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Background: This study compares dexmedetomidine and buprenorphine as potential adjuvants for spinal anesthesia. Dexmedetomidine enhances sensory block and minimizes the need for pain medication, while buprenorphine, a long-acting opioid, exhibits a favorable safety profile compared to traditional opioids., Methods: PubMed, Cochrane and EMBASE were systematically searched in December 2023., Eligibility Criteria: RCTs with patients scheduled for lower abdominal, pelvic, or lower limb surgeries; undergoing spinal anesthesia with a local anesthetic and buprenorphine or dexmedetomidine., Results: Eight RCTs involving 604 patients were included. Compared with dexmedetomidine, buprenorphine significantly reduced time for sensory regression to S1 (Risk Ratio [RR = -131.28]; 95% CI -187.47 to -75.08; I 2 = 99%) and motor block duration (RR = -118.58; 95% CI -170.08 to -67.09; I 2 = 99%). Moreover, buprenorphine increased the onset time of sensory block (RR = 0.42; 95% CI 0.03 to 0.81; I 2 = 93%) and increased the incidence of postoperative nausea and vomiting (RR = 4.06; 95% CI 1.80 to 9.18; I ² = 0%). No significant differences were observed in the duration of analgesia, onset time of motor block, time to achieve the highest sensory level, shivering, hypotension, or bradycardia., Conclusions: The intrathecal administration of buprenorphine, when compared to dexmedetomidine, is linked to reduction in the duration of both sensory and motor blocks following spinal anesthesia. Conversely, buprenorphine was associated with an increased risk of postoperative nausea and vomiting and a longer onset time of sensory block. Further high-quality RCTs are essential for a comprehensive understanding of buprenorphine's effects compared with dexmedetomidine in spinal anesthesia., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Sociedade Brasileira de Anestesiologia. Published by Elsevier España S.L.U. All rights reserved.)

Importance: Short-term and long-term opioid treatment have been associated with increased pain sensitivity (ie, opioid-induced hyperalgesia). Treatment of opioid use disorder (OUD) mainly involves maintenance with methadone and buprenorphine, and observations of heightened cold pain sensitivity among patients are often considered evidence of opioid-induced hyperalgesia., Objective: To critically examine the evidence that hyperalgesia in patients with OUD is related to opioid use., Data Sources: Web of Science, PubMed, and Embase between March 1, 2023, and April 12, 2024, were searched., Study Selection: Studies assessing cold pressor test (CPT) pain responses during treatment seeking, pharmacological treatment, or abstinence in patients with OUD history were included., Data Extraction and Synthesis: Multilevel random-effects models with robust variance estimation were used for all analyses. Study quality was rated with the JBI checklist. Funnel plots and Egger regression tests were used to assess reporting bias., Main Outcomes and Measures: Main outcomes were pain threshold, tolerance, and intensity in patients and healthy controls, and unstandardized, standardized (Hedges g), and percentage differences (%Δ) in these measures between patients and controls. The association between pain sensitivity and opioid tolerance, withdrawal, and abstinence indices was tested with meta-regression., Results: Thirty-nine studies (1385 patients, 741 controls) met the inclusion criteria. Most studies reported CPT data on patients undergoing opioid agonist treatment. These patients had a mean 2- to 3-seconds lower pain threshold (95% CI, -4 to -1; t test P = .01; %Δ, -22%; g = -0.5) and 29-seconds lower pain tolerance (95% CI, -39 to -18; t test P < .001; %Δ, -52%; g = -0.9) than controls. Egger tests suggested that these differences may be overestimated. There were some concerns of bias due to inadequate sample matching and participant dropout. Meta-regressions yielded no clear support for hyperalgesia being opioid related., Conclusion and Relevance: Patients receiving opioid agonist treatment for OUD are hypersensitive to cold pain. It remains unclear whether hyperalgesia develops prior to, independent of, or as a result of long-term opioid treatment. Regardless, future studies should investigate the impact of hyperalgesia on patients' well-being and treatment outcomes.

Abstract: Naltrexone, buprenorphine, and methadone are Food and Drug Administration-approved medications for the treatment of opioid use disorder in the United States. Naltrexone, an opioid antagonist, can precipitate opioid withdrawal if administered too quickly after the use of full or partial opioid agonists for those with either dependence or use disorder. We describe a case of severe precipitated opioid withdrawal syndrome after reported buprenorphine extended-release (XR) administration, despite the patient having been stable on buprenorphine-XR for several years, with no missed doses or recent opioid use. Naltrexone levels were sent and helped to diagnose suspected inadvertent naltrexone-XR administration in this patient, which was likely the etiology of his precipitated opioid withdrawal syndrome. We suggest the use of high-dose buprenorphine, as well as adjunctive medications including benzodiazepines, as a treatment strategy for naltrexone-XR precipitated withdrawal in the setting of chronic buprenorphine-XR treatment., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 American Society of Addiction Medicine.)

Background and Objectives: Opioid maintenance treatment (OMT), with methadone or buprenorphine, is a key approach for managing opioid use disorder (OUD) during pregnancy. Despite buprenorphine's superior short-term outcomes, its long-term effects remain understudied. This study aims to evaluate the effects of prenatal OMT exposure on the incidence of childhood neurodevelopmental disorders (NDDs) considering timing effect., Methods: A retrospective cohort study using Rhode Island Medicaid data linked to vital statistics from 2008 to 2018 was conducted. The study included pregnancies having live birth from 2008 to 2016 with continuous Medicaid insurance and OUD diagnosis within 3 months preceding conception until delivery. At least one buprenorphine dispensing or a claim of methadone was required for exposure definition. Exposure was evaluated during early (0-90 days) or late (>90 days) gestation, or at any pregnancy phase. NDDs, including autism, attention-deficit/hyperactivity disorder (ADHD), learning disabilities, speech/language disorders, developmental coordination disorder, intellectual disability, and behavioral disorders, were identified using validated algorithms. Applying Cox proportional-hazard models with propensity score overlap weighting, adjusted hazard ratios (aHR) were calculated, mitigating potential confounders. Children were followed up from birth until NDD diagnosis, disenrollment, or study end., Results: Of 416 mother-child dyads with OUD, 40% used methadone and 20% had buprenorphine exposure during pregnancy. NDDs were observed in 36% of children with early methadone exposure compared to 17% in the early buprenorphine exposed group (aHR: 2.75; 95% confidence interval [CI]: 1.42-5.35). Further comparison to late buprenorphine exposure, late methadone exposure was associated with higher NDD risk (aHR: 2.05; 95% CI: 1.09-3.86). Compared to unexposed group, children exposed to methadone during early and late periods showed higher NDD incidences (aHR: 2.33; 95% CI: 1.51-3.60 and aHR: 2.42; 95% CI: 1.54-3.80, respectively)., Discussion: The study suggests that buprenorphine is a good treatment option for OUD during pregnancy due to minimal long-term neurodevelopmental impacts on children. However, further extensive research is necessary to rule-out potential confounding., (© 2024 Pharmacotherapy Publications, Inc.)

