Probing different paradigms of morphine withdrawal on sleep behavior in male and female C57BL/6J mice.

Opioid misuse has dramatically increased over the last few decades resulting in many people suffering from opioid use disorder (OUD). The prevalence of opioid overdose has been driven by the development of new synthetic opioids, increased availability of prescription opioids, and more recently, the COVID-19 pandemic. Coinciding with increases in exposure to opioids, the United States has also observed increases in multiple Narcan (naloxone) administrations as a life-saving measures for respiratory depression, and, thus, consequently, naloxone-precipitated withdrawal. Sleep dysregulation is a main symptom of OUD and opioid withdrawal syndrome, and therefore, should be a key facet of animal models of OUD. Here we examine the effect of precipitated and spontaneous morphine withdrawal on sleep behaviors in C57BL/6 J mice. We find that morphine administration and withdrawal dysregulate sleep, but not equally across morphine exposure paradigms. Furthermore, many environmental triggers promote relapse to drug-seeking/taking behavior, and the stress of disrupted sleep may fall into that category. We find that sleep deprivation dysregulates sleep in mice that had previous opioid withdrawal experience. Our data suggest that the 3-day precipitated withdrawal paradigm has the most profound effects on opioid-induced sleep dysregulation and further validates the construct of this model for opioid dependence and OUD.

Immunomodulatory effects of pharmaceutical opioids and antipyretic analgesics: Mechanisms and relevance to infection.

Understanding how pharmaceutical opioids and antipyretic analgesics interact with the immune system potentially has major clinical implications for management of patients with infectious diseases and surgical and critical care patients. An electronic search was carried out on MEDLINE, EMBASE, PsycINFO, CENTRAL and the Cochrane library to identify reports describing the immunomodulatory effects of opioid analgesics and antipyretic analgesics, and their effects in infectious diseases. In adaptive immunity, nonsteroidal anti-inflammatory drugs have divergent effects: augmenting cell-mediated immunity but inhibiting humoral immunity. Nonsteroidal anti-inflammatory drugs have demonstrated a beneficial role in Mycobacterium tuberculosis infection and histoplasmosis in animals, and may be plausible adjuvants to antimicrobial agents in these diseases. There is a need to evaluate these findings rigorously in human clinical trials. There is preliminary evidence demonstrating antiviral effects of indomethacin in SARS CoV-2 in vitro; however, uncertainty regarding its clinical benefit in humans needs to be resolved in large clinical trials. Certain opioid analgesics are associated with immunosuppressive effects, with a developing understanding that fentanyl, morphine, methadone and buprenorphine suppress innate immunity, whilst having diverse effects on adaptive immunity. Morphine suppresses key cells of the innate immunity and is associated with greater risk of infection in the postsurgical setting. Efforts are needed to achieve adequate analgesia whilst avoiding suppression of the innate immunity in the immediate postoperative period caused by certain opioids, particularly in cancer surgery.

Impact of a tiered discharge opioid algorithm on prescriptions and patient-reported outcomes after open gynecologic surgery.

OBJECTIVE: To compare discharge opioid refills, prescribed morphine equivalent dose and quantity, and longitudinal patient-reported outcomes before and after implementation of a tiered opioid prescribing algorithm among women undergoing open gynecologic surgery within an enhanced recovery after surgery program. METHODS: We compared opioid prescriptions, clinical outcomes, and patient-reported outcomes among 273 women. Post-discharge symptom burden was collected up to 42 days after discharge using the validated 27-item MD Anderson Symptom Inventory and analyzed using linear mixed effects models and Kaplan-Meier curves for symptom recovery. RESULTS: Among 113 pre-implementation and 160 post-implementation patients there was no difference in opioid refills (9.7% vs 11.3%, p=0.84). The post-implementation cohort had a significant reduction in median morphine equivalent dose (112.5 mg vs 225 mg, p<0.01), with no difference in median hospital length of stay (3 days vs 3 days, p=1.0) or 30-day readmission rate (9.4% vs 7.1%, p=0.66). There was no difference in patient-reported pain between the pre- and post-implementation cohorts on the day of discharge (severity 4.93 vs 5.14, p=0.53) or in any patient-reported symptoms, interference measures, or composite scores by post-discharge day 7. The median recovery time for most symptoms was 7 days, except for pain (14 days), fatigue (18 days), and physical interference (21 days), with no differences between cohorts. CONCLUSIONS: After implementation of a tiered opioid prescribing algorithm, the quantity and dose of discharge opioids prescribed decreased with no change in post-operative refills and without negatively impacting patient-reported symptom burden or interference, which can be used to educate and reassure patients and providers.

Pharmacokinetics and pharmacodynamics of meperidine after intramuscular and subcutaneous administration in horses.

OBJECTIVE: To describe the pharmacokinetics and pharmacodynamics of meperidine after IM and subcutaneous administration in horses. STUDY DESIGN: prospective, randomized, blinded, crossover trial. ANIMALS: Six adult horses weighing 494 ± 33 kg. METHODS: Treatments included meperidine 1 mg/kg IM with saline 6 mL subcutaneously, meperidine 1 mg/kg subcutaneously with saline 6 mL IM, and saline 6 mL subcutaneously and 6 mL IM, with a 7-day washout between treatments. Plasma meperidine concentrations and pharmacodynamic values (thermal and mechanical thresholds, physiological variables, fecal production) were collected at various time points for 24 hours. Accelerometry data were obtained for 8 hours to measure locomotor activity. Data were analyzed with a mixed effects model, and α was set at .05. RESULTS: Meperidine terminal half-life (T1/2 ), maximal plasma concentrations, and time to maximal concentration were 186 ± 59 and 164 ± 56 minutes, 265.7 ± 47.2 and 243.1 ± 80.1 ng/mL at 17 ± 6, and 24 ± 13 minutes for IM at subcutaneous administration, respectively. No effect of treatment or time was observed on thermal or mechanical thresholds, heart rate, respiratory rate, locomotor activity, frequency of defecations, or fecal weight (P > .2 for all). CONCLUSION: Maximum meperidine concentrations were achieved quickly with a short T1/2 in both treatment groups. Neither IM nor subcutaneous meperidine influenced thermal or mechanical threshold or physiological variables. CLINICAL SIGNIFICANCE: The short half-life and lack of detectable antinociceptive effect do not support IM or subcutaneous administration meperidine at 1 mg/kg for analgesia in horses.

