High-dose Buprenorphine Research Articles

Case Report: Buprenorphine-precipitated fentanyl withdrawal treated with high-dose buprenorphine

Background: Buprenorphine, a partial agonist of the mu-opioid receptor, is an increasingly prescribed medication for maintenance treatment of opioid use disorder. When this medication is taken in the context of active opioid use, precipitated withdrawal can occur, leading to acute onset of opioid withdrawal symptoms. Fentanyl complicates use of buprenorphine, as it slowly releases from body stores and can lead to higher risk of precipitated withdrawal. Objectives: Describe the successful management of buprenorphine precipitated opioid withdrawal from fentanyl with high doses of buprenorphine. We seek to highlight how no adverse effects occurred in this patient and illustrate his stable transition to outpatient treatment. Case report: We present the case of a patient with severe opioid use disorder who presented in moderately severe opioid withdrawal after taking non-prescribed buprenorphine-naloxone which precipitated opioid withdrawal from daily fentanyl use. He was treated with high doses of buprenorphine, 148 mg over the first 48 hours, averaging 63 mg per day over four days. The patient reported rapid improvement in withdrawal symptoms without noted side effects and was able to successfully taper to 16 mg twice daily by discharge. Conclusions: This case demonstrates the safety and effectiveness of buprenorphine at high doses for treatment of precipitated withdrawal. While other options include symptomatic withdrawal management, initiating methadone or less researched options like ketamine, utilizing buprenorphine can preserve or re-establish confidence in this life-saving medication. This case also increases the previously documented upper boundary on buprenorphine dosing for withdrawal and should provide additional confidence in its use.

Buprenorphine for High-dose Tramadol Dependence: A Case Report of Successful Outpatient Treatment.

IntroductionDuring the coronavirus disease 2019 pandemic caused by the severe acute respiratory syndrome coronavirus 2, deaths from opiate drug overdoses reached their highest recorded annual levels in 2020. Medication-assisted treatment for opiate use disorder has demonstrated efficacy in reducing opiate overdoses and all-cause mortality and improving multiple other patient-centered outcomes. Treatment of tramadol dependence in particular poses unique challenges due to its combined action as opioid agonist and serotonin-norepinephrine reuptake inhibitor. Tramadol puts patients with dependence at risk for atypical withdrawal syndromes when attempting to reduce use. Little evidence is available to guide treatment of tramadol dependence.Case ReportWe present a case of high-dose tramadol addiction that began with misuse of medically prescribed tramadol for treatment of musculoskeletal back pain. The patient’s use reached oral consumption of 5000–6000 milligrams of illicit tramadol daily. She complained of common complications of tramadol use disorder including memory impairment, excessive sedation, and tramadol-induced seizures. The patient was referred to the emergency department in a withdrawal crisis seeking treatment where she was successfully managed with buprenorphine and phenobarbital and then linked to ongoing outpatient treatment.ConclusionOur report adds to the limited guidance currently available on the acute management of tramadol withdrawal and treatment of tramadol use disorder. Our case suggests the initiation of high-dose buprenorphine may be an effective and feasible option for emergency clinicians.

A Case Study of Pain Management at End-of-Life for a Patient on High-Dose Buprenorphine.

In Australia, high-dose sublingual buprenorphine and long-acting injectable buprenorphine are available. High-dose buprenorphine is used predominantly in the setting of opioid use disorder and has a role in chronic pain. Palliative care specialists are increasingly involved in pain management and end-of-life care for patients on these medications, yet there is a lack of education and training about high-dose buprenorphine for palliative care specialists. We describe our experience caring for John (fictional name), a gentleman with chronic pain and a new high-grade post-transplant lymphoproliferative disorder prescribed high-dose buprenorphine. We share the challenges and experience in caring for John as he deteriorated into the terminal phase and died of his illness. We include potential management options and the rationale for our decision to rotate John from high-dose sublingual buprenorphine to subcutaneous oxycodone. We conclude with practice implications and suggestions for improved patient care and clinician experience, including increased collaboration between palliative medicine, acute pain, and addiction medicine services, increased education and training for palliative care specialists about high-dose buprenorphine, and ultimately the development of consensus high-dose buprenorphine to oral morphine equivalence guidelines.

