2-ethylidene-1,5-dimethyl-3,3diphenylpyrrolidene (EDDP) Safe in stable liver disease Long acting

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1 2012 AAHPM & HPNA Annual Assembly March 7-10, 2012 Denver, CO Methadone the Taming of the Shrew Stefan J. Friedrichsdorf, M.D. Medical Director Department of Pain Medicine, Palliative Care & Integrative Medicine Advantages Neither I nor any member of my immediate family has a financial relationship or interest with any proprietary entity producing health care goods or services related to the content of this CME activity. I do intend to discuss unapproved or investigative use of commercial products or devices (= off-label). 2-ethylidene-1,5-dimethyl-3,3diphenylpyrrolidene (EDDP) Safe in stable liver disease Long acting (pharmacologically inactive) Incomplete cross tolerance Very effective in chronic pain relief Inexpensive Effective in neuropathic pain NMDA receptor blocker (helps preventing tolerance) Rapid onset of action (!) Lower incidence of constipation No active metabolites Safe in renal failure Disadvantages Wide dosing variation Long half-life (may lead to accumulation; quick titration difficult) Equianalgesic conversion more complex Stigma? Methadone N-demethylation: Cytochrome P450 CYP3A4 CYP2B6 CYP2C19 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline (EMDP) (pharmacologically inactive) Methadole and Normethadole (minor activity) Mechanism of Action µ (δ,κ) - opioid receptor agonist (L [R-]methadone) NMDA-receptor antagonist (D-[S] and Lmethadone) Presynaptic blocker of serotonin and norepinephrine re-uptake in periaqueductal gray (D-methadone) Pharmacokinetics Oral bioavailability: % (usually > 60-90%) Peak Plasma concentration: hrs Gourlay GK, Cherry DA, Cousins MJ. A comparative study Liphophilicity: of the efficacy and pharmacokinetics of oral methadone and morphine in the treatment of severe pain in patients with cancer. Pain Jun;25(3): Onset of analgesia: minutes Duration of analgesia: initially 4-6 hours (after repeated dosing 8-12 hours) Reservoir 99%: Liver Storage Adipose Stores Protein binding 60-90% Half-Life: mean 8-59 hours [4-190 hours] 19.2 (13.6) [3.8-62] hours in children 1-18 years Berde C (1998) Anesthesiology Alpha-1-acid-glycoprotein = acute phase reactant [elevated in cancer] Blood 1 %: 67:A519 Long half-life does NOT match the duration of analgesia (adults: 6-12 hours) No correlation between plasma concentration and dose OR analgesic effect Säwe J (1981) BMJ 282:771-3 urine excretion feces Renal and/or hepatic impairment does not alter clearance or dosing of methadone (possibility in severe disease?) 1

2 Inducers and Inhibitors of CYP enzymes Decreases level Carbamazepine Phenytoin Phenobarbital Rispiridone Autoinduction (clearance higher once reached steady-state) Increases level SSRI Azols Macrolid antibiotics Grapefruit juice Nifedepin Tricyclic antidepressants The British Method Morley J and Makin M (1998) Pain Reviews. 5:51-8 Example: 200 mg IV morphine/day = 600 mg PO/day Discontinue current opioid Start PO Methadone 10% of prior daily PO morphine dose PRN (max. 30 mg) 30 mg PO STAT; then 30 mg Q3h PO PRN On Day 6, calculate total amount of methadone taken during previous 48 hours and divide by 4 -> Dose Q12h Day 4 & 5: 8 doses = 240 mg = 120 mg/d = 60 mg Q12h With rescue dose equal or smaller Q3h PRN mg PRN Q3h Starting Dose (Opioid Naïve): mg/kg/dose [2.5-5 mg PO Q6-12] Conversion Ratio: Total Daily Oral Morphine Dose Estimated Daily Oral Methadone Requirement Gazelle G (2002) ROXANE LABORATORIES, INC. Columbus, OH Toombs JD (2005) Americ Family Physician 71(7): Total Daily Oral Morphine Dose Estimated Daily Oral Methadone Requirement Less Target More < 100 mg 3:1 10:1 13:1 42:1 3:1 4:1 [x3] 2:1 1:1 1:2 < 100 mg 3:1 20% - 30% 33 % 101mg - 300mg 5:1 10% - 20% 20 % 301mg - 600mg 10:1 8% - 12% 10 % 101mg - 300mg 5:1 10:1 [x2] 11:1 17:1 27:1 301mg - 600mg 10:1 16:1 60:1 10:1 601mg - 800mg 12:1 5% - 10% 8 % 801mg mg 15:1 5% - 10% 7 % > 1000mg 20:1 < 5 % 5 % 17 children 2-18 years PO: Day 5: total daily dose divided by 3 => Q8h plus 10% of daily dose Q2H PRN IV: 80% of PO dose; breakthrough 1/3-1 of hourly dose Davie D (2008) Pediatr Blood Cancer n=42 starting dose mg/kg/day [median 0.32] PO/NG (IV x3) 41% side effects: incl. sedation (n=10), nausea (6), constipation (6); no pruritus, no respiratory depression Anghelescu DL, Faughnan LG, Hankins GM et.al: Methadone use in children and young adults at a cancer center: A retrospective study. J Opioid Managm (5): INITIAL OPIOID BASAL / hour NEW OPIOID BASAL / hour PCA bolus (lockout 15 min) Morphine 10 mg Methadone 1 mg 1 mg 5 mg CLINICIAN ACTIVATED BOLUS Hydromorphone 1.5 mg Methadone 0.3 mg 0.3 mg 5 mg Fentanyl 250 mcg Methadone 1.25 mg 1.25 mg 5 mg methadone by 25-50% for high previous opioid doses (e.g. morphine 50 mg/hr) by 25-50% for low doses (e.g. 5 mg/hr morphine) Manfredi PL (2003) J Support Oncol 1:

