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14 Articles in Volume 12, Issue #2
Chronic Pain in the Elderly: Special Challenges
Chronic Pain School
Diagnosis and Management Of Myofascial Pain Syndrome
ECG Screening Prior to Initiating Methadone: Is it Really Necessary?
HCG and Testosterone
How to Manage Unmotivated Pain Patients
March 2012 Pain Research Updates
Methadone for Pain Management
PPM Editorial Board Discusses Methadone Prescription Safety Measures
PPM Launches Online Opioid Calculator
Spontaneous Low Back Pain, Radiculopathy, And Weakness in a 28-Year-Old
Tapering a Patient Off Opioids
The Comorbidity of Chronic Pain and Mental Health Disorders: How to Manage Both
What Are Best Safety Practices For Use of Methadone In the Treatment Of Pain?

Methadone for Pain Management

Over the past 20 years there has been renewed interest in using methadone as an analgesic—raising concerns about its safety. This educational review discusses the efficacy and safety of methadone when used in chronic pain management.

Methadone is a synthetic opioid agent that was initially introduced in the United States as an analgesic in the 1940s.1-3 In the 1960s, methadone became widely used as a maintenance drug for the treatment of opioid addiction.3,4 It is a Schedule II controlled substance that, when used for the treatment of addiction, may only be prescribed by providers registered with the Drug Enforcement Agency for this purpose. When used for the treatment of pain, methadone may be prescribed by any provider registered to prescribe Schedule II controlled substances.5 Over the past 20 years there has been renewed interest in using methadone as an analgesic. In fact, from 1999 to 2002 sales of methadone in the United States increased 70.7%.6 This increase was largely a result of methadone’s use outside of narcotic treatment programs. Although methadone has become increasingly popular for the treatment of pain, concerns regarding its safety also are on the rise. In fact, although methadone accounts for less than 5% of prescription opioids, it has been linked to one-third of opioid-related deaths.7 This educational review discusses the efficacy and safety of methadone when used for chronic pain management.

Pharmacology and Pharmacokinetics
Methadone possesses a number of properties that are unique among the opioid class of drugs. Methadone is a racemic mixture; the L isomer has approximately 50 times higher affinity for the opioid receptors than the S isomer.1,3 In addition to its affinity for the opioid receptors, methadone is an antagonist at the N-methyl-d-aspartate receptor as well as a serotonin norepinephrine reuptake inhibitor.1,2,8 Binding at these receptors may account for decreased tolerance and improved efficacy in neuropathic pain states compared with other opioids, although evidence for this is lacking.4,8,9

Methadone exhibits large interindividual variation in both bioavailability and elimination half-life.2,10 Following oral administration, bioavailability has been reported to be between 36% and 100%, while the half-life ranges from 8 to 59 hours (up to 120 hours has been reported).2,8 There is a disconnect between the 6- to 12-hour duration of analgesia and the prolonged time to elimination from the body; thus, accumulation of methadone resulting in respiratory suppression is a concern.8 Methadone is metabolized by a number of cytochrome P450 (CYP) enzymes including CYP3A4, CYP2B6, and CYP2C19.2 The enzymes CYP2C9 and CYP2D6 are involved to a lesser extent. Physicians need to be cautious when prescribing methadone to avoid unwanted drug interactions.

Two advantageous pharmacokinetic properties of methadone when compared with morphine are its lack of active metabolites and minimal accumulation in patients with renal disease.2,8 Although patients with liver disease may accumulate methadone, this has not been well studied.

Place in Therapy
The analgesic efficacy of methadone primarily has been studied in patients with cancer pain. The National Comprehensive Cancer Network (NCCN) has developed guidelines for the treatment of these patients.11 The guidelines recommend morphine as the typical first-choice opioid. However, methadone is not a preferred initial treatment because of its long half-life, which makes it difficult to titrate. Other problems noted with methadone are its high potency and interindividual pharmacokinetic variability. When methadone is chosen for pain management in cancer patients, careful initiation or conversion from another opioid must take place. Generally, methadone is administered three to four times daily and is not recommended for breakthrough pain.

