Pain management part Pain management part 3: Methadone: 3: Methadone: Goals of Goals of this lecturethis lecture

Improve understanding of Improve understanding of methadone use and methadone use and pharmacokinetics pharmacokinetics

Be able to use methadone Be able to use methadone safely in hospice patientssafely in hospice patients

Methadone: Methadone: IntroductionIntroduction

Methadone is a Synthetic opioid Methadone is a Synthetic opioid developed in 1937 in Germany developed in 1937 in Germany

Manufactured in USA since 1947Manufactured in USA since 1947 Mechanism of ActionMechanism of Action

1.1. Mu receptor agonist Mu receptor agonist Major effects hereMajor effects here

2.2. Delta receptor agonist Delta receptor agonist

3.3. N-methyl-d-aspartate (NMDA) antagonist N-methyl-d-aspartate (NMDA) antagonist (same as NAMENDA)(same as NAMENDA)

4.4. Norepinephrine and serotonin reuptake Norepinephrine and serotonin reuptake inhibitor (like antidepressants)inhibitor (like antidepressants)

MethadoneMethadone

Pharmacokinetics are not simplePharmacokinetics are not simple Overdose/drug interaction can be Overdose/drug interaction can be

fatalfatal Danger caused by lack of knowledge Danger caused by lack of knowledge

and training in its useand training in its use Safe and effective >40 yrs with Safe and effective >40 yrs with

adequate training and follow-upadequate training and follow-up C-II Legal for substance abuse C-II Legal for substance abuse

programs and for pain managementprograms and for pain management

Morphine and Morphine and MethadoneMethadone

What is different about What is different about Methadone?Methadone? Side effectsSide effects

– Same as MSSame as MS: respiratory depression, : respiratory depression, potential bronchospasm, hypotension,potential bronchospasm, hypotension,

– Perhaps less sedating at effective dose Perhaps less sedating at effective dose – hallucinations, twitching at high doseshallucinations, twitching at high doses– Possibly differentPossibly different: Less constipating, : Less constipating,

extra effect on neuropathic painextra effect on neuropathic pain– Different: Prolongs QT increasing chance Different: Prolongs QT increasing chance

of arrythmias, less tolerance over timeof arrythmias, less tolerance over time– More drug interactionsMore drug interactions

NMDA?NMDA? N-methyl D aspartateN-methyl D aspartate Synthetic compound that marks a Synthetic compound that marks a

subset of glutamate receptors in the subset of glutamate receptors in the CNS and Spinal pain pathways that CNS and Spinal pain pathways that act as potentiatorsact as potentiators

Blockage of NMDA prevents Blockage of NMDA prevents escalation of pain stimulus (damps it escalation of pain stimulus (damps it down)down)

Blockage of NMDA helps prevent Blockage of NMDA helps prevent tolerance from developingtolerance from developing

Methadone Methadone

Initiation: adequate dose, right Initiation: adequate dose, right dose proper follow updose proper follow up

Change in dose: again follow up is Change in dose: again follow up is keykey

Change in other coadministered Change in other coadministered medications or foodsmedications or foods

Change in metabolic abilityChange in metabolic ability Acid base statusAcid base status

PharmacokineticsPharmacokinetics

First dose similar to MS dose effectFirst dose similar to MS dose effect Effect within about 30 min after oral Effect within about 30 min after oral

administrationadministration Metabolism slow AND variable from Metabolism slow AND variable from

patient to patient (No active Metabs)patient to patient (No active Metabs) Lipid soluble, and protein binding: Lipid soluble, and protein binding:

enters tissues and builds up over timeenters tissues and builds up over time Half life 10-75 hrsHalf life 10-75 hrs

MethadoneMethadone Half life longer in older patientsHalf life longer in older patients May be used despite renal or liver May be used despite renal or liver

diseasedisease

Methadone Methadone PharmacokineticsPharmacokinetics Serum methadone level is the Serum methadone level is the

main indicator of pain control, main indicator of pain control, and driver of metabolism/removaland driver of metabolism/removal

Most of active drug in the body Most of active drug in the body during steady state is not in blood during steady state is not in blood but in body tissues (1%)but in body tissues (1%)

