1. Eastern States Residency Conference Dosing of Methadone in the Palliative Care Setting Samantha Bryant, Pharm.D., BCPS PGY2 Drug Information Resident Robert Wood Johnson University Hospital May 2016

2. Disclosures There is no commercial support associated with this educational activity. Each presenter and planning committee member has disclosed no relationship with any commercial company. There will be no presentation of off-label use of any drug or medical device. 2

3. Objectives Describe the appropriate dosing of methadone for both opioid naïve and opioid tolerant patients List the various adverse effects that may be seen with the use of methadone 3

4. BACKGROUND 4 Microsoft ClipArt

5. What is Methadone? 5 Synthetic opioid –Agonist at the mu receptor –Antagonist at the N-methyl-D-aspartate (NMDA) receptor Indications –Treatment of opioid dependence –Treatment of moderate to severe pain in patients with life-limiting illnesses Duration of analgesic effect: 4-8 hours Half-life: up to 59 hours Dolophine Hydrochloride [Package Insert]. Columbus, OH: Roxane Laboratories, Inc. 2015. Available from: http://www.fda.gov/cder/foi/label/2006/006134s028lbl.pdf [accessed March 11, 2016 ]

6. Advantages of Methadone Efficacy Long half-life Convenient dosing schedule Low cost 6 Lugo RA, Satterfield KL, Kern SE. Pharmacokinetics of methadone. J Pain Palliat Care Pharmacother. 2005;19:13-24.

7. Disadvantages Dosing can be challenging Pharmacokinetic properties are highly variable and patient specific Sequesters in multiple body compartments Interacts with numerous other medications Conversion from other opioids to methadone is not linear 7 Lugo RA, Satterfield KL, Kern SE. Pharmacokinetics of methadone. J Pain Palliat Care Pharmacother. 2005;19:13-24.

8. Warnings November 2006, the FDA issued a Public Health Advisory: “Methadone use for pain control may result in death and life-threatening changes in breathing and heartbeat.” Other BBWs: –Addiction, abuse, misuse; accidental ingestions; neonatal opioid withdrawal syndrome; conditions for distribution and use of methadone products for the treatment of opioid addiction 8 FDA Public Health Advisory: Methadone use for pain control may result in death and life-threatening changes in breathing and heart beat [Internet]. US Food and Drug Administration. White Oak, MD. Available from: http://www.fda.gov/cder/drug/advisory/methadone.htm [accessed March 11, 2016]

9. Adverse Effects Common –Hypotension –Diaphoresis –Constipation, Nausea, Vomiting –Asthenia, Dizziness, Lightheadedness, Sedated Serious –Decreased vascular flow, Prolonged QT interval, Torsades de pointes –Hypoglycemia –Respiratory acidosis, Respiratory arrest, Respiratory depression –Drug dependence 9 Dolophine Hydrochloride [Package Insert]. Columbus, OH: Roxane Laboratories, Inc. 2015. Available from: http://www.fda.gov/cder/foi/label/2006/006134s028lbl.pdf [accessed March 11, 2016] Webster LR. Methadone Side Effects: Constipation, Respiratory Depression, Sedation, Sleep-Disordered Breathing, and the Endocrine System. In: Cruciani RA, Knotkova H, editors. Handbook of Methadone Prescribing and Buprenorphine Therapy. New York: Springer; 2013. p. 39-49.

10. Question #1 Which of the following is an adverse effect that may be seen with the use of methadone? a.Constipation b.Nausea c.QTc prolongation d. Respiratory Depression e.All of the above 10

11. Question #1 Which of the following is an adverse effect that may be seen with the use of methadone? a.Constipation b.Nausea c.QTc prolongation d.Respiratory Depression e.All of the above 11

12. Opioid Naive Usual starting dose is 2.5 to 10mg PO/IV every 8-12 hours, slowly titrated to effect 12 Dolophine Hydrochloride [Package Insert]. Columbus, OH: Roxane Laboratories, Inc. 2015. Available from: http://www.fda.gov/cder/foi/label/2006/006134s028lbl.pdf [accessed March 11, 2016] Chou R, Fanciullo GJ, Fine PG, et al: Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain 2009; 10(2):113-130.

