General Properties and Utility
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Identify the unique pharmacological properties
of methadone that distinguish it from other
opioids
Learn key properties of methadone lending
itself to treatment of cancer pain, neuropathy
pain, and opioid addiction.
Recognize potential side effects and unique
challenges to properly managing methadone
for analgesia
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Schedule II opioid developed in Germany in 1940s as
spasmolytic
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Synthetically derived
6-dimethylamino-4,4-diphenyl-3-heptanone
1960s - usage in treatment of heroin addiction
Mid 1970s - usage as general analgesic
Today –treatment of opioid addiction, chronic pain,
cancer pain, neuropathy, renal and hepatic failure.
social stigma and lack of familiarity amongst
physicians
Differs from other opioids in terms of bioavailability,
multiple receptor affinities, low cost, lack of toxic
metabolites
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Structurally unrelated to other opioids
Racemic mixture 2 isomers:
D-isomer: (S-met) – NMDA receptor antagonist +
inhibits uptake of norepi & serotonin
 L-isomeer (R-met) – mu and delta agonist
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High lipophilicity with oral bioavailability 40-99%
Large tissue reservoir
 Acts as both IR (onset 20-30min) and SR
 Exists in all conventional formulations
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Pka 9.2 (basic)
Highly bound to alpha-1-acid-glycoprotein,
unbound fraction 12% highly variable
Peak plasma conc 2.5-4 hrs
T ½ 30
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Analgesic 4-6 hrs initially, up to8-12 with repeated dosing
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Biphasic Elimination
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Alpha – 8-12 hr, rapid redistribution (analgesia)
Beta – 30-60hrs, sufficient to prevent withdrawal only
Extensive hepatic metabolism by cytochrome P450
family via N-methylation
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Traditionally attributed to CYP3A isoenzyme
 2009 Evan et al. Demonstrated >90% inhibition of hepatic &
intestinal CYP3A activity by ritonavir/indinavir lead to
slighltly increased N-demethylation but no significant effect
on methadone plasma concentration, bioavailability, hepatic
extraction orsystemic clearance, suggesting little or no role of
CYP3A in methadone clearance and metabolism
 Suggests CYP3A-based guidelines may be incorrect
 Totah et al. suggests CYP2B6 primary isoenzyme for bulk of
methadone metabolism
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P450 metabolism
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Methadone metabolism produces no active
metabolites!
Fecal elimination (primary)
Renal elimination (minor)
 Varies depending on urinary pH
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Cancer Pain
Neuropathic Pain
Drug interactions
Opioid Addiction
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>80% Cancer pts require opioid analgesics for
intractable pain prior to death
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No ceiling effect
Efficacy limited by toxicity:
 N, V, constipation, sedation, hallucinations, myoclonus
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Opioid Rotation Indications:
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Toxicity
Tolerance
Refractory pain
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Advantages of Methadone
Excellent oral & rectal bioavailability
 Incomplete cross tolerance
 Long T ½ with rapid onset
 No toxic metabolites
 Multpile Receptors involved
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 Mu and delta agonist
 NMDA antagonist – hyperalgesia, chronic pain states,
neuropathic pain
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Less constipation
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Methadone may be first-line opioid choice
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NMDA antagonism
 -neuropathic pain modulator
 -believed to attenuate development of morphine
tolerance
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Inhibition of Seretonin & Norepi reuptake
 Ie TCA’s
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High lipophilicity = 3x bioavailability of MSO4
 IR & SR action
 Duration up to 10h with chronic dosing
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Minimal renal excretion & lack of metabolites
well suited for diabetic neuropathy w/ renal
insufficiency
Evidence of efficacy largely anecdotal
 Limited to case studies
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 Nadege et al. retrospective study with questionair
(n=13) patients with neuropathic pain poorly controlled
on conventional analgesic. S/p 12 mo methadone
therapy avg 43% pain relief, 47% improvement quality
of life, 30% improvement quality of sleep. 62%
experienced improvement all areas.
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Comprehensive literture review by Sandoval et
all Clin. Jounal of pain 2005
1 randomized trial, 13 case reports, 7 case
series, 545 pts
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“no consistent evidence-based substantiation of
methadone’s clinical impact in the treatment of
noncancer pain”
Usage Trends:
 1.) failed convention opioid therapy from toxicity,
tolerance, side effects
 2.) first-line tx for certain classes of chronic pain
 3.) pain treatment in addicts
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Estimated 1 million long term opioid users in
U.S.A.
Methadone Maintenance Programs
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GOALS
 Block effect of other opiods
 Ie 80-120mg/day blocks effects of IV heroin, hydromorphone,
methadone (“agonist blockade”)
 10-20 mg/day to stems withdrawal but not craving
 Reduced cravings
 Relieves withdrawal symptoms
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BENEFITS
 Mortality reduction: U.S. untreated heroin addicts 8.3%
yearly mortality versus 0.8% treated.
