Availability and Opportunities for Expansion of Buprenorphine for the Treatment of Opioid Use Disorder.

There is an urgent need to expand access to treatment for persons with opioid use disorder (OUD). As neurologists may frequently encounter patients with chronic pain who have developed OUD, they are in a position to serve as advocates for treatment. Buprenorphine is the most scalable medication for OUD in the United States, yet expansion has plateaued in recent years despite growing treatment needs. Reluctance of providers to establish treatment with new patients, challenges with rural expansion, stigma related to buprenorphine-based care, and pharmacy pressures that incentivize low dispensing and inventories may have stalled expansion. This review introduces these challenges before outlining actionable and evidenced-based strategies that warrant investigation, including methods to improve patient access to care (remotely delivered care, mobile delivery programs, Bridge programs) and provider retention and confidence in prescribing (expert consults, Extension for Community Healthcare Outcomes, a telementoring model, hub-and-spoke services), as well as novel innovations (virtual reality, artificial intelligence, wearable technologies). Overall, fortifying existing delivery systems while developing new transformative models may be necessary to achieve more optimal levels of buprenorphine treatment expansion.

Polymorphisms in the A118G SNP of the OPRM1 gene produce different experiences of opioids: A human laboratory phenotype-genotype assessment.

Allelic variations in the A118G SNP of the OPRM1 gene change opioid signaling; however, evaluations of how allelic differences may influence opioid effects are lacking. This human laboratory paradigm examined whether the AA versus AG/GG genotypes determined opioid response profiles. Individuals with limited opioid exposure (N = 100) completed a five-day within-subject, double-blind, placebo-controlled, residential study. Participants were admitted (Day 1), received 4 mg hydromorphone (Day 2) and 0 mg, 2 mg and 8 mg hydromorphone in randomized order (Days 3-5) and completed self-reported visual analog scale (VAS) ratings and Likert scales, observed VAS, and physiological responses at baseline and for 6.5 h post-dose. Outcomes were analysed as peak/nadir effects over time as a function of genotype (available for N = 96 individuals; AG/GG = 13.5%, AA = 86.4%). Participants with AG/GG rated low and moderate doses of hydromorphone as significantly more positive (e.g., Good Effects VAS, coasting, drive, friendly, talkative, stimulation) with fewer negative effects (e.g., itchy skin, nausea, sleepiness), and were also observed as being more talkative and energetic relative to persons with AA. Persons with AG/GG were less physiologically reactive as determined by diastolic blood pressure and heart rate, but had more changes in core temperature compared with those with AA. Persons with AA also demonstrated more prototypic agonist effects across doses; persons with AG/GG showed limited response to 2 mg and 4 mg. Data suggest persons with AG/GG genotype experienced more pleasant and fewer unpleasant responses to hydromorphone relative to persons with AA. Future studies should replicate these laboratory findings in clinical populations to support a precision medicine approach to opioid prescribing.

Transplant of organs from donors with positive SARS-CoV-2 nucleic acid testing: A report from the organ procurement and transplantation network ad hoc disease transmission advisory committee.

BACKGROUND: Decisions to transplant organs from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid test-positive (NAT+) donors must balance risk of donor-derived transmission events (DDTE) with the scarcity of available organs. METHODS: Organ Procurement and Transplantation Network (OPTN) data were used to compare organ utilization and recipient outcomes between SARS-CoV-2 NAT+ and NAT- donors. NAT+ was defined by either a positive upper or lower respiratory tract (LRT) sample within 21 days of procurement. Potential DDTE were adjudicated by OPTN Disease Transmission Advisory Committee. RESULTS: From May 27, 2021 (date of OTPN policy for required LRT testing of lung donors) to January 31, 2022, organs were recovered from 617 NAT+ donors from all OPTN regions and 53 of 57 (93%) organ procurement organizations. NAT+ donors were younger and had higher organ quality scores for kidney and liver. Organ utilization was lower for NAT+ donors compared to NAT- donors. A total of 1241 organs (776 kidneys, 316 livers, 106 hearts, 22 lungs, and 21 other) were transplanted from 514 NAT+ donors compared to 21 946 organs from 8853 NAT- donors. Medical urgency was lower for recipients of NAT+ liver and heart transplants. The median waitlist time was longer for liver recipients of NAT+ donors. The match run sequence number for final acceptor was higher for NAT+ donors for all organ types. Outcomes for hospital length of stay, 30-day mortality, and 30-day graft loss were similar for all organ types. No SARS-CoV-2 DDTE occurred in this interval. CONCLUSIONS: Transplantation of SARS-CoV-2 NAT+ donor organs appears safe for short-term outcomes of death and graft loss and ameliorates the organ shortage. Further study is required to assure comparable longer term outcomes.

