Rapid Methadone Induction in a General Hospital Setting: A Retrospective, Observational Analysis.

BACKGROUND: Outpatient methadone guidelines recommend starting at a low dose and titrating slowly. As fentanyl prevalence and opioid-related mortality increases, there is a need for individuals to rapidly achieve a therapeutic methadone dose. Hospitalization offers a monitored setting for methadone initiation, however dosing practices and safety are not well described. METHODS: Retrospective, observational analysis of hospitalized patients with opioid use disorder seen by an inpatient addiction consult team in an academic medical center who were newly initiated on methadone between 2016 and 2022. We calculated initial daily dose, maximum daily dose, timing interval of dose escalation, whether patients were connected to an opioid treatment program (OTP) prior to discharge, whether adverse effects or safety events occurred during the hospitalization, and whether such events were definitely or probably related versus possibly related or unrelated to methadone. RESULTS: One hundred twelve patients were included. The mean initial daily methadone dose administered was 32 mg (range: 10-90 mg). The mean maximum dose reached was 76.8 mg (range 30-165 mg). The mean number of days from initial to peak dose was 5.6 days (range 1-19 days). Overall, 30% of patients experienced a safety event, most commonly sedation. Only 4 safety events were deemed probably or definitely related to methadone. In regression analyses, there was no significant difference between starting doses among patients with or without sedation but there was a relationship between last dose and the likelihood of any possibly related event, with those ending at a dose of 100 mg or higher having a higher likelihood event, compared to those ending at lower doses (47.8% vs 12.4%, P < .001). Seventy-six percent were connected to OTP before discharge. CONCLUSION: Among hospitalized patients initiating methadone, rapid dose titration was infrequently associated with related safety events and most were connected to community-based methadone treatment before discharge.

Large-scale phenotyping of an accurate genetic mouse model of JNCL identifies novel early pathology outside the central nervous system.

Cln3(Δex7/8) mice harbor the most common genetic defect causing juvenile neuronal ceroid lipofuscinosis (JNCL), an autosomal recessive disease involving seizures, visual, motor and cognitive decline, and premature death. Here, to more thoroughly investigate the manifestations of the common JNCL mutation, we performed a broad phenotyping study of Cln3(Δex7/8) mice. Homozygous Cln3(Δex7/8) mice, congenic on a C57BL/6N background, displayed subtle deficits in sensory and motor tasks at 10-14 weeks of age. Homozygous Cln3(Δex7/8) mice also displayed electroretinographic changes reflecting cone function deficits past 5 months of age and a progressive decline of retinal post-receptoral function. Metabolic analysis revealed increases in rectal body temperature and minimum oxygen consumption in 12-13 week old homozygous Cln3(Δex7/8) mice, which were also seen to a lesser extent in heterozygous Cln3(Δex7/8) mice. Heart weight was slightly increased at 20 weeks of age, but no significant differences were observed in cardiac function in young adults. In a comprehensive blood analysis at 15-16 weeks of age, serum ferritin concentrations, mean corpuscular volume of red blood cells (MCV), and reticulocyte counts were reproducibly increased in homozygous Cln3(Δ) (ex7/8) mice, and male homozygotes had a relative T-cell deficiency, suggesting alterations in hematopoiesis. Finally, consistent with findings in JNCL patients, vacuolated peripheral blood lymphocytes were observed in homozygous Cln3(Δ) (ex7/8) neonates, and to a greater extent in older animals. Early onset, severe vacuolation in clear cells of the epididymis of male homozygous Cln3(Δ) (ex7/8) mice was also observed. These data highlight additional organ systems in which to study CLN3 function, and early phenotypes have been established in homozygous Cln3(Δ) (ex7/8) mice that merit further study for JNCL biomarker development.