The clinical stakes are laid bare in the opening case. Mr. Warren, hospitalized with bacteremia caused by resistant gram-negative bacteria, repeatedly requested discharge because standard withdrawal treatments were not controlling his symptoms. His care team started with methadone, his preferred medication for opioid use disorder, along with clonidine and symptomatic adjuncts. When those measures failed and he again moved to leave, the team turned to high doses of intravenous hydromorphone, delivered through a patient-controlled analgesia pump that allowed smaller, more frequent doses with lockout periods. The objective signs of withdrawal, including elevated heart rate, dilated pupils, yawning, tremors, goosebumps, vomiting, diarrhea, and sweating, all ceased. What remained were cravings, which the author identifies as a cornerstone symptom of withdrawal and the predominant driver of the patient’s urge to leave.

The central argument of the viewpoint is that opioid withdrawal, including uncontrolled cravings, should be treated as an acute, life-threatening illness requiring prompt management, just as sepsis or diabetic ketoacidosis would be. Rose contends that the historical framing of withdrawal as uncomfortable but benign has bred complacency. In reality, untreated or undertreated withdrawal is a common cause of premature hospital discharge and a rapid return to fentanyl use, which acutely raises mortality both through overdose and through complications of foregone medical care. Avoidance of withdrawal, he notes, is also a major reason patients with opioid use disorder continue to use opioids in the first place.

Fentanyl has magnified these dangers. As the dominant non-prescribed opioid across the United States, it carries a markedly higher overdose risk than heroin or prescription opioids. Its brief duration of action increases injection frequency, compounding risks of infectious complications such as endocarditis and viral hepatitis. Its potency also raises patient tolerance, and its accumulation in tissues prolongs withdrawal, often making traditional methadone titrations unbearable and increasing the risk of precipitated withdrawal when buprenorphine is initiated. Clinicians are therefore increasingly confronting hospitalized patients with severe illness whose withdrawal and cravings cannot be controlled by conventional protocols alone.

The pharmacological rationale for intravenous therapy follows established practice in other acute conditions. For pathologies ranging from sepsis to heart failure to diabetic ketoacidosis, intravenous medications are initially required to achieve faster clinical improvement and offer superior titratability. The same logic applies to other withdrawal syndromes, such as alcohol withdrawal, and to opioid use for acute pain. Intravenous opioids produce a rapid rise in drug concentrations that facilitates swift symptomatic relief, while their short half-lives reduce the risk of accumulation. Patient-controlled analgesia pumps, which require active patient participation and enforce lockout intervals, can safely deliver the large morphine-equivalent doses demanded by patients with especially high fentanyl-driven tolerances while granting them a measure of autonomy over their own treatment.

Short-acting opioids, whether intravenous or oral, already have a recognized adjunctive role in the literature. They can fill residual opioid agonism deficits during methadone titrations. During buprenorphine initiation, they can be used for symptom control while fentanyl clears from the body, alongside buprenorphine during low-dose initiations, or to treat precipitated withdrawal if it occurs. This adjunctive use is described as an increasingly accepted harm reduction practice. What remains undefined, and what the viewpoint seeks to address, is the specific role of the intravenous route, whose absence from formal guidance has produced uncertain and inconsistent use across hospitals.

A crucial element of the argument is the assessment of risk. Clinicians rightly worry that the association between receiving opioids and relief from distress or cravings could reinforce, rather than reverse, the learned behavior that opioids are a solution to stressors. Faster time to peak effect, a hallmark of intravenous administration, is known to increase this reinforcing potential. However, Rose argues that for hospitalized patients with severe opioid use disorder, fentanyl use, and uncontrolled withdrawal, the risk of worsening the disorder is low while the benefit of controlling symptoms, thereby facilitating ongoing medical care including addiction treatment, is high. As time and treatment suppress withdrawal and cravings and the acute medical illness improves, the risk-benefit calculus reverses, and short-acting opioids should be discontinued.

The viewpoint is emphatic that intravenous opioids are never a substitute for evidence-based treatment. Medications for opioid use disorder should be recommended to all patients and serve as the backbone of withdrawal management, with buprenorphine or methadone identified as the most effective treatments even for patients uninterested in continuing them after discharge. Alpha-2 agonists such as clonidine or lofexidine should be first-line adjunctive therapies unless contraindicated. Symptomatic treatment with anxiolytics like hydroxyzine, antiemetics like ondansetron, antispasmodics like dicyclomine, antidiarrheals like loperamide, and non-opioid pain medications such as NSAIDs should also be deployed as needed. Short-acting opioids enter the picture only for patients with residual symptoms despite these measures, or in rare instances where patients decline buprenorphine and methadone entirely and the medications are used to facilitate hospital-based care.

Route selection and expectation setting form the practical core of the proposed guidance. Because the reinforcing risk of rapid-onset opioids is amplified with prolonged use, oral opioids should be prioritized once initial withdrawal symptoms have improved and effective doses have been identified. This transition also smooths drug exposures, offering more consistent symptom control throughout the day. Plans to move from intravenous to oral therapy and eventually to discontinue short-acting opioids altogether should be established with patients early. Once patients reach therapeutic buprenorphine doses, typically 16 to 24 milligrams daily, short-acting opioids should no longer be required. Methadone initiation is typically slower, and patients should understand that short-acting opioids will be tapered as methadone is increased, a process that growing evidence suggests can be expedited through more rapid titration schedules.

The case concludes with hard-won but partial success. Mr. Warren’s symptoms improved on the patient-controlled pump, which was transitioned to oral therapy over subsequent days. As methadone was uptitrated, the short-acting opioids were tapered and eventually discontinued. He remained hospitalized for fourteen days of intravenous antibiotics, his first full treatment course in years. On the eve of transfer to rehabilitation, he again packed his bag and requested discharge, and this time no argument could dissuade him. He left with naloxone, a month’s supply of his medications, and a handshake. His infection was cured and he was alive, but not yet ready for recovery. That outcome, the viewpoint suggests, is precisely the point: intravenous opioids did not cure addiction, but they kept a critically ill patient in the hospital long enough to cure the infection that would otherwise have killed him, and they bought time that conventional withdrawal management alone could not.

Subject of Research: Use of intravenous opioids to manage opioid withdrawal in hospitalized patients with opioid use disorder

Article Title: The Role of IV Opioids for Opioid Withdrawal in Hospitalized Patients

Article References: Rose, M. R. (2026). The Role of IV Opioids for Opioid Withdrawal in Hospitalized Patients. Journal of General Internal Medicine. https://doi.org/10.1007/s11606-026-10856-y

Image Credits: AI Generated

DOI: 10.1007/s11606-026-10856-y

Keywords: opioid withdrawal, intravenous opioids, opioid use disorder, fentanyl, methadone, buprenorphine, hospitalized patients, harm reduction, patient-controlled analgesia, medications for opioid use disorder, withdrawal management, internal medicine

The scale of the underlying problem is enormous. Hospitalizations related to alcohol use disorder and opioid use disorder contribute to substantial illness and rising costs, collectively amounting to nearly 50 billion dollars in healthcare spending in 2022 alone. Randomized trials have long supported the use of guideline-recommended medications for these conditions, which meaningfully reduce alcohol or opioid use and improve treatment retention among patients with opioid use disorder. Observational studies have also suggested that these medications could reduce acute healthcare utilization, such as emergency department visits and hospital admissions. Against that evidence base, the treatment rates reported in national surveys are strikingly low: in 2025, only about 3 percent of Americans aged 12 years and older with alcohol use disorder reported receiving medication treatment, and only 16 percent of those with opioid use disorder reported receiving medication in the past year.

Pham and colleagues addressed the relationship between medication use and healthcare utilization using a cross-sectional analysis of US adults from the 2022–2023 National Survey on Drug Use and Health, a nationally representative survey that assesses substance use disorders based on formal diagnostic criteria. Their weighted sample represented 57.5 million adults with past-year alcohol use disorder and 2.9 million adults with past-year opioid use disorder. Within that population, only 2 percent of those with alcohol use disorder and 30 percent of those with opioid use disorder reported using medication treatment within the past year. Perhaps the most consequential single number in the analysis is this: among patients who did not receive medication treatment, the mean number of past-year outpatient visits was 3.3. In other words, many untreated patients were already seeing doctors regularly, which suggests that lack of contact with the healthcare system is not the primary barrier keeping them from evidence-based pharmacotherapy.

