ABSTRACT
Objective:
Given the prevalence of methadone poisoning, this study was conducted to compare the cardiovascular complications following acute methadone poisoning in patients with and without a history of long-term methadone use.
Methods:
In this retrospective study, information related to patients with acute methadone poisoning hospitalized at Al-Zahra and Khorshid hospitals in Isfahan-Iran was collected from hospital archives and analyzed. Patients were divided into two groups with and without a history of long-term methadone use.
Findings:
The mean of corrected QT interval (QTc), QRS, and heart rate showed no significant differences between the two groups at three-time points: baseline (upon admission), 12 h, and 24 h after admission (P > 0.05). The mean QT dispersion upon admission and 12 h after admission did not differ significantly between the groups (P > 0.05). However, the observation at 24 h postadmission indicated a significant increase in QT dispersion in the group with a history of long-term methadone use, showing a mean of 47.53 ± 10.62 ms compared to the without a history of long-term use group, with a mean of 26.78 ± 6.75 ms (P = 0.041).
Conclusion:
The results indicate that among the cardiovascular findings when analyzing the electrocardiograms of patients with acute methadone poisoning, only QT dispersion differed between patients with and without a history of long-term methadone use. Cardiovascular events resulting from methadone poisoning are the significant factors contributing to patient mortality, highlighting the need for the careful management of methadone use in these patients.
KEYWORDS: Electrocardiogram, Heart, Methadone, QT dispersion, Toxicity
INTRODUCTION
Methadone is a derivative of diphenylheptanes that is used as a clinical analgesic.[1] It is a slow metabolism synthetic opioid, leading to substantial accumulation in the adipose tissue resulting in a longer duration of action compared to morphine-based opioids. The half-life of this drug varies between 15 and 60 h, depending on patient conditions such as genetic differences, age, and concomitant medications.[2,3] In Iran, methadone maintenance treatment began in 2003 and has gradually expanded.[4]
After administration, methadone levels in the blood slowly reach their peak within 4 h. Methadone has a narrow therapeutic index, and the difference between therapeutic and toxic levels in the blood is small; therefore, the initial dose of methadone should be administered under close supervision to prevent potential adverse effects such as respiratory depression, as the same dose can have various effects on different individuals.[5,6] Tolerance and physical dependence develops more slowly than morphine. The highest risk of methadone toxicity occurs in the early days of treatment, during which balance is achieved between the levels of methadone in tissues and blood, established through regular use by the patient.[7] Despite the proven success of this treatment method with methadone in many countries, careless and irresponsible prescribing can lead to risks. Even low doses combined with other substances and medications can pose significant dangers; thus, prescribing must be done with great care and caution.[8]
Methadone toxicity can lead to clinical manifestations including decreased alertness, reduced respiratory rate (RR), and cardiovascular disturbances such as hypotension, cardiac arrhythmias, prolonged QT interval, nausea and vomiting, seizures, and miosis.[9,10]
There have been the reports of sudden deaths following the use of this medication, which appear to be related to prolonged QT intervals and the drug-induced onset of torsade de pointes arrhythmia. Some studies have indicated that the risk of cardiac complications from methadone use is minimal, suggesting that electrocardiogram monitoring in these patients is not indicated. However, others contend that at doses of higher than 100 mg per day, the risk of QT prolongation increases. Given the accessibility and low cost of electrocardiograms, it is advisable to conduct cardiac evaluations for all patients considering methadone treatment before starting and after any dosage changes.[11,12] Several factors increase the risk of QT interval prolongation in methadone users among them, in addition to high doses of methadone, the simultaneous use of medications that also prolong the QT interval or affect the metabolism of methadone should be noted. The presence of genetic factors, a positive family history of long QT syndrome, underlying arrhythmias, cardiac diseases, and electrolyte imbalances such as hypokalemia and hypomagnesemia are the predisposing factors for this cardiac complication in methadone users.[13,14]
Approximately 30% of patients undergoing methadone treatment are prone to prolonged QTc (corrected QT interval). High doses of methadone (100–400 mg/day) are a strong risk factor for prolonged QTc,[15] although the exact dose of methadone leading to prolonged QT was not determined in the study by Gheshlaghi et al.[15,16] Although methadone appears to be a safe drug, it can lead to cardiovascular complications and sudden death. Cardiac complications can occur across a wide range of methadone doses.[17,18] Given the high prevalence of methadone use and toxicity in the poisoning referral department of Isfahan province, along with the health threats it poses to patients, this study was conducted to compare the cardiovascular complications following acute methadone toxicity in patients with and without a history of long-term methadone use among the referrals to the poisoning departments of Al-Zahra and Khorshid hospitals in Isfahan.
