Methadone

Methadone is a synthetic opioid commonly used in opioid dependence, chronic cancer pain, and rarely chronic non cancer pain (particularly neuropathic pain). 
Methadone may have some efficacy in treating neuropathic pain due to its dual action as both an opioid receptor agonist and an N-methyl-D-aspartate (NMDA) receptor antagonist. This NMDA receptor antagonism may help modulate the abnormal pain signaling often seen in neuropathic conditions. However, its use requires careful monitoring due to its complex metabolism and risk of accumulation, especially in long-term therapy.
== Pharmacology ==
=== Mechanism of Action ===
Methadone is a synthetic opioid primarily acting as a full agonist at the mu-opioid receptor, providing analgesia similar to morphine. However, methadone also exhibits several unique properties:
NMDA Receptor Antagonism: This feature contributes to its potential efficacy in treating neuropathic pain by modulating abnormal pain signals, although the exact role remains uncertain.
Kappa and Sigma Opioid Receptor Agonism: Methadone also binds to these receptors, contributing to its wide range of effects.
5-HT3 Antagonism and Serotonin/Norepinephrine Reuptake Inhibition: These additional pharmacodynamic properties may play a role in both its analgesic and side effect profiles, including mood and gastrointestinal effects.
=== Pharmacokinetics ===
Absorption: Methadone is well absorbed, with bioavailability ranging from 36–100%, making it more predictable than other opioids.
Distribution: Methadone has a high volume of distribution (189–470 L), indicating widespread tissue distribution, including the brain, liver, lungs, and muscles. It binds primarily to α1-acid glycoprotein and albumin, with significant binding to tissue proteins.
Metabolism: Methadone undergoes hepatic metabolism, primarily via CYP3A4, CYP2B6, and CYP2C19. Enzyme activity can be highly variable, contributing to its wide range of half-lives (15–207 hours). Genetic polymorphisms (such as in CYP2B6) can significantly affect drug clearance, with some individuals metabolizing methadone much more slowly, leading to increased risk of toxicity.
Elimination: Methadone is primarily excreted in urine, with both parent drug and inactive metabolites being cleared via renal and fecal routes.
=== Pharmacodynamics ===
Analgesia and Respiratory Depression: Methadone depresses the brainstem’s respiratory centers, leading to a risk of delayed and prolonged respiratory depression. Its peak respiratory effects occur later and last longer than its peak analgesic effects, increasing the risk of overdose, particularly during dose titration.
QT Prolongation: Methadone can block cardiac potassium channels, leading to QT interval prolongation, which is dose-dependent. Higher doses (>200 mg/day) significantly increase the risk of torsades de pointes, a potentially fatal arrhythmia.
== Dosing ==
=== Considerations ===
Methadone is sometimes dosed twice daily despite its long half-life due to its pharmacokinetic properties and clinical considerations. Methadone exhibits a biphasic elimination pattern: an initial α-elimination phase with a half-life of 8-12 hours, which correlates with its analgesic effects, and a longer β-elimination phase with a half-life of 30-60 hours, which is sufficient to prevent withdrawal symptoms but not necessarily to provide continuous analgesia.
The American Pain Society and the College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society, highlight that methadone's long and variable half-life necessitates cautious titration to avoid accumulation and potential toxicity. However, the analgesic effect of methadone typically lasts only 6-8 hours, which may not be adequate for managing pain throughout a 24-hour period. Therefore, split dosing can help maintain more consistent analgesic coverage and improve pain control.
Additionally, in certain clinical scenarios, such as during pregnancy, split dosing may be necessary to manage increased metabolism and volume of distribution, ensuring adequate methadone levels to prevent withdrawal symptoms and cravings.
=== Specific Guidelines ===
For elderly patients, the American Academy of Pain Medicine and the American Pain Society recommend starting methadone at 2.5 mg every 8 hours for opioid-naïve individuals, with dose increases no more frequently than weekly. This cautious approach is due to the increased risk of adverse effects and the variable pharmacokinetics in this population.
