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Methadone (R,S-methadone) can prolong the QT interval. R-methadone inhibits cardiac potassium channel function less than S-methadone. We tested if switching from methadone to R-methadone would reduce corrected QT (QTc) intervals in methadone maintenance treatment (MMT) patients. Nine patients, with automatically read QTc intervals ≥450 ms, were required to detect a 20 ms (clinically relevant) reduction in QTc intervals with 15 ms standard deviation (SD) and 90% power. Nine stabilized MMT patients, using median (range) 70 (40-120) mg methadone, were included. Data (ECG recordings, serum samples, and withdrawal symptoms) were collected both before drug intake (Cmin ) and at 3 h after drug intake (Cmax ), and were collected on the day before the switch from methadone to equipotent R-methadone dose and at 14 and 28 days after the switch. A cardiologist calculated QTc intervals retrospectively. Serum electrolytes and methadone concentrations were measured. Mean QTc intervals at Cmin were 472 ms and 422 ms on methadone (automatically and manually read) and 414 ms on R-methadone (manually read). Mean (SD) change in QTc intervals was -8 (10) ms (p = 0.047) at Cmin but non-significant at Cmax . R-methadone showed a concentration-dependent relationship with QTc intervals. Switching to R-methadone reduced QTc intervals, but far less than the 20 ms considered clinically relevant.

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Methadone is a chiral synthetic opioid primarily used to treat heroin and prescription-opioid addiction: the (R)-enantiomer (Levomethadone) activates the µ-opioid receptor more potently than the (S)-enantiomer, which is a more potent blocker of the hERG potassium channels, resulting in QTc prolongation. The purpose of this retrospective study was to assess the effect of methadone on the QTc interval and to investigate the benefits of Levomethadone. The electrocardiograms of 165 patients taking methadone at various dosages and for different periods of time were examined: the QTc value was manually measured and then adjusted using Bazett's formula. Data analysis revealed a linear association between the dosage of methadone and QTc length; no correlation was found between the QTc value and gender, age, or duration of therapy. In total, 14% of the sample (23 patients) showed a prolongation of the QTc interval (>470 ms in males and >480 ms in females); 10 of the 23 patients with QTc elongation underwent a change of therapy from Methadone to Levomethadone-in 90% of these patients, a normalization in the QTc length was established. This study confirmed the role of methadone, specifically its dosage, in QTc prolongation and the efficiency of Levomethadone as an adequate therapeutic substitute in these circumstances. This study validates the importance of careful electrocardiographic monitoring in methadone-treated patients.

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A multicenter-observational study was performed to assess the effectiveness of rac-methadone, levomethadone, and buprenorphine in opioid-dependent patients in polytherapy in Southern Italy. The primary endpoint was the reduction of urinary positivity to the substances and the maintaining doses. Patients (N = 266, age = 44.80 ± 5.65, male = 79.70%, female = 20.30%) have been recruited. At recruitment, 75% of them were on treatment with rac-methadone, levomethadone, and buprenorphine/naloxone. The patients were grouped into three clusters. The levomethadone patients of Cluster A (N patients = 211), after 180 days, showed stability in urinary methadone positivity, with a marked decrease in heroin -53 ± 4%, cannabinol's -48 ± 2%, and cocaine -37 ± 6% positivity, with no differences between treatments. A lower QTcF value of 426 ± 8.4 ms was recorded in the levomethadone patients (delta = -19 ms) vs. rac-methadone, at significantly lower doses of levomethadone (-34%, -50.2% in males) (p < 0.05). The Cluster B data were collected from 37 patients, with a high prevalence of comorbidity infections (HIV/HCV/HPV), monitored for 21 months during COVID-19. High doses of levomethadone (58.33 ± 31.58 mg/day) were needed to stabilize those that were negative for opioids and cannabinoids, in contrast to the rac-methadone and buprenorphine/naloxone patients that showed positive toxicology. Eighteen patients of the Cluster C in double diagnosis (major depressive 38.90%, bipolar 27.78%, and schizophrenia 16.67%) were stabilized with high doses of racemate 97.5 ± 8 mg/day, 51.8 ± 5 mg/day of levomethadone (-46.8% vs. rac-methadone; -71% in men), and 2.5 ± 1 mg/day of buprenorphine/naloxone. Three patients in remission were treated with tapering doses of levomethadone. Significantly reduced QTcF values were recorded with levomethadone (delta -32 ms vs. rac-methadone) in the bipolar patients, as well as the schizophrenia patients in remission (delta -45.19 ms vs. rac-methadone). Our patients were safely stabilized. Levomethadone, compared to the racemate, contributes to reducing the illicit use, especially of opioids and cannabinoids at significantly lower doses with cardiovascular safety, which, in bipolar patients, is clinically significant.