Effect of Different Doses of Buprenorphine in Combination with Bupivacaine in the Management of Postoperative Analgesia: A Comparative Study.

Background:Longer duration of analgesia, ceiling effect on respiratory depression, and the antihyperalgesia property make buprenorphine a good adjuvant for managing moderate-to-severe postoperative pain.Aims:The aim of this study is to evaluate the onset and duration of postoperative analgesia of three different doses of buprenorphine of 60, 100, and 150 μg given intrathecally along with hyperbaric bupivacaine in patients undergoing lower limb surgeries.Setting and Design:This prospective observational study was carried out in the anesthesia department of a tertiary care hospital.Materials and Methods:The study included 90 patients of either sex, aged 18–60 years, scheduled for elective lower limb surgery under subarachnoid block. Patients were randomly allocated into three groups (30 each) receiving different doses of buprenorphine. In addition, all patients received 3 mL of 0.5% hyperbaric bupivacaine.Statistical Analysis Used:The Chi-square test or Fisher's exact test was used to find out the association between the categorical variables. The association of quantitative variables between the groups was assessed by Kruskal–Wallis test while within the groups was assessed by repeated-measures analysis of variance test.Results:Baseline characteristics such as age, gender, and American Society of Anesthesiologist physical status classification were comparable among the three groups. Sensory block, motor block, and total duration of analgesia were significantly higher with higher doses of buprenorphine. The mean difference in the duration of analgesia was comparable in patients receiving 100 μg (720 min) and 150 μg (825 min) of buprenorphine. Bradycardia as a side effect was only in patients receiving 150 μg of buprenorphine.Conclusion:Risk–benefit of different doses of buprenorphine suggests that 100 μg may be the ideal dose for a better quality of spinal block and maintaining hemodynamic stability.

High-Dose Buprenorphine in the ED Effective for OUD

High-Dose Buprenorphine in the ED Effective for OUD

High-dose buprenorphine in the ED could be safe for some patients

Doses of buprenorphine well above the established standards (>12 mg) administered in the emergency department are safe and well-tolerated in individuals experiencing opioid withdrawal symptoms, says a new case series published by Herring and colleagues in the July 2021 issue of JAMA. The authors’ findings suggest that a relatively high buprenorphine induction dose, in certain patient populations that do not respond to current recommended induction regimens, may allow for a paradigm shift in common opioid use disorder (OUD) treatment modalities. The clinical algorithm presented in the study’s design allows for a more rapid response to withdrawal symptoms while also removing barriers to short-term medication access. The authors hope that by rapidly achieving therapeutic levels of buprenorphine and extending buprenorphine’s duration of action, it will potentially improve patient engagement in longer-term addiction treatment programs. Herring and colleagues conducted a retrospective review of patient electronic health record data from Highland Hospital Emergency Department in Oakland, CA in 2018. The authors identified specific OUD patients who did not have their withdrawal symptoms relieved by current guideline-recommended buprenorphine induction therapy as outlined by the Substance Abuse and Mental Health Services Administration (SAMHSA). Patients who had a COWS score (Clinical Opioid Withdrawal Scale) of 8 or more after receiving 8 mg to 12 mg of buprenorphine in the ED could be escalated to what the authors refer to as the “high-dose induction pathway,” in which the patient could receive up to 32 mg of buprenorphine, provided they showed no clinical signs of sedation, respiratory depression, or other complicating factors. Additionally, the participating providers could discharge the patient with a prescription for 16 mg of buprenorphine daily until follow-up at an addiction treatment clinic. Of the 579 opioid withdrawal ED visits during the study’s timeframe, 366—or 63.2%—were escalated to the high-dose induction pathway. Additionally, of all the buprenorphine dose totals, nearly one-fourth of them were equal to 28 mg or more. The high-dose intervention appears to have been very well-tolerated, with only one case experiencing precipitated withdrawal symptoms after receiving 24 mg of buprenorphine. In fact, of the 5 total cases of precipitated withdrawal recorded, 4 of them occurred after 8 mg of buprenorphine, but resolved after their doses were escalated to 28 mg total. Overall, there were no serious adverse effects related to buprenorphine recorded during the study, including sedation, hypoxia, or naloxone rescue in the ED 24 hours after discharge. It has been well-established that allowing withdrawal treatment through EDs improves patient engagement in addiction treatment programs. However, according to buprenorphine (specifically SUBUTEX) drug label information from 2017, “in some studies, gradual induction over several days led to a high rate of drop-out of buprenorphine patients during the induction period.” The drug labeling recommends that an adequate treatment dose, titrated to clinical effectiveness, should be achieved as rapidly as possible. Currently, the 2021 Treatment Improvement Protocols—the official guidance document by SAMHSA—recommends buprenorphine 2 mg to 4 mg, followed by a second dose of 2 mg to 4 mg after approximately 2 hours, with a maximum of 8 mg to 12 mg on day 1 and 16 mg on day 2 via a referred addiction clinic. However, this guidance may be too uniform and not adequate for patients who require a higher dosing strategy. The authors imply that the current standard often prolongs the time for maximum saturation of μ-opioid receptors and reduction in cravings. Furthermore, they state that it assumes the patient has adequate access to a buprenorphine prescription for the second day, which is often not the case. The treatment algorithm presented by Herring and colleagues is a good step forward for redefining current recommendations with regard to opioid addiction treatment in the ED. While the study may be a retrospective case series at a single site, it represents a practical application (with a well-represented patient population) for adopting a relatively safe high-dose treatment algorithm into routine practice. This new treatment technique could help prevent the inadvertent prolongation of withdrawal symptoms that current guidance may yield and improve patient follow-up and retention with addiction centers.