A 2008 Cochrane systematic review identified nine randomized controlled trials that compared methadone to morphine or other opioids for the treatment of cancer pain.12 No meta-analysis was performed due to the high variability among the studies; however, the authors concluded that methadone was similar to morphine in its analgesic efficacy. The authors did express concern over the fact that only one study was long-term (28 days); thus, there is limited literature evaluating methadone use that mimics clinical practice. Although comparative trials have described decreased need for escalating doses of methadone in cancer patients compared with morphine, this was refuted in a 2004 publication that demonstrated similar opioid dose-escalation indices for methadone and morphine.13-15

Guidelines from the American Pain Society (APS) and American Academy of Pain Medicine (AAPM) describe a role for methadone in the management of chronic pain that is unrelated to cancer.16 They suggest that it be used cautiously due to safety concerns and poor quality evidence surrounding its efficacy.9,16 In fact, only one small, randomized crossover trial for the treatment of noncancer pain has been published.17 Morley and colleagues compared methadone 10 mg per day (Phase I) or 20 mg per day (Phase II) to placebo in 19 patients with treatment-resistant neuropathic pain. Patients received active methadone therapy or placebo on odd days and no medication on even days during each 20-day treatment period. The results of 18 patients were reported for Phase I. No significant differences were found between methadone and placebo for maximum intensity or average intensity pain scores on a 100-mm visual analog scale (VAS); however, the scores were numerically better with methadone. There were significant differences in VAS scores between groups in the 11 patients who completed Phase II of the study. The mean maximum intensity score was an average of 9.25 points lower with methadone 20 mg per day and the mean average intensity score was an average of 6.56 points lower (P<0.02) compared with placebo. The external validity of this study is questionable based on the fact that patients received methadone every other day, which is not done in clinical practice.

Methadone has been evaluated for a variety of pain types in uncontrolled studies including back pain, neuropathic pain, chronic headache, and complex regional pain syndrome.18 In a review of 20 uncontrolled studies in patients with chronic noncancer pain (CNCP), 59% had meaningful pain relief with methadone (meaningful was defined as statistically significant changes in any of the quantitatively measured outcomes, satisfactory or acceptable pain relief in categorical outcomes, or worthwhile relief determined by consensus of the reviewers).18 Initial methadone doses ranged from 2.5 to 80 mg per day and the maximum doses varied from 20 to 930 mg per day.

Methadone Dosing and Conversion
When methadone is prescribed for pain in opioid-naïve patients the key to safe, successful therapy is to start with low doses and titrate slowly. Methadone should only be initiated by healthcare professionals familiar with its use.11,16The APS/AAPM guidelines recommend that a safe initial oral methadone dose in opioid-naïve patients with CNCP is 2.5 mg every 8 hours with a minimum of 1 week between dose titrations.16 The NCCN guidelines for adult cancer patients with pain do not specifically recommend an initial methadone dose but do recommend that the dose can be titrated in 5 mg per dose increments every 5 to 7 days.11

Converting from other opioid agents to methadone in opioid-tolerant patients is challenging. A number of methods for conversion to and from methadone have been posed in the literature.19 The APS’ Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain describes one method.20 For this method, the previous opioid is stopped prior to methadone initiation. If converting from an opioid other than morphine, that opioid must first be converted to morphine equivalents. The total daily dose of methadone based on conversion from morphine equivalents is divided by three and administered every 8 hours. The details of this method are presented in Table 1. The guidelines also recommend that patients using methadone may have 10% of the daily methadone dose available for breakthrough pain.

In the method described by the APS, the initial opioid is stopped and completely replaced by an equianalgesic dose of methadone (“stop-and-go” method); however, another method that may be employed involves reducing the initial opioid by one-third every day and replacing it with an equianalgesic methadone dose such that by the end of 3 days the patient is converted to methadone. The 3-day switch method was recently compared with the stop-and-go method.21 Patients randomized to the stop-and-go method had a greater pain intensity score at day 14 and more serious adverse events (AEs) than patients in the 3-day switch group. This was a small trial (21 patients per group), and more study on the optimal method of converting from morphine, or other opioids, to methadone is necessary.

The NCCN guidelines recommend similar dose-conversion ratios as those from the APS; however, they additionally recommend that the calculated methadone dose then be reduced by 25% to 50% to allow for interpatient variability and incomplete cross-tolerance.11,20 When the opioid analgesic dose is greater than 800 mg per day of oral morphine equivalents, the guidelines suggest that even higher dose ratios are necessary and that pain or palliative care specialists should be consulted. The APS/AAPM guidelines do not recommend a particular conversion method when switching from another opioid agent to methadone; however, they state that conversion ratios of 0.1% to 10% morphine equivalents have been reported with lower conversion ratios at higher opioid doses.16 Furthermore, an initial dose of 30 to 40 mg per day of methadone should not be exceeded even in patients taking high doses of other opioids.

