Methadone has been used therapeutically to alleviate pain in patients with chronic disease and to reduce and control withdrawal syndrome in patients who suffer opioid dependency syndrome in methadone maintenance treatment (MMT) clinics [11]. It has a high potential for abuse and may be used illicitly by opioid-dependent patients [11].
Methadone is well known for its long duration of action and potential for fatality in overdose. This places significant health care and economic burdens on society, especially where death occurs. Mortality costs attributed to methadone accounted for approximately 6.5 million dollars in 2009 in the US [12]. Other studies showed that patients who receive methadone to alleviate chronic pain in pain clinics are at higher risk of mortality [11]. Patients who have chronic pain tend to be older individuals in poorer health who may be receiving multiple medications and experiencing high levels of depression and anxiety. Methadone may be abused by individuals with opioid misuse disorder, which increases its risks [11]. Our study demonstrated that rates of methadone toxicity in the US, as reflected in the ToxIC database, appeared to increase until 2013–2014, after which there was a decline. Since the ToxIC database is a reflection of cases for which medical toxicology consultation was required, it is likely that more trivial cases are not included. Thus, these data should be interpreted as reflecting significant poisonings.
Another study with different study period has shown that hospital discharge frequency for methadone poisoning rose dramatically through 1997–2007, and then significantly declined through 2007–2014 [13]. This discrepancy may be due to the different study periods and study populations. In that study, the authors analyzed national trends in inpatient and emergency department discharges for opioid abuse, dependence, and poisoning, but in this study, we analyzed just inpatient methadone poisoning cases. In 2005, the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System reported that there was a correlation between the increasing trend in methadone prescriptions and the degree of diversion and abuse, with no meaningful difference in the number of people on methadone maintenance therapy [14]. More recently, the number prescriptions for all opioids has decreased, associated with awareness by practitioners of the dangers of opioids, and national, state, and local measures for reducing the prescribing of opioids [13, 15,16,17].
The US Centers for Disease Control and Prevention reported that prescriptions for opioids peaked in 2012, with greater than 255 million filled (81.3 prescriptions for every 100 persons). The total national opioid prescription frequency then decreased between 2012 and 2017, with the lowest rate in the last ten years in 2017, at 58.7 prescriptions for every 100 persons. However, this still represents more than 191 million opioid prescriptions filled [18]. This is consistent with our data. We showed a peak in methadone poisoning in 2013 and 2014, and after that, there was a decline in the number of methadone poisoning cases.
In our study, the mortality rate due to methadone poisoning was 1.4%. However, our patients were admitted to hospitals and thus were alive at presentation. It is possible, however, that the rate of death from methadone poisoning in cases that do not reach a hospital is much higher [19].
Methadone abuse is an important ongoing epidemic, and the 2017 data from the National Poisoning Data System illustratively contains 1054 single methadone poisonings, 456 intentional methadone overdoses, and 56 deaths associated with methadone [20]. Similarly, in a study by Dart et al., methadone was the leading opioid as a cause of death in the NPDS, with 178 cases in 2012 [4].
Coma and respiratory depression were the most common signs of severe methadone toxicity in our study. In a cohort of prescription opioid overdose patients, methadone was the second most commonly prescribed opioid after oxycodone. They showed that the risk factors for severe respiratory depression in patients with prescription opioid overdose include drug misuse (pertinent for methadone), increased age, and the specific opioid medication involved. In that study, methadone had a much higher risk of severe respiratory depression [21]. Other studies revealed that a history of a substance use disorder was closely associated with the development of opioid-induced respiratory depression, with an odds ratio of 12.7 [22].
Patients experiencing these complications ingested a mean of 104 mg, which is a lower average dose than our entire cohort. This is likely because non-opioid-tolerant patients are the most vulnerable to adverse effects of opioids, even at lower doses, and there was an over-representation of acute ingestions in the group with coma and respiratory depression. Almost 3% of patients had QTc prolongation, a known, yet uncommon, adverse effect of methadone [1]. It should be noted that the ToxIC Registry does not record minor prolongations of the QT interval. The criterion for QTc prolongation in our database is for it to be over 500 milliseconds. Thus, the actual number of cases that had less consequential QT prolongation was undoubtedly higher. However, complications such as torsade de pointes are unlikely at these lower QTc intervals. Nine and a half percent of our patients had acute kidney injury (AKI). Methadone-induced AKI, which may be a consequence of rhabdomyolysis, has been previously reported [23].
Interestingly, we found that 2% of patients experienced seizures. Most of these patients ingested a high dose of methadone. Methadone-induced seizure has been previously reported [24]. Few studies have evaluated the convulsive effects of methadone and the mechanism behind it. Animal studies showed that acute administration of methadone could substantially reduce the seizure threshold. NMDA and μ-opioid receptors may be involved in methadone’s convulsive activity in the acute methadone overdose [25].
In our study, it was found that just half of the patients with respiratory depression received naloxone. Similarly, Aghabiklooei et al. evaluated 322 serious pure methadone-poisoned patients. In their study, naloxone was administered for the treatment of respiratory depression to 40% of cases in the emergency department or during hospitalization [26]. As with any opioid poisoning, patients with respiratory depression or hypoxia require either naloxone administration or mechanical respiratory support [27].
Limitations
The number of centers in the ToxIC Registry has changed over time. This is because the quality control procedures in ToxIC have caused poorly performing centers to be dropped, while new centers have joined the Consortium. The total number of cases reported each year has not varied widely, suggesting that the time trends we observed were not due to changes in the total number of cases reported to the ToxIC Registry. Further, as reviewed above, our time trends of serious methadone poisoning cases comport with those seen for all methadone poisonings in other national studies.
Secondly, we have reported the rates of consultations to medical toxicology services and not actual poisoning rates. Thus, our report likely represents the frequency of more serious cases of methadone toxicity. Because the treatment of methadone poisoning has not changed substantially over the study period, it is unlikely that the rate of consultation for serious cases could explain the decline starting in 2015. This suggests that professional and national efforts to curtail opioid toxicity have resulted in a trend of decreasing numbers of cases of serious methadone intoxication.
Understanding the pattern of opioid use in the US is necessary before effective measures to reduce morbidity and mortality from opioid use can be instituted. The opioid epidemic continued to increase after 2017; however, we could not present that data after 2018. Despite this, the time trends represent a component of the overall dynamic of “waves of the opioid epidemic.” By 2018, the “third wave” created by fentanyl and its analogs was underway, with methadone playing a lesser role.
