Doses Of Buprenorphine Research Articles

Randomised clinical trial of a 16 mg vs 24 mg maintenance daily dose of buprenorphine to increase retention in treatment among people with an opioid use disorder in Rhode Island: study protocol paper

IntroductionBuprenorphine is a highly effective treatment for opioid use disorder (OUD). However, provider observations and preliminary research suggest that the current standard maintenance dose may be insufficient for suppressing withdrawal...

Limited acceptance of buprenorphine in recovery residences in South Florida: A secret shopper survey

BackgroundBuprenorphine is a first-line treatment for opioid use disorder (OUD), essential for reducing opioid overdose mortality and improving treatment retention. Despite federal policies that mandate the acceptance of buprenorphine in recovery residences, individuals in South Florida taking this medication often face significant barriers to admission. This study uses a secret shopper survey to examine whether federal policies regarding prescribed buprenorphine use are being violated in South Florida recovery residences. MethodsWe selected recovery residences in South Florida due to the region's high opioid overdose death rate and its prominence as a recovery hub. From a list of 141 Florida Association of Recovery Residences (FARR)-certified residences in Palm Beach, Broward, and Miami-Dade, we randomly surveyed 100 programs across all treatment levels (I-IV) using a standardized script. The primary outcome was whether residences accepted individuals taking buprenorphine, classified into three categories: (1) unconditional acceptance, where any person taking buprenorphine was accepted; (2) denial, where admission was refused for all individuals taking buprenorphine; and (3) conditional acceptance, where admission was granted under specific conditions. Secondary outcomes included requirements for conditional acceptance, such as dose limits or tapering policies. ResultsThe distribution of the 100 surveyed recovery residences was comparable to the 141 FARR-certified facilities: 67 % were in Palm Beach, 31 % in Broward, and 2 % in Miami-Dade. Most residences (55 %) were level II certified, followed by 26 % level IV, 14 % level I, and 5 % level III. Sixteen percent of residences permitted admission of individuals taking any buprenorphine dose, 31 % had conditional policies, and 53 % prohibited buprenorphine. The maximum acceptance across all counties and levels was 20 %. No significant differences were observed by county (p = 0.61) or facility level (p = 0.29). Of 31 residences with conditional policies, 25.8 % (n = 8) required a mandatory taper, 38.7 % (n = 12) allowed a maximum 8 mg daily dosage, 12.9 % (n = 4) had a maximum 12 mg daily dosage, 6.5 % (n = 2) had a maximum 16 mg daily dosage, 6.5 % (n = 2) required a provider letter, and 9.7 % (n = 3) did not provide further information. ConclusionsAccess to FARR-certified recovery residences is severely limited for individuals in South Florida taking buprenorphine. Urgent action is needed to improve access to evidence-based OUD treatments, address complexities influencing recovery residence policy and practice, and ensure appropriate allocation of public funds like State Opioid Response dollars.

Variation in Opioid Agonist Dosing in Clinical Trials by Race and Ethnicity

Racial and ethnic disparities in access to treatment and quality of treatment for opioid use disorder (OUD) have been identified in usual care settings. In contrast, disparities in treatment quality within clinical trials are relatively unexamined. To estimate racial and ethnic differences in the dose of opioid agonist treatment for OUD in the first 4 weeks of treatment in clinical trials. This cohort study performed analysis of the methadone and buprenorphine treatment arms of 3 trials conducted by the National Institute on Drug Abuse Clinical Trials Network between May 2006, and January 31, 2017, at multiple Clinical Trials Network sites across the US. Trial participants who were randomized to and initiated buprenorphine or methadone treatment and who identified as Hispanic, non-Hispanic Black, or non-Hispanic White were included in the present study. Data were analyzed from November 1, 2023, to August 5, 2024. Combined race and ethnicity as self-classified by the patient at trial enrollment. The maximum daily dose of buprenorphine or methadone received in each week for the first 4 weeks of treatment. The mean dose and the percentage of patients receiving a higher dose (buprenorphine ≥16 mg and methadone ≥60 mg) were compared across race and ethnicity groups. A total of 1748 patients (1263 who initiated buprenorphine and 485 who initiated methadone treatment) were included in the analysis (1168 [66.8%] male; median age, 33 [IQR, 26-45] years). Of these, 138 patients (7.9%) identified as Black, 273 (15.6%) as Hispanic, and 1337 (76.5%) as White. In week 4, Black patients received buprenorphine doses 2.5 (95% CI -4.6 to -0.5) mg lower and methadone doses 16.7 (95% CI, -30.7 to -2.7) mg lower compared with White patients, after standardizing by age and sex. In week 4, the percentage of patients receiving a higher dose of medication (buprenorphine ≥16 mg; methadone ≥60 mg) was 16.9 (95% CI, -31.9 to -1.9) points lower for Black patients compared with White patients. Hispanic and White patients received similar buprenorphine doses; Hispanic patients received lower methadone doses than White patients. In this cohort study of data from 3 clinical trials, White patients generally received higher doses of medication than Black patients. Future research is needed to understand the mechanisms of and interventions to reduce disparities in OUD treatment quality and how such disparities impact generalizability of trial results.

