Severe Withdrawal Research Articles

ADVANCEMENTS IN UNDERSTANDING AND MANAGING ALCOHOL WITHDRAWAL SYNDROME: A COMPREHENSIVE REVIEW

Alcohol withdrawal syndrome (AWS) is a clinically significant condition that can arise upon abrupt cessation or reduction of alcohol consumption in individuals with alcohol dependence. This review article provides a comprehensive overview of AWS, encompassing its epidemiology, pathophysiology, clinical manifestations, assessment tools, and management strategies. We discuss the neurobiological mechanisms underlying AWS, including the role of neurotransmitter systems such as gamma-aminobutyric acid (GABA) and glutamate, as well as neuroadaptive changes that occur with chronic alcohol use. Furthermore, we explore the spectrum of clinical manifestations associated with AWS, ranging from mild withdrawal symptoms to severe complications such as delirium tremens and seizures. Diagnostic tools and scoring systems commonly used for assessing AWS severity are examined, along with evidence-based approaches for pharmacological and non-pharmacological management of AWS. Additionally, we highlight emerging research areas and future directions in the field of AWS, including novel treatment modalities and potential biomarkers for predicting withdrawal severity and treatment response. This comprehensive review aims to provide clinicians, researchers, and healthcare professionals with a thorough understanding of AWS to facilitate early recognition, appropriate management, and improved outcomes for individuals affected by this condition.

Severe alcohol withdrawal during pregnancy or early postpartum: maternal and fetal outcomes.

Alcohol withdrawal syndrome (AWS) during pregnancy is under-researched despite growing concerns about increased alcohol use among pregnant women. This study aims to explore the severity of AWS and its impact on maternal and fetal outcomes. This retrospective study reviewed the medical records of patients admitted to the Mayo Clinic who underwent the CIWA-Ar protocol for AWS from June 2019 through June 2022. Pregnant women identified in this cohort had their pregnancy, labor, and neonatal data analyzed for alcohol-related complications and outcomes. Out of the medical records reviewed, 8 cases involved pregnant women experiencing AWS. These cases showed a high severity of withdrawal symptoms, with a median peak CIWA-Ar score of 17 (IQR = 14). Maternal complications included a high rate of ICU admissions (37.5%; n = 3) and significant rates of miscarriage and stillbirth (37.5%; n = 3). Fetal outcomes were concerning, with 1 out of 5 (20%) neonates requiring NICU admission and experiencing conditions such as respiratory failure and neonatal abstinence syndrome. Developmental problems were noted in 2 out of 5 (40%) newborns. The findings highlight the severe implications of AWS during pregnancy, impacting both maternal and fetal health. The severity of AWS requires attentive clinical management and preventative interventions. Future research should focus on larger, prospective studies to better understand and address the risks associated with AWS in pregnant women and to improve health outcomes for mothers and their children. • Severe AWS during pregnancy leads to high ICU admissions and adverse neonatal outcomes. • 37.5% of pregnant women with AWS experienced miscarriage or stillbirth. • 20% of newborns from mothers with AWS required NICU admission for serious conditions; 40% of newborns had developmental problems. • Findings underscore the need for specialized treatment protocols to improve outcomes for pregnant women and their newborns.

Prevalence, Patterns and Predictors of Prescribing Medications for Opioid Use Disorder (MOUD) in the Inpatient Setting

BackgroundThere are many barriers to prescribing medications for opioid use disorder (MOUD). This study evaluates the prevalence, patterns, and predictors of inpatient MOUD prescribing at discharge to patients with a diagnosis of opioid use/opioid use disorder (OUD) that developed opioid withdrawal during their hospital stay. MethodsThis multicenter, retrospective cross-sectional study occurred at three hospitals in Arizona. Patients who developed opioid withdrawal during their hospitalization and had a documented opioid-related disorder between January 1, 2021, and January 1, 2022, were included in the study. Patient-specific factors were evaluated as predictors of MOUD prescribing at hospital discharge using descriptive, multivariate regression. ResultsA total of 382 encounters were included; 249 had documented OUD (65.2%), 75 of which were discharged with MOUD (75/249; 30.1%). Patients with moderate/moderately severe opioid withdrawal had higher odds of being discharged with MOUD compared to those with mild opioid withdrawal (OR 2.87 [1.44-5.69], p=0.003). Patients admitted to the largest hospital in Phoenix had higher odds of being prescribed MOUD compared to the largest hospital in Tucson (OR 8.23 [3.02-22.49], p<0.001), as were patients who underwent a routine discharge compared to patient directed discharges (7.63 [2.35-24.71], p=0.001). ConclusionsLess than one-third of patients with OUD that developed opioid withdrawal during their hospitalization were prescribed MOUD at discharge. Treatment facility, opioid withdrawal severity, and discharge disposition were predictors of MOUD prescribing. Inpatient health-systems and policymakers may consider these data when developing policies/procedures aimed at increasing MOUD prescribing rates.

