ever studied in animal, let alone humans.
SUMMARY: Kratom, as a preparation and how it is utilized is different around the world.
METHODS: After institutional approval and written informed consent, patients received a brief remifentanil infusion during continuous monitoring of ventilation. We compared minute ventilation in 30 patients with moderate-to-severe obstructive sleep apnea diagnosed by polysomnography and 20 controls with no to mild obstructive sleep apnea per polysomnography. Effect site concentrations were estimated by a published pharmacologic model. We modeled minute ventilation as a function of effect site concentration and the estimated carbon dioxide. Obstructive sleep apnea status, body mass index, sex, age, use of continuous positive airway pressure, apnea/hypopnea events per hour of sleep, and minimum nocturnal oxygen saturation measured by pulse oximetry in polysomnography were tested as covariates for remifentanil effect site concentration at half-maximal depression of minute ventilation (Ce50) and included in the model if a threshold of 6.63 (P < 0.01) in the reduction of objective function was reached and improved model fit.
RESULTS: Our model described the observed minute ventilation with reasonable accuracy (22% median absolute error). We estimated a remifentanil Ce50 of 2.20 ng · ml (95% CI, 2.09 to 2.33). The estimated value for Ce50 was 2.1 ng · ml (95% CI, 1.9 to 2.3) in patients without obstructive sleep apnea and 2.3 ng · ml (95% CI, 2.2 to 2.5) in patients with obstructive sleep apnea, a statistically nonsignificant difference (P = 0.081). None of the tested covariates demonstrated a significant effect on Ce50. Likelihood profiling with the model including obstructive sleep apnea suggested that the effect of obstructive sleep apnea on remifentanil Ce50 was less than 5%.
CONCLUSIONS: Obstructive sleep apnea status, apnea/hypopnea events per hour of sleep, or minimum nocturnal oxygen saturation measured by pulse oximetry did not influence the sensitivity to remifentanil-induced ventilatory depression in awake patients receiving a remifentanil infusion of 0.2 μg · kg of ideal body weight per minute.
DESIGN: This study was designed as a retrospective cohort study.
SETTING AND PARTICIPANTS: In this study, we analysed the prescription databases of tertiary hospitals in Malaysia. This study included patients aged ≥18 years with at least one opioid prescription (buprenorphine, morphine, oxycodone, fentanyl, dihydrocodeine or tramadol) between 1 January 2011 and 31 December 2016. These patients had no opioid prescriptions in the 365 days prior, and were followed up for 365 days after the initial opioid prescription.
MAIN OUTCOME MEASURES: The main outcome measures were the number of short-term (<90 days) and long-term opioid users (≥90 days), initial opioid prescription period and daily dose.
RESULTS: There were 33 752 opioid-naïve patients who received opioid prescriptions (n=43 432 prescriptions) during the study period. Of these, 29 824 (88.36%) were short-term opioid users and 3928 (11.64%) were long-term opioid users. The majority of these short-term (99.09%) and long-term users (96.18%) received an initial daily opioid dose of <50 mg/day with a short-acting opioid formulation. Short-term opioid users were predominantly prescribed opioids for 3-7 days (59.06%) by the emergency department (ED, 60.56%), while long-term opioid users were primarily prescribed opioids for ≥7 days (91.85%) by non-ED hospital departments (91.8%). The adjusted model showed that the following were associated with long-term opioid use: increasing opioid daily doses, prescription period ≥7 days and long-acting opioids initiated by non-EDs.
CONCLUSIONS: The majority of opioid-naïve patients in tertiary hospital settings in Malaysia were prescribed opioids for short-term use. The progression to long-term use among opioid-naïve patients was attributed to the prescription of higher opioid doses for a longer duration as well as long-acting opioids initiated by non-ED hospital departments.
METHODS: The whole study was carried out on 48 adult Wistar rats (24 male: 12 obese and 12 lean and 24 female: 12 obese and 12 lean). Each male and female rat group was further subdivided into two groups (n = 6/group) and treated with normal saline/tramadol for 5 days. On the fifth day, 15 min after tramadol/normal saline treatment, animals were tested for pain perception toward noxious stimuli. Later, endogenous 17 beta-estradiol and free testosterone levels in serum were estimated through ELISA methods.
RESULTS: The present study revealed that female rats experienced more pain sensitivity to noxious stimuli compared to male rats. High-fat diet-induced obese rats experienced more pain sensations to noxious stimuli than lean rats. Obese male rats were found to have significantly low free testosterone and high 17 beta-estradiol levels compared to lean male rats. An increase in serum 17 beta-estradiol level led to increased pain sensation to noxious stimuli. While an increase in free testosterone level resulted in the lowering of pain sensation to noxious stimuli.
CONCLUSION: The analgesic effect of tramadol was more pronounced in male rats compared to female rats. The analgesic effect of tramadol was more marked in lean rats compared to obese rats. Additional research to elucidate obesity-induced endocrine changes and the mechanisms driving sex hormones in pain perception is needed to foster future interventions to reduce disparities in pain.
OBJECTIVES: The present study was performed to investigate the discriminative stimulus effects of MG in rats. The pharmacological mechanism of MG action and its derivative, 7-hydroxymitragynine (7-HMG) with a specific focus on opioid receptor involvement was examined in rats trained to discriminate morphine from vehicle. In order to study the dual actions of MG, the effect of cocaine substitution to the MG discriminative stimulus was also performed in MG-trained rats.
METHODS: Male Sprague Dawley rats were trained to discriminate MG from vehicle in a two-lever drug discrimination procedure under a tandem variable-interval (VI 60') fixed-ratio (FR 10) schedule of food reinforcement.
RESULTS: Rats acquired the MG discrimination (15.0 mg/kg, i.p.) which was similar to the acquisition of morphine discrimination (5.0 mg/kg, i.p.) in another group of rats. MG substituted fully to the morphine discriminative stimulus in a dose-dependent manner, suggesting pharmacological similarities between the two drugs. The administration of 7-HMG derivative in 3.0 mg/kg (i.p.) dose engendered full generalisation to the morphine discriminative stimulus. In addition, the MG stimulus also partially generalised to cocaine (10.0 mg/kg, i.p.) stimulus.
CONCLUSION: The present study demonstrates that the discriminative stimulus effect of MG possesses both opioid- and psychostimulant-like subjective effects.