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OBJECTIVE: To compare the sedative effects of intramuscular xylazine alone or combined with levomethadone or ketamine in calves before cautery disbudding. STUDY DESIGN: Randomized, blinded, clinical trial. ANIMALS: A total of 28 dairy calves, aged 21 ± 5 days and weighing 61.0 ± 9.3 kg (mean ± standard deviation). METHODS: Calves were randomly allocated to three groups: xylazine (0.1 mg kg-1) and levomethadone (0.05 mg kg-1; group XL), xylazine (0.1 mg kg-1) and ketamine (1 mg kg-1; group XK) and xylazine alone (0.2 mg kg-1; group X). Local anaesthesia (procaine hydrochloride) and meloxicam were administered subcutaneously 15 minutes after sedation and 15 minutes before disbudding. The calves' responses to the administration of local anaesthesia and disbudding were recorded. Sedation was assessed at baseline and at intervals up to 240 minutes postsedation. Times of recumbency, first head lift and first standing were recorded. Drug plasma concentrations were measured. RESULTS: Data were obtained from 27 animals. All protocols resulted in sedation sufficient to administer local anaesthesia and to perform disbudding. Sedation scores significantly correlated with drug plasma concentrations (p ≤ 0.002). Times to recumbency did not differ among protocols (2.8 ± 0.3, 3.1 ± 1.1 and 2.1 ± 0.8 minutes for groups XL, XK and X, respectively), whereas interval from drug(s) administration until first head lift was significantly shorter in group XK than X (47.3 ± 14.1, 34.4 ± 5.3 and 62.6 ± 31.9 minutes for groups XL, XK and X, respectively). The area under the time-sedation curve was significantly greater in group X than XK or XL (754 ± 215, 665 ± 118 and 1005 ± 258 minutes for groups XL, XK and X, respectively). CONCLUSIONS AND CLINICAL RELEVANCE: Levomethadone or ketamine with a low dose of xylazine produced short but sufficient sedation for local anaesthesia and disbudding with minimum resistance.

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OBJECTIVE: To evaluate the antinociceptive effect of a bolus of intravenous levomethadone administered to horses during romifidine constant rate infusion (CRI). STUDY DESIGN: Prospective, randomized, masked, crossover experimental study. ANIMALS: A group of eight adult Warmblood horses (seven geldings, one mare) aged 6.6 ± 4.4 years, weighing 548 ± 52 kg [mean ± standard deviation (SD)]. METHODS: Levomethadone 0.1 mg kg-1 or an equivalent volume of saline (control) was administered intravenously to standing horses 60 minutes after starting a romifidine CRI. Blood samples to quantify romifidine and levomethadone plasma concentrations by capillary electrophoresis were collected up to 150 minutes after levomethadone administration. The nociceptive withdrawal reflex threshold (NWRT) was determined continuously using an automated threshold tracking device. Sedation and cardiopulmonary variables were assessed at regular intervals. A pharmacokinetic-pharmacodynamic (PK-PD) model was elaborated. Data are presented as mean ± SD or median (interquartile range, 25%-75%) where appropriate. Differences between groups were considered statistically significant for p < 0.05. RESULTS: Horses exhibited higher NWRTs after levomethadone administration than after saline (123 ± 9% versus 101 ± 9% relative to baseline, p < 0.05). The PK-PD model identified a contribution of levomethadone to the NWRT increase. Effect size was variable among individuals. No adverse reactions to levomethadone administration were observed. A slight effect of levomethadone on sedation scores was evident for the 60 minutes following its administration. CONCLUSIONS AND CLINICAL RELEVANCE: A single injection of levomethadone has the potential to increase the NWRT during romifidine CRI in horses and can be administered in combination with α2-adrencoceptor agonists to enhance antinociception in horses. However, individual variation is marked.

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BACKGROUND/AIMS: Opioid dependence is a severe disease which is associated with a high risk of relapse, even in cases of successful withdrawal therapy. Studies have shown alterations of the hypothalamic-pituitary-gonadal axis in opioid-dependent patients, such as decreased testosterone serum levels in affected males. Sex hormones and the steroid 5-alpha-reductase 2 (SRD5A2) V89L polymorphism are associated with craving during alcohol withdrawal, but little is known about their impact on symptomatology of opioid dependence. METHODS: In this study, we analyzed 2 independent male cohorts of opioid-dependent patients for possible alterations in testosterone serum levels compared to non-opioid-dependent controls. In one of the cohorts, we additionally investigated associations of testosterone serum levels and 3 SRD5A2 polymorphisms with symptoms of opioid dependence, measured by the Heroin Craving Questionnaire (HCQ). RESULTS: In the patient groups, we found significantly decreased testosterone serum levels compared to the control groups. Furthermore, we found significant associations of both the testosterone serum levels and the SRD5A2 V89L polymorphism with opioid craving assessed by the HCQ. CONCLUSION: Our data show a possible role of testosterone metabolism in opioid dependence, which may be relevant for the establishment of future treatment strategies.

