To our knowledge, this is the first study to investigate reporting of syncope in a population treated for heroin dependence. Syncope is difficult to deal with as it is very rare and a large number of patients are required to measure the incidence. In this special population, syncope can be caused by many factors—for example, use of heroin and other drugs. Alternating use of benzodiazepines can also lead to epileptic convulsions and syncope.
We have found an increasing incidence of syncope with higher doses of methadone. This could be explained by more excessive misuse of opioids by patients at a higher methadone dose. According to the self‐reported misuse of opioids during the past week, this is probably not the case. We found that misuse of opioid decreases with higher doses of methadone. Another explanation could be that methadone causes QT prolongation, which increases the incidence of TdP. Even though the direct evidence cannot be provided from this study, this explanation seems plausible as it has been shown that methadone can block HERG‐channel,6
and blockade of these channels causes QT and QTc prolongation that can lead to TdP.17
In this population, we also found that a longer QTc is associated with higher odds for the reporting of syncope. Other studies have shown an association between the prolongation of QT/QTc interval and sudden death in populations without evidence of cardiac dysfunction.18,19
Potassium‐channel blockade could also be associated with syncope without TdP. A small study indicated that patients with genetic defects in potassium channels might faint due to neurocardiogenic reasons.20
Autonomic neuropathy could also account for syncope in this population. Villa et al21
have shown that autonomic neuropathy is present in a population which mostly comprised of drug users. According to Cencetti et al
autonomic neuropathy can affect the control of cerebral circulation and thereby cause syncope not related to cardiac arrhythmias.
In this study, we also found a significant association between methadone dose and QT and QTc interval. This finding is in agreement with Martell et al
who, in a prospective study, found a significant QTc prolongation during 6‐ and 12‐months treatment with methadone. Similarly, Kornick et al24
showed a dose‐dependent QTc prolonging effect of intravenous methadone compared with intravenous morphine. In a retrospective study, Ehret et al25
have also found an association between methadone dose and QTc interval. This study also showed that discontinuation of methadone was associated with shorter QTc interval. However, Maremmani et al26
did not find any correlation between oral methadone dosage and QTc, although they found that patients on long‐term methadone maintenance therapy had longer QT interval compared with people not on long‐term methadone of the same sex and age. The reason that Maremmani et al
did not find a correlation might be the measuring technique applied by them. Measuring QT intervals is not easy especially when U waves are present. In this study, U waves are not included in the QT interval. Martell et al
also describe strict criteria for including the U wave in the QT interval. Maremmani et al
do not describe their technique regarding the inclusion of the U wave or whether the QT intervals are measured manually or automatically.
In the multivariate linear regression of the data from participants who gave blood sample, it was found that the QT lengthening effect of 200 mg methadone was roughly equivalent to that of a l mM lower s‐potassium. The duration of the methadone‐maintenance therapy was not associated with the length of the QT interval. The fact that the current dose rather than cumulated dose affects the QT interval indicates a purely reversible mechanism such as temporary blocking of ion channels. This supports Katchman et al6
who did voltage‐clamp recordings on cells expressing the HERG gene which codes for the ion channel leading the Ikr
current. These voltage‐clamp experiments showed that methadone blocks the HERG channels, mimicking the molecular defect in LQT2. This is also in agreement with Ehret et al25
who showed that discontinuation of methadone was associated with shorter QTc interval.
This study is the first to investigate the association between buprenorphine and the QT interval in a group of patients treated with buprenorphine. The buprenorphine group was much smaller than the methadone group, but it corresponds to the proportion of patients treated with buprenorphine in the total population of heroin dependents in the city of Copenhagen. The patients treated with buprenorphine were on an average 3.2 years younger than the patients treated with methadone. Despite the differences between the two groups, we believe that this group is a better control group than a normal population. We did not find any patient with prolonged QT interval in the group treated with buprenorphine and we were not able to find any correlation between buprenorphine and QT interval or QTc. Buprenorphine is known to block HERG in vitro, but only at concentrations much higher than those found in patients treated with buprenorphine. Katchman et al6
found that the IC50:Cmax ratio for buprenorphine was 208, whereas it was only 2.7 for methadone.
The fact that the patients treated with buprenorphine only received low doses made us cautious in excluding a QT prolonging effect of buprenorphine at higher doses. However, Krantz et al27
have reported that a patient with methadone‐related TdP was successfully treated with buprenorphine instead of methadone.