Hikikomori in the Middle East: The role of problematic gaming, social media use, and loneliness

Hikikomori, a form of severe social withdrawal has been found to be associated with behavioral addictions such as gaming addiction and problematic social media use (PSMU). Since literature related to hikikomori is lacking in the Middle East, this study aimed to determine whether there are significant differences in hikikomori-like traits between two different types of social media users and gamers and investigate loneliness as a potential mediator between hikikomori and the two types of problematic behaviors. A cross-sectional, correlational design was employed, collecting a final sample of 220 participants residing in Middle Eastern countries using a mixture of convenience and snowball sampling. Results showed that passive social media users demonstrated significantly greater hikikomori-like traits compared to active users. Furthermore, hikikomori-like traits exhibited significant positive associations with problematic gaming, PSMU, and loneliness. Two separate mediation analyses, the first with PSMU and a second with problematic gaming as predictors, revealed that loneliness acted as a significant mediator between both these problematic behaviors and hikikomori-like traits.

A case report of benzodiazepine withdrawal delirium due to accidental discontinuation of benzodiazepines in cancer perioperative period.

Benzodiazepines are known for their possible risk of delirium, especially when administered to older adults or during the perioperative period. However, the risk of sudden discontinuation of benzodiazepines and subsequent withdrawal delirium seems to be underappreciated and not properly recognized in cancer treatment, even among healthcare workers. A man in his late 70s was diagnosed with rectal cancer and had a history of taking etizolam and alprazolam for over 15 years. After hospitalization for cancer, these benzodiazepines were discontinued abruptly 2 days before the surgery, due to concerns about benzodiazepine-related delirium. After half a day, severe benzodiazepine withdrawal symptoms, such as disorientation, agitation, tachycardia, diaphoresis, and muscle twitching, appeared. The patient was diagnosed with delirium associated with benzodiazepine withdrawal, and his symptoms subsided soon after re-administration of benzodiazepines. Despite development of mild postoperative delirium, the operation was performed safely. The rapid and abrupt discontinuation of benzodiazepines before cancer surgery could impose a high risk of benzodiazepine withdrawal delirium in patients, which makes the management of psychiatric symptoms in the perioperative period more complex and difficult. We believe that it is necessary to highlight the risks of withdrawal delirium and abrupt benzodiazepine discontinuation in cancer treatment. Moreover, re-education on this topic is essential for healthcare workers.

Relationship of Biochemical and Hematological Markers With Alcohol Withdrawal Severity

Relationship of Biochemical and Hematological Markers With Alcohol Withdrawal Severity

The ultrasonic vocalization (USV) syllable profile during neonatal opioid withdrawal and a kappa opioid receptor component to increased USV emissions in female mice.