Background: Discontinuing sublingual buprenorphine (SL-BUP) has been identified by some patients as a potential outcome of success for opioid use disorder treatment. The process of tapering SL-BUP can be lengthy as unpleasant opioid withdrawal symptoms limit the pace of dose adjustments. Uncontrolled withdrawal symptoms pose a risk for return to illicit opioid use and more patient-centered options for tapering SL-BUP are needed. Previous case reports have identified using extended-release subcutaneous buprenorphine (ER-BUP) to minimize withdrawal symptoms as the dose self-decreases very gradually. Ideal dosing strategies, appropriate patient characteristics, and duration of buprenorphine release with the ER-BUP injection are not well described., Patient Cases: We present 8 cases where a single 100 mg ER-BUP injection was administered to patients experiencing intolerable withdrawal symptoms during SL-BUP taper. Patients were taking between 2 and 6 mg SL-BUP daily prior to injection. Three patients experienced mild adverse effects the day after receiving injection, all of which were taking lower SL-BUP doses (2-3 mg). In the 12 months following injection, 3 patients experienced mild, but tolerable withdrawal symptoms at variable intervals. Two patients returned to taking SL-BUP and no patients returned to illicit opioid use. Buprenorphine urine toxicology showed elimination of buprenorphine occurred after 24 weeks., Discussion: Findings from these cases support current evidence-based guidance that ER-BUP tapering is better tolerated than traditional SL-BUP tapering. These patient cases and pharmacokinetic modeling of ER-BUP suggest that a target preinjection dose of 2 to 6 mg SL-BUP will minimize the risk of more severe adverse effects or withdrawal symptoms. Patients and providers should ensure that remission is well-established before initiating SL-BUP taper. A shared decision-making approach can help support patient autonomy and understanding safety risks of discontinuing SL-BUP. Future prospective studies with larger populations could further refine dosing strategies with various SL-BUP preinjection doses and newer ER-BUP formulations., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Buprenorphine is a partial mu opioid receptor agonist with high affinity to its receptor, which raises concerns of blocking or displacing full opioid agonists when used during the perioperative period of surgical patients. However, buprenorphine itself has high analgesic potency and discontinuing buprenorphine may lead to suboptimal pain control and risk for opioid use disorder relapse. There is limited data for the continuation of buprenorphine perioperatively., Methods: This study is a retrospective cohort study of adult surgical patients taking buprenorphine for opioid use disorder at an urban, teaching, level 1 trauma center. Patients were split into two groups based on whether buprenorphine was continued (n = 46) or held (n = 28) within the first 48 h after surgery., Results: Those who had buprenorphine continued in the first 48 h postoperatively required half the dose of nonbuprenorphine opioids compared to those who had buprenorphine held (113.25 versus 255.75 oral morphine equivalents, P = 0.0040). Both groups had a similar level of analgesia and incidence of adverse events. Nearly all patients who continued buprenorphine in the first 48 h postoperatively were discharged on this agent, while only half of patients who had buprenorphine held were restarted on it at discharge (92.68% versus 56.52%, P = 0.0013)., Conclusions: This present study found lower nonbuprenorphine opioid requirements in patients with continued versus held perioperative buprenorphine use with no difference in degree of analgesia., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Importance: Buprenorphine combined with naloxone is commonly used to treat opioid use disorders outside of pregnancy. In pregnancy, buprenorphine alone is generally recommended because of limited perinatal safety data on the combination product., Objective: To compare perinatal outcomes following prenatal exposure to buprenorphine with naloxone vs buprenorphine alone., Design, Settings, and Participants: Population-based cohort study using health care utilization data from Medicaid-insured beneficiaries in the US from 2000 to 2018. The cohort was restricted to pregnant individuals linked to their liveborn infants, with maternal Medicaid enrollment from 3 months before pregnancy to 1 month after delivery and infant enrollment for the first 3 months after birth, unless they died sooner., Exposure: Use of buprenorphine with naloxone vs buprenorphine alone during the first trimester based on outpatient dispensings., Main Outcomes and Measures: Outcomes included major congenital malformations, low birth weight, neonatal abstinence syndrome, neonatal intensive care unit admission, preterm birth, respiratory symptoms, small for gestational age, cesarean delivery, and maternal morbidity. Confounder-adjusted risk ratios were calculated using propensity score overlap weights., Results: This study identified 3369 pregnant individuals exposed to buprenorphine with naloxone during the first trimester (mean [SD] age, 28.8 [4.6] years) and 5326 exposed to buprenorphine alone or who switched from the combination to buprenorphine alone by the end of the first trimester (mean [SD] age, 28.3 [4.5] years). When comparing buprenorphine combined with naloxone with buprenorphine alone, a lower risk for neonatal abstinence syndrome (absolute risk, 37.4% vs 55.8%; weighted relative risk, 0.77 [95% CI, 0.70-0.84]) and a modestly lower risk for neonatal intensive care unit admission (absolute risk, 30.6% vs 34.9%; weighted relative risk, 0.91 [95% CI, 0.85-0.98]) and small for gestational age (absolute risk, 10.0% vs 12.4%; weighted relative risk, 0.86 [95% CI, 0.75-0.98]) was observed. For maternal morbidity, the comparative rates were 2.6% vs 2.9%, respectively, and the weighted relative risk was 0.90 (95% CI, 0.68-1.19). No differences were observed with respect to major congenital malformations overall, low birth weight, preterm birth, respiratory symptoms, or cesarean delivery. Results were consistent across sensitivity analyses., Conclusions and Relevance: There were similar and, in some instances, more favorable neonatal and maternal outcomes for pregnancies exposed to buprenorphine combined with naloxone compared with buprenorphine alone. For the outcomes assessed, compared with buprenorphine alone, buprenorphine with naloxone during pregnancy appears to be a safe treatment option. This supports the view that both formulations are reasonable options for the treatment of opioid use disorder in pregnancy, affirming flexibility in collaborative treatment decision-making.

Importance: Buprenorphine treatment of opioid use disorder (OUD) is safe and effective, but opioid withdrawal during treatment initiation is associated with poor retention in care. As fentanyl has replaced heroin in the drug supply, case reports and surveys have indicated increased concern for buprenorphine-precipitated withdrawal (PW); however, some observational studies have found a low incidence of PW., Objective: To estimate buprenorphine PW incidence and assess factors associated with PW among emergency department (ED) or hospitalized patients., Design, Setting, and Participants: This retrospective cohort study at 3 academic hospitals in Philadelphia, Pennsylvania, included adults with OUD who underwent traditional or high-dose buprenorphine initiation between January 1, 2020, and December 31, 2021. Exclusion criteria included low-dose buprenorphine initiation and missing documentation of opioid withdrawal severity within 4 hours of receiving buprenorphine., Exposure: Buprenorphine initiation with an initial dose of at least 2 mg of sublingual buprenorphine after a Clinical Opiate Withdrawal Scale (COWS) score of 8 or higher. Additional exposures included 4 predefined factors potentially associated with PW: severity of opioid withdrawal before buprenorphine (COWS score of 8-12 vs ≥13), initial buprenorphine dose (2 vs 4 or ≥8 mg), body mass index (BMI) (<25 vs 25 to <30 or ≥30; calculated as weight in kilograms divided by height in meters squared), and urine fentanyl concentration (0 to <20 vs 20 to <200 or ≥200 ng/mL)., Main Outcome and Measures: The main outcome was PW incidence, defined as a 5-point or greater increase in COWS score from immediately before to within 4 hours after buprenorphine initiation. Logistic regression was used to estimate the odds of PW associated with the 4 aforementioned predefined factors., Results: The cohort included 226 patients (150 [66.4%] male; mean [SD] age, 38.6 [10.8] years). Overall, 26 patients (11.5%) met criteria for PW. Among patients with PW, median change in COWS score was 9 points (IQR, 6-13 points). Of 123 patients with confirmed fentanyl use, 20 (16.3%) had PW. In unadjusted and adjusted models, BMI of 30 or greater compared with less than 25 (adjusted odds ratio [AOR], 5.12; 95% CI, 1.31-19.92) and urine fentanyl concentration of 200 ng/mL or greater compared with less than 20 ng/mL (AOR, 8.37; 95% CI, 1.60-43.89) were associated with PW., Conclusions and Relevance: In this retrospective cohort study, 11.5% of patients developed PW after buprenorphine initiation in ED or hospital settings. Future studies should confirm the rate of PW and assess whether bioaccumulated fentanyl is a risk factor for PW.

Introduction: Extended-release subcutaneous buprenorphine is an increasingly common treatment for opioid use disorder. Serious adverse events are rare and may be poorly understood. This report describes an early surgical intervention to address tissue necrosis resulting from misplaced subcutaneous buprenorphine injection. We review identifying characteristics that distinguish the necrotic reaction from other adverse effects of subcutaneous buprenorphine and offer guidance to continue treatment with subcutaneous buprenorphine., Case Report: A 33-year-old patient returned to clinic within an hour of his buprenorphine injection, reporting pain and skin changes unlike his previous injections. Non blanching erythema consistent with early necrosis was evident, and the patient was referred for surgical removal of his buprenorphine depot. The patient had uncomplicated healing of the surgical site and was provided sublingual buprenorphine before returning to continue treatment with subcutaneous buprenorphine., Discussion: Although skin necrosis is known to be a rare complication of subcutaneous buprenorphine injection, early surgical excision to limit injury has not been described. Signs and symptoms of skin necrosis must be better understood to facilitate early intervention and continued treatment., Conclusions: This case affirms that a patient may continue treatment with subcutaneous buprenorphine despite suffering skin necrosis and demonstrates the value of early surgical intervention after superficial placement of extended-release buprenorphine., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 American Society of Addiction Medicine.)

