Medications to treat substance use disorders (SUDs) remain suboptimal or, in the case of stimulants and cannabis, non-existent. Many factors have contributed to this paucity, including the biological complexity of addiction, regulatory challenges, and a historical lack of enthusiasm among pharmaceutical companies to commit resources to this disease space. Despite these headwinds, the recent opioid crisis has highlighted the devastating consequences of SUDs for both individuals and society, stimulating urgent efforts to identify novel treatment approaches. In addition, several neurobiological systems have been recently implicated in unique aspects of drug reward, opening the door to candidate medications with novel mechanisms of action. Here, we provide an overview of efforts to target several of these new systems, with a focus on those that are the subject of ongoing clinical trials as well as being areas of interest among the authors' research groups (MHJ, MTB, NAE). Specifically, we discuss new classes of medications targeting the serotonin 2A receptor (i.e., psychedelics), glucagon-like peptide 1 receptor, cannabidiol, dynorphin/kappa opioid receptor, orexin/hypocretin, and oxytocin receptor systems, as well as emergent approaches for modulating the more canonical dopaminergic system via agonist therapies for stimulant use disorders. Collectively, innovations in this space give reason for optimism for an improved therapeutic landscape for substance use disorders in the near future.

Data indicate that one in five patients with cancer might be at risk for nonmedical opioid use and its extreme form, opioid use disorder (OUD). Buprenorphine is one of the few medications available for the management of patients with co-occurring OUD and chronic pain. Care for these patients can be challenging and require the expertise of specialist clinicians with a deep understanding of addiction and cancer pain. Regrettably, these specialist clinicians may not always be available and accessible when patients are admitted to the hospital. Reports on how primary non-specialist clinicians without access to specialist addiction services navigate the care of such patients in the inpatient setting are limited. We hereby describe the care of three patients with OUD receiving buprenorphine who were hospitalized for cancer pain.

Initiation of buprenorphine for treatment of opioid use disorder (OUD) in acute care settings improves access and outcomes, however patients who use methamphetamine are less likely to link to ongoing treatment. We describe the intervention and design from a pilot randomized controlled trial of an intervention to increase linkage to and retention in outpatient buprenorphine services for patients with OUD and methamphetamine use who initiate buprenorphine in the hospital.

The study is a two-arm pilot randomized controlled trial (N = 40) comparing the mHealth Incentivized Adherence Plus Patient Navigation (MIAPP) intervention to treatment as usual. Development of the MIAPP intervention was guided by the information-motivation-behavioral skills model and combines financial rewards via mobile health-based adherence monitoring with the "human touch" of a patient navigator. Participants receive financial incentives for submitting videos of themselves taking buprenorphine via smartphone. The Patient Navigator reviews videos and provides treatment adherence coaching, care coordination and motivational enhancement. The intervention is introduced prior to hospital discharge and is offered for 30 days. The primary outcome is linkage to outpatient buprenorphine care within 30 days of hospital discharge. Secondary outcomes include retention on buprenorphine 90 days post discharge, hospital readmissions, and past 30-day methamphetamine use.

Interventions are needed to increase linkage and retention to outpatient buprenorphine among hospitalized patients with OUD, especially for people who co-use methamphetamine. We will examine the MIAPP intervention to improve buprenorphine adherence and linkage to outpatient treatment in a pilot randomized controlled trial which will provide valuable insights about research approaches for hospitalized patients with substance use disorder.

NCT06027814. Date of Initial Release: 08/30/2023.

03/21/2024.

The opioid epidemic continues to have a staggering impact on millions of individuals and families across all socioeconomic levels and communities. Recent studies suggest high numbers of patients presenting for surgery with reported opioid misuse and/or opioid use disorder (OUD). Anesthesiologists often lack basic education to treat patients suffering with OUD or patients in recovery from this treatable disease. This manuscript will provide a review of the American Society of Anesthesiology and Pain Medicine Multisociety Working Group Practice Advisory recommendations on existing OUD treatment barriers and perioperative management best practices; it will also demonstrate the benefits that greater involvement of the anesthesiologist can have in managing patients with OUD perioperatively.

Intranasal administration of the neuropeptide oxytocin has been explored as a potential therapeutic agent for substance use disorder including opioid use disorder (OUD).

This phase 1, crossover, randomized, double-blind, placebo-controlled trial tested the safety, tolerability, and efficacy of intranasal oxytocin (80 IU) twice a day for 7 days in participants (N = 20) with OUD who were taking an opioid agonist therapy. In the laboratory, participants underwent opioid cue exposure paired with noradrenergic activation produced by yohimbine (32.4 mg) or placebo. Assessments included, 1) subjective response: craving, withdrawal, anxiety, and stress; 2) biomedical markers: hypothalamic-pituitary-adrenal axis response (cortisol) and noradrenergic activation (α-amylase); and 3) safety measures: hemodynamics and adverse event evaluation. Generalized linear model with model-based estimator in the covariance matrix was used, with medication (oxytocin/placebo) and noradrenergic activation (yohimbine/placebo) as within-subject factors.

Oxytocin significantly reduced opioid-like withdrawal, anxiety symptoms, and cortisol levels elicited by cue exposure under noradrenergic activation produced by yohimbine. This effect was specific because oxytocin did not reduce craving, hemodynamics, or α-amylase levels increased by yohimbine administration. A single dose of yohimbine elicited the noradrenergic stimulation, and 7-day oxytocin administration was safe and well tolerated among individuals diagnosed with OUD and taking opioid agonist therapy.

The findings of this study suggest that oxytocin alleviates opioid-like withdrawal symptoms and anxiety by modulating the hypothalamic-pituitary-adrenal axis.

Regulatory authorities typically require bioequivalence to be demonstrated by comparing pharmacokinetic parameters like area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax). Because in certain cases, AUC and Cmax alone may not be adequate to identify formulation differences in early and/or late segments of the dosing interval, partial AUCs (pAUCs) have been proposed as additional metrics to evaluate bioequivalence. Even though cut-off points for pAUCs are usually decided based on clinical relevance, the identification of the correct cut-off range remains elusive in many other cases and tends to contribute to increased pAUC estimate variabilities. The choice of meaningful cut-off points in pAUC estimates can be especially difficult in the case of long-acting injectable (LAI) products, where long dosing intervals and complex pharmacokinetic (PK) and pharmacodynamic (PD) profiles apply, but most importantly, because there is not always a clear PK/PD relationship established. In this communication, authors discuss the usefulness and challenges associated with the estimation of pAUCs in the development of generic LAI products through the review of six case studies under the lens of regulatory requirements from the two major authorities, namely the FDA and EMA.

Opioid use disorder (OUD) is a global concern. Urine drug screening uses opioid immunoassays to monitor OUD treatment response but is limited to yes/no results. Analytical cutoff variation complicates interstudy comparisons. This study investigated whether quantitative urinalysis can provide additional clinically meaningful treatment efficacy information and assessed the impact of different cutoffs on treatment differences.

Quantitative urine drug test data were analyzed from a randomized, active-controlled, parallel-group, double-blind, 31-week phase 3 trial (N = 428; December 29, 2015, to October 19, 2016) assessing CAM2038 subcutaneous (SC) buprenorphine (BPN) extended-release injections compared to daily sublingual (SL) BPN/naloxone (BPN/NX) tablets, and equivalent placebos, in OUD treatment (NCT02651584). Urine samples were analyzed by gas or liquid chromatography with mass spectrometry. The European Medicines Agency (EMA)-directed primary endpoint, based on opioid detection above the lower limit of quantification (LLOQ), was explored using different cutoffs.