Opioid use during pregnancy can lead to negative infant health outcomes, including neonatal opioid withdrawal syndrome (NOWS). NOWS comprises gastrointestinal, autonomic nervous system, and neurological dysfunction that manifest during spontaneous withdrawal. Variability in NOWS severity necessitates a more individualized treatment approach. Ultrasonic vocalizations (USVs) in neonatal mice are emitted in isolation as a stress response and are increased during opioid withdrawal, thus modeling a negative affective state that can be utilized to test new treatments. We sought to identify the behavioral and USV profile, brainstem transcriptomic adaptations, and role of kappa opioid receptors in USVs during neonatal opioid withdrawal. We employed a third trimester-approximate opioid exposure model, where neonatal inbred FVB/NJ pups were injected twice-daily with morphine (10mg/kg, s.c.) or saline (0.9%, 20 ul/g, s.c.) from postnatal day(P) 1 to P14. This protocol induces reduced weight gain, hypothermia, thermal hyperalgesia, and increased USVs during spontaneous morphine withdrawal. On P14, there were increased USV emissions and altered USV syllables during withdrawal, including an increase in Complex 3 syllables in FVB/NJ females (but not males). Brainstem bulk mRNA sequencing revealed an upregulation of the kappa opioid receptor (Oprk1), which contributes to withdrawal-induced dysphoria. The kappa opioid receptor (KOR) antagonist, nor-BNI (30 mg/kg, s.c.), significantly reduced USVs in FVB/NJ females, but not males during spontaneous morphine withdrawal. Furthermore, the KOR agonist, U50,488h (0.625 mg/kg, s.c.), was sufficient to increase USVs on P10 (both sexes) and P14 (females only) in FVB/NJ mice. We identified an elevated USV syllable, Complex 3, and a female-specific recruitment of the dynorphin/KOR system in increased USVs associated with neonatal opioid withdrawal severity.

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

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

Phenobarbital Versus Benzodiazepines for Alcohol Withdrawal in the Medical Intensive Care Unit (ICU): A Retrospective Cohort Study.

Background: Phenobarbital (PHB) is a safe and efficacious alternative to benzodiazepines (BZD) for treating severe alcohol withdrawal (AWS). However, the safety of utilizing PHB for patients initially treated with BZD is unknown. Objective: To evaluate the safety and efficacy of PBH compared to BZDs in severe AWS in the medical intensive care unit (ICU). Methods: This was a retrospective cohort study comparing critically ill patients admitted for AWS who received BZDs or PHB. The primary outcome was time to persistent resolution of altered mentation. Secondary outcomes included development and duration of delirium, need for mechanical ventilation, development of withdrawal seizures, and ICU and hospital length of stay. Results: Ninety-five patients were evaluated (53 in PHB group, 42 in BZD group). Before study medication, less BZD patients demonstrated abnormal mentation compared with PHB patients (RASS < -2: 2.39% vsvs. 28.12%, respectively, and RASS > +2: 9.9% vsvs. 48.76%; P <0.001 for both). No difference was seen between groups for the primary outcome (1.8 hours for BZD cohort vsvs. 13.81 hours for PHB cohort; P =0.22). More patients in the BZD cohort developed a seizure after study medication administration (5.67% vs 0%, respectively; P =0.02). No significant difference was seen in other secondary outcomes. Conclusions: This study provides support for use of PHB after BZD if patients remain in uncontrolled withdrawal. Despite significant doses of BZDs before PHB, patients in the PHB cohort demonstrated similar clinical and safety outcomes compared to BZD alone.

Buprenorphine-Precipitated Withdrawal Among Hospitalized Patients Using Fentanyl

Buprenorphine treatment of opioid use disorder (OUD) is safe and effective, but opioid withdrawal during treatment initiation is associated with poor retention in care. As fentanyl has replaced heroin in the drug supply, case reports and surveys have indicated increased concern for buprenorphine-precipitated withdrawal (PW); however, some observational studies have found a low incidence of PW. To estimate buprenorphine PW incidence and assess factors associated with PW among emergency department (ED) or hospitalized patients. This retrospective cohort study at 3 academic hospitals in Philadelphia, Pennsylvania, included adults with OUD who underwent traditional or high-dose buprenorphine initiation between January 1, 2020, and December 31, 2021. Exclusion criteria included low-dose buprenorphine initiation and missing documentation of opioid withdrawal severity within 4 hours of receiving buprenorphine. Buprenorphine initiation with an initial dose of at least 2 mg of sublingual buprenorphine after a Clinical Opiate Withdrawal Scale (COWS) score of 8 or higher. Additional exposures included 4 predefined factors potentially associated with PW: severity of opioid withdrawal before buprenorphine (COWS score of 8-12 vs ≥13), initial buprenorphine dose (2 vs 4 or ≥8 mg), body mass index (BMI) (<25 vs 25 to <30 or ≥30; calculated as weight in kilograms divided by height in meters squared), and urine fentanyl concentration (0 to <20 vs 20 to <200 or ≥200 ng/mL). The main outcome was PW incidence, defined as a 5-point or greater increase in COWS score from immediately before to within 4 hours after buprenorphine initiation. Logistic regression was used to estimate the odds of PW associated with the 4 aforementioned predefined factors. The cohort included 226 patients (150 [66.4%] male; mean [SD] age, 38.6 [10.8] years). Overall, 26 patients (11.5%) met criteria for PW. Among patients with PW, median change in COWS score was 9 points (IQR, 6-13 points). Of 123 patients with confirmed fentanyl use, 20 (16.3%) had PW. In unadjusted and adjusted models, BMI of 30 or greater compared with less than 25 (adjusted odds ratio [AOR], 5.12; 95% CI, 1.31-19.92) and urine fentanyl concentration of 200 ng/mL or greater compared with less than 20 ng/mL (AOR, 8.37; 95% CI, 1.60-43.89) were associated with PW. In this retrospective cohort study, 11.5% of patients developed PW after buprenorphine initiation in ED or hospital settings. Future studies should confirm the rate of PW and assess whether bioaccumulated fentanyl is a risk factor for PW.

