Post-operative pain control in patients on buprenorphine or methadone for opioid use disorder.

OBJECTIVE: This study aimed to determine whether there is a difference in pain scores and opioid consumption after elective surgery in patients maintained on methadone or buprenorphine for opioid use disorder (OUD). Additionally, we investigated the impact of continuing or discontinuing methadone or buprenorphine on post-operative pain outcomes. DESIGN: A single-center retrospective cohort study. SETTING: Tertiary care medical center. PATIENTS AND PARTICIPANTS: Adults aged 18 years or older with OUD maintained on buprenorphine or methadone who underwent elective surgery between January 1, 2017, and January 1, 2021. INTERVENTIONS: Patients were identified through electronic medical records, and demographic and clinical data were collected. MAIN OUTCOME MEASURES: The primary outcome was opioid consumption at 24 hours post-operatively, measured in milligram morphine equivalents. The secondary outcome was opioid consumption and pain scores up to 72 hours post-operatively, assessed using a numeric rating scale. RESULTS: This study included 366 patients (64 percent on buprenorphine and 36 percent on methadone). Opioid utilization significantly increased when buprenorphine was not administered post-operatively. Both groups exhibited comparable total opioid consumption during the post-operative period. In the buprenorphine cohort, pain scores differed significantly based on the receipt of medications for OUD post-operatively. CONCLUSIONS: This study reinforces existing evidence supporting the continuation of medications for opioid use disorder, specifically buprenorphine and methadone, during the perioperative period. Dissemination of guideline recommendations is essential to ensure optimal post-operative pain management for this patient population.

Methadone versus other opioids for refractory malignant bone pain: a pilot randomised controlled study.

PURPOSE: Refractory cancer-induced bone pain (CIBP) affects a patient's functional capacity and quality of life, but there is limited evidence to guide opioid choice. We assessed the feasibility, tolerability and possible efficacy of methadone rotation (MR) compared to other opioid rotations (OOR) in this cohort. METHODS: Adults with CIBP and worst pain intensity ≥ 4/10 and/or opioid toxicity graded ≥ 2 on the Common Terminology Criteria for Adverse Events were randomised 1:1 to methadone or another opioid rotation. Standardised assessment tools were used at pre-defined study time points up to 14 days. RESULTS: Of 51 eligible participants, 38 (74.5%) consented, and 29 (76.3%, MR: 14, OOR: 15) completed the fourteen days follow-up post-opioid rotation. Both groups displayed significant reduction in average (MR: d = - 1.2, p = 0.003, OOR: d = - 0.8, p = 0.015) and worst pain (MR: d = - 0.9, p = 0.042, OOR: d = - 0.6, p = 0.048) and total pain interference score (MR: d = - 1.1, p = 0.042, OOR: d = - 0.7, p = 0.007). Oral morphine equivalent daily dose was reduced significantly in MR compared to the OOR group (d = - 0.8, p = 0.05). The incidence of opioid-related adverse events following MR was unchanged but lower in the OOR group (d = 0.9, 95% CI 0.1,1.7, p = 0.022). There were no within-group or between-group differences in satisfaction with analgesia at the end of the study. CONCLUSION: This pilot study demonstrated that MR and OOR in patients with refractory CIBP are feasible, safe and acceptable to patients. Appropriately powered multi-centre randomised controlled studies are needed to confirm the efficacy of MR and OOR in this cohort. TRIAL REGISTRATION: ACTRN12621000141842 registered 11 February 2021.

Evaluating adherence to ECG monitoring protocols for methadone patients in primary care.

