METHADONE

1. METHADONE MELLAR DAVIS, WAEL LASHEEN, DECLAN WALSH

2. METHADONE • SYNTHETIC PSEUDOPIPERDINE DEVELOPED OVER 50 YEARS AGO • DISTINCTLY DIFFERENT FROM ALKALOID OPIOIDS (MORPHINE) (CODEINE) AND SYNTHETIC THEBAINE DERIVATIVES (OXYCODONE) 2

3. METHADONE R (L) AND S (D) ENANTIOMER • R ENANTIOMER BINDS WITH SIMILAR AFFINITY TO MU RECEPTORS AS MORPHINE (KM 3.5NM AND 1.4NM RESPECTIVELY) • BOTH R AND S ENANTIOMERS BIND TO N-METHYL-D-ASPARTATE RECEPTORS • TWICE THE INTRINSIC EFFICACY OF MORPHINE 3

4. METHADONE • DELTA OPIOID RECEPTOR AGONIST (R AND S) • SEROTONIN AND NOREPINEPHRINE REUPTAKE INHIBITOR (R AND S) • HIGH DOSES BLOCK POTASSIUM CHANNELS 4

5. ABSORPTION • ABSORPTION RAPID AND COMPLETE (47 - 91%) • DRUG LEVELS CAN BE MEASURED 30 MINUTES AFTER ORAL DOSING, PEAK CONCENTRATIONS OCCUR AT 2.5 HOURS • INTESTINAL CYP3A4 AND P-GLYCOPROTEIN MAY REDUCE ABSORPTION • NOT A MAJOR FACTOR IN THE LARGE INTER-INDIVIDUAL DIFFERENCES IN KINETICS 5

6. ABSORPTION • PKA IS 9.2 (BETTER ABSORBED IN AN ALKALINE ENVIRONMENT) • REDUCED ACIDITY (OMEPRAZOLE) INCREASES ABSORPTION • NON-SATURABLE KINETICS • PRESYSTEMIC CLEARANCE (ABSORPTION AND BIOAVAILABILITY) IS 21% • UNALTERED BY DIET 6

7. RECTAL METHADONE • SIMILAR ABSORPTION AND BIOAVAILABILITY AS ORAL METHADONE • MICROENEMAS > HYDROGENATED OIL BASE SUPPOSITORIES 7

8. SUBLINGUAL METHADONE • ABSORPTION IS 34% (51% FENTANYL AND 18% MORPHINE) • BUFFERING THE PH TO 8.5 DOUBLES ABSORPTION (75%) 8

9. METABOLISM • BIEXPONENTIAL KINETICS • EXTRACTION RATIO 0.08 - 0.16 • DEMETHYLATED TO AN INACTIVE METABOLITE (EDDP) BY CYP3A4 • INDUCTION OF CYP3A4 BY METHADONE WITH CHRONIC DOSING 9

10. CYTOCHROME ENZYMES • CYP3A4 > CYP2D6, CYP1A2, CYP2C9, CYP2C19 • ULTRARAPID METABOLIZERS HAVE HALF THE METHADONE DRUG LEVELS AS POOR METABOLIZERS (HOMOZYGOTE CYP2D6 MUTATIONS) 10

11. METHADONE CLEARANCE • METHADONE CLEARANCE CAN VARY BETWEEN INDIVIDUALS 100-FOLD (0.023 - 2.1 LITERS PER MINUTE) WITH A MEAN OF 0.095 LITERS PER MINUTE 11

12. CAUSES OF INTERINDIVIDUAL DIFFERENCES IN METHADONE • MU OPIOID RECEPTOR GENETICS • P-GLYCOPROTEIN ACTIVITY • CYP3A4 BASAL AND INDUCTION ACTIVITY • CYP2D6, CYP1A2, CYP2C9, CYP2C19 • GENOTYPE OF ALPHA1 ACID GLYCOPROTEIN • CO-MEDICATIONS 12