Revisiting dezocine for opioid use disorder: A narrative review of its potential abuse liability.

Opioid use disorder (OUD) remains a serious public health problem. Opioid maintenance treatment is effective but under-utilized, hard to access under existing federal regulations, and, once patients achieve OUD stability, challenging to discontinue. Fewer than 2% of persons with OUD stop using opioids completely. There have been calls from public advocacy groups, governmental agencies, and public health officials for new treatments for OUD. Dezocine, a non-scheduled opioid previously used in the United States and currently widely prescribed in China for pain management, could be a candidate for a novel OUD treatment medication in the U.S. Nonetheless, to date, there have been no reviews of the clinical and preclinical literature detailing dezocine's abuse potential, a key consideration in assessing its clinical utility. There are no English language reports of human abuse, dependence, or overdose of dezocine, despite years of extensive clinical use. There are a few case reports of dezocine abuse in the Chinese literature, but there are no reports of overdose deaths. Dezocine is perceived as an opioid and is "liked" by opioid-experienced human and non-human primates, properties that are not dose-dependent and are mitigated by ceiling effects-higher doses do not result in more "liking." There is little withdrawal, spontaneous or precipitated, in humans, monkeys, rats, or mice treated chronically with dezocine alone. However, at some doses, dezocine can precipitate withdrawal in humans and monkeys dependent on other opioids. In rodents, dezocine reduces the severity of morphine withdrawal and the rewarding properties of other opioids. Although dezocine is reinforcing in humans and monkeys with prior or concurrent opioid use within a restricted dose range, there are only a few anecdotal reports of dezocine abuse despite of the long history of use in humans. Given the evidence of dezocine's limited abuse potential, it could be useful both as a treatment for OUD. However, in-depth studies would be required for dezocine to be re-considered for clinical use.

The ultrasonic vocalization (USV) syllable profile during neonatal opioid withdrawal and a kappa opioid receptor component to increased USV emissions in female mice.

Opioid use during pregnancy can lead to negative infant health outcomes, including neonatal opioid withdrawal syndrome (NOWS). NOWS comprises gastrointestinal, autonomic nervous system, and neurological dysfunction that manifest during spontaneous withdrawal. Variability in NOWS severity necessitates a more individualized treatment approach. Ultrasonic vocalizations (USVs) in neonatal mice are emitted in isolation as a stress response and are increased during opioid withdrawal, thus modeling a negative affective state that can be utilized to test new treatments. We sought to identify the behavioral and USV profile, brainstem transcriptomic adaptations, and role of kappa opioid receptors in USVs during neonatal opioid withdrawal. We employed a third trimester-approximate opioid exposure model, where neonatal inbred FVB/NJ pups were injected twice-daily with morphine (10mg/kg, s.c.) or saline (0.9%, 20 ul/g, s.c.) from postnatal day(P) 1 to P14. This protocol induces reduced weight gain, hypothermia, thermal hyperalgesia, and increased USVs during spontaneous morphine withdrawal. On P14, there were increased USV emissions and altered USV syllables during withdrawal, including an increase in Complex 3 syllables in FVB/NJ females (but not males). Brainstem bulk mRNA sequencing revealed an upregulation of the kappa opioid receptor (Oprk1), which contributes to withdrawal-induced dysphoria. The kappa opioid receptor (KOR) antagonist, nor-BNI (30 mg/kg, s.c.), significantly reduced USVs in FVB/NJ females, but not males during spontaneous morphine withdrawal. Furthermore, the KOR agonist, U50,488h (0.625 mg/kg, s.c.), was sufficient to increase USVs on P10 (both sexes) and P14 (females only) in FVB/NJ mice. We identified an elevated USV syllable, Complex 3, and a female-specific recruitment of the dynorphin/KOR system in increased USVs associated with neonatal opioid withdrawal severity.

