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-narcotic medications or as an alternative if the pain is unresponsive to other opioid drugs. Methadone is used as an analgesic in cancer patients or other terminally ill patients, and chronic pain pathologies. Before starting methadone for noncancer chronic pain, the patient should undergo evaluation of risk factors that can lead to drug abuse, diversion, and also to 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.
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.
Methadone is a commonly prescribed drug to treat severe, cancer-related, or neuropathic pain in pediatric populations. 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.
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. Clinicians must evaluate the availability of methadone in pharmacies when referring patients to such programs, as licensing and availability can vary significantly across states.
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 involve the use of methadone to treat signs of NAS. Although used for the treatment of opioid withdrawal symptoms in neonates, methadone use for this condition 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. However, studies show buprenorphine may be more efficacious in improving neonatal outcomes, including birth weight and length of stay in hospital compared to methadone.
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 a variety of 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.
Methadone is also a non-competitive antagonist to the N-methyl-d-aspartate (NMDA) receptor, possibly further adding to its benefits for neuropathic pain. 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.
Methadone is available as a lipophilic hydrochloride salt in oral, IM, IV, subcutaneous, epidural, and intrathecal formulations. 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.
As with other opioid medications, general adverse effects of methadone are related to excess opioid receptor activity including but not limited to :
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.
Examples of drugs that may increase methadone effects and risk overdose symptoms:
Examples of drugs that may decrease methadone effects and risk withdrawal symptoms:
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. 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. 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. 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. 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:
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.
Assessing the use of methadone in different clinical scenarios requires specialized knowledge regarding its pharmacologic attributes and its legal limitations. Deaths associated with non-prescription 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 a team of physicians, nurses, pharmacists, lab technicians, therapists, and social workers to then provide a safety net for monitoring risks of its use. Monitoring can prevent overdose, toxicity, withdrawal, drug diversion, and to assess comorbid psychiatric diseases or other social determinants related to better patient outcomes. Healthcare teams should be cognizant of the following when caring for patients who require methadone :
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 with 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 on medication interactions and assess dosing requirements for patients with comorbidities to prevent adverse events and provide proper analgesia to patients. 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.
|||Chou R,Fanciullo GJ,Fine PG,Adler JA,Ballantyne JC,Davies P,Donovan MI,Fishbain DA,Foley KM,Fudin J,Gilson AM,Kelter A,Mauskop A,O'Connor PG,Passik SD,Pasternak GW,Portenoy RK,Rich BA,Roberts RG,Todd KH,Miaskowski C, Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. The journal of pain : official journal of the American Pain Society. 2009 Feb; [PubMed PMID: 19187889]|
|||Hudak ML,Tan RC, Neonatal drug withdrawal. Pediatrics. 2012 Feb; [PubMed PMID: 22291123]|
|||Toce MS,Chai PR,Burns MM,Boyer EW, Pharmacologic Treatment of Opioid Use Disorder: a Review of Pharmacotherapy, Adjuncts, and Toxicity. Journal of medical toxicology : official journal of the American College of Medical Toxicology. 2018 Dec; [PubMed PMID: 30377951]|