89EMF The Utility of High Dose Buprenorphine in Producing Prolonged Suppression of Opioid Withdrawal

89EMF The Utility of High Dose Buprenorphine in Producing Prolonged Suppression of Opioid Withdrawal

Is buprenorphine maternal dose associated with neonatal opioid withdrawal syndrome severity?

Neonatal opioid withdrawal syndrome (NOWS) is a drug withdrawal syndrome occurring mainly after in utero opioid exposure. Buprenorphine is commonly used for opioid withdrawal. Studies are conflicted about a potential dose effect OBJECTIVE: The aim of our study was to investigate the impact of buprenorphine maternal maintenance therapy on the NOWS based on NOWS duration, birth weight and therapy. We conducted a retrospective study analysing data from infants admitted for NOWS in two Neonatal Intensive Care Unit between January 2010 and December 2020. Nonpreterm infants born to mothers who were treated with buprenorphine or therapy during pregnancy and who had a Lipsitz score of 4 or higher. A total of 75 term newborns were hospitalized for the treatment of NOWS from mother substituted with buprenorphine during the study inclusion period. The duration of NOWS differed significantly between all dose cohorts, with higher doses of maternal buprenorphine maintenance correlating with longer length of NOWS duration. Infants exposed to high doses required 17 days [10; 23], while infants exposed to intermediate doses required 7 days [2; 16] and infants exposed to low doses required 3 days [2; 5], with p-values < .003. Infants exposed to high doses required a longer time to regain their birth weight and higher morphine doses as therapy compared to others. Infants exposed to low doses, intermediate doses, and high doses of buprenorphine demonstrated dose-dependent increases in the durations of hospitalization, respectively. Increased doses of maternal buprenorphine during pregnancy are correlated with NOWS severity. Our study shows that increased doses of maternal buprenorphine during pregnancy are correlated with NOWS severity. Exploring low doses and having different ranges are a new argument to define the impact of maternal buprenorphine consumption.

Parenteral Buprenorphine for Opioid Withdrawal.

Buprenorphine is the standard of care for treatment of opioid withdrawal. However, when sublingual (SL) administration is not appropriate or practical, parenteral administration by the intravenous (IV) or intramuscular (IM) route may be a reasonable substitute. Although previously used intravenously for the treatment of pain, current practitioners have limited experience with parenteral use of buprenorphine. This is a case series using retrospective chart review of patients at an urban public hospital who received IV or IM buprenorphine for treatment of opioid withdrawal. A query of the electronic health record (EHR) was performed to identify patients who had received IV or IM buprenorphine from January 2020 to December 2021. Charts were reviewed for patient demographics, medical history, substance use history, urine drug screens, clinical scenario, indication for parenteral buprenorphine, dose of buprenorphine, vital sign trends, and any measure of change in withdrawal. Eight patients were identified. The most frequent initial dose of parenteral buprenorphine was 0.3 mg, and if buprenorphine needed to be re-dosed it was most commonly administered every six hours. The most common indications for use were delirium or intractable nausea and vomiting related to opioid withdrawal. Withdrawal improved in 6 of the 8 cases, and often allowed for subsequent use of SL buprenorphine. There were no adverse effects identified. Parenteral buprenorphine was successfully used to treat opioid withdrawal in a select group of patients. Further studies are needed to identify the optimal use parameters of parenteral buprenorphine.