3 Breakthrough dose Recommendations vary 10% of daily dose (? interval) American Pain Society: Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain % of daily dose Q2H PRN Davie D (2008) Pediatr Blood Cancer Rescue dose equal or smaller BID dose Q3h PRN Morley J and Makin M (1998) Pain Reviews. 5:51-8 PCA bolus = hourly continuous dose Q15min Manfredi PL (2003) J Support Oncol 1: Route of Administration Oral Sublingual Rectal Intravenous Adverse effects Sedation, nausea, consipation Higher doses: opioid-induced neurotoxicity (myoclonus, hallucinations, nightmares), respiratory depression To ECG or Not to ECG That is Still the Question. PO Methadone QTc prolongation / torsades de pointes: Evidence limited to case reports Krantz MJ (2002) Ann Intern Med 137:501-4 No relation in retrospective study Reddy S (2004) J Pain Symptom Manage 28(4):301-3 IV Methadone Direct correlation between dose and QTc prolongation USA: commercial solution Dolophine : 1 ml = 10 mg methadone plus 5 mg chlorbutanol Chlorbutanol or chlorbutanol plus methadone rather than methadone alone, may be cause of cardiac toxicity Kornick C (2003) Pain 105(3): Prospective study: n=100 palliative care patients, 28% QTc prolongation at baseline; 1/64 (>500msec) at week 2; study supports the safety of methadone use for pain control in patients with advanced cancer in the palliative care setting [median week 2: 23 mg (3-90) - i.e. none > 100 mg] The Effect of Oral Methadone on the QTc Interval in Advanced Cancer Patients: A Prospective Pilot Study. Reddy S, Hui D, El Osta B, de la Cruz M,Walker P, Palmer JL, Bruera, E. J Palliative Med (1):33-38 Center for Substance Abuse Treatment ECG at baseline, 30 days, annual ECG if > 100mg/d or unexplained syncopes/seizures QTc ms: Discuss risks/benefits QTc > 500 ms: consider discontinuation or dose decrease Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MC. QTc interval screening in methadone treatment. Ann Intern Med Mar 17;150(6): Caution should prevail - low threshold for EKG Cruciani RA: Methadone: To ECG or Not to ECG That is Still the Question. J Pain Symptom Managem (5): Caution with inhibitors of CYP 2D6 and 3A4 SSRI Azols (Fluconazol etc.) Macrolid antibiotics Grapefruit juice Nifedepin Tricyclic antidepressants 3

4 Patients with risk factors for QT-prolongation, or in case of concomitant treatment with drugs that have a potential for QTprolongation, ECG monitoring is recommended prior to methadone treatment, with a further ECG test at dose stabilization. ECG monitoring is recommended, in patients without recognised risk factors for QT prolongation, before dose titration above 100mg/d and at seven days after titration Myoclonus with high-dose parenteral use observed: Dose reduction Change of application route? Adjuvant use of ketamine Ito S, Liao S: Myoclonus associated with high-dose parenteral methadone. J Palliat Med (6): Beth Israel (Pain & Palliative Care): EKG if dose > 100mg/day (PO & IV) Does need for analgesia (at end-of life) outweigh risk of cardiac toxicity? If excellent analgesia on conversion day 1 or 2 - consider dose reduction? Rescue dose: methadone or other opioid? PO: IV => 50% or 80%? Short duration of analgesia early in therapy: Q4h day 1, Q6h day 2, Q8h day 3, (Q12h day 4)? Or previous opioid for breakthrough pain? 12/13 patients unable to complete rotation due to pain and dysphoria Moryl N, Santiago-Palma J, Kornick C, Derby S, Fischberg D, Payne R, Manfredi PL: Pitfalls of opioid rotation: substituting another opioid for methadone in patients with cancer pain. Pain (3): /39 successful conversion Methadone : oral morphine = 1:13.5 (IV); 1:4.7 (PO) Walker PW, Palla S, Pei BL, Kaur G, Zhang K, Hanohano J, Munsell M, Bruera E: Switching from methadone to a different opioid: what is the equianalgesic dose ratio? J Palliat Med (8):1103-8" Conversion from Methadone to other Opioid: Over 3 days reducing methadone by 1/3 per day? Switch to levorphanol? Excellent opioid choice in the hands of experienced practitioner With close monitoring, methadone therapy can be done safely in pediatric patient populations in both inpatient and outpatient settings Advantages High effectiveness in chronic pain relief as well as in the management of neuropathic pain NMDA receptor antagonist mechanism (helps preventing tolerance) Lower incidence of constipation Disadvantages Long half-life (may lead to accumulation; making quick titration difficult) More complex equianalgesic conversion, which requires a much longer and closer patient observation than other opioids. 4