Using the LLOQ, the mean percentage of opioid-negative samples was 35.1% and 28.4% for CAM2038 and SL BPN/NX, respectively (mean difference [95% confidence interval], 6.7% [-0.1% to 13.6%]). Using standard cutoffs (1 ng/mg creatinine [fentanyl/norfentanyl], 300 ng/mg creatinine [other opioids]), results were 41.2% and 32.2% (9.0% [1.8%-16.1%]). Increasing cutoffs led to greater differences favoring CAM2038. Significant differences in mean concentrations over time and cumulative distribution of exposure to different opioids also favored CAM2038. The difference in fentanyl exposure between treatments was nonsignificant.

Quantitative urinalysis provides insights into opioid use beyond assessment of abstinence. Study outcomes are impacted by analytical thresholds, which should be carefully considered when designing, interpreting, and comparing clinical trial results.

This work aimed to assess the association between sleep apnea syndrome (SAS) and opioid substitution treatments (OST) dose/timing of administration in patients receiving methadone or buprenorphine for an opioid use disorder (OUD).

We conducted a retrospective cross-sectional study by including files of adult patients treated between November 2015 and January 2023 with methadone or buprenorphine and who had a nocturnal respiratory polygraphy. We collected information on treatments and polygraphical recording data such as the apnea-hypopnea index (AHI).

We enrolled 60 patients on methadone and 15 on buprenorphine. The sample encompassed 72% of males, and the mean age was 36±7.49years. Moderate to severe and severe SAS were significantly associated with the daily dose and the evening administration but was not predicted by the type of OST. However, the mean and median values of AIH were significantly greater with methadone. Contrary to methadone, there was no significant correlation between the buprenorphine daily dose and the AHI. The best sensitivities and specificities for the prediction of an AHI≥15 events/h and an AHI≥30 events/h were respectively obtained with methadone dose thresholds of 77.5mg/day.

In this sample, the methadone daily dose of 77.5mg was the best cut-point to predict moderate to severe SAS, especially while taken in the evening, and we found no correlation between buprenorphine and the AHI. These results draw clinicians' attention to buprenorphine use as an alternative for patients treated with methadone and having SAS.

Buprenorphine was synthesized in the 1960s as a result of a search for a safe and effective opioid analgesic. Present formulations of buprenorphine are approved for the treatment of both acute and chronic pain. Its long duration of action, high affinity, and partial agonism at the µ-opioid receptor have established it as a mainstay treatment for opioid use disorder (OUD). Full agonist opioids (FAOs) remain a primary choice for perioperative pain in both opioid-naïve and opioid-tolerant patients despite well-known harms and new emphasis on multimodal analgesia strategies prioritizing nonopioid analgesics. We review the evidence supporting the use of buprenorphine as an effective analgesic alternative to more commonly prescribed FAOs in acute and chronic pain management. For the patient prescribed buprenorphine for OUD, prior conventionalism advised temporary discontinuation of buprenorphine preoperatively; this paradigm has shifted toward continuing buprenorphine throughout the perioperative period. Questions remain whether dose adjustments may improve patient outcomes.

Opioid use disorder (OUD) is considered a global health issue that affects various aspects of patients' lives and poses a considerable burden on society. Due to the high prevalence of remissions and relapses, novel therapeutic approaches are required to manage OUD. Deep brain stimulation (DBS) is one of the most promising clinical breakthroughs in translational neuroscience. It involves stereotactically implanting electrodes inside the brain and transmitting electrical pulses to targeted areas. To date, the nucleus accumbens has been recognized as the most successful DBS target for treating different types of drug addiction. Nevertheless, further preclinical research is required to determine the optimal brain target and stimulation parameters. On the other hand, the lateral hypothalamic area (LHA) plays a crucial role in many motivated behaviors including food intake and drug-seeking. Additionally, it projects widely throughout the brain to reward-related areas like the ventral tegmental area. Therefore, this chapter reviews studies investigating the potential positive effects of DBS administration in the LHA in animal models of opioid dependence and other pathological conditions. Findings reveal that LHA has the potential to be targeted for DBS application to treat a wide variety of disorders such as opioid dependence, obesity, and sleep disorders without significant adverse events. However, in the context of opioid dependence, more studies are needed, based on more valid animal models of addiction, including self-administration paradigms and varying stimulation patterns, to indicate that LHA is a safe and effective target for DBS in subjects with refractory opioid dependence.

Opioid overdose survivors present to emergency departments (EDs) and many EDs have developed programs to initiate buprenorphine. The impact of the increasing use of buprenorphine in ED and by other providers is unknown while opioid mortality continues to rise. Public mortality data do not distinguish buprenorphine from other prescription opioids. Our objective was to determine when changes in overdose mortality trends occurred comparing deaths involving buprenorphine to oxycodone, hydrocodone, and methadone.

This observational study utilized the drug-involved mortality database including US death certificates (2010‒2017) in which buprenorphine, oxycodone, hydrocodone, or methadone were contributing causes of death (determined through textual analysis). Population- and drug utilization-adjusted mortality rates were examined using disjointed linear regression. Buprenorphine-involved deaths were stratified by polysubstance involvement.

The population-adjusted mortality rates for buprenorphine-involved deaths were lowest compared to other opioids; however, the change in rate for buprenorphine increased faster than oxycodone, hydrocodone, and methadone at 8.9% each quarter-year (95% confidence interval [CI]: 8.0, 9.8) from 2010 to mid-2016 when it stabilized. After adjusting for changes in dispensing over the study period, buprenorphine-involved mortality rates were increasing at 5.3% (95% CI: 4.6, 6.1) each quarter-year. In 2017, 94% buprenorphine-involved deaths had at least one other drug contributing to the cause of death.

Given the low mortality, high proportions of polysubstance mortality, and the mixed agonist/antagonist mechanism of action, use of buprenorphine alone likely presents a lower risk for overdose than comparators. Mortality rose faster than dispensing, signaling need to ensure people understand buprenorphine risks, particularly polysubstance use, balanced against importance for treating opioid use disorders.

Long-acting injectable buprenorphine (LAI-bup) formulations have advantages over transmucosal buprenorphine (TM-bup), but barriers may limit their utilization. Several policies shifted during the COVID-19 pandemic to promote buprenorphine access. The federal government expanded telemedicine treatment for opioid use disorder and Kentucky (KY) Medicaid lifted prior authorization requirements (PAs) for LAI-bup (i.e., Sublocade®). This retrospective cohort study evaluated changes in LAI-bup access, utilization, and retention before and after these policy changes in KY.

Individual-level TM-bup and LAI-bup dispensing record data from KY's prescription drug monitoring program examined LAI-bup utilization and retention, without a >30-day gap in coverage, for patients starting a new episode of LAI-bup treatment. Two key time periods were examined: pre-policy changes (Apr 1, 2019 - Dec 31, 2019) and post-policy changes (Apr 1, 2020 - Dec 31, 2020). Data on PA requests among Medicaid managed care organizations and availability of LAI-bup Risk Evaluation and Mitigation Strategy (REMS)-certified pharmacies were also obtained. A multivariable Cox proportional hazard regression model analysis compared pre- versus post-policy period treatment discontinuation.