METHODS
This retrospective study was done after obtaining ethical approval from the ethics committee of Isfahan University of Medical Sciences (IR.MUI.MED.REC.1400.094). All patients with acute methadone poisoning who were hospitalized in the poisoning wards of Al-Zahra and Khorshid hospitals in Isfahan during 1399 (2020) were included in a census manner.
Exclusion criteria included a history of heart disease, concomitant use of antiarrhythmic medications, treatment with antipsychotic drugs, cardiovascular drugs, and drug-induced QT prolongation, including antiarrhythmics, antipsychotics, and antidepressants, as well as patient discharge before the scheduled time at their request and the concurrent use of any narcotic or stimulant substances with methadone.
Patients were divided into two groups based on their history of long-term methadone use (more than 1 month) or no history of long-term methadone use. At the time of admission to the study, information was collected from the patient or a companion about the timing of methadone use, the dosage that led to toxicity, the concurrent use of other medications, the history of chronic methadone use (at least 4 weeks before admission), and the use of other opioids. In addition, the medical history and underlying health conditions were documented in the patient’s files. Other required data, including electrocardiogram (ECG) readings, heart rate (HR), RR, blood oxygen saturation percentage (SpO2), and systolic and diastolic blood pressure (SBP, DBP), were recorded at the time of hospital admission, as well as 12 h and 24 h after admission.
Three modified QT variables based on gender (QTc), QRS duration, and QT dispersion were also calculated using the recorded ECGs. ECG of the patients was evaluated upon admission to the hospital, 12 h later, and 24 h after hospitalization. For patients who were discharged before these time points, an electrocardiogram was conducted at the time of discharge, and if they were discharged after 24 h, an ECG was taken 24 h after admission.[19]
Although the QT interval is defined from the beginning of the QRS wave to the end of the T-wave, it tends to be longer at lower HRs and shorter at higher HRs. Therefore, many correction formulas have been proposed, among which the Bazett formula is reported here.
The QT dispersion variable is defined as the difference between the maximum and minimum QT interval between 12 ECG leads as follows.[20]
QT Dispertion = QTmax − QTmin
Finally, the collected information was entered into the Statistical Package for Social Sciences (SPSS) (version 26, SPSS Inc., Chicago, IL). Data were reported as mean ± standard deviation or frequency (percentage). At the level of inferential statistics, tests such as the Chi-square test, independent t-test, and one-way analysis of variance were used. In all analyses, the significance level was considered <0.05.
RESULTS
In the current study, 73 eligible patients were included in the study; of these, 46 patients had a long-term history of methadone use and 27 patients had no history of long-term methadone use. In the group with a history of long-term methadone use, 19 (70.4%) were male and 8 (29.6%) were female, with a mean age of 36.32 ± 10.71 years, and in the group without a history of long-term methadone use, there were 28 (60.9%) males and 18 (39.1%) females, with the mean age of 33.33 ± 18.21 years (P > 0.05). The highest frequency distribution of the cause of poisoning in the group with a history of long-term methadone use was due to abuse and in the group without a history of long-term methadone use was suicide (P < 0.001). In addition, in the group with a history of long-term methadone use, most of the people were poisoned by syrup, and in the group without a history of long-term methadone use, most of the people were poisoned by pills (P < 0.05). There was no significant difference between the mean number of tablets and the amount of syrup consumed between the two groups (P > 0.05). Furthermore, the two groups had no significant difference in terms of the patient’s clinical symptoms at the time of admission, treatment measures, length of hospitalization, and the treatment outcome (P > 0.05) [Table 1].
Table 1.