MethadoneMethadone

Oral bioavailablity 60-80% of drugOral bioavailablity 60-80% of drug Easily absorbed orally, SL, rectally Easily absorbed orally, SL, rectally

(liquids tablets, suppositories)(liquids tablets, suppositories) Also used IM, IV all routesAlso used IM, IV all routes

Cost comparisonCost comparison of 20mg/d methadone of 20mg/d methadone Cost is of 120mg/day of MS is 25x Cost is of 120mg/day of MS is 25x

higher ($200/mo) (generic MSC or Ka)higher ($200/mo) (generic MSC or Ka) Cost of Generic fentanyl patch 50mcg Cost of Generic fentanyl patch 50mcg

is 33x higher ($260/month)is 33x higher ($260/month) Cost of oxycontin 100mg is 43x higher Cost of oxycontin 100mg is 43x higher

($339/month)($339/month) Cost of 20mg Methadone/d ($8/month)Cost of 20mg Methadone/d ($8/month)

Methadone Methadone

P-glycoprotein (P-gp) which is a P-glycoprotein (P-gp) which is a protein pump functioning at the protein pump functioning at the intestinal cell and blood brain barrier intestinal cell and blood brain barrier controlling access to cell interiors. It controlling access to cell interiors. It removes methadone from the cell. removes methadone from the cell.

Variability in expression of this Variability in expression of this enzyme is another source of enzyme is another source of variability of SML and effect on brainvariability of SML and effect on brain

CYP450 EnzymesCYP450 Enzymes

CYP3ACYP3A44

Important methadone metabolizer. Important methadone metabolizer. Most abundant enzyme of class. Found Most abundant enzyme of class. Found in liver and intestine in variable in liver and intestine in variable amounts. Varies person to person 30- amounts. Varies person to person 30- fold. fold.

CYP2B6CYP2B6 Less effect but drug interactions may Less effect but drug interactions may happen here also.happen here also.

CYP2D6CYP2D6 Lesser role but absent completely in 1 Lesser role but absent completely in 1 out of 15 persons, also extra high out of 15 persons, also extra high activity in someactivity in some

CYP1A2CYP1A2 Lesser roleLesser role

Methadone pharmaMethadone pharma

Inducers are drugs that induce Inducers are drugs that induce the enzymes that remove the enzymes that remove methadone, these effects often methadone, these effects often happen over one week or so of happen over one week or so of coadministrationcoadministration

Example: steady methadone Example: steady methadone dosing but addition of decadrondosing but addition of decadron

Methadone pharmaMethadone pharma Inhibitors of methadone metabolism Inhibitors of methadone metabolism

(CYP3A4) Addition may cause rapid (CYP3A4) Addition may cause rapid rise in methadone levelsrise in methadone levels

Or cause unexpected sensitivity to Or cause unexpected sensitivity to methadonemethadone

Example: 47 yo man with lung ca Example: 47 yo man with lung ca who hallucinated on just 5mg bid who hallucinated on just 5mg bid – drank grapefruit juice daily. drank grapefruit juice daily.

Other inhibitors of CYP3A4Other inhibitors of CYP3A4

Methadone pharmaMethadone pharma Substrates for CYP enzymesSubstrates for CYP enzymes Many drugs are substrates for Many drugs are substrates for

same enzymes (50% of drugs for same enzymes (50% of drugs for CYP3A4)CYP3A4)

May competitively inhibit May competitively inhibit metabolismmetabolism

When starting or stopping a When starting or stopping a medication be alert for changes in medication be alert for changes in SMLSML

CardiovascularCardiovascular Methadone increases QT intervalMethadone increases QT interval Adverse effects occur in low number of Adverse effects occur in low number of

pts TdP pts TdP Adverse effects occur at high doses Adverse effects occur at high doses

>100mg/day>100mg/day Adverse effects occur in pts with risk Adverse effects occur in pts with risk

factors for arrythmia: CHF or other factors for arrythmia: CHF or other medications that predispose to arrythmiamedications that predispose to arrythmia

Risk is small but rec risk factor screening Risk is small but rec risk factor screening for cardiac arrythmias,(not EKG), and care for cardiac arrythmias,(not EKG), and care if other medications might prolong QTif other medications might prolong QT

Drugs that prolong QTDrugs that prolong QT Antiarrhythmics: all*Antiarrhythmics: all* AntihistaminesAntihistamines Serotonin agonists and Serotonin agonists and

antagonists: ondansetronantagonists: ondansetron Antimicrobials: all classesAntimicrobials: all classes Antipsychotics Antipsychotics AnticonvulsantsAnticonvulsants StimulantsStimulants Too many to remember! Too many to remember!

