How Should Methadone Be Started and Titrated in Opioid-Naïve and Opioid-Exposed Patients?

Introduction and Scope of the Problem

Methadone is a powerful tool for treating pain in patients with serious illness. Initially synthesized in the late 1940s, methadone has grown in popularity as an analgesic in recent years. Due to action at multiple sites, including agonism at the mu opioid receptor and antagonism at the N-methyl-D-aspartate (NMDA), serotonin, and norepinephrine receptors, methadone can provide effective analgesia with fewer side effects than traditional opioids for selected patients. Furthermore, methadone has a high oral bioavailability, has a long duration of action, is safe in patients with renal failure or morphine allergy, is available in a wide variety of formulations, and is low cost. These properties make methadone an increasingly useful opioid for patients in the palliative care setting.

Methadone has unique characteristics, however, that require a clinician to have specialized knowledge to prescribe it safely. As a result, despite its many favorable qualities, methadone is often considered a second-line treatment for pain due to its complex pharmacokinetics and pharmacodynamics, potential for drug interactions, and lack of provider comfort and experience.

This chapter will provide guidance on appropriate patient selection, initiation of methadone in both opioid-naïve and opioid-tolerant patients, safety considerations and monitoring, and utilization of methadone in special populations. Given the nuances of prescribing methadone, it is recommended that clinicians unfamiliar with methadone seek further guidance from an expert.

Relevant Pharmacology

Methadone has an average oral bioavailability of approximately 70% to 80%, but ranges from 36% to 100% as compared to 26% for oral morphine. It is a highly lipophilic synthetic opioid, allowing it to be delivered by oral, parenteral, subcutaneous, intramuscular, epidural, intrathecal, and rectal routes. It is rapidly absorbed in the stomach and distributed systemically to the brain, liver, kidney, muscles, and lungs. Because methadone has a greater affinity for tissue than plasma proteins, accumulation in tissues can occur with repeated dosing. Given this deposition in the tissues, methadone may be reabsorbed and present in the plasma even weeks after cessation of the drug. Of the plasma proteins, methadone avidly binds to alpha-1-acid glycoprotein (AAG), which is altered by the presence of other medications such as tricyclic antidepressants and is decreased in liver disease, thus affecting methadone’s bioavailability. Methadone is metabolized in the liver via the cytochrome P450 (CYP450) enzyme system, which accounts for multiple drug interactions. For a patient with hepatic impairment, metabolism is affected, so methadone should be titrated conservatively. After metabolism in the liver, methadone is excreted by the kidneys and biliary system as inactive metabolites. Because the metabolites are inactive, methadone dosage typically does not have to be adjusted for renal impairment.

Onset of action for methadone is comparable to other oral opioids at 30 to 60 minutes, with peak effect at 2.5 to 4 hours. Duration of analgesia upon initiation of methadone is 4 to 6 hours; however, upon reaching steady state, methadone’s duration of analgesia can be 8 to more than 12 hours. Given the duration of action, methadone is typically dosed every 8 hours, though in some cases it can be dosed every 6 or every 12 hours. Arguments for prescribing methadone twice daily include decreased pill burden and improved medication adherence. Of note, this frequency of dosing is in contrast to the once-daily dosing of methadone used to treat opioid use disorder. Methadone has a long two-phase elimination, resulting in an average half-life of 30 hours, but depending on a patient’s metabolism, half-life can range anywhere from 5 to 150 hours. Steady state is reached after 5 half-lives, approximately 5 to 7 days.

Because of methadone’s long half-life and variable pharmacokinetics, patients are at greatest risk for adverse effects in the time leading up to steady state. To mitigate the risks of oversedation and respiratory depression, it is essential to provide patients and their families with detailed safety instructions; for example, to call the prescribing clinician if pain relief occurs too quickly (after the first 1 to 2 days of methadone initiation), and to monitor for signs of sedation and respiratory depression. The clinician should also plan for close follow-up after initiation.

