Continuing Education Activity

Methadone is a medication used to manage and treat opioid use disorder and as an analgesic in chronic pain. It is a synthetic long-term opioid agonist medication. This activity reviews the indications, mechanism of action, and contraindications for methadone as a valuable agent in treating chronic pain and the management of opioid use disorders. This activity will highlight the mechanism of action, adverse effect profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the healthcare team in the management of patients with opioid use disorder and chronic pain.

Objectives:

• Review indications for prescribing methadone.
• Outline the mechanism of action of methadone.
• Summarize potential adverse effects when using methadone.
• Explain the importance of collaboration and communication amongst the interprofessional team to improve patient outcomes affected by opioid use disorder and chronic pain.

Indications

Indications

1. Moderate to severe pain non-responsive to non-narcotic drugs (FDA Approved)[1]
2. Detoxification and treatment of opioid use disorder as part of medication-assisted treatment (FDA Approved)[1]  
3. Treatment of neonatal abstinence syndrome (Not FDA Approved, Class C Drug)[2]

Indication 1: Moderate to Severe Pain Non-responsive to Non-narcotic Drugs 

Methadone is FDA approved for use in moderate to severe pain that has not responded to non-opioid medications or as an alternative if the pain is unresponsive to other opioid drugs. Methadone is an analgesic used in cancer patients or other terminally ill patients and in chronic pain pathologies. Before starting methadone for noncancer chronic pain, the patient should undergo an evaluation of risk factors that can lead to drug misuse or diversion and establish that benefit of therapy overweighs the harms. The evaluation should include psychosocial reasons for underlying chronic pain like comorbid psychiatric disorders and social support issues.[1][3]

Methadone is an alternative in treating patients with opioid tolerance as they may not respond to traditional analgesic regimens. In such patients, methadone dosages are adjusted or combined with other opioids as adjuvant treatments to enhance response to analgesic interventions.[3][4]

Methadone is a commonly prescribed drug to treat severe, cancer-related, or neuropathic pain in pediatric populations.[5] However, in pediatric populations, the use of opioid medications for analgesia is considered off-label due to scant clinical data to elaborate on the harms versus benefits in this population.[6]

Indication 2: Detoxification and Treatment of Opioid Use Disorder as Part of Medication-assisted treatment

Methadone and buprenorphine are FDA approved to treat opioid use disorder as part of federally regulated opioid treatment programs. Methadone prescriptions are for detoxification and maintenance therapy. Methadone is a useful agent for opioid withdrawal symptoms such as tachycardia, diaphoresis, nausea, vomiting, diarrhea, etc. Abstinence rates from opioid use are better when patients undergo long-term versus short-term methadone treatment. Methadone has been shown to improve retention in treatment and detoxification programs and has shown improvement in mortality rates for opioid abusers.[3] Clinicians must evaluate the availability of methadone in pharmacies when referring patients to such programs, as licensing and availability can vary significantly across states.[3][7]

Indication 3: Treatment of Neonatal Abstinence Syndrome

Neonatal abstinence syndrome (NAS) can be due to a variety of substance abuse during pregnancy, such as alcohol, tobacco, and opioids, all of which can cross the placenta to affect the neonate. Typically treatment is supportive for neonates with milder cases. Pharmacologic intervention is employed when there are moderate to severe signs of withdrawal in neonates (e.g., seizures) and often involves using methadone to treat signs of NAS.[2] Although used to treat opioid withdrawal symptoms in neonates, using methadone for this indication is not FDA-approved. Comparisons have been made in some studies using morphine or buprenorphine as alternatives to treating NAS. Methadone showed better efficacy in treating NAS compared to morphine.[8] However, studies show buprenorphine may be more efficacious in improving neonatal outcomes, including birth weight and length of stay in the hospital, compared to methadone.[2][9]

Mainstreaming Addiction Treatment (MAT) Act

The Mainstreaming Addiction Treatment (MAT) Act provision updates federal guidelines to expand the availability of evidence-based treatment to address the opioid epidemic. The MAT Act empowers all health care providers with a standard controlled substance license to prescribe buprenorphine for opioid use disorder (OUD), just as they prescribe other essential medications. The MAT Act is intended to help destigmatize a standard of care for OUD and will integrate substance use disorder treatment across healthcare settings. 