BACKGROUND: Opioid Agonist Treatment (OAT) is the gold standard for managing Opioid Use Disorder (OUD). It is highly effective at reducing all-cause mortality and drug-related harms. Prescribing OAT, particularly methadone, is becoming increasingly complex as Scotland's OUD population ages. Older patients, with increased polypharmacy and multimorbidity, are more susceptible to QTc interval prolongation associated with methadone use. Therefore, adherence to ECG monitoring guidelines for patients prescribed methadone is crucial, though insights from substance use services indicate suboptimal compliance. Medically Assisted Treatment guidelines established by the Scottish Government advocate for shared care agreements, thus transferring OAT prescribing responsibilities to primary care. Understanding ECG monitoring guideline implementation in non-specialist services is vital for developing safe OAT services in primary care. AIM: This audit assessed adherence to NICE guidelines for ECG monitoring in OUD patients prescribed methadone in a Scottish primary care practice. METHOD: The notes of patients prescribed methadone were assessed using NICE criteria to determine eligibility for ECG monitoring. Eligible patients' medical records were reviewed to identify previous ECG investigations. RESULTS: Of 21 patients prescribed methadone, 16 qualified for ECG monitoring. Only 25% of eligible patients received ECG monitoring per NICE guideline, meaning 75% did not. CONCLUSION: These findings highlight that the issue of poor compliance with ECG monitoring guidelines is not limited to specialist services, but also affects primary care. Further exploration of barriers to guideline implementation is essential. Perhaps more resources are needed to integrate OAT services into primary care, which has taken on increased responsibilities without corresponding investment.

Inhibition of the protective effects of preconditioning in ischemia-reperfusion injury by chronic methadone: the role of pAkt and pSTAT3.

Cardiac ischemic preconditioning (Pre) reduces cardiac ischemia-reperfusion injury (IRI) by stimulating opioid receptors. Chronic use of opioids can alter the signaling pathways. We investigated the effects of chronic methadone use on IRI and Pre. The experiments were performed on isolated hearts of male Wistar rats in four groups: IRI, Methadone + IRI (M-IRI), Pre + IRI (Pre-IRI), Methadone + Pre + IRI (M-Pre-IRI). The infarct size (IS) in the Pre-IRI group was smaller than the IRI group (26.8% vs. 47.8%, P < 0.05). In the M-IRI and M-Pre-IRI groups, the infarct size was similar to the IRI group. Akt (Ak strain transforming) phosphorylation in the Pre-IRI, M-IRI, and M-Pre-IRI groups was significantly higher than in the IRI group (0.56 ± 0.15, 0.63 ± 0.20, and 0.93 ± 0.18 vs 0.28 ± 0.17 respectively). STAT3 (signal transducer and activator of transcription 3) phosphorylation in the Pre-IRI and M-Pre-IRI groups (1.38 ± 0.14 and 1.46 ± 0.33) was significantly higher than the IRI and M-IRI groups (0.99 ± 0.1 and 0.98 ± 0.2). Thus, chronic use of methadone not only has no protective effect against IRI but also destroys the protective effects of ischemic preconditioning. This may be due to the hyperactivation of Akt and changes in signaling pathways.

Methadone in combination with magnesium, ketamine, lidocaine, and dexmedetomidine improves postoperative outcomes after coronary artery bypass grafting: an observational multicentre study.

BACKGROUND: An optimal pharmacological strategy for fast-track cardiac anesthesia (FTCA) is unclear. This study evaluated the effectiveness and safety of an FTCA program using methadone and non-opioid adjuvant infusions (magnesium, ketamine, lidocaine, and dexmedetomidine) in patients undergoing coronary artery bypass grafting. METHODS: This retrospective, multicenter observational study was conducted across private and public teaching sectors. We studied patients managed by a fast-track protocol or via usual care according to clinician preference. The primary outcome was the total mechanical ventilation time in hours adjusted for hospital, body mass index, category of surgical urgency, cardiopulmonary bypass time and EuroSCORE II. Secondary outcomes included successful extubation within four postoperative hours, postoperative pain scores, postoperative opioid requirements, and the development of postoperative complications. RESULTS: We included 87 patients in the fast-track group and 88 patients in the usual care group. Fast-track patients had a 35% reduction in total ventilation hours compared with usual care patients (p = 0.007). Thirty-five (40.2%) fast-track patients were extubated within four hours compared to 10 (11.4%) usual-care patients (odds ratio: 5.2 [95% CI: 2.39-11.08; p < 0.001]). Over 24 h, fast-track patients had less severe pain (p < 0.001) and required less intravenous morphine equivalent (22.00 mg [15.75:32.50] vs. 38.75 mg [20.50:81.75]; p < 0.001). There were no significant differences observed in postoperative complications or length of hospital stay between the groups. CONCLUSION: Implementing an FTCA protocol using methadone, dexmedetomidine, magnesium, ketamine, lignocaine, and remifentanil together with protocolized weaning from a mechanical ventilation protocol is associated with significantly reduced time to tracheal extubation, improved postoperative analgesia, and reduced opioid use without any adverse safety events. A prospective randomized trial is warranted to further investigate the combined effects of these medications in reducing complications and length of stay in FTCA. TRIALS REGISTRATION: The study protocol was registered in the Australian New Zealand Clinical Trials Registry ( https://www.anzctr.org.au/ACTRN12623000060640.aspx , retrospectively registered on 17/01/2023).