In summary, given its unpredictable pharmacodynamics and long time to achieve steady state, methadone is not a first-line opioid for acute pain management. Its long half-life, however, makes methadone a good agent for providing effective basal analgesia for persistent pain.

Summary of Evidence Regarding Treatment Recommendations

Patient Selection

Table 5.1 highlights patient characteristics that should be considered when weighing the appropriateness of methadone therapy.

Table 5.1

Patient Selection for Methadone for Pain Management

Indications	Contraindications
Pain refractory to other opioids	Prognosis less than time to steady state
Requiring high opioid dose	No access to knowledgeable clinician to continue management
Adverse effects from other opioids	Poor medication adherence
Mixed nociceptive and neuropathic pain	Active use of substances that would increase risks of adverse effects (e.g., heroin, benzodiazepines)
Renal impairment	At risk for QTc prolongation
Morphine allergy	Obstructive or central sleep apnea
History of dysphagia	Severe hepatic impairment
Lower cost	Paralytic ileus

Methadone is available at a fraction of the cost of other long-acting opioids, an advantage for patients who may find the cost of medications prohibitive. Liquid methadone or crushed tablets can be administered via a feeding tube to provide long-acting basal pain control for patients who cannot take oral medications. In comparison, most other long-acting opioids come in specialized pill formulations that cannot be crushed. Disadvantages of methadone therapy for certain patients include a proven association between methadone and sleep-disordered breathing, central sleep apnea, and obstructive sleep apnea; there is also a particularly dangerous additive effect in the setting of concomitant benzodiazepine use. Of note, management with positive pressure treatments has frequently been ineffective in instances of sleep apnea related to methadone therapy. In addition, patients with underlying congestive heart failure and cardiac disease had a statistically significant increased risk of prolonged corrected QT interval on electrocardiogram (QTc) while on methadone therapy. Monitoring of QTc interval and contraindications for methadone therapy will be discussed in further detail below in “Safe Prescribing: Side Effects, EKG Monitoring, Drug Interactions.”

Initiating Methadone in Opioid-Naïve Patients or Those Using Low-Dose Opioids

While methadone is not commonly used as a first-line agent for patients requiring opioid therapy, studies suggest it can be a safe and effective option for analgesia at low doses. In a retrospective observational study of hospice patients, Salpeter reported good pain control with very low doses of methadone. Similarly, a case series of frail older adults by Bach demonstrated improvement in neuropathic pain control with the addition of very low doses of methadone (starting doses of 0.5 mg to 1 mg oral methadone) as an adjuvant to low-dose opioids. When initiating methadone for pain management, both patients without prior exposure to opioids and patients using less than 60 mg of oral morphine equivalent (OME) daily should be considered opioid naïve. Guidelines released by the American Academy of Hospice and Palliative Medicine (AAHPM) recommend starting at a maximum of 7.5 mg of oral methadone daily for this group of patients. For frail patients, the group suggests starting with a dose as low as 1 mg twice daily.

For breakthrough pain, many palliative care clinicians would recommend using a short-acting opioid, such as morphine or hydromorphone, rather than “as-needed” doses of additional methadone, given the more predictable pharmacokinetics of short-acting opioids. In addition, utilizing a short-acting opioid for breakthrough doses ensures that as-needed doses are not impacting the final methadone steady-state level.

Clinicians should inform patients and their families that methadone may take a few days to provide adequate pain relief. Patients should be encouraged to use short-acting opioid breakthrough doses while awaiting methadone steady state. On the other hand, patients should be advised that if they experience complete pain relief too quickly (i.e., 1 to 2 days after starting methadone), they should call their clinician. In such cases, the dose may need to be decreased due to concerns about oversedation or respiratory depression once the medication has ultimately reached steady state. In the outpatient setting, consider timing the initiation or increase of methadone to achieve steady state during a weekday, when a palliative care team member can more readily monitor and follow up with the patient.

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