Basic and clinical characteristics of patients in the two groups
| Variables | With history of long-term methadone use (n=27), n (%) | Without history of long-term methadone use (n=46), n (%) | P |
|---|---|---|---|
| Sex | |||
| Male | 19 (70.4) | 28 (60.9) | 0.411 |
| Female | 8 (29.6) | 18 (39.1) | |
| Age (years) | 36.32±10.71 | 33.33±18.21 | 0.456 |
| Causes of poisoning | |||
| Substance abuse | 27 (100) | 14 (30.4) | <0.001 |
| Suicide | 0 | 24 (52.2) | |
| Accidental | 0 | 4 (8.7) | |
| Unknown | 0 | 4 (8.7) | |
| Ways of poisoning | |||
| Syrup | 17 (63) | 16 (34.8) | 0.021 |
| Pill | 10 (37) | 30 (65.2) | |
| Comorbidity | |||
| Cardiovascular | 0 | 3 (6.5) | 0.122 |
| Mental disorders | 6 (22.2) | 4 (8.7) | |
| Hypertension | 4 (14.8) | 3 (6.5) | |
| Diabetes | 1 (3.7) | 0 | |
| Thyroid disorders | 2 (7.4) | 3 (6.5) | |
| History of substance abuse | 25 (92.6) | 15 (32.6) | <0.001 |
| History of suicide attempts | 2 (7.4) | 7 (15.2) | <0.280 |
| Clinical signs of the patient upon admission | |||
| Pupil size | |||
| Miosis | 10 (37) | 32 (69.5) | 0.033 |
| Mydriasis | 1 (3.7) | 1 (2.2) | |
| Normal | 16 (59.3) | 13 (28.3) | |
| Level of consciousness status | |||
| Alert | 6 (22.2) | 13 (28.3) | 0.934 |
| Lethargy | 12 (44.4) | 20 (43.5) | |
| Obtundation | 6 (22.2) | 8 (17.4) | |
| Stupor | 1 (3.7) | 2 (4.3) | |
| Respiratory status | |||
| Respiratory depression | 4 (14.8) | 13 (28.3) | 0.497 |
| Respiratory distress | 2 (7.4) | 1 (2.2) | |
| Apnea | 1 (3.7) | 1 (2.2) | |
| Laboratory findings | |||
| Hypomagnesemia | 0 | 2 (4.3) | 0.390 |
| Hypokalemia | 1 (3.7) | 4 (8.7) | 0.380 |
| Therapeutic interventions* | |||
| Gastric lavage and charcoal therapy | 11 (40.7) | 24 (52.2) | 0.344 |
| Administration of naloxone | 17 (63) | 30 (65.2) | 0.805 |
| Treatment outcome | |||
| Recovery without complication | 22 (81.5) | 31 (67.4) | 0.447 |
| Recovery with complication | 2 (7.4) | 6 (13) | |
| Discharge with personal consent | 1 (3.7) | 4 (8.7) | |
| Dosage of the pill (mg) | 25.2±5.6 | 26.8±18.7 | 0.933 |
| Dosage of the syrup (mg) | 90±30 | 116.4±21.2 | 0.581 |
| Duration of hospitalization (h) | 41.7±7.50 | 38.81±4.33 | 0.723 |
| Time from medication to transfer to the hospital (min) | 7.02±1.01 | 9.25±2.43 | 0.497 |
*The patient may have received more than one therapeutic intervention
The mean of SpO2 levels between the two groups showed no significant differences at any of the follow-up times (P > 0.05). However, SBP in the 24 h following admission was significantly higher in the with a history of long-term methadone use group, with a mean of 122.44 ± 12.87 mmHg, compared to the without a history of long-term methadone use group, with a mean of 113.11 ± 10.81 mmHg (P = 0.002). In addition, DBP at 12 and 24 h after admission in the long-term methadone use group was significantly greater, with the mean of 74.43 ± 9.13 mmHg and 78.65 ± 9.86 mmHg, respectively, compared to the without history of long-term methadone use group, with the mean of 70.60 ± 8.72 mmHg and 72.63 ± 8.43 mmHg (P < 0.05). HR at 12 and 24 h after admission in the long-term methadone use group also showed a significant decrease, with the mean of 74.33 ± 14.63 bpm and 74.35 ± 13.34 bpm, respectively, compared to those without a history of long-term methadone use group, with the mean of 81.45 ± 12.56 bpm and 80.66 ± 12.87 bpm (P < 0.05).
In the reports obtained from the patient’s ECG, QTc duration and QRS duration were not significantly different between the two groups in any of the follow-up times (P > 0.05); While QT dispersion in 24 h after hospitalization in the long-term methadone use group with the mean of 47.53 ± 10.62 ms was significantly more than the without history of long-term methadone use group of the mean of 26.78 ± 6.75 ms (P = 0.041) [Table 2].