Iteration is not solving the opioid crisis, it's time for transformation.

Opioid use disorder (OUD) produces exceedingly high rates of morbidity and mortality in the United States and throughout the world. Almost 90% of persons qualifying for treatment do not enter treatment and 72% of those who initiate treatment leave within 60 days. This Perspective posits that over the past decade our OUD treatment system has produced only small iterative gains in treatment access because, in part, it is founded in a series of top-down regulatory policies dating back more than 100 years. These policies prioritized restricting persons with OUD from having access to opioid agonists over empirical discovery of treatment best practice. It further suggests that for persons who are not already responding positively to our existing treatments, we may need to fundamentally transform care to enact true, meaningful change. Four potential considerations are outlined: expanding beyond long-acting opioids for treatment, embracing safe use as a viable therapeutic target, ending closed medication distribution systems, and partnering with our patients. The overarching aim of this discussion is to motivate broader thinking about new solutions for the patients for whom the existing strategies are not working and who may benefit from more transformative approaches. Though efforts to-date to expand existing treatment systems and find new ways to promote existing MOUDs have been important, these efforts have represented iterative changes. For us to meet our goal of substantially reducing opioid-related harms, it may be time to consider strategies that represent true transformation.

Factors Associated with High-Risk Substance Use in Persons Receiving Psychiatric Treatment for a Primary Trauma- and Stressor-Related Disorder Diagnosis.

OBJECTIVE: Although mental health disorders and high-risk substance use frequently co-occur, they are typically investigated independently. Clinical trials focused on treatment for individuals with trauma- and stressor-related disorders often exclude individuals with high-risk substance use. Little is also known about the role of gender in the relationship between trauma- and stressor-related disorders and high-risk substance use. We examined the relationship between trauma- and stressor-related disorders, high-risk substance use, and gender. METHODS: Using the Mental Health Client-Level Data dataset, we examined 15,772 adults receiving treatment in psychiatric hospitals in the United States from 2013 to 2019. RESULTS: A logistic regression model showed that for men, relative to women, having multiple mental health diagnoses and having a serious mental illness or serious emotional disturbance was associated with greater odds of high-risk substance use. CONCLUSIONS: This study underscores the value of comprehensive gender-centered treatment for people with trauma- and stressor-related disorders engaging in high-risk substance use.

Buprenorphine treatment retention and comorbidities among patients with opioid use disorder in a primary care setting.

BACKGROUND AND OBJECTIVES: More information is needed about comorbidities among patients receiving buprenorphine maintenance treatment and their relationship with retention. METHODS: Retrospective electronic health record data over a 5-year period from primary care patients receiving buprenorphine for the treatment of opioid use disorder were examined (N = 899). The present analysis determined the prevalence of comorbidities and examined associations with treatment retention as defined by cumulative duration of buprenorphine prescription. RESULTS: Tobacco use and comorbidities including hypertension were prevalent but did not predict retention according to survival analyses controlling for demographic characteristics. Retention was poorer among patients testing positive for cocaine (HR = 1.38, 95% CI: 1.09-1.74, p = .007) and patients with hepatitis C virus (HR = 1.17, 95% CI: 1.01-1.37, p = .04). CONCLUSION AND SCIENTIFIC SIGNIFICANCE: This study provides new knowledge of previously unexamined associations between comorbidities (e.g., hypertension) and buprenorphine treatment retention. The robust association between cocaine use and poorer buprenorphine retention serves to resolve prior conflicting data in the literature.

Kratom use as more than a "self-treatment".

