Opioid Withdrawal Research Articles

To assess documented substance use indicators and the probable role of substance use disorders (SUDs) in deaths occurring in US Immigration and Customs Enforcement (ICE) custody between April 2018 and May 2025. A retrospective cross-sectional review was conducted using all 69 publicly available ICE Detainee Death Reviews (DDRs) during the study period. Medically licensed reviewers analyzed each DDR for documented substance use indicators, clinical screening or diagnosis, referral, treatment, and emergency response. Additional variables included demographic information, psychiatric symptoms, and access to medical or mental health care. Among 27 deaths involving a probable substance use history or related medical/psychiatric conditions, none showed documentation of SUD diagnosis, referral, or evidence-based treatment. Nine individuals (33.3%) died from complications potentially related to untreated substance use, including opioid and alcohol withdrawal. Over half of these cases showed documented signs of delayed emergency response. Although DDRs frequently noted patient "refusal" of care (n=11), none documented formal assessments of decision-making capacity. Most individuals in the sample had resided in the United States for over 2 decades before ICE detention. Our findings reveal probable gaps in the documented identification and treatment of SUD among individuals who died in ICE custody. Standardized behavioral health protocols, timely emergency response, and greater transparency are needed to address substance-related risks in immigration detention settings.

Treatment and recovery from opioid use disorder: The role of pain severity in individuals with moderate to severe pain.

Antibiotic treatment improves gut dysbiosis and depression-like behavior induced by morphine withdrawal.

Perinatal fentanyl exposure drives enduring addiction risk and central amygdala gene dysregulation.

The successful use of buprenorphine to manage kratom withdrawal secondary to self-treatment of opioid withdrawal

Objectives: Prolonged opioid use leads to tolerance and hyperalgesia in patients with chronic pain. Apart from an increase in pain, opioid use also leads to several other adverse effects. Nevertheless, the prevalence of opioid use as a treatment for chronic pain remains high, and opioid withdrawal interventions deserve more attention. This study evaluates the effects of a guideline for an opioid withdrawal intervention method that is nested in cognitive behavioral treatment (CBT) and is specifically for patients with a history of long-term opioid use and chronic pain. Methods: We conducted a clinical, exploratory, and mixed-methods study involving pre- and post-measurements on opioid use and health-related quality of life (SF-36), as well as a qualitative analysis of patient experiences (interviews) to evaluate the program. Results: A total of 29 patients were included in the study; 23 of these patients no longer used opioids, and some continued withdrawal under the guidance of their general practitioner. Quality of life improved in all domains, including the amount of pain experienced. No patients reported increased pain levels, and most experienced significantly fewer adverse side effects. Patient satisfaction was high, with no negative long-term side effects of the intervention reported. Conclusions: In light of the results of this study, it is important to address opioid use in patients with chronic pain. There are strong arguments in favor of motivating patients to withdraw from using opioids to treat chronic pain, which can be achieved in combination with CBT.

The increasing prevalence of opioid use disorder (OUD) represents an important global public health crisis, often referred to as the 'opioid epidemic'. Opioids are known for their potent pain-relieving effects, but also have serious side effects, including OUD and respiratory depression, which can lead to fatal overdoses. To address this growing concern, we require a better understanding of the mechanisms underlying OUD, which typically begins with either medical or recreational opioid use and evolves into a complex and chronic brain disorder. In this Review, we highlight recent advances in our understanding of opioid receptors and the neural circuits in which they operate (including the broad network of circuits involved in reward and relief processing), focusing on the changes that follow long-term opioid exposure, abstinence and withdrawal. Additionally, we discuss recent findings that highlight the importance of the local cellular environment in shaping responses to these drugs. Overall, we aim to provide an updated overview of the field that may give us new insights into the multifaceted landscape of OUD.

Postictal Catatonia Following Opioid Withdrawal Seizure: A Case Report

Assessing the Cardiac Safety of a Multimodal Protocol for 'Tranq Dope' Withdrawal: A Retrospective QTc Analysis.

Antenatal Exposure to Medication for Opioid Use Disorder and Infant Outcomes in the ESC-NOW Randomized Controlled Trial.