68 High First Dose Buprenorphine to Accelerate Induction in Emergency Department Opioid Use Disorder Patients

Assess the implementation, feasibility and patient outcomes of an accelerated buprenorphine treatment pathway where a first dose of 16 mg sublingual (SL) or greater is administered to treatment seeking emergency department (ED) patients with opioid use disorder (OUD).

High-Dose Buprenorphine Induction in the Emergency Department for Treatment of Opioid Use Disorder

Emergency departments (EDs) sporadically use a high-dose buprenorphine induction strategy for the treatment of opioid use disorder (OUD) in response to the increasing potency of the illicit opioid drug supply and commonly encountered delays in access to follow-up care. To examine the safety and tolerability of high-dose (>12 mg) buprenorphine induction for patients with OUD presenting to an ED. In this case series of ED encounters, data were manually abstracted from electronic health records for all ED patients with OUD treated with buprenorphine at a single, urban, safety-net hospital in Oakland, California, for the calendar year 2018. Data analysis was performed from April 2020 to March 2021. ED physicians and advanced practice practitioners were trained on a high-dose sublingual buprenorphine induction protocol, which was then clinically implemented. Vital signs; use of supplemental oxygen; the presence of precipitated withdrawal, sedation, and respiratory depression; adverse events; length of stay; and hospitalization during and 24 hours after the ED visit were reported according to total sublingual buprenorphine dose (range, 2 to >28 mg). Among a total of 391 unique patients (median [interquartile range] age, 36 [29-48] years), representing 579 encounters, 267 (68.3%) were male and 170 were (43.5%) Black. Homelessness (88 patients [22.5%]) and psychiatric disorders (161 patients [41.2%]) were common. A high dose of sublingual buprenorphine (>12 mg) was administered by 54 unique clinicians during 366 (63.2%) encounters, including 138 doses (23.8%) greater than or equal to 28 mg. No cases of respiratory depression or sedation were reported. All 5 (0.8%) cases of precipitated withdrawal had no association with dose; 4 cases occurred after doses of 8 mg of buprenorphine. Three serious adverse events unrelated to buprenorphine were identified. Nausea or vomiting was rare (2%-6% of cases). The median (interquartile range) length of stay was 2.4 (1.6-3.75) hours. These findings suggest that high-dose buprenorphine induction, adopted by multiple clinicians in a single-site urban ED, was safe and well tolerated in patients with untreated OUD. Further prospective investigations conducted in multiple sites would enhance these findings.

Factors Associated with Long-Term Retention in Buprenorphine-Based Addiction Treatment Programs: a Systematic Review.