Background: Mitragyna speciosa (kratom) is increasingly used in the United States for its pharmacological effects. Kratom's relative novelty makes for a dynamic situation, such that use motivations are not firmly established and may be changing. Investigators and clinicians require frequent updates on kratom trends.Objectives: To assess the current state of kratom-use initiation, sourcing, motivations, preference, conceptualizations, and perceived stigma, using survey responses from current and former users.Methods: Between April-May 2021 we recontacted 289 respondents who reported lifetime kratom use (on an unrelated survey) to answer kratom-specific questions.Results: The sample (N=129) was majority female (51.9%) and white (71.9%). Most (69.0%) reported first trying kratom after 2015. Mean age of use initiation (29.9 years) was older than for other substances, including opioids. Kratom ranked as a preferred substance by 48.5%. The strongest drug association with past-year kratom use was vaped nicotine (OR=3.31,95% CI 1.23-8.88). Use was less likely among those prescribed buprenorphine in the past year (OR=0.03, CI 0.01-0.28). Past-month cannabis use (OR=4.18,CI 1.80-9.72) had the strongest association with past-month kratom use. Over 40 use motivations were endorsed, many (but not all) supporting the "self-treatment" narrative of kratom use, including use as an opioid, alcohol, or stimulant substitute. Treatment shortfalls were associated with decisions to try kratom.Conclusions: Kratom use motivations are diversifying, with multiple factors driving use. As sales continue to increase, the public-health, clinical, and policy responses to kratom should be grounded in rigorous bench-to-bedside scientific research. Comprehensive study of kratom is currently lacking.

Need for clarity and context in case reports on kratom use, assessment, and intervention.

This Letter to the Editor is a response to Broyan and colleagues who recently published a Case Report presenting data on 28 patients in the United States who identified kratom as their primary substance of use and who were subsequently induced on buprenorphine/naloxone for a reported diagnosis of kratom use disorder. We applaud the authors for helping to advance the science on kratom and recognize the difficulties in conducting kratom-related clinical assessment and research. However, a number of inconsistences and generalizations were identified in this Case Report, which also lacked some critical context. Importantly, such inconsistencies and generalizations can be observed throughout kratom-specific case reports. We feel this is now an important opportunity to highlight these issues that are present in the Broyan and colleagues Case report but emphasize that they are not unique to it. We do this with the hope that by acknowledging these issues it can help inform editors, clinicians, and researchers who may not be familiar with kratom and, as a result of this unfamiliarity, may inadvertently present findings in a manner that could confuse readers and even misinform clinical researchers and practitioners.

Method for Successfully Inducting Individuals Who Use Illicit Fentanyl Onto Buprenorphine/Naloxone.

BACKGROUND AND OBJECTIVES: Individuals exposed to fentanyl are at risk of precipitated withdrawal using typical buprenorphine/naloxone induction procedures. METHODS: This case series describes buprenorphine/naloxone inductions of four individuals who tested positive for fentanyl. RESULTS: Buprenorphine-precipitated withdrawal was observed in two individuals who completed a conventional buprenorphine/naloxone induction strategy. Two more individuals completed a revised buprenorphine/naloxone induction strategy that did not precipitate withdrawal. DISCUSSION AND CONCLUSION: Using multiple 2 mg doses of buprenorphine/naloxone in patients already in mild/moderate withdrawal improved outcomes. SCIENTIFIC SIGNIFICANCE: Persons who use illicit fentanyl might be less likely to experience precipitated withdrawal from this revised buprenorphine/naloxone induction strategy. (Am J Addict 2021;30:83-87).

Challenges for Women Entering Treatment for Opioid Use Disorder.

PURPOSE OF REVIEW: Women with opioid use disorder (OUD) face unique challenges the moment they enter treatment. This narrative review focused on recent literature regarding sex- and gender-based issues that could affect treatment outcomes in women with OUD. RECENT FINDINGS: Women respond differently to opioids based on hormonal factors, are more likely to present to treatment with mental health conditions, especially depression, and are more likely to have experienced trauma via intimate partner violence compared with men. Women also face stigma when entering OUD treatment, particularly if they have children. Future research to improve OUD treatment outcomes in women should account for sex as a biological variable and gender as a social construct. Women have a fundamentally different experience than men during the course of OUD and upon treatment entry. Programs that address childcare/family support, mental health, and trauma are warranted for women with OUD.

Preliminary evidence of different and clinically meaningful opioid withdrawal phenotypes.