Additive sedation and Additive sedation and respiratory depressionrespiratory depression Like many of the medications we Like many of the medications we

use, the sedative effects may be use, the sedative effects may be additiveadditive

Example: Pt on Ativan, morphine, Example: Pt on Ativan, morphine, neurontin and remeron, could they neurontin and remeron, could they have methadone too?have methadone too?

No absolute ceiling/based on pt No absolute ceiling/based on pt response: drowsiness, resp rateresponse: drowsiness, resp rate

Give driving and alcohol warningsGive driving and alcohol warnings

Methadone drug Methadone drug

interactionsinteractions: : general principlesgeneral principles

Chose the safer drug: Erythromycin inhibits Chose the safer drug: Erythromycin inhibits CYP3A4, but azithromycin(z-pack) does not. CYP3A4, but azithromycin(z-pack) does not. Carbamazepine(tegretol) is a potent Carbamazepine(tegretol) is a potent inhibitor but Valproic acid(depakote) is notinhibitor but Valproic acid(depakote) is not

If drug interaction is expected, adjust the If drug interaction is expected, adjust the methadone based on pt response rather methadone based on pt response rather than in advancethan in advance

Remember to ask the pharmacist or check Remember to ask the pharmacist or check yourself for interactions when adding a yourself for interactions when adding a med.med.

In addition…In addition…

Pt may not adhere to complex Pt may not adhere to complex regimenregimen

(pt example)(pt example) May add illicit substances, food, May add illicit substances, food,

other meds from other sources.other meds from other sources. Educate pt and caregivers about Educate pt and caregivers about

signs of rising SML or falling SMLsigns of rising SML or falling SML

Methadone dosing Methadone dosing effectseffects

TOO MUCH METHADONE: rising TOO MUCH METHADONE: rising SMLSML

Pt is sleeping too much but Pt is sleeping too much but arousable as in normal sleeparousable as in normal sleep

PT has lower respiratory rate PT has lower respiratory rate Pt has little or no pain complaintsPt has little or no pain complaints Progression to Myoclonic jerks and Progression to Myoclonic jerks and

hallucinations followed by deep hallucinations followed by deep comacoma

OPIOID OVERDOSE SYNDROMEOPIOID OVERDOSE SYNDROME

Methadone dosing Methadone dosing effectseffects TOO LITTLE METHADONE: drop in TOO LITTLE METHADONE: drop in

usual SMLusual SML Shaky, tremors, flushed, Shaky, tremors, flushed,

nauseatednauseated Vomitng, diarrhea, sweatyVomitng, diarrhea, sweaty Painful and restlessPainful and restless OPIOID WITHDRAWL SYNDROMEOPIOID WITHDRAWL SYNDROME

Initiation of Initiation of MethadoneMethadone Choice of patientChoice of patient Conversion or upwards titrationConversion or upwards titration Follow up scheduleFollow up schedule

Ideal patients for Ideal patients for MethadoneMethadone Pain more chronic than acutePain more chronic than acute Patient stable enough to live Patient stable enough to live

>one week >one week No major arrythmia history esp. No major arrythmia history esp.

for higher doses for higher doses No Antiviral HIV drugsNo Antiviral HIV drugs Some Liver or renal disease OKSome Liver or renal disease OK

Opioid RotationOpioid Rotation

Improves efficacy of narcoticImproves efficacy of narcotic

Avoids toxicity (sedation, Avoids toxicity (sedation, hallucinations, twitching, itching, hallucinations, twitching, itching, urinary retention)urinary retention)

Estimating the new dose is not an Estimating the new dose is not an exact science!exact science!