BackgroundReducing opioid use is challenging due to limited evidence-based weaning methods and a lack of interventions to mitigate withdrawal symptoms. An emerging intervention using transcutaneous auricular neurostimulation (tAN) is being developed to reduce opioid withdrawal symptoms, but its mechanisms of action are not yet well understood. This is a clinical trial performed to investigate the mechanisms of tAN in managing pain and opioid withdrawal during opioid taper in adults with chronic pain.MethodsThis is a single-site, randomized, double-blind, and sham-controlled superiority framework trial during an inpatient opioid taper for participants on long-term opioid therapy for chronic pain. Participants are recruited for an inpatient stay at a large, academic medical center in the United States. Included participants are adults between 18 and 75 years of age who have the presence of pain more than half of the days in the past 6 months, are prescribed opioid medication, have a willingness to taper the opioid dose by at least 10%, and have a urine drug screen positive for the prescribed opioid but negative for illicit drugs and nonprescribed opioids. Participants are excluded with a condition affecting their safety of participation (e.g., epileptic seizures, current suicidal ideation, current abuse of illicit drugs or alcohol, pregnancy), a condition that precludes fMRI assessment (implanted medical device, claustrophobia), or a status affecting pain medication intake (e.g., surgery in the past month, opioid prescription dose > 200 morphine milligram equivalents per day, history of neurological diseases or traumatic brain injury, active treatment for cancer).Participants are randomized to receive either active tAN (n = 20) or sham tAN (n = 20). Both groups undergo a mild-to-moderate opioid taper on day 1 and are maintained at the reduced level for 4 days under inpatient medical supervision. The primary outcome measure, brain functional magnetic resonance imaging (fMRI), is used to measure BOLD signals and resting functional connectivity (z-value) of pain networks. Secondary outcome measures are self- and clinician-observed opioid withdrawal scales, behavioral assessment questionnaires, and quantitative sensory testing (QST) data.The first subject enrollment was completed from July 25 to 28, 2023. The total enrollment count was set to 40 with two arms of equal ratios. Randomization stratification by gender at birth was performed. The study physician, intervention-providing staff member, and outcome-assessing study coordinator each perform recruitment, and each is blinded to treatment group assignment.Safety and harm measures of opioid withdrawal will be assessed with the Clinical and Subject-reported Opiate Withdrawal Scores. Vital signs will be assessed three times per day, and adverse events will be recorded and reported as necessary.DiscussionUnderstanding the mechanisms of action of tAN will lead to the development of more effective future non-pharmacologic treatments in mitigating withdrawal while gradually tapering participants off prescription opioid management.Trial registrationClinicaltrials.gov, NCT05555485. Registered on 15 September 2022.

In the United States, the alarming increase in opioid use disorder diagnoses during pregnancy in the last decade has increased the incidence of neonatal opioid withdrawal syndrome (NOWS). Although 8 per 1,000 newborns are diagnosed with NOWS each year, the lack of prospective studies is a roadblock in the development of approaches to reduce adverse health outcomes in this vulnerable population. This study used a preclinical model to assess short- and long-term effects of preconceptional and gestational fentanyl exposure on morphometrics, hormonal plasma profile, and sensitivity to opioid re-exposure in the offspring. Sprague Dawley female rats self-administered fentanyl citrate (FEN, FR1, 2.5µg/kg) or vehicle (NaCl 0.9%) during preconception and until gestational day 21. In utero fentanyl exposure (IUFE) did not influence neonatal weight and morphometrics; however, IUFE pups exhibited a higher frequency of behaviors indicative of somatic withdrawal, compared with controls (CTL). In male and female weanlings, IUFE induced the dysregulation of endogenous opioid peptides (EOPs) and increased metanephrine levels compared with CTL counterparts. However, only adult females with IUFE showed increased EOPs and metaneprhine levels, fentanyl-induced hyperalgesia and greater fentanyl-induced hypotensive and bradycardic effects compared with CLT counterparts. This preclinical model suggests a long-lasting association between IUFE-induced neuroendocrine dysregulation and adverse effects to opioid re-exposure in female offspring.