Experience of Patients With Heroin Addiction Receiving Methadone Maintenance Treatment in Community Settings in Taiwan.

BACKGROUND: The World Health Organization has identified methadone maintenance therapy (MMT) as the most effective treatment for reducing patient dependence on heroin. In Taiwan, MMT has been used as a heroin harm reduction strategy since 2006. Although the effectiveness of MMT in reducing heroin addiction has been examined quantitatively in prison samples, little attention has been paid to the experiences and perspectives of patients with heroin addiction receiving MMT. This study was designed to address this gap in scientific knowledge. PURPOSE: The aim of this study was to investigate the experiences of individuals struggling with heroin addiction who are receiving MMT in the community. METHODS: A qualitative descriptive research approach and semistructured interviews were used in this study. We interviewed 14 participants who had received MMT in a medical center in central Taiwan. All of the interview data were recorded, transcribed, and analyzed using qualitative content analysis. RESULTS: Four themes emerged: (a) a chance to change one's life, (b) the helpfulness of MMT, (c) a sense of being restricted and controlled, and (d) need for support. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: This article fills a gap in current scholarly understanding of patient experiences and their perspectives on the helpfulness of MMT. Understanding patient experiences and perspectives is critical to informing and developing concrete strategies for clinical practice and MMT policy. Clinical professionals should assess patient needs and concerns to determine whether they are met by current treatment programs. Policymakers should design more flexible policies to facilitate easier access by patients to methadone to reduce the risk of relapse.

Intraoperative Methadone Use Is Associated With Reduced Postoperative Pain and More Rapid Opioid Weaning After Coronary Artery Bypass Grafting.

OBJECTIVE: To explore the association between intraoperative methadone use, postoperative pain, and opioid consumption after coronary artery bypass grafting (CABG) surgery. DESIGN: Retrospective cohort study. SETTING: Single academic medical center. PARTICIPANTS: Patients undergoing isolated CABG over a 5-year period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographic data, comorbidities, and intraoperative anesthetic medications were recorded. Primary study outcomes were average and maximum pain scores and morphine milligram equivalent consumption on the first 2 postoperative days (PODs). Linear mixed-effects regression models were used to examine the effect of intraoperative methadone use on study outcomes. Among 1,338 patients, 78.6% received intraoperative methadone (0.2 mg/kg). Patients who did not receive methadone had higher average (estimated [Est], 0.48; 95% confidence interval [CI], 0.22-0.73; p < 0.001) and maximum postoperative (Est, 0.49; 95% CI, 0.23-0.75; p < 0.001) pain scores over PODs 0 to 2. For postoperative opioid consumption, there was a significant intraoperative methadone use-time interaction effect on postoperative opioid use (odds ratio [OR], 2.21; 95% CI, 1.74-2.80; p < 0.001). Across PODs 0 to 2, patients who received intraoperative methadone had a faster decline in postoperative opioid use than those who did not receive intraoperative methadone. Patients who did not receive intraoperative methadone were extubated slightly faster (OR, 0.82; 95% CI, 0.72-0.93; p < 0.01). CONCLUSIONS: Our data suggest that the use of intraoperative methadone is safe, reduces postoperative pain, and expedites weaning from postoperative opioids after CABG surgery.