Table 2.
Vital signs and electrocardiogram examination of patients in the two groups
| Variables | With a history of long-term methadone use (n=27) | Without a history of long-term methadone use (n=46) | P |
|---|---|---|---|
| SPO2 (%) | |||
| Baseline | 88.32±8.90 | 89.11±11.11 | 0.761 |
| 12 h after admission | 87.02±10.00 | 85.01±9.21 | 0.668 |
| 24 h after admission | 94.30±8.26 | 95.11±10.15 | 0.161 |
| SBP (mmHg) | |||
| Baseline | 118.9±12.03 | 117.7±13.20 | 0.691 |
| 12 h after admission | 118.5±12.50 | 113.8±12.22 | 0.122 |
| 24 h after admission | 122.44±12.87 | 113.11±10.81 | 0.002 |
| DBP (mmHg) | |||
| Baseline | 71.04±11.10 | 73.12±9.77 | 0.700 |
| 12 h after admission | 74.43±9.13 | 70.60±8.72 | 0.041 |
| 24 h after admission | 78.65±9.86 | 72.63±8.43 | 0.004 |
| HR (bpm) | |||
| Baseline | 87.80±16.21 | 83.91±15.87 | 0.321 |
| 12 h after admission | 74.33±14.63 | 81.45±12.56 | 0.020 |
| 24 h after admission | 74.35±13.34 | 80.66±12.87 | 0.031 |
| QTc duration (ms) | |||
| Baseline | 398.70±40.71 | 395.77±27.72 | 0.777 |
| 12 h after admission | 377.52±70.05 | 396.63±26.64 | 0.145 |
| 24 h after admission | 381.91±39.90 | 387.60±22.93 | 0.625 |
| QRS duration (ms) | |||
| Baseline | 97.81±25.01 | 93.80±22.93 | 0.493 |
| 12 h after admission | 101.00±25.50 | 92.47±20.78 | 0.187 |
| 24 h after admission | 97.94±22.23 | 97.36±27.14 | 0.967 |
| QT dispersion (ms) | |||
| Baseline | 53.00±5.30 | 51.35±4.32 | 0.811 |
| 12 h after admission | 38.00±8.12 | 38.83±4.01 | 0.930 |
| 24 h after admission | 26.78±6.75 | 47.53±10.62 | 0.041 |
SBP=Systolic blood pressure, DBP=Diastolic blood pressure, HR=Heart rate, QTc=Corrected QT interval, SPO2=Oxygen saturation
DISCUSSION
In the current study, among those without a history of long-term methadone use group, 52.2% of patients intentionally used this drug for suicide, while 30.4% experienced poisoning due to substance abuse. In contrast, in the long-term methadone use group, all patients (100%) were poisoned due to substance abuse. In line with this, some previous studies have also indicated that over 50% of patients intentionally used methadone.[21,22,23] For example, Taheri et al. investigated all the cases of methadone poisoning who referred to the Noor Center in Isfahan from 2010 to 2012 and reported that common clinical symptoms included drowsiness, miosis, respiratory depression, and hypotension. The symptoms of the central nervous system, such as drowsiness, are the significant indicators of methadone poisoning, likely due to acetylcholine blockade in the reticular activating system. Respiratory depression is also a major diagnostic sign in methadone poisoning, observed in 50% of patients.[22]
In many other studies, the most common clinical findings included miosis of the pupils, drowsiness, and a decrease in RR, with a significant percentage of patients showing SBP <90 mmHg.[24,25,26] The findings from the current study also revealed that 59.3% of patients in the group with a history of long-term methadone use had normal pupil size, while 37% were miosis. In the group without of history of long-term methadone use, 69.5% of patients exhibited miosis. In addition, 44.4% and 43.5% of patients with and without a history of long-term methadone use groups, respectively, were lethargic upon arrival at the emergency department. Other common clinical symptoms observed in both groups included respiratory depression and a decrease in the number of breaths per minute, which did not show statistically significant differences. These findings align with other studies on methadone toxicity.[22,27,28]
Recovery without complication in the two groups with and without a history of long-term methadone use was 81.5% and 67.4%, respectively. In addition, 7.4% and 13% of patients in the two groups with and without a history of long-term methadone use experienced recovery with complications.