The utilization findings themselves were nuanced and, at first glance, counterintuitive. In stratified analyses, healthcare utilization was generally more frequent among patients who received medications for alcohol use disorder, but no consistent association emerged for those who received medications for opioid use disorder. In unadjusted analyses of patients with alcohol use disorder, past-year medication use was associated with more emergency department visits, with an incidence rate ratio of 3.10 (95 percent confidence interval 1.98–4.83), more nights hospitalized, with an incidence rate ratio of 4.10 (95 percent confidence interval 2.17–7.75), and more outpatient visits, with an incidence rate ratio of 1.76 (95 percent confidence interval 1.18–2.62). When the analysts controlled for sociodemographic factors and comorbidities, the associations with emergency department visits and nights hospitalized remained statistically significant but attenuated, at 1.91 (95 percent confidence interval 1.19–3.06) and 2.03 (95 percent confidence interval 1.09–3.79) respectively, while the association with outpatient visits was no longer significant at 1.22 (95 percent confidence interval 0.91–1.63).

For patients with opioid use disorder, the picture was different. The only significant adjusted association between medication treatment and healthcare utilization was for nights hospitalized, with an incidence rate ratio of 2.08 (95 percent confidence interval 1.22–3.55). The divergence between the two conditions is one of the study’s most intriguing puzzles, and the cross-sectional design of the dataset precludes any definitive explanation. One possibility is that patients with alcohol use disorder are offered treatment later in the course of their disease, after alcohol-associated chronic medical conditions have already developed that predispose them to higher rates of healthcare utilization. Another possibility is that the findings reflect a genuine differential effect of medication treatment across the two conditions, given that medications for opioid use disorder are generally considered more effective than those for alcohol use disorder. It also remains unknown how utilization differs depending on which specific medication is initiated and whether psychosocial treatments are delivered concurrently across different medical settings.

The demographic profile of who received treatment adds an important layer of interpretation. Adults who received medications were generally older and more socioeconomically disadvantaged than those who did not: they were less often married, less educated, more often unemployed, and had lower incomes. They also carried more medical comorbidities and had greater severity of their alcohol or opioid use disorder. To some extent, this pattern is reassuring, because it indicates that medications are reaching the population with the highest degree of social vulnerability and clinical need—the patients who stand to benefit from them the most. On the other hand, it suggests that patients are often not receiving treatment earlier in their disease course, at a point when intervention could prevent the downstream social and medical consequences of untreated addiction before they accumulate.

That late start may also help explain another persistent problem: extremely poor persistence with these medications. Prior research has documented high rates of discontinuation of medications for alcohol use disorder and limited retention in buprenorphine treatment for opioid use disorder. The greater socioeconomic disadvantage and disease severity observed among treated patients may themselves act as barriers to staying on treatment, compounding the challenge of retention. This points toward structured interventions that address social vulnerability directly—such as care navigation programs that help patients overcome logistical, financial, and coordination obstacles—as potentially necessary complements to medication prescribing if treatment is to be sustained over time.

Several methodological limitations shape how these findings should be read. Because the study is cross-sectional, the timing of medication use relative to healthcare encounters cannot be determined: it is impossible to know whether healthcare encounters preceded or followed medication initiation, so no causal relationship can be ascribed to the observation that patients receiving medications for alcohol use disorder had higher utilization. The utilization outcomes were self-reported and therefore prone to recall bias, a common trade-off in addiction health services research. National surveys like the National Survey on Drug Use and Health rely on self-reported data, but that approach yields reliable population-level prevalence estimates based on formal diagnostic criteria. Administrative data, by contrast, are compromised by selective and non-standardized screening for alcohol and opioid use disorder in many health systems, which makes case ascertainment less reliable. Future studies could explore novel data linkages or health systems with more standardized screening and documentation procedures to close this gap.

A final interpretive caution concerns the meaning of healthcare utilization itself. Even acute utilization is context-dependent and does not inherently represent a negative outcome. For a patient with an acute health condition, presenting to the emergency department may be a desirable outcome rather than a failure, particularly compared with delaying care and risking disease progression. The survey data used in this study cannot identify which healthcare encounters were preventable or directly attributable to alcohol or opioid use disorder, so higher utilization among treated patients cannot be automatically framed as harm or as treatment failure.

What the study cannot do is establish the effect of these medications on healthcare utilization, and the editorial emphasizes that any interpretation must be situated within decades of randomized trial evidence demonstrating meaningful clinical benefit. What the study does provide is a stark reminder of underutilization—even among patients who are already engaged with the healthcare system and seeing clinicians multiple times a year. The path forward, the editorial argues, lies in high-quality hybrid effectiveness-implementation trials that test strategies to increase uptake of medications for alcohol and opioid use disorder across emergency departments, inpatient wards, and outpatient settings, while simultaneously assessing clinical outcomes including subsequent healthcare utilization. With nearly 50 billion dollars in annual spending tied to alcohol- and opioid-related hospitalizations and treatment rates stuck in the single digits for alcohol use disorder, the economic and human stakes of closing that gap could hardly be higher.

Subject of Research: The association between medications for alcohol and opioid use disorder and healthcare utilization among US adults

Article Title: What is the Relationship Between Addiction Medications and Healthcare Utilization?

Article References: Bernstein, E. Y. (2026). What is the Relationship Between Addiction Medications and Healthcare Utilization?. Journal of General Internal Medicine. https://doi.org/10.1007/s11606-026-10885-7

Image Credits: AI Generated

DOI: 10.1007/s11606-026-10885-7

Keywords: alcohol use disorder, opioid use disorder, medication treatment, healthcare utilization, NSDUH, emergency department visits, hospitalization, treatment retention, addiction medicine, health services research, Journal of General Internal Medicine, treatment gap

The research team, led by emergency physician Hazar Khidir of Henry Ford Hospital and including investigators at Stanford University, the University of Washington, and Yale University, assembled one of the largest cohorts ever used to study this question. Drawing on 100 percent Medicaid claims files from 2016 through 2019, they identified 234,944 acute opioid-related events among 169,721 beneficiaries aged 18 to 64. To qualify, an encounter had to involve a nonfatal emergency department visit, an acute inpatient admission, or an inpatient rehabilitation or detoxification stay tied to opioid overdose, opioid withdrawal, or an infection caused by injection drug use. These are precisely the clinical junctures that addiction medicine specialists call teachable moments, when a patient has survived an overdose or been hospitalized for a serious infection and may be uniquely receptive to starting treatment.

The technical design of the study matters for interpreting its results. The researchers tracked three primary outcomes: whether patients filled a buprenorphine prescription within 30 days of discharge, whether they filled a naloxone prescription, the nasal spray that reverses opioid overdoses, within the same window, and whether they achieved what the field calls buprenorphine retention, defined as at least 150 days of the medication on hand within 180 days of the encounter. They also examined early engagement, measured as fills within just three days. To isolate the effect of race and ethnicity from other factors, the team used hierarchical logistic regression, a statistical approach well suited to claims data because it accounts for patients being clustered within states and years. The models adjusted for age, sex, comorbid medical conditions, prior treatment history, the specific diagnosis that brought the patient in, the state of residence, and the calendar year.

The baseline numbers alone are sobering. Across all 234,944 events, only 14.08 percent of patients filled a buprenorphine prescription within 30 days, and just 3.78 percent filled naloxone. Only 4.62 percent were retained on buprenorphine at 180 days. In other words, after surviving an overdose or being hospitalized for a life-threatening infection from injection drug use, fewer than one in seven Medicaid beneficiaries started the medication most strongly associated with keeping them alive, and fewer than one in twenty stayed on it long enough to derive its full protective effect. The cohort was 68.1 percent White, 11.5 percent Black, and 11.1 percent Hispanic, with a mean age of 37.48 years and 43.36 percent female.

When the researchers compared racial and ethnic groups after statistical adjustment, the disparities emerged clearly and consistently. Compared with non-Hispanic White patients, Black patients had significantly lower adjusted odds of filling buprenorphine within 30 days across every setting studied: the odds were 21 percent lower after emergency department visits (adjusted odds ratio 0.79, 95 percent confidence interval 0.71 to 0.88), 28 percent lower after inpatient admissions (0.72, 0.63 to 0.83), and 17 percent lower after rehab or detox stays (0.83, 0.71 to 0.97). Hispanic patients fared similarly, with 20 percent lower odds after emergency visits (0.80, 0.73 to 0.88) and 17 percent lower odds after inpatient admissions (0.83, 0.75 to 0.93). These are not marginal differences confined to one corner of the health system; they span the entire acute care continuum.

