Everything You Wanted to Know about Methadone Prescribing

Methadone has been increasingly used as a treatment for patients with chronic pain in the last 10-15 years, but as the number of prescriptions written for use of methadone as an analgesic have increased, so too have the number of deaths associated with this medication. As part of a symposium presented Saturday, May 8, at the American Pain Society 29th Annual Scientific Meeting, Perry Fine, MD, discussed the risks and benefits of methadone compared to other opioids in the pain management setting, including precautions that providers should take when prescribing this medication.

Perry Fine, MD, Professor of Anesthesiology, Pain Research Center, School of Medicine, University of Utah, and President elect of the AAPM, discussed a variety of issues involved in the safe prescribing of methadone. Noting that the number of methadone prescriptions has increased nearly four-fold in the last 10-15 years -- not because of increased use a substitute medication for patients who are addicted to morphine or heroin addiction but rather for analgesia in patients with chronic and other forms of pain — Fine outlined several reasons why methadone is a viable option in the chronic pain setting, including the fact that methadone is an effective mu opioid analgesic with NMDA receptor agonist properties, it has a very low cost relative to other opioid medications, it offers versatile dosing, it has a long duration of action, and features a favorable metabolic profile.

However, Fine noted, there are also several concerns that prescribers should consider when dispensing this medication for patients with pain, including the drug’s “highly variable pharmacokinetics. Methadone also has quite a long half-life compared to its analgesic duration of action, it is associated with nonlinear dose conversion (high variability from patient to patient), and safely prescribing it requires a vigilant prescriber who possesses methadone-specific knowledge. In fact, Fine noted, safe methadone prescribing also requires a highly responsible patient and/or caregiver for monitoring medication use and effects, especially during dose titration.

Other issues to consider when prescribing methadone for patients with chronic pain include being mindful of potential reactions with monoamine oxidase inhibitors, the potential for cardiac toxicity (prolonged QTc interval), an increase in serum levels by CYP 2B6 and 3A4 inhibitors (which has been associated with multiple overdose deaths), and a strong association between methadone and sudden death, even at therapeutic levels (even in patients who have been at stable doses for a long duration). Fine particularly emphasized the dangers associated with tehpotential for cardiac toxicity with methadone, noting that there is a long list of drugs that increase QT interval that providers should be aware of, which is especially important in light of the fact that patients nowadays commonly get prescriptions from multiple providers.

Fine cited the APS-AAPM guidelines on methadone prescribing, which remind providers that methadone is characterized by complicated and variable pharmacokinetics and pharmacodynamics, and should be initiated and titrated cautiously, by clinicians familiar with its use and risks. This recommendation is classified as a “strong recommendation” that is backed by moderate-quality evidence.

“What is a reasonable starting dose for methadone when used to treat patients with chronic pain?” Fine asked the audience. He said that a reasonable starting dose in most opioid-naïve patients is 2.5 mg/8 hours, with a dose increase after a minimum of 10 days. In older patients, or those with renal or hepatic comorbidities, less frequent dosing and more cautious dose titration are recommended. Fine warned that because of its long half-life and variable pharmacokinetics, methadone should NOT be used to treat breakthrough pain. Recommended dose titration for frail or older patients, or patients with possible sleep apnea is 1-2 mg q 8 hours; for robust younger patients recommended titration is 2.5 -5 mg q 8 hours. Upward titration should be q 5-7 days.

Conversion from other drugs to methadone (nonlinear proportionality), at less than 100mg oral morphine/oral methadone is 3/1 (3mg morphine = 1 mg methadone), ratio increases as morphine dose escalates

Outpatient/caregiver education is another essential aspect of safe methadone prescribing. Patients and caregivers should be reminded that adequate pain relief with methadone may not be achieved for days or weeks, and that they cannot increase the dose because “it’s not working.” Patients should be strongly warned to only take methadone exactly as directed by their provider. Use short-acting rescue doses until sufficient baseline analgesia has been achieved. Patients should also post emergency phone numbers for caregivers to call if they detect any sign of increased sedation, mental cloudiness, or other cognitive deficit. Patients who have been prescribed methadone absolutely should not use alcohol, benzodiazepines, or any illicit drugs.

Adequate monitoring for complications and side effects is also a key component of safe and effective methadone prescribing, said Fine. Clinicians or office staff should follow up with every-other day phone contact during dose titration. It is recommended that patients should receive an EKG for monitoring, but opinions vary as to the frequency and timing of administration: definitely at baseline and following initial dose, but some call for additional testing intra-titration, at dose stabilization, and during follow-up (especially for high-risk patients). In-person evaluations should be conducted weekly at least until dose stabilization.

Fine reiterated that overdose deaths involving prescription drugs are rising, and the reasons are multifactorial. Data are incomplete, but good evidence points to several likely contributing factors. To minimize harm when prescribing opioids and other psychotherapeutics, Fine recommended that clinicians observe eight prescribing guidelines created by the National Pain Foundation:

• Evaluate patients for risk of abuse before starting opioid therapy and manage accordingly.
• Watch for and treat co-morbid mental disease when it occurs.
• Use conventional conversion tables cautiously when rotating from one opioid to another.
• Advise your patients to avoid combining benzodiazepines with opioids, especially during sleep hours.
• Start methadone at a very low dose and titrate slowly regardless of whether the patient is opioid tolerant or not.
• Assess for sleep apnea in patients on high daily doses of methadone or other opioids and in patients with a predisposition for the condition.
• Tell patients on long-term opioid therapy to reduce opioid dose during upper respiratory infections or asthmatic episodes.
• Avoid using long-acting opioid formulations for acute post-operative or trauma-related pain.

In conclusion, Fine stated that “All medication management must be tailored to individual patient’s needs and circumstances. Ongoing critical thinking, sound judgment, and clinical experience can never be replaced by formulae.”