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BACKGROUND: Opioid Use Disorder (OUD) is a substance use disorder with a chronic course associated with comorbid mental and somatic disorders, a high burden of psychosocial problems and opioid maintenance treatment (OMT) as a standard treatment. In the US, OUD imposes a significant economic burden on society, with annual societal costs estimated at over 55 billion dollars. Surprisingly, in Europe and especially in Germany, there is currently no detailed information on the healthcare costs of patients with OUD. The goal of the present research is to gather cost information about OUD patients in OMT with a focus on maintenance medication and relapses. METHODS: We analysed health claims data of four million persons covered by statutory health insurance in Germany, applying a cost-of-illness approach and aimed at examining the direct costs of OMT patients in Germany. Patients with an ICD-10 code F11.2 and at least one claim of an OMT medication were stratified into the treatment groups buprenorphine, methadone or levomethadone, based on the first prescription in each of the follow-up years. Costs were stratified for years with and without relapses. Group comparisons were performed with ANOVA. RESULTS: We analysed 3165 patient years, the total annual sickness funds costs were on average 7470 € per year and patient. Comparing costs of levomethadone (8400 €, SD: 11,080 €), methadone (7090 €, SD: 10,900 €) and buprenorphine (6670 €, SD: 7430 €) revealed significant lower costs of buprenorphine compared to levomethadone (p < 0.0001). In years with relapses, costs were higher than in years without relapses (8178 € vs 7409 €; SD: 11,622, resp. 10,378 €). In years with relapses, hospital costs were the major cost driver. CONCLUSIONS: The present study shows the costs of OUD patients in OMT for the first time with a German dataset. Healthcare costs for patients with an OUD in OMT are associated with more than two times the cost of an average German patients. Preventing relapses might have significant impact on costs. Patients in different OMT were dissimilar which may have affected the cost differences.

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AIMS: The nerve growth factor (NGF) and the vascular endothelial growth factor-A (VEGF-A) may be of importance for psychiatric diseases including substance use disorders. The aim of the study was to identify differences in the regulation of both neuropeptides via the DNA-methylation status of the promotor regions of NGF and VEGF-A in different forms of maintenance therapy for opioid dependence and the related stress regulation via the hypothalamic-pituitary-adrenal axis. METHODS: We compared methylation levels of opioid-dependent patients receiving treatment with diamorphine (n = 28) or levomethadone (n = 54) and similar levels in a healthy control group (n = 72). RESULTS: There was a significantly higher methylation of VEGF-A in opioid-maintained patients with levomethadone compared to that in the control group (estimated marginal means [EMM] [SE]): 0.036 [0.003] vs. 0.020 [0.003]; p < 0.001). We performed a cluster analysis for NGF, splitting up the results in 4 clusters. We found significant changes in methylation rates of the opioid-maintained patients compared to the controls in cluster I ([EMM] [SE]: 0.064 [0.005] vs. 0.084 [0.006]; p = 0.03), cluster II ([EMM] [SE]: 0.133 [0.013] vs. 0.187 [0.014]; p < 0.001) and cluster III ([EMM] [SE]: 0.190 [0.014] vs. 0.128 [0.016]; p < 0.001). CONCLUSIONS: The results are of importance, as they indicate that long-term changes in stress regulation regulated by neurotrophines are a crucial part of the symptomatology of opioid dependence, thus influencing drug consumption and the different forms of opioid-maintenance therapies.

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To study drug safety and the reporting behavior of adverse drug reactions (ADR) related to agents used for opioid replacement therapy (ORT) we conducted a cross-sectional questionnaire-based telephone survey among physicians who provide outpatient ORT in Germany (n=176; response rate=55.7%). Most respondents (n=97/55.1%) reported that they observe ADR related to buprenorphine, (dihydro)codeine, and (levo)methdone rarely (n=38/21.6%), very rarely (n=39/22.2%) or never (n=20/11.4%). Methadone was reported to be most frequently associated with the occurrence of ADR (n=82/46.6%), followed by levomethadone (n=33/18.8%), buprenorphine (n=6/3.4%), and dihydrocodeine (n=3/1.7%). Frequently observed ADR related to these agents were gastrointestinal, nervous system/psychiatric disorders, and hyperhidrosis. Methadone and levomethadone (not buprenorphine) were frequently associated with fatigue, weight gain, and sexual dysfunction. Hundred twenty nine participants (73.3%) stated that they never report ADR related to ORT; n=19 (10.8%) did so when referring to ADR related to their complete medical practice (X2=141.070; df=1; p<0.001). Similar patterns of ADR related to outpatient ORT as those reported in the product information or in pain therapy were found. Motivation to report ADR related to ORT may be reduced compared to ADR related to the general medical practice.

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