The retention findings were even more alarming. Among patients who did manage to start buprenorphine, Black patients had 36 percent lower adjusted odds of being retained at 180 days after an emergency department encounter (0.64, 0.55 to 0.74), 49 percent lower odds after an inpatient stay (0.51, 0.43 to 0.60), and 37 percent lower odds after rehab or detox (0.63, 0.48 to 0.82). Hispanic patients showed 30 percent lower odds after emergency visits (0.70, 0.62 to 0.79) and 34 percent lower odds after inpatient admissions (0.66, 0.56 to 0.78). An odds ratio of 0.51 means that, after accounting for every measured confounder, a Black patient hospitalized for an opioid-related crisis had roughly half the chance of a comparable White patient of still being on medication six months later. Retention is the single most important predictor of buprenorphine’s mortality benefit; studies have shown that interruptions in medication dramatically raise overdose risk.

The study’s focus on Medicaid is deliberate and consequential. Medicaid is the dominant payer for people with opioid use disorder in the United States, covering a population that bears a disproportionate share of the overdose burden. Because the program insures patients across state lines and across every type of acute care setting, it offers a rare, near-complete window into how the treatment system actually performs. Prior work had already documented a racial divide in buprenorphine access: a 2023 analysis in the New England Journal of Medicine found racial inequality in the receipt of medications for opioid use disorder, and studies of emergency departments across five health systems showed that Black patients were less likely to be started on buprenorphine during their visits. The new study extends that evidence to the post-discharge period and to inpatient and detoxification settings, using a multi-state design that rules out the possibility that the gaps are an artifact of any single state’s policy or any single hospital’s practice.

Why do these disparities persist even after adjusting for diagnosis, comorbidity, and prior treatment? The authors and the broader literature point to a layered set of mechanisms. On the provider side, clinicians may offer buprenorphine less often to patients of color, a pattern documented in emergency department studies and consistent with a bifurcated treatment system in which White patients are more often steered toward office-based medication while Black and Hispanic patients are channeled toward abstinence-oriented or criminal-legal pathways. On the structural side, counties with high levels of racial and ethnic segregation have less treatment capacity for opioid use disorder, meaning that even a motivated patient may leave a hospital without a nearby prescriber. Medicaid itself adds friction: prior authorization requirements and managed care formulary restrictions vary by state and can delay or block fills, and pharmacy deserts are more common in predominantly Black and Latino neighborhoods. Naloxone distribution, meanwhile, has historically under-reached communities of color even as fentanyl has made overdose risk universal.

The consequences of these gaps are measured in lives. Buprenorphine reduces mortality during treatment, and the period immediately after an overdose or hospital discharge is one of extreme vulnerability, with overdose risk elevated for weeks. Every failure to initiate or sustain medication during a transitional window compounds that risk. The study’s authors argue that improved transitional care, warm handoffs from emergency departments and hospitals to community-based treatment, overdose education, take-home naloxone, and follow-up appointments, combined with targeted Medicaid reforms such as streamlined coverage of medications and enhanced payment for transitional care management, could close the gap. The elimination of the federal buprenorphine waiver requirement, often called the MAT Act, has removed one prescriber-level barrier, but the new findings suggest that prescriber-level change alone will not be sufficient.

What makes this study resonate beyond the specialty literature is its scale and its consistency. Nearly a quarter of a million acute opioid-related events, spanning 19 states and four years, all point in the same direction: at the moments when the health system has the greatest leverage over the trajectory of opioid use disorder, Black and Hispanic patients are systematically less likely to receive and keep the treatment that best prevents death. The opioid crisis has often been described as having shifted demographically, with rising overdose rates among Black Americans in recent years, yet the treatment infrastructure has not kept pace with that shift. As policymakers weigh Medicaid reforms and health systems build out addiction consult services and emergency department buprenorphine programs, the study offers a clear benchmark: equitable access must be measured not just in who walks through the door, but in who leaves with a prescription filled, and who is still taking their medication six months later.

Subject of Research: Racial and ethnic disparities in buprenorphine and naloxone receipt and retention among Medicaid beneficiaries after acute opioid-related care

Article Title: Racial and Ethnic Disparities in Buprenorphine and Naloxone among Medicaid Beneficiaries after Emergency Department Visits and Hospitalizations

Article References: Khidir, H., Nedelec, L., Sebok-Syer, S. S., Sabbatini, A. K., Shin, I., Melnick, E. R., & Lin, M. P. (2026). Racial and Ethnic Disparities in Buprenorphine and Naloxone among Medicaid Beneficiaries after Emergency Department Visits and Hospitalizations. Journal of General Internal Medicine. https://doi.org/10.1007/s11606-026-10838-0

Image Credits: AI Generated

DOI: 10.1007/s11606-026-10838-0

Keywords: opioid use disorder, buprenorphine, naloxone, Medicaid, health disparities, emergency department, hospitalization, treatment retention, overdose, addiction medicine, health equity, transitional care

The study’s central innovation lies not in inventing new algorithms but in applying them to a problem that has resisted conventional clinical workflows for decades. The researchers drew their training data from the National Epidemiologic Survey on Alcohol and Related Conditions-III, a nationally representative US survey that includes both detailed diagnostic interviews and a rich array of background variables resembling the kinds of information captured in real-world health records. This design allowed the team to create an EHR-like dataset in which every person had a ground-truth diagnostic status, something almost never available in actual medical systems, where definitive diagnostic data on substance use is sparse and often contaminated by treatment-seeking behavior.

Because the survey contained standardized DSM-5 diagnostic assessments, the researchers could label each respondent as having or not having an untreated alcohol use disorder, opioid use disorder, or cocaine use disorder. The models were trained to predict these labels using only features that plausibly map onto data already present in health records: demographic characteristics, socioeconomic indicators, healthcare utilization patterns, and other routinely collected variables. Crucially, the team performed much of the modeling in two configurations, one excluding and one including psychiatric comorbidity information, so that they could assess how much predictive signal persists when mental health diagnostic data is unavailable, a common situation in primary care settings.

The technical pipeline reflects careful attention to the pitfalls that have undermined many machine learning studies in medicine. The authors benchmarked several algorithm families, including logistic regression, balanced random forests, extreme gradient boosting, and Gaussian naive Bayes, and tuned hyperparameters through grid search with nested cross-validation to prevent optimistic bias. They avoided relying on area under the receiver operating characteristic curve as the sole performance metric, citing well-documented critiques that this measure can be misleading for imbalanced classification problems like rare disorder detection. Instead, they optimized models for precision and recall, the quantities that matter most clinically: how many flagged patients actually have an untreated disorder, and how many true cases are successfully caught.

The headline result is striking. When models were optimized to balance precision and recall, the number of people who would need to be screened to identify one untreated case of alcohol use disorder fell dramatically relative to universal screening. In several scenarios, the reduction exceeded an order of magnitude, meaning that a healthcare system using the model as a triage tool could find the same number of hidden cases by conducting structured assessments on a small fraction of the population. For a public health problem as large as untreated alcohol use disorder, which affects tens of millions of Americans, such efficiency gains translate into enormous savings of clinician time, screening costs, and patient burden.

Interpretability was another pillar of the study. Rather than treating the models as opaque black boxes, the researchers used Shapley additive explanations, a game-theoretic attribution method that decomposes each prediction into the contributions of individual features. This approach, rooted in the Shapley value framework from cooperative game theory, allows clinicians to see exactly why a particular patient was flagged: which combination of demographic factors, utilization patterns, and other variables pushed the risk estimate upward. In an era when healthcare algorithms face legitimate scrutiny over transparency and accountability, building explanation into the tool from the ground up is a deliberate design choice with practical consequences for clinical trust and adoption.

The findings for opioid and cocaine use disorders were more preliminary but still encouraging. Because these disorders are less prevalent in the general population than alcohol use disorder, the number of positive cases available for training was small, limiting the statistical power of the exploratory models. The authors are candid about this constraint: the opioid and cocaine models showed promise but were limited by sample size. This honesty matters, because the field of clinical machine learning has repeatedly been criticized for overstating the readiness of tools trained on thin data. The study’s framing of these results as exploratory signals rather than validated instruments reflects a more mature approach to model development.

The broader context of this research includes a growing literature applying machine learning to addiction science. Previous studies have used neuroimaging data to classify nicotine dependence, resting-state functional connectivity to predict smoking status, and behavioral markers such as impulsivity dimensions to identify cocaine dependence. Others have built predictive models for opioid use disorder, including the Veterans Health Administration’s Stratification Tool for Opioid Risk Mitigation, which was developed to improve opioid safety and prevent overdose and suicide. What distinguishes the new work is its focus on untreated disease in a general population sample and its grounding in data types that real health systems actually collect at scale, rather than specialized research measurements.