In a study by Eizadi-Mood et al. conducted in Iran, it was found that 19.7% of patients had used other medications in addition to methadone. Furthermore, a total of 387 patients (90.3%) were rescued and discharged in good overall condition from the hospital.[27] In the study by Lee et al., out of 1594 cases of methadone toxicity, 26 patients died, while the others were discharged in good overall condition from the hospital.[29]
In another study on children under 18 years of age who were poisoned with methadone, mortality of 5.7% was reported.[30] It seems that the difference observed in the above studies and the present study is due to the different sample sizes, the inclusion of only people older than 18 years, and the exclusion of poisoning with narcotic drugs or other stimulants at the same time with methadone use.
The findings of the present study showed that the mean of QTc and QRS complex intervals were not significantly different between the two groups in any of the three times. Furthermore, the mean of QT dispersion at the beginning of admission and 12 h after admission was not significantly different between the two groups, but at the time of discharge, the mean of QT dispersion in the group with history of long-term methadone use was significantly lower than the group of without history of long-term methadone use. According to the definition, a QTc interval >440 ms in men and 460 ms in women is considered a long QTc, and in the present study, the mean of QTc in both groups and at different times was not higher than the above values.
In this context, Sheibani et al. found no significant difference in the QTc mean between the two groups with and without a history of long-term methadone use,[23] although a higher value was reported in both groups compared to the current study. In the study by Soroosh et al., the mean QTc value was 483 ms in the group with methadone poisoning, which was higher than the values observed in the present study.[31] Another study calculated the mean QT dispersion, QRS complex duration, and QTc to be 41, 50, and 450 ms, respectively,[32] with only the QT dispersion aligning with the results of the current study. The discrepancy in the ECG findings of patients with methadone poisoning in the current study compared to previous studies could be attributed to the different sample sizes.
This study has limitations that should be considered when using the results. Failure to determine serum methadone concentration to show the severity of poisoning is a major limitation that can help in comparing different variables in the two studied groups. The retrospective nature of the study and lack of documentation about some variables in the files were other limitations. The type of present study was cross-sectional and, in such studies, it is not possible to deal with causal relationships. Furthermore, due to reporting the results based on the files registered in the hospital, the level of accuracy and correctness of the received data can be thoughtful and subject to review. In this regard, it is recommended to conduct other prospective studies with a larger sample size in the future.
It should be mentioned that regarding the limitations of the study, it can be said that considering that the toxic dose is different depending on the history of addiction, and on the other hand, the average dose consumed in the form of syrup was much higher than that of tablets, it may affect the changes in the ECG. Due to the small sample size, it was not possible to consider this issue and analyze based on it.
According to the results of this study, the mean QT Dispersion, which reflects the dispersion of ventricular recovery time, was similar at the beginning of admission in both groups with and without a history of long-term methadone use. In the group with a history of long-term use, QT dispersion gradually decreased until discharge. However, in the group without a history of long-term use, the QT dispersion rate was variable during hospitalization and was still high at the time of discharge, which means that in the group without a history of long-term methadone use in case of acute poisoning, the time of ventricles recovery in different leads is more dispersion than the group with a history of long-term methadone use that can make this group more susceptible to arrhythmia.
The mean of SBP and DBP in the group with a history of long-term methadone use gradually increased during hospitalization and approached normal values, but in the group of without history of long-term methadone use, it was still in the low range during hospitalization and did not change much, so that during discharge, systolic and diastolic pressures in the group of without history of long-term methadone use were lower than the group of with a history of long-term methadone use.
According to the study, the mean QTc interval in acute methadone poisoning was within the normal range and there was no significant difference between the two groups with and without long-term methadone use, but it seems that, unlike the QTc interval, its dispersion is more important.
According to the above interpretations, following acute methadone poisoning, in the event of a drop in blood pressure and an increase in the QT dispersion time (which indicates the time difference of ventricular recovery in different leads), the group with a history of long-term methadone use will reach the normal range sooner, and therefore, their cardiovascular system is better prepared for adaptation.
AUTHORS’ CONTRIBUTION
S. Zoofaghari and N. Eizadi Mood contributed to the literature search, data collection, and writing the original manuscript. S. Zoofaghari and G. Dorooshi were responsible for the study design and writing the original manuscript. M. Shirmohammadi, F. Gheshlaghi and A. Otroshi helped in data collection and analysis, and manuscript writing. All authors approved the final paper.
Conflicts of interest
There are no conflicts of interest.
Funding Statement
Nil.
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