5 12-year-old Boy with metastatic neuroblastoma with increasing nociceptive (VAS 7/10) and neuropathic (VAS 9/10) pain; no over sedation Current Opioids Fentanyl Patches: 2 x 100mcg/hr Q72h Oxycontin: 30 mg BID PO Percocet* (5/325mg): 7 tablets/day Morphine: 10 mg x 12/ day PO No needless death, no needless pain, no unwanted waits, no helplessness, and no waste. Don Berwick, MD, 2003 *Oxycodone/Acetaminophen Total: 264 mg IV Morphine = 792 mg PO/day Fentanyl Patches: 2 x 100mcg/hr Q72h 200mcg/hr x 24 = 4800 mcg/day x 40 = Oxycontin: 30 mg BID PO 60 mg/day Percocet (5/325mg): 7 tablets/day 7 x 5 = 35 mg + 60 mg = 95mg/day = 95 mg PO Morphine / 3 = Morphine: 10 mg x 12 / day 10 x 12 = 120 mg /3 = IV Morphine/24h 192 mg 32 mg 40 mg Total: 264 mg Total Daily Oral Morphine Dose Estimated Daily Oral Methadone Requirement Gazelle G (2002) ROXANE LABORATORIES, INC. Columbus, OH < 100 mg 3:1 20% - 30% 33 % 101mg - 300mg 5:1 10% - 20% 20 % 301mg - 600mg 10:1 8% - 12% 10 % 601mg - 800mg 12:1 5% - 10% 8 % 801mg mg 15:1 5% - 10% 7 % Toombs JD (2005) Americ Family Physician 71(7): mg mg 62 mg > 1000mg 20:1 < 5 % 5 % Alternatively: Day 1: 5 mg PO Q4h Day 2: 7.5 mg PO Q6h Day 3: 10 mg PO Q8h mg 60 mg 10% of 780 mg => 50% 35 mg PO Q1h PRN Morphine 50 % Dose Reduction? 30 mg 10 mg PO TID PRN 3-5 mg PO Q3h PRN Methadone? 12 mg PO TID He had excellent pain control for 4 weeks on Methadone 12 mg PO Q8h (6mg PRN once every 2 days) - he develops significant nausea and vomiting and refuses to swallow medication 12 mg PO TID 12 mg SL TID 6 mg PO Q3h PRN 6 mg SL Q3h PRN PCA Dose 1.2 mg Lockout (15-) 30 min Max 2 -(4) boluses/hr 80% 9.6 mg IV TID Plus 4.8 mg IV Q3h PRN 36 mg PO / Day 80% 28.8 mg IV / Day / mg IV / hour 5

6 5th Annual Pediatric Pain Master Class June 9-15, 2012 Jake would like to thank you for your excellent opioid analgesia management. Center to Advance Palliative Care (CAPC) - Pediatric Palliative Care Leadership Center (PCLC) Training Stefan J. Friedrichsdorf, MD Medical Director Department of Pain Medicine, Palliative Care & Integrative Medicine Children's Hospitals and Clinics of Minnesota 2525 Chicago Ave S Minneapolis, MN USA phone fax Children s Institute of Pain & Palliative Care Children s Hospitals and Clinics of MN Minneapolis, MN CIPPC@childrensmn.org stefan.friedrichsdorf@childrensmn.org 6

7 Opioid Conversion Stefan J. Friedrichsdorf Page 1 Case 2 Case 1 Jake is a 12-year-old Boy with metastatic neuroblastoma with increasing somatic (VAS 7/10) and neuropathic (VAS 9/10) pain; no over sedation Current Opioids Fentanyl Patches: Oxycontin: Percocet (5/325mg): Morphine: 2 x 100mcg/hr Q72h 30 mg BID PO 7 tablets/day 10 mg x 14/ day PO You decide to switch Jake to oral Methadone. Please write the order: He had excellent pain control for 4 weeks on Methadone mg PO Q8h ( recently only mg PRN once every 2 days) - he develops significant nausea and vomiting and refuses to swallow medication. Please switch Jake to (a) IV Methadone and (b) alternatively Methadone PCA.

8 Opioid Conversion Stefan J. Friedrichsdorf Page 2 Methadone Conversion Ratio Total Daily Oral Morphine Dose Estimated Daily Oral Methadone Requirement < 100 mg Gazelle G (2002) 3:1 ROXANE LABORATORIES, INC. Columbus, OH % - 30% Toombs JD (2005) Americ Family Physician 71(7): % 101mg - 300mg 5:1 10% - 20% 20 % 301mg - 600mg 10:1 8% - 12% 10 % 601mg - 800mg 12:1 5% - 10% 8 % 801mg mg 15:1 5% - 10% 7 % > 1000mg 20:1 < 5 % 5 %