13. ROUTES • ORAL • SUBLINGUAL (1:1) • RECTAL (1:1) • SUBCUTANEOUS (2:1) • INTRAVENOUS (2:1) 13

14. SAFE COMBINATIONS • RIFAMBUTIN (FOR RIFAMPICIN) • FAMOTIDINE (FOR CIMETIDINE) • MIRTAZAPINE (FOR SSRI) • HALOPERIDOL OR OLANZAPINE (FOR RESPERIDONE) • VALPROIC ACID, GABAPENTIN (FOR PHENOBARBITOL, PHENYTOIN, CARBAMAZEPINE) 14

15. METHADONE TOXICITY • SIMILAR TO OTHER OPIOIDS • REDUCED CONSTIPATION COMPARED TO MORPHINE • TORSADES DE POINTES AND PROLONGED QTC WITH INCREASED RISK PARTICULAR WITH PARENTERAL 15

16. DEATH FROM METHADONE • MORE COMMON WITH INITIAL THERAPY • DEATHS AT STEADY STATE ARE RELATED TO: • INTERFERING CO-MEDICATION • ILLICIT DRUG TAKING (DIAZEPAM, ALCOHOL, COCAINE, CANNABIS, OTHER OPIOIDS) 16

17. METHADONE AND CANCER PAIN • THE ORIGINAL MANUFACTURER’S RECOMMENDATION OF 2.5 - 10MG EVERY 3 - 4 HOURS IS EXCESSIVE. • EQUIANALGESIA TABLES THAT PUT EQUIVALENTS NEAR UNITY WITH MORPHINE ARE DANGEROUS. 17

18. METHADONE AND CANCER PAIN • METHODS OF OPIOID ROTATION INVOLVE A “STOP-START” STRATEGY • A Q 3-HOUR AS NEEDED SCHEDULE • LINEAR RATIO BASED UPON MORPHINE EQUIVALENTS EVERY 8 HOURS ATC 18

19. EQUIVALENTS AND DOSING • MORPHINE:METHADONE • 4:1 < 90MG MORPHINE DAILY • 8:1 90 - 300MG MORPHINE DAILY • 12:1 300 - 1000MG MORPHINE DAILY • 20:1 > 1000MG MORPHINE DAILY • DIVIDE DOSE INTO 3 AND GIVE EVERY 8 HOURS • OPIOID NAÏVE; 3 - 5MG EVERY 8 HOURS OR 7.5MG EVERY 12 HOURS 19

20. EQUIVALENTS AND DOSING • STOP-START • USE 10% OF TOTAL MORPHINE (OR MORPHINE EQUIVALENTS) UP TO A SINGLE MAXIMUM DOSE OF 30MG METHADONE • DOSE EVERY 3 HOURS AS NEEDED • STEADY STATE OCCURS AT DAY 4 AND 5 • TOTAL DOSES ON DAY 4 AND 5, DIVIDE BY 4 AND GIVE EVERY 12 HOURS 20

21. METHADONE DOSING • SHOULD BE DONE BY SOMEONE WITH EXPERIENCE • DO NOT ADD BENZODIAZEPINES DURING TITRATION, AVOID ALCOHOL • USE ACETOMINOPHEN IF PAIN RECURS BEFORE THREE HOURS 21

22. EQUIVALENTS WITH OTHER OPIOIDS • HYDROMORPHONE • PARENTERAL HYDROMORPHONE TO ORAL METHADONE 1.07 + 0.9 • FENTANYL • FENTANYL 25µG TO 0.1MG PARENTERAL METHADONE 22

23. NEUROPATHIC PAIN • DOSE RATIOS BETWEEN MORPHINE AND METHADONE ARE NOT DEPENDENT UPON THE TYPE OF PAIN GROND S. PAIN 1999 GAGNON B. JPSM 1999 23

24. CANDIDATES FOR METHADONE • REFRACTORY PAIN • PATIENTS ON HIGH DOSE OPIOIDS WITH BURDENSOME COSTS • PATIENTS WITH LIMITED FINANCES • HOSPICES • NEUROPATHIC PAIN • CHEAP SUSTAINED RELEASE OPIOID Ripamonte C. Pain 1997 24

25. METHADONE PROS 1) LACK OF ACTIVE METABOLITES 2) SAFETY IN ORGAN FAILURE 3) HIGH LIPID SOLUBILITY 4) HIGH BIOAVAILABILITY 5) VERSATILITY 6) LOW COST CONS 1) UNPREDICTABLE AND LONG HALF-LIFE 2) INTERINDIVIDUAL VARIABILITY 3) CHANGING EQUIANALGESIC POTENCY WITH DOSE 25