The number of patients initiating LAI-bup increased from 211 to 481 over the two periods. By the end of the post-policy period, 24.3 % of eligible patients were retained on LAI-bup, versus 12.5 % in the pre-policy change period. The adjusted hazard ratio, comparing discontinuation during the post- versus pre-policy change periods, was 0.70 (95 % confidence interval: 0.55-0.89). There were also more REMS-certified pharmacies and providers in the post-policy change period.

LAI-bup access, utilization, and retention increased after several policy changes.

Over the past decade, treatment for opioid use disorder has expanded to include long-acting injectable and implantable formulations of medication for opioid use disorder (MOUD), and integrated treatment models systematically addressing both behavioral and physical health. Patient preference for these treatment options has been underexplored. Gathering data on OUD treatment preferences is critical to guide the development of patient-centered treatment for OUD. This cross-sectional study assessed preferences for long-acting MOUD and integrated treatment using an online survey.

An online Qualtrics survey assessed preferences for MOUD formulation and integrated treatment models. The study recruited participants (n = 851) in October and November 2019 through advertisements or posts on Facebook, Google AdWords, Reddit, and Amazon Mechanical Turk (mTurk). Eligible participants scored a two or higher on the opioid pain reliever or heroin scales of the Tobacco, Alcohol Prescription Medication and other Substance Use (TAPS) Tool. Structured survey items obtained patient preference for MOUD formulation and treatment model. Using stated preference methods, the study assessed preference via comparison of preferred options for MOUD and treatment model.

In the past year, 824 (96.8 %) participants reported non-prescribed use of opioid pain relievers (mean TAPS score = 2.72, SD = 0.46) and 552 (64.9 %) reported heroin or fentanyl use (mean TAPS score = 2.73, SD = 0.51). Seventy-four percent of participants (n = 631) reported currently or previously receiving OUD treatment, with 407 (48.4 %) receiving MOUD. When asked about preferences for type of MOUD formulation, 452 (53.1 %) preferred a daily oral formulation, 115 (13.5 %) preferred an implant, 114 (13.4 %) preferred a monthly injection and 95 (11.2 %) preferred a weekly injection. Approximately 8.8 % (n = 75) would not consider MOUD regardless of formulation. The majority of participants (65.2 %, n = 555) preferred receiving treatment in a specialized substance use treatment program distinct from their medical care, compared with receiving care in an integrated model (n = 296, 34.8 %).

Though most participants expressed willingness to try long-acting MOUD formulations, the majority preferred short-acting formulations. Likewise, the majority preferred non-integrated treatment in specialty substance use settings. Reasons for these preferences provide insight on developing effective educational tools for patients and suggesting targets for intervention to develop a more acceptable treatment system.

Patients with substance use disorders (SUDs) exhibit low healthcare utilization despite high medical need. Telehealth could boost utilization, but variation in uptake across SUDs is unknown.

Using Wisconsin Medicaid enrollment and claims data from December 1, 2018, to December 31, 2020, we conducted a cohort study of telemedicine uptake in the all-ambulatory and the primary care setting during telehealth expansion following the COVID-19 public health emergency (PHE) onset (March 14, 2020). The sample included continuously enrolled (19 months), nonpregnant, nondisabled adults aged 19 to 64 years with opioid (OUD), alcohol (AUD), stimulant (StimUD), or cannabis (CannUD) use disorder or polysubstance use (PSU). Outcomes: total and telehealth visits in the week, and fraction of visits in the week completed by telehealth. Linear and fractional regression estimated changes in in-person and telemedicine utilization. We used regression coefficients to calculate the change in telemedicine utilization, the proportion of in-person decline offset by telemedicine uptake ("offset"), and the share of visits completed by telemedicine ("share").

The cohort (n = 16 756) included individuals with OUD (34.8%), AUD (30.1%), StimUD (9.5%), CannUD (9.5%), and PSU (19.7%). Total and telemedicine utilization varied by group post-PHE. All-ambulatory: total visits dropped for all, then rose above baseline for OUD, PSU, and AUD. Telehealth expansion was associated with visit increases: OUD: 0.489, P < .001; PSU: 0.341, P < .001; StimUD: 0.160, P < .001; AUD: 0.132, P < .001; CannUD: 0.115, P < .001. StimUD exhibited the greatest telemedicine share. Primary care: total visits dropped for all, then recovered for OUD and CannUD. Telemedicine visits rose most for PSU: 0.021, P < .001; OUD: 0.019, P < .001; CannUD: 0.011, P < .001; AUD: 0.010, P < .001; StimUD: 0.009, P < .001. PSU and OUD exhibited the greatest telemedicine share, while StimUD exhibited the lowest. Telemedicine fully offset declines for OUD only.

Telehealth expansion helped maintain utilization for OUD and PSU; StimUD and CannUD showed less responsiveness. Telehealth expansion could widen gaps in utilization by SUD type.

The health and economic consequences of inadequately treated opioid use disorder (OUD) are substantial. Healthcare systems in the United States (US) and other countries are facing a growing healthcare crisis due to opioids. Although effective medications for OUD exist, relying solely on clinical information is insufficient for addressing the opioid crisis.

In this review, the role of pharmacoeconomic studies in informing evidence-based medication treatment for OUD is discussed, with a particular emphasis on the US healthcare system, where the economic burden is significantly higher than the global average. The scope/objective of pharmacoeconomics as a distinct scientific research program is briefly defined, followed by a discussion of existing evidence informed by data from systematic reviews, in addition to a convenience sample of recently published pharmacoeconomic studies and protocols. The review also explores the need for methodological advancements in the field.

Despite the potential of pharmacoeconomic research in shaping evidence-based medicine for OUD, significant challenges limiting its real-world application remain. How to address these challenges are explored, including how to combine cost-effectiveness and budget impact analyses to address the needs of the healthcare system as a whole and specific stakeholders interested in adopting new OUD treatment strategies.

Long-acting injectable buprenorphine (LAIB) has demonstrated a good profile for opioid use disorder (OUD) management. However, there is scarce information on LAIB in OUD patients with comorbid mental disorders (dual disorder patients).

We present a case report on OUD patients with a comorbid mental disorder who have received LAIB for at least 3 months.

Two women and one man with OUD and another comorbid mental disorder were prescribed with LAIB ranging from three to twelve months. Good adherence and opioid abstinence were observed during the follow-up. Psychopathological issues related to comorbid mental disorders were stabilized. A deep discussion on LAIB in this profile of patients is conducted.

LAIB in OUD patients with comorbid mental disorders may be a safe and well tolerated option, similar to OUD patients without comorbid mental disorders. LAIB's impact on psychopathological issues requires further high-quality research to understand the real impact of LAIB on OUD and comorbid mental disorders.

Buprenorphine is used to treat opioid use disorder (OUD). Weekly and monthly subcutaneous long-acting buprenorphine injections (CAM2038) provide more stable buprenorphine plasma levels and reduce the treatment burden, misuse, and diversion associated with sublingual transmucosal buprenorphine formulations. To characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship, a maximum inhibition (Imax) model was developed relating CAM2038 buprenorphine plasma concentration to drug liking maximum effect (Emax) visual analog scale (VAS; bipolar) score after intramuscular hydromorphone administration. Data included time-matched observations of buprenorphine plasma concentration and drug liking Emax VAS score after hydromorphone 18 mg administration in 47 non-treatment-seeking adults with moderate to severe OUD in a phase 2 study. Analysis used non-‍linear mixed-effects modeling (NONMEM®). The final Imax model adequately described the PK/PD relationship between buprenorphine plasma concentration and drug liking Emax VAS score. Simulations showed drug liking was effectively blocked at low buprenorphine plasma concentrations (0.4 ng/mL) where the upper 95% confidence interval of the drug liking Emax VAS score was below the pre-defined 11-point complete blockade threshold. The buprenorphine plasma concentration required to achieve 90% of the maximal effect (IC90) of drug liking was 0.675 ng/mL. Interindividual variability in responses to buprenorphine was observed; some participants experienced fluctuating responses, and a few did not achieve drug liking blockade even with higher buprenorphine plasma concentrations. This affirms the need to individualize treatment and titrate doses for optimal treatment outcomes. PK/PD models were also developed for desire to use VAS and Clinical Opiate Withdrawal Scale (COWS) scores, with results aligned to those for drug liking.

