Subjective Symptoms and Serum Methadone Concentration: What Should Guide Dose Adjustments in Methadone Maintenance Treatment? A Naturalistic Cohort Study From Norway

BackgroundThere is little evidence-based guidance on how to optimize methadone dosage among patients with opioid addiction undergoing methadone maintenance treatment (MMT). This study aims to investigate whether self-perceived opioid withdrawal symptoms, adverse effects and self-reported substance use in patients on MMT are related to serum methadone concentration and what role these could play in clinical decisions on dose adjustments.MethodsIn this naturalistic cohort study clinical and laboratory measurements from 83 patients undergoing MMT in outpatient clinics in Bergen, Norway during May 2017-January 2020 were included. Information on age, gender, methadone daily doses and serum concentrations, subjective opioid withdrawal symptoms (SOWS), self-reported adverse effects and substance use were obtained. Linear mixed modelling was used for analyzing the data.ResultsMean age was 45 years and 34% were women. 55% reported subjective opioid withdrawal symptoms, and all had experienced at least one subjective adverse effect. Self-reported substance use was recorded in 88% of the interviews. Total SOWS score (P<0.001), and the specific subjective withdrawal symptoms of anxiety (P=0.004), bone- and muscle ache (P=0.003), restlessness (P=0.017) and shaking (P=0.046) out of the 16 symptoms in standard SOWS questionnaire, as well as the use of heroin (P=0.015) and alcohol (P=0.011) were associated with lower methadone concentrations, whereas cannabis use was associated with higher methadone concentrations (P=0.049). Conclusions More subjective opioid withdrawal symptoms and more self-reported use of heroin and alcohol were associated with lower serum methadone concentrations. More use of cannabis was related to higher serum methadone concentrations. These findings suggest that patient's self-perceived symptoms and current clinical condition can be applied as the main guide in methadone dose adjustments. In some aberrant cases, measurement of serum concentration together with other individual assessments may be considered to support the clinical decision.

Cytotoxic and Senolytic Effects of Methadone in Combination with Temozolomide in Glioblastoma Cells

Methadone is an analgesic drug used for pain treatment and heroin substitution. Recently, methadone has been proposed to be useful also for cancer therapy, including glioblastoma multiforme (GBM), the most severe form of brain cancer, because experiments on cultured glioma cells treated with doxorubicin showed promising results. Doxorubicin, however, is not used first-line in GBM therapy. Therefore, we analyzed the cytotoxic effect of methadone alone and in combination with temozolomide, a DNA-alkylating drug that is first-line used in GBM treatment, utilizing GBM-derived cell lines and a human fibroblast cell line. We show that methadone is cytotoxic on its own, inducing apoptosis and necrosis, which was observed at a concentration above 20 µg/mL. Methadone was similar toxic in isogenic MGMT expressing and non-expressing cells, and in LN229 glioblastoma and VH10T human fibroblasts. The apoptosis-inducing activity of methadone is not bound on the opioid receptor (OR), since naloxone, a competitive inhibitor of OR, did not attenuate methadone-induced apoptosis/necrosis. Administrating methadone and temozolomide together, temozolomide had no impact on methadone-induced apoptosis (which occurred 3 days after treatment), while temozolomide-induced apoptosis (which occurred 5 days after treatment) was unaffected at low (non-toxic) methadone concentration (5 µg/mL), and at high (toxic) methadone concentration (20 µg/mL) the cytotoxic effects of methadone and temozolomide were additive. Methadone is not genotoxic, as revealed by comet and γH2AX assay, and did not ameliorate the genotoxic effect of temozolomide. Further, methadone did not induce cellular senescence and had no effect on temozolomide-induced senescence. Although methadone was toxic on senescent cells, it cannot be considered a senolytic drug since cytotoxicity was not specific for senescent cells. Finally, we show that methadone had no impact on the MGMT promoter methylation. Overall, the data show that methadone on glioblastoma cells in vitro is cytotoxic and induces apoptosis/necrosis at doses that are above the level that can be achieved in vivo. It is not genotoxic, and does not ameliorate the cell killing or the senescence-inducing effect of temozolomide (no synergistic effect), indicating it has no impact on temozolomide-induced signaling pathways. The data do not support the notion that concomitant methadone treatment supports temozolomide-based chemotherapy.