The clinical deployment pathway the authors envision is clinical decision support. Integrated into electronic health record systems, such a model could continuously evaluate incoming patient data and flag individuals who warrant a structured substance use assessment, in the way that suicide risk prediction models have been trialed in large health systems. The literature on computerized decision support suggests these tools can produce absolute improvements in care when they are well designed and properly implemented, though the track record is mixed and depends heavily on workflow integration, alert fatigue, and clinician trust. A screening nudge that reduces the number of assessments needed per case found by more than tenfold is precisely the kind of efficiency that could make universal detection ambitions feasible in under-resourced primary care.

The study also engages seriously with the ethical dimensions of psychiatric prediction. Screening for stigmatized conditions raises questions about privacy, labeling, and the possibility that algorithmic flags could lead to discrimination if mishandled. The authors acknowledge concerns about bias in artificial intelligence applications for mental health, noting the field-wide calls to assess and mitigate algorithmic bias, and they emphasize that interpretability is essential for accountability when automated tools influence clinical decisions. Questions about who takes responsibility for algorithmic recommendations, how patients consent to being flagged, and how flagged individuals are approached with sensitivity to stigma all remain live issues that must be resolved before deployment. The treatment gap this technology targets is enormous and costly: untreated substance use disorders impose substantial burdens on individuals, families, and health systems, and most people who meet diagnostic criteria never seek care. By showing that routinely collected, EHR-like data carries enough signal to identify these hidden cases efficiently and transparently, the study offers a concrete technical foundation for closing a gap that has persisted through decades of conventional screening efforts, while making clear that careful validation in real health systems will be the decisive next step.

Subject of Research: Machine learning detection of untreated substance use disorders from electronic health record-like data

Article Title: Supervised machine learning enables identification of people with untreated substance use disorders using EHR-like data

Article References: Supervised machine learning enables identification of people with untreated substance use disorders using EHR-like data. (n.d.). https://doi.org/10.1038/s44220-026-00717-2

Image Credits: AI Generated

DOI: 10.1038/s44220-026-00717-2

Keywords: machine learning, substance use disorders, electronic health records, alcohol use disorder, opioid use disorder, cocaine use disorder, clinical screening, clinical decision support, interpretability, Shapley values, NESARC-III, early detection

The three-day rule is a provision of federal regulation that permits practitioners who are not affiliated with an OTP to administer methadone to a patient for the purpose of relieving acute withdrawal symptoms while arranging referral to a licensed program. The allowance is capped at three days, and it cannot be renewed within the same month. In practice, it has historically been used sparingly, because clinicians have worried about safety and because the short window seems ill-suited to overcoming the administrative delays that often accompany OTP enrollment. The new research, published in the journal Addiction Science & Clinical Practice, offers a detailed real-world test of the approach as implemented at the San Francisco General Hospital Bridge Clinic, a low-threshold service designed to meet patients where they are.

The study team, led by Sarah Rosenwohl-Mack of UCSF’s Department of Family and Community Medicine, conducted a retrospective case series covering every patient who initiated methadone under the three-day rule at the Bridge Clinic between June 2024 and July 2025. The setting is notable for an unusual piece of geography: the hospital also houses an opioid treatment program in the same building. When that program could not complete an intake, for example because a patient arrived outside scheduled intake hours or the program was at capacity, staff could refer the person down to the Bridge Clinic, where a dose of methadone could be started immediately under the three-day provision. This bidirectional referral pathway became the study’s central variable.

The researchers tracked two primary outcomes. The first was linkage to an OTP within seven days of receiving the initial Bridge Clinic dose, a window that extends beyond the three-day medication allowance and therefore captures whether the bridge actually carried patients to permanent care. The second was retention in OTP treatment at 30 days, a marker of early stability that addiction medicine researchers view as a meaningful predictor of longer-term benefit. Because methadone carries its own risks, particularly when combined with other sedatives, the team also built in a safety monitoring framework that reviewed urine drug screens, emergency department visits, hospitalizations within seven days, and Medical Examiner overdose reports.

The results are striking for a population that conventional systems routinely lose. Among 166 unique patients who received at least one dose of three-day methadone at the Bridge Clinic, 63 percent, or 104 individuals, successfully linked to an opioid treatment program within seven days. Of those who linked, 62 percent, or 64 patients, were still retained in treatment at the 30-day mark. In a field where attrition between first contact and enrollment has long been considered one of the most stubborn leaks in the continuum of care, the finding suggests that a short bridge of medication can hold a substantial fraction of patients long enough for the formal system to catch up with them.

The most consequential finding, however, concerned the direction of the referral. Using multivariable logistic regression to adjust for other factors, the researchers found that patients who arrived at the Bridge Clinic by referral from the co-located OTP had 3.1-fold higher odds of remaining in treatment at 30 days compared with patients who came through other routes. The interpretation is not that the referral itself dispensed a pharmacological benefit, but that the pathway reflects a coordinated system in which the OTP and the Bridge Clinic function as two doors into the same building of care. A patient handed off from the OTP arrives with an established clinical relationship, a documented treatment plan, and a clear route back, whereas a patient walking in cold must navigate enrollment largely on their own after the three-day window closes.

On the safety side, the record was clean in ways that will reassure clinicians who have hesitated to use the three-day rule. The study identified no methadone-related emergency department visits, no hospitalizations, and no deaths within 30 days of receiving methadone at the Bridge Clinic. The urine drug screen review, designed to flag unexpected results such as methadone positivity in patients not prescribed it or the absence of non-prescribed opioids suggesting diversion, surfaced only one notable case: a single patient who, on closer chart review, turned out to have already been enrolled in methadone treatment elsewhere before receiving a dose at the Bridge Clinic. That finding points to a practical quality-control challenge, ensuring that bridge dosing does not duplicate existing treatment, but it does not undermine the overall safety signal.

The technical logic of the intervention deserves attention. Methadone is a long-acting full mu-opioid receptor agonist with a half-life that supports once-daily dosing, which is precisely why it smooths the cycle of withdrawal and craving that drives much of the daily chaos in untreated opioid use disorder. When a patient presents in withdrawal, the clinical task is to provide enough of the medication to relieve symptoms without accumulating toxicity, which is why Bridge Clinic protocols begin with conservative doses and titrate carefully. The three-day rule fits neatly into this pharmacology: three days of supervised dosing is enough to stabilize a patient physiologically and to interrupt the withdrawal-driven urgency that otherwise pushes people back to fentanyl and other illicit opioids, while the referral machinery works in parallel to secure a permanent slot at an OTP.

The San Francisco team acknowledges intellectual debts in the paper, crediting the Faster Paths Emergency Opioid Withdrawal Protocol at Boston Medical Center, whose published approach informed the local protocol. That lineage matters because it illustrates how low-threshold models are spreading through a kind of open-source clinical adaptation, with programs borrowing and refining each other’s protocols rather than waiting for multi-year trials. The study itself was deemed exempt by the UCSF Institutional Review Board and used retrospectively collected anonymized data, a design that trades the rigor of randomization for the realism of observing how an intervention performs inside the ordinary friction of a public hospital.

The implications reach well beyond one clinic. Opioid treatment programs remain the only legal channel for methadone maintenance in the United States, and their geographic maldistribution means that many counties have no OTP at all. The three-day rule cannot substitute for structural reform, but the study demonstrates that when a low-threshold bridge service and a licensed OTP are deliberately networked, the rule becomes a functional handoff mechanism rather than a rarely used legal footnote. The 3.1-fold retention advantage associated with OTP referral suggests that the return on investment lies in building those connections, ensuring that every bridge dose is paired with a warm pathway back into licensed care. For a lethal epidemic that has proven resistant to conventional outreach, the message is deceptively simple: meet people in withdrawal with medication the same day, and engineer the system so that the door they entered stays open behind them.