Buprenorphine is a medication for opioid use disorder that reduces mortality. This study aims to investigate the less well-understood relationship between the dose in the early stages of treatment and the subsequent risk of death.

We used Kentucky prescription monitoring data to identify adult Kentucky residents initiating transmucosal buprenorphine medication for opioid use disorder (January 2017 to November 2019). Average daily buprenorphine dose for days covered in the first 30 days of treatment was categorized as ≤8 mg, >8 to ≤16 mg, and >16 mg. Patients were followed for 365 days after the first 30 days of buprenorphine treatment. Endpoints were opioid-involved overdose death and death from other causes. Causes and dates of death were obtained using Kentucky death certificate records. Associations were evaluated using multivariable Fine and Gray models adjusting for patient baseline characteristics.

In the cohort of 49,857 patients, there were 227 opioid-involved overdose deaths and 459 deaths from other causes. Compared with ≤8 mg, the adjusted subdistribution hazard ratio (aSHR) of opioid-involved overdose death decreased by 55% (aSHR, 0.45; 95% confidence interval [CI], 0.34-0.60) and 64% (aSHR, 0.36; 95% CI, 0.25-0.52) for patients receiving doses of >8 to ≤16 mg and >16 mg, respectively. The incidence of death from other causes was lower in patients receiving >8 to ≤16 mg (aSHR, 0.78; 95% CI, 0.62-0.98) and >16 mg (aSHR, 0.62; 95% CI, 0.47-0.80) versus ≤8 mg dose.

Higher first 30-day buprenorphine doses were associated with reduced opioid-involved overdose death and death from other causes, supporting benefit of higher dosing in reducing mortality.

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.

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.

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.

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).

In recent decades, opioid overdoses have increased dramatically in the United States and peer countries. Given this, emergency medicine physicians have become adept in reversing and managing complications of acute overdose. However, many remain unfamiliar with initiating medication for opioid use disorder such as buprenorphine, a high-affinity partial opioid agonist. Emergency department-based buprenorphine initiation is supported by a significant body of literature demonstrating a marked reduction in mortality in addition to increased engagement in care. Buprenorphine initiation is also safe, given both the pharmacologic properties of buprenorphine that reduce the risk of diversion or recreational use, and previously published literature demonstrating low rates of respiratory depression, sedation, and precipitated withdrawal. Further, barriers to emergency department-based initiation have been reduced in recent years, with publicly available dosing and up-titration schedules, numerous publications overviewing best practices for managing precipitated withdrawal, and removal of USA policies previously restricting patient access and provider prescribing, with the removal of the X-waiver via the Medication Access and Training Expansion Act. Despite reductions in barriers, buprenorphine initiation in the emergency room remains underutilized. Poor uptake has been attributed to numerous individual and systemic barriers, including inadequate education, provider stigma, and insufficient access to outpatient follow-up care. The following practice innovation aims to summarize previously published evidence-based best practices and provide an accessible, user-friendly initiation guide to increase emergency physician comfortability with buprenorphine initiation going forward.

Both increases and decreases in patients' prescribed daily opioid dose have been linked to increased overdose risk, but associations between 30-day dose trajectories and subsequent overdose risk have not been systematically examined.

To examine the associations between 30-day prescribed opioid dose trajectories and fatal opioid overdose risk during the subsequent 15 days.

Statewide cohort study using linked prescription drug monitoring program and death certificate data. We constructed a multivariable Cox proportional hazards model that accounted for time-varying prescription-, prescriber-, and pharmacy-level factors.

All patients prescribed an opioid analgesic in California from March to December, 2013 (5,326,392 patients).

Dependent variable: fatal drug overdose involving opioids. Primary independent variable: a 16-level variable denoting all possible opioid dose trajectories using the following categories for current and 30-day previously prescribed daily dose: 0-29, 30-59, 60-89, or ≥90 milligram morphine equivalents (MME).

Relative to patients prescribed a stable daily dose of 0-29 MME, large (≥2 categories) dose increases and having a previous or current dose ≥60 MME per day were associated with significantly greater 15-day overdose risk. Patients whose dose decreased from ≥90 to 0-29 MME per day had significantly greater overdose risk compared to both patients prescribed a stable daily dose of ≥90 MME (aHR 3.56, 95%CI 2.24-5.67) and to patients prescribed a stable daily dose of 0-29 MME (aHR 7.87, 95%CI 5.49-11.28). Patients prescribed benzodiazepines also had significantly greater overdose risk; being prescribed Z-drugs, carisoprodol, or psychostimulants was not associated with overdose risk.

Large (≥2 categories) 30-day dose increases and decreases were both associated with increased risk of fatal opioid overdose, particularly for patients taking ≥90 MME whose opioids were abruptly stopped. Results align with 2022 CDC guidelines that urge caution when reducing opioid doses for patients taking long-term opioid for chronic pain.

In clinical practice, sublingual (SL) buprenorphine-naloxone is prescribed as once daily or split daily dosing for the management of opioid use disorder (OUD). Evidence is lacking that assesses how split daily buprenorphine-naloxone affects OUD outcomes. This study aims to evaluate how the dosing frequency of SL buprenorphine-naloxone impacts therapy effectiveness when treating patients with OUD.

This retrospective analysis included adult outpatients prescribed treatment with SL buprenorphine-naloxone for OUD between July 1, 2016, and March 1, 2020. The study excluded patients with sickle cell disease, recent methadone treatment, or pregnancy. We characterized study groups by dosing frequency, either once daily or split dosing. The study compared retention in treatment, medication adherence, adherence to treatment program, and hospital encounters between groups.

The study screened eight-hundred and seven patients, and included 250 patients newly prescribed SL buprenorphine-naloxone. Fifty-seven patients (22.8 %) were prescribed once daily dosing and 193 patients (77.2 %) were prescribed split daily dosing. The study found no significant differences noted in 12-month rates of treatment retention (52.6 % vs. 45.6 %, p = .35). These outcomes remained similar when assessed at three and six months. Within a year of buprenorphine-naloxone initiation, the study found no differences in the percentage of patients with hospitalizations (26.3 % vs. 38.3 %, p = .10), median number of hospitalizations (2 vs. 2), or proportion of days covered by a prescription ≥80 % (93.3 % vs. 92.0 %, p = .82).

In this study, patients receiving once daily buprenorphine-naloxone had similar treatment outcomes to patients receiving split dosing. Further controlled studies are necessary to evaluate which patients are more likely to benefit from split dosing.