Introduction: Adverse effects of opioids are common among older individuals, and undertreatment as well as overuse can be an issue. Epidemiological data on opioid use in older individuals are available, but scarce in hospitalized patients. Aims: The aim of this study is to examine the one-day prevalence of opioid use among older inpatients and identify the factors associated with both opioid use and dosage. Materials and methods: One-day cross-sectional study with data collected from geriatric units across 14 Belgian hospitals. The primary focus of the study is to assess the prevalence of opioid use and dosage, along with identifying associated factors. To achieve this, a multiple binary logistic regression model was fitted for opioid use, and a multiple linear regression model for opioid dose. Results: Opioids were used in 24.4% of 784 patients, of which 57.9% was treated with tramadol, 13.2% with oxycodone or morphine and 28.9% with transdermal buprenorphine or fentanyl. The odds for opioid use were 4.2 times higher in patients in orthogeriatric units compared to other patients (OR=4.2, 95% CI=2.50-7.05). The prevalence of opioid use was 34% higher in patients without dementia compared to patients with dementia (OR=0.66, 95% CI=0.46-0.95). The overall mean daily dosage was 14.07mg subcutaneous morphine equivalent. After adjustment for age, gender and dementia, dosage was only associated with type of opioid: the estimated mean opioid dose was 70% lower with tramadol (mean ratio=0,30,95% CI=0,23-0,39) and 67% lower with oxycodone and morphine (mean ratio=0,33, 95% CI=0,22-0,48) compared to transdermal buprenorphine and transdermal fentanyl. Conclusions: One in four patients received opioid treatment. It is not clear whether this reflects under- or overtreatment, but these results can serve as a benchmark for geriatric units to guide future pain management practices. The utilization of transdermal fentanyl and buprenorphine, resulting in higher doses of morphine equivalent, poses significant risks for side effects.

Aim: Explore the safety of Belbuca® (buprenorphine buccal film), buprenorphine transdermal patches and oral opioids for chronic low back pain (cLBP) treatment. Methods: The retrospective analysis of the MarketScan Commercial database (2018-2021) included treatment-naive cLBP adults. The first date of buprenorphine (Belbuca and transdermal patch) or opioid prescription was index date. Cohorts were defined based on the index medication. Observation included a 6-month pre-index period, while post-index lasted until the end of continuous insurance coverage. There were 44 relevant treatment-emergent adverse events (TEAEs) identified in the literature. Incidence rate ratio (IRR) and incidence rate difference (IRD) were used to compare serious TEAE rates (in 1000 person-years) between cohorts. Propensity-score matching minimized the selection bias. Results: Buprenorphine had lower rates of 15 serious TEAEs than oral opioids (all p ≤ 0.037), while higher rates only for serious dizziness (IRR 2.44, p = 0.011; driven by Belbuca), opioid abuse/dependence (IRR 3.13, p = 0.004; driven by patches) and cholecystitis (IRD 20.25, p = 0.044; an outlier). Additionally, a comparison between Belbuca and oral opioids showed lower rates of 13 serious TEAEs (all p ≤ 0.024) and a higher serious dizziness rate (IRR 3.17, p = 0.024). Although the rates of serious opioid abuse/dependence were similar (24.60 vs 26.93, p = 0.921), all Belbuca patients and none of the opioid patients had a positive history of these events. Belbuca also had lower rates of five serious TEAEs than transdermal patches (all p ≤ 0.018), including a serious opioid abuse/dependence (IRR 0.04, p < 0.001), but higher rates of serious cholecystitis (IRD 52.17, p = 0.035; an outlier) and suicidal ideation (IRD 156.50, p < 0.001; an outlier). Conclusion: Buprenorphine had a better safety profile than oral opioids in cLBP treatment. Belbuca showed a more favorable TEAE profile than buprenorphine transdermal patches and oral opioids.

Background: The association between opioid use and the risk of ventricular arrhythmias (VA) is poorly understood., Aims: The objective of this study was to synthesize the evidence on the risk of VA associated with opioid use., Materials & Methods: We systematically searched the Cochrane Library, Embase, MEDLINE, and CINAHL databases in July 2022. Risk of bias was assessed using the Cochrane risk for bias tool for randomized controlled trials (RCTs) and ROBINS-I for observational studies. Certainty of evidence was assessed using GRADE., Results: We included 15 studies (12 observational, 2 post hoc analyses of RCTs, 1 RCT). Most studies focused on opioid use for maintenance therapy (n = 9), comparing methadone to buprenorphine (n = 13), and reported QTc prolongation (n = 13). Six observational studies had a critical risk of bias, and one RCT was at high risk of bias. Two studies could not be included in the meta-analysis as they reported a different outcome and studied an opioid antagonist. Meta-analysis of 13 studies indicated that the use of methadone was associated with an increased risk of VA compared to the use of buprenorphine, morphine, placebo, or levacetylmethadol (risk ratio [RR], 2.39; 95% CI, 1.31-4.35; I 2  = 60%). The pooled estimate varied greatly between observational studies (RR, 2.12; 95% CI, 1.15-3.91; I 2  = 62%) and RCTs (RR, 14.09; 95% CI, 1.52-130.61; I 2  = 0%), but both indicated an increased risk., Conclusion: In this systematic review and meta-analysis, we found that methadone use is associated with more than twice the risk of VA compared to comparators. However, our findings should be interpreted cautiously given the limited quality of the available evidence., (© 2024 The Author(s). Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Background: Buprenorphine may be safer and better-tolerated than full mu opioid receptor (MOR) agonists. Whether it effectively controls cancer-related pain is unclear. A prior review (Cochrane 2015) did not support prioritizing buprenorphine over full MOR agonists for cancer-associated pain., Purpose/hypothesis: We conducted an updated systematic review of buprenorphine's effect on cancer- related pain including both new studies and additional study designs. Procedures/data/observations: We searched Cochrane, OVID Medline, EMBASE, EBSCO and Web of Science for studies published in any language up to May 2023 for studies that examined buprenorphine's impact upon pain severity/intensity in patients with active cancer. Risk of bias and study quality were assessed using the Cochrane Collaboration tool for randomized controlled trials (RCTs), and the Newcastle-Ottawa Scale for cohort and casecontrol studies. Data were synthesized using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria., Conclusions/applications: 2322 publications were identified and 42 studies were included (14 RCTs, 10 pre-post uncontrolled, 5 cohort, and 2 case-control studies). All had moderate-high risk of bias. One RCT showed buprenorphine was superior to placebo. 11 RCTs (12 papers) showed buprenorphine was as effective as full MOR agonists for cancer pain. 10-30 percent of cancer patients trialing buprenorphine did not achieve adequate response.

Background: The CPG's updated recommendation is supported by buprenorphine's lower risk of overdose and misuse.(1) In comparison to full mu-opioid agonists, buprenorphine possesses a superior safety profile with respect to respiratory depression, even in non-dependent individuals, and fatal overdose, when not combined with other sedating medications.(2-5) Purpose/hypothesis: This project identifies prescribing trends of buprenorphine for chronic pain before and after implementing two pharmacy interventions. Procedures/data/observations: Patient charts were reviewed before and after removal of a drug authorization key in the electronic health record and development of an educational presentation for providers. In the pre-intervention group, 19 patients were included and 13 patients in the post-intervention group. Prescriptions for buprenorphine decreased by 31.5% from the pre-intervention to post-intervention period, but three new prescriptions were started after interventions., Conclusions/applications: Adverse reactions were the cause of the decrease in prescriptions, most commonly nausea and vomiting. This data may be valuable to providers as they expand their knowledge about buprenorphine's analgesic use. This is a longitudinal project and identifying barriers that may limit prescribing of buprenorphine may be beneficial for future educational interventions.

Background: Although buprenorphine use has increased dramatically over the past decade, its unique pharmacologic and pharmacokinetic profile often leads to misconceptions about its overall utility and has created a drastic underrepresentation in patients with chronic non-can- cer pain. A common misnomer associated with buprenorphine is because of 'partial agonist' activity, it exhibits a plateauing of typical opioid-related side effects (including respiratory depression, constipation, euphoria, and hypogonadal axis suppression), but additionally it must exhibit a plateauing effect of overall analgesic potential. However, novel downstream molecular and cellular mechanisms offer new insights that help support the clinical potential that buprenorphine's analgesic actions may not have a ceiling, like its side effect profile. This interactive symposium will provide an enhanced review of the evolving research that helps unravel the complexity around buprenorphine's varying pharmacologic effects including actions on various opioid receptors, promiscuity to elicit varying actions on mu-opioid receptors coupled with different isoforms of G~ subunits, role in the intracellular recruitment of beta-arrestin, binding to different splice variants of mu-opioid receptors, and greater spinal versus supraspinal activity. The final half of this symposium will be designed to substantiate evidence with various human clinical trial data to further support buprenorphine's place on the analgesic ladder.

