According to the results, methadone led to QTc interval prolongation in 25% of the war casualties studied. However, no statistically significant relationship could be found between QTc prolongation on the one hand and methadone dosage, duration of treatment, and patients’ age on the other hand. Several large studies have been carried out to evaluate the relationship between the methadone duration of treatment and dosage on the one hand and QTc interval prolongation on the other hand. Some have reported significant relationship while others could not find such relationship.[1
] In the study carried out by Maremmoni et al. on 83 patients, who on average received daily 87 mg methadone (ranging from 10-600 mg/day), it was showed that 83% of the patients had QTc interval longer than the standard value for their age and sex. Nevertheless, the relationship between the QTc interval and methadone dosage was not statistically significant.[13
] Peles et al. performed a study on 138 patients who on average received daily 170.9 mg methadone (40-290 mg/day). They found a weak relationship between the QTc interval and dosage of methadone. However, the relationship was not statistically significant (P
= 0.1, R
] In another study, Huh et al. evaluated 130 patients, out of whom 90 patients used on average 30 mg methadone daily (5-80 mg/day). They also could not find a statistically significant relationship between methadone dosage and QTc interval (P
] In contrast, in some other study, an obvious relationship was found between methadone dosage and QTc interval. For instance, Ehret et al. studied 247 hospitalized patients, among whom 167 patients received on average 100 mg methadone daily (4-600 mg/day), and reported a statistically significant relationship between methadone dosage and QTc interval P
< 0.01, R
] In the study carried out by Cruciani et al. on 140 patients with the daily average receive of 110 mg methadone (20-1200 mg/day), it was observed that there was a statistically significant relationship between methadone dosage and QTc interval (P
= 0.0009, R
] Martell et al. carried out 2 studies; one on 132 patients with the daily dose of 30-150 mg/day of methadone and the other one on 160 patients with an average daily dose of 90 mg (20-200 mg/day), and reported a significant relationship between methadone dosage and QTc interval (P
= 0.03, R
] In several published cases and case reports, it has been reported that methadone with the daily doses of above 100 mg can cause torsade de pointes
arrhythmia and by reducing the methadone dose, the QTc interval became normal.[18
] Fanoe et al. reported that the QTc interval increased 10 ms by an increase of 50 mg in methadone dose (CI: 1.1-1.4, odds ratio: 1.2).[21
The above-mentioned studies were performed in prospective and retrospective manner and under various conditions, and a general conclusion cannot be obtained from them. However, it is important for physician to know that sudden death have been reported with methadone even at the dose of 29 mg/day.[1
] This suggests that arrhythmia may occur in a wide range of therapeutic doses, including the doses frequently used in treatment of chronic pains and addicts.[1
] As it was mentioned, in the current study, a significant relationship could not be found between the prolongation of QTc interval on the one hand, and dosage of methadone, duration of taking the drug, and the patients’ age on the other hand. It was demonstrated that QTc prolongation may occur at the mean daily methadone doses of 85.2 ± 59.0 mg; therefore, a safe dose cannot be suggested in this respect. The current study had some limitations in its methodology; for instance, lack of baseline ECG. But, as it was mentioned in the Methods section, we tried to reduce the confounding variables as much as possible by performing physical examination and history taking, evaluation of serum electrolyte levels, and exclusion of patients who received drugs that may prolong QTc interval.
As it was mentioned, electrolyte abnormalities like hypokalemia and also some drugs, such as tricyclic and tetracyclic antidepressants, SSRIs, antipsychotic agents, anti-arrhythmic drugs, antibiotics, and antihistamines may lead to QTc interval prolongation. These conditions and agents may interact with methadone in QTc prolongation,[1
] therefore, to prevent cardiac arrhythmia and sudden death in those taking methadone, suggestions are provided:
In a study, replacement of R-S-methadone with R-methadone was suggested[24
] since it seems that R-methadone leads to hERG channel block less frequently.
The authors provide the following recommendations for prevention of cardiac arrhythmia and sudden death in war casualties and those who receive methadone for any cause. The suggestions can be employed as a screening protocol by physicians prescribing methadone: (1)
Physicians are better to take a complete history of the patients on the history of structural diseases of heart, arrhythmia, and syncope. Physicians are better to warn patients on the risk of cardiac arrhythmia occurrence. Physicians should be aware of drug interactions of methadone with the agents which may prolong QTc interval or decrease an excretion of methadone.
Before initiating methadone, take an ECG from the patient and calculate the QTc interval. Moreover, in the follow-ups, one month after initiating the drug and annually, take ECG. In case of taking methadone doses above 100 mg or an occurrence of unexplainable syncope or convulsion, taking ECG at shorter intervals is recommended. If the QTc interval was more than 450 ms and less than 500 ms, the risks and benefits of the drug should be explained to the patient and monitor him / her more closely. If the QTc interval became more than 500 ms, the drug should be discontinued or the dose be reduced. Furthermore, the predisposing factors of hypokalemia should be removed, and if drugs with the risk of QTc prolongation are used simultaneously with methadone, they or methadone should be discontinued and an alternative medicine be prescribed.