Opioid use disorder (OUD) is a public health crisis. Differences in opioid withdrawal severity that predict treatment outcome could facilitate the process of matching patients to treatments. This is a secondary analysis of a randomized controlled trial (RCT) that enrolled treatment seeking heroin-users (N = 89, males = 78) into a residential study. Participants maintained on morphine (30 mg, subcutaneous, four-times daily) underwent a naloxone (0.4 mg, IM = intramuscular) challenge session to precipitate withdrawal. Area-under-the-curve (AUC) values from self-reported withdrawal ratings during the challenge session were analyzed using K-means clustering, revealing two phenotype groups. Withdrawal and retention from the subsequent 14-day double-blind, double-dummy RCT comparing three study medications (clonidine, tramadol-ER, and buprenorphine) were evaluated as a function of phenotype. Cluster analyses suggested HIGH (N = 37; mean [SD] subjective opiate withdrawal scale [SOWS]-AUC 123.7 [65.8]) and LOW (N = 52; SOWS-AUC 68.0 [47.7]) withdrawal phenotype groups. HIGH participants were significantly more female and had lower body mass indices than LOW participants; no drug-use variables were significant. Regarding RCT outcomes, HIGH phenotype participants were less likely to be retained in the study (P = 0.02) and had higher mean self-reported withdrawal (P = 0.05) than LOW phenotype participants. A significant interaction in RCT retention was observed between phenotype (P = 0.02) and study medication (P < 0.01). Self-reported withdrawal was significant for phenotype (P = 0.02); study medication trended towards significance (P = 0.07). Results suggest patients have meaningfully different experiences of opioid withdrawal that may predict differential response to opioid pharmacotherapies during supervised withdrawal. Additional prospective research to replicate and more thoroughly evaluate withdrawal phenotype correlates and sex differences is warranted.

Non-Opioid Neurotransmitter Systems that Contribute to the Opioid Withdrawal Syndrome: A Review of Preclinical and Human Evidence.

Opioid misuse and abuse is a major international public health issue. Opioid use disorder (OUD) is largely maintained by a desire to suppress aversive opioid withdrawal symptoms. Opioid withdrawal in patients seeking abstinence from illicit or prescribed opioids is often managed by provision of a µ-opioid agonist/partial agonist in combination with concomitant medications. Concomitant medications are administered based on their ability to treat specific symptoms rather than a mechanistic understanding of the opioid withdrawal syndrome; however, their use has not been statistically associated with improved treatment outcomes. Understanding the central and/or peripheral mechanisms that underlie individual withdrawal symptom expression in humans will help promote medication development for opioid withdrawal management. To support focused examination of mechanistically supported concomitant medications, this review summarizes evidence from preclinical (N = 68) and human (N = 30) studies that administered drugs acting on the dopamine, serotonin, cannabinoid, orexin/hypocretin, and glutamate systems and reported outcomes related to opioid withdrawal. These studies provide evidence that each of these systems contribute to opioid withdrawal severity. The Food and Drug Administration has approved medications acting on these respective systems for other indications and research in this area could support the repurposing of these medications to enhance opioid withdrawal treatment. These data support a focused examination of mechanistically informed concomitant medications to help reduce opioid withdrawal severity and enhance the continuum of care available for persons with OUD.

Gabapentin Enacarbil Extended-Release for Alcohol Use Disorder: A Randomized, Double-Blind, Placebo-Controlled, Multisite Trial Assessing Efficacy and Safety.