Background: Bone marrow transplant (BMT) offers potential cure for cancer and a spectrum of otherwise incur- able diseases. The BMT process can cause multi-systemic pain in patients with sickle cell disease (SCD) refractory to high-dose opioid analgesics during BMT because of their pre-existing opioid-tolerance. Because of frequent pain resulting in hyperalgesia and chronic opioid use, SCD patients undergoing BMT often experience excruciating pain uncontrolled by exceedingly high-dose opioids with severe and intolerable adverse effects., Purpose/hypothesis: There is a small but growing body of literature about the successful buprenorphine effect for SCD's chronic pain management that had failed sufficient pain relief by the traditional full-agonist opioids in the outpatient setting. However, the buprenorphine use for acute inpatient pain management has not been previously researched. Pilot prospective clinical trial with buprenorphine-based pain management for acute BMT-related pain was initiated for SCD patients' pain uncontrolled by full-agonist opioids. Procedures/data/observations: Buprenorphine was started as scheduled and as-needed analgesics, supplemented by full-agonist opioids upon consultation for uncontrolled BMT-related pain of SCD patients. Patients' 24-hour opioid requirement by morphine equivalent daily doses (MEDD) were assessed at 3 time points: 1)immediately before pain escalation; 2)consultation; 3)discharge. MEDDs were compared to those of patients treated with full-agonist opioids only. Cases treated by full-agonist opioids (morphine/hydromorphone/fentanyl/methadone/oxycodone) had MEDD escalation by 1230-16300% by discharge compared to immediately before BMT-related pain escalation. Buprenorphine-supported cases had significantly smaller MEDD increase by 220-317%., Conclusions/applications: Our case series suggests superior pain control by adding Buprenorphine prior to opioid dose escalation during BMT for SCD. Buprenorphine may provide the advantageous effect for other patients with complex pain background and experiencing difficult pain management during BMT due to pre-existing hyperalgesia and high opioid-tolerance. The evidence for buprenorphine's analgesic effect is moderate but growing, and more randomized controlled trials comparing the buprenorphine and other standard opioids are needed.

Background: There is a great deal of confusion associated with conversion from CII opioid to buprenorphine products. The data presented supports that patients can be converted from high dose opioid medication to buprenorphine products safely and effectively. This presentation will provide a road map to help guide practitioners who are interested in applying this to their clinical practice., Purpose/hypothesis: Thepurposeoftheresearchwasnotonlytodiscoverifconversiontoapartialagonist CIII medication from full agonist CII medications would be achieveable without sacrificing analgesia, but also to provide guidance to providerswhoareinterestedinpursuingthisoptioninclinicalpractice. Procedures/data/observations: Patients who met inclusion criteria were stratified into subgroups on the basis of pre- conversion morphine milligram equivalents, whether they remained on opioids for breakthrough pain postconversion, and pre- and postconversion numerical rating scale pain scores. Outcomes of interest included the differences between pre- and postconversion numerical rating scale pain scores and daily morphine milligram equivalents for each sub-group. Of 157 patients reviewed, 87.9% were successfully converted to buprenor-phine buccal film. Overall, numericalrating scale pain scores were stable after conversion. Statistically significant reductions were demonstrated in the <90 daily morphine milligram equivalent subgroup. Postconversion daily morphine milligram equivalents decreased by 85.4% from baseline. Change in daily morphine milligram equivalents is representative of patients who remained on breakthrough pain medication., Conclusions/applications: Results demonstrate continued analgesia after conversion to buprenorphine buccal film despite reductions in daily morphine milligram equivalents. Most patients were able to convert directly from their long-acting opioid to buprenorphine buccal film and stabilized without the use of concomitant opioids for breakthrough pain. Aggressive titration strategies were associated with greater success. This data proves that conversion from full agonist CII medications is possible without sacrificing analgesia while reducing the risk of adverse events associated with full agonist CII medications.

Background: Opioids remain the cornerstone for the treatment of moderate to severe cancer pain. Due to benefits over full agonist opioids (FAO), buprenorphine has emerged as an alternative treatment., Purpose/hypothesis: Buprenorphine is only approved for the treatment of pain that is chronic non-cancer. Cancer-related pain is often progressive with breakthrough pain. There is limited evidence for using short-acting FAO in combination with buprenorphine. There are concerns about withdrawal and the efficacy of pain control using buprenorphine. We hypothesize buprenorphine, in combination with short-acting FAOs, can adequately control cancer- related pain without causing withdrawal symptoms. Procedures/data/observations: Our prospective, single-arm, open-label study enrolls patients with cancer-related pain who are on buprenorphine in combination with an FAO at > 30 mg OME/day, either requiring long-acting pain relief or their pain is not controlled with an FAO alone. Our study is ongoing, with 15 patients enrolled and a target of 50. The patient's pain is self-assessed daily using a mobile application. Withdrawal is assessed regularly using a modified Clinical Opioid Withdrawal Scale (COWS) score., Conclusions/applications: Buprenorphine appears to be effective for the treatment of cancer pain without causing withdrawal in combination with short-acting FAO >30 mg/day.

Background: Now that the X-wavier is a thing of the past, patients with Opioid Use Disorder (OUD) who previously lacked access to buprenorphine may have access to lower barrier care and may be looking to make the transition from either methadone or illicit fentanyl to buprenorphine. This can be quite challenging and both fentanyl and methadone are hihghly potent drugs and can result in a difficult transtition to buprenorphine., Purpose/hypothesis: A transition from high potency opioids to buprenorphine is challenging and can cause discomfort or withdrawal in patients. Procedures/data/observations: Patients tend to have a difficult time when undergoing a transition from significant fentanyl use (> 1 bundle/day) or high dose methadone to buprenorphine. Over the last year, we've supported this transition for our hospitalized patients and have learned some tips and tricks to ease the transitions. Through our work we've come up with a strategy to transition patients that includes utilizing full mu agonists while initiating a low dose buprenorphine induction. We have developed an informal protocol for this transition that takes advantage of the flexibility of low dose buprenorphine induction strategies and includes the use of non-opioid adjuvant medications to control symptoms of discomfort and withdrawal., Conclusions/applications: A transition from the use of significant fentanyl or high dose methadone to buprenorphine is possible and can take place over a matter of a few days. Such a transition requires careful attention to patient symptoms, availability of as needed short acting opioids, and the judicious use of non-opioid adjuvants.

Background: Buprenorphine-naloxone treatment may confer substantial benefits for the treatment of opioid use disorder (OUD) during pregnancy including lower risk for overdose/death, less diversion potential and reduced use of other substances. Treatment may also result in less severe Neonatal Abstinence Syndrome (NAS), but little is known about the effects of this medication on fetal neurodevelopment., Methods: The purpose of the current study is to evaluate neurobehaviors among fetuses exposed to buprenorphine-naloxone at four time points over the second and third trimesters of gestation in pregnant women with OUD on buprenorphine-naloxone therapy. Sixty minutes of continuous fetal monitoring via fetal actocardiograph with a single wide array abdominal transducer took place at times of peak and trough buprenorphine-naloxone levels in 24 pregnant women. Data collection, which included measures of fetal heart rate and motor activity, was conducted between 24 and 36 weeks gestation, with the majority (84.6%) monitored at two or more gestational ages. Medication dose and other substance use was monitored throughout the study and infant NAS severity was assessed., Results: Fetal heart rate (FHR), FHR variability, accelerations in FHR, and motor activity were suppressed when buprenorphine-naloxone levels were at pharmacologic peak as compared to trough concentrations at 36 weeks, but not earlier in gestation. Maternal medication dose was unrelated to infant NAS severity., Conclusions: Conclusions: There were evident subclinical fetal neurophysiological responses at times of peak maternal buprenorphine/naloxone levels in later gestation, similar to those previously described for buprenorphine only. Further studies evaluating the effects of these changes in fetal neurobehaviors on the longer-term infant development are needed., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lauren Jansson reports financial support was provided by National Institute on Drug Abuse. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., (© 2024 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Background: Naltrexone is a medication used to treat both opioid and alcohol use disorder with limited experience in pregnant individuals, particularly in comparison to more commonly utilized treatments such as buprenorphine-naloxone. The long-term outcomes of infants exposed to naltrexone has not been previously examined., Aims: To compare the neurobehavioral outcomes of naltrexone versus buprenorphine-naloxone exposed infants., Study Design: Multi-centered prospective cohort study., Subjects: Pregnant people on prescribed buprenorphine-naloxone or naltrexone were enrolled during pregnancy and the dyad followed until 12 months after delivery., Outcome Measures: Infants were evaluated at 4-6 weeks corrected gestational age (CGA) using the NICU Neonatal Neurobehavioral Scale (NNNS) and at the 12-month CGA visit using the Ages and Stages Questionnaire, Third Edition (ASQ-3)., Results: There were 7 dyads in the naltrexone group and 34 in the buprenorphine-naloxone group. On the NNNS, infants exposed to naltrexone had higher median scores for arousal and excitability, and lower median scores for attention and regulation at 4-6 weeks CGA compared to the buprenorphine-naloxone group. None of the infants in the naltrexone group were monitored for NOWS and had shorter length of hospital stay compared with the buprenorphine-naloxone group. Although no statistically significant differences were observed, more infants in the buprenorphine-naloxone group were identified as at risk for development delays in the communication, problem solving, and personal social domains of the ASQ-3 at 12 months CGA. Results should be interpreted with caution given this study's small sample size and lack of a prospective comparison cohort., Conclusions: In this small cohort, there are differences noted in infant neurobehavior by NNNS at 4-6 weeks of age when comparing the buprenorphine-naloxone and naltrexone groups. At 12 months, ASQ-3 scores were similar but with percentage differences in potential development delay risk observed between the two groups. Larger cohort studies are needed to determine the long-term child outcomes after naltrexone exposure in pregnancy., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2024. Published by Elsevier B.V.)