Two doses of subcutaneous methadone for postoperative analgesia in dogs undergoing tibial plateau levelling osteotomies.

OBJECTIVES: To evaluate analgesia, sedation and adverse effects of two doses of subcutaneous methadone in dogs undergoing tibial plateau levelling osteotomy. MATERIALS AND METHODS: Seventeen client-owned dogs undergoing unilateral tibial plateau levelling osteotomy were randomly allocated to receive either 0.25 mg/kg methadone (eight dogs) or 0.5 mg/kg methadone (nine dogs). All dogs were premedicated with methadone and 2 to 6 mcg/kg dexmedetomidine subcutaneously. They were induced and maintained on a standard protocol. All animals received a second dose of methadone subcutaneously 4 hours after premedication and a 4.4 mg/kg dose of carprofen subcutaneously at 8 hours after premedication. During surgery, blood pressure, heart rate and temperature were assessed every 5 minutes. Postoperatively, sedation scores, temperature, heart rate and Glasgow composite modified pain score - short form were assessed for 12 hours postoperatively. RESULTS: One of 17 (5.9%) dogs had intraoperative hypotension, nine of 17 dogs had intra-operative bradyarrhythmias and 17 of 17 dogs had intra-operative hypothermia. No dogs required intra-operative rescue. Composite modified pain score - short form scores were below the threshold for intervention in 16 of 17 (94.1%) animals. Only one of 17 (5.9%) dogs required rescue analgesia. Median sedation score was 0 by the T8 time point. Adverse events were rare in both groups with only vocalisation and hypothermia reported commonly postoperatively. CLINICAL SIGNIFICANCE: Two doses of methadone at either 0.25 or 0.5 mg/kg administered via subcutaneous injections pre-operatively and 4 hours later, along with 4.4 mg/kg carprofen subcutaneously 8 hours after the first methadone dose appear to provide sufficient pain control for up to 12 hours in dogs undergoing tibial plateau levelling osteotomy.

Simultaneous determination of methadone and tramadol in serum samples by ultrasonic-assisted micro solid phase extraction and gas chromatography-mass spectrometry.

Ultrasonic-assisted dispersive micro solid phase extraction (UA-DMSPE) is proposed as a fast and easy technique for the extraction and preconcentration of methadone and tramadol from serum samples. Different sorbents including carbon nanotubes, oxidized carbon nanotubes, and TiO2 nanoparticles were compared to extract methadone and tramadol. The best performance was obtained using oxidized carbon nanotubes due to the strong affinity between the drugs and carbon nanotube adsorbents. Final analysis of drugs performed by using gas chromatography-mass spectrometric detection. Different parameters affecting the extraction efficiency, such as the sample volume, amount of adsorbent, desorption solvent type and volume, centrifugation time, and speed were investigated and optimized. The striking features of this technique are correlated to its speed and the small volumes of sample (about 1 mL), desorption solvent (about 50 µL), and adsorbent (about 0.001 g) for analysis of drugs, and finally, milder centrifugation conditions relative to the previously reported adsorbent. The optimal parameters were achieved as follows: pH value was set at 9, the sample volume was adjusted to 1200 µL, the amount of adsorbent used was 1 mg, the extraction time was set at 5 min, and the volume of the desorption solvent was adjusted to 50 µL. The limits of detections (0.5 and 0.8 ng mL-1) and quantifications (1.5 and 2.5 ng mL-1) were obtained for methadone and tramadol, respectively. The developed method also showed good repeatability, relative standard deviation (RSD) of 9.49 % and 7.47 % (n = 5), for the spiked aqueous solution at the concentration level of 10, 50, and 100 ng mL-1 for analytes, and linearity, R ≥ 0.9809. The results showed that UA-DMSPE is a quick, relatively inexpensive, and environmentally friendly alternative technique for the extraction of opiate drugs from serum samples.

Intraoperative methadone for day-case gynaecological laparoscopy: A double-blind, randomised controlled trial.