Standard induction (SI) using transmucosal buprenorphine-naloxone is challenging in individuals who inject opioids, use high doses of opioids, or use synthetic opioids (eg, fentanyl). To compare the effectiveness and safety of rapid induction (RI; single 4-mg dose of buprenorphine-naloxone) vs SI (≥7 days of buprenorphine-naloxone) followed by extended-release buprenorphine injection. This multicenter, open-label randomized clinical trial was conducted from October 26, 2021, to January 19, 2024, at 28 outpatient treatment centers in the US and Canada. Treatment-seeking participants with moderate or severe opioid use disorder who inject opioids, use high doses of opioids, or use fentanyl were studied. Participants were randomized 2:1 to RI or SI before 300-mg injection of extended-release buprenorphine. The primary end point, retention rate difference at injection 2 (1 week after injection 1), was estimated by a bayesian approach. Posterior probability was estimated for noninferiority of RI to SI (RI - SI >-10%) and superiority (RI - SI >0%). Adverse events (AEs), including investigator-assessed opioid withdrawal symptoms, were reported. Subgroup analyses compared participants with positive or negative fentanyl urine drug screen results. Analyses included 729 randomized participants (mean [SD] age, 40.7 [10.4] years; 406 [55.7%] male) who initiated transmucosal buprenorphine per protocol, including 474 in the RI arm and 255 in the SI arm. A total of 560 participants received extended-release buprenorphine injection 1 (409 [86.3%] in the RI arm and 151 [59.2%] in the SI arm), and 452 received injection 2 (314 [66.2%] in the RI arm and 138 [54.1%] in the SI arm). At injection 2, RI was noninferior with higher retention than SI (difference, 11.8%; 95% credible interval [CrI], 4.3%-19.0%; posterior probability greater than 0 was 99.9%). Similarly, among participants with a positive test result for fentanyl, the retention rate differential in favor of RI was 14.8% (95% CrI, 6.5%-23.7%; posterior probability greater than 0 was greater than 99.9%). AE incidence was not statistically different between RI and SI participants (202 [42.6%] vs 93 [35.5%]; difference, 6.1%; 95% CrI, -1.3% to 13.4%). Up to injection 2, most AEs were associated with opioid withdrawal. In this multicenter randomized clinical trial, RI had higher retention than SI overall and in patients who tested positive for fentanyl through extended-release buprenorphine injection 2. Administration of injection 2 after 1 week was well tolerated and minimized time below target therapeutic levels of 2 ng/mL or greater compared with injection after 1 month. ClinicalTrials.gov Identifier: NCT04995029.

The rising rates of substance misuse have resulted in the upsurge of neonatal abstinence syndrome (NAS) worldwide, including India. Neonatal opioid withdrawal syndrome (NOWS) is a subset of NAS resulting from chronic in-utero exposure to opioids. Diagnosing NOWS can be particularly difficult because its symptoms can be vague, and mothers may intentionally withhold information about their drug use. Till now, only a limited number of cases of NOWS have been reported from India. We present a case of NOWS presenting as status epilepticus. There was no history of maternal substance misuse on initial enquiry, and the baby was being managed as a case of idiopathic neonatal seizures. It was only after being informed by the mother’s psychiatrist that she had a history of opioid misuse and was non-compliant with maintenance medications that the probable diagnosis of NOWS could be made. Seizures were managed with phenobarbitone and phenytoin. The baby was discharged on a maintenance dose of phenobarbitone. Due to the rising incidence of substance misuse in our country, a high index of suspicion should be kept for the diagnosis of NAS or NOWS in neonates with unexplained neurological symptoms in the first few days of life.

Evaluate associations between antenatal exposure to medication for opioid use disorder (MOUD), including MOUD type, and neonatal outcomes for infants with neonatal opioid withdrawal syndrome (NOWS). Data from 768 neonates with NOWS born between 36-0/7 to 41-6/7 weeks gestation were retrospectively collected from 13 United States hospitals. Compared to neonates with antenatal exposure to non-MOUD opioids, neonates with antenatal exposure to MOUD opioids had a 51% lower odds of delivery before 39 weeks and 2.72-fold greater odds of breastfeeding. Compared to neonates with antenatal exposure to prescribed methadone, neonates exposed to prescribed buprenorphine or buprenorphine/naloxone had increased mean head circumference z-scores (0.31 and 0.48 units respectively), decreased odds of pharmacologic treatment (49% and 58%, respectively), and a reduced mean length of hospital stay (35% and 39%, respectively). Antenatal exposure to MOUD opioids, specifically prescribed buprenorphine, was associated with significantly improved neonatal outcomes. INFORM NOW: N/A.