Extended-release formulations of buprenorphine offer less frequent dosing, provide consistent medication delivery, and improve adherence for treatment of opioid use disorder (OUD). Although buprenorphine is a partial agonist with seemingly less precipitated withdrawal and easier initiation than full opioid agonists used for OUD, its use is not benign and understanding of the different extended-release formulations is necessary. We report a case of a patient that received a long-acting buprenorphine formulation (Sublocade®) administered subcutaneously that presented to the emergency department with tachycardia, hyperglycemia, elevated anion gap, and sustained nausea and vomiting refractory to pharmacotherapy requiring surgical removal of the buprenorphine depot for resolution of nausea and vomiting symptoms., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: The aim of the study is to review and synthesize the literature on high-dose buprenorphine initiation (>12-mg total dose on day of initiation)., Methods: A scoping review of literature about high-dose buprenorphine initiation was conducted. MEDLINE, Embase, PsycINFO, and Cochrane Central were searched. Randomized controlled trials, prospective and retrospective cohort studies, and case studies/reports published in English before February 13, 2023, were included., Results: Fifteen studies reporting outcomes from 580 high-dose buprenorphine initiations were included. Eight studies were in inpatient settings, 3 in emergency departments, 3 in outpatient settings, and 1 in a first-responder setting. Four studies reported high-dose initiations among individuals exposed to fentanyl. There were no reported events of fatal or nonfatal overdose or respiratory depression, although adverse event reporting was inconsistent in published reports. The most reported side effects with high-dose buprenorphine initiation were nausea or vomiting (n = 17) and precipitated withdrawal (n = 7). The most serious reported adverse event was hypotension requiring oral hydration (n = 2). Most studies reported improvements in subjective or objective withdrawal symptoms. The duration of follow-up ranged from none to 8 months., Conclusions: High-dose buprenorphine initiation has not been associated with reported cases of overdose or respiratory depression. However, the current literature about high-dose buprenorphine is limited by inconsistent side effect reporting, limited power to detect rare safety events such as respiratory depression, limited follow-up data, and few comparison studies between high-dose and regular initiation protocols. Further prospective data are needed to evaluate the safety and effectiveness of this initiation strategy., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 American Society of Addiction Medicine.)

Purpose of Review: The opioid epidemic remains a constant and increasing threat to our society with overdoses and overdose deaths rising significantly during the COVID-19 pandemic. Growing evidence suggests a link between perioperative opioid use, postoperative opioid prescribing, and the development of opioid use disorder (OUD). As a result, strategies to better optimize pain management during the perioperative period are urgently needed. The purpose of this review is to summarize the most recent multimodal analgesia (MMA) recommendations, summarize evidence for efficacy surrounding the increased utilization of Enhanced Recovery After Surgery (ERAS) protocols, and discuss the implications for rising use of buprenorphine for OUD patients who present for surgery. In addition, this review will explore opportunities to expand our treatment of complex patients via transitional pain services., Recent Findings: There is ample evidence to support the benefits of MMA. However, optimal drug combinations remain understudied, presenting a target area for future research. ERAS protocols provide a more systematic and targeted approach for implementing MMA. ERAS protocols also allow for a more comprehensive approach to perioperative pain management by necessitating the involvement of surgical specialists. Increasingly, OUD patients taking buprenorphine are presenting for surgery. Recent guidance from a multisociety OUD working group recommends that buprenorphine not be routinely discontinued or tapered perioperatively. Lastly, there is emerging evidence to justify the use of transitional pain services for more comprehensive treatment of complex patients, like those with chronic pain, preoperative opioid tolerance, or substance use disorder., Summary: Perioperative physicians must be aware of the impact of the opioid epidemic and explore methods like MMA techniques, ERAS protocols, and transitional pain services to improve the perioperative pain experience and decrease the risks of opioid-related harm., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To assess various aspects of visual function in school children prenatally exposed to opioid maintenance therapy (OMT) and to explore possible outcome differences between prenatal methadone and buprenorphine exposure., Methods: In a cross-sectional case-control study, 63 children aged 5-13 years with prenatal OMT exposure were compared with 63 age- and gender-matched, non-exposed controls regarding important visual parameters, such as visual acuity, orthoptic status, refractive state, colour vision, and visual field., Results: The OMT-exposed children had significantly poorer visual acuity, both for the best eye, the worst eye and binocularly. Two children had mild visual impairment. Manifest strabismus was more frequent in the OMT group, 30%, vs. 4.8% in the control group. The most frequent types of strabismus were accommodative esotropia and intermittent exotropia. Manifest nystagmus was present in 10 (16%) of the exposed children compared to one among the non-exposed children. The accommodative amplitude was decreased in the OMT group compared to the controls. After adjusting for polydrug exposure and SGA (small-for-gestational-age), the between-group differences in visual acuity, strabismus, and nystagmus remained. The methadone-exposed children had poorer visual acuity, increased frequency of strabismus and a higher percentage of nystagmus, hypermetropia and astigmatism compared to the buprenorphine-exposed children., Conclusions: School-age children exposed to methadone or buprenorphine in utero had a higher prevalence of strabismus and nystagmus, and a lower visual acuity and accommodation amplitude. Buprenorphine exposure was associated with more favourable results than methadone exposure on most visual outcome measures and should be the preferred substance in OMT., (© 2023 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Objective: To determine if the agonistic effects of buprenorphine and methadone affect drug use., Method: Quantitative examination of urine drug concentrations of patients treated with buprenorphine and methadone., Results: Patients on buprenorphine had less opioid and methamphetamine drug use than those on methadone., Conclusion: Patients on buprenorphine therapy appear to use less illicit drugs.

Transitioning a patient with chronic pain from a fentanyl patch to a buprenorphine patch has not been well described in the literature. Even after a patient removes their fentanyl patch, the residual fentanyl in the skin continues to be absorbed for hours. Due to the risk of precipitated withdrawal when initiating buprenorphine, this transition is a more challenging opioid rotation to plan safely. We report a case of a patient who had been using a fentanyl patch for over 10 years and was successfully rotated directly to a buprenorphine patch.

Introduction: Precipitated opioid withdrawal syndrome (OWS) is a severe and intolerable situation that may occur by a pharmaceutical agent. Reactivation of inhibited N-methyl-d-aspartate (NMDA) receptor in person with prolonged opioid use can led to severe OWS. We conducted a double-blind, randomized clinical trial to assess the effect of magnesium sulfate (MGSO 4 ) as an NMDA receptor antagonist on OWS., Materials and Methods: The study randomly divided forty patients with precipitated OWS due to partial agonist (buprenorphine) use referred to the emergency unit of Toxicology Department of Mashhad University of Medical Sciences, Iran; into two groups. The control group received conventional therapies, including clonidine 0.1 mg tablet each hour, intravenous infusion of 10 mg diazepam every 30 min, and IV paracetamol (Acetaminophen) 1 g, while the intervention group received 3 g of MGSO 4 in 20 min and then 10 mg/kg/h up to 2 h, in addition to the conventional treatment. The clinical opiate withdrawal scale (COWS) evaluated OWS at the start of the treatment, 30 min, and 2 h later., Results: Both groups had similar demographic, opiate types, and COWS severity at the start of the intervention. COWS was lower in the intervention than the control group at 30 min (11.20 ± 2.86 and 14.65 ± 2.36, respectively, P = 0.002) and at 2 h (3.2 ± 1.61 and 11.25 ± 3.27, respectively, P < 0.001) after treatment. The intervention group received lesser doses of clonidine (0.12 ± 0.51 and 0.17 ± 0.45 mg, P = 0.003) and Diazepam (13.50 ± 5.87, 24.0 ± 6.80 mg, P = 0.001) than the control group. Serum magnesium levels raised from 1.71 ± 0.13 mmol/L to 2.73 ± 0.13 mmol/L in the intervention group., Conclusion: Magnesium can significantly reduce the severity of OWS. Additional studies are required to confirm these results., Competing Interests: Declaration of competing interest None declared., (Copyright © 2024. Published by Elsevier Inc.)