Less-Invasive Technique for Non-stabilized Mandibular Fracture in Mouse Models.

Non-stabilized fractures can be made at mandibular sites in mice, thus making it possible to analyze bone repair using an endochondral ossification mode. To most accurately reflect this process in vivo, it is necessary to have a standardized protocol to avoid excessive bone loss and soft tissue damage, particularly at the mandibular site, an anatomical site characterized by minimal access. To our knowledge, we describe for the first time a less-invasive protocol of non-stabilized mandibular fracture in mice. Adult mice are anesthetized with isoflurane and receive a preoperative dose of buprenorphine by subcutaneous injection. A submandibular approach is performed, with a skin incision made along the inferior border of the mandible. The masseter muscle is elevated in a subperiosteal plane along the mandibular ramus with a periosteal elevator. A vertical and complete fracture of the ramus is performed from the basilar border to the coronoid notch (between condylar and coronoid processes), using a piezoelectric bone surgery device under saline serum irrigation at the basilar edge and scissors to complete the fracture of the mandibular ramus. The skin approach is closed by silk sutures. This detailed procedure for non-stabilized mandibular fractures offers an efficient procedure allowing minimal bone loss and soft tissue damage. This technique ensures successful and consistent results to accurately reflect the process of endochondral bone repair in mouse models.

Association of Daily Doses of Buprenorphine With Urgent Health Care Utilization

Higher buprenorphine doses may benefit the increasing number of individuals using fentanyl and other synthetic opioids, but there is little empirical evidence on the efficacy of such higher doses. To examine the association between higher buprenorphine doses (above 16 mg and 24 mg) and subsequent emergency department (ED) or inpatient service use among patients diagnosed with opioid use disorder. This cross-sectional study was a retrospective analysis of health data from Optum's deidentified Clinformatics Data Mart Database from 2016 to 2021 for commercially insured individuals aged 18 years or older diagnosed with opioid use disorder (OUD). Eligible participants initiated buprenorphine after at least 90 days of enrollment and were dispensed at least a 14-day supply of buprenorphine. Data were analyzed from September 2023 through February 2024. Maximum buprenorphine dose received by a patient for 14 or more days: more than 24 mg, more than 16 mg to 24 mg, more than 8 mg to 16 mg, or 1 mg to 8 mg. Days from initiation of the maximum buprenorphine dose to an ED or inpatient visit for a behavioral health diagnosis, controlling for patient demographics, comorbid conditions, time to reaching maximum dose, buprenorphine discontinuation, and pre-buprenorphine health care utilization. A total of 35 451 individuals with an OUD diagnosis who began buprenorphine treatment were identified (mean [SD] age, 46.2 [15.1] years; 20 983 male [59.2%]; 3326 Black [9.4%], 2411 Hispanic [6.8%], 26 712 White [75.3%]). The most common dose was more than 8 mg to 16 mg daily (14 802 patients [42.9%]), with 9669 patients (27.3%) in the 1 mg to 8 mg tier, 10 329 patients (29.1%) in the 8 mg to 16 mg tier, and 651 patients (1.8%) in the tier receiving more than 24 mg. Among all patients receiving buprenorphine, 12.5% experienced an ED or inpatient visit. Survival analysis shows patients receiving doses more than 24 mg and between 16 mg to 24 mg had longer times to ED or inpatient use than patients receiving from 8 mg to 16 mg (time ratio [TR], 1.11; 95% CI, 1.02 to 1.20) and more than 24 mg (TR, 1.37; 95% CI, 1.04 to 1.81). Findings for doses above 16 mg daily were consistent for observation windows as short as 365 days (more than 24 mg: TR, 1.48; 95% CI, 1.01-2.18; more than 16 mg to 24 mg: TR, 1.19; 95% CI, 1.06-1.32). These findings contribute to the sparse empirical research regarding potential benefits of higher-dose buprenorphine treatment of individuals with OUD. Clinicians should be aware of the potential effects of higher buprenorphine doses on health care utilization while policymakers work to ensure equitable access to individuals who could potentially benefit from higher doses.