As of December 2022, the MAT Act has eliminated the DATA-Waiver (X-Waiver) program. All DEA-registered practitioners with Schedule III authority may now prescribe buprenorphine for OUD in their practice if permitted by applicable state law, and SAMHSA encourages them to do so. Prescribers who were registered as DATA-Waiver prescribers will receive a new DEA registration certificate reflecting this change; no action is needed on the part of registrants.

There are no longer any limits on the number of patients with OUD that a practitioner may treat with buprenorphine. Separate tracking of patients treated with buprenorphine or prescriptions written is no longer required. 

Pharmacy staff can now fill buprenorphine prescriptions using the prescribing authority's DEA number and does not need a DATA 2000 waiver from the prescriber. However, depending on the pharmacy, the dispensing software may still require the X-Waiver information in order to proceed. Practitioners are still required to comply with any applicable state limits regarding the treatment of patients with OUD.  Contact information for State Opioid Treatment Authorities can be found here: https://www.samhsa.gov/medicationassisted-treatment/sota.

Mechanism of Action

Methadone is a synthetic opioid and full agonist at the μ-opioid receptor and induces other opioid receptors. The μ-opioid receptors, located in the CNS (e.g., brainstem, locus coeruleus, periaqueductal gray matter) and parts of the gastrointestinal tract, act to modulate various neurochemical activities involved in analgesia, euphoria, and sedation. Activation of the μ-receptors by methadone activates the same pathways. It induces downstream effects via G-protein signaling, including inhibition of neuronal transmission of pain afferents from the spinal cord, producing analgesic effects, and receptor internalization and recycling, contributing to less opioid tolerance in patients.[10][11]

Methadone is also a noncompetitive antagonist to the N-methyl-d-aspartate (NMDA) receptor, possibly further adding to its benefits for neuropathic pain.[6][10][12] When using methadone to treat opioid addiction, the clinician titrates the methadone to a higher daily dose that prevents withdrawal signs and causes narcotic blockade to prevent euphoria from other shorter-acting opioids. Due to the longer half-life of methadone (8 to 60 hours), the withdrawal time-course and symptoms are less severe.[10][11][13]

Administration

Methadone is available as a lipophilic hydrochloride salt in oral, IM, IV, subcutaneous, epidural, and intrathecal formulations.[14][15] Different dosing and formulations depend on the purpose of use, but oral formulations in either tablet or concentrated syrup form are the most commonly used. A general guideline for dosing regimens is listed. 

• Pain management: 
• Opioid-naive: Oral, 2.5 mg every eight hours with incremental dose increase if needed about once every week.[15] 
• Opioid-Tolerant: Oral, 10 mg of methadone is approximately equivalent to a 15 mg dose of oral morphine. Follow dosing charts for equivalent dosing and conversion factors tailored to the individual patient.[15]
• Opioid use disorder: 
• General: Oral dosing starts at 30 to 40 mg/day and is titrated upwards by 10 to 20 mg/week to an optimal of 80 to 150 mg/day.[13] Long-term treatment is optimal if it lasts for at least 14 months.[7]
• Pregnancy: Continue maintenance treatment in women who are pregnant and have opioid use disorder. Consider treating with buprenorphine instead due to less sedation on the neonate.[16]
• Opioid withdrawal:
• Adults: Oral dosing starts at 10 to 20 mg and is increased by 10 mg increments until the withdrawal symptoms are controlled, usually about 40 mg. Stabilize dosing for 2 to 3 days and then reduce dose by 10 to 20% daily and monitor for withdrawal symptoms. 
• Neonates: Oral, 0.05 to 0.1 mg/kg every 6 hours until withdrawal symptoms stabilize. Then reduce the dose by 10 to 20% daily and continue serial monitoring of withdrawal symptoms [2].