26. SUMMARY • METHADONE IS UNIQUE PHARMACOLOGICALLY • MULITPLE RECEPTOR AGONIST, NMDA ANTAGONISTS AND MONOAMINE REUPTAKE INHIBITORS • RELATIVELY SAFE IN ORGAN FAILURE • DOSING SCHEMES ARE DIFFERENT THAN WITH OTHER OPIOIDS 26

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28. METHADONE AND CARDIAC TOXICITY 28

29. INTRODUCTION • METHADONE HAS BEEN ASSOCIATED WITH PROLONGED QTC AND TORSADES DE POINTES (TDP) • UNIQUE BLOCK OF IONIC CURRENT THROUGH SPECIFIC TYPE CARDIAC K+ CHANNELS • CARDIAC K+ CHANNELS ARE DERIVED FROM HUMAN ETHER-A-GO-GO-RELATED GENE (HERG) 29

30. INTRODUCTION • DELAYED REPOLARIZATION LEADS TO PROLONGED QTC INTERVALS (>500 MSEC) AND VENTRICULAR TACHYCARDIA (TDP) • ALSO INTERLEAD VARIATION BETWEEN QTC INTERVALS ON SURFACE LEADS 30

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32. SUMMARY OF ORAL METHADONE AND QTc • METHADONE INCREASES QTC IN 30% • QTC > 500 MSEC RANGE 0 – 16% (5%) • POOR CORRELATION WITH DOSE • MAY BE ASSOCIATION WITH HYPOKALEMIA, STRUCTURAL HEART DISEASE, LIVER DISEASE AND DRUGS THAT INHIBIT CYTOCHROMES OR PROLONG QTC 32

33. RECOMMENDATIONS • NO MONITORING FOR LOW RISK INDIVIDUALS • AT RISK INDIVIDUALS, BASELINE ECG REPEAT IF: • BASELINE QTC > 430 M SEC • HIGH DOSE SYMPTOMS (SYNCOPE, PALPITATION, DYSPNEA) • CO-MEDICATIONS THAT PROLONG QTC 33

34. MANAGEMENT OF PROLONGED QTc METHADONE • DOSE REDUCE, ADD ADJUVANT • DELETE MEDICATIONS WHICH PROLONG QTC OR BLOCK CYTOCHROMES • ROTATE TO MORPHINE OR BUPRENORPHINE OR FENTANYL 34

35. IV METHADONE AND QTc • TOXICITY CAN OCCUR AT LOW DOSES (0.4 MG/H) • BASELINE ECG AND REPEAT 24 – 72 HOURS • MONITOR K+ • AVOID DRUGS THAT PROLONG QTC • OPTIONS IF QTC >500 MSEC • SWITCH TO ORAL METHADONE • DELETE CO-MEDICATIONS THAT PROLONG QTC • DOSE REDUCE/ADD AN ADJUVANT • ROTATE TO MORPHINE, BUPRENORPHINE 35

36. FDA BLACK BOX WARNING • DEATHS: UNINTENTIONAL OVERDOSE, DRUG INTERACTIONS, AND CARDIAC TOXICITY (QT PROLONGATION AND TDP) • PHYSICIAN’S NEED TO UNDERSTAND TOXICITY AND UNIQUE METHADONE PROPERTIES • DOSES SHOULD BE CAREFULLY CHOSEN AND SLOWLY TITRATED • CAREFULLY MONITOR WHEN SWITCHING TO METHADONE AND CHANGING DOSE 36

37. SUMMARY • LOW RISK WITH ORAL METHADONE • AT RISK INDIVIDUALS REQUIRE MONITORING • RISK GREATER WITH PARENTERAL METHADONE DUE TO CHLOROBUTANOL • PARENTERAL METHADONE REQUIRES ROUTINE ECG MONITORING • RISK AND BENEFITS OF METHADONE MUST BE WEIGHED IF NO OTHER TREATMENT OPTIONS ARE AVAILABLE IN TERMINAL PATIENTS 37