Incidence of buprenorphine-precipitated opioid withdrawal in adults with opioid use disorder: A systematic review.

Buprenorphine is an evidence-based treatment for opioid use disorder, and the risk of precipitated withdrawal contributes to its underuse. The goal of this systematic review was to determine the incidence of buprenorphine-precipitated withdrawal in adults with opioid use disorder. This systematic review was registered on PROSPERO (CRD42023437634). We searched Medline, Embase Classic + Embase, and Cochrane CENTRAL from inception to 10 November 2023, and included original research that reported the incidence of sublingual buprenorphine-precipitated withdrawal in adults with opioid use disorder. Primary screening was completed by four independent reviewers. Full text review, data extraction and risk of bias assessments using the Newcastle Ottawa Scale and the Cochrane Risk of Bias 2 tool were completed by two independent reviewers. The primary outcome was precipitated withdrawal. Secondary outcomes were baseline opioids used, induction dose, initial Clinical Opiate Withdrawal Scale (COWS) score, location of induction, definition and severity of precipitated withdrawal and adverse events. The range of incidence of precipitated withdrawal across studies was described. Our search yielded 10 197 unique citations. Twenty-one cohort and five randomized trials met inclusion criteria (n = 4497, range 20-1293). The overall incidence of precipitated withdrawal ranged from 0 to 13.2%. Nine studies defined precipitated withdrawal; definitions were inconsistent. Most patients used heroin at baseline. The most common initial dose of buprenorphine was between 2mg and 8mg (range: 0.075 mg-24 mg). Initial minimum COWS score ranged from 5 to 13. Induction locations included home, inpatient, emergency department, pre-hospital, outpatient and residential units. Of the fifteen studies with cases of precipitated withdrawal, nine studies did not report the severity of withdrawal experienced. Other induction-related adverse events varied. The overall quality of included studies was poor. The best available evidence suggests the incidence of buprenorphine-precipitated withdrawal in adults with opioid use disorder is low and should not be a barrier to use.

Commentary on D'Agata Mount et al.: Higher dose buprenorphine to improve retention in opioid use disorder treatment, prevent relapse, and optimize integrated care interventions.

Commentary on D'Agata Mount et al.: Higher dose buprenorphine to improve retention in opioid use disorder treatment, prevent relapse, and optimize integrated care interventions.

Alternative Reinforcers Enhance the Effects of Opioid Antagonists, but Not Agonists, on Oxycodone Choice Self-Administration in Nonhuman Primates.

Clinical reports suggest that the most effective strategies for managing opioid use disorder comprise a comprehensive treatment program of both pharmacological and nonpharmacological approaches. However, the conditions under which these combinations are most effective are not well characterized. This study examined whether the presence of an alternative reinforcer could alter the efficacy of Food and Drug Administration-approved opioid antagonist or agonist medications, as well as the nonopioid flumazenil, in decreasing oxycodone choice self-administration in nonhuman primates. Adult squirrel monkeys (n = 7; four females) responded under concurrent second-order fixed-ratio (FR)-3(FR5:S);TO45s schedules of reinforcement for intravenous oxycodone (0.1 mg/kg) or saline on one lever and 30% sweetened condensed milk or water on the other. Doses of naltrexone (0.00032-1.0 mg/kg), nalbuphine (0.32-10 mg/kg), buprenorphine (0.0032-0.032 mg/kg), methadone (0.32-1.0 mg/kg), or flumazenil (1-3.2 mg/kg) were administered intramuscularly prior to oxycodone self-administration sessions that occurred with either milk or water as the alternative. Naltrexone, a μ-opioid receptor antagonist, was >30-fold more potent when milk was available compared with water and abolished oxycodone intake (injections/session) while concomitantly increasing milk deliveries at the highest dose tested. Pretreatment with the low-efficacy μ-agonist nalbuphine was most effective in the presence of milk compared with water, decreasing oxycodone preference to <50% of control values. The higher efficacy μ-agonists, methadone and buprenorphine, and the benzodiazepine antagonist flumazenil did not appreciably alter the reinforcing potency of oxycodone under either condition. These results suggest that antagonist medications used in combination with alternative reinforcers may be an effective strategy to curtail opioid abuse-related behaviors. SIGNIFICANCE STATEMENT: Clinical treatment programs for opioid use disorder use a combination of pharmacological and nonpharmacological approaches. However, the conditions under which these combinations are most effective have not been fully characterized. This study examined whether the effectiveness of μ-opioid medications to decrease oxycodone self-administration is altered in the presence of an alternative reinforcer. The results suggest that alternative reinforcers enhance the effects of antagonist or low-efficacy partial agonists, suggesting they may be a more effective strategy to curtail opioid use.

