Methadone Administration in Critically Ill Patients in the Intensive Care Unit and Risk of Prolonged QTc and Cardiac Arrythmia

Continuous infusion of short-acting synthetic opioids, primarily remifentanil, is widely used for anesthesia and analgesia in ventilated patients in the intensive care unit (ICU) due to its short half-life, which is independent of hepatic or renal clearance, which may be reduced or unpredictable in these patients [1,2]. However, prolonged exposure results in rapid development of drug tolerance, opioid-induced hyperalgesia (OIH), and severe iatrogenic opioid withdrawal syndrome (IOWS) with abrupt discontinuation or rapid down-titration of the drug [1-3]. IOWS is characterized by withdrawal symptoms including delirium, restlessness, increased blood pressure, onset of sharp pain, increased respiratory and heart rates, and consequently increased metabolic demand. All of the above are undesirable and potentially dangerous in critically ill patients, and may compromise the chances of successful respiratory withdrawal in these patients [2,4].

To alleviate these symptoms and facilitate successful respiratory withdrawal, a long-acting opioid, such as methadone, can be used as a bridge. The use of a long-acting opioid may help prevent opioid withdrawal syndrome. Clinical protocols exist for the use of enteral methadone (oral or via gavage) for this purpose [2,4,5]. Methadone is a fully synthetic μ-opioid receptor agonist with high gastrointestinal bioavailability (>80%) and a long half-life (15-60 hours) [2,6]. This pharmacokinetic profile provides sustained plasma concentrations that avoid the sharp troughs associated with infusion of a short-acting opiate [5,6]. Furthermore, methadone acts as a non-competitive antagonist at the N-methyl-D-aspartate (NMDA) receptor [6,7]. By reducing central NMDA-mediated sensitization, methadone reduces OIH and attenuates acute tolerance that develops during chronic exposure to remifentanil, making it an effective pharmacological "bridger" in intensive care [2,5,7]. Methadone's activity at the NMDA receptor also has an analgesic effect that is not mediated through opioid receptors. Methadone is not cleared renally, so renal failure, which is common in critically ill patients, does not affect its clearance. Even in situations of hepatic insufficiency, very severe liver damage is required to have an effect on methadone clearance, an additional advantage of its use in critically ill patients. In addition, compared to other opioids (such as OxyContin or Fentanyl), methadone does not produce a significant euphoric feeling, which reduces its potential for addiction.

Although methadone is an old and well-known substance, and despite its advantages as discussed above, along with the existence of treatment protocols [4,5], the use of methadone in the intensive care unit remains limited due to concerns about the potential for the development of fatal cardiac arrhythmias with its use [1,8]. Methadone inhibits the delayed rectifier potassium current (I_Kr) by blocking the anthraquinone-related gene (hERG) potassium channel, which may delay ventricular repolarization, prolong the corrected QT interval (QTc), and predispose patients to dangerous arrhythmias such as torsades de pointes (TdP [1,8,9]. Furthermore, many patients in intensive care receive other medications that may prolong the QTc interval (macrolide or fluoroquinolone antibiotics, antipsychotics for the treatment of delirium such as haloperidol or Zyprexa, gastrointestinal motility agents such as peramin or erythromycin, etc.) and/or have other disorders that may prolong the QTc interval, such as hypokalemia, hypomagnesemia, or hypocalcemia.

However, current perceptions regarding Methadone-induced arrhythmias are largely derived from patients receiving methadone maintenance therapy (MMT) in outpatient settings for the treatment of chronic opioid use disorder [1,3,8]. These outpatient treatment groups differ substantially from critically ill patients in intensive care undergoing short-term opiate withdrawal protocols [1,8,9]. MMT regimens routinely use high, sometimes escalating doses of methadone (often >100-120 mg/day) over years, these patients often take other unregulated illicit substances in addition to their "legal" methadone treatment (opioid drugs, drugs from other classes, or prescription drugs taken illegally), and these patients often have other metabolic disorders resulting from their general poor condition (malnutrition, dehydration, untreated electrolyte abnormalities, and other chronic diseases). [1,8,9]. In contrast, protocols for administering methadone to patients in intensive care include significantly lower doses of the drug administered for a relatively short period of time (days to weeks, in exceptional cases months, typical doses of 20-60 mg per day for most patients), patients are under continuous cardiac monitoring (ECG monitor, in some cases, as in our unit, there is also continuous monitoring of the QTc interval throughout the day), monitoring of potassium, magnesium and calcium values and clinical pharm