38. PATIENT CONTROLLED ANALGESIA (PCA) MELLAR DAVIS, WAEL LASHEEN, DECLAN WALSH 38

39. BACKGROUND • CONCEPT • INTER-INDIVIDUAL VARIABILITY • OPTIMIZE OPIOID ADMINISTRATION • IMMEDIATE ACCESS • ON DEMAND > CONVENTIONAL DOSING 39

40. PCA MODALITIES • FIRST PCA PUMP 1976 • MODALITIES • DEMAND ONLY • CONTINUOUS INFUSION + DEMAND • INFUSION RATE BASED ON DEMAND • VARIABLE RATE • VARIABLE RATE FEEDBACK 40

41. OPIOIDS • ALL OPIOIDS • SHORT ACTING ARE SAFER THAN LONG ACTING • NON-OPIOIDS • MOST COMPATIBLE WITH OPIOIDS • ATROPINE, DEXAMETH, DIAZEPAM, LORAZEPAM, KETEROLAC, HALDOL, LEVOPROME, METOCHLOPRAMIDE • PHYENYTOIN IS NOT COMPATIBLE WITH OPIOIDS PCA SETUP: DRUG CHOICE 41

42. PCA ROUTES OF DELIVERY 42

43. PCA STRATEGY • LOADING DOSE • DEMAND DOSE • LOCKOUT INTERVAL • CONTINUOUS INFUSION • DOSE LIMITS 43

44. PCA ADVANTAGES • PATIENT • REMOVES DELAY DEMAND / DELIVERY • PATIENT CONTROL / SECURITY • DETERMINE PAIN THRESHOLDS • DOSING • ASSESS ANALGESIC REQUIREMENTS • INFLUENCES TRADITIONAL DOSING PROTOCOLS • ADAPTABLE • INTERINDIVIDUAL REQUIREMENTS • TEMPORAL PAIN PATTERN 44

45. AGE • HEAD INJURY • SLEEP APNEA • OBESITY • RESPIRATORY FAILURE • BENZODIAZEPINES • HYPONATREMIA • RENAL FAILURE PATIENT RISK FACTORS 45

46. COMPLICATIONS • OPERATOR ERRORS • PROGRAMMING ERRORS • ACCIDENTAL BOLUS • INAPPROPRIATE • DOSE • LOCKOUT • DRUG SELECTION • SURROGATE ACTIVATION • PUMP MALFUNCTION 46

47. PATIENT SELECTION • AGE = > 5 YRS • COGNITIVE ABILITY • UNDERSTAND THE RELATIONSHIPS BETWEEN PAIN, ACTIVATING THE PUMP, AND GOALS OF PAIN RELIEF • INTACT MEMORY • PHYSICAL ABILITY TO ACTIVATE THE BUTTON • PSYCHOLOGICAL: NEED TO MAINTAIN CONTROL • EXTREME FEAR OF SIDE EFFECTS • PRESENCE OF A RELIABLE SURROGATE 47

48. PCA IN CANCER MAYBE USED IN: • INCIDENT PAIN • KIDNEY FAILURE (DEMAND ONLY) • EXCESSIVE SIDE EFFECTS (N&V, SEDATION) • INTESTINAL OBSTRUCTION • IMPAIRED ORAL INTAKE • CIRCARDIAN VARIATION IN PAIN INTENSITY • INITIAL TITRATION 48

49. PCA DOSING (INTRODUCTION) • LOADING DOSE • DEMAND DOSING & CONTINUOUS INFUSION(CI) • A DOSE SHOULD RESULT IN PERCEPTIBLE ANALGESIA • TITRATION • LOCKOUT INTERVAL • PHARMACOKINETICS / DYNAMICS, CNS DWELL TIME • LONG ENOUGH FOR THE PATIENT TO EXPERIENCE BENEFIT • LONGER IF CONCOMITTENT CONTINUOUS INFUSION 49

50. PCA DOSING IN CANCER • OPIOID NAIVE: 0.5MG/H CI , DEMAND 1MG Q2H • OPOID TOLERANT: THE HOURLY MORPHINE DOSE Q2HRS, RARELY Q1HR • RATIONALE LONG CNS DWELL TIME • DEMAND DOSE IS TITRATED TO BREAKTHROUGH PAIN SEVERITY AND DURATION 50