Baclofen, a gamma-aminobutyric acid type B (GABA-B) receptor agonist commonly used for spasticity management, is known to cause withdrawal symptoms after abrupt discontinuation. Unique clinical presentations of oral baclofen withdrawal are not well documented, and severe hyperalgesia-like pain disproportionate to expected postoperative recovery has not been well described in the context of oral baclofen withdrawal. This case study depicts a rare presentation of oral baclofen withdrawal in a 46-year-old woman with complete paraplegia and chronic spasticity (Modified Ashworth Scale Grade 4) following an inadvertent 75% dose reduction in her home baclofen regimen (postoperative day 0) at an outside facility during transitions between healthcare facilities. The patient presented with agitation, tachycardia, diaphoresis, insomnia, severe postoperative lower extremity pain, increased pain sensitivity out of proportion to expected postoperative recovery, and progressive muscle spasms after ankle surgery one week prior. On Hospital Day 1, she required 141.25 oral morphine equivalents (OMEs), including scheduled, one-time, and as-needed opioid doses. Her pain symptoms were worsening despite escalating opioid therapy and the absence of postoperative signs of infection or hardware malfunction on Hospital Day 2. A detailed medication reconciliation on Hospital Day 3 revealed that her chronic baclofen dose of 20 mg four times daily was mistakenly reduced to 20 mg once daily on the day of her surgery. She was given two additional doses of baclofen 20 mg on Hospital Day 3, and her OME was 117.5. Following restoration of her full home baclofen regimen on Hospital Day 4, the patient experienced significant improvement in pain, spasticity, sleep quality, and a proportionate decrease of opioid requirements (OME of 75). This case highlights the diagnostic challenge of oral baclofen withdrawal when it presents as refractory postoperative pain and emphasizes the clinical finding of hyperalgesia-like pain and rebound spasticity as a potentially unrecognized presentation of oral baclofen withdrawal. Further, it highlights the importance of accurate medication reconciliation, continuity of antispasmodic therapy, and patient education during transitions of care to prevent avoidable complications of baclofen withdrawal and unnecessary escalations of analgesic management.

Xylazine is a veterinary anesthetic and α2-adrenoceptor agonist found in illicit drug supplies. Injection of opioids adulterated with xylazine is correlated with necrotic tissue injury and a withdrawal syndrome including anxiety. Planarians are flatworms with a simple nervous system and no circulatory system that exhibit several characteristics, including regenerative capacity and negative phototaxis (light avoidance). Because regeneration reflects tissue repair and negative phototaxis constitutes defensive behavior, planarians provide a simple in vivo system to explore possible effects of xylazine on planarian wound repair and anxiety-like behavior. Using planarians, we investigated the effects of xylazine on cephalic regeneration and defensive responding (i.e., determined by time spent on light side of a dish divided into light and dark compartments). In decapitated planarians, chronic xylazine exposure (0.001-0.1µM, over 2 weeks) reduced head regeneration rate. For intact worms, acute xylazine (1µM, 5min) caused a reduction in defensive responding (i.e., increased time in light) that was abolished by yohimbine (0.001µM), an α2-adrenoceptor antagonist. Clonidine (0.01-1µM), another α2-adrenoceptor agonist, mimicked xylazine's defensive responding effects. We next assessed effects of xylazine withdrawal on defensive responding. Early xylazine abstinence (0.01-1µM, 5 and 30min), like acute xylazine, reduced defensive responding. In contrast, during later xylazine abstinence (0.001-1µM, 60min), defensive responding robustly increased with no significant changes in motility. Our data show that xylazine impairs planarian regeneration and bidirectionally impacts planarian defensive behaviors with distinct acute and withdrawal-dependent effects. These results suggest that some effects of xylazine on tissue injury and anxiety-like behavior are conserved in planarians.

Estimation of optimal individualized treatment rules (ITRs) tailored to patient characteristics is a crucial component of precision medicine. When such problems arise in multicenter randomized trials with known treatment assignment probabilities, the optimal ITR may vary across sites because of site-level heterogeneity, and directly pooling data across centers can lead to biased ITR estimation. Meanwhile, privacy constraints often prevent investigators from accessing individual-level data from all centers. We therefore propose Heterogeneous Distributed Learning (HD-learning) to estimate optimal site-specific ITRs using only summary-level data from each site in a single communication round. The method uses a distributed mixed-effects model to accommodate common fixed effects and site-specific random effects. We further develop Shrinkage HD-learning (SHD-learning) for moderate- or high-dimensional covariates. Under suitable conditions, we establish asymptotic properties of the proposed estimators. Simulations show that our methods are lossless relative to the corresponding pooled estimator and outperform methods that ignore heterogeneity. We illustrate the proposed methods using the acute upper respiratory tract infections (AURTIs) study and the opioid withdrawal study.

Kratom is an emerging substance in the United States that is commonly used to manage chronic pain and withdrawal symptoms from opioids. Kratom products are federally unregulated and legal in many states, and prolonged use can lead to the development of a substance use disorder. For pregnant persons, there are additional risks of maternal and infant withdrawal symptoms. Treatment of kratom use disorder (KUD) is complicated by misperception of the substance's harmful effects as well as limited screening options to identify and track use. There are few reports on the management of perinatal KUD and outcomes following childbirth. Buprenorphine has limited evidence for the treatment of KUD in the general population. This medication is supported for the treatment of opioid use disorder in pregnancy, but only 3 cases describe its application for pregnant persons with KUD. Key considerations for this treatment approach include identifying an effective buprenorphine dose and using collaborative care to address patient concerns. This case study illustrates strategies for the diagnosis and management of KUD in pregnancy.

The opioid epidemic remains a persistent public health challenge in the United States, leaving many people affected by or vulnerable to opioid use disorder (OUD). Although US Food and Drug Administration-approved medications for OUD improve the odds of recovery and reduce mortality, relapse rates remain high and access, adherence, and individual response variabilities limit their overall impact. The ongoing burden of OUD therefore underscores the need to develop additional therapeutics that target complementary biological mechanisms and support long-term recovery. One strategy of interest is to delineate the biological overlap between OUD and other motivated behaviors, particularly the neurobiology underlying appetitive and reward-driven processes. The orexigenic peptide hormone ghrelin, often referred to as the "hunger hormone," regulates energy homeostasis, hedonic feeding, and reward sensitivity by binding to the growth hormone secretagogue receptor 1α (GHS1αR), a receptor expressed in mesolimbic circuits implicated in addiction. In the present study, we used the inverse agonist/antagonist PF5190457 to assess the impact of full GHS1αR blockade on fentanyl-mediated behaviors in preclinical models. We found that PF5190457 significantly reduced fentanyl self-administration and attenuated drug-seeking during cue tests while maintaining a favorable pharmacological and safety profile in risk assessment assays, including measures of withdrawal and respiratory depression. Collectively, these findings demonstrate a functional role for ghrelin-GHS1αR signaling in the reinforcing effects of fentanyl and positions GHS1αR inverse agonism as a promising, mechanistically novel therapeutic strategy for OUD treatment. SIGNIFICANCE STATEMENT: The present work demonstrates that the growth hormone secretagogue receptor 1α (GHS1αR) inverse agonist/antagonist PF5190457 reduces fentanyl self-administration and drug-seeking while maintaining a favorable safety profile in male rats, supporting ghrelin-GHS1αR modulation as a promising therapeutic strategy for opioid use disorder.