A summary of other select literature reporting conversion methods can be found in Table 2.22-24

The process remains complicated when converting from methadone to another opioid analgesic. The NCCN guidelines state that the dose ratios used when converting to methadone are inappropriate for use in the reverse process because methadone’s effects persist as a result of its extended elimination half-life.11 The initial dose-conversion ratio of oral morphine (or equivalent) to oral methadone must be conservatively estimated depending on the dose of morphine, and the prescriber must vigilantly monitor for increasing need of the alternative opioid as methadone is eliminated. A short-acting opioid should be available for use as needed during this conversion.

Safety
From 1999 to 2002, methadone-related deaths increased by more than 200%.6 The exact cause of methadone-related mortality is unknown; however, a panel convened by the Center for Substance Abuse Treatment of the Substance Abuse and Mental Health Services Administration (SAMHSA) identified the four potential risk factors listed in Table 3.25 A summary of key points from the 2006 FDA safety warning is also provided in the table.26

Methadone can cause nausea, constipation, and sedation similar to other opioid analgesics; however, some studies have shown fewer of these AEs with methadone than with morphine.8 Unfortunately, methadone has been associated with serious AEs including respiratory depression and cardiac conduction abnormalities.2,8,27 The prescribing information includes a boxed warning regarding the drug’s association with deaths resulting from cardiac toxicity or respiratory depression.2

QT prolongation occurs as a result of methadone blocking potassium channels and has been associated with the ventricular arrhythmia, torsades de pointes.2,27 It is unknown how frequently prolongation of the QT interval occurs in methadone-treated patients as studies have shown a wide range of 9% to 83%.28 There appears to be some association with higher doses but this has not been consistently shown.28,29 Generally, patients experiencing drug-related torsades de pointes have an additional risk factor for the arrhythmia.28 Risk factors for torsades de pointes include corrected QT interval greater than 500 milliseconds, underlying heart disease (eg, heart failure, myocardial infarction), age older than 65 years, female sex, electrolyte abnormalities, diuretic treatment, impaired hepatic metabolism, or bradycardia.30 A consensus panel published five recommendations for prescribers of methadone to reduce the risk for arrhythmias in 2009.31 These recommendations included a baseline electrocardiogram (ECG) for all patients. This committee reconvened and proposed a modified set of recommendations that no longer recommends a baseline ECG for all patients.32 Both recommendations are summarized in Table 4.31,32

An important consideration for using methadone safely in patients with chronic pain is the avoidance of drug interactions. Inhibitors of the CYP450 enzymes, especially CYP3A4, can result in increased effects of methadone, whereas inducers of these enzymes can reduce the serum concentrations and, potentially, the clinical efficacy.2,8 Additionally, methadone is an inhibitor of CYP2D6; thus, it can potentially increase serum concentrations of medications metabolized by this enzyme.33 Prescribers should be aware of drugs that are inhibitors or inducers of the aforementioned CYP enzymes as well as drugs that prolong the QT interval. The Arizona Center for Education and Research on Therapeutics maintains a list of drugs that prolong the QT interval or are associated with torsades de pointes.34 This information is available at www.qtdrugs.org.

In 2009, the FDA and SAMHSA responded to concerns over methadone’s safety with an educational program designed to educate both consumers and healthcare professionals on the safe use of methadone.5 The program is called “Follow Directions: How to Use Methadone Safely.”

Summary
Methadone is an effective analgesic for the treatment of chronic pain. It primarily has been studied in the treatment of cancer pain but limited information supports its use in chronic pain outside of this patient population. Despite its efficacy, methadone can be difficult to manage. Conversion to or from other opioids is difficult as methadone exhibits incomplete cross-tolerance, high interpatient pharmacokinetic variability, and an elimination half-life that greatly exceeds its analgesic efficacy. Clinicians must use caution when converting patients from other opioid agents; those receiving higher opioid doses should be converted using higher morphine-to-methadone dose ratios. Methadone has been associated with QT prolongation and torsades de pointes and healthcare professionals should adhere to recommendations in order to avoid serious AEs.

Last updated on: March 5, 2019
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