Pain management part 3: Methadone: Goals of this lecture

1. Pain management part 3: Methadone: Goals of this lecture • Improve understanding of methadone use and pharmacokinetics • Be able to use methadone safely in hospice patients

2. Methadone: Introduction • Methadone is a Synthetic opioid developed in 1937 in Germany • Manufactured in USA since 1947 • Mechanism of Action • Mu receptor agonist Major effects here • Delta receptor agonist • N-methyl-d-aspartate (NMDA) antagonist (same as NAMENDA) • Norepinephrine and serotonin reuptake inhibitor (like antidepressants)

3. Methadone • Pharmacokinetics are not simple • Overdose/drug interaction can be fatal • Danger caused by lack of knowledge and training in its use • Safe and effective >40 yrs with adequate training and follow-up • C-II Legal for substance abuse programs and for pain management

4. Morphine and Methadone

5. What is different about Methadone? • Side effects • Same as MS: respiratory depression, potential bronchospasm, hypotension, • Perhaps less sedating at effective dose • hallucinations, twitching at high doses • Possibly different: Less constipating, extra effect on neuropathic pain • Different: Prolongs QT increasing chance of arrythmias, less tolerance over time • More drug interactions

6. NMDA? • N-methyl D aspartate • Synthetic compound that marks a subset of glutamate receptors in the CNS and Spinal pain pathways that act as potentiators • Blockage of NMDA prevents escalation of pain stimulus (damps it down) • Blockage of NMDA helps prevent tolerance from developing

8. Methadone • Initiation: adequate dose, right dose proper follow up • Change in dose: again follow up is key • Change in other coadministered medications or foods • Change in metabolic ability • Acid base status

9. Pharmacokinetics • First dose similar to MS dose effect • Effect within about 30 min after oral administration • Metabolism slow AND variable from patient to patient (No active Metabs) • Lipid soluble, and protein binding: enters tissues and builds up over time • Half life 10-75 hrs

10. Methadone • Half life longer in older patients • May be used despite renal or liver disease

11. Methadone Pharmacokinetics • Serum methadone level is the main indicator of pain control, and driver of metabolism/removal • Most of active drug in the body during steady state is not in blood but in body tissues (1%)

12. Methadone • Oral bioavailablity 60-80% of drug • Easily absorbed orally, SL, rectally (liquids tablets, suppositories) • Also used IM, IV all routes

13. Cost comparison of 20mg/d methadone • Cost is of 120mg/day of MS is 25x higher ($200/mo) (generic MSC or Ka) • Cost of Generic fentanyl patch 50mcg is 33x higher ($260/month) • Cost of oxycontin 100mg is 43x higher ($339/month) • Cost of 20mg Methadone/d ($8/month)

14. Methadone • P-glycoprotein (P-gp) which is a protein pump functioning at the intestinal cell and blood brain barrier controlling access to cell interiors. It removes methadone from the cell. • Variability in expression of this enzyme is another source of variability of SML and effect on brain

15. CYP450 Enzymes

16. Methadone pharma • Inducers are drugs that induce the enzymes that remove methadone, these effects often happen over one week or so of coadministration • Example: steady methadone dosing but addition of decadron

17. Methadone pharma • Inhibitors of methadone metabolism (CYP3A4) Addition may cause rapid rise in methadone levels • Or cause unexpected sensitivity to methadone • Example: 47 yo man with lung ca who hallucinated on just 5mg bid • drank grapefruit juice daily. • Other inhibitors of CYP3A4

18. Methadone pharma • Substrates for CYP enzymes • Many drugs are substrates for same enzymes (50% of drugs for CYP3A4) • May competitively inhibit metabolism • When starting or stopping a medication be alert for changes in SML

19. Cardiovascular • Methadone increases QT interval • Adverse effects occur in low number of pts TdP • Adverse effects occur at high doses >100mg/day • Adverse effects occur in pts with risk factors for arrythmia: CHF or other medications that predispose to arrythmia • Risk is small but rec risk factor screening for cardiac arrythmias,(not EKG), and care if other medications might prolong QT

20. Drugs that prolong QT • Antiarrhythmics: all* • Antihistamines • Serotonin agonists and antagonists: ondansetron • Antimicrobials: all classes • Antipsychotics • Anticonvulsants • Stimulants • Too many to remember!

21. Additive sedation and respiratory depression • Like many of the medications we use, the sedative effects may be additive • Example: Pt on Ativan, morphine, neurontin and remeron, could they have methadone too? • No absolute ceiling/based on pt response: drowsiness, resp rate • Give driving and alcohol warnings

22. Methadone drug interactions: general principles • Chose the safer drug: Erythromycin inhibits CYP3A4, but azithromycin(z-pack) does not. Carbamazepine(tegretol) is a potent inhibitor but Valproic acid(depakote) is not • If drug interaction is expected, adjust the methadone based on pt response rather than in advance • Remember to ask the pharmacist or check yourself for interactions when adding a med.