Subject of Research: Three-day methadone bridging at a low-threshold clinic to improve linkage and retention in opioid treatment programs

Article Title: Implementing three-day methadone in a low-threshold Bridge Clinic: impact of OTP referral pathways on treatment retention

Article References: Rosenwohl-Mack, S., Suen, L. W., Hart, R., Steiger, S., Hom, J. K., & Snyder, H. (2026). Implementing three-day methadone in a low-threshold Bridge Clinic: impact of OTP referral pathways on treatment retention. Addiction Science & Clinical Practice. https://doi.org/10.1186/s13722-026-00725-8

Image Credits: AI Generated

DOI: 10.1186/s13722-026-00725-8

Keywords: methadone, opioid use disorder, opioid treatment program, Bridge Clinic, three-day rule, treatment retention, harm reduction, San Francisco General Hospital, low-threshold care, withdrawal management, addiction medicine, medication for opioid use disorder

The social-ecological framework, first articulated by developmental psychologist Urie Bronfenbrenner, holds that health decisions are never made in a vacuum. Instead, they emerge from interacting layers of influence: personal beliefs and motivations at the core, surrounded by family and peer networks, then the clinics and neighborhoods where people live, and finally the policies, laws and dominant social attitudes that govern treatment itself. The research team applied a modified version of this model to understand how recently incarcerated patients navigate a treatment landscape that has shifted dramatically in the past five years. Federal regulators have expanded take-home methadone doses, reducing the number of days patients must appear in person at an opioid treatment program, and removed the cap on how many patients a provider may prescribe buprenorphine to. Long-acting injectable buprenorphine has also entered the market, bringing its own barriers of cost and limited clinic availability.

Between March and August 2025, the team conducted semi-structured interviews averaging 50 minutes with adults who had received methadone or buprenorphine during an incarceration in the past year. Participants were recruited through opioid treatment programs, office-based providers and recovery centers across the state, with purposive efforts to balance representation by medication type. The sample, on average, had been released just over five months before the interview, was 37.6 years old on average, and included 16 men and 12 women. Most participants were White and non-Latino. At the time of interview, 25 of the 28 participants were receiving methadone and only three were on buprenorphine, even though most had received methadone during incarceration as well. Interviews were transcribed, coded using template-style thematic analysis with both deductive and inductive codes, and analyzed in NVivo until thematic saturation was achieved.

The first and most personal theme concerned perceived benefits. Participants continued MOUD when they felt it clearly worked — helping them avoid withdrawal, illicit opioid use and reincarceration, three outcomes that participants described as deeply intertwined. Many reported that methadone curbed their cravings more effectively than buprenorphine, a difference that proved decisive. One participant who could not reach a methadone clinic after release discontinued treatment entirely because buprenorphine, though easier to obtain with only monthly provider visits, did not adequately suppress his cravings; he resumed methadone only after moving closer to a clinic. This finding underscores a technical point with major clinical implications: patient preference is not merely about convenience but about pharmacological fit, and when the medication that works best is inaccessible, some patients opt for no medication at all.

Paradoxically, nearly all participants — even those who credited MOUD with stabilizing their recovery — expressed an intention to taper off within the next couple of years. Many described methadone or buprenorphine as a band-aid, a short-term tool rather than a chronic therapy, reflecting what the authors identify as an internalized abstinence narrative. This belief had concrete consequences for treatment selection: some participants rejected long-acting injectable buprenorphine precisely because its monthly dosing removed the daily control that would let them stop when they chose. The researchers argue that distinguishing between patients whose desire to discontinue is clinically congruent and those whose desire is driven by stigma or structural barriers is essential for designing interventions that improve retention during the highest-risk period.

At the interpersonal level, the study found that supportive family involvement was invaluable but rare. A few participants relied on relatives for transportation to daily methadone dosing, a logistical lifeline that made treatment feasible. Far more common was stigma within families, where methadone was perceived as simply swapping one drug for another. Several participants concealed their treatment from loved ones, describing it as embarrassing, and this concealment bred isolation. In one striking account, a participant who had been stable after a previous release — employed, housed, engaged in methadone treatment — stopped the medication because of his mother’s disapproval, relapsed into illicit opioid use, and experienced worsening mental health. Others deliberately shrank their social circles to avoid substance use triggers or exposure. Against this backdrop, many participants emphasized self-reliance, framing their recovery as something they had to accomplish alone, and some even preferred buprenorphine’s relative lack of wraparound services because it demanded less dependence on institutions.

Community and organizational factors proved to be powerful levers of access. Housing proximity to an opioid treatment program, access to a working vehicle, and reliable bus routes determined whether daily methadone dosing was realistic. Free transportation services funded through public insurance helped some participants, but others were unaware of these programs, lost passes, or found multi-bus commutes prohibitive. One woman who had to make lengthy near-daily trips by bus concluded that methadone simply did not work for someone without a car and expressed regret over starting it during incarceration, saying she would prefer a monthly injectable so she would not have to worry about dosing every day. The physical environment around clinics also mattered: visible drug activity near treatment sites triggered discomfort and cravings for some patients, deterring them from clinics even when those clinics were close to home.

Clinic practices themselves shaped treatment trajectories. Participants described anxiety over whether they could receive same-day dosing at community intake, hearsay about waitlists, unclear urine drug screening policies, and fear of missing doses when entering residential programs. Although no participant experienced significant gaps in care after reaching a clinic, the psychological cost of fearing withdrawal was real, and for some it motivated a desire to taper off entirely. One participant, facing a warned urine drug screen from his buprenorphine prescriber shortly after release, chose to stop treatment and continue using before later switching to methadone. These accounts illustrate how restrictive or opaque clinic rules can convert a treatable condition into a cycle of disengagement, use and re-engagement.

At the structural level, the fentanyl-dominant drug supply emerged as a decisive force. Participants who were still using opioids feared precipitated withdrawal if they initiated buprenorphine with fentanyl in their system, rendering buprenorphine and its injectable formulation non-viable options in their eyes. Methadone, by contrast, was seen as robust in the fentanyl era, though a few participants described developing a double habit — concurrent methadone and illicit fentanyl use that pushed their methadone doses upward and left them uncomfortable if either substance was unavailable. Methadone also carried a unique legal advantage: its mandatory counseling satisfied probation requirements for some participants, helping them avoid re-arrest, a benefit no buprenorphine recipient reported. Meanwhile, expanded take-home methadone policies motivated engagement for some, but patients with instability indicators often could not accrue take-homes quickly enough, and the threat of losing privileges after hospitalization or reincarceration discouraged others. Systemic stigma in employment and housing further eroded commitment, with participants questioning whether they could be hired as nurses or in other careers while on methadone.

The authors conclude that MOUD preferences and intentions after incarceration are entangled with multilevel barriers, and that improving retention will require interventions at every layer: pre-release education to counter misinformation and stigma, stronger linkage to MOUD-affirming recovery communities and peer support specialists, transportation solutions, and lower-barrier delivery models including community-based post-release dosing. Peer support specialists were described as helpful by the few participants who encountered them, but their scarcity reflects the slow integration of these roles into treatment systems. Given that discontinuing MOUD sharply elevates overdose risk, particularly when cessation occurs early, the stakes of preference-congruent care could not be higher. This study offers a detailed, patient-centered map of why people leaving incarceration choose, keep or abandon their medications — knowledge the authors say is essential for building treatment systems that keep people alive through the perilous transition home.

Subject of Research: Social-ecological determinants of medication preferences and receipt for opioid use disorder after incarceration

Article Title: Social-ecological factors shape preferences for and receipt of medications to treat opioid use disorder in the post-incarceration period

Article References: Bailey, A., Hughto, J. M., Kelly, P. J., Dunsiger, S. I., & Martin, R. A. (2026). Social-ecological factors shape preferences for and receipt of medications to treat opioid use disorder in the post-incarceration period. SSM – Mental Health, 10, Article 100705. https://doi.org/10.1016/j.ssmmh.2026.100705

Image Credits: AI Generated

DOI: 10.1016/j.ssmmh.2026.100705

Keywords: opioid use disorder, methadone, buprenorphine, post-incarceration, social-ecological model, stigma, overdose risk, fentanyl, opioid treatment programs, peer support, reentry, qualitative research

The research team, led by Justin Berk of Alpert Medical School at Brown University and the Center for Health and Justice Transformation, focused on a system that has become a national reference point. The Rhode Island Department of Corrections is a unified state system housing both pretrial and sentenced individuals, and it has operated one of the longest-running medications for opioid use disorder programs in the United States, in place since 2016. That longevity made it an ideal setting to ask a question that clinical trials rarely capture: what does medication-assisted treatment actually do to the daily workings of a correctional institution over years of implementation?

Methodologically, the study relied on semi-structured qualitative interviews with nineteen incarcerated individuals and ten correctional and medical facility staff. The interviews explored the cultural and operational context of medication implementation, including experiences with extended-release injectable buprenorphine, a long-acting formulation administered monthly that has become increasingly important in correctional settings. All interviews were audio-recorded and transcribed, and the researchers analyzed them using applied thematic analysis, a systematic qualitative method that identifies recurring patterns of meaning across participant accounts. The study received approval from the Brown University Health Institutional Review Board and the Rhode Island Department of Corrections Medical Research Advisory Group, and all participants provided written informed consent.