BACKGROUND: Several single-site alcohol treatment clinical trials have demonstrated efficacy for immediate-release (IR) gabapentin in reducing drinking outcomes among individuals with alcohol dependence. The purpose of this study was to conduct a large, multisite clinical trial of gabapentin enacarbil extended-release (GE-XR) (HORIZANT® ), a gabapentin prodrug formulation, to determine its safety and efficacy in treating alcohol use disorder (AUD). METHODS: Men and women (n = 346) who met DSM-5 criteria for at least moderate AUD were recruited across 10 U.S. clinical sites. Participants received double-blind GE-XR (600 mg twice a day) or placebo and a computerized behavioral intervention (Take Control) for 6 months. Efficacy analyses were prespecified for the last 4 weeks of the treatment period. RESULTS: The GE-XR and placebo groups did not differ significantly on the primary outcome measure, percentage of subjects with no heavy drinking days (28.3 vs. 21.5, respectively, p = 0.157). Similarly, no clinical benefit was found for other drinking measures (percent subjects abstinent, percent days abstinent, percent heavy drinking days, drinks per week, drinks per drinking day), alcohol craving, alcohol-related consequences, sleep problems, smoking, and depression/anxiety symptoms. Common side-effects were fatigue, dizziness, and somnolence. A population pharmacokinetics analysis revealed that patients had lower gabapentin exposure levels compared with those in other studies using a similar dose but for other indications. CONCLUSIONS: Overall, GE-XR at 600 mg twice a day did not reduce alcohol consumption or craving in individuals with AUD. It is possible that, unlike the IR formulation of gabapentin, which showed efficacy in smaller Phase 2 trials at a higher dose, GE-XR is not effective in treating AUD, at least not at doses approved by the U.S. Food and Drug Administration for treating other medical conditions.

Randomized comparison of two web-based interventions on immediate and 30-day opioid overdose knowledge in three unique risk groups.

BACKGROUND: In response to the opioid overdose epidemic, scalable interventions that instruct at-risk populations how to prevent and respond to overdose scenarios are needed. METHOD: The following groups of at-risk individuals were recruited online: (1) Acute Pain patients with an opioid prescription, (2) Chronic Pain patients with an opioid prescription, and (3) persons without pain who use Illicit Opioids. Participants were tested on their opioid overdose knowledge using the Brief Opioid Overdose Knowledge (BOOK) questionnaire and randomized to one of two web-based interventions that contained 25 educational content slides. One intervention consisted of embedded questions with corrective feedback (Presentation + Mastery, n = 58), the other did not (Presentation, n = 61). Participants completed the BOOK again at the end of the intervention and 30 days later. Overdose risk behaviors were assessed at baseline and 30-days. RESULTS: Relative to baseline, both Presentation and Presentation + Mastery interventions increased total BOOK scores immediately and 30 days later. There was a significant effect of Group on BOOK Knowledge, whereby those with Acute Pain had lower scores across time, regardless of intervention, relative to those with Chronic Pain and Illicit Opioid Use. Compared to baseline, all three groups reported fewer instances of using opioids alone or concurrently with alcohol at the 30-day follow-up. CONCLUSIONS: A web-based intervention increased opioid overdose knowledge and decreased overdose risk behavior immediately and at a one-month follow-up, suggesting that this brief, practical, and scalable program could have utility in several populations who are at-risk of opioid overdose.

Individuals with Chronic Pain Who Misuse Prescription Opioids Report Sex-Based Differences in Pain and Opioid Withdrawal.

Objective Individuals with chronic pain who misuse prescription opioids are at high risk for developing opioid use disorder and/or succumbing to opioid overdose. The current study conducted a survey to evaluate sex-based differences in pain catastrophizing, opioid withdrawal, and current pain in persons with co-occurring chronic pain and opioid misuse. We hypothesized that women with chronic pain who misused prescription opioids would self-report higher pain ratings compared with men and that the relationship between pain catastrophizing and self-reported current pain would be moderated by symptoms of opioid withdrawal in women only. Design Survey assessment of the relationship between pain and opioid misuse. Setting Online via Amazon Mechanical Turk. Participants Persons with ongoing chronic pain who also misused prescription opioids on one or more days in the last 30 days were eligible (N = 181). Methods Participants completed demographic and standardized assessments including the Brief Pain Inventory (BPI), Pain Catastrophizing Scale (PCS), and Subjective Opiate Withdrawal Scale (SOWS). Results Women reported higher levels of current (P < 0.001), average (P < 0.001), and worst (P = .002) pain in the last 24 hours compared with men. Women also endorsed higher scores on the PCS (P = 0.006) and marginally higher past-30-day SOWS ratings (P = 0.068) compared with men. SOWS ratings moderated the relationship between PCS and BPI Worst Pain in women (ΔR2 < 0.127, ΔF(1, 78) = 12.39, P = 0.001), but not in men (ΔR2 < 0.000, ΔF(1, 98) = 0.003, P = 0.954). Conclusions These data suggest a strong relationship between opioid withdrawal, pain catastrophizing, and the experience of pain in women with chronic pain who misuse opioids.