|||Mercadante S,Ferrera P,Villari P,Casuccio A,Intravaia G,Mangione S, Frequency, indications, outcomes, and predictive factors of opioid switching in an acute palliative care unit. Journal of pain and symptom management. 2009 Apr; [PubMed PMID: 19345298]|
|||Anghelescu DL,Faughnan LG,Hankins GM,Ward DA,Oakes LL, Methadone use in children and young adults at a cancer center: a retrospective study. Journal of opioid management. 2011 Sep-Oct; [PubMed PMID: 22165034]|
|||Mulder DJ,Sherlock ME,Lysecki DL, NMDA-receptor Antagonism in Pediatric Pancreatitis: Use of Ketamine and Methadone in a Teenager With Refractory Pain. Journal of pediatric gastroenterology and nutrition. 2018 May; [PubMed PMID: 29394214]|
|||Salsitz E,Wiegand T, Pharmacotherapy of Opioid Addiction: [PubMed PMID: 26567033]|
|||Davis JM,Shenberger J,Terrin N,Breeze JL,Hudak M,Wachman EM,Marro P,Oliveira EL,Harvey-Wilkes K,Czynski A,Engelhardt B,D'Apolito K,Bogen D,Lester B, Comparison of Safety and Efficacy of Methadone vs Morphine for Treatment of Neonatal Abstinence Syndrome: A Randomized Clinical Trial. JAMA pediatrics. 2018 Aug 1; [PubMed PMID: 29913015]|
|||Staszewski CL,Garretto D,Garry ET,Ly V,Davis JA,Herrera KM, Comparison of buprenorphine and methadone in the management of maternal opioid use disorder in full term pregnancies. Journal of perinatal medicine. 2020 Jul 20; [PubMed PMID: 32681781]|
|||Fredheim OM,Moksnes K,Borchgrevink PC,Kaasa S,Dale O, Clinical pharmacology of methadone for pain. Acta anaesthesiologica Scandinavica. 2008 Aug; [PubMed PMID: 18331375]|
|||Walwyn WM,Miotto KA,Evans CJ, Opioid pharmaceuticals and addiction: the issues, and research directions seeking solutions. Drug and alcohol dependence. 2010 May 1; [PubMed PMID: 20188495]|
|||Teixeira MJ,Okada M,Moscoso AS,Puerta MY,Yeng LT,Galhardoni R,Tengan S,Andrade DC, Methadone in post-herpetic neuralgia: A pilot proof-of-concept study. Clinics (Sao Paulo, Brazil). 2013 Jul; [PubMed PMID: 23917673]|
|||Kreek MJ,Reed B,Butelman ER, Current status of opioid addiction treatment and related preclinical research. Science advances. 2019 Oct; [PubMed PMID: 31616793]|
|||Wiffen PJ,Wee B,Derry S,Bell RF,Moore RA, Opioids for cancer pain - an overview of Cochrane reviews. The Cochrane database of systematic reviews. 2017 Jul 6; [PubMed PMID: 28683172]|
|||Toombs JD,Kral LA, Methadone treatment for pain states. American family physician. 2005 Apr 1; [PubMed PMID: 15832538]|
|||Klaman SL,Isaacs K,Leopold A,Perpich J,Hayashi S,Vender J,Campopiano M,Jones HE, Treating Women Who Are Pregnant and Parenting for Opioid Use Disorder and the Concurrent Care of Their Infants and Children: Literature Review to Support National Guidance. Journal of addiction medicine. 2017 May/Jun; [PubMed PMID: 28406856]|
|||Krantz MJ,Martin J,Stimmel B,Mehta D,Haigney MC, QTc interval screening in methadone treatment. Annals of internal medicine. 2009 Mar 17; [PubMed PMID: 19153406]|
|||Moryl N,Pope J,Obbens E, Hypoglycemia during rapid methadone dose escalation. Journal of opioid management. 2013 Jan-Feb; [PubMed PMID: 23709301]|
|||Ling W,Mooney L,Hillhouse M, Prescription opioid abuse, pain and addiction: clinical issues and implications. Drug and alcohol review. 2011 May; [PubMed PMID: 21545561]|
|||Dowell D,Haegerich TM,Chou R, CDC Guideline for Prescribing Opioids for Chronic Pain--United States, 2016. JAMA. 2016 Apr 19; [PubMed PMID: 26977696]|
|||Vazquez V,Gury C,Laqueille X, [Methadone: from pharmacokinetic profile to clinical pharmacology]. L'Encephale. 2006 Jul-Aug; [PubMed PMID: 17099560]|
|||Ferrari A,Coccia CP,Bertolini A,Sternieri E, Methadone--metabolism, pharmacokinetics and interactions. Pharmacological research. 2004 Dec; [PubMed PMID: 15501692]|
|||Manchikanti L,Kaye AM,Knezevic NN,McAnally H,Slavin K,Trescot AM,Blank S,Pampati V,Abdi S,Grider JS,Kaye AD,Manchikanti KN,Cordner H,Gharibo CG,Harned ME,Albers SL,Atluri S,Aydin SM,Bakshi S,Barkin RL,Benyamin RM,Boswell MV,Buenaventura RM,Calodney AK,Cedeno DL,Datta S,Deer TR,Fellows B,Galan V,Grami V,Hansen H,Helm Ii S,Justiz R,Koyyalagunta D,Malla Y,Navani A,Nouri KH,Pasupuleti R,Sehgal N,Silverman SM,Simopoulos TT,Singh V,Solanki DR,Staats PS,Vallejo R,Wargo BW,Watanabe A,Hirsch JA, Responsible, Safe, and Effective Prescription of Opioids for Chronic Non-Cancer Pain: American Society of Interventional Pain Physicians (ASIPP) Guidelines. Pain physician. 2017 Feb; [PubMed PMID: 28226332]|