The average length of buprenorphine treatment for opioid use disorder is less than 6 months. We conducted a systematic review to determine what factors were associated with longer retention in buprenorphine treatment. We searched Medline, Embase, and Cochrane Database of Systematic Reviews in February 2018. Articles were restricted to randomized controlled trials on human subjects, written in English, which contained ≥ 24 weeks of objective data on retention in buprenorphine treatment. We assessed whether dose of buprenorphine, treatment setting, or co-administration of behavioral therapy was associated with retention rates. Over 14,000 articles were identified. Thirteen articles (describing 9 studies) met inclusion criteria. Measures of retention varied widely. Three studies compared doses of buprenorphine between 1 and 8 mg and showed significantly higher rates of retention with higher doses (p values < 0.01). All other studies utilized buprenorphine doses between 8 and 24 mg daily, without comparison. No study found a significant difference in retention between buprenorphine alone and buprenorphine plus behavioral therapy (p values > 0.05). Initiating buprenorphine while hospitalized or within criminal justice settings prior to outpatient treatment programs was significantly associated with retention in buprenorphine treatment (p values < 0.01 respectively). Setting of treatment initiation and a higher buprenorphine dose are associated with improved long-term treatment retention. More objective data on buprenorphine treatment programs are needed, including a standardized approach to defining retention in buprenorphine treatment programs. This review was registered with PROSPERO (#CRD42019120336) in March 2019.

Retrospective investigation of an association between high-dose buprenorphine and perpetuation of post-anesthesia hyperthermia in cats following ovariohysterectomy.

We evaluated a potential association between the administration of high-dose buprenorphine and perpetuation of hyperthermia in cats following ovariohysterectomy (OVH). We hypothesized that buprenorphine 0.24 mg/kg subcutaneously (SC) would result in longer-lasting postoperative hyperthermia in cats vs a group receiving morphine 0.1 mg/kg SC. Anesthetic records from cats admitted for OVH as part of surgical exercises for second year veterinary medicine students in 2018 and 2019 were collected. All cats were sedated with dexmedetomidine 20 µg/kg and morphine 0.1 mg/kg intramuscularly. Anesthesia was induced with propofol and maintained with isoflurane in oxygen. At extubation, cats received morphine 0.1 mg/kg SC in 2018 and buprenorphine 0.24 mg/kg SC in 2019. Temperature was measured rectally prior to sedation, esophageally during anesthesia and rectally at 1, 4 and 16-20 h after extubation. Demographic data and temperature prior to administration of postoperative opioids were compared with t-tests. The effects of treatment (opioids) and time on postoperative rectal temperature and on the incidence of hyperthermia (temperature >39.2°C) were evaluated with mixed and generalized linear mixed-effect models. Significance was set at P <0.05. There were no differences in demographic characteristics between treatment groups (all P ⩾0.2). Intraoperative esophageal temperature was lower in cats scheduled to receive morphine (mean ± SD 36.6 ± 0.2) than in those receiving buprenorphine (36.9 ± 1.0) (P <0.0001). Postoperative temperature was higher for cats receiving buprenorphine than for those receiving morphine (P <0.0001). The incidence of hyperthermia 16-20 h after opioid administration was 56% for morphine and 73% for buprenorphine (P = 0.03). Buprenorphine 0.24 mg/kg SC for postoperative analgesia in cats was associated with hyperthermia that persisted for 16-20 h after administration, and the incidence of hyperthermia for this group was higher than in the cats that received morphine 0.1 mg/kg SC.

Adherence to buprenorphine: An analysis of prescription drug monitoring program data

BackgroundAlthough buprenorphine is an evidence-based treatment for opioid use disorder (OUD), many individuals discontinue treatment soon after starting. This study assesses predictors of buprenorphine adherence using Prescription Drug Monitoring Program (PDMP) data. MethodsPDMP data for Philadelphia, Pennsylvania were used to measure 180-day adherence to buprenorphine among new initiates. Adherence was classified using percent days covered (PDC), and new initiates with PDC ≥ 0.80 were classified as adherent. Multivariable logistic regression was conducted to determine factors associated with buprenorphine adherence. ResultsBetween January 2017 and December 2018, 10,669 Philadelphia residents initiated buprenorphine and 26.6 % remained adherent after 180 days. Demographic factors associated with greater odds of adherence included age category and female sex (aOR: 1.37; 95 % CI: 1.25–1.50). Those filling an opioid prescription, other than buprenorphine, during the follow-up period had lower odds of adherence than those who did not fill an opioid prescription (aOR: 0.62; 95 % CI: 0.50−0.77). Odds of adherence was greater for those on the film formulation (aOR: 1.37; 95 % CI: 1.25–1.50) than the tablet formulation. Those filling medium (aOR: 1.76; 95 % CI: 1.55–2.00) and high dose (aOR: 5.11; 95 % CI: 4.30–6.17) buprenorphine prescriptions had higher odds of adherence than those filling low dose prescriptions. ConclusionsIndividual demographics, receipt of an opioid prescription, buprenorphine formulation, and buprenorphine dose were all associated with adherence to buprenorphine. Ongoing strategies to address OUD need to prioritize increasing retention in long-term evidence-based buprenorphine treatment while also encouraging providers to regularly consult the PDMP to ensure patient compliance.

