Acute Methadone Overdose Research Articles

Time-Dependent Changes in the Serum Levels of Neurobiochemical Factors After Acute Methadone Overdose in Adolescent Male Rat.

Acute methadone toxicity is a major public health concern which has adverse effects on brain tissue and results in recurrent or delayed respiratory arrest. Our study aimed to investigate the time-dependent changes in several serum biochemical markers of brain damage, spatial working memory, and the brain tissue following acute methadone overdose. Adolescent male rats underwent an intraperitoneal (i.p.) injection of 15mg/kg methadone. In case of apnea occurrence, resuscitation was performed by a ventilatory pump and administrating naloxone (2mg/kg; i.p.). The animals were classified into groups of treated rats; methadone and naloxone-Apnea (M/N-Apnea), M/N-Sedate, Methadone, Naloxone, and control (saline) groups. The serum levels of S100B, neuron-specific enolase (NSE), myelin basic protein factors, and (Lactate/Pyruvate) L/P ratio were evaluated at the time-points of 6, 24, and 48h (h). We found that the alterations of S100B and L/P ratio were considerable in the M/N-Apnea and Methadone groups from the early hours post-methadone overdose, while NSE serum levels elevation was observed only in M/N-Apnea group with a delay at 48h. Further, we assessed the spatial working memory (Y-maze test), morphological changes, and neuronal loss. The impaired spontaneous alternation behavior was detected in the M/N-Apnea groups on days 5 and 10 post-methadone overdose. The morphological changes of neurons and the neuronal loss were detectable in the CA1, striatum, and cerebellum regions, which were pronounced in both M/N-Apnea and Methadone groups. Together, our findings suggest that alterations in the serum levels of S100B and NSE factors as well as L/P ratio could be induced by methadone overdose with the presence or absence of apnea before the memory impairment and tissue injury in adolescent male rats.

Delay-Dependent Impairments in Memory and Motor Functions After Acute Methadone Overdose in Rats.

Methadone is used as a substitution drug for the treatment of opioid dependence and chronic pain. Despite its widespread use and availability, there is a serious concern with respect to the relative safety of methadone. The purpose of this study was to characterize how acute methadone overdose affects the cognitive and motor performance of naïve healthy rats. The methadone overdose was induced by administering an acute toxic dose of methadone (15 mg/kg; ip; the equivalent dose of 80% of LD50) to adolescent rats. Resuscitation using a ventilator pump along with a single dose of naloxone (2 mg/kg; ip) was administered following the occurrence of apnea. The animals which were successfully resuscitated divided randomly into three apnea groups that evaluated either on day 1, 5, or 10 post-resuscitation (M/N-Day 1, M/N-Day 5, and M/N-Day 10 groups) in the Y-maze and novel object memory recognition tasks as well as pole and rotarod tests. The data revealed that a single toxic dose of methadone had an adverse effect on spontaneous behavior. In addition, Recognition memory impairment was observed in the M/N-Day 1, 5, and 10 groups after methadone-induced apnea. Further, descending time in the M/N-Day 5 group increased significantly in comparison with its respective Saline control group. The overall results indicate that acute methadone-overdose-induced apnea produced delay-dependent cognitive and motor impairment. We suggest that methadone poisoning should be considered as a possible cause of delayed neurological disorders, which might be transient, in some types of memory or motor performance in naïve healthy rats.

Risk Factors for Mortality and Endotracheal Intubation after Methadone Intoxication.

This was a retrospective chart review to evaluate various risk factors associated with in-hospital mortality and intubation risk in acute methadone overdose. All patients admitted to an academic hospital in Tehran, Iran, during a 10-year period (2000-2009) constituted the study sample. Exclusion criteria were significant comorbidities and age under 18 years. Outcome variables were in-hospital mortality and being intubated during admission. A total of 802 patients were enrolled in the study. There were 15 (1.8%) deaths due to methadone overdose or its complications. The number of yearly admissions was 15 patients in 2000, 16 in 2001, 16 in 2002, 18 in 2003, 23 in 2004, 38 in 2005, 59 in 2006, 110 in 2007, 206 in 2008 and 301 in 2009. Based on logistic regression analysis, the most important independent variable predicting mortality was length of admission in toxicology ward [OR (95% CI): 1.6 (1.1-2.3)]. For the prediction of intubation, independent variables were Glasgow Coma Scale (GCS) score of 5-9 [OR (95% CI): 356.5 (9.8-12907.4)] in the emergency department (ED), miosis in the ED [356.9 (1.4-87872.5)] and respiratory rate in the ED [1.5 (1.1-2.1)]. Linear regression model for length of hospitalization showed patient age as the most important variable for prediction of this outcome. Despite a relatively low mortality rate, the increasing number of methadone-poisoned patients requires special attention to this common intoxication. Careful disposition of patients from ED to ordinary wards or intensive care units and also from higher to lower levels of care should be considered in methadone overdose.