Saliva Lipids May Determine Alprazolam Toxicity: An FTIR Study

Background: Alprazolam, a commonly prescribed benzodiazepine, poses risks of toxicity and severe withdrawal symptoms. There is an urgent need for a rapid and sensitive diagnostic method for detecting alprazolam poisoning. Objectives: This study aimed to detect alprazolam poisoning through Fourier-transform infrared (FTIR) analysis of saliva, addressing the need for a quick, cost-effective, and sensitive diagnostic method for poison control and differential diagnosis. Methods: Saliva samples were collected from 45 individuals with benzodiazepine toxicity, therapeutic consumption, and normal health status, as well as from a control group. The samples were analyzed using FTIR spectroscopy. The resulting spectra were processed with OriginPro software, and statistical analyses were performed using receiver operating characteristic (ROC) and analysis of variance (ANOVA). Results: The average age of the studied population was approximately 45 years, with women being the most affected by poisoning. Fourier-transform infrared analysis revealed significant differences in the structure of lipids between poisoned individuals, therapeutic receivers, and healthy individuals (P &lt; 0.0001). Conclusions: Fourier-transform infrared analysis of saliva is a fast and accurate method for diagnosing alprazolam poisoning within minutes, enabling prompt and appropriate treatment during critical life-threatening situations. This non-invasive technique has the potential to guide treatment staff toward effective treatment options.

Diurnal sex differences in morphine withdrawal revealed by continuous assessment of voluntary home cage wheel running in the rat

Animal studies modeling recreational opioid use show more severe withdrawal symptoms in male compared to female rats, whereas our study modeling opioid use for pain showed a greater withdrawal-induced decrease in wheel running in female rats. The objective of this experiment was to determine whether sex differences in spontaneous morphine withdrawal are caused by differences in assessment method (i.e., wheel running vs. somatic symptoms). Twice daily injections of morphine (5 – 20 mg/kg, s.c.) for 5 days produced a dose and time dependent decrease in wheel running that was greater in male compared to female rats. Termination of morphine administration resulted in an overall decrease in running and a decrease in the amount of running during the dark phase of the light cycle from 95 % to approximately 75 %. In male rats, this decrease in the percent of dark running was caused by a large decrease in dark phase running, whereas female rats had a slightly higher increase in light phase running. Withdrawal also reduced maximal running speed and caused a decrease in body weight that was larger in male than female rats. Withdrawal symptoms were greatest on the day following the last morphine injection, but persisted for all 3 days of assessment. Morphine withdrawal produced a greater decrease in dark phase wheel running and body weight in male rats and a greater increase in light phase running in female rats. Voluntary home cage wheel running provides a continuous measure of opioid withdrawal that is consistent with other measures of opioid withdrawal.

Implementation of an Evidence-Based Treatment Protocol and Order Set for Alcohol Withdrawal Syndrome.

Alcohol withdrawal syndrome (AWS) is highly prevalent in hospital inpatients. Recent evidence supports use of phenobarbital and gabapentin in certain patients, and screening tools for severe withdrawal risk can be used to guide care. Inpatients with AWS should also be considered for evidence-based treatment for alcohol use disorder (AUD). The purpose of this quality improvement study was to monitor clinical outcomes and prescribing habits after updating an electronic order set for inpatient AWS management at a large, academic hospital. Protocol updates included use of the Prediction of Alcohol Withdrawal Severity Scale, phenobarbital and gabapentin protocols, and linkage to treatment resources. Data were collected for 10 months before and 14 months after implementation. Intensive care unit (ICU) transfer rate decreased by 2.3%, whereas length of stay and readmissions were not significantly different. In patients treated with the order set, ICU transfer and length of stay outcomes were superior. Patients treated through the order set were more likely to receive evidence-based treatment for AWS and AUD. Electronic order sets can promote evidence-based practice for AWS. The updated protocol will remain in place at the study institution, with future efforts focused on education and ease of use to increase order set utilization.