Objective: Individual patient-level measures of adverse social determinants of health are associated with neonatal opioid withdrawal syndrome (NOWS), but the relative impact of community-level adverse social determinants of health remains to be defined. We examined the association between community-level social vulnerability and NOWS among pregnant individuals receiving buprenorphine for opioid use disorder., Study Design: We conducted a secondary analysis of an established cohort of pregnant individuals and their infants participating in a multidisciplinary prenatal/addiction care program from 2013 to 2021. Addresses were geocoded using ArcGIS and linked at the census tract to the Centers for Disease Control and Prevention 2018 Social Vulnerability Index (SVI), incorporating 15 census variables. The primary exposure was the SVI as a composite measure of community-level social vulnerability, and secondarily, individual scores for four thematic domains (socioeconomic status, household composition and disability, minority status and language, and housing type and transportation). The primary outcome was a clinical diagnosis of NOWS defined as withdrawal requiring pharmacological treatment following buprenorphine exposure., Results: Among 703 pregnant individuals receiving buprenorphine, 39.8% (280/703) of infants were diagnosed with NOWS. Among our patinets, those who were nulliparous, had post-traumatic stress disorder, a term birth (≥ 37 weeks) and had a male infant were more likely to have an infant diagnosed with NOWS. Individuals with and without an infant diagnosed with NOWS had similarly high community-level social vulnerability per composite SVI scores (mean [standard deviation]: 0.6 [0.4-0.7] vs. 0.6 [0.4-0.7], p  = 0.2]. In adjusted analyses, SVI, as a composite measure as well as the four domains, was not associated with NOWS diagnosis., Conclusion: Among pregnant persons receiving buprenorphine enrolled in a multidisciplinary prenatal and addition care program, while individual risk factors that measure adverse social determinants of health were associated with an NOWS diagnosis in the infant, community-level social vulnerability as measured by the SVI was not associated with the outcome., Key Points: · Community-level SVI was not associated with neonatal opioid use disorder.. · Certain individual risk factors were identified as being associated with NOWS.. · Homogeneity of composite SVI scores may have led to lack of significant findings.., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: There is currently a clinical dilemma in treating acute pain in patients receiving long-term buprenorphine products., Methods: This is a retrospective cohort review involving patients receiving long-term buprenorphine therapy who either underwent a surgical procedure or presented to an emergency department (ED) for acute pain between January 1, 2012 and January 1, 2022. Patients were excluded if opioids were prescribed 30 days before the index date. Chart reviews were conducted to characterize buprenorphine treatment strategies and the addition of new pain medications. Chart review revealed (1) incidence of opioid use disorder (OUD) relapse, (2) hospital re-presentation for pain or OUD, (3) fatal and non-fatal overdose, and (4) all-cause mortality and suicidality. Descriptive statistics were used to analyze results., Results: A total of 70 of 259 screened patients met inclusion criteria. The mean (±SD) age was 50.3 ± 13 years, 92.9% male, 64.3% White, and 78.6% had an OUD diagnosis. While 84.3% presented to the ED, 15.7% underwent surgical procedures. For the primary endpoint, the total daily dose of buprenorphine or buprenorphine/naloxone from index date to discharge was continued in 90.0%, increased in 2.9%, decreased in 1.4%, and discontinued in 5.7% of cases. At discharge, 46.2% were prescribed an additional pain medication. A total of 7.1% re-presented for pain or OUD relapse, 15.7% experienced an OUD relapse, 1.4% experienced new-onset suicidality, and 1.4% experience all-cause mortality within 90 days of the index date. No fatal or non-fatal opioid overdoses were observed., Conclusion: The most commonly observed practice was continuing buprenorphine doses in patients with acute or postsurgical pain, which was effective and safe. Although further data is necessary to fully elucidate these findings, the data herein may suggest that clinicians can safely continue buprenorphine doses in the acute pain setting in patients receiving these products chronically., Competing Interests: Disclosure The authors declare no relevant conflicts of interest or financial relationships., (Published by Elsevier Inc.)

Purpose: Postoperative pneumonia remains a common complication of surgery, despite increased attention. The purpose of our study was to determine the effects of routine surgery and post-surgical opioid administration on airway protection risk., Methods: Eight healthy adult cats were evaluated to determine changes in airway protection status and for evidence of dysphagia in two experiments. (1) In four female cats, airway protection status was tracked following routine abdominal surgery (spay surgery) plus low-dose opioid administration (buprenorphine 0.015 mg/kg, IM, q8-12 h; n = 5). (2) Using a cross-over design, four naive cats (2 male, 2 female) were treated with moderate-dose (0.02 mg/kg) or high-dose (0.04 mg/kg) buprenorphine (IM, q8-12 h; n = 5)., Results: Airway protection was significantly affected in both experiments, but the most severe deficits occurred post-surgically as 75% of the animals exhibited silent aspiration., Conclusion: Oropharyngeal swallow is impaired by the partial mu-opioid receptor agonist buprenorphine, most remarkably in the postoperative setting. These findings have implications for the prevention and management of aspiration pneumonia in vulnerable populations., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Opioids are well-known to cause respiratory depression, but despite clinical evidence of dysphagia, the effects of opioids on swallow excitability and motor pattern are unknown. We tested the effects of the clinically relevant opioid buprenorphine on pharyngeal swallow and respiratory drive in male and female rats. We also evaluated the utility of 5-HT 1A agonists (8-OH-DPAT and buspirone) to improve swallowing and breathing following buprenorphine administration. Experiments were performed on 44 freely breathing Sprague-Dawley rats anesthetized with sodium pentobarbital. Bipolar fine wire electrodes were inserted into the mylohyoid, thyroarytenoid, posterior cricoarytenoid, thyropharyngeus, and diaphragm muscles to measure electromyographic (EMG) activity of swallowing and breathing. We evaluated the hypotheses that swallowing varies by stimulus, opioids depress swallowing and breathing, and that 5-HT 1A agonists improve these depressions. Our results largely confirmed the following hypotheses: 1 ) swallow-related EMG activity was larger during swallows elicited by esophageal distension plus oral water infusion than by either stimulus alone. 2 ) Buprenorphine depressed swallow in both sexes, but females were more susceptible to total swallow suppression. 3 ) Female animals were also more vulnerable to opioid-induced respiratory depression. 4 ) 8-OH-DPAT rescued breathing following buprenorphine-induced respiratory arrest, and pretreatment with the partial 5-HT 1A agonist buspirone prevented buprenorphine-induced respiratory arrest in female animals. 5 ) 8-OH-DPAT enhanced mylohyoid and thyropharyngeus EMG amplitude during swallow but did not restore excitability of the swallow pattern generator following total suppression by buprenorphine. Our results highlight sex-specific and behavior-specific effects of buprenorphine and provide preclinical evidence of a 5HT 1A agonist for the treatment of respiratory depression and dysphagia. NEW & NOTEWORTHY This is the first study, to our knowledge, to evaluate sex-specific effects of opioid administration on pharyngeal swallow. We expand on a small but growing number of studies that report a lower threshold for opioid-induced respiratory depression in females compared with males, and we are the first to produce this effect with the partial μ-opioid-receptor agonist buprenorphine. This is the first demonstration, to our knowledge, that activation of 5-HT 1A receptors can improve swallow and breathing outcomes following systemic buprenorphine administration.

Hypogonadism is a highly prevalent complication of chronic opioid use associated with a constellation of affective, algesic, and cognitive symptoms as well as decreased quality of life. Given that the mainstays of pharmacologic opioid use disorder (OUD) treatment - methadone and buprenorphine - are themselves agonists or partial agonists at the mu opioid receptor, opioid-induced hypogonadism (OIH) remains an underappreciated clinical concern throughout the course of OUD treatment. Prominent theoretical frameworks for OUD emphasize the importance of negative reinforcement and hyperkatifeia, defined as the heightened salience of negative emotional and motivational states brought on by chronic opioid use. In this perspective article, we highlight the striking parallels between the symptom domains of hyperfakifeia and hypogonadism in males, who comprise the vast majority of existing clinical research on OIH. By extension we propose that future research and ultimately clinical care should focus on the identification and treatment of OIH in OUD patients to help address the longstanding paradox of poor treatment retention despite efficacious therapies, particularly in the setting of the current opioid overdose epidemic driven by high potency synthetic opioids such as fentanyl. We then review evidence from chronic pain patients that testosterone replacement provides clinically significant benefits to men with OIH. Finally, using this framework, we compare extant OUD therapeutics and discuss critical gaps in the clinical literature-including the relative dearth of data regarding hypothalamic-pituitary-gonadal function in females who use opioids-where future study should be focused.