Persons with opioid use disorder (OUD) are receiving extended-release buprenorphine (ER-buprenorphine) for treatment of OUD. There are no clinical guidelines for management of patients with OUD on ER-buprenorphine experiencing acute or chronic pain. This case report describes 3 patient-involved, multidisciplinary approaches for pain management in various clinical scenarios, including a scheduled knee replacement, emergent surgery for an ischemic limb, and management of chronic pain from metastatic malignancy. These cases illustrate that adequate analgesia for patients who have received ER-buprenorphine is possible, and approaches can be individualized, with shared decision making between providers and patients addressing all barriers to optimize treatment outcomes. Options for acute pain management that can be considered include supplemental sublingual buprenorphine, nonopioid adjuncts, and short courses of full opioid agonists. Potential barriers that impact OUD and acute/chronic pain are provider bias, limited access to palliative care clinicians with addiction medicine training, and payor restrictions to adding sublingual buprenorphine for patients that are on ER-buprenorphine. Additional training for clinicians and other members of the health care team is recommended to improve patient-involved care of persons with OUD experiencing pain.

Concomitant use of cannabinoids with other drugs may result in pharmacokinetic drug-drug interactions, mainly due to the mechanism involving Phase I and Phase II enzymes and/or efflux transporters. Cannabinoids are not only substrates but also inhibitors or inducers of some of these enzymes and/or transporters. This narrative review aims to provide the available information reported in the literature regarding human data on the pharmacokinetic interactions of cannabinoids with other medications. A search on Pubmed/Medline, Google Scholar, and Cochrane Library was performed. Some studies were identified with Google search. Additional articles of interest were obtained through cross-referencing of published literature. All original research papers discussing interactions between cannabinoids, used for medical or recreational/adult-use purposes, and other medications in humans were included. Thirty-two studies with medicinal or recreational/adult-use cannabis were identified (seventeen case reports/series, thirteen clinical trials, and two retrospective analyses). In three of these studies, a bidirectional pharmacokinetic drug-drug interaction was reported. In the rest of the studies, cannabinoids were the perpetrators, as in most of them, concentrations of cannabinoids were not measured. In light of the widespread use of prescribed and non-prescribed cannabinoids with other medications, pharmacokinetic interactions are likely to occur. Physicians should be aware of these potential interactions and closely monitor drug levels and/or responses. The existing literature regarding pharmacokinetic interactions is limited, and for some drugs, studies have relatively small cohorts or are only case reports. Therefore, there is a need for high-quality pharmacological studies on cannabinoid-drug interactions.

The aim of this review is to educate healthcare professionals regarding buprenorphine for the use of opioid use disorder (OUD) as well as for chronic pain management. This review provides physicians and practitioners with updated information regarding the distinct characteristics and intricacies of prescribing buprenorphine.

Buprenorphine is approved by the US Food and Drug Administration (FDA) for acute pain, chronic pain, opioid use disorder (OUD), and opioid dependence. When compared to most other opioids, buprenorphine offers superior patient tolerability, an excellent half-life, and minimal respiratory depression. Buprenorphine does have notable side effects as well as pharmacokinetic properties that require special attention, especially if patients require future surgical interventions. Many physicians are not trained to initiate or manage patients on buprenorphine. However, buprenorphine offers a potentially safer alternative for medication management for patients who require chronic opioid therapy for pain or have OUD. This review provides updated information on buprenorphine for both chronic pain and OUD.

Weekly and monthly CAM2038 (Brixadi®) extended-release subcutaneous buprenorphine (XR bup) has been available in Europe and Australia for several years and was approved by the Food and Drug Administration in May 2023. Little is known about the clinical experience of patients and providers using this new medication during prenatal care. Two cases of pregnant persons with opioid use disorder receiving weekly XR bup in an ongoing randomized multi-site outpatient clinical trial are presented along with a brief review of the pharmacology and literature on XR bup formulations. The cases in pregnancy illustrate how treatment with the weekly formulation is initiated including how to make dose adjustments, which may be necessary given the longer half-life; it takes 1 month to achieve steady state. Injection site pain with medication administration was time limited and managed readily. Other injection site reactions experienced included subcutaneous erythema and induration that was delayed in onset and typically mild, resolving with minimal intervention. Delivery management and breastfeeding recommendations while on weekly XR bup were not different compared to sublingual buprenorphine (SL bup). Weekly XR bup is a new treatment for opioid use disorder that may be used in the obstetric population. Obstetric and addiction medicine clinicians should be aware of this new formulation as its use is expected to increase.

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.

This was a retrospective, parallel, cohort study.

General medical or surgical ICUs of a quaternary, urban hospital in Sydney, NSW, Australia.

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.

None.

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).

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.

Southern Appalachia is a region of the United States that is disproportionately affected by the opioid epidemic and by increasing rates of neonatal abstinence syndrome (NAS). NAS rates increased approximately 400% between 1999 and 2012. Buprenorphine prescriptions written to treat opioid use disorder also increased dramatically. The present study was undertaken to ascertain any relationship between the number of buprenorphine prescriptions compared with NAS rates in southern Appalachia.

A total of 250 southern Appalachian counties across seven states, including all of West Virginia and portions of Virginia, Kentucky, Maryland, North Carolina, Ohio, and Tennessee were identified. A retrospective cohort analysis of these counties was conducted for the years 2005-2018. All of the data were obtained from publicly accessible sources or direct communication with government offices. Measures from each county in southern Appalachia included annual NAS rates, buprenorphine prescription rates, drug-induced death rates, and opioid prescribing rates. Associations among these variables were examined using a generalized linear regression.

Significant linear associations exist between the rising rate of NAS diagnoses and the rising rate of buprenorphine prescriptions (r = 0.977, R2 = 95.53%, P < 0.001) and between the rising rate of buprenorphine prescriptions and the increase in drug-induced deaths (r = 0.712, R2 = 50.82%, P = 0.031).

This is the first report that documents an association between rising NAS rates and increasing buprenorphine prescribing. Between the years 2010 and 2018, the NAS rate in southern Appalachia rose by 335%, and the number of buprenorphine prescriptions rose by 413%. Discussions regarding the current policies for buprenorphine management during pregnancy are warranted. We suggest a reevaluation of buprenorphine prescribing recommendations during pregnancy and further research on establishing the lowest effective buprenorphine dose for each pregnant patient.

The primary objectives of this study were to describe the demographics and clinical characteristics of patients who were treated with buprenorphine extended-release versus buprenorphine-naloxone sublingual tablets versus methadone in a real-world setting and to evaluate the difference in nonfatal overdose events between treatment cohorts.

This study was a retrospective chart review of patients with opioid use disorder initiating opioid agonist therapy in Canada during the outset of the COVID-19 pandemic (March 11, 2020 to October 31, 2021). Three treatment cohorts were defined by the initial prescribed opioid agonist therapy regimen: buprenorphine extended-release, buprenorphine-naloxone sublingual tablets, and methadone. Baseline characteristics, as well as treatment status, overdose events, and substance use 6 months after treatment initiation were collected using a standardized form.

Nine clinics provided data on 379 patient cases. The incidence rate (number of events per 100 person-years) for a self-reported nonfatal overdose was 46.8 (n = 18), 19.3 (n = 10), and 1.7 (n = 1) in the methadone, buprenorphine-naloxone sublingual tablets, and buprenorphine extended-release cohorts, respectively. The risk-adjusted difference for the proportion of patients with nonfatal overdose was 8.59% (95% confidence interval, 3.10-14.08%; P = 0.0022) for methadone versus buprenorphine extended-release and 6.51% (95% confidence interval, 1.46-11.56%; P = 0.0115) for buprenorphine-naloxone sublingual tablets versus buprenorphine extended-release.