Dosing and Misuse of Buprenorphine in the New Jersey Department of Corrections.

Opioid use disorder is common in incarcerated persons, and concern about the diversion of buprenorphine is a barrier to treatment. We conducted a retrospective chart review of incarcerated persons in the New Jersey Department of Corrections who received charges for misuse of medication, including buprenorphine, hypothesizing that the prescription of buprenorphine monoproduct, multiple tabs or films of buprenorphine, or higher doses of buprenorphine would be associated with more diversion incidents. Within the dosing range of 2 to 12 mg, there were more incidents of diversion of buprenorphine monoproduct (24.3%) compared with buprenorphine-naloxone (10.7%, p = .004). More incidents of diversion were seen when multiple films or tabs of buprenorphine product were prescribed (21.7%, comparison 12.7%, p = .01). This observation held when considering multiple buprenorphine-naloxone films, but not multiple buprenorphine tablets. No statistically significant association was found for institutional diversion charges related to higher doses of buprenorphine products. These results suggest that, within the dosing range of buprenorphine used in the New Jersey Department of Corrections, misuse charges were not associated with higher doses although were associated with prescribing buprenorphine monoproduct and multiple films of buprenorphine-naloxone.

Characterization of Oral Ketamine Use: A Retrospective Review

Ketamine is an N-methyl D-aspartate (NMDA) receptor antagonist used to treat pain at subanesthetic doses. Ketamine is beneficial for pain control in patients who have a high tolerance to opioids and are experiencing opioid-induced hyperalgesia. This study characterizes oral ketamine use for analgesia at a large academic hospital and reports safety outcomes for hospitalized patients. This study was a retrospective electronic health record (EHR) review of patients ≥ 18 years or older receiving oral ketamine. The primary endpoint was median ketamine starting dose and maximum dose (mg/kg/day) during treatment duration. Secondary outcomes included oral Morphine Milligram Equivalents (MMEs), buprenorphine dose, minimum and maximum pain scores on the first and last day of therapy. Safety endpoints were reported. The median starting dose was 1 mg/kg/day, and the median maximum dose was 1.6 mg/kg/day. Median MMEs decreased from the first day to the last day of oral ketamine therapy. The study population experienced a low incidence of safety events overall. Oral ketamine was administered safely for analgesia, with patients receiving ketamine doses that were on the lower end of the established therapeutic range. Evaluation of the efficacy and safety of oral ketamine use for analgesia should be further studied.

The "Micro"cosm: Magnifying the Nuance of Low Dose Buprenorphine Inductions.

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. 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. 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.

Buprenorphine-Precipitated Withdrawal Among Hospitalized Patients Using Fentanyl

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. To estimate buprenorphine PW incidence and assess factors associated with PW among emergency department (ED) or hospitalized patients. 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. 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). 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. 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. 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.

A Pharmacologic Evaluation of Buprenorphine in Pregnancy and the Postpartum Period.

