Methadone is a µ-opioid receptor agonist and NMDA receptor antagonist which is often indicated for the management of severe refractory cancer or non-cancer pain, as well as for opioid addiction. This two-part article provides an overview of methadone use in pain management, and its use in opioid addiction will not be covered here. Methadone has several advantages over other opioids. These advantages include extended analgesic activity, multiple routes of administration, longer bioavailability, lack of active metabolites, predominantly intestinal excretion, and its relatively low cost compared to other opioids. This makes methadone an appealing option for patients with impaired creatinine clearance and for those facing financial constraints in obtaining medications. On the other hand, there are notable concerns with this medication that make its use more complex than of other opioids. Methadone has a variable individual plasma half-life that can lead to accumulation and toxicity, and extensively utilizes cytochrome CYP450, therefore its metabolism can be affected when used in conjunction with inducers and especially inhibitors of this cytochrome system. Methadone has also variable and quite complicated conversion formulas when transitioning from other opioids. Additionally, there is a risk for abuse that can lead to accidental overdose or even death. Finally, methadone can cause QT interval prolongation that may result in dangerous cardiac arrhythmias such as torsades de points and ventricular tachyarrhythmia. Despite its multiple advantages in pain control, cautionary messages from the European Association for Palliative Care (EAPC) and National Comprehensive Cancer Network (NCCN) advise for use of methadone only by experienced clinicians. It is highly recommended that patients are counseled extensively on methadone safety use due to its numerous risks.
Metadona este o substanţă opioidă cu activitate agonistică pe receptorii µ şi antagonistică pe receptorii NMDA, fiind indicată atât pentru durerea din cancer, cât şi pentru durerea necanceroasă. Metadona este, de asemenea, indicată şi pentru tratamentul adicţiei la opioide, însă subiectul nu va fi abordat în acest articol. Avantajele utilizării metadonei în comparaţie cu alte opioide sunt multiple, cele mai cunoscute fiind: activitate antialgică prelungită; multiple căi de administrare; biodisponibilitate mai îndelungată; posibilitatea utilizării la pacienţii cu probleme renale datorită eliminării preponderent intestinale; lipsa de metaboliţi activi; costul scăzut. Pe de altă parte, metadona trebuie utilizată cu precauţie, din următoarele motive: timp de înjumătăţire care variază de la un pacient la altul; metabolism hepatic care poate fi influenţat prin utilizarea concomitentă a metadonei cu substanţe care funcţionează ca inhibitori sau stimulanţi ai sistemului de citocromi CYP450; formule de conversie de la alte opioide care pot fi destul de complicate; risc de abuz, care poate duce la moarte accidentală; prelungirea intervalului QT, care poate cauza aritmii cardiace, cum ar fi torsades de points şi tahiaritmia ventriculară. The European Association for Palliative Care (EAPC) şi National Comprehensive Cancer Network (NCCN) recomandă ca metadona să fie utilizată de către clinicieni cu experienţă, pentru a asigura bunăstarea şi siguranţa pacientului.
The second part of this article will focus on the most commonly encountered side effects of methadone, including effects on the gastrointestinal, genito-urinary, central nervous, dermatologic, hematologic, respiratory, and cardiovascular systems.
1. Gastrointestinal: nausea, vomiting, bloating, and opioid-induced constipation (OIC) are common side effects seen with all opioids. However, literature suggests methadone carries some advantage over morphine, requiring ten times less laxatives and two times less antiemetics(10).
The European Society for Medical Oncology (ESMO) guidelines recommend metoclopramide and other antidopaminergic drugs for the treatment of opioid-related nausea and vomiting(17). A review of OIC was published in the February 2018 edition of the Oncolog-Hematolog.ro journal(18).
A less known and studied entity is the narcotic bowel syndrome (NBS), defined as chronic and recurrent abdominal pain that worsens with continued or escalating doses of opioids, in conjunction with the following criteria:
The pain worsens or incompletely resolves with persistent or increasing doses of opioids.
The pain worsens when the opioid dose wanes and improves when opioids are reinstituted (soar and crash).
Progressive increase in the frequency, duration and intensity of the pain episodes.
The nature and intensity of the pain cannot be explained by other gastrointestinal problems(19).
2. Genito-urinary: urinary hesitancy or retention, amenorrhea, and decreased libido and potency are also seen with opioids. The latter side effects are most likely the result of the opioid-induced hypogonadism (OIH), initially reported in 1970 in male heroin and methadone users who were found to have low testosterone levels. OIH has a prevalence of anywhere between 21% and 86% and seems to occur more frequently in men or in patients on high-dose opioids, especially by intrathecal route(20,21).