Buprenorphine extended-release was associated with lower rates of nonfatal overdose events compared with daily opioid agonist therapy. Given the limitations of this naturalistic, retrospective design, further prospective studies are needed to validate these findings and demonstrate the potential for long-acting opioid agonist therapy in addressing the opioid crisis.

The goal of this review is to provide a recent examination of the pharmacodynamics as well as pharmacokinetics, misuse potential, toxicology, and prenatal consequences of buprenorphine. Buprenorphine is currently a Schedule III opioid in the US used for opioid-use disorder (OUD) and as an analgesic. Buprenorphine has high affinity for the mu-opioid receptor (MOR), delta (DOR), and kappa (KOR) and intermediate affinity for the nociceptin (NOR). Buprenorphine's active metabolite, norbuprenorphine, crosses the blood-brain barrier, is a potent metabolite that attenuates the analgesic effects of buprenorphine due to binding to NOR, and is responsible for the respiratory depressant effects. The area under the concentration curves are very similar for buprenorphine and norbuprenorphine, which indicates that it is important to consider this metabolite. Crowding sourcing has identified a buprenorphine street value (USD 3.95/mg), indicating some non-medical use. There have also been eleven-thousand reports involving buprenorphine and minors (age < 19) at US poison control centers. Prenatal exposure to clinically relevant dosages in rats produces reductions in myelin and increases in depression-like behavior. In conclusion, the pharmacology of this OUD pharmacotherapy including the consequences of prenatal buprenorphine exposure in humans and experimental animals should continue to be carefully evaluated.

In treating opioid use disorder (OUD), subcutaneous (SC) extended-release buprenorphine (BPN) depots, e.g., CAM2038, have been shown to provide smaller and less frequent fluctuations in BPN plasma concentrations and pharmacodynamic responses, improve outcomes, reduce treatment burden, and lower risks of misuse and diversion compared to daily sublingual (SL) BPN. This analysis characterized the pharmacokinetics (PK) of BPN following intravenous and SL administration, and administration of SC CAM2038 weekly and monthly.

Pharmacokinetic data from two Phase 1 and two Phase 2 trials in healthy participants and participants with OUD, respectively, were used to develop a population PK model using non-linear mixed effects modelling. The analysis included data from 252 participants and 10,658 BPN observations.

The disposition of BPN was best described by a three-compartment model with first-order elimination, and absorption of SL BPN and SC CAM2038 weekly and monthly by dual parallel absorption pathways. Model diagnostics indicated good predictive performance of BPN concentrations. Buprenorphine plasma concentration-time profiles were simulated for treatment initiation, switching from SL BPN to CAM2038 weekly and monthly, and tapering after interrupting treatment with CAM2038. Simulations predicted CAM2038 weekly and monthly doses that provided BPN plasma maximum concentration (Cmax) and trough concentration (Ctrough) values at steady state within those observed following SL BPN administration.

This population PK model supports the use of CAM2038 doses as individualized treatment for OUD across different treatment stages, including initiation, switching from SL BPN according to established dose conversion schedules, and tapering.

ISRCTN41550730 (05/19/2014), ISRCTN24987553 (07/29/2014), NCT02611752 (11/23/2015), NCT02710526 (03/16/2016).

Opioid maintenance treatment (OMT) has the potential to reduce mortality rates substantially. We aimed to compare all-cause and overdose mortality among OMT patients while in or out of OMT in two different countries with different approaches to OMT.

Two nation-wide, registry-based cohorts were linked by using similar analytical strategies. These included 3,637 male and 1,580 female patients enrolled in OMT in Czechia (years 2000-2019), and 6,387 male and 2,078 female patients enrolled in OMT in Denmark (years 2007-2018). The direct standardization method using the European (EU-27 plus EFTA 2011-2030) Standard was employed to calculate age-standardized rate to weight for age. All-cause and overdose crude mortality rates (CMR) as number of deaths per 1,000 person years (PY) in and out of OMT were calculated for all patients. CMRs were stratified by sex and OMT medication modality (methadone, buprenorphine, and buprenorphine with naloxone).

Age-standardized rate for OMT patients in Czechia and Denmark was 9.7/1,000 PY and 29.8/1,000 PY, respectively. In Czechia, the all-cause CMR was 4.3/1,000 PY in treatment and 10.8/1,000 PY out of treatment. The overdose CMR was 0.5/1,000 PY in treatment and 1.2/1,000 PY out of treatment. In Denmark, the all-cause CMR was 26.6/1,000 PY in treatment and 28.2/1,000 PY out of treatment and the overdose CMR was 7.3/1,000 PY in treatment and 7.0/1,000 PY out of treatment.

Country-specific differences in mortality while in and out of OMT in Czechia and Denmark may be partly explained by different patient characteristics and treatment systems in the two countries. The findings contribute to the public health debate about OMT management and may be of interest to practitioners, policy and decision makers when balancing the safety and accessibility of OMT.

As overdose deaths from fentanyl continue to increase, optimizing use of medications for opioid use disorder has become increasingly important. Buprenorphine is a highly effective medication for reducing the risk of overdose death, but only if a patient remains in treatment. Shared decision making between prescribers and patients is important to establish a dose that meets each patient's treatment needs. However, patients frequently face a dose limit of 16 or 24 mg/d based on dosing guidelines on the Food and Drug Administration's package label.

This review discusses patient-centered goals and clinical criteria for determining dose adequacy, reviews the history of buprenorphine dose regulation in the United States, examines pharmacological and clinical research results with buprenorphine doses up to 32 mg/d, and evaluates whether diversion concerns justify maintaining a low buprenorphine dose limit.

Pharmacological and clinical research results consistently demonstrate buprenorphine's dose-dependent benefits up to at least 32 mg/d, including reductions in withdrawal symptoms, craving, opioid reward, and illicit use while improving retention in care. Diverted buprenorphine is most often used to treat withdrawal symptoms and reduce illicit opioid use when legal access to it is limited.

In light of established research and profound harms from fentanyl, the Food and Drug Administration's current recommendations on target dose and dose limit are outdated and causing harm. An update to the buprenorphine package label with recommended dosing up to 32 mg/d and elimination of the 16 mg/d target dose would improve treatment effectiveness and save lives.

Opioid use disorder (OUD) is a rising public health crisis, impacting millions of individuals and families worldwide. Anesthesiologists can play a key role in improving morbidity and mortality around the time of surgery by informing perioperative teams and guiding evidence-based care and access to life-saving treatment for patients with active OUD or in recovery. This article serves as an educational resource for the anesthesiologist caring for patients with OUD and is the second in a series of articles published in Anesthesia & Analgesia on the anesthetic and analgesic management of patients with substance use disorders. The article is divided into 4 sections: (1) background to OUD, treatment principles, and the anesthesiologist; (2) perioperative considerations for patients prescribed medications for OUD (MOUD); (3) perioperative considerations for patients with active, untreated OUD; and (4) nonopioid and nonpharmacologic principles of multimodal perioperative pain management for patients with untreated, active OUD, or in recovery. The article concludes with a stepwise approach for the anesthesiologist to support OUD treatment and recovery. The anesthesiologist is an important leader of the perioperative team to promote these suggested best practices and help save lives.