Increased risk of severe neonatal opioid withdrawal syndrome in pregnancies with low placental ABCB1 DNA methylation.

Neonatal opioid withdrawal syndrome (NOWS) is unpredictable. We assessed relationships between placental DNA methylation with in-utero opioid exposure and NOWS severity. Secondary analysis of a prospective multicenter cohort study of pregnancies on methadone or buprenorphine, ≥34 weeks, singleton, 18 or greater. Placental biopsies were collected. Placental DNA methylation levels of ABCG1, ABCG2, CYP19A1, and HSD11B2 were quantified via pyrosequencing following bisulfite conversion. CYP19A1 mRNA levels and umbilical cord drug levels were determined by RT-qPCR and LC-MS respectively. Severe NOWS was diagnosed through Finnegan scoring. P value < 0.05 was significant. Thirty-eight dyads were included. Promoter region methylation for placental ABCB1 was lower in severe NOWS compared to non-severe NOWS (p = 0.04). Placental CYP19A1 methylation was inversely related to CYP19A1 mRNA levels and associated with umbilical cord norbuprenorphine levels (p < 0.01), but not umbilical cord methadone levels. Lower placental ABCB1 methylation was associated with severe NOWS. Higher placental CYP19A1 methylation correlated with higher umbilical cord norbuprenorphine levels.

Efficacy of transdermal buprenorphine patch for managing withdrawal symptoms in patients with cancer physically dependent on prescription opioids.

The physical dependence on prescription opioids among cancer survivors remains an under-investigated area, with a scarcity of well-designed prospective studies. This single-arm, phase-2 clinical trial in Korea assessed the efficacy and safety of a transdermal buprenorphine patch (TBP) in managing physical dependence on prescription opioids in cancer survivors, as confirmed through the DSM-5 criteria or psychiatric consultation for opioid withdrawal. This study involved a 4-phase treatment protocol of screening, induction/stabilization, discontinuation, and monitoring. The primary outcome was the rate of successful opioid discontinuation, as measured by a negative urine-drug screening at 8 weeks. Key secondary outcomes included the resumption of prescribed opioids, changes in both the Clinical Opioid Withdrawal Scale (COWS) and morphine equivalent daily dose (MEDD), and assessments related to the psychological and physiological aspects of dependence and safety. Thirty-one participants were enrolled. In the intention-to-treat population, the success rate of opioid discontinuation was 58%, with only 2 participants experiencing a resumption of prescribed opioids. Significant reductions were observed in MEDD, which decreased from 98 to 26mg/day (P < .001), and COWS scores, which decreased from 5.5 to 2.8 (P < .001). Desire to use opioids reduced from 7.0 to 3.0 on a 10-point numeric rating scale (P < .001). Toxicities related to TBP were mild and manageable, without severe precipitated withdrawal symptoms. TBP may be considered as an alternative therapeutic option in cancer survivors physically dependent on prescription opioids, especially where sublingual formulations are unavailable.

Extended-Release 7-Day Injectable Buprenorphine for Patients With Minimal to Mild Opioid Withdrawal