 Morbidity reduction: ↓ IVDU, recidivism, crime, ↓ sexual
risk behaviors
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Controversial – Trading one addiction for another?
Methadone Maintenance Programs
 Heavily regulated
 By law, physician CANNOT prescribe methadone to tx
opioid withdrawal from office
 Any M.D. with DEA # can prescribe “for pain”
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Methadone’s unique physical and
pharmacological properties present unique
challenges to proper management in the areas
of:
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Overdose
Equianalgesia
Interindiviual variability of metabolism
Dangerous side effects
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Primary danger in prescribing for analgesia is
risk of delayed respiratory depression
Variable but long T ½ → steady state my take >1
week to achieve
 Delayed side effects in outpatient setting
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 Methadone for analgesia ↑ 1,300% 1997-2003
 Adverse events
↑ 1800% 1997-2007
 Fatalities
↑ 390% 1997-2007
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Widely variable plasma concentrations with
similar dosages
Mechanism no clearly understood
Possible explanations include
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Differences in alpha-1-glycoprotein binding
Effects of urinary pH on renal clearance
Multiple drugs can affect P450 system
 Methadone => hepatic autoinduction
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Morphine:Methadone ratios vary depending
on prior opioid exposure.
Highly tolerant individuals require LESS
methadone for equianalgesia than opioid naïve
pts
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incomplete cross tolerance
Methadone is a mixed mu-delta agonist
Methadone NMDA antagonism may also reduce
cross tolerance
END RESULT:  patients tolerant to high dose opioids are
at increased risk of toxicity
Example of equianalgesia table
Daily MSO4
<100mg
101-300mg
301-600mg
601-800mg
801-1,000mg
>1,000mg
Coversion Ratio to Methadone
3:1
5:1
10:1
12:1
15:1
20:1
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QTc prolongation dose dependent at
>60mg/day
Advised to check QTc interval prior to and
during methadone titration
Pain Medications that Prolong QTc Interval
Anticonvulsants
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Gabapentin
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Lyrica
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Fosphenytoin
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Pheytoin
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SSRI
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Citalopram
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Sertraline
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Fluoxetin
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Paroxetine
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Escitalopram
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TCA
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Amitriptyline
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Doxepin
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Nortiptyline
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Desipramine
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Clomipramine
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Imipramin
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Protriptyline
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mirtazapin
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Misc Antidepressants
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Duloxetine (cymbalta)
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Venlafaxine
Muscle Relaxants
Cyclobenzapine (Flexeril)
Tizanidine
NSAIDS
Celecoxib
Diclofenac
Etodolac
Ibuprofen
Meloxicam
Sulinda
Ketoprofen
OPIATES
Fentanyl
Sufentanil
Alfentanil
Hydromorphone
Levorphanol
Methadone
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Methadone is unique among opioids in terms of its
high bioavailability, multiple receptor affinities ,
extended half-life, and lack of active metabolizes.
These properties lend itself to the treatment of
opioid tolerant pain syndromes such as cancer,
potentially neuropathic pain, and treatment of
opioid addiction.
Aside from social stigma, the unpredictable nature
of interindividual metabolism, counter intuitive
equianalgesic dosing, and risk of delayed toxicity
make methadone a challenging drug to manage in
the outpatient setting.

Benzon, HT. Essentials of Pain Medicine and Regional Anesthesia, Second Edition. Copyright
2005.
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Hayes, Lewis et al. Use of Methadone for the Treatment of Diabetic Neuropathy. Diabetes
Care, Vol 28, No 2 February 2005, Pp 345-313
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Mancini, Isabelle et al. Opioid Switch to Oral Methadone in Cancer Pain. Current Opinion
in Oncology, Vol 12, 2000. Pp 308-313
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Nadege, Altier et al. Management of Chronic Neuruopathic Pain with Methadone: A
Review of 13 Cases. Clinical Journal of Pain, Vol 21, No 4, July/Aug 2005, Ps 364-369
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Alberto, Juan et al. Oral Methadone for Chronic Noncancer Pain: A Systematic Literature
Review of Reasons for Administration, Prescription Pattersn, Effectiveness, and Side
Effects. Clinical Journal of Pain, Vol 21, No 6, Nov/Dec 2005, Pp503-512
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Clifford Gevirtz, Methadone’s Role in Pain Management: New Dangers Revealed, Topics
in Pain Management, Vol 23, No 5, December 2007, Pp 1-5
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Vocci, Frank et al. Medication Development for Addictive Disorders: The State of
Science. American Journal of Psychiatry, Vol 162, No 8, Aug 2008. Pp 1432-1440
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Kharasch, Evan et al. Methadone Pharmacokinetic Are Independent of Cytochrome
P450A (CYP3A) Activity and Gastrointestinal Drug Transport: Insights from Methadone
Interactions with Ritonavir/Indinavir, Anesthesiology, Vol 110, No 3, March 2009, Pp660672