Impact of Buprenorphine on Learning and Memory Ability, Oxidative Status and Inflammation in the Hippocampus of Rats.

Buprenorphine (BUP), a "synthetic derivative of the opioid alkaloid thebaine", may be associated with cellular damage in the central nervous system. This study was designed to investigate the effects of low and high doses of BUP on oxidative and inflammatory indices in the hippocampus and learning and memory behavior in an animal model. The association between BUP administration and oxidative and inflammatory damage and also learning and memory impairment is not clear. For this reason, twenty-four male Wistar rats were randomly allocated into one control and two BUP-treated groups (0.3 and 1 mg/kg, SC), (n=8, for each group). After 4 weeks, learning and memory abilities were assessed by using Y-maze test. Then, oxidative stress indices including glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) were assessed in the serum and hippocampus of each animal by using spectrophotometer. Inflammatory parameters such as tumor necrotic factor-α (TNF-α), interleukin- 6 (IL-6), and interleukin-1β (IL-1β) were also measured in the serum and hippocampus of rats by using ELISA. The present findings indicated that the memory and learning time was lengthened in BUP (1mg/kg)-treated rats versus control animals (p<0.05). Additionally, it was observed that BUP (1 mg/kg) significantly increased the serum and hippocampal levels of MDA and TNF-α and also decreased GSH levels versus the control group (p< 0.05). The results of the present study revealed that BUP may cause learning and memory dysfunction by inducing oxidative stress and inflammation in the hippocampus.

Buprenorphine Field Initiation of ReScue Treatment by Emergency Medical Services (Bupe FIRST EMS): A Case Series

The opioid epidemic is currently a leading health crisis in the United States, and evidence supports Medication for Opioid Use Disorder (MOUD) as the most effective treatment (2). In our EMS system we are observing an ever increasing number of patients who, due to refusing transport after naloxone rescue, represent an access void at the point of overdose. We present a case series to illustrate a new treatment paradigm utilizing front line EMS paramedic units and high dose buprenorphine to treat withdrawal symptoms with next day bridge to long term care. The three patients described are exemplary cases, meant to represent overall characteristics of the intervention prior to complete data collection. Each patient was revived from opioid overdose with naloxone. Paramedics then treated each patient with 16 mg of buprenorphine to relieve and prevent withdrawal symptoms. Patients were provided with outpatient follow up irrespective of ED transport. To the best of our knowledge, this is the first EMS agency in the United States providing MOUD in the prehospital setting at the point of overdose. This innovative program provides EMS with education and tools to promote patient engagement. While still in its infancy, this approach utilizes existing EMS resources to bring MOUD to the prehospital setting, offering a new avenue to long term care. Keywords: Opioid, buprenorphine, emergency medical services, medication assisted therapy, naloxone, overdose

Buprenorphine to reverse respiratory depression from methadone overdose in opioid-dependent patients: a prospective randomized trial