Unpredictable and Unusual Cause of Death Due to Methadone Intoxication: A New Disaster in Healthy Human Being, the Problems of Toxicology Investigation and Pathology Diagnosis: A Case Report

Objective: To demonstrate the medical morbidity risk factors of methadone intoxication in normal persons and non-opioid-user, and to show that methadone is a new disaster in Thailand. Case Report: A 35-year-old man was found dead with an unknown cause. No evidence of violence was found at the scene of death. Autopsy confirmed that death was not related to any injuries or diseases. Gross and microscopic pathologies of pulmonary and brain edema were obvious, which were caused by anoxia. No other abnormal evidence of definite pathology was found. In the present case, toxicological analyses of toxic substances and drugs were performed by liquid chromatography-mass spectrophotometry-mass spectrophotometry (LC-MS-MS) and found that the blood methadone concentration was at the lethal concentration. Therefore, the cause of death in this case was methadone toxicity. The blood concentrations of methadone and 2-ethylidene-1, 5-dimethyl-3,3-diphenylpyrrolidine (EDDP) were 1.9 µg/ml and 0.058 µg/ml, respectively. The concentration ratio of methadone and EDDP was 32.7:1, which was more than the previous death cases of methadone toxicity. The other addictive substances, such as heroin, morphine, cocaine, or ethanol, were not detected in the present case by LC-MS-MS. Conclusion: Methadone was the cause of death in this case. There was no evidence of other causes of death, especially other opiates or opioids substances. This is a big problem, because methadone is used as the substitute for heroin addiction in Thailand. The authors claim that it will be the new disaster substance and become an important cause of death in Thailand and other parts of the world, because it has been prescribed worldwide for patients undergoing a program of opioid maintenance treatment (OMT). Methadone is not controlled well. The authors demonstrated that the deceased was not in the OMT program, and the cause of death was methadone intoxication, which was a very rare case. Keywords: Methadone, Opioids, EDDP, Morphine, Ethanol, Drug substitution

Effect of intramuscular methadone on pharmacokinetic data and thermal and mechanical nociceptive thresholds in the cat

Objectives The aim of the study was to assess simultaneous pharmacokinetics and thermal and mechanical antinociception after intramuscular methadone (0.6 mg/kg) in 10 cats. Methods Thermal and mechanical threshold (TT and MT, respectively) testing and blood collection were conducted at baseline and up to 24 h after administration. Methadone plasma concentrations were determined by liquid chromatography–tandem mass spectrometry and pharmacokinetic parameters were estimated by a non-compartmental method. TT and MT were analysed using ANOVA ( P <0.05). Time of maximum plasma concentration (Tmax), time of onset of antinociception and time of reaching cut-out threshold (TT 55°C; MT 30 Newtons [N]) were determined. Results TT and MT increased above baseline from 20–240 mins and 5–40 mins, respectively, after intramuscular (IM) administration ( P <0.005). Mean maximum delta T (measured as TT minus baseline threshold) was 7.9°C (95% confidence interval [CI] 4.3–11.6) at 60 mins and mean maximum delta F (measured as MT minus baseline threshold) was 4.2 (95% CI 1.6–6.7) N at 45 mins. IM methadone concentration–time data decreased curvilinearly, and gave a clearance estimate of mean 9.1 ml/kg/min (range 5.2–15.7) with median Tmax at 20 mins (range 5–360 mins). Conclusions and relevance IM data followed classical disposition and elimination in all cats. Plasma concentrations after IM administration were associated with an antinociceptive effect, including negative hysteresis. These data can be used for devising dosing schedules for methadone in clinical feline practice.