Three major themes emerged from the analysis, and the first concerns what researchers call facility climate. Participants perceived that the availability of opioid use disorder medications reduced contraband drug use, violence, and disciplinary infractions within the facilities. This is a significant finding because contraband opioids, particularly illicit fentanyl, have become a central security and public health threat in jails across the country. When incarcerated people can obtain evidence-based treatment that relieves cravings and prevents withdrawal, the black-market demand that drives smuggling, debt, and violence may shrink. Interviewees also described improvements in social functioning, including greater participation in court proceedings and rehabilitative programming, suggesting that stabilized patients engage more constructively with the legal and institutional processes they must navigate.

The second theme directly addresses the objection most often raised by skeptics of prison-based addiction treatment: diversion, the practice of saving or trading medication doses for other purposes. Diversion did occur in the Rhode Island system, participants reported, often to get high or to manage withdrawal symptoms. But interviewees perceived it as limited in scope, and most patients were perceived to use their medications as prescribed. Importantly, participants emphasized that diversion is not unique to opioid treatment medications; it also occurs with other prescribed drugs in correctional settings. From a security-management perspective, this reframes diversion from a disqualifying danger into a routine, manageable clinical and operational problem comparable to those already handled with other medications every day.

Extended-release injectable buprenorphine emerged as a particularly effective tool in this regard. Because the medication is a monthly depot injection administered under clinical supervision rather than a daily tablet that passes through many hands, it was widely regarded by participants as a strategy that reduces both diversion risk and operational burden. Daily observed dosing of medication is labor-intensive for medical staff and creates choke points that custody staff must manage; a monthly injection collapses that logistical challenge. For administrators weighing the costs of running a medication program, the injectable formulation appears to offer a practical compromise that preserves clinical benefit while addressing the security concerns that most commonly stall implementation.

The third theme is the most culturally revealing: even in a system with nearly a decade of continuous program operation, stigma toward these medications persisted among some custody staff and some incarcerated peers. Skepticism about whether opioid agonist treatment constitutes real recovery, or whether it merely substitutes one drug for another, remains a durable cultural artifact within corrections. The study identifies education and leadership support as the critical levers for overcoming this resistance. Programs that invested in training and in visible, sustained buy-in from leadership were better positioned to convert skeptics and to integrate addiction treatment into the institutional identity rather than treating it as an exception or an imposition.

Notably, the researchers found that medication implementation created opportunities for improved collaboration between medical and security staff, even though some tensions remained. In many facilities, healthcare units and custody operations function as parallel hierarchies with different priorities: one oriented toward health, the other toward order. A shared program like medications for opioid use disorder forces the two sides into regular coordination, from dosing logistics to responding to diversion incidents, and participants described how this contact could build mutual understanding. The tensions that persisted did not disappear, but the study suggests the medication program itself can serve as a structure through which interdisciplinary working relationships develop.

The implications extend well beyond Rhode Island. Most jails and prisons in the United States still do not offer all three FDA-approved medications for opioid use disorder, and diversion fears remain the most commonly cited barrier. People leaving incarceration face a dramatically elevated risk of fatal overdose in the days and weeks after release, a phenomenon documented repeatedly in the public health literature, because tolerance lost during abstinence meets unchanged patterns of use. Treatment that begins inside and continues after release is among the strongest known protective factors. If implementing such treatment also reduces violence and disciplinary problems inside, as this study’s participants perceived, then the institutional case for medication programs becomes considerably harder to dismiss on purely administrative grounds.

The authors caution, appropriately, that these are perceptions gathered from a single state system with an unusually mature program, and qualitative findings describe lived experience rather than measuring outcomes directly. But the study’s conclusions are clear and actionable: medications for opioid use disorder in correctional settings can support a safer, more stable facility environment, diversion concerns appear manageable and comparable to those of other medications, and programs that invest in education, leadership engagement, and medical-security partnerships are best positioned to overcome resistance. For a nation whose jails have become de facto frontline institutions of the overdose crisis, the Rhode Island experience suggests that the contraband-versus-medicine debate may finally be resolving in favor of medicine, and that the benefits flow to security officers, medical staff, incarcerated people, and the communities they return to alike.

Subject of Research: Qualitative study of how medications for opioid use disorder reshape culture, operations, and safety in correctional facilities

Article Title: From contraband to collaboration: a qualitative study of how medications for opioid use disorder can reshape correctional culture and safety

Article References: Berk, J., Martin, M., Cook, M., Miller, C., Suh, M., Murphy, C., Jack, H. E., Rich, J. D., Brinkley-Rubinstein, L., & Guthrie, K. M. (2026). From contraband to collaboration: a qualitative study of how medications for opioid use disorder can reshape correctional culture and safety. BMC Public Health. https://doi.org/10.1186/s12889-026-29554-9

Image Credits: AI Generated

DOI: 10.1186/s12889-026-29554-9

Keywords: opioid use disorder, medications for opioid use disorder, buprenorphine, correctional health, jails and prisons, diversion, harm reduction, implementation science, qualitative research, overdose prevention, correctional culture, public health

The μ-opioid receptor, or MOR, is the primary molecular target for most clinically used analgesic opioids, from morphine to fentanyl. Decades of research have focused on what happens at the plasma membrane, where activated receptors are phosphorylated, bind β-arrestin, and are pulled into the cell by endocytosis. Chronic exposure to certain agonists reduces the number of receptors displayed on the cell surface, a process widely believed to contribute to tolerance and dependence. But the new work shifts attention to a much earlier stage of the receptor’s life: its maturation and export from the endoplasmic reticulum, the cellular factory where membrane proteins are synthesized and folded.

Studying this early phase in normal receptors is difficult because MORs traffic efficiently to the plasma membrane, leaving almost nothing in the endoplasmic reticulum to observe. To overcome this obstacle, the research team, led by Matthew J. Mulcahy, Stephen N. Grant, and Henry A. Lester, used a rare mutant called MOR[N190K], which is substantially retained in the endoplasmic reticulum. When cells expressing this mutant were treated with the antagonists naltrexone or naloxone, fluorescently tagged receptors suddenly appeared outlining the cell surface, reaching a distribution resembling that of the wild-type receptor. The drugs, in other words, had rescued the mutant receptor’s journey to the membrane.

The mechanism behind this rescue appears to involve endoplasmic reticulum exit sites, or ERES, specialized regions of the organelle where newly folded cargo is packaged into coat protein vesicles for transport to the Golgi apparatus. To visualize these structures, the researchers used a fluorescently tagged version of Sec24D, a core component of the ERES machinery. First, they needed to confirm that the receptor and Sec24D actually interact. Using sensitized emission Förster resonance energy transfer, a live-cell technique that detects when two fluorescently labeled proteins come within a few nanometers of each other, they showed that MOR[N190K] sits in close proximity to Sec24D inside the endoplasmic reticulum. A control experiment with Rab5, a marker of early endosomes, produced no comparable signal, ruling out the possibility that the interaction was happening after the receptor had already reached the cell surface and been internalized.

With that interaction established, the team turned to three-dimensional confocal microscopy to ask what happens to ERES when cells are flooded with opioid drugs. They measured the fraction of the cytoplasmic volume occupied by ERES, a metric chosen because, as earlier work by Heinzer and colleagues reasoned, expanding the size of exit sites is a more effective way to boost secretory flux than simply adding more of them. After twelve hours of treatment with ten micromolar concentrations of drug, four ligands stood out: naltrexone, naloxone, morphine, and fentanyl all significantly increased the ERES fraction. Buprenorphine, methadone, and two positive allosteric modulators, BMS 986122 and BMS 986124, did not.

The pattern held up under several additional tests. N-methyl-naltrexone, a permanently charged derivative of naltrexone that crosses the plasma membrane far less readily, produced only a modest shift in ERES levels, consistent with the idea that the drug must physically enter the cell and reach the endoplasmic reticulum to chaperone the receptor. A shorter four-hour incubation with naltrexone yielded only a partial increase, suggesting that the process builds over time as receptors cycle through the secretory pathway. And when the researchers blocked COPI-dependent retrograde transport with brefeldin A, naltrexone and naloxone lost their ability to raise ERES levels entirely. That last result implies that the mutant receptor must make multiple round trips between the endoplasmic reticulum and the Golgi before it is fully matured and ready for the plasma membrane, a requirement that mirrors findings from pharmacological chaperoning studies of other receptor families.