BackgroundNaloxone is the usual drug used in opioid-induced respiratory depression but it has a short half-life, precipitates withdrawal in dependent patients, and thus for persistent reversal of long-acting opioids has to be given by titrated doses and infusions. The partial agonist buprenorphine has a much longer duration of action and causes less severe withdrawal, but still should largely reverse respiratory depression induced by full agonist opioids. We aimed to compare the efficacy/safety of buprenorphine and naloxone in reversing respiratory depression in methadone-poisoned opioid-dependent patients.MethodsPatients with methadone-induced respiratory depression were randomized to receive naloxone (titrated doses), or lower or higher doses of buprenorphine (10 μg/kg or 15 μg/kg). The primary outcome was immediate reversal of respiratory depression. We also recorded acute opioid withdrawal, need for intubation/recurrent apnea, repeated doses of opioid antagonists, length of hospital stay, other morbidity, and mortality. The study was registered with the Iranian Registry of Clinical Trials (Trial ID: 18265; Approval code: IRCT2015011020624N1).ResultsEighty-five patients were randomized; 55/56 patients who received buprenorphine had rapid reversal of respiratory depression, which persisted for at least 12 h. Naloxone was effective in 28/29 patients, but often required very high titrated doses (thus delaying time to respond) and prolonged infusions. Intubation (8/29 vs 5/56) and opioid withdrawal (15/29 vs 7/56) were less common with buprenorphine. There were no serious complications or deaths in those receiving buprenorphine. The 15-μg/kg buprenorphine dose appeared to provide a longer duration of action, but precipitated withdrawal more frequently than the 10-μg/kg dose.ConclusionBuprenorphine appears to be a safe and effective substitute for naloxone in overdosed opioid-dependent patients. Further studies are warranted to explore the optimal dosing strategy for buprenorphine to consistently maintain reversal of respiratory depression but not precipitate withdrawal.Trial registration numberIRCT2015011020624N1. Registered 30 September 2015.

Efficacy of multimodal analgesic treatment of severe traumatic acute pain in mice pretreated with chronic high dose of buprenorphine inducing mechanical allodynia

Managing severe acute nociceptive pain in buprenorphine-maintained individuals for opioid use disorder management is challenging owing to the high affinity and very slow dissociation of buprenorphine from μ-opioid receptors that hinders the use of full agonist opioid analgesics.In a translational approach, the aim of this study was to use an animal setting to investigate the effects of a chronic high dose of buprenorphine treatment on nociceptive thresholds before and after applying a severe acute nociceptive traumatic surgery stimulus and to screen postoperative pharmacological analgesic strategies.A chronic treatment of mice with a high dose of buprenorphine (BUP HD, 2 × 200 μg/kg/day; i.p.) revealed significant mechanical allodynia. One and two days after having discontinued buprenorphine administration and having induced a severe nociceptive acute pain by a closed tibial fracture, acute administration of morphine at a dose which has analgesic effects in absence of pretreatment (4.5 mg/kg; i.p.), was ineffective to reduce pain in the BUP HD group. However, mimicking multimodal analgesia strategy used in human postoperative context, the combination of morphine (administered at the same dose) with a NMDA receptor antagonist (ketamine) or an NSAID (ketoprofen) produced antinociceptive responses in these animals.The mouse model of closed tibial fracture could be useful to identify analgesic strategies of postoperative pain for patients with chronic exposure to opioids and suffering from hyperalgesia.

Buprenorphine Metabolism in Human Liver, Human Placenta, and Recombinant Cyp19 Microsomes

Background and Hypothesis: Buprenorphine (BUP), a partial opioid agonist, is commonly used to treat opioid use disorder in pregnant women. BUP is metabolized in the liver by cytochrome P450s (CYP) and UDPGlucuronosyltransferases (UGT). Compared to non-pregnant women, higher doses of BUP are needed during pregnancy to maintain therapeutic concentrations. We hypothesize that the placenta has a role in the metabolism of BUP, thus contributing to the need for higher doses during pregnancy.&#x0D; Experimental Design or Project Methods: : BUP was incubated with human liver microsome (HLM), human placenta microsome (HPM) or recombinant CYP19 microsome (rCYP19). Norbuprenorphine (Nor-BUP) formation was measured by HPLC/MS/MS (Thermo TSQ Quantum Ultra). Positive controls included midazolam for HLMs and testosterone for HPMs and rCYP19, and negative controls were without NADPH. Initial experiments assessed linearity with time and protein concentration. Subsequently, BUP concentrations were varied and Nor-BUP formation vs. BUP concentration was fitted to the Michaelis–Menten equation (GraphPad Prism) to calculate Km and Vmax.&#x0D; Results: The Km was 11.89 μM and Vmax was 0.4627 μmol/min/mg for Nor-BUP formation following incubation of BUP (0-20 µM) with HLM. Higher concentrations of BUP indicated non-typical Michaelis–Menten kinetics. Results from the HPM show metabolism of BUP to Nor-BUP is present in the placenta. Incubation of BUP in rCYP19, an enzyme known to be in human placenta, resulted in Nor-BUP formation, indicating its role in BUP metabolism.&#x0D; Conclusions and Potential Impact: : The Km and Vmax values generated from concentrations of 5-20 μM in HLM is comparable with existing data. Because multiple enzymes breakdown BUP with different Km and Vmax values, a curve not adhering to the normal Michaelis–Menten shape over 20 μM BUP is reasonable in HLMs. Formation of Nor-BUP following incubation of BUP in rCYP19 and HPMs suggest their role in the metabolism of BUP in pregnant women. Understanding the role of placenta in metabolizing BUP will provide insight to fetal drug exposure. Placental metabolism of BUP would possibly indicate lower exposure to BUP but higher exposure to nor-BUP to the fetus. Future directions of this study will quantify placental metabolism of BUP, investigate other pathways of BUP metabolism in the placenta, and determine drug interactions that may exacerbate Neonatal Abstinence Syndrome when coadministered with BUP.