Opioids are known to disrupt the secretion of gonadotropin-releasing hormone, resulting in decreased release of luteinizing hormone and follicle stimulating hormone from the pituitary gland, which in turn leads to diminished production of the testosterone or estradiol in the gonads. Another possible mechanism for OIH is opioid-related hyperprolactinemia that leads to decreased production and release of gonadotropin-releasing hormone. The workup should include testing for serum prolactin, estradiol, gonadotropin, testosterone, free testosterone, dehydroepiandrosterone (DHEA), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels, along with bone density. The management of OIH involves reducing the dose of opioids, substituting with other antalgics or hormone replacement therapy with testosterone in men, and estrogen with or without progesterone in women(20,21).
3. Central nervous system (CNS): lightheadedness, drowsiness, sedation, and opioid-induced neurotoxicity (OIN). The last one is represented by cognitive impairment, confusion, hallucinations, myoclonus, seizures, hyperalgesia, and allodynia.
A panel of American and Canadian hospice and palliative care experts recommend intense monitoring for sedation for at least 5 to 7 days after initiating methadone, due to its variable time to steady state concentrations. This observation period could be increased to 10-14 days in elderly patients or those with multiple comorbidities(12).
OIN is a multifactorial syndrome that tends to develop days after initiating an opioid, particularly an opioid with active metabolites, with concomitant use of psychoactive medications (e.g., benzodiazepines, tricyclic antidepressants), or in frail patients with comorbid conditions such as renal failure, preexisting delirium, or severe infections. Methadone is less likely to cause OIN compared to other opioids because it has inactive metabolites, making it well tolerated in renal insufficiency.
There is little evidence for the use of psychostimulants like methylphenidate or modafinil in the management of opioid-induced sedation, and ESMO recommends using these medications only after other methods have been tried and failed(5,22).
4. Dermatologic: diaphoresis and pruritus. Pruritus can be addressed by opioid rotation or use of antihistamines and 5-HT3 (serotonin) antagonists(3).
5. Hematologic: reversible thrombocytopenia has been noted in opioid addicts with chronic hepatitis(13).
6. Respiratory: pulmonary edema and respiratory depression. All opioids can cause respiratory depression, although methadone requires additional caution because its peak respiratory depressant effect occurs later and persists longer than its peak analgesic effect. Consequently, there is higher risk of respiratory depression with very rapid dose escalations during treatment initiation or dose titration, for which reason methadone should not be adjusted sooner than 3-5 days at minimum. Special precautions need to be taken when prescribing methadone in patients suffering from asthma, chronic obstructive pulmonary disease, or any condition causing hypoxia or hypercapnia, where even standard therapeutic doses of methadone may decrease respiratory drive to the point of apnea. It is recommended to use the lowest effective dose of methadone or to try other analgesics including non-opioids for these patients. It is strongly recommended to rapidly use µ-opioid receptor antagonists (e.g., naloxone) if respiratory depression is suspected(3,13,17).
7. Cardiovascular: hypotension, palpitations, arrhythmias, bradycardia or tachycardia, cardiomyopathy, heart failure, acquired QT interval prolongation, torsade de pointes (TdP), ventricular fibrillation and ventricular tachycardia are all potential risks of methadone use.
The QT interval represents the ventricular repolarization on an electrocardiogram (ECG), but because it tends to vary with the heart rate, it is advisable to get the corrected QT interval (QTc) adjusted for the heart rate. The Bazzett’s formula is one of the most used to calculate the QTc:
QTc = QT interval ÷ √RR interval
The guidelines of the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) have defined QTc prolongation as an interval longer than 450 ms in males and 470 ms in females. QTc intervals over 500 ms are considered significantly prolonged and associated with an increased risk for TdP(23,24).
QTc prolongation occurs quite frequently in percentages anywhere between 18% and 52%. QTc interval prolongation, with its major complication represented by TdP, is associated with increased risk of cardiovascular mortality. Literature mentions that the risk for a cardiac event is increased by approximately 6% for each 10 ms increase in the QTc(26).
The most common risk factors for QTc prolongation are:
Age > 65 years old.
Genetic predisposition, such as:
congenital long QT syndrome (LQTS)
family history of sudden death at age younger than 50 years old
kidney disease that could cause inadequate elimination of QT prolonging drugs
hepatic disease that could affect the metabolism of the QT prolonging drugs via CYP450 cytochrome system
neurological events: hemorrhage, stroke etc.
Other: fast intravenous infusion that could lead to rapid accumulation of QT prolonging drugs
Polypharmacy: concomitant administration of several QT prolonging agents represents the main culprit for QTc prolongation(24-32). The most frequently encountered medications that could cause QTc prolongation are included in Table 4.
Patients with cancer are at increased risk of developing QTc prolongation. They may have poor oral intake with persistent nausea and vomiting, particularly during chemotherapy, or diarrhea that may expose them to various electrolyte imbalances. Additionally, they often have multiple comorbidities and are frequently exposed to multiple drugs with QT prolonging activity, such as chemotherapy agents, antiemetics, antidepressants, diuretics and antibiotics(28). It is estimated that methadone prolongs the QTc interval by blocking hERG (human Ether-à-go-go-Related Gene) potassium channel, which causes an inhibition of the outward potassium current during myocardial repolarization, leading to a prolonged repolarization time. The risk for QTc prolongation seems to be higher with i.v. methadone compared to oral formulations, possibly related to the preservative chlorobutanol in the i.v. preparation, which has been shown to independently prolong the QTc interval(3,25).
