Transcript Methadone - Grand Rapids Medical Education Partners

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
Methadone: Introduction
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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)
Methadone
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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
Morphine and Methadone
What is different about
Methadone?
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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
NMDA?
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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
Methadone
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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
Pharmacokinetics
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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
Methadone
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Half life longer in older patients
May be used despite renal or liver
disease
Methadone
Pharmacokinetics
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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%)
Methadone
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Oral bioavailablity 60-80% of drug
Easily absorbed orally, SL, rectally
(liquids tablets, suppositories)
Also used IM, IV all routes
Cost comparison
of 20mg/d methadone
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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)
Methadone
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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
CYP450 Enzymes
CYP3A4
Important methadone metabolizer. Most
abundant enzyme of class. Found in liver and
intestine in variable amounts. Varies person
to person 30- fold.
CYP2B6
Less effect but drug interactions may happen
here also.
CYP2D6
Lesser role but absent completely in 1 out of
15 persons, also extra high activity in some
CYP1A2
Lesser role
Methadone pharma
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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
Methadone pharma
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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.
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Other inhibitors of CYP3A4
Methadone pharma
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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
Cardiovascular
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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
Drugs that prolong QT
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Antiarrhythmics: all*
Antihistamines
Serotonin agonists and
antagonists: ondansetron
Antimicrobials: all classes
Antipsychotics
Anticonvulsants
Stimulants
Too many to remember!
Additive sedation and
respiratory depression
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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
Methadone drug interactions:
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.
In addition…
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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
Methadone dosing effects
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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
Methadone dosing effects
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TOO LITTLE METHADONE: drop in
usual SML
Shaky, tremors, flushed, nauseated
Vomitng, diarrhea, sweaty
Painful and restless
OPIOID WITHDRAWL SYNDROME
Initiation of Methadone
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Choice of patient
Conversion or upwards titration
Follow up schedule
Ideal patients for
Methadone
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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
Opioid Rotation
Improves efficacy of narcotic
Avoids toxicity (sedation, hallucinations,
twitching, itching, urinary retention)
Estimating the new dose is not an exact
science!
Factors complicating
opioid conversions
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Absorption/routes
Individual Metabolic differences
Pain receptor heterogeneity
Patient compliance factors
Drug interactions
Methadone dosing
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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
Methadone conversion
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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
Simplest: less than 100 4:1
about 500 10:1
about 1000 20:1
Calculating Doses
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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)
Example Case 1
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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
Example Case 1
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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
Example Case 2
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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
Example Case 2
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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
Example Case 3
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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.
Example Case 3
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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.
Example Case 3
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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
Example Case 3
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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
Example Case 4
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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.
Example Case 4
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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.
Example Case 4
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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?
Example case 5
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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.
Example case 5
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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?
Example case 5
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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.
Methadone Summary
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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
Happier patients