Methadone for pain management: Why , W hen & How

1. Methadone for pain management:Why, When & How Masil George, MD Associate Professor, UAMS Department of Geriatrics Associate Professor, UAMS Division of Medical Humanities Director, Geriatric Palliative Care Program, UAMS Medical Director, Baptist Hospice 10/02/2019

2. Objectives • Explain why Methadone is a potent and effective pain reliever • Describe unique properties of Methadone and precautions to be taken to minimize serious side effects • Discuss when Methadone would be ideal to use for pain relief

3. Opioids for Chronic Pain • Chronic pain affects 100 million US adults and is estimated to cost $635 billion each year in treatment, lost wages, and reduced productivity. • Opioid therapy for chronic noncancer pain is being called into question. • 2016 guideline from the US Centers for Disease Control and Prevention has called for more limited and judicious use of opioids in primary care. • Nevertheless, long-term opioid therapy is probably helpful in some circumstances and will likely continue to have a role in chronic pain management for the foreseeable future. Von Korff M, Kolodny A, Deyo RA, Chou R. Long-term opioid therapy reconsidered. Ann Intern Med 2011

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7. 1. Why Methadone is a potent and effective pain reliever

8. The Story of Methadone • Methadone (6-dimethylamino-4, 4-diphenyl-3-heptanone) was first synthesized in 1937 by Bockmühl and Ehrhart • Methadone was introduced as an analgesic in the mid-1940s but soon lost favor because of its side effect profile • Systematic studies were undertaken in 1958 to treat opiate addiction • Methadone was introduced in 1965 for opiate addiction • Oral administration & longer duration of action- better compliance and better control of symptoms • Tolerance does not develop to the essential effects of methadone (prevention of opiate abstinence symptoms and prevention of drug hunger or craving) as used in maintenance treatment Pharmacology and Medical Aspects of Methadone Treatment The National Academy of Science, Engineering, Medicine (1995)

9. The Story of Methadone (cont..) • In 1973, three types of opioid receptors were identified—mu, delta, and kappa • In 1975, the first class of endogenous opioid peptide ligands, the enkephalins, were discovered and generically called "endorphins“ • Methadone binds primarily or exclusively to the mu type of opiate receptor, with greater selectivity than other opiates

10. Symptoms of Opioid Withdrawal • A reproducible syndrome occurs when an opiate addict goes through withdrawal. • Yawning, lacrimation, piloerection, fever, perspiration, mydriasis, tremor, restlessness, myalgia, anorexia, nausea, vomiting, abdominal cramps, diarrhea, hyperpnea, and hypertension. • When prolonged, the syndrome includes weight loss and, sleep disturbances, irritability, restlessness, and poor concentration which can be present for months or years. • Both acute and chronic tolerance are physiological phenomena and are influenced by environmental variables, such as setting, conditioning, and learning. Pharmacology and Medical Aspects of Methadone Treatment The National Academy of Science, Engineering, Medicine (1995)

11. Characteristics of Methadone • Methadone is a highly lipophilic molecule that is suitable for a variety of administration routes. • Methadone is approved for oral and intramuscular use, it also is used rectally, intravenously, subcutaneously, epidurally, and intrathecally. • Oral methadone has a bioavailability close to 80 percent compared with 26 percent for morphine • Tissue binding predominates over binding to plasma proteins, and accumulation of the drug occurs in these tissues with repeated dosing.Methadone reabsorption from the tissues may continue for weeks after administration has ceased. • Methadone is metabolized in the liver with no active metabolites. It has an elimination half-life of about 22 hours, but metabolism varies in each person Toombs JD, Kral LA Methadone treatment for pain states. Am Fam Physician 2005 Apr 1; 71 (7): 1353-8

12. Characteristics of Methadone (continued) • The duration of analgesia is approximately three to six hours when methadone therapy is initiated, and this duration typically extends to eight to 12 hours with repeated dosing. • Methadone is a muopioid agonist. Analgesia and typical opioid side effects are the result of action at the muopioid receptor. Toombs JD, Kral LA Methadone treatment for pain states. Am Fam Physician 2005 Apr 1; 71 (7): 1353-8