Optimal pain relief in day-case surgery is imperative to patient comfort and timely discharge from hospital. Short-acting opioids are commonly used for analgesia in modern anaesthesia, allowing rapid recovery after surgery. Plasma concentration fluctuations from repeated dosing of short-acting opioids can cause patients to oscillate between analgesia with potential adverse effects, and inadequate analgesia requiring rescue dosing. Methadone's unique pharmacology may offer effective and sustained analgesia with less opioid consumption, potentially reducing adverse effects. Using a double-blind, randomised controlled trial, we compared post-anaesthesia care unit opioid consumption between day-case gynaecological laparoscopy patients who received either intravenous methadone (10 mg), or short-acting opioids intraoperatively. The primary outcome was post-anaesthesia care unit opioid consumption in oral morphine equivalents. Secondary outcomes included total opioid consumption, discharge opioid consumption, pain scores (0-10) until discharge, adverse effects (respiratory depression, postoperative nausea and vomiting, excess sedation), and rate of admission. Seventy patients were randomly assigned. Patients who received methadone consumed on average 9.44 mg fewer oral morphine equivalents in the post-anaesthesia care unit than the short-acting group (18.02 mg vs 27.46 mg, respectively, 95% confidence interval 0.003 to 18.88, P = 0.050) and experienced lower postoperative pain scores at every time point, although absolute differences were small. There was no evidence of lower hospital or discharge opioid consumption. No significant differences between the methadone and short-acting groups in other outcomes were identified: respiratory depression 41.2% versus 31.4%, Padjusted >0.99; postoperative nausea and vomiting 29.4% versus 42.9%, Padjusted >0.99; overnight admission 17.7% versus 11.4%, Padjusted >0.99; excess sedation 8.82% versus 8.57%, Padjusted >0.99. This study provides evidence that, although modestly, methadone can reduce post-anaesthesia care unit opioid consumption and postoperative pain scores after day-case gynaecological laparoscopy. There were no significant differences in any secondary outcomes.

Opioid use disorder in pediatric populations: considerations for perioperative pain management and precision opioid analgesia.

INTRODUCTION: Opioids are commonly used for perioperative analgesia, yet children still suffer high rates of severe post-surgical pain and opioid-related adverse effects. Persistent and severe acute surgical pain greatly increases the child's chances of chronic surgical pain, long-term opioid use, and opioid use disorder. AREAS COVERED: Enhanced recovery after surgery (ERAS) protocols are often inadequate in treating a child's severe surgical pain. Research suggests that 'older' and longer-acting opioids such as methadone are providing better methods to treat acute post-surgical pain. Studies indicate that lower repetitive methadone doses can decrease the incidence of chronic persistent surgical pain (CPSP). Ongoing research explores genetic components influencing severe surgical pain, inadequate opioid analgesia, and opioid use disorder. This new genetic research coupled with better utilization of opioids in the perioperative setting provides hope in personalizing surgical pain management, reducing pain, opioid use, adverse effects, and helping the fight against the opioid pandemic. EXPERT OPINION: The opioid and analgesic pharmacogenomics approach can proactively 'tailor' a perioperative analgesic plan to each patient based on underlying polygenic risks. This transition from population-based knowledge of pain medicine to individual patient knowledge can transform acute pain medicine and greatly reduce the opioid epidemic's socioeconomic, personal, and psychological strains globally.

A new coaxial flow-through probe for electromembrane extraction of methadone from clinical samples on-line coupled to capillary electrophoresis.