Other Considerations

• Methadone has high oral bioavailability, with plasma levels measurable after 30 minutes and a decline in plasma levels occurring after 24 hours, all of which should be considered in frail patients or patients with altered hepatic clearance to prevent overdose.[13] 
• CYP 3A4 and CYP 2B6 hepatically metabolize methadone to non-active metabolites, and interactions with other hepatically metabolized drugs merit consideration and monitoring.[13]
• As methadone is hepatically metabolized, dosing adjustments are typically not needed in patients with renal issues, but care should still be advisable in end-stage renal disease.[3]
• The recommended dose for parenteral administration is between 50 to 80% of the oral dose, and caution is necessary when switching to methadone from another opioid. Dosing ratios can be useful to calculate the appropriate dose.[10]

Adverse Effects

As with other opioid medications, general adverse effects of methadone are related to excess opioid receptor activity, including but not limited to [15]:

• Diaphoresis/flushing
• Pruritis
• Nausea
• Dry mouth
• Constipation
• Sedation
• Lethargy
• Respiratory depression

Methadone is also associated with QTc prolongation (>450 ms), leading to cardiac dysfunction and severe hypoglycemia in certain patient populations.[17][18]

Contraindications

Methadone can cause CNS depression and respiratory compromise; hence it should be used with extreme caution in patients with CNS-related pathologies such as trauma, increased intracranial pressure, dementia, delirium, etc. Methadone should not be used in conjunction with medications or substances with similar depressant effects such as other opioids, benzodiazepines, alcohol, antipsychotics, etc., unless necessary. Drugs that may increase the clearance of methadone or decrease its effects must also be used with caution to prevent precipitating withdrawal symptoms. The following examples are not an exhaustive list of drug interactions but provide some commonly documented drug interactions to monitor when using methadone.[15]

Examples of drugs that may increase methadone effects and risk overdose symptoms: 

• Ciprofloxacin
• Benzodiazepines
• Alcohol
• Fluconazole
• Cimetidine
• Fluoxetine
• Urine alkalizing agents

Examples of drugs that may decrease methadone effects and risk withdrawal symptoms: 

• Efavirenz
• Phenobarbital
• Phenytoin
• Rifampin
• Ritonavir
• Carbamazepine
• Urine acidifying agents 

Monitoring

Monitor patients for adverse outcomes based on assessment tools for determining risk level for opioid abuse, loss to treatment, diversion of drugs, adverse effects, and overdose.[19][20] Assessment tools are available to set criteria for urine drug screens, clinical health assessments, and psychosocial determinants. Before starting treatment, establish a clinical baseline, and assess comorbid conditions. Clinicians should also review prescription drug monitoring (PDMP) data to cross-reference opioid prescription history.[20] Once treatment begins, titrate dosage carefully as methadone has a narrow therapeutic index. The recommended target value for therapeutic drug monitoring is 400 μg/ml.[21] Reassess individuals frequently during initial therapy and when changing doses. Individuals at low risk for adverse outcomes should be monitored once every three to six months after reaching therapeutic levels of methadone. For individuals at high risk for adverse outcomes, monitoring can be done every week.

Follow guidelines to monitor for more severe adverse effects such as QTc prolongation, drug interactions, and hypoglycemia:

• QTc Prolongation >450 ms
• Obtain baseline electrocardiogram for all patients and repeat within 30 days to assess for acute changes. Repeat electrocardiogram annually.
• If the methadone dose exceeds 100 mg/dL or the patient is symptomatic, do further cardiac assessments.
• If the QTc interval exceeds 500 ms, reduce the methadone dose or discontinue, and use alternative therapy such as buprenorphine-naloxone.[17]
• Drug interactions due to CYP3A4 metabolism
• Methadone levels can be increased or decreased depending on the drug interaction precipitating either overdose or withdrawal symptoms.
• Monitor patients carefully on drugs that may affect clearance, watching out for signs of withdrawal or overdose.[22] 
• Hypoglycemia 
• Patients at high risk for this complication include cancer patients and patients who have a rapid dose escalation. Patients benefit from regular serum glucose screening. 
• Indications a patient is hypoglycemic include unexplained lethargy, perspiration, and palpitations.[18]