Careful examination of the patient’s family and medical history and medication list for a potential drug to drug interaction at CYP450 cytochrome level needs to be employed prior to initiating methadone. Dose reduction is recommended when using methadone concurrently with other QT interval prolonging medications or medications that act as CYP450 cytochrome inhibitors and result in decreased methadone metabolism. Table 1 in the first part of this article presents the frequently encountered CYP450 cytochromes inhibitors and inducers.
Various panels of experts proposed the recommendations listed below when prescribing methadone for pain or addiction to patients seeking curative, life-prolonging measures:
A. Inform patients of methadone side effects, particularly arrhythmia. Patients should be counseled to immediately seek medical assistance if experiencing syncope, fainting, palpitations, or dizzy spells after initiating methadone.
B. Review the patient’s family and medical history and medication list to look for possible interactions between methadone and other drugs that possess QTc interval prolonging properties or could slow the elimination of methadone.
C. Obtain a baseline ECG before initiating methadone, particularly in patients with positive risk factors, prior ECG with QTc>450 ms, or prior history of cardiac arrhythmia.
D. Do not initiate methadone if screening ECG shows a QTc interval >500 ms.
E. Get a follow-up ECG. There are discrepancies regarding the timing for the follow-up ECG. Some authors recommend repeating the ECG 24 hours after initiating therapy with methadone and four days after achieving a steady state. Others recommend repeating the ECG after the patient is at a stable dose of methadone for one week, or one week after increasing the methadone. Finally, other articles mention repeating the ECG in 2-4 weeks.
F. Obtain additional ECGs when the total daily dose of methadone exceeds 40, 60, or 100 mg (opinions differ), when new risk factors for QTc prolongation are detected, when proarrhythmic drugs are added, or if the patient has unexplained syncope or seizures.
G. Discuss the risks and benefits of methadone therapy if the QTc is greater than 450 ms but less than 500 ms, and consider decreasing the dose of methadone or eliminating other drugs that could prolong QTc interval. Monitor more frequently.
H. Taper the methadone or consider an opioid rotation and eliminate other QTc prolonging medications if QTc interval is greater than 500 ms.
I. Keep in mind that each 10 ms increase in QTc exponentially increases the risk for TdP and discontinue medications with QTc prolonging properties if the QTc interval increases by more than 60 ms after addition of such drugs(3,11,12,25,28,33).
All these recommendations, particularly ECG monitoring, are not indicated in patients enrolled in hospice services or at the end of life, where adequate and aggressive pain and symptom management are of paramount importance.
8. Potential for misuse and abuse. The National Comprehensive Cancer Network (NCCN) defines misuse as an intentional or unintentional inappropriate use of a prescription drug regardless of the motivation (such as impairment). The same organization defines abuse as a maladaptive pattern of use of a prescription medication, leading to significant clinical impairment and/or distress(15).
Methadone, like all µ-opioid receptor agonists, can be abused and plays an unfortunate role in the so-called opioid epidemic that has become a serious national crisis affecting the American public health and social and economic welfare. Abuse of methadone poses a risk of overdose and death, risk which is significantly increased by concomitant use or abuse of other CNS depressants.
Data from the Center for Disease Control and Prevention shows that the number of deaths involving methadone jumped by 468% from 1999 to 2005, with close to 80% of these deaths being unintentional(34). However, after 2006, deaths from methadone-involved overdose declined by about 6.5% per year, whereas diversion started to decline by an average of 12.8% per year starting from 2010. Methadone claimed an unfortunate toll of 3,287 lives in 2017(35). Data related to opioid overdose deaths are summarized in Figure 2.
In conclusion, methadone is an excellent pain killer, relatively inexpensive, favored in renal insufficiency due to its intestinal elimination and lack of active metabolites, as well as for refractory pain especially with a neuropathic component. However, it requires manipulation by expert hands due to its extensive metabolism via CYP450 cytochrome system and its numerous possible side effects, thus requiring close monitoring, especially at the time of initiation or up titration.
Conflict of interests: The authors declare no conflict of interests.
Abbreviation list: CNS: Central Nervous System; DHEA: Dehydroepiandrosterone; EAPC: European Association for Palliative Care; ECG: Electrocardiogram; ESMO: European Society for Medical Oncology; FDA: Food and Drug Administration; FSH: Follicle Stimulating Hormone; hERG: human Ether-à-go-go-Related Gene; i.v.: Intravenous; LH: Luteinizing Hormone; OIC: Opioid-Induced Constipation; OIH: Opioid-Induced Hypogonadism; OIN: Opioid-Induced Neurotoxicity; NBS: Narcotic Bowel Syndrome; QTc: Corrected QT; TCA: Tricyclic antidepressants; TdP: Torsade de Pointes
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