Perhaps the most intriguing result came from a double mutant. Serine 375, a residue in the receptor’s C-terminal tail, is a well-known phosphorylation site that governs arrestin recruitment and receptor internalization at the cell surface. When the researchers mutated this serine to alanine in the ER-retained background, creating MOR[N190K][S375A], naltrexone still chaperoned the receptor effectively, but morphine and fentanyl lost their chaperoning power altogether. This suggests that the agonists’ ability to promote receptor export depends on S375, possibly because they can induce phosphorylation of the residue even while the receptor is still maturing inside the endoplasmic reticulum. It also reveals an unexpected, “inside-out” role for a residue that has almost exclusively been studied in the context of events at the plasma membrane.

The team also tested and rejected an alternative explanation for the upregulation. One hypothesis held that antagonists raise intracellular cyclic AMP levels, which in other cell types has been shown to coincide with a global increase in protein trafficking. Because MOR activation suppresses cAMP, blocking basal receptor activity with an antagonist could plausibly raise cAMP and thereby accelerate trafficking generally. But a competitive ELISA assay on cell lysates showed no significant cAMP increase after twelve hours of naltrexone treatment, while the positive control, forskolin, produced the expected rise. With the cAMP pathway ruled out, the pharmacological chaperoning hypothesis stands as the leading explanation for how these ligands expand ERES levels and push the mutant receptor toward the cell surface.

The clinical stakes of this basic cell biology are considerable. Naltrexone and naloxone are the two most commonly prescribed opioid antagonists, given to people recovering from opioid use disorder. Chronic antagonist treatment is known to increase the number of opioid receptors on the cell surface, producing a supersensitivity that can persist for weeks after the final dose. If a patient relapses during that window, the expanded receptor population raises the risk of a fatal overdose. Understanding that antagonists may drive this upregulation, at least in part, by chaperoning receptors through the early secretory pathway opens a potential strategy for decoupling the therapeutic benefits of antagonist therapy from its most dangerous side effect.

The authors are careful about the limits of their findings. In pilot experiments, neither naltrexone nor the other ligands increased ERES levels or surface expression of the wild-type receptor, so the chaperoning mechanism demonstrated here applies only to the rare MOR[N190K] mutant, and the microscopy approach cannot yet be applied to native neurons in intact neural circuits. Generalizing the mechanism to explain supersensitivity in animals with normal receptors will require additional, still unknown elements of the chaperoning process, much as the mechanisms behind nicotine’s selective upregulation of nicotinic receptors in certain cell types remain only partly resolved. Interestingly, buprenorphine’s known ability to rescue the mutant receptor’s surface expression despite failing to raise ERES levels suggests that it acts through a different, ERES-independent trafficking step, hinting that multiple routes to the plasma membrane can be targeted by small molecules.

Even with those caveats, the study makes a strong case that pharmacological chaperoning deserves a place in any complete account of a drug’s efficacy profile. Ligands long classified purely by their actions at the cell surface, agonists and antagonists alike, turn out to influence the internal processing of their own receptors, changing how cells respond to drug exposure from the inside out. As the authors note, this principle now appears to span several drugs of abuse, from nicotine to opioids, and the hope is that future experiments will keep following opioid receptors into the endoplasmic reticulum and Golgi, far from the plasma membrane where most of their story has been told until now.

Subject of Research: Pharmacological chaperoning of the μ-opioid receptor by opioid agonists and antagonists via endoplasmic reticulum exit sites

Article Title: Naltrexone, Naloxone, Morphine, and Fentanyl Pharmacologically Chaperone a Mutant μ‐Opioid Receptor via an Endoplasmic Reticulum Exit Site‐Dependent Pathway

Article References: Grant, S. N., Mulcahy, M. J., & Lester, H. A. (2026). Naltrexone, Naloxone, Morphine, and Fentanyl Pharmacologically Chaperone a Mutant μ‐Opioid Receptor via an Endoplasmic Reticulum Exit Site‐Dependent Pathway. Pharmacology Research & Perspectives, 14(5), Article e70315. https://doi.org/10.1002/prp2.70315

Image Credits: AI Generated

DOI: 10.1002/prp2.70315

Keywords: μ-opioid receptor, pharmacological chaperoning, naltrexone, naloxone, fentanyl, morphine, endoplasmic reticulum exit sites, Sec24D, opioid use disorder, receptor trafficking, S375 phosphorylation, inside-out pharmacology

The scale of the problem is staggering. According to the review, an estimated 4.3 million people in the United States meet diagnostic criteria for stimulant use disorder, nearly a quarter of them aged 25 or younger. National overdose deaths involving stimulants rose nearly 34-fold between 2002 and 2022, and 182,502 stimulant-related overdose deaths were reported between 2021 and 2024. More than 60,000 stimulant-related overdose deaths have been recorded annually in recent years, with 43.1 percent of stimulant-involved deaths between January 2021 and June 2024 also involving opioids. Black or African American and American Indian or Alaska Native communities have experienced disproportionately steep increases in stimulant-involved deaths, adding an urgent health equity dimension to the crisis.

Yet while medications exist for opioid, alcohol, and tobacco use disorders, stimulant use disorder remains one of the few major substance use disorders with no FDA-approved drug therapy, leaving clinicians dependent on behavioral interventions with limited long-term efficacy. It is against this backdrop that the LSU team examined the theoretical potential of Brixadi. Brixadi is an extended-release injectable buprenorphine that uses a fluid-crystal depot delivery system: after subcutaneous injection, the solution solidifies into a viscous crystalline gel that gradually releases the drug over one week or one month, producing stable plasma concentrations and sustained receptor occupancy. Peak plasma levels occur roughly 20 hours after injection, and steady state is reached by the fourth dose, with half-lives ranging from 3 to 5 days for weekly injections and 19 to 26 days for monthly ones.

Buprenorphine’s pharmacology is what makes the hypothesis plausible. The drug is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor, binding with exceptionally high affinity—reported inhibition constants of approximately 0.2 nanomolar at the mu receptor and 0.07 nanomolar at the kappa receptor—and dissociating slowly. That ceiling effect on respiratory depression and euphoria underpins its favorable safety profile, while its high affinity allows it to displace full agonists such as fentanyl and heroin from receptors. But for stimulant addiction, the kappa receptor is the critical piece. Kappa-opioid receptors respond to dynorphins, endogenous peptides that suppress dopamine signaling in the mesolimbic reward pathway and generate dysphoria, stress responses, and drug craving. Chronic stimulant use upregulates prodynorphin transcription, elevating dynorphin levels and pushing the brain into a low-dopamine state that drives further drug seeking in a self-reinforcing loop.

Animal research supports this framework. Methamphetamine exposure increases dynorphin expression in the nucleus accumbens and preclinical cortex, and in mouse studies by Whitfield and colleagues, kappa receptor activation during abstinence appeared to create neuroadaptations that made methamphetamine more appealing, essentially fueling relapse through negative reinforcement. Conversely, pharmacologic blockade of the kappa receptor has, in some animal models, reduced drug-seeking behavior or methamphetamine self-administration, although the effects have not been uniform across species and paradigms. In rodents and rhesus monkeys, buprenorphine has also been shown to decrease cocaine self-administration and cocaine-seeking behavior, and rodent studies suggest buprenorphine reduces methamphetamine consumption and drug seeking partly through activation of the nociceptin/orphanin FQ peptide receptor.

Human evidence remains thin but intriguing. A double-blind randomized clinical trial by Ahmadi and Razeghian Jahromi found that buprenorphine reduced methamphetamine craving during withdrawal more effectively than methadone, though the 17-day trial could not determine whether the effect persisted or prevented relapse. Trials of concurrent opioid and cocaine dependence have reported reductions in cocaine use and craving with buprenorphine, and a combination of buprenorphine and naltrexone blocked compulsive cocaine intake in rodents without producing opioid dependence. Buprenorphine’s antidepressant-like effects in animal models—mediated through kappa receptors and stress modulation—further suggest it may blunt the hyperkatifeia, the intensified negative emotional state, that fuels relapse during stimulant withdrawal.