Cyclosporine-inhibitable Cerebral Drug Transport Does Not Influence Clinical Methadone Pharmacodynamics

Background: Interindividual variability and drug interaction studies suggest that blood–brain barrier drug transporters mediate human methadone brain biodistribution. In vitro and animal studies suggest that methadone is a substrate for the efflux transporter P-glycoprotein, and that P-glycoprotein–mediated transport influences brain access and pharmacologic effect. This investigation tested whether methadone is a transporter in humans sample contents. Methods: Healthy volunteers received oral (N = 16) or IV (N = 12) methadone in different crossover protocols after nothing (control) or the validated P-glycoprotein inhibitor cyclosporine (4.5 mg/kg orally twice daily for 4 days, or 5 mg/kg IV over 2 h). Plasma and urine methadone and metabolite concentrations were measured by mass spectrometry. Methadone effects were measured by miosis and thermal analgesia (maximally tolerated temperature and verbal analog scale rating of discreet temperatures). Results: Cyclosporine marginally but significantly decreased methadone plasma concentrations and apparent oral clearance, but had no effect on methadone renal clearance or on hepatic N-demethylation. Cyclosporine had no effect on miosis or on R-methadone concentration–miosis relationships after either oral or IV methadone. Peak miosis was similar in controls and cyclosporine-treated subjects after oral methadone (1.4 ± 0.4 and 1.3 ± 0.5 mm/mg, respectively) and IV methadone (3.1 ± 1.0 and 3.2 ± 0.8 mm, respectively). Methadone increased maximally tolerated temperature, but analgesia testing was confounded by cyclosporine-related pain. Conclusions: Cyclosporine did not affect methadone pharmacodynamics. This result does not support a role for cyclosporine-inhibitable transporters mediating methadone brain access and biodistribution.

Maternal Methadone Dose, Placental Methadone Concentrations, and Neonatal Outcomes

BACKGROUND Few investigations have used placenta as an alternative matrix to detect in utero drug exposure, despite its availability at the time of birth and the large amount of sample. Methadone-maintained opioid-dependent pregnant women provide a unique opportunity to examine the placental disposition of methadone and metabolite [2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)], to explore their correlations with maternal methadone dose and neonatal outcomes, and to test the ability to detect in utero exposure to illicit drugs. METHODS We calculated the correlations of placental methadone and EDDP concentrations and their correlations with maternal methadone doses and neonatal outcomes. Cocaine- and opiate-positive placenta results were compared with the results for meconium samples and for urine samples collected throughout gestation. RESULTS Positive correlations were found between placental methadone and EDDP concentrations (r = 0.685), and between methadone concentration and methadone dose at delivery (r = 0.542), mean daily dose (r = 0.554), mean third-trimester dose (r = 0.591), and cumulative daily dose (r = 0.639). The EDDP/methadone concentration ratio was negatively correlated with cumulative daily dose (r = −0.541) and positively correlated with peak neonatal abstinence syndrome (NAS) score (r = 0.513). Placental EDDP concentration was negatively correlated with newborn head circumference (r = −0.579). Cocaine and opiate use was detected in far fewer placenta samples than in thrice-weekly urine and meconium samples, a result suggesting a short detection window for placenta. CONCLUSIONS Quantitative methadone and EDDP measurement may predict NAS severity. The placenta reflects in utero drug exposure for a shorter time than meconium but may be useful when meconium is unavailable or if documentation of recent exposure is needed.

Concentrations of Methadone in Breast Milk and Plasma in the Immediate Perinatal Period

This study evaluates concentrations of methadone in breast milk and plasma among a sample of methadone-maintained women in the immediate perinatal period. Twelve methadone-maintained, lactating women provided blood and breast milk specimens 1, 2, 3, and 4 days after delivery. Specimens were collected at the time of trough (just before methadone dose) and peak (3 hours after dosing) maternal methadone levels. Paired specimens of foremilk (prefeed) and hindmilk (postfeed) were obtained at each sampling time. Although there was a significant increase in methadone concentration in breast milk over time for the peak postfeed sampling time, t (22) = 2.40, P = .0255, methadone concentrations in breast milk were small, ranging from 21 to 314 ng/mL, and were unrelated to maternal methadone dose. Results obtained from this study contribute to the recommendation of breastfeeding for methadone-maintained women regardless of methadone dose. J Hum Lact. 23(2):184-190.