The dosing regimen in the package insert for sublingual buprenorphine is similar for pregnant and nonpregnant people despite the physiologic changes seen during pregnancy. To compare plasma buprenorphine pharmacokinetics during and after pregnancy and relate buprenorphine concentration to the pharmacodynamic endpoints of pupil diameter, Clinical Opioid Withdrawal Scale (COWS), and craving scores. Prospective cohort of 22 pregnant people undergoing 33 pharmacologic studies (6-8 hours each) during pregnancy or postpartum. Participants were on a stable daily dose of 2-8 mg sublingual buprenorphine every 6 or 8 hours. The dosing frequency was selected by the participant. On study day, baseline measurements of plasma buprenorphine, pupil diameter, COWS, and craving scores were obtained, then the usual morning dose was taken, and measurements were repeated several times over 1 dosing interval. The dose-normalized area under the plasma buprenorphine concentration time curve was significantly (P = 0.036) lower during pregnancy (155 ± 52 ng × min/mL) than postpartum (218 ± 113 ng × min/mL). Buprenorphine trough concentrations were similar at the start (1.1 ± 0.7 ng/mL) and end of a dosing cycle (1.2 ± 0.8 ng/mL) regardless of dosing frequency. Pupillary diameter, COWS, and craving scores returned to baseline as buprenorphine concentrations approached ~1 ng/mL. Pregnant people require a higher dose of buprenorphine to achieve concentrations comparable to nonpregnant people. There is a temporal relationship between the plasma buprenorphine concentration and the pharmacodynamic markers of pupillary diameter, COWS, and craving scores. An average plasma concentration of ~1 ng/mL was associated with the lowest level of COWS and craving scores.

Ketamine-assisted buprenorphine initiation: a pilot case series

BackgroundMany people with opioid use disorder who stand to benefit from buprenorphine treatment are unwilling to initiate it due to experience with or fear of both spontaneous and buprenorphine-precipitated opioid withdrawal (BPOW). An effective means of minimizing withdrawal symptoms would reduce patient apprehensiveness, lowering the barrier to buprenorphine initiation. Ketamine, approved by the FDA as a dissociative anesthetic, completely resolved BPOW in case reports when infused at a sub-anesthetic dose range in which dissociative symptoms are common. However, most patients attempt buprenorphine initiation in the outpatient setting where altered mental status is undesirable. We explored the potential of short-term use of ketamine, self-administered sublingually at a lower, sub-dissociative dose to assist ambulatory patients undergoing transition to buprenorphine from fentanyl and methadone.MethodsPatients prescribed ketamine were either (1) seeking transition to buprenorphine from illicit fentanyl and highly apprehensive of BPOW or (2) undergoing transition to buprenorphine from illicit fentanyl or methadone and experiencing BPOW. We prescribed 4–8 doses of sublingual ketamine 16 mg (each dose bioequivalent to 3–6% of an anesthetic dose), monitored patients daily or near-daily, and adjusted buprenorphine and ketamine dosing based on patient response and prescriber experience.ResultsOver a period of 14 months, 37 patients were prescribed ketamine. Buprenorphine initiation was completed by 16 patients, representing 43% of the 37 patients prescribed ketamine, and 67% of the 24 who reported trying it. Of the last 12 patients who completed buprenorphine initiation, 11 (92%) achieved 30-day retention in treatment. Most of the patients who tried ketamine reported reduction or elimination of spontaneous opioid withdrawal symptoms. Some patients reported avoidance of severe BPOW when used prophylactically or as treatment of established BPOW. We developed a ketamine protocol that allowed four of the last patients to complete buprenorphine initiation over four days reporting only mild withdrawal symptoms. Two patients described cognitive changes from ketamine at a dose that exceeded the effective dose range for the other patients.ConclusionsKetamine at a sub-dissociative dose allowed completion of buprenorphine initiation in the outpatient setting in the majority of patients who reported trying it. Further research is warranted to confirm these results and develop reliable protocols for a range of treatment settings.

Qualitative Assessment of Barriers to Buprenorphine Access: The Role of Pharmacies

Background Patients continue to face challenges accessing medication for opioid use disorder (MOUD) despite attempts to loosen prescribing restrictions and streamline service provision. Past research has mainly focused on potential barriers surrounding prescribing practices for buprenorphine, but has had limited investigation into the role of pharmacies. Objective This study investigates the role of both pharmacists and pharmacies in creating or circumventing barriers to accessing buprenorphine for individuals in Georgia seeking medication for opioid use disorder (MOUD). Methods Semi-structured interviews of pharmacists across 12 access and no access pharmacies were used to create a codebook of 179 discreet statements. The (N = 12) 20–35-minute phone interviews included questions addressing substance use, pharmacy practices, treatment, harm reduction, and psychoeducation. Results Pharmacists widely agreed that opioid use has caused negative effects on community members (N = 11), that buprenorphine formulation stocking decisions are made based on patient needs (N = 11), and that buprenorphine is relatively easy to stock (N = 10). Additionally, respondents generally stated that buprenorphine is a helpful tool for treating opioid use disorder (OUD) (N = 12) but some reported positive experiences while others reported challenging or negative experiences with patients receiving buprenorphine (N = 7). Finally, few (N = 4) pharmacists agreed that they could benefit from extra training despite many asserting that training is important to inform their own practice (N = 8). Conclusion Results from respondents generally show that training may be beneficial for pharmacists to develop an enhanced understanding of addiction and treatment. Enhanced effort to stock different formulations or dosages of buprenorphine and develop relationships with prescribers may increase community access.