The strongest practical argument, however, may lie in polysubstance use. Toxicologic data show that 89.6 percent of individuals presenting for opioid use disorder treatment test positive for more than one substance, with a mean of 3.3 substances per person and up to 11 detected in some cases. Approximately one-third of individuals with opioid use disorder use stimulants concurrently, methamphetamine use in this population has risen by more than 80 percent, and over half of US overdose deaths from 2018 to 2024 involved concurrent opioid and stimulant use. Because opioid and stimulant use disorders converge on overlapping dopamine, reward, and stress circuitry—psychostimulants acting directly on dopaminergic transporters and opioids disinhibiting dopamine release indirectly—stabilizing the opioid component may disrupt the reinforcing environment sustaining stimulant use. Notably, when patients remained in buprenorphine treatment, one study found a 15 percent absolute reduction in methamphetamine use at six months, even though methamphetamine use predicted lower treatment retention overall.

Brixadi’s depot formulation may add distinct advantages in this population. Long-acting buprenorphine formulations have achieved treatment retention rates above 60 to 70 percent at six months, and maintenance on buprenorphine is associated with a greater than 50 percent reduction in all-cause mortality compared with no treatment. Monthly or weekly injections remove the daily adherence burden that trips up patients experiencing housing instability or limited transportation, minimize peak-to-trough fluctuations, and keep patients engaged in care long enough to benefit from behavioral therapies such as contingency management, the intervention with the best evidence for stimulant use disorder. The authors frame this as harm reduction: buprenorphine does not directly treat stimulant craving, but stabilizing opioid dependence may reduce chaotic polysubstance patterns, lower overdose risk, and create openings for broader therapeutic engagement.

The review is candid about its limitations. Brixadi is not approved for any stimulant use disorder, no clinical trial has demonstrated that buprenorphine reduces methamphetamine or cocaine use as a primary outcome, and much of the kappa-antagonism rationale rests on preclinical models and neurobiologic theory. Larger, well-controlled clinical trials are needed to determine whether the proposed mechanisms translate into meaningful reductions in stimulant use, craving, and relapse. Still, the convergence of an unmet clinical need, a well-characterized safety profile, plausible stress-and-craving pharmacology, and enormous polysubstance overlap makes the proposition difficult to ignore. With more than 60,000 stimulant-related deaths each year and no approved medication in sight, the authors argue that Brixadi’s extended-release profile and potential to counter withdrawal-related dysphoria and stress-induced drug seeking present a compelling case for accelerated clinical investigation.

Subject of Research: Evaluation of extended-release injectable buprenorphine (Brixadi) as a potential pharmacotherapy for stimulant use disorder

Article Title: Brixadi for Stimulant Use Disorder: Evolving Pharmacologic Considerations and Clinical Implications

Article References: Brixadi for Stimulant Use Disorder: Evolving Pharmacologic Considerations and Clinical Implications. (n.d.). https://doi.org/10.1007/s12325-026-03772-4

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03772-4

Keywords: Brixadi, buprenorphine, stimulant use disorder, methamphetamine, cocaine, kappa-opioid receptor, dynorphin, polysubstance use, opioid use disorder, harm reduction, pharmacotherapy, addiction

The research, led by Karen L. Roper of the University of Kentucky College of Medicine’s Department of Family and Community Medicine, addresses a well-documented gap in the treatment landscape. Medications for opioid use disorder, commonly abbreviated as MOUD, are demonstrably effective at reducing illicit opioid use, overdose mortality, and relapse, yet the majority of people with opioid use disorder in the United States receive no pharmacological treatment at all. Buprenorphine, a partial opioid agonist that suppresses cravings and withdrawal without producing the full euphoric effect of full agonists, can be prescribed in office-based settings, making primary care an ideal delivery channel. Despite this, many primary care practitioners, or PCPs, cite a thicket of barriers: worry about staff and patient reactions, limited appointment time, reimbursement uncertainty, and a lack of confidence in managing a condition long stigmatized as outside the generalist’s lane.

What distinguishes this intervention is its deliberate grounding in the science of behavior change. Rather than producing generic continuing education content, the team scripted videos specifically tailored to the primary care environment, and especially to the realities of rural practice. The central video was delivered by a rural-setting PCP who described her extensive firsthand experience treating patients with buprenorphine, directly confronting the negative perceptions and practical barriers that clinicians most often raise. Supplementary videos were designed around two distinct motivational pathways: one emphasizing external motivation, such as clinic-level and societal benefits of expanding MOUD access, and the other emphasizing internal motivation, including the personal and professional rewards of treating addiction.

Methodologically, the study took the form of cross-sectional surveys administered through a continuing education platform alongside the videos. Participation was open to family and internal medicine professionals in Kentucky, including physicians, doctors of osteopathy, advanced practice registered nurses, and physician assistants. The survey instrument captured demographic information and career satisfaction, and used a Post/Retrospective-Pre format to assess change in the perceived importance of 19 distinct barriers to MOUD practice, along with confidence in four relevant practice areas. The retrospective-pre design asks respondents to rate their views before the intervention in hindsight after completing it, a technique that can capture shifts that participants might not have recognized in real time. The primary outcome was the learner’s stated intention to explore MOUD, while secondary measures rated the educational content for gains in clinical knowledge and skills and for usefulness of information.

The results, though drawn from a modest sample of 37 professional learners, were statistically meaningful. After viewing the videos, participants rated several prominent barriers as significantly less important, including concern about negative attitudes and perceptions across the practice, spanning staff, other practitioners, and patients; limited appointment time; and reimbursement of clinical visits. Fisher’s non-parametric tests yielded p-values at or below 0.05 for these reductions, suggesting the changes were unlikely to be due to chance alone. Perhaps most strikingly, the intervention appeared to touch something deeper than logistics: participants reported a strengthened sense that offering MOUD fits with one’s calling as a physician, an internal-motivation construct that the supplementary videos were explicitly designed to activate.

Behavioral intentions shifted as well. Viewers reported an increased likelihood to screen patients for opioid use disorder, a critical first step in the treatment cascade, since undiagnosed opioid use disorder cannot be treated. The study also uncovered an intriguing correlate: practitioners who scored higher on career satisfaction were more likely to consider board certification as an Addiction Medicine Specialist. This finding hints that clinician well-being and workforce development in addiction medicine may be intertwined, and that educational interventions could be tailored to leverage the professional fulfillment that many physicians derive from treating a condition they once avoided.

Open-ended feedback collected in the survey added qualitative texture to the quantitative findings, probing viewers’ reactions to specific aspects of the video content and its general impact. While the published abstract does not detail individual responses, the inclusion of these questions reflects a deliberate effort to understand not just whether the videos worked, but why, information that will be essential for scaling the approach beyond a single state. The educational content itself was rated positively for gains in clinical knowledge and skills and for the usefulness of the information presented, suggesting the format succeeded as continuing education even before its attitudinal effects are considered.

The significance of this work lies less in any single statistic than in its proof of concept. Expanding buprenorphine access has been a federal policy priority for years, with regulatory reforms eliminating the former X-waiver requirement and encouraging mainstreaming of addiction treatment into general medicine. Yet policy change alone has not moved the needle far enough, because the remaining barriers are psychological and cultural as much as regulatory. By demonstrating that brief, peer-delivered, behaviorally targeted video education can reduce the perceived salience of those barriers, the Kentucky team offers a low-cost, scalable template. A rural physician speaking to her peers in their own professional language may accomplish what guidelines and mandates have not.

The study’s limitations invite caution. With 37 participants drawn from a single state through a continuing education platform, the sample is small and self-selected; clinicians motivated enough to watch addiction-focused education may already be predisposed toward MOUD. The cross-sectional design cannot establish long-term durability of attitude change, and stated intention to explore MOUD does not guarantee that viewers will ultimately obtain the training and workflow supports needed to prescribe. Still, the authors conclude that education conceived for and specifically responsive to the primary care environment, and especially to the challenges of rural practice, can help overcome perceived barriers and promote consideration of MOUD service in primary care settings. In a crisis that claims tens of thousands of American lives annually, converting even a fraction of the nation’s primary care clinicians into buprenorphine prescribers could translate directly into saved lives, and this study suggests the conversion may begin with nothing more complicated than a colleague telling her story on camera.

Subject of Research: Impact of targeted educational videos on primary care practitioners' attitudes and intentions toward providing buprenorphine for opioid use disorder

Article Title: Changing minds on MOUD: impact of messages to motivate expanded access to buprenorphine in primary care settings

Article References: Changing minds on MOUD: impact of messages to motivate expanded access to buprenorphine in primary care settings. (n.d.). https://doi.org/10.1186/s13722-026-00719-6

Image Credits: AI Generated

DOI: 10.1186/s13722-026-00719-6

Keywords: buprenorphine, opioid use disorder, primary care, MOUD, rural health, continuing education, behavior change, addiction medicine, clinician attitudes, Kentucky, cross-sectional survey, career satisfaction