Importance: Use of buprenorphine or methadone to treat opioid use disorder is recommended in pregnancy; however, their teratogenic potential is largely unknown., Objective: To compare the risk of congenital malformations following in utero exposure to buprenorphine vs methadone., Design, Setting, and Participants: This population-based cohort study used health care utilization data from publicly insured Medicaid beneficiaries in the US from 2000 to 2018. A total of 13 360 pregnancies with enrollment from 90 days prior to pregnancy start through 1 month after delivery and first trimester use of buprenorphine or methadone were included and linked to infants. Data were analyzed from July to December 2022., Exposure: A pharmacy dispensing of buprenorphine or a code for administration of methadone in the first trimester., Main Outcomes and Measures: Primary outcomes included major malformations overall and malformations previously associated with opioids (any cardiac malformations, ventricular septal defect, secundum atrial septal defect/nonprematurity-related patent foramen ovale, neural tube defects, clubfoot, and oral clefts). Secondary outcomes included other organ system-specific malformations. Risk differences and risk ratios (RRs) were estimated comparing buprenorphine with methadone, adjusting for confounders with propensity score overlap weights., Results: The cohort included 9514 pregnancies with first-trimester buprenorphine exposure (mean [SD] maternal age, 28.4 [4.6] years) and 3846 with methadone exposure (mean [SD] maternal age, 28.8 [4.7] years). The risk of malformations overall was 50.9 (95% CI, 46.5-55.3) per 1000 pregnancies for buprenorphine and 60.6 (95% CI, 53.0-68.1) per 1000 pregnancies for methadone. After confounding adjustment, buprenorphine was associated with a lower risk of malformations compared with methadone (RR, 0.82; 95% CI, 0.69-0.97). Risk was lower with buprenorphine for cardiac malformations (RR, 0.63; 95% CI, 0.47-0.85), including both ventricular septal defect (RR, 0.62; 95% CI, 0.39-0.98) and secundum atrial septal defect/nonprematurity-related patent foramen ovale (RR, 0.54; 95% CI, 0.30-0.97), oral clefts (RR, 0.65; 95% CI, 0.35-1.19), and clubfoot (RR, 0.55; 95% CI, 0.32-0.94). Results for neural tube defects were uncertain given low event counts. In secondary analyses, buprenorphine was associated with a decreased risk of central nervous system, urinary, and limb malformations but a greater risk of gastrointestinal malformations compared with methadone. These findings were consistent in sensitivity and bias analyses., Conclusions and Relevance: In this cohort study, the risk of most malformations previously associated with opioid exposure was lower in buprenorphine-exposed infants compared with methadone-exposed infants, independent of measured confounders. Malformation risk is one factor that informs the individualized patient decision regarding medications for opioid use disorder in pregnancy.

Abstract: Monthly long-acting injectable buprenorphine (LAI-BUP) is a treatment option for moderate to severe opioid use disorder. Safe administration of LAI-BUP requires preexisting opioid tolerance to prevent sedation and respiratory depression. In the event of adverse medication effects including oversedation, LAI-BUP can be surgically excised up to 14 days after administration ( https://www.sublocadehcp.com/dosing-administration ). However, the manufacturer does not provide guidance on the proper procedure for excision, and no case reports have been published documenting this procedure. We report a case of a man with methamphetamine use disorder and multiple unintentional fentanyl overdoses who inadvertently received LAI-BUP for overdose protection. This resulted in significant sedation for days, ultimately necessitating excision 5 days after administration. His sedation improved moderately at 24 hours after excision and significantly by 36 hours after excision. Providers seeking to use LAI-BUP to prevent overdose among those with unintentional opioid exposure must ensure sublingual buprenorphine tolerance before injection to avoid iatrogenic harm. Although manufacturer instructions mention that LAI-BUP can be excised under local anesthesia within 14 days of insertion, ideal excision is best performed in a setting with surgical instruments and cautery-such as the operating room-as the depot can adhere strongly to the surrounding subcutaneous tissue., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 American Society of Addiction Medicine.)

Background: Although both nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids are used for analgesia in acute pancreatitis (AP), the analgesic of choice is not known. We compared buprenorphine, an opioid, and diclofenac, an NSAID, for analgesia in AP., Methods: In a double-blind randomized controlled trial, AP patients were randomized to receive intravenous diclofenac or intravenous buprenorphine. Fentanyl was used as rescue analgesia, delivered through a patient-controlled analgesia pump. Primary outcome was the difference in the dose of rescue fentanyl required. Secondary outcomes were the number of effective and ineffective demands of rescue fentanyl, pain-free interval, reduction in visual analogue scale (VAS) score, adverse events, and organ failure development., Results: Twenty-four patients were randomized to diclofenac and 24 to buprenorphine. The 2 groups were matched at baseline. The total amount of rescue fentanyl required was significantly lower in the buprenorphine group:130 μg, interquartile range (IQR), 80-255 vs 520 μg, IQR, 380-1065 (P < .001). The number of total demands was 32 (IQR, 21-69) in the diclofenac arm vs 8 (IQR, 4-15) in the buprenorphine arm (P < .001). The buprenorphine group had more prolonged pain-free interval (20 vs 4 hours; P < .001), with greater reduction in the VAS score at 24, 48, and 72 hours compared with the diclofenac group. These findings were confirmed in the subgroup of moderately severe/severe pancreatitis. Adverse events profile was similar in the 2 groups., Conclusions: Compared with diclofenac, buprenorphine appears to be more effective and equally safe for pain management in AP patients, even in the subcohort of moderately severe or severe pancreatitis (Trial Registration number: CTRI/2020/07/026914)., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Medications for opioid use disorder (OUD) may influence neurocognitive functions. Inadequate power, confounders, and practice effects limit the validity of the existing research. We examined the change in cognitive functions in patients with OUD at 6-month buprenorphine (naloxone) posttreatment and compared the cognitive performance of the buprenorphine-treated group with control subjects., Methods: We recruited 498 patients with OUD within a week of initiating buprenorphine. Assessments were done twice-at baseline and 6 months. Those abstinent from illicit opioids and adherent to treatment (n = 199) underwent follow-up assessments. Ninety-eight non-substance-using control subjects were recruited from the community. The neurocognitive assessments comprised the Wisconsin Card Sorting Test, Iowa Gambling Task, Trail-Making Tests A and B (TMT-A and TMT-B), and verbal and visual N-Back Test. We controlled for potential effect modifiers., Results: Twenty-five of the 32 test parameters significantly improved with 6 months of buprenorphine treatment; 20 parameters withstood corrections for multiple comparisons (P < 0.001). The improved test domains spread across cognitive tests: Wisconsin Card Sorting Test (perseverative errors and response, categories completed, conceptual responses), TMTs (time to complete), verbal and visual N-Back Tests (hits, omission, and total errors). After treatment, OUD (vs control subjects) had less perseverative response and error (P < 0.001) and higher conceptual response (P = 0.004) and took lesser time to complete TMT-A (P < 0.001) and TMT-B (P = 0.005). The baseline neurocognitive functions did not differ between those who retained and those who discontinued the treatment., Conclusion: Cognitive functions improve in patients with OUD on buprenorphine. This improvement is unlikely to be accounted for by the practice effect, selective attrition, and potential confounders., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Prior research has suggested buprenorphine-containing medications may be associated with an increased risk of dental disorders. However, published data describing adverse dental reactions in buprenorphine users by active ingredient composition and route of administration are limited., Objective: The purpose of this study was to evaluate the influence of formulation on spontaneous reporting of dental disorders among patients treated with buprenorphine., Methods: Adverse event reports submitted to the United States Food and Drug Administration Adverse Event Reporting System (FAERS) between 2015 and 2022 were analyzed. Reporting odds ratios (ROR) and 95% confidence intervals (CI) were calculated to measure disproportionality of dental disorder reporting as classified by 39 Medical Dictionary for Regulatory Activities preferred terms., Results: Compared to pooled reports for all other drugs across FAERS, both buprenorphine monotherapy (ROR 3.09; 95% CI 2.61-3.66) and combination buprenorphine/naloxone (ROR 14.61; 95% CI 13.34-16.01) were associated with positive disproportionality signals. Signals of disproportionate dental disorder reporting were also detected for buprenorphine medicines administered by sublingual (ROR 20.03; 95% CI 18.04-22.24), buccal (ROR 4.46; 95% CI 3.00-6.61) and oral (ROR 7.17; 95% CI 5.03-10.22) routes, but not for other modalities. In considering active ingredient and route together, sublingual buprenorphine monotherapies (ROR 23.55; 95% CI 17.84-31.11) and sublingual buprenorphine/naloxone (ROR 19.47; 95% CI 17.39-21.80) were each associated with disproportionate reporting of dental disorders., Conclusion: Subject to the limitations of spontaneous adverse event data, this study identified significantly disproportionate reporting of dental disorders to FAERS among patients treated with buprenorphine- containing medications, including formulations administered by sublingual, buccal and oral routes. These findings are consistent with prior data and suggest that regular oral care and proper dental hygiene be emphasized for patients undergoing therapy with orally dissolving buprenorphine., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aims: This study aimed to evaluate the hepatotoxicity of buprenorphine in lactating rat pups of buprenorphine-injected mothers. Buprenorphine (BUP), a semisynthetic opioid, is increasingly administrated as a first-line standard maintenance treatment for opioid dependence due to its high safety and efficacy compared to other opioids. Numerous studies have confirmed the safety of BUP maintenance treatment in addicted patients., Objectives: This study was designed to assess the effects of BUP on the activities of liver enzymes, oxidative parameters, and liver histopathological changes in pups born to a mother exposed to this drug during lactation., Methods: BUP at a dose of 0.5 or 0.1 mg/kg was subcutaneously administrated to lactating rats for 28 days. At the end of the experiment, the pups were anesthetized, and blood samples were obtained from their hearts for measuring liver enzymes. Then the livers of the animals were dissected to measure oxidative stress parameters. In addition, the liver samples were fixed for histopathological evaluation., Results: The findings indicated a decrease in the activities of serum liver enzymes (ALT and AST) of the pups born to mothers exposed to 0.5 and 1 mg/kg of BUP during lactation. BUP could not change malondialdehyde (MDA), glutathione (GSH), nitric oxide (NO) levels, nor superoxide dismutase (SOD) activity in the liver tissue of animals. Some vacuolated hepatocytes with dark, eccentric nuclei, necrosis with karyolytic nuclei, mitotic figures, and multiple binucleated cells were seen in the pups which received 1 mg/kg of BUP., Conclusion: In conclusion, BUP may induce liver dysfunction in pups born to mothers exposed to this drug during lactation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Because of a risk of precipitated withdrawal occurring from buprenorphine induction in people who use fentanyl, low-dose inductions are becoming increasingly common. However, little evidence exists on the use of this method in pregnant people., Methods: We conducted a case series of all pregnant people treated for opioid use disorder with low-dose buprenorphine induction at the University of Maryland Medical Center between January 1, 2021, and August 22, 2022. Primary outcome was completion of induction regimen. Secondary outcomes were self-report of withdrawal, continuation of buprenorphine until delivery, and return to or continuation of illicit opioid use., Results: Six pregnant people were prescribed a total of 10 buprenorphine inductions. Five of the 6 pregnant people (83.3%) completed at least 1 induction, none of whom experienced precipitated withdrawal. Two of 6 (33.3%) continued buprenorphine until the time of delivery, and 1 of 6 (16.7%) abstained from illicit opioid use., Conclusions: The low-dose buprenorphine induction regimen described was successful in 5 of 6 pregnant individuals. Further research, particularly regarding continuation rates, is needed., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 American Society of Addiction Medicine.)