BACKGROUND: A new design of a flow-through coaxial electromembrane extraction (EME) probe that can be on-line coupled with CE instrument is described and tested. The supporting base of the probe is a PDMS microchip with T-shaped channels into which two coaxially arranged capillaries for inlet and outlet solutions are inserted. The extraction part of the probe is a porous polypropylene hollow fiber, sealed at one end and modified with nitrophenyloctyl ether (NPOE) extraction fluid. The internal volume of the extraction probe is 1.1 µL. RESULTS: The EME probe was tested on laboratory samples and methadone was extracted into 3.0 M AcOH as acceptor. The concentration dependence was linear in the range of 0.1-1.0 µg mL-1 at EME 300 s/150 V and in the range of 0.5-10.0 µg mL-1 at EME 100 s/150 V. The enrichment factor was greater than 30 and the LOD was 0.21 µg mL-1. The EME of methadone in clinical samples showed a linear concentration dependence in human urine and a nonlinear concentration dependence in serum. The distribution of methadone in each phase of the extraction system and the effect of extraction membrane thickness on the enrichment factor were studied. The EME probe can be applied repeatedly. SIGNIFICANCE: The supporting base of EME probe and flow gating interface (FGI) are realized by a microfluidic PDMS microchips cast in the laboratory without the use of lithography. A supporting PDMS chip with coaxially arranged capillaries and extraction membrane forms a compact analytical instrument. The entire EME/CE analysis process is performed on a laboratory-made instrument and automated by LabView.

Evaluation of urinary trace element levels in patients with opioid use disorder undergoing methadone treatment in western Iran.

The monitoring of essential and toxic elements in patients with Opioid Use Disorder (OUD) undergoing methadone treatment (MT) is important, and there is limited previous research on the urinary levels of these elements in MT patients. Therefore, the present study aimed to analyze certain elements in the context of methadone treatment compared to a healthy group. In this study, patients with opioid use disorder undergoing MT (n = 67) were compared with a healthy group of companions (n = 62) in terms of urinary concentrations of some essential elements (selenium (Se), zinc (Zn), copper (Cu), iron (Fe), manganese (Mn), calcium (Ca)) and toxic elements (lead (Pb), cadmium (Cd), arsenic (As), and chromium (Cr)). Urine samples were prepared using the acid digestion method with a mixture of nitric acid and perchloric acid and assessed using the ICP-MS method. Our results showed that the two groups had no significant differences in terms of gender, education level, occupation, and smoking status. Urinary concentrations of Se, Cu, and Fe levels were significantly lower in the MT group compared to the healthy subjects. However, the concentrations of Pb, Cd, As, Mn, Cr, and Ca in the MT group were higher than in the healthy group (p < 0.05). No significant difference was established between the levels of Zn in the two groups (p = 0.232). The results of regression analysis revealed that the differences between the concentration levels of all metals (except Zn) between two groups were still remained significant after adjusting for all variables (p < 0.05). The data obtained in the current study showed lower urinary concentrations of some essential elements and higher levels of some toxic elements in the MT group compared to the healthy subjects. These findings should be incorporated into harm-reduction interventions.

A comparative analysis of opioid-free and opioid-sparing anaesthesia techniques for laparoscopic ovariectomy in healthy dogs.

OBJECTIVE: To compare the perioperative analgesic effects of an opioid-free (OFA) and an opioid-sparing (OSA) anaesthetic protocol in dogs undergoing laparoscopic ovariectomy. STUDY DESIGN: Prospective, randomized, blinded, clinical trial. ANIMALS: A group of 28 client-owned dogs. METHODS: Dogs were allocated to one of two groups. The OFA group was administered intramuscular (IM) dexmedetomidine 5 µg kg-1 and ketamine 1 mg kg-1, followed by two intraoperative constant rate infusions (CRIs) of dexmedetomidine (3 µg kg-1 hour-1) and lidocaine (1 mg kg-1 loading dose, 2 mg kg-1 hour-1). The OSA group was administered IM dexmedetomidine 5 µg kg-1, ketamine 1 mg kg-1 and methadone 0.2 mg kg-1, followed by two intraoperative saline CRIs. In both groups, anaesthesia was induced with intravenous (IV) propofol 2 mg kg-1 and diazepam 0.2 mg kg-1 and maintained with isoflurane. Rescue dexmedetomidine (0.5 µg kg-1) was administered IV if there was a 20% increase in cardiovascular variables compared with pre-stimulation values. Ketorolac (0.5 mg kg-1) was administered IV when the surgery ended. Postoperative analgesia was evaluated using the Short Form-Glasgow Composite Measure Pain Scale and methadone (0.2 mg kg-1) was administered IM if the pain score was ≥ 6/24. Statistical analysis included mixed analysis of variance, Chi-square test and Mann-Whitney U test. RESULTS: There were no significant differences in the intraoperative monitored variables between groups. The OFA group showed a significantly lower intraoperative rescue analgesia requirement (p = 0.016) and lower postoperative pain scores at 3 (p =0.001) and 6 (p < 0.001) hours. No dogs were administered rescue methadone postoperatively. CONCLUSIONS AND CLINICAL RELEVANCE: Although both groups achieved acceptable postoperative pain scores with no need for further intervention, the analgesic efficacy of the OFA protocol was significantly superior to that of the OSA protocol presented and was associated with a lower intraoperative rescue analgesia requirement and early postoperative pain scores.