Buprenorphine is an effective yet underused treatment for opioid use disorder (OUD). To evaluate the feasibility (acceptability, tolerability, and safety) of 7-day injectable extended-release buprenorphine in patients with minimal to mild opioid withdrawal. This nonrandomized trial comprising 4 emergency departments in the Northeast, mid-Atlantic, and Pacific geographic areas of the US included adults aged 18 years or older with moderate to severe OUD and Clinical Opiate Withdrawal Scale (COWS) scores less than 8 (minimal to mild), in which scores range from 0 to 7, with higher scores indicating increasing withdrawal. Exclusion criteria included methadone-positive urine, pregnancy, overdose, or required admission. Outcomes were assessed at baseline, daily for 7 days by telephone surveys, and in person at 7 days. Patient recruitment occurred between July 13, 2020, and May 25, 2023. Injection of a 24-mg dose of a weekly extended-release formulation of buprenorphine (CAM2038) and referral for ongoing OUD care. Primary feasibility outcomes included the number of patients who (1) experienced a 5-point or greater increase in the COWS score or (2) transitioned to moderate or greater withdrawal (COWS score ≥13) within 4 hours of extended-release buprenorphine or (3) experienced precipitated withdrawal within 1 hour of extended-release buprenorphine. Secondary outcomes included injection pain, satisfaction, craving, use of nonprescribed opioids, adverse events, and engagement in OUD treatment. A total of 100 adult patients were enrolled (mean [SD] age, 36.5 [8.7] years; 72% male). Among the patients, 10 (10.0% [95% CI, 4.9%-17.6%]) experienced a 5-point or greater increase in COWS and 7 (7.0% [95% CI, 2.9%-13.9%]) transitioned to moderate or greater withdrawal within 4 hours, and 2 (2.0% [95% CI, 0.2%-7.0%]) experienced precipitated withdrawal within 1 hour of extended-release buprenorphine. A total of 7 patients (7.0% [95% CI, 2.9%-13.9%]) experienced precipitated withdrawal within 4 hours of extended-release buprenorphine, which included 2 of 63 (3.2%) with a COWS score of 4 to 7 and 5 of 37 (13.5%) with a COWS score of 0 to 3. Site pain scores (based on a total pain score of 10, in which 0 indicated no pain and 10 was the worst possible pain) after injection were low immediately (median, 2.0; range, 0-10.0) and after 4 hours (median, 0; range, 0-10.0). On any given day among those who responded, between 29 (33%) and 31 (43%) patients reported no cravings and between 59 (78%) and 75 (85%) reported no use of opioids; 57 patients (60%) reported no days of opioid use. Improving privacy (62%) and not requiring daily medication (67%) were deemed extremely important. Seventy-three patients (73%) were engaged in OUD treatment on day 7. Five serious adverse events occurred that required hospitalization, of which 2 were associated with medication. This nonrandomized trial of the feasibility of a 7-day buprenorphine injectable in patients with minimal to mild opioid withdrawal (COWS scores, 0-7) found the formulation to be acceptable, well tolerated, and safe in those with COWS scores of 4 to 7. This new medication formulation could substantially increase the number of patients with OUD receiving buprenorphine. ClinicalTrials.gov Identifier: NCT04225598.

Diagnosis and Treatment of Presumed Naltrexone-XR-precipitated Opioid Withdrawal in a Patient Chronically Treated With Buprenorphine-XR: A Case Report.

Naltrexone, buprenorphine, and methadone are Food and Drug Administration-approved medications for the treatment of opioid use disorder in the United States. Naltrexone, an opioid antagonist, can precipitate opioid withdrawal if administered too quickly after the use of full or partial opioid agonists for those with either dependence or use disorder. We describe a case of severe precipitated opioid withdrawal syndrome after reported buprenorphine extended-release (XR) administration, despite the patient having been stable on buprenorphine-XR for several years, with no missed doses or recent opioid use. Naltrexone levels were sent and helped to diagnose suspected inadvertent naltrexone-XR administration in this patient, which was likely the etiology of his precipitated opioid withdrawal syndrome. We suggest the use of high-dose buprenorphine, as well as adjunctive medications including benzodiazepines, as a treatment strategy for naltrexone-XR precipitated withdrawal in the setting of chronic buprenorphine-XR treatment.

How Should Risks and Benefits of Short-Acting Opioids Be Evaluated in the Care of Inpatients With OUD?

Severe opioid withdrawal, risk of patient-initiated discharge, and some inpatients' use of unregulated substances prompt clinical and ethical questions considered in this commentary on a case. Short-acting opioids can be used to manage inpatients' pain and opioid use disorder (OUD) withdrawal symptoms. Including evidence-based interventions-such as naloxone kits, substance use equipment, and supervised consumption-in some inpatients' care plans may make those patients safer and reduce their risk of death. These and other strategies align with clinicians' ethical duties to minimize harms and maximize benefits for inpatients with OUD.