Factors complicating Factors complicating opioid conversionsopioid conversions Absorption/routesAbsorption/routes Individual Metabolic differences Individual Metabolic differences Pain receptor heterogeneityPain receptor heterogeneity Patient compliance factorsPatient compliance factors Drug interactionsDrug interactions

Methadone dosingMethadone dosing

Start with daily oral morphine doseStart with daily oral morphine dose < 100 mg use 3:1< 100 mg use 3:1 101-300 mg use 5:1101-300 mg use 5:1 301-600 mg use 10:1301-600 mg use 10:1 601-800 mg use 12:1601-800 mg use 12:1 801-1000 mg use 15:1801-1000 mg use 15:1 >1001 mg use 20:1 >1001 mg use 20:1

Methadone conversionMethadone conversion

For patients on <100 of oral MS divide by 4For patients on <100 of oral MS divide by 4 For patients on 100-300 of MS divide by 8For patients on 100-300 of MS divide by 8 For patients on >300mg of MS divide by 10For patients on >300mg of MS divide by 10 Super high doses >600mg MS divide by 20Super high doses >600mg MS divide by 20

Simplest: less than 100 4:1Simplest: less than 100 4:1 about 500 10:1about 500 10:1 about 1000 20:1about 1000 20:1

Calculating DosesCalculating Doses For patients taking oral narcotics in For patients taking oral narcotics in

short-acting form, ready to add short-acting form, ready to add long- acting medication: You can long- acting medication: You can give a small dose of Methadone Q give a small dose of Methadone Q 8 or 12 hours and allow them to 8 or 12 hours and allow them to continue to use their short acting continue to use their short acting med for breakthrough, (make sure med for breakthrough, (make sure they have good BT med)they have good BT med)

Example Case 1Example Case 1

60 year old male with lung Ca60 year old male with lung Ca Current regimen: MScontin 300mg Q Current regimen: MScontin 300mg Q

12 hours, MS 40-60 q3-4 hours prn12 hours, MS 40-60 q3-4 hours prn Last few days using 60mg MS 5 Last few days using 60mg MS 5

times a daytimes a day Complains of sedation and twitchingComplains of sedation and twitching Total daily opioid=900mgTotal daily opioid=900mg

Example Case 1Example Case 1

So 900mg divided by 20=45mg.So 900mg divided by 20=45mg. Divide it into three equal doses Divide it into three equal doses

Methadone 15mg q 8 hrsMethadone 15mg q 8 hrs Provide teaching to pt and familyProvide teaching to pt and family Reassess at 3 and at 5 days if Reassess at 3 and at 5 days if

possiblepossible

Example Case 2Example Case 2

66year old man with prostate Ca66year old man with prostate Ca Pain in R hip/pelvis worsening over Pain in R hip/pelvis worsening over

2 weeks2 weeks Taking 240mg Oxycontin q8 hrTaking 240mg Oxycontin q8 hr Breakthrough has increased to Breakthrough has increased to

40mg OxyIR q 2 hrs while awake40mg OxyIR q 2 hrs while awake In last 24 hours used 360mg OxyIRIn last 24 hours used 360mg OxyIR Total Oxycodone=1080mg/dayTotal Oxycodone=1080mg/day

Example Case 2Example Case 2 Is the pt taking adjuvants?Is the pt taking adjuvants? Is his anxiety and spiritual pain Is his anxiety and spiritual pain

addressed?addressed? Is he really taking all that?Is he really taking all that? Should we try opiate rotation?Should we try opiate rotation? Oxycodone over 1000/dayOxycodone over 1000/day Convert to MS 1000/daily doseConvert to MS 1000/daily dose Divide by 20 gives you 50/day of Divide by 20 gives you 50/day of

Methadone. Maybe try 20mg q 8 Methadone. Maybe try 20mg q 8 or 25 q12or 25 q12

Example Case 3Example Case 3

46 yo man with Esophageal Ca on 46 yo man with Esophageal Ca on Duragesic 200mcg patch, complains Duragesic 200mcg patch, complains of pain with swallowing and new of pain with swallowing and new burning pain and numbness around burning pain and numbness around ribs left side of chestribs left side of chest

Pain control inadequate using 20mg Pain control inadequate using 20mg Roxanol q2 hour (8 doses in last 24 Roxanol q2 hour (8 doses in last 24 hrs) and rating pain at 8.hrs) and rating pain at 8.