Institutional and Regional Variation in Opioid Prescribing for Hospitalized Infants in the US.

Importance: High-risk infants, defined as newborns with substantial neonatal-perinatal morbidities, often undergo multiple procedures and require prolonged intubation, resulting in extended opioid exposure that is associated with poor outcomes. Understanding variation in opioid prescribing can inform quality improvement and best-practice initiatives. Objective: To examine regional and institutional variation in opioid prescribing, including short- and long-acting agents, in high-risk hospitalized infants. Design, Setting, and Participants: This retrospective cohort study assessed high-risk infants younger than 1 year from January 1, 2016, to December 31, 2022, at 47 children's hospitals participating in the Pediatric Health Information System (PHIS). The cohort was stratified by US Census region (Northeast, South, Midwest, and West). Variation in cumulative days of opioid exposure and methadone treatment was examined among institutions using a hierarchical generalized linear model. High-risk infants were identified by International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes for congenital heart disease surgery, medical and surgical necrotizing enterocolitis, extremely low birth weight, very low birth weight, hypoxemic ischemic encephalopathy, extracorporeal membrane oxygenation, and other abdominal surgery. Infants with neonatal opioid withdrawal syndrome, in utero substance exposure, or malignant tumors were excluded. Exposure: Any opioid exposure and methadone treatment. Main Outcomes and Measures: Regional and institutional variations in opioid exposure. Results: Overall, 132 658 high-risk infants were identified (median [IQR] gestational age, 34 [28-38] weeks; 54.5% male). Prematurity occurred in 30.3%, and 55.3% underwent surgery. During hospitalization, 76.5% of high-risk infants were exposed to opioids and 7.9% received methadone. Median (IQR) length of any opioid exposure was 5 (2-12) cumulative days, and median (IQR) length of methadone treatment was 19 (7-46) cumulative days. There was significant hospital-level variation in opioid and methadone exposure and cumulative days of exposure within each US region. The computed intraclass correlation coefficient estimated that 16% of the variability in overall opioid prescribing and 20% of the variability in methadone treatment was attributed to the individual hospital. Conclusions and Relevance: In this retrospective cohort study of high-risk hospitalized infants, institution-level variation in overall opioid exposure and methadone treatment persisted across the US. These findings highlight the need for standardization of opioid prescribing in this vulnerable population.

Comparison of analgesic efficacy of tramadol, morphine and methadone in cats undergoing ovariohysterectomy.