Review: Sex-Based Differences in Treatment Outcomes for Persons With Opioid Use Disorder.

BACKGROUND AND OBJECTIVES: In order to address the current opioid crisis, research on treatment outcomes for persons with opioid use disorder (OUD) should account for biological factors that could influence individual treatment response. Women and men might have clinically meaningful differences in their experience in OUD treatment and might also have unique challenges in achieving successful, long-term recovery. This review summarizes and synthesizes the current literature on sex-based differences in OUD treatment outcomes. METHODS: Relevant literature was identified via automated and manual searches using the terms "opioid treatment outcome sex [or gender] differences" and "opiate treatment outcome sex [or gender] differences." Search methodology was consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), and were conducted within the PubMed electronic database during March and April of 2018. RESULTS: The initial PubMed search yielded 241 manuscripts and 31 original research articles that met inclusion/exclusion criteria were synthesized in this review. Several important trends emerged, including findings that women are more likely than men to present to treatment with co-occurring mental health conditions such as depression, and that women might respond particularly well to buprenorphine maintenance. DISCUSSION AND CONCLUSIONS: While much of the literature on this topic is subject to potential cohort effects, interventions that address co-occurring mental health conditions and psychosocial stress might improve treatment outcomes for women with OUD. SCIENTIFIC SIGNIFICANCE: Funding agencies and researchers should focus attention toward human laboratory studies and clinical trials that are prospectively designed to assess sex-based differences in OUD recovery. (Am J Addict 2019;28:246-261).

Systematic review of sex-based differences in opioid-based effects.

There are several biological factors that might play a role in physiological response to opioids and/or the onset of problematic opioid use; however, sex-based differences in non-analgesic opioid-based effects are poorly understood. The goal of this review is to provide a current analysis of the pre-clinical literature on sex-based differences in response to endogenous and exogenous opioids, including the interplay between sex hormones and opioid receptor-mediated neuronal activity and associated behaviours. A systematic search was performed on the following terms within PubMed between March and April 2018: 'opioid oestrogen', 'opioid progesterone', 'opioid oestradiol', and 'opioid testosterone'. Pre-clinical research on the non-analgesic, sex-based effects of opioids is disparate, both in terms of methodology and outcomes, which prohibits a cohesive summary of the results. Themes from the pre-clinical literature suggest that opioid receptor binding, coupling, and density vary as a function of hormone exposure. Findings also suggest that interactions between endogenous opioid and stress systems may differ between males and females as a function of ovarian hormones. Given the current opioid-related public health crisis, there is a pressing need to increase systematic pre-clinical and clinical research on sex-based differences in opioid-effects and opioid use disorder.

Opioid Overdose History, Risk Behaviors, and Knowledge in Patients Taking Prescribed Opioids for Chronic Pain.

OBJECTIVE: More than 100 million adults in the United States experience chronic pain, and prescription opioids are the third most widely prescribed class of medications. Current opioid overdose prevention efforts almost exclusively target illicit opioid users, and little is known about the experience of overdose among patients being treated for chronic pain (CP) with a prescription opioid. METHODS: Patients experiencing CP for three or more months and receiving a prescription opioid for pain management (N = 502) completed a self-report survey that asked questions about opioid overdose history, past 30-day risk factors, and knowledge of opioid overdose, overdose risk, and naloxone. RESULTS: Approximately one in five CP participants reported experiencing a lifetime overdose. CP participants reported engaging in several behaviors associated with overdose risk and were unlikely to have been trained to administer naloxone. Fewer than 50% of participants answered any knowledge item correctly. The likelihood of having experienced an overdose increased as the scores on the SOAPP-R and DSM-5 opioid use disorder checklist increased, and a SOAPP-R score of 7 or higher or meeting DSM-5 mild opioid use disorder criteria were significantly associated with reporting a lifetime overdose (85% and 84% of participants who experienced an overdose, respectively). CONCLUSIONS: Opioid overdose occurs at a high rate among CP participants, and this group is relatively uninformed about risk factors for overdose. Established SOAPP-R and DSM thresholds provide an opportunity to identify participants at elevated risk for having experienced an opioid overdose. These data support development of additional concentrated efforts to prevent overdose among chronic pain patients.