Background: Improving neonatal abstinence syndrome (NAS) management is an important concern, and objective measures of its physiologic impact remain elusive. We sought to determine whether near-infrared spectroscopy (NIRS)-derived tissue oxygenation (rSO2) and fractional tissue oxygen extraction (FTOE) demonstrated physiologically plausible changes correlating with standard NAS scoring., Methods: Thirty subjects (mean 39 weeks' GA and 3 127 g BW) underwent cerebral and peripheral muscle NIRS monitoring on Days of Life (DOL) Three, Five, and Seven. We examined correlations between NAS scores and FTOE and assessed the impact of non-pharmacologic swaddling and cuddling., Results: No statistically significant correlations between NAS scores and FTOE were observed; however, plausible trends were demonstrated between NAS scores and cerebral measurements. Buprenorphine-exposed babies (57%) showed significantly lower FTOE when swaddled (DOL7)., Conclusions: Tissue oxygenation monitoring demonstrates potential to provide objective, clinically relevant physiologic information on infants at risk for NAS. Further study is required to determine whether NIRS-derived measures could assist in individualizing NAS care.

Objectives: The objective of this study was to compare pain control and opioid consumption in critically ill patients who were treated with buprenorphine sublingual or oxycodone oral/enteral during ICU admission., Design: This was a retrospective, parallel, cohort study., Setting: General medical or surgical ICUs of a quaternary, urban hospital in Sydney, NSW, Australia., Patients: Data were obtained for all patients admitted to two general medical or surgical ICU from January 2019 to January 2023. Patients were grouped as those who received buprenorphine sublingual versus oxycodone oral/enteral., Interventions: None., Measurements and Main Results: Pain control was compared between a propensity score matched cohort of patients who received buprenorphine versus oxycodone. The primary outcome was the probability of significant pain. A significant pain score was defined as greater than or equal to 4 on the 0-10 Numeric Rating Scale or greater than or equal to 6 on the Behavioral Pain Scale. The study cohort included 1,070 patients (288 buprenorphine and 782 oxycodone). After propensity score matching, there were 288 patients in each group. The mean age of the matched cohort was 64 ± 16 years, 295 (51%) were male, and 359 (62%) had a surgical admission. The median probability of significant pain was 0.16 with buprenorphine and 0.17 with oxycodone (median difference, 0.01; 95% CI, -0.02 to 0.04; p = 0.50). Median opioid consumption in oral morphine milligram equivalents (MMEs) was 65 with buprenorphine and 70 with oxycodone (median difference, -1 mg; 95% CI, -10 to 10 mg; p = 0.73). Median MME per ICU day was 22 with buprenorphine and 22 with oxycodone (median difference, 1 mg; 95% CI, -2 to 5 mg; p = 0.38)., Conclusions: Buprenorphine sublingual is as effective as oxycodone oral/enteral with regard to pain control and opioid consumption in the ICU. Buprenorphine sublingual is an appropriate option for patients in the ICU who are unable to take oral/enteral medications., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: A novel buprenorphine (BUP) extended-release formulation (BUP-XR) produced as a lipid-encapsulated, low viscosity BUP suspension for subcutaneous (SC) injection to control pain was evaluated for pharmacokinetics and safety in four adult male cynomolgus monkeys., Methods: Each animal was given 0.2 mg/kg reformulated BUP-XR SC. Clinical observations were made during the course of the study. Blood samples were obtained from each animal before BUP-XR administration, 6, 24, 48, 72, and 96 h post-BUP-XR injection. Plasma levels of buprenorphine were analyzed using HPLC-MS/MS. The PK values calculated included peak plasma concentration of the BUP analyte, time to peak plasma concentration, plasma half-life, area under the plasma concentration-time curve, clearance, apparent volume of distribution, and elimination rate constant (C max , T max , T ½ , AUC 0-t , CL, Vd, and Ke, respectively)., Results: Observable adverse clinical signs were not detected. BUP concentration peaked from 6 to 48 h, then declined in a linear fashion. Quantifiable plasma BUP was measured in all monkeys at all time points. Results indicate that a single BUP-XR dose at 0.2 mg/kg can reliably provide plasma levels of BUP reported in the literature to be therapeutically relevant for up to 96 h., Conclusions: Because of the lack of any clinical observations or adverse effects at the injection site or absence of observable abnormal behaviors, it may be concluded that the use of BUP-XR is safe and efficacious in this species of non-human primate at the dose regimen described in this study for up to 96 h post-administration., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The aim of this study was to compare patients' satisfaction, experience, objectives, and opinion based on their current opioid substitution therapy (OST) (buprenorphine/naloxone (B/N) or methadone). The PREDEPO study is an observational, cross-sectional, multicentric study performed in Spain. Adult patients diagnosed with opioid use disorder (OUD) receiving OST were included. They were asked to fill in a questionnaire regarding their current OST. A total of 98 patients were enrolled (B/N: 50%, methadone: 50%). Mean age was 47 ± 8 years old and 80% were male. Treatment satisfaction was similar between groups. The most frequently reported factor for being "very/quite satisfied" was "being able to distribute the dose at different times throughout the day" (44% B/N vs. 63% methadone; p = .122). A significantly lower proportion of patients in the B/N group versus the methadone group reported that having to collect the medication daily was "very/quite annoying" (19% vs. 52%, p = .032). Treatment objectives reported by the majority of patients were similar between groups ("not feeling in withdrawal anymore", "reduce/definitely stop drug use", "improve my health", and "stop thinking about using daily") except for "not having money problems anymore" (73% B/N vs. 92% methadone; p = .012).  These results suggest there are several unmet expectations regarding current OST. There is a need for new treatments that reduce the burden of OUD, avoid the need for daily dosing, and are less stigmatizing which in turn could improve patient management, adherence and, quality of life.