Letter to the Editor in Response to: The Correlation Between Prolonged Corrected QT Interval with the Frequency of Respiratory Arrest, Endotracheal Intubation, and Mortality in Acute Methadone Overdose

Letter to the Editor in Response to: The Correlation Between Prolonged Corrected QT Interval with the Frequency of Respiratory Arrest, Endotracheal Intubation, and Mortality in Acute Methadone Overdose

The correlation between prolonged corrected QT interval with the frequency of respiratory arrest, endotracheal intubation, and mortality in acute methadone overdose.

Corrected QT interval (QTc) prolongation is long considered as a predisposing factor for the occurrence of torsade de pointes (TdP) and sudden cardiac arrest in methadone maintenance treatment. We aimed to elucidate the correlation between QTc prolongation and in-hospital death, respiratory arrest, and endotracheal intubation in acute methadone-intoxicated patients presenting to the emergency department and to assess the value of QTc in predicting these outcomes. A prospective cross-sectional study with a convenience sample of patients with acute methadone overdose was done. Participants were 152 patients aged 15-65 with negative urinary dipstick test for cyclic antidepressants, no history of other QTc-prolonging conditions and co-ingestions, no severe comorbidities affecting the outcomes, and positive urinary dipstick results for methadone. QTc intervals were measured and calculated in triage-time electrocardiogram (ECG). Death was correlated with QTc (P=0.014) and length of ICU admission (P<0.001). In multivariable analysis, death was independently associated only with length of ICU admission [odds ratio (OR) 95% confidence intervals (95% CI) 1.36 (1.14-1.61)]. Intubation and respiratory arrest were independently associated with QTc interval [OR (95% CI) 1.03 (1.02-1.04) and 1.02 (1.01-1.03), respectively]. The receiver operating characteristics curves drawn to show the ability of QTc to predict death, intubation, and respiratory arrest showed thresholds of 470, 447.5, and 450ms with sensitivity (95% CI) and specificity (95% CI) of 87.5 (47.3-99.7), 86.8 (74.7-94.5), and 77.3 (62.2-88.5), respectively. Our study showed that QTc is a potential predictor for adverse outcomes related to acute methadone intoxication. The correlations shown in this study between triage-time QTc and in-hospital respiratory arrest or intubation in methadone overdose may be of clinical value, whether these outcomes are hypothesized to be a reflection of background TdP or intoxication severity.

Methadone toxicity: comparing tablet and syrup formulations during a decade in an academic poison center of Iran

Context. Due to an increase in the number of methadone maintenance clinics in the past decade in Iran, acute methadone overdose has become one of the common poisonings in our society. Objective. To compare the characteristics of methadone poisoning between syrup and tablet formulation as well as to discuss the relative advantages and disadvantages of poisoning from the perspective of toxicity. Material and methods. In a retrospective cross-sectional study from 2000 to 2010, sampled data of all hospitalized methadone-overdosed patients were collected through chart review of hospital records. Concurrently, the total number of methadone sales was gathered. Results. A total of 1426 patients with methadone poisoning had been hospitalized, including 1072 cases who consumed syrup or tablet solely. Mean ± SD milligram ingested dose of syrup and tablet were 153 ± 339 and 88 ± 274, respectively (p < 0.001). The mean time elapsed since ingestion was 9 ± 9 and 7 ± 7 h, respectively. Most of the accidental poisoning cases occurred as a result of syrup formulation, particularly by children under 12 years old after being mistaken for cough mixture or water. Conversely, exposure to methadone tablets was more common in patients with suicidal intent. There was no statistically significant difference between the rates of intubation and death between the two groups. Discussion. Higher doses of methadone in the syrup form appear to exert a similar severity of poisoning and outcomes compared to lesser doses of that in the tablet form. Similarities in outcomes, despite differences in exposure history, may reflect relatively prompt transfer to hospital and adequate provision of clinical care, including supportive care and naloxone. Conclusion. In order to reduce the rate of poisoning, we recommend the use of child-resistant containers for dispensing syrup, reduction in methadone concentration, adding a coloring agent, special flavor, and education of patients on the safe storage of methadone in their home in order to reduce the occurrence of accidental poisonings.

Effectiveness of Naltrexone in the Prevention of Delayed Respiratory Arrest in Opioid-Naive Methadone-Intoxicated Patients

Acute methadone toxicity is a major public health concern in Iran. Methadone-intoxicated patients are in a great risk of recurrent or delayed respiratory arrest despite the prescription of initial doses of naloxone. This study aimed to evaluate the effectiveness of oral naltrexone in the management of acute methadone overdose in opioid-naive patients and check if it could be a substitute of continuous infusion of naloxone in maintaining adequate ventilation. In a randomized, double-blind, placebo-controlled study, a total of 54 opioid-naive patients with acute methadone toxicity were enrolled. The patients received either oral naltrexone or placebo capsules after awakening by naloxone. All patients underwent close monitoring of respiration. Frequency of respiratory depression or arrest, need for another dose of naloxone, duration of hospital stay, and adverse outcomes compared between the two groups. The incidence of respiratory depression was significantly less in those who had received naltrexone. Our results show that single oral dose of naltrexone is quite efficient in the prevention of recurrent or delayed respiratory arrest in opioid-naive methadone-intoxicated patients. It can shorten the duration of hospitalization and, as a consequence, decreased the risk of complications. Further studies are warranted before the generalization of this approach to other patient populations.