Long-acting buprenorphine formulations have been recently marketed for the Opioid Agonist Treatment (OAT) of opioid use disorder (OUD) associated with medical, social, and psychological support. Their duration of action ranges from one week up to 6 months. The non-medical use of opioids is increasing with a parallel rise in lethal overdoses. Methadone and buprenorphine are the standard treatment for opioid dependence. Methadone Maintenance Treatment (MMT) is widely recognized as one of the most effective ways of reducing the risks of overdose, crime, and transmission of HIV (Human Immunodeficiency Virus) in people who use opioids; however, its effectiveness has been hindered by low rates of uptake and retention in treatment. Furthermore, both methadone and buprenorphine are widely diverted and misused. Thus, a crucial aspect of treating OUD is facilitating patients' access to treatment while minimizing substance-related harm and improving quality of life. The newly developed long-acting buprenorphine formulations represent a significant change in the paradigm of OUD treatment, allowing an approach individualized to patients' needs. Strengths of this individualized approach are improved adherence (lack of peaks and troughs in blood concentrations) and a reduced stigma since the patient doesn't need to attend their clinic daily or nearly daily, thus facilitating social and occupational integrations as the quality of life. However, less frequent attendance at the clinic should not affect the patient-physician relationship. Therefore, teleconsulting or digital therapeutic services should be developed in parallel. In addition, diversion and intravenous misuse of buprenorphine are unlikely due to the characteristics of these formulations. These features make this approach of interest for treating OUD in particular settings, such as subjects staying or when released from prison or those receiving long-term residential treatment for OUD in the therapeutic communities. The long-lasting formulations of buprenorphine can positively impact the OUD treatment and suggest future medical and logistic developments to maximize their personalized management and impact.

Pain is an unpleasant sensory and emotional experience that affects every aspect of a patient's life and which may be treated through different pharmacological and non-pharmacological approaches. Analgesics are the drugs most commonly used to treat pain, and in specific situations, the use of opioids may be considered with caution. These drugs, in fact, do not always induce optimal analgesia in patients, and several problems are associated with their use. The purpose of this narrative review is to describe the pharmacological approaches currently used for the management of chronic pain. We review several aspects, from the pain-scale-based methods currently available to assess the type and intensity of pain, to the most frequently administered drugs (non-narcotic analgesics and narcotic analgesics), whose pharmacological characteristics are briefly reported. Overall, we attempt to provide an overview of different pharmacological treatments while also illustrating the relevant guidelines and indications. We then report the strategies that may be used to reduce problems related to opioid use. Specifically, we focus our attention on therapeutic drug monitoring (TDM), a tool that could help clinicians select the most suitable drug and dose to be used for each patient. The actual potential of using TDM to optimize and personalize opioid-based pain treatments is finally discussed based on recent scientific reports.

To quantify the association between opioid agonist treatment (OAT) and overdose death by age group; test the hypothesis that across different age groups, opioid overdose mortality is lowest during OAT with buprenorphine compared with time out of treatment or OAT with methadone; and test associations between OAT and opioid overdose mortality in the presence of chronic circulatory, respiratory, liver and kidney diseases.

Retrospective observational cohort study using linked administrative data.

New South Wales, Australia.

A total of 37 764 people prescribed OAT, 1 August 2002 and 31 December 2017.

OAT exposure, opioid overdose mortality and key confounders were measured using linked population data sets on OAT entry and exit, hospitalization, mental health care, incarceration and mortality. ICD-10 codes were used to define opioid overdose mortality and chronic disease groups of interest.

Relative to time out of treatment, time in OAT was associated with a lower risk of opioid overdose death across all age groups and chronic diseases. Among people aged 50 years and older, there was weak evidence that buprenorphine may be associated with greater protection against opioid overdose death than methadone [generalized estimating equation (GEE) adjusted incident rate ratio (aIRR) = 0.47; 95% confidence interval (CI) = 0.21, 1.02; marginal structural models (MSM) aIRR = 0.49; 95% CI = 0.17, 1.41]. Buprenorphine was associated with greater protection against overdose death than methadone for clients with circulatory (MSM aIRR = 0.27; 95% CI = 0.11, 0.67) or respiratory (MSM aIRR = 0.26; 95% CI = 0.07, 0.94) diseases, but not liver (MSM aIRR = 0.59; 95% CI = 0.14, 2.43) or kidney (MSM aIRR = 1.16; 95% CI = 0.31, 4.36) diseases.

Opioid agonist treatment (OAT) appears to reduce mortality risk in people with opioid use disorder who are older or who have physical comorbidities. Opioid overdose mortality during OAT with buprenorphine appears to be lower and reduced in clients with circulatory and respiratory diseases compared with OAT with methadone.

Buprenorphine treatment significantly reduces morbidity and mortality for people with opioid use disorder. Fear of precipitated withdrawal remains a barrier to starting buprenorphine for patients who use synthetic opioids, particularly fentanyl. We aim to evaluate the development and implementation of a buprenorphine low dose overlap initiation (LDOI) protocol in an urban public health community pharmacy.

We performed a retrospective chart review of patients with nonprescribed fentanyl use (N = 27) to examine clinical outcomes of a buprenorphine LDOI schedule, named the Howard Street Method, dispensed from a community pharmacy in San Francisco from January to December 2020.

Twenty-seven patients were prescribed the Howard Street Method. Twenty-six patients picked up the prescription and 14 completed the protocol. Of those who completed the protocol, 11 (79%) reported no symptoms of withdrawal and 3 (21%) reported mild symptoms. Four patients (29%) reported cessation of full opioid agonist use and 10 (71%) reported reduction in their use by the end of the protocol. At 30 days, 12 patients (86%) were retained in care and 10 (71%) continued buprenorphine. At 180 days, 6 patients (43%) were retained in care and 2 (14%) were still receiving buprenorphine treatment.

We found that a LDOI blister-pack protocol based at a community pharmacy was a viable intervention for starting buprenorphine treatment and a promising alternative method for buprenorphine initiation in an underresourced, safety-net population of people using fentanyl.

Buprenorphine is a partial agonist at the µ-opioid receptor and an antagonist at the delta and kappa opioid receptors. It has high affinity and low intrinsic activity at the µ-opioid receptor. Buprenorphine demonstrates no ceiling effect for clinical analgesia, but demonstrates this for respiratory depression and euphoria. It may provide effective analgesia while producing less adverse effects, making it a promising opioid analgesic. A systematic review and meta-analysis were performed to examine the analgesic efficacy of buprenorphine for patients with chronic noncancer pain.

PubMed, MEDLNE, Embase, and the Cochrane Library were searched up to January 2022. Randomized controlled trials were included if they compared buprenorphine versus placebo or active analgesic in patients with chronic noncancer pain, where pain score was an outcome. Nonrandomized controlled trials, observational studies, qualitative studies, case reports, and commentaries were excluded. Two investigators independently performed the literature search, study selection, and data collection. A random-effects model was used. The primary outcome was the effect of buprenorphine on pain intensity in patients with chronic noncancer pain based on standardized mean difference (SMD) in pain score. Quality of evidence was assessed using the Grade of Recommendations Assessment, Development, and Evaluation (GRADE) approach.

Two separate literature searches were conducted for patients with and without opioid use disorder (OUD). Only one study met the search criteria for those with OUD. Fourteen randomized controlled trials were included for those without OUD. Buprenorphine was associated with reduced pain score (SMD = -0.368, P < .001, I 2 = 89.37%) compared to placebo or active analgesic. Subgroup meta-analyses showed statistically significant differences in favor of buprenorphine versus placebo (SMD = -0.404, P < .001), for chronic low back pain (SMD = -0.383, P < .001), when administered via the transdermal route (SMD = -0.572, P = .001), via the buccal route (SMD = -0.453, P < .001), with length of follow-up lasting <12 weeks (SMD = -0.848, P < .05), and length of follow-up lasting 12 weeks or more (SMD = -0.415, P < .001). There was no significant difference when compared to active analgesic (SMD = 0.045, P > .05). Quality of evidence was low to moderate.