The plausible mechanisms of tramadol for treatment of COVID-19.

Currently, no single medication has been approved for the management of coronavirus disease-2019 (COVID-19) caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, drug repositioningby investigating the use of existing drugs for management of COVID-19 patients is considered a desperate need. Tramadol is a commonly prescribed analgesic drug for treatment of moderate to severe pain with less potential for dependence and respiratory depression. Multiple evidence support that tramadol is a promising drug for treatment of COVID-19 patients. Herein, we discuss the possible beneficial effects of using tramadol against SARS-CoV-2 infection and their underlying mechanism of action. The anti-inflammatory effect of tramadol may help to suppress the COVID-19 related cytokine storm through decreasing interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP). Besides, tramadol activates natural killer (NK) and T-cells and enhances IL-2 secretion, which produce immune-enhancing effect against SARS-CoV-2. Recent studies confirmed that COVID-19 patients with acute respiratory failure showed increased fibrin formation and polymerization that may lead to thrombosis. Tramadol owing to its hypocoagulable effect may protect against venous thromboembolism in these patients. Moreover, tramadol can exert a cardioprotective effect via decreasing lactate dehydrogenase (LDH) level which is elevated in most of patients with COVID-19. Furthermore, the severity and mortality of COVID-19 have been correlated with old age patients, which may be due to the lack of antioxidant mechanisms and increased oxidative damage. Tramadol could protect COVID-19 patient from disease complications by increases the antioxidant enzymes superoxide dismutase and glutathione peroxidase while diminished malondialdehyde. More interestingly, tramadol as an effective analgesic and antitussive may have a beneficial effect on COVID-19 patients suffering from cough, headache, ache, and pain. The tramadol anti-psychotic effect may also protect against psychiatric disorders associated with SARS-CoV-2 infection. Moreover, tramadol has bactericidal activity against a wide range of pathogens including Pseudomonas aeruginosa which is common in severe COVID-19 patients leading to pneumonia with worse clinical outcomes. Therefore, we hypothesize that tramadol might be a promising adjuvant therapeutic option against SARS-CoV-2 infection. Based on that, tramadol should be considered as adjuvant therapy for COVID-19 clinical trials.

Temporal Factors Associated With Opioid Prescriptions for Patients With Pain Conditions in an Urban Emergency Department.

Importance: Opioid prescriptions for treatment of pain in emergency departments (EDs) are associated with long-term opioid use. The temporal pattern of opioid prescribing in the context of the opioid epidemic remains unknown. Objective: To examine the temporal pattern of opioid prescribing within an ED for varying pain conditions between 2009 and 2018. Design, Setting, and Participants: A population-based, cross-sectional study was conducted at the ED of an urban academic medical center. All patients treated within that ED between January 1, 2009, and December 31, 2018, were included. Main Outcomes and Measures: The proportion of patients prescribed an opioid for treatment of pain in the ED temporally by condition, condition type, patient demographics, and physician prescriber. Results: Between 2009 and 2018, 556 176 patient encounters took place in the ED, with 70 218 unique opioid prescriptions ordered. A total of 316 632 patients (55.9%) were female, 45 070 (42.6%) were of white race, and 43 412 (40.6%) were privately insured; the median age group was 41 to 45 years. Yearly opioid prescriptions decreased by 66.3% (from 16.3 to 5.5 opioids per 100 encounters) between 2013 and 2018, with a yearly adjusted odds ratio (aOR) of 0.808 (95% CI, 0.802-0.814) compared with the prior year. In patients with musculoskeletal pain (back, joint, limb, and neck pain), opioid prescribing decreased by 71.1% (from 36.7 to 10.6 opioids per 100 encounters between 2013 and 2018; aOR, 0.758; 95% CI, 0.744-0.773). In patients with musculoskeletal trauma (fracture, sprain, contusion, and injury), opioid prescribing decreased by 58.0% (from 34.2 to 14.8 opioids per 100 encounters; aOR, 0.811; 95% CI, 0.797-0.824). In patients with nonmusculoskeletal pain (abdominal pain, kidney stone, respiratory distress, and pharyngitis) opioid prescribing decreased by 53.7% (from 20.1 to 9.3 opioids per 100 encounters; aOR, 0.850; 95% CI, 0.834-0.868). Between 2009 and 2018, patients who were black (aOR, 0.760; 95% CI, 0.741-0.779) and those who were Asian (aOR, 0.714; 95% CI, 0.665-0.764) had the lowest odds of receiving an opioid compared with other racial/ethnic groups. Conclusions and Relevance: There was a substantial temporal decrease in the number of opioid prescriptions within this ED during the study period. This decrease was associated with substantial relative reductions in opioid prescribing for treatment of musculoskeletal pain compared with fractures and kidney stones.