Example Case 3Example Case 3

Check on patch adherence, and Check on patch adherence, and think about adipose tissue reservoir.think about adipose tissue reservoir.

New pain has neuropathic quality so New pain has neuropathic quality so may want to add adjuvant therapy. may want to add adjuvant therapy.

Methadone may do better than Methadone may do better than patch for neuropathic component of patch for neuropathic component of pain.pain.

Example Case 3Example Case 3

Convert patch to oral MS equivalentsConvert patch to oral MS equivalents Using rough estimate of 2 to 1 to Using rough estimate of 2 to 1 to

convert Duragesic to MS convert Duragesic to MS 200mcg=400mg MS200mcg=400mg MS

Plus BT use of MS 160mg=560 total Plus BT use of MS 160mg=560 total daily oral MS equivalentsdaily oral MS equivalents

Convert 10:1 to Methadone=56mg Convert 10:1 to Methadone=56mg

Example Case 3Example Case 3

So round up to 60mg of So round up to 60mg of Methadone can be split into 20mg Methadone can be split into 20mg po q8 hours and use same doses po q8 hours and use same doses of breakthrough roxanol as of breakthrough roxanol as before.before.

Reassess 3 and 5 daysReassess 3 and 5 days

Example Case 4Example Case 4

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

Example Case 4Example Case 4 One week tylenol did not seem to One week tylenol did not seem to

soothe her fussy times. She got soothe her fussy times. She got several small doses of Roxanol several small doses of Roxanol which seemed effective but she which seemed effective but she needed it often. After 3 days of needed it often. After 3 days of this she was converted to this she was converted to Methadone to allow her more Methadone to allow her more consistency with fewer doses.consistency with fewer doses.

She had taken 6 doses of MS in the She had taken 6 doses of MS in the last 24 hours 10mg/dose.last 24 hours 10mg/dose.

Example Case 4Example Case 4 So daily oral MS equivalents=60mgSo daily oral MS equivalents=60mg Divide by 4=15mg daily MethadoneDivide by 4=15mg daily Methadone We started her on 5mg q12 hoursWe started her on 5mg q12 hours Day 1 she was comfortableDay 1 she was comfortable Day 2 she was very comfortable, Day 2 she was very comfortable,

sleeping all day… What to do now? sleeping all day… What to do now?

Example case 5Example case 5

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

Family was planning a transfer to Family was planning a transfer to AL facility. Facility did not take AL facility. Facility did not take patients with pumps. On first patients with pumps. On first night of pump he wandered night of pump he wandered upstairs and pulled catheter upstairs and pulled catheter apart. Call from pain clinic…apart. Call from pain clinic…

Replace the catheter or different Replace the catheter or different plan?plan?

Example case 5Example case 5

Example case 5Example case 5

Discussion of methadone initiation:Discussion of methadone initiation: Does not want pump/has poor short Does not want pump/has poor short

acting coverage/needs rapid titration.acting coverage/needs rapid titration. Started 5mg q 8 hr and 5mg q 4 hr Started 5mg q 8 hr and 5mg q 4 hr

prn. prn. Pt transferred to AL and remained Pt transferred to AL and remained

comfortable on 5mg q 8 hr x 2 more comfortable on 5mg q 8 hr x 2 more months.months.

Methadone SummaryMethadone Summary Concerns include: complex Concerns include: complex

pharmokinetics, stigma of addiction pharmokinetics, stigma of addiction therapy, potential arrythmiastherapy, potential arrythmias

Benefits: many routes, NMDA Benefits: many routes, NMDA antagonist, higher potency, lower cost, antagonist, higher potency, lower cost, longer intervals of administration, no longer intervals of administration, no active metabolites, rapid onset, long active metabolites, rapid onset, long half life, more favorable side effect half life, more favorable side effect profile, low rate of induction of profile, low rate of induction of tolerance, more effective for severe tolerance, more effective for severe painpain

Happier patientsHappier patients