Goals of this lecture
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Improve understanding of methadone use and pharmacokinetics
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Be able to use methadone safely in hospice patients

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

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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

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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

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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

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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

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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

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

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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%)

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

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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)

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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

CYP3A4
CYP2B6
Important methadone metabolizer. Most abundant enzyme of class. Found in liver and intestine in variable amounts. Varies person to person 30- fold.
Less effect but drug interactions may happen here also.
CYP2D6
CYP1A2
Lesser role but absent completely in 1 out of
15 persons, also extra high activity in some
Lesser role

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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

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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

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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

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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

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Antiarrhythmics: all*
Antihistamines
Serotonin agonists and antagonists: ondansetron
Antimicrobials: all classes
Antipsychotics
Anticonvulsants
Stimulants
Too many to remember!

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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

general principles
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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.

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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

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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

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TOO LITTLE METHADONE: drop in usual SML
Shaky, tremors, flushed, nauseated
Vomitng, diarrhea, sweaty
Painful and restless
OPIOID WITHDRAWL SYNDROME

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Choice of patient
Conversion or upwards titration
Follow up schedule

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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

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

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Absorption/routes
Individual Metabolic differences
Pain receptor heterogeneity
Patient compliance factors
Drug interactions

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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

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

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For patients taking oral narcotics in short-acting form, ready to add longacting 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)

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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

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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

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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

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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

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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.

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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.

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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

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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

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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.

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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.

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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?

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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.

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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?

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Discussion of methadone initiation:
Does not want pump/has poor short acting coverage/needs rapid titration.
Started 5mg q 8 hr and 5mg q 4 hr prn.
Pt transferred to AL and remained comfortable on 5mg q 8 hr x 2 more months.

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Concerns include: complex pharmokinetics, stigma of addiction therapy, potential arrythmias
Benefits: many routes, NMDA antagonist, higher potency, lower cost, longer intervals of administration, no active metabolites, rapid onset, long half life, more favorable side effect profile, low rate of induction of tolerance, more effective for severe pain