Impact of childhood adversity on acute subjective effects of stimulant and opioid drugs: Evidence from placebo-controlled studies in healthy volunteers.

Early-life adversities are known to alter drug reward processing in rodents. Despite the well-known link between early adversity and the risk of substance use disorder, few studies have measured how childhood adversity affects human drug reward. Here, we assessed the relationship between historical childhood adversities and responses to single doses of methamphetamine, d-amphetamine or buprenorphine in healthy participants. Using a secondary analysis approach, we assessed the impact of childhood adversity on drug effects from three randomised, placebo-controlled studies in which healthy volunteers received methamphetamine (20 mg oral; n = 35), d-amphetamine (20 mg oral; n = 54) or buprenorphine (0.2 mg sublingual; n = 35). Ratings of feeling effect, liking, disliking, feeling high and wanting more of the drug were collected 15-210 min post-administration, and heart rate changes were analysed using random-intercept mixed-effect models. The area under the curve from these and previous studies was calculated to visualise the relationship between childhood adversity severity and drug effects. Greater childhood adversity was associated with reduced feel effects (significant three-way interactions b = -0.07, 95% CI [-0.12, -0.02], p = 0.009), like effects (b = -0.07, 95% CI [-0.13, -0.00], p = 0.038) and feel high (b = -0.06, 95% CI [-0.10, -0.01], p = 0.020) towards the stimulant drugs 90-180 min post-administration. Childhood adversity was not significantly associated with other subjective or heart rate responses to the drugs. Overall, participants with more childhood adversities reported dampened subjective responses to stimulant drugs, but not to buprenorphine. Future studies should examine the generalisability of these relationships, to identify the mechanisms underlying the link between childhood adversity and drug responsiveness.

Reconsidering the usefulness of long-term high-dose buprenorphine.

Buprenorphine has been successfully used for decades in the treatment of opioid use disorder, yet there are complexities to its use that warrant attention to maximize its utility. While the package insert of the combination product buprenorphine\naloxone continues to recommend a maximum dose of 16 mg daily for maintenance, the emergence of fentanyl and synthetic analogs in the current drug supply may be limiting the effectiveness of this standard dose. Many practitioners have embraced and appropriately implemented novel practices to mitigate the sequelae of our current crisis. It has become common clinical practice to stabilize patients with 24 - 32 mg of buprenorphine daily at treatment initiation. Many of these patients, however, are maintained on these high doses (>16 mg/d) indefinitely, even after prolonged stability. Although this may be a necessary strategy in the short term, there is little evidence to support its safety and efficacy, and these high doses may be exposing patients to more complications and side effects than standard doses. Commonly known side effects of buprenorphine that are likely dose-related include hyperhidrosis, sedation, decreased libido, constipation, and hypogonadism. There are also complications related to the active metabolite of buprenorphine (norbuprenorphine) which is a full agonist at the mu opioid receptor and does not have a ceiling on respiratory suppression. Such side effects can lead to medical morbidity as well as decreased medication adherence, and we, therefore, recommend that after a period of stabilization, practitioners consider a trial of decreasing the dose of buprenorphine toward standard dose recommendations. Some patients' path of recovery may never reach this stabilization phase (i.e., several months of adherence to medications, opioid abstinence, and other clinical indicators of stability). Side effects of buprenorphine may not have much salience when patients are struggling for survival and safety, but for those who are fortunate enough to advance in their recovery, the side effects become more problematic and can limit quality of life and adherence.