Owing to its high clinical efficacy, methadone is used for intractable cancer pain for which other opioid analgesics are not sufficiently effective; however, it is likely that QT interval prolongation is a serious side effect [3, 4, 9]. High-dose methadone administration and electrolyte imbalances have been listed as risk factors for QT interval prolongation [10], and testing these is thus recommended when starting methadone [11]. In addition, the concomitant use of drugs with a risk of QT interval prolongation increases the risk of QT interval prolongation due to methadone [6]. In fact, Winton et al. reported a case of QT interval prolongation due to a combination of methadone and azithromycin [12].

The PubMed database (MeSH terms: methadone and levofloxacin) did not include reports on QT interval prolongation in combination with methadone for LVFX, which was administered to prevent brain abscess recurrence. Because LVFX can increase the risk of QT interval prolongation [7], we considered switching to other antibacterial agents before introducing methadone. However, we continued with LVFX. Although this was not a high-dose methadone administration case, because it was used in combination with drugs that have a risk of QT interval prolongation, we assumed that the risk of QT interval prolongation could have increased and performed frequent electrocardiograms (ECGs). A 12-lead ECG was performed once every seven days for routine examination. In addition, a pharmacist took simple ECG measurements using a health monitor (Checkme ProX, SAN-EI MEDISYS, Japan). Based on the results of the simple ECG, we performed an additional 12-lead ECG test in addition to the regular examination if there was a possibility of QT interval prolongation when the QTc value was 500 ms or more, or when the QTc was increased by 25% or more from baseline (QTc before methadone introduction) [9]. Before the introduction of methadone, QTc was within the normal range on both the 12-lead ECG and simple ECG. However, on day 3, after initiating methadone in combination with LVFX (day 16), a simple ECG revealed an 8.4% QTc increase from baseline (Fig. 3). Although the criteria for performing an emergency 12-lead ECG were not met, QTc tended to be prolonged in combination with a drug with a risk of QT interval prolongation. At this time, no decrease in respiratory rate during sleep was observed; therefore, we judged that the prolonged QTc was not derived from methadone overdosage (Fig. 4). Therefore, we considered it necessary to switch from the LVFX to another antibiotic. Considering the results of the bacterial culture of pus during brain abscess treatment, we changed LVFX to ST for preventing the recurrence of the brain abscess. Subsequently, a simple ECG on day 17 improved QTc to the same level as the baseline, and a 12-lead ECG on day 18 did not show an increase in QTc (Fig. 3). As such, we responded before the QTc increased enough to meet the diagnostic criteria for QT interval prolongation and prevent the occurrence of drug-induced long QT syndrome and torsades de pointes.

Other risk factors for QT interval prolongation in this case may include abnormal laboratory values and other concomitant medications. Hypokalemia, hypocalcemia, and hypomagnesemia are factors known to increase the risk of QT interval prolongation due to methadone; however, these abnormalities were not observed in tests conducted before and after starting methadone (Table 1). The risk of QT interval prolongation with concomitant medications other than methadone and LVFX has been reported in ST [13, 14], Lactulose [15], and Vonoprazan [16] (Table 2). Regarding QT interval prolongation due to ST, mutations in MinK-related peptide 1, a subunit of the cardiac potassium channel involved in hereditary long QT syndrome, are involved, and the effect is negligible in the wild type [14]. In addition, QTc decreased after changing from LVFX to ST, which suggests that our judgment was valid. Yuan et al. reported an increase in QTc due to lactulose, but they noted that this may be due to the effects of severe liver dysfunction in the patient’s background, rather than the effect of lactulose itself [15]. Therefore, it is difficult to think that the QT interval prolongation in this case was caused by lactulose. There exists a case report regarding the effect of Vonoprazan on QT interval prolongation [16]. However, in a phase I randomized trial of Vonoprazan, it did not affect the QT/QTc interval in healthy participants, its safety for the heart was confirmed [17], and it is unlikely to be considered a typical side effect. Therefore, we posit that the effect on QTc increase was negligible in this case. No marked decrease in renal function, which is the main excretion route of LVFX and is an indicator of dosage, was observed. Therefore, the QTc increase was considered unlikely to be due to LVFX overdose (Table 1). Regarding liver function, which is thought to affect the metabolism of methadone, an increase above the standard value was observed before starting methadone due to the influence of a metastatic liver tumor (Table 1). However, as mentioned above, no significant decrease in respiratory rate was observed during sleep onset; therefore, although it is possible that methadone metabolism had some effect, the increase in QTc is unlikely to be due to methadone overdose. Further, when the interaction between methadone and LVFX was evaluated using the Drug Interaction Probability Scale (DIPS) [18], the DIPS score was “4” and judged as “Possible.” Considering this in conjunction with the clinical course, the QTc increase in this case may be owing to the combined use of methadone and LVFX, which improved by switching to ST.

When considering the use of methadone for intractable cancer pain, it is important to eliminate possible risk factors for QT interval prolongation as much as possible. However, as it may be difficult to discontinue concomitant drugs owing to comorbidities, there may be cases in which the risk of QT interval prolongation could increase, even with the introduction of low-dose methadone. In such cases, frequent monitoring, even with simple measurements, such as those used in this case, is likely to detect adverse events at an early stage and prevent progression to more serious conditions.