23. In addition… • Pt may not adhere to complex regimen (pt example) • May add illicit substances, food, other meds from other sources. • Educate pt and caregivers about signs of rising SML or falling SML

24. Methadone dosing effects • TOO MUCH METHADONE: rising SML • Pt is sleeping too much but arousable as in normal sleep • PT has lower respiratory rate • Pt has little or no pain complaints • Progression to Myoclonic jerks and hallucinations followed by deep coma • OPIOID OVERDOSE SYNDROME

25. Methadone dosing effects • TOO LITTLE METHADONE: drop in usual SML • Shaky, tremors, flushed, nauseated • Vomitng, diarrhea, sweaty • Painful and restless • OPIOID WITHDRAWL SYNDROME

26. Initiation of Methadone • Choice of patient • Conversion or upwards titration • Follow up schedule

27. Ideal patients for Methadone • Pain more chronic than acute • Patient stable enough to live >one week • No major arrythmia history esp. for higher doses • No Antiviral HIV drugs • Some Liver or renal disease OK

32. Opioid Rotation Improves efficacy of narcotic Avoids toxicity (sedation, hallucinations, twitching, itching, urinary retention) Estimating the new dose is not an exact science!

33. Factors complicating opioid conversions • Absorption/routes • Individual Metabolic differences • Pain receptor heterogeneity • Patient compliance factors • Drug interactions

34. Methadone dosing • Start with daily oral morphine dose • < 100 mg use 3:1 • 101-300 mg use 5:1 • 301-600 mg use 10:1 • 601-800 mg use 12:1 • 801-1000 mg use 15:1 • >1001 mg use 20:1

35. Methadone conversion • For patients on <100 of oral MS divide by 4 • For patients on 100-300 of MS divide by 8 • For patients on >300mg of MS divide by 10 • Super high doses >600mg MS divide by 20 • Simplest: less than 100 4:1 • about 500 10:1 • about 1000 20:1

37. Calculating Doses • For patients taking oral narcotics in short-acting form, ready to add long- acting medication: You can give a small dose of Methadone Q 8 or 12 hours and allow them to continue to use their short acting med for breakthrough, (make sure they have good BT med)

38. Example Case 1 • 60 year old male with lung Ca • Current regimen: MScontin 300mg Q 12 hours, MS 40-60 q3-4 hours prn • Last few days using 60mg MS 5 times a day • Complains of sedation and twitching • Total daily opioid=900mg

39. Example Case 1 • So 900mg divided by 20=45mg. • Divide it into three equal doses Methadone 15mg q 8 hrs • Provide teaching to pt and family • Reassess at 3 and at 5 days if possible

40. Example Case 2 • 66year old man with prostate Ca • Pain in R hip/pelvis worsening over 2 weeks • Taking 240mg Oxycontin q8 hr • Breakthrough has increased to 40mg OxyIR q 2 hrs while awake • In last 24 hours used 360mg OxyIR • Total Oxycodone=1080mg/day

41. Example Case 2 • Is the pt taking adjuvants? • Is his anxiety and spiritual pain addressed? • Is he really taking all that? • Should we try opiate rotation? • Oxycodone over 1000/day • Convert to MS 1000/daily dose • Divide by 20 gives you 50/day of Methadone. Maybe try 20mg q 8 or 25 q12

42. Example Case 3 • 46 yo man with Esophageal Ca on Duragesic 200mcg patch, complains of pain with swallowing and new burning pain and numbness around ribs left side of chest • Pain control inadequate using 20mg Roxanol q2 hour (8 doses in last 24 hrs) and rating pain at 8.

43. Example Case 3 • Check on patch adherence, and think about adipose tissue reservoir. • New pain has neuropathic quality so may want to add adjuvant therapy. • Methadone may do better than patch for neuropathic component of pain.

44. Example Case 3 • Convert patch to oral MS equivalents • Using rough estimate of 2 to 1 to convert Duragesic to MS 200mcg=400mg MS • Plus BT use of MS 160mg=560 total daily oral MS equivalents • Convert 10:1 to Methadone=56mg

45. Example Case 3 • So round up to 60mg of Methadone can be split into 20mg po q8 hours and use same doses of breakthrough roxanol as before. • Reassess 3 and 5 days

46. Example Case 4 • A.S. was a woman with end stage dementia in a facility with hospice services. She usually did not seem to have pain. She was bed bound and rarely made eye contact. She barely maintained her nutrition with ensure and milkshakes. At times she would be “fussy” with moaning and grimacing, when she was turned especially.

47. Example Case 4 • One week tylenol did not seem to soothe her fussy times. She got several small doses of Roxanol which seemed effective but she needed it often. After 3 days of this she was converted to Methadone to allow her more consistency with fewer doses. • She had taken 6 doses of MS in the last 24 hours 10mg/dose.

48. Example Case 4 • So daily oral MS equivalents=60mg • Divide by 4=15mg daily Methadone • We started her on 5mg q12 hours • Day 1 she was comfortable • Day 2 she was very comfortable, sleeping all day… What to do now?

49. Example case 5 • 88yo man with deep metastatic melanoma in groin and hip socket. Severe pain treated incompletely with vicodin. Referred to hospice as his pain clinic doctor was planning an implanted epidural pump. Had epidural catheter placed on day 2 of hospice care. In pain clinic he was comfortable with bolus of bupivicaine and fentanyl via epidural catheter.

50. Example case 5 • Family was planning a transfer to AL facility. Facility did not take patients with pumps. On first night of pump he wandered upstairs and pulled catheter apart. Call from pain clinic… • Replace the catheter or different plan?