Buprenorphine was associated with a statistically significant and small reduction in pain intensity compared to placebo. Both the transdermal and buccal routes provided pain relief. There was more evidence supporting its use for chronic low back pain.

The emergence of structurally diverse new synthetic opioids (NSOs) has caused the opioid crisis to spiral to new depths. Little information is available about the pharmacology of most novel opioids when they first emerge. Here, using a β-arrestin 2 recruitment assay, we investigated the in vitro μ-opioid receptor (MOR) activation potential of dipyanone, desmethylmoramide, and acetoxymethylketobemidone (O-AMKD) - recent NSOs that are structurally related to the prescription opioids methadone and ketobemidone. Our findings indicate that dipyanone (EC₅₀=39.9 nM; E_max=155% vs. hydromorphone) is about equally active as methadone (EC₅₀=50.3 nM; E_max=152%), whereas desmethylmoramide (EC₅₀=1335 nM; E_max=126%) is considerably less active. A close structural analogue of ketobemidone (EC₅₀=134 nM; E_max=156%) and methylketobemidone (EC₅₀=335 nM; E_max=117%), O-AMKD showed a lower potency (EC₅₀=1262 nM) and efficacy (E_max=109%). Evaluation of the opioid substitution product buprenorphine and its metabolite norbuprenorphine confirmed the increased in vitro efficacy of the latter. In addition to in vitro characterization, this report details the first identification and full chemical analysis of dipyanone in a seized powder, as well as a postmortem toxicology case from the USA involving the drug. Dipyanone was quantified in blood (370 ng/mL), in which it was detected alongside other NSOs (e.g., 2-methyl AP-237) and novel benzodiazepines (e.g., flualprazolam). While dipyanone is currently not commonly encountered in forensic samples worldwide, its emergence is worrisome and representative of the dynamic NSO market. Graphical Abstract.

Even prior to the COVID-19 pandemic, rates of ambulatory surgeries and ambulatory patients presenting with substance use disorder were increasing, and the end of lockdown has further catalyzed the increasing rates of ambulatory patients presenting for surgery with substance use disorder (SUD). Certain subspecialty groups of ambulatory procedures have already established protocols to optimize early recovery after surgery (ERAS), and these groups have subsequently enjoyed improved efficiency and reduced adverse outcomes as a result. In this present investigation, we review the literature as it relates to substance use disorder patients, with a particular focus on pharmacokinetic and pharmacodynamic profiles, and their resulting impact on the acute- or chronic user ambulatory patient. The systematic literature review findings are organized and summarized. We conclude by identifying areas of opportunity for further study, specifically with the aim of developing a dedicated ERAS protocol for substance use disorder patients in the ambulatory surgery setting. - Healthcare in the USA has seen an increase in rates of both substance use disorder patients and separately in ambulatory surgery cases. - Specific perioperative protocols to optimize outcomes for patients who suffer from substance use disorder have been described in recent years. - Agents of interest like opioids, cannabis, and amphetamines are the top three most abused substances in North America. - A protocol and recommend further work should be done to integrate with concrete clinical data, in which strategies should be employed to confer benefits to patient outcomes and hospital quality metrics like those enjoyed by ERAS protocol in other settings.

Opioid use disorder is a worldwide societal problem and public health burden. Strategies for treating opioid use disorder can be divided into those that target the opioid receptor system and those that target non-opioid receptor systems, including the dopamine and glutamate receptor systems. Currently, the clinical drugs used to treat opioid use disorder include the opioid receptor agonists methadone and buprenorphine, which are limited by their abuse liability, and the opioid receptor antagonist naltrexone, which is limited by poor compliance. Therefore, the development of effective medications with lower abuse liability and better potential for compliance is urgently needed. Based on recent advances in the understanding of the neurobiological mechanisms underlying opioid use disorder, potential treatment strategies and targets have emerged. This review focuses on the progress made in identifying potential targets and developing medications to treat opioid use disorder, including progress made by our laboratory, and provides insights for future medication development. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.

Perioperative management of buprenorphine is increasingly characterized by continuation of buprenorphine throughout the perioperative period while coadministering full agonist opioids for analgesia. Although this "simultaneous strategy" is commonly used for the shorter-acting sublingual buprenorphine formulations, there is little to guide management of the extended-release formulations of buprenorphine. Here we report the perioperative experience of an individual maintained on extended-release buprenorphine who successfully underwent major surgeries utilizing a strategy of performing the surgeries at the time of the next scheduled dose.

Buprenorphine is widely used in the treatment of opioid use disorder (OUD). There are few pharmacokinetic models of buprenorphine across diverse populations. Population pharmacokinetics (POPPK) allows for covariates to be included in pharmacokinetic studies, thereby opening the potential to evaluate the effect of comorbidities, medications, and other factors on buprenorphine pharmacokinetics. This pilot study used POPPK to explore buprenorphine pharmacokinetics in patients with and without HIV receiving buprenorphine for OUD.

Plasma buprenorphine levels were measured in 54 patients receiving buprenorphine for OUD just prior to and 2-5 h following regular buprenorphine dosing. A linear one-compartment POPPK model with first-order estimation was used to evaluate buprenorphine clearance (CL/F) and volume of distribution (V/F). Covariates included weight and HIV status.

All HIV+ patients reported complete past-month adherence to taking antiretroviral therapy that included either efavirenz or nevirapine. Buprenorphine CL/F was 76% higher in HIV+ patients (n = 17) than HIV- patients (n = 37). Buprenorphine V/F was 41% higher in the HIV+ patients.

POPPK can be used to model buprenorphine pharmacokinetics in a real-world clinical population. While interactions between ART and buprenorphine alter buprenorphine CL/F, we also found alteration in V/F. Proportionate changes in CL/F and V/F might indicate a primary effect on bioavailability (F) rather than two separate effects. These findings indicate reduced buprenorphine bioavailability in patients with HIV.

Thirty-eight million people worldwide are living with HIV, PWH, a major public health problem. Antiretroviral therapy (ART) revolutionized HIV treatment and significantly increased the lifespan of PWH. However, approximately 15-50% of PWH develop HIV associated neurocognitive disorders (HIV-NCI), a spectrum of cognitive deficits, that negatively impact quality of life. Many PWH also have opioid use disorder (OUD), and studies in animal models of HIV infection as well as in PWH suggest that OUD can contribute to HIV-NCI. The synthetic opioid agonist, buprenorphine, treats OUD but its effects on HIV-NCI are unclear. We reported that human mature inflammatory monocytes express the opioid receptors MOR and KOR, and that buprenorphine reduces important steps in monocyte transmigration. Monocytes also serve as HIV reservoirs despite effective ART, enter the brain, and contribute to HIV brain disease. Using EcoHIV infected mice, an established model of HIV infection and HIV-NCI, we previously showed that pretreatment of mice prior to EcoHIV infection reduces mouse monocyte entry into the brain and prevents NCI. Here we show that buprenorphine treatment of EcoHIV infected mice with already established chronic NCI completely reverses the disease. Disease reversal was associated with a significant reduction in brain inflammatory monocytes and reversal of dendritic injury in the cortex and hippocampus. These results suggest that HIV-NCI persistence may require a continuing influx of inflammatory monocytes into the brain. Thus, we recommend buprenorphine as a potential therapy for mitigation of HIV brain disease in PWH with or without OUD.