Toxicity

Overdose of methadone can cause severe respiratory depression and can lead to demise. Signs of overdose include extreme lethargy, somnolence, stupor, coma, miosis, bradycardia, hypotension, respiratory sedation, and cardiac arrest. The patient's oxygenation and ventilation should have close monitoring in case of overdose. The patient is treated with naloxone if an overdose is suspected.[3] 

Enhancing Healthcare Team Outcomes

Assessing the use of methadone in different clinical scenarios requires specialized knowledge regarding its pharmacologic attributes and its legal limitations. Deaths associated with the nonprescription use of opioids are a leading cause of mortality in the United States. Federal programs for detoxification and maintenance using methadone or buprenorphine-naloxone are considered crucial in reducing those numbers.

Close communication between a patient's healthcare team will be vital to providing the best outcomes. Identifying patients who would benefit from methadone requires an interprofessional team of physicians, nurses, pharmacists, lab technicians, therapists, and social workers to then provide a safety net for monitoring the risks of its use. Monitoring can prevent overdose, toxicity, withdrawal, drug diversion, and assess comorbid psychiatric diseases or other social determinants related to better patient outcomes. The interprofessional team should be cognizant of the following when caring for patients who require methadone [23]: 

• Have clear communication regarding the risks and benefits of opioid use with patients [Level 1] 
• Methadone use is recommended only after the failure of other opioids for chronic pain. [Level 1]
• Understand legalities for prescribing methadone depending on state and federal laws, and cross-reference state prescription drug monitoring program (PDMP) databases [Levels 1-2]. 
• Assess current opioid use status and monitor with regular urine drug screens [Level 2]
• Assess baseline clinical function with cardiac clearance, serum glucose, and psychiatric assessments and determine benefit vs. harm ratios depending on other comorbidities. [Levels 1-3]
• Obtain medication recommendations regarding drug interactions if the patient uses other medications. [Level 1-2]
• Assess social support, accessibility to methadone clinics, and the likelihood of retention in methadone programs if being treated for opioid use disorder.
• Provide adjunct therapy or addiction specialist consultations to patients who are at high risk of adverse outcomes. 
• Monitor patients regularly for adverse effects and adjust medications accordingly [Level 1]
• In overdose situations, administer naloxone to prevent fatalities [Level 1] [3]

Patient care involving methadone is still an evolving subject, and knowledge of regular updates to the literature is essential to establishing the best patient care possible. Physicians must determine whether methadone is an appropriate drug to prescribe, follow through with patient care, and communicate clearly and effectively regarding a patient's consent and understanding of the risks and benefits of methadone use.

Nurses are first-line in administering drugs, monitoring patients for adverse reactions, and are purveyors of overall patient clinical status, adherence, and improvement. Pharmacists must advise the team regarding medication interactions and assess dosing requirements for patients with comorbidities to prevent adverse events and provide proper analgesia. Lab technicians will run tests evaluating adherence, abuse, and overdose in patients.

Psychiatrists, mental health therapists, and addiction specialists can provide behavioral therapy, treat comorbid psychiatric diseases, and monitor adherence as part of medication-assisted treatment programs.

Social workers can help provide support outside hospital settings, connecting patients to the right resources, and evaluate social determinants of opioid abuse and retention in maintenance programs. A team of healthcare professionals is essential to cover all aspects of patient care when prescribing methadone. Clear communication amongst the team will be vital to maintaining an accurate plan of care for patients that reduces associated risks, improves patient outcomes, and provides the best quality of care possible.