Association of Maternal Buprenorphine or Methadone Dose with Fetal Growth Indices and Neonatal Abstinence Syndrome.

Our objective was to compare fetal growth and incidence of neonatal abstinence syndrome requiring treatment across pregnant women with opioid use disorders on two types and two dose categories of medication-assisted treatment. A retrospective cohort study was conducted in a comprehensive, perinatal program in western North Carolina comparing growth percentiles on third-trimester ultrasound and at birth, and diagnosis of neonatal abstinence syndrome requiring treatment. Singletons were exposed in utero to low- to moderate-dose buprenorphine (≤16 mg/day; n = 70), high-dose buprenorphine (≥17 mg/day; n = 36), low- to moderate-dose methadone (≤89 mg/day; n = 41), or high-dose methadone (≥90 mg/day; n = 74). Multivariate analysis of variance with posthoc Bonferroni comparisons (p ≤ 0.01) and multinomial logistic regressions (adjusted odds ratio, 99% confidence interval) were conducted. Differences in neonatal outcomes reached statistical significance for larger head circumference for buprenorphine doses (p = 0.01) and for longer length (p < 0.01) and lower odds of neonatal abstinence syndrome requiring treatment (p < 0.01) with low- to moderate-dose buprenorphine versus high-dose methadone. Among pregnant women using medication-assisted treatment for opioid use disorders, low- to moderate-dose buprenorphine (≤16 mg/day) was associated with the most favorable neonatal outcomes. However, more rigorous control of confounders with a larger sample is necessary to determine if low- to moderate-dose buprenorphine is the better treatment choice.

Single high-dose buprenorphine for opioid craving during withdrawal

BackgroundOpioid use disorder is one of the most prevalent addiction problems worldwide. Buprenorphine is used as a medication to treat this disorder, but in countries where buprenorphine is unavailable in combination with naloxone, diversion can be a problem if the medication is given outside a hospital setting.ObjectiveThe objective of this research is to evaluate the effect of a single, high dose of buprenorphine on craving in opioid-dependent patients over 5 days of abstinence from use of other opioids. The primary goal was to determine the safety and efficacy of buprenorphine during withdrawal in a hospital setting.MethodsNinety men who used opium, heroin, or prescribed opioids and met DSM-5 criteria for opioid use disorder (severe form) were randomized to three groups (n = 30 per group) to receive a single, sublingual dose of buprenorphine (32, 64, or 96 mg). The study was conducted in an inpatient psychiatric ward, with appropriate precautions and monitoring of respiratory and cardiovascular measures. Buprenorphine was administered when the patients were in moderate opiate withdrawal, as indicated by the presence of four to five symptoms. A structured clinical interview was conducted, and urine toxicology testing was performed at baseline. Self-reports of craving were obtained at baseline and on each of the 5 days after buprenorphine administration.FindingsCraving decreased from baseline in each of the three groups (p < 0.0001), with a significant interaction between group and time (p < 0.038), indicating that groups with higher doses of buprenorphine had greater reduction.ConclusionsA single, high dose of buprenorphine can reduce craving during opioid withdrawal; additional studies with follow-up are warranted to evaluate safety.