Buprenorphine (BUP), a partial mu-opioid receptor (MOR) agonist, is an effective analgesic and is standard-of-care for treating opioid use disorder (OUD). Transitioning from full MOR agonists to stable BUP dosing can be challenging as some patients experience BUP-precipitated opioid withdrawal (BPOW) due to its ability to displace full MOR agonists. To improve patient tolerability low-dose BUP initiation protocols deliver small, progressively escalating BUP doses, allowing gradual displacement of other opioids and replacement with BUP. We describe a case series using a novel intravenous BUP "micro-infusion" protocol for rapid medication transition with no patients meeting the operational criteria for BPOW. A retrospective case series of patients who received an 8-hour 1200mcg BUP infusion (150mcg/hr) and one (or more) sublingual BUP doses after medical or nonmedical full MOR agonist administration. Variables included demographic characteristics, presence of OUD, opioid medications, BUP continuation/prescription fill rates, and evidence of BPOW based on Clinical Opiate Withdrawal Scale (COWS) scores. Of 23 patients included, 8 presented with current OUD (34.8%) and 15 were treated with full MOR agonists for analgesia (65.2%) before BUP micro-infusion. There were no instances of BPOW. Among the 8 patients with OUD, 5 (62.5%) continued sublingual BUP and filled their prescription for BUP upon discharge. Overall, the 8-hour intravenous 1200mcg BUP micro-infusion protocol was well-tolerated with no clinically apparent cases of BPOW and similar rates of continued sublingual BUP treatment post-discharge among patients with OUD compared with other low-dose BUP initiation protocols.

ObjectiveThis study aimed to evaluate whether metformin can alleviate heroin withdrawal symptoms and explore its underlying mechanisms, focusing on its reducing microglia-related neuroinflammation in the CA3 region of hippocampus.MethodsWe set up a heroin withdrawal mouse model by the administration of naloxone in heroin-treated mice. To reduce experimental variables, only male mice were considered in this study. The behaviors of withdrawal model mice with saline, naloxone (5 mg/kg), or metformin (100 mg/kg) treatment (n = 12 for each group) were evaluated by Open Field Test (OFT) and Elevated Plus Maze Test. After the behavior tests, brain tissues were collected for histological staining experiments. Our study mainly focused on the hippocampal CA3 region. Protein expression levels of TLR4 (inflammation related) and BAX were analyzed using immunofluorescence staining.ResultsMetformin was proved to be capable of improving movement-related and posture-related behavioral changes caused by the naloxone-induced heroin withdrawal. Furthermore, the results of the Open-Field Test and Elevated Plus Maze test were used to demonstrate metformin’s role in softening anxiety levels, which was due to its reducing microglia-related neuroinflammation in the CA3 region of hippocampus. This neuronal protection was achieved by downregulating the expression of TLR4 (inflammation related) and BAX (apoptosis marker) protein.ConclusionOverall, our data suggests that prophylactic administration of metformin has a therapeutic effect on glial-induced neuroinflammation and neuronal apoptosis in heroin withdrawal mice. Histological experiments suggested that metformin reduced microglia-mediated neuroinflammation and downregulated TLR4 and BAX expressions in the hippocampus.