13. 2. Unique properties of Methadone • Methadone has nonopioid actions, including inhibition of the reuptake of monoamines (e.g., serotonin, norepinephrine) and inhibition of N-methyl-D-aspartate (NMDA) receptors—pharmacologic actions that result in additional analgesia.8 • Activation of the NMDA receptor can produce central sensitization (i.e., lowering central nervous system pain thresholds), so blocking this receptor may help prevent the development of tolerance. Toombs JD, Kral LA Methadone treatment for pain states. Am Fam Physician 2005 Apr 1; 71 (7): 1353-8

14. Opioids for Chronic Noncancer Pain Management • Safe and effective chronic opioid therapy (COT) for chronic noncancer pain requires clinical skills and knowledge in both the principles of opioid prescribing and in the assessment and management of risks associated with opioid abuse, addiction, and diversion. • Clinician has to be educated on risk stratification, informed consent and opioid management plans, initiation and titration of COT, use of methadone, monitoring of patients, use of opioids in high-risk patients, assessment of aberrant drug-related behaviors, dose escalations and high-dose opioid therapy, opioid rotation, indications for discontinuation of therapy, prevention and management of opioid-related adverse effects, driving and work safety, identifying a medical home and when to obtain consultation, and management of breakthrough pain. Chou R, Pol Arch Med Wewn 2009 Jul- Aug; 119(7-8) 2009 Clincial Guidelines from The American Pain Society and The American Academy of Pain Medicine on the use of Chronic noncancer pain: what are the key messages for clinical practice?

15. Methadone on the Analgesic Ladder

16. Advantages of Long Acting Opioids • Stable blood levels of opioids • Decreased risk for addiction • Fewer adverse effects • Improved analgesia Von Korff M, Merrill JO, Rutter CM, Sullivan M, Campbell CI, Weisner C. Time-scheduled vs. pain-contingent opioid dosing in chronic opioid therapy. Pain. 2011;Vol 152:1256–1262.

17. Advantages of using Methadone • Covered by insurance or incredibly cheap • Methadone tablets are available in low doses • Methadone has a half-life that ranges from 15 to 60 hours in most patients and is usually around 30 hours • (It typically takes 3.5 to 4 half-lives for drug levels to reach steady state. Methadone the levels will continue to go up for 4 to 5 days before it reaches steady state) Acpinternist.org/archives/2014/09/methadone.htm (last accessed 10/02/2019)

18. Specific Indications for Methadone • Opioid neurotoxicity • Opioid tolerance and opioid hyperalgesia • Uncontrolled neuropathic pain • True Morphine allergy • Treatment of severe pain for patients on chronic methadone maintenance therapy • Patients with renal failure and/ or on dialysis Palat G, Chary S. Practical Guide for Using Methadone in Pain and Palliative Care Practice. Ind J Palliat Care. 2018

19. Caution with using Methadone • Methadone can also result in prolonged QTc intervals and put patients at risk for fatal arrhythmias. • Do not use with impulsive patients! • Educate, educate, educate! • Consider Narcan prescription

20. 3. Methadone for Pain Management • When other options for pain management have been attempted and exhausted • Patient selection, Patient Education • Initiate at low dose, follow up often, titrate slowly • Opioid Conversion (Science & Art)

21. Methadone for Pain: Regulations • Methadone is listed on schedule II of the Controlled Substances Act. • Initially, its use was limited to “detoxification treatment” or “maintenance treatment” within U.S. Food and Drug Administration–approved narcotic addiction programs. • This restriction was removed in 1976; all physicians with appropriate Drug Enforcement Agency registration now are allowed to prescribe methadone for analgesia. •  An indication, such as “for chronic pain,” may be added to the written prescription to clarify its purpose. • State laws vary regarding this documentation requirement. • Not all pharmacies stock methadone because of its association with the treatment of heroin addiction. Toombs JD, Kral LA Methadone treatment for pain states. Am Fam Physician 2005 Apr 1; 71 (7): 1353-8

22. Methadone Conversion Ratios Methadone Conversion Table

23. Caution! • Methadone should not be used to treat pain conditions such as fibromyalgia, chronic migraine, or chronic tension headache, and other pain conditions best treated with adjuvant medications. • If a practitioner is not familiar with the use of methadone and wants to use it for a pain condition, we strongly advise that the clinician seek help from someone who knows how to use methadone

25. Tales from the FM/ Geri/ Hospice Care • My first experience with Methadone as a FM resident • My geriatric outpatient clinic experience • My Hospice experience

26. Questions about the Topic Continuing Education Credit: TEXT: 501-406-0076 Activity Code: 32907-30782