For adults, the American Pain Society and the College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society, suggest a similar starting dose of 2.5 mg every 8 hours for opioid-naïve patients. For those on low doses of other opioids (e.g., <40–60 mg/day of morphine equivalents), the same starting dose is recommended, with dose increases of no more than 5 mg/day every 5 to 7 days. For adults switching from higher doses of other opioids, methadone should be started at a dose 75 to 90% less than the calculated equianalgesic dose, not exceeding 30 to 40 mg/day, with dose increases of no more than 10 mg/day every 5 to 7 days.
Close monitoring for sedation and other adverse effects is crucial during the initiation and titration phases for both elderly and adult patients. Methadone should not be used for breakthrough pain or as an as-needed medication due to its long half-life
== Safety and Side Effects ==
The most frequently observed adverse reactions include lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. 
Respiratory depression is a major hazard of methadone, which can lead to respiratory arrest, shock, cardiac arrest, and death. Methadone also has a significant risk of QT interval prolongation, which can predispose patients to torsades de pointes, a potentially life-threatening ventricular arrhythmia. The American Pain Society and the College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society, highlight the importance of monitoring for QT prolongation and recommend ECG screening in patients at risk.
Other serious adverse effects include serotonin syndrome, adrenal insufficiency, and severe hypotension. Methadone can also cause endocrinologic effects such as hypogonadism, leading to reduced libido, erectile dysfunction, and amenorrhea. Gastrointestinal side effects like constipation and biliary tract spasm are common, necessitating proactive management strategies.
== Monitoring ==
The protocol for methadone monitoring in chronic non-cancer neuropathic pain involves several key steps to ensure patient safety and effective pain management. According to the American Pain Society and the College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society, the following recommendations are made:
# Adverse Effects Monitoring: Patients receiving methadone should be monitored for common opioid adverse effects, including constipation, nausea, sedation, respiratory depression, pruritus, and endocrinologic effects. Proactive management of these adverse effects should be part of routine therapy.
# QTc Interval Monitoring: Methadone is associated with QTc interval prolongation, which can lead to serious cardiac arrhythmias. Baseline and follow-up electrocardiograms (ECGs) are recommended, especially in patients with risk factors for QT prolongation or those on higher doses of methadone.
# Substance Abuse and Mental Health Monitoring: Periodic monitoring for the development of substance abuse and other mental health disorders is recommended. This includes reviewing state prescription drug monitoring program data to identify patients obtaining opioids from multiple providers.
# Urine Drug Testing (UDT): UDT should be performed prior to initiating methadone and at regular intervals thereafter, especially in patients with risk factors for drug abuse. This helps identify aberrant drug-related behaviors and guide appropriate management.
# Initial and Follow-Up Assessments: Face-to-face or phone assessments should be conducted within 3 to 5 days after initiating methadone and after each dose increase to monitor for adverse events, particularly respiratory depression and arrhythmias.
# Electrolyte Monitoring: Regular monitoring of electrolytes, such as potassium and magnesium, is important as abnormalities can exacerbate the risk of QTc prolongation.
== Tapering and Discontinuation ==
According to the CDC Clinical Practice Guideline for Prescribing Opioids for Pain, tapering should be slow enough to minimize withdrawal symptoms, with a general recommendation of reducing the dose by approximately 10% per month for patients on long-term opioid therapy (≥1 year). For patients on shorter-term opioid therapy, a decrease of 10% of the original dose per week until approximately 30% of the original dose is reached, followed by a weekly decrease of approximately 10% of the remaining dose, is suggested.
The American Pain Society and the College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society, also emphasize the importance of a gradual tapering process. They recommend dose reductions of less than 10% of the established tolerance or maintenance dose, with 10- to 14-day intervals between dose reductions to minimize withdrawal symptoms and reduce the risk of relapse.
Additionally, a population-based retrospective cohort study found that longer taper durations (12-52 weeks or more) and gradual, stepped tapering schedules with dose decreases in only 25-50% of the weeks provided higher odds of sustained success.
== References ==
Category:Pharmacology