13. Opioid Experienced/Tolerant Conversion to methadone is not linear Potency increases over time and with repeated dosing Incomplete cross-tolerance 13 Dolophine Hydrochloride [Package Insert]. Columbus, OH: Roxane Laboratories, Inc. 2015. Available from: http://www.fda.gov/cder/foi/label/2006/006134s028lbl.pdf. [accessed March 11, 2016] Total Daily Baseline Oral Morphine Dose Estimated Daily Oral Methadone Requirement as Percent of Total Daily Morphine Dose <100 mg20-30% 100 to 300 mg10-20% 300 to 600 mg8-12% 600 to 1000 mg5-10% > 1000 mg<5%

14. IV to PO When converting from parenteral methadone to oral methadone, one should use a 1:2 ratio –Example: 10 mg IV methadone is equal 20 mg PO methadone 14 Dolophine Hydrochloride [Package Insert]. Columbus, OH: Roxane Laboratories, Inc. 2015. Available from: http://www.fda.gov/cder/foi/label/2006/006134s028lbl.pdf [accessed March 11, 2016]

15. End of Life NPO Patients Convert by a ratio of 1:1 oral to buccal Give desired dose using 10 mg/mL solution to oral cavity between the lower molars and buccal mucosa MAX 1.5 mL in each buccal space Hold for several minutes for transmucosal absorption and gently massage cheek 15 Spaner D. Effectiveness of the buccal mucosa route for methadone administration at the end of life. J Palliat Med 2014; 17:1262-1265.

16. Question #2 Patient AB is on Morphine 50mg ER tablets BID. Calculate the approximate starting dose of oral methadone to be given every eight hours. a.20mg TID b.15mg TID c.10mg TID d.5mg TID 16

17. Question #2 Patient AB is on Morphine 50mg ER tablets BID. Calculate the approximate starting dose of oral methadone to be given every three hours. a.20mg TID b.15mg TID c.10mg TID d.5mg TID 17

18. Take Home Points Methadone is an affordable long-acting opioid analgesic It is effective for some patients There are several serious adverse effects and drug interactions with methadone that need to be considered Unique pharmacologic properties of methadone call for caution and expertise in prescribing it 18

19. References 1.Dolophine Hydrochloride [Package Insert]. Columbus, OH: Roxane Laboratories, Inc. 2015. Available from: http://www.fda.gov/cder/foi/label/2006/006134s028lbl.pdf [accessed March 11, 2016] 2.Lugo RA, Satterfield KL, Kern SE. Pharmacokinetics of methadone. J Pain Palliat Care Pharmacother. 2005;19:13-24. 3.FDA Public Health Advisory: Methadone use for pain control may result in death and life-threatening changes in breathing and heart beat [Internet]. US Food and Drug Administration. White Oak, MD. Available from: http://www.fda.gov/cder/drug/advisory/methadone.htm [accessed March 11, 2016] 4.Webster LR. Methadone Side Effects: Constipation, Respiratory Depression, Sedation, Sleep-Disordered Breathing, and the Endocrine System. In: Cruciani RA, Knotkova H, editors. Handbook of Methadone Prescribing and Buprenorphine Therapy. New York: Springer; 2013. p. 39-49. 5.Chou R, Fanciullo GJ, Fine PG, et al: Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain 2009; 10(2):113-130. 6.Spaner D. Effectiveness of the buccal mucosa route for methadone administration at the end of life. J Palliat Med 2014; 17:1262-1265 19

20. Questions? 20 Microsoft ClipArt

21. Eastern States Residency Conference Dosing of Methadone in the Palliative Care Setting Samantha Bryant, Pharm.D., BCPS PGY2 Drug Information Resident Robert Wood Johnson University Hospital May 2016