Pharmacokinetics of low-dose and high-dose buprenorphine in cats after rectal administration of different formulations.

A prospective experimental study was performed in nine young healthy cats to investigate a pharmacokinetic profile and the clinical relevance of rectally administered buprenorphine. Rectal pH value was measured in all nine cats. Blood was collected 15, 30, 60, 90, 120, 240 and 480 mins and 24 h after the rectal administration of a suppository and a gel at doses between 0.02 mg/kg and 0.1 mg/kg buprenorphine to determine the plasma concentration of buprenorphine. Rectal pH was measured with pH paper. Upon pharmacokinetic non-compartment analysis of high-dose buprenorphine (0.1 mg/kg), average maximal plasma concentration was found to be 1.13 ng/ml, time to maximal plasma concentration was 45 mins and area under the plasma concentration-time curve was 94.19 ng*min/ml, representing low but potential bioavailability. Mean residual time was 152.2 mins and the half-life was 92.6 mins. A wide range of plasma concentrations within the cohort was measured and two of the cats had to be excluded from statistical analysis owing to incomplete uptake. Vital parameters of all cats were considered to be normal but three of the cats showed mydriasis up to 8 h after application. After the administration of a low-dose suppository or a rectal gel (0.02 mg/kg) within pilot studies, no buprenorphine was detected in cat plasma. Rectal pH in all cats was between 7.7 and 8. The rectal application of buprenorphine at a dose of 0.1 mg/kg revealed a potential but weak uptake in cats. Regarding effective concentrations in previous pharmacokinetic investigations, rectal administration is currently not recommended for good provision of opioid analgesia in cats. Pharmacological investigations of formulation and galenics in order to improve the rectal bioavailability of buprenorphine remain to be clarified before further dose-finding and pharmacokinetic/pharmacodynamic studies are performed.

High-dose buprenorphine: a last resort drug for treatment-resistant alcohol use disorder. Preliminary results of a compassionate observational pilot study.

In France, 1-2 million drinkers suffer from alcohol use disorder (AUD). Fewer than 200,000 patients are treated for their AUD whereas 1.4 million patients are treated for alcohol-related consequences. Established pharmacological treatments have modest efficacy and no drugs are in development. AUD is underpinned by alterations of the endogenous opioid system which is currently modulated by naltrexone or nalmefene. Mu- and kappa-transmissions are respectively down- and upregulated. This imbalance may contribute to chronic stress and dysphoria in AUD patients and consequently to the persistence of consumption and relapse [1]. Long acting opioid agonists (LAOA) such as high-dose buprenorphine (HDB) may provide effective therapy. In opioid use disorder (OUD), individualized dose adaptations of LAOA allow patients to reduce or stop use of short acting opioids and associated substances such as alcohol [2]. The effect on alcohol consumption was also reported in rodents [3]. LAOA have psychotropic properties, as they can relieve psychiatric disorders (mood, suicidal ideation) in non-addicted subjects [4]. These symptoms are common in severe AUD and resistant to antidepressants when alcohol intake persists. Because HDB appears more effective and safer than methadone in reducing alcohol consumption, we assessed HDB in an ambulatory pilot study, including 17 patients (male: 47 %) with treatment-resistant and life-threatening AUD and free of OUD. Wilcoxon tests were used to compare clinical characteristics between the inclusion and each time of the evaluation (month 1, 3, 6, 12) for each group of patients evaluated (17, 15, 10 and 5, respectively). According to the preliminary results, a careful HDB titration led to significant decreases in daily consumption of alcohol from (mean (SD)) 98 (126) to 30 (42) and 14 (31) g/day, after 1 and 12 months of treatment respectively, without safety issues (transient dizziness, nausea), including HDB misuse. In patients with non-daily alcohol use but episodic heavy drinking days (HDD) (n=7), HDB decreased the number of HDD, from 7.3 (6.8) to 4 (7.3) and 0 at month 6 and 12, respectively. HDB, a safe medication used for 23 years in France, could constitute a last resort therapeutic option usable in outpatient settings, allowing long-lasting reduction in alcohol consumption and related harmful consequences with low safety issues.