Abstract Background Buprenorphine is a synthetic opioid derived from thebaine. It is structurally and pharmacologically similar to morphine, but is 20-30 times more potent. It is a partial agonist receptor modulator and has a longer duration of action relative to morphine due to its unusual slow rate of dissociation from its receptor. Buprenorphine produces a variety of symptoms including, but not limited to addiction, life-threatening respiratory depression, neonatal opioid withdrawal syndrome, severe hypotension. After administration in humans, buprenorphine is primarily metabolized through N-dealkylation to form norbuprenorphine. Both buprenorphine and norbuprenorphine undergo further metabolism via conjugation with D-glucuronic acid to form buprenorphine-glucuronide and norbuprenorphine-glucuronide. Pharmaceutical buprenorphine is a medication used to treat opioid use disorders (OUDs) and manage severe pain that necessitates an opioid analgesic when other treatments are insufficient. Furthermore, it has occasionally been used off-label (i.e., for purposes not approved by the FDA) via injection, including applications in perineural anesthesia and managing withdrawal in hospitalized patients dependent on heroin. In 2002, buprenorphine, including its salts, isomers and salts of isomers, became a Schedule III narcotic substance under the Controlled Substances Act for its potential for abuse and risk of dependence. ARK Diagnostics has developed the ARK Buprenorphine Assay to detect buprenorphine and its metabolites at a cutoff concentration of 5 ng/mL of buprenorphine with high cross-reactivity to its metabolites, norbuprenorphine, buprenorphine-glucuronide, and norbuprenorphine-glucuronide without additional treatment of glucuronidase. Methods The ARK Buprenorphine Assay is a liquid stable homogeneous enzyme immunoassay, consisting of two reagents, with a cutoff concentration of 5 ng/mL and semi-quantitative range up to 100 ng/mL. The performance of this assay was evaluated on the Beckman Coulter AU680 Automated Clinical Chemistry Analyzer. Precision, analytical recovery, specificity, Histogram Overlap Analysis of ± 40% controls and the cutoff, and method comparison with LC-MS/MS were evaluated. Results In semi-quantitative mode, total precision ranged from 4.0 to 8.0 % CV. Spiked recovery ranged from 94.0% to 103.4 % for the samples spanning 2.0 to 100.0 ng/mL. The major metabolites, norbuprenorphine, buprenorphine-glucuronide, and norbuprenorphine-glucuronide, showed approximate equivalences to the 5 ng/mL buprenorphine cutoff at 10.0 ng/mL (50.0 % cross-reactivity), 5.8 ng/mL (86.2 % cross-reactivity), and 8.5 ng/mL (58.8% cross-reactivity), respectively. Histogram overlap analysis showed no overlap between cutoff and control levels. Method correlation with LC-MS/MS using authentic urine samples showed an excellent agreement with specificity and sensitivity. Conclusion The ARK Buprenorphine Assay measures buprenorphine and its major metabolites, norbuprenorphine, buprenorphine glucuronide, and Norbuprenorphine glucuronide in human urine with good analytical performance. The assay has superior specificity as other opiates and opioids do not cross react. The assay is sensitive, rapid, and applicable to a wide range of clinical chemistry analyzers.

Abstract Background Xylazine is a veterinary sedative primarily used to sedate large animals. Although it is not approved for human use due to its severe effect on the central nervous system, xylazine has increasingly appeared as a drug of abuse. The rise of xylazine abuse was often observed mixed with opioids like fentanyl due to its ability to prolong opioid highs. Unlike opioids, xylazine does not respond to naloxone, complicating overdose treatment. Reports of xylazine-laced fentanyl have surged, aggravating the opioid crisis. In parallel, the chemical compounds found in kratom, mitragynine and 7-OH-mitragynine, have gained attention for their opioid-like effects. While mitragynine was initially used to ease opioid withdrawal, it has currently become a concern for potential substance dependence and abuse. Methods A retrospective study on drug abuse trends involved analyzing past data over a three-year period (2022-2024) to identify usage patterns of xylazine and mitragynine. While xylazine is being observed for its co-occurrence with fentanyl due its increasing presence in opioid-related overdoses, mitragynine was commonly used alone. This study relies on existing records from medical reports and toxicology screenings to assess the prevalence and fluctuations of drug use and to provide insights into emerging drug trends. Results Between 2023 and 2024, there was a notable decline in both total opioid cases and fentanyl-related cases. In 2023, there were 2,399 total opioid cases, with 477 (19.9%) involving fentanyl. By 2024, total opioid cases had decreased to 2,022 cases, concurrently fentanyl-related cases saw an even steeper drop of 279 (13.8%). In parallel, xylazine-related incidents fluctuated between 2022 and 2024, increasing from 114 cases in 2022 to 189 in 2023 before declining to 107 in 2024. In the observed trend, most of the positive xylazine samples simultaneously tested positive for fentanyl. Upon comparing the co-occurrence of fentanyl to xylazine, xylazine abuse appears to have followed the decreasing trend observed in fentanyl, where xylazine-fentanyl abuse dropped from 42.3% in 2023, to 38.4% in 2024. This suggests a significant reduction in fentanyl’s presence within opioid cases, which could indicate shifts in drug use patterns. In the meantime, mitragynine use remained stable at 14 cases in both 2022 and 2023 but surged to 34 in 2024, indicating a growing trend in its misuse. Conclusion The fluctuating trends in xylazine, fentanyl, and mitragynine use highlight the evolving nature of drug abuse. While fentanyl and xylazine cases declined in 2024, the rise in mitragynine use signals shifting patterns.

Effects of suvorexant on diurnal cortisol and patient-reported stress during opioid withdrawal in a randomized trial.