OBJECTIVES: The aim of this study was to compare the analgesic efficacy and the effect on physiological variables and behavior of the use of tramadol, methadone and morphine as preoperative analgesia in healthy cats undergoing elective ovariohysterectomy. METHODS: Cats undergoing ovariohysterectomy were randomly assigned to receive one of the following premedication treatments intramuscularly: methadone (0.2 mg/kg; n = 10); morphine (0.2 mg/kg; n = 10); or tramadol (3 mg/kg; n = 10). Induction of anesthesia was done with propofol, and maintenance of anesthesia was done with isoflurane. Intraoperative heart rate, arterial blood pressure, respiratory rate, end-tidal isoflurane concentration and frequency of rescue analgesia (fentanyl 2.5 µg/kg) were compared between groups. Postoperative analgesia was assessed using the UNESP-Botucatu Multidimensional Composite Pain Scale, and perioperative serum glucose, cortisol concentrations and postoperative rescue analgesia were evaluated. RESULTS: Intraoperative rescue analgesia was required in 76.5% of cats at some time during surgery, and 27% of cats required postoperative rescue analgesia up to 6 h after extubation. There were no significant differences between groups with respect to intraoperative and postoperative rescue analgesia, pain scale scores and end-tidal isoflurane concentrations. In the immediate postoperative period, after extubation, most of the patients presented with hypothermia; however, 1-6 h postoperatively, hyperthermia was observed in most of the patients, and was most common in the tramadol group. CONCLUSIONS AND CLINICAL RELEVANCE: Under the conditions of this study, methadone, morphine and tramadol produced satisfactory postoperative analgesia in most of the cats undergoing ovariohysterectomy, and the effects lasted up to 6 h postoperatively. Intraoperative analgesia was not sufficient in most cases. Significant cardiovascular or respiratory effects contraindicating the use of these drugs were not found. Postanesthetic hyperthermia occurred with all opioids studied and was more frequent in the tramadol group.

Intrauterine exposure to maternal opioid maintenance treatment and associated risk factors may impair child growth.

AIM: How maternal opioid maintenance treatment (OMT) affects children is under-researched. This population-based registry study investigated child growth and somatic health following intrauterine exposure to this treatment. METHODS: Children born between 1 March 2011 and 30 May 2021 to mothers who used buprenorphine, buprenorphine-naloxone, or methadone throughout their pregnancies were followed for 2 years at the Helsinki University Hospital, Finland. Appropriate statistical tests were used to compare the treatment groups. RESULTS: Of the 67 neonates, 52% were male, 96% were born full-term and 63% were treated for neonatal opioid withdrawal syndrome. Otherwise, the children were predominantly healthy, although relatively small: 22% were small for gestational age, the methadone group children being the smallest. Foetal exposure to maternal methadone treatment, illicit drugs, hepatitis C and smoking were associated with small for gestational age; the former two were also associated with later slower growth, especially head growth and weight gain (p < 0.001). However, 29% were overweight at 2 years. CONCLUSION: Using child growth as the outcome, we found that buprenorphine-naloxone and buprenorphine-monotherapy had equal effects as forms of maternal OMT. Exposure to multiple risk factors may harm foetal and subsequent growth. We recommend long-term follow-up of children exposed to maternal OMT.

Methadone Requires the Co-Activation of µ-Opioid and Toll-Like-4 Receptors to Produce Extracellular DNA Traps in Bone-Marrow-Derived Mast Cells.

Methadone is an effective and long-lasting analgesic drug that is also used in medication-assisted treatment for people with opioid use disorders. Although there is evidence that methadone activates µ-opioid and Toll-like-4 receptors (TLR-4s), its effects on distinct immune cells, including mast cells (MCs), are not well characterized. MCs express µ-opioid and Toll-like receptors (TLRs) and constitute an important cell lineage involved in allergy and effective innate immunity responses. In the present study, murine bone-marrow-derived mast cells (BMMCs) were treated with methadone to evaluate cell viability by flow cytometry, cell morphology with immunofluorescence and scanning electron microscopy, reactive oxygen species (ROS) production, and intracellular calcium concentration ([Ca2+]i) increase. We found that exposure of BMMCs to 0.5 mM or 1 mM methadone rapidly induced cell death by forming extracellular DNA traps (ETosis). Methadone-induced cell death depended on ROS formation and [Ca2+]i. Using pharmacological approaches and TLR4-defective BMMC cultures, we found that µ-opioid receptors were necessary for both methadone-induced ROS production and intracellular calcium increase. Remarkably, TLR4 receptors were also involved in methadone-induced ROS production as it did not occur in BMMCs obtained from TLR4-deficient mice. Finally, confocal microscopy images showed a significant co-localization of µ-opioid and TLR4 receptors that increased after methadone treatment. Our results suggest that methadone produces MCETosis by a mechanism requiring a novel crosstalk pathway between µ-opioid and TLR4 receptors.