METHADONEGeneral Properties and Utility

Learning Objective

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

General Information

Schedule II opioid developed in Germany in 1940s as spasmolytic 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

Chemical Properties

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

Pharmacology

High lipophilicity with oral bioavailability 40-99% Large tissue reservoir Acts as both IR (onset 20-30min) and SR Exists in all conventional formulations

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

Analgesic 4-6 hrs initially, up to8-12 with repeated dosing

Pharmacology

Biphasic Elimination 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 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

Metabolism & Elimination

P450 metabolism Methadone metabolism produces no active

metabolites!

Fecal elimination (primary) Renal elimination (minor)

Varies depending on urinary pH

Areas of Special Utility

Cancer Pain Neuropathic Pain Drug interactions Opioid Addiction

Cancer Pain

>80% Cancer pts require opioid analgesics for intractable pain prior to death No ceiling effect Efficacy limited by toxicity:

N, V, constipation, sedation, hallucinations, myoclonus

Opioid Rotation Indications: Toxicity Tolerance Refractory pain

Cancer Pain

Advantages of Methadone Excellent oral & rectal bioavailability Incomplete cross tolerance Long T ½ with rapid onset No toxic metabolites Multpile Receptors involved

Mu and delta agonist NMDA antagonist – hyperalgesia, chronic pain

states, neuropathic pain Less constipation

Neuropathic Pain

Methadone may be first-line opioid choice NMDA antagonism

-neuropathic pain modulator -believed to attenuate development of morphine

tolerance Inhibition of Seretonin & Norepi reuptake

Ie TCA’s High lipophilicity = 3x bioavailability of MSO4

IR & SR action Duration up to 10h with chronic dosing

Neuropathic Pain

Minimal renal excretion & lack of metabolites well suited for diabetic neuropathy w/ renal insufficiency Evidence of efficacy largely anecdotal Limited to case studies

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.

Chronic Noncancer Pain

Comprehensive literture review by Sandoval et all Clin. Jounal of pain 2005

1 randomized trial, 13 case reports, 7 case series, 545 pts “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

Methadone and Addiction

Estimated 1 million long term opioid users in U.S.A. Methadone Maintenance Programs

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

BENEFITS Mortality reduction: U.S. untreated heroin addicts 8.3%

yearly mortality versus 0.8% treated. Morbidity reduction: ↓ IVDU, recidivism, crime, ↓ sexual

risk behaviors

Methadone and Addiction

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”

Unique Concerns

Methadone’s unique physical and pharmacological properties present unique challenges to proper management in the areas of: Overdose Equianalgesia Interindiviual variability of metabolism Dangerous side effects

Overdose

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

Methadone for analgesia ↑ 1,300% 1997-2003 Adverse events ↑ 1800% 1997-2007 Fatalities ↑ 390% 1997-2007

Interindividual Variability in Metabolism

Widely variable plasma concentrations with similar dosages

Mechanism no clearly understood Possible explanations include

Differences in alpha-1-glycoprotein binding Effects of urinary pH on renal clearance Multiple drugs can affect P450 system

Methadone => hepatic autoinduction

Equianalgesia

Morphine:Methadone ratios vary depending on prior opioid exposure.

Highly tolerant individuals require LESS methadone for equianalgesia than opioid naïve pts 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

Equianlagesia

Example of equianalgesia table

Daily MSO4 Coversion Ratio to Methadone<100mg 3:1101-300mg5:1301-600mg10:1601-800mg12:1801-1,000mg 15:1>1,000mg 20:1

QT Prolongation

QTc prolongation dose dependent at >60mg/day

Advised to check QTc interval prior to and during methadone titration

QTc ProlongationPain Medications that Prolong QTc

IntervalAnticonvulsants

Gabapentin Lyrica Fosphenytoin Pheytoin

SSRI Citalopram Sertraline Fluoxetin Paroxetine Escitalopram

TCA Amitriptyline Doxepin Nortiptyline Desipramine Clomipramine Imipramin Protriptyline mirtazapin

Misc Antidepressants Duloxetine (cymbalta) Venlafaxine

Muscle RelaxantsCyclobenzapine (Flexeril)Tizanidine

NSAIDSCelecoxibDiclofenacEtodolacIbuprofenMeloxicamSulindaKetoprofen

OPIATESFentanylSufentanilAlfentanilHydromorphoneLevorphanolMethadone

Summary

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.

References Benzon, HT. Essentials of Pain Medicine and Regional Anesthesia, Second Edition. Copyright

2005.

Hayes, Lewis et al. Use of Methadone for the Treatment of Diabetic Neuropathy. Diabetes Care, Vol 28, No 2 February 2005, Pp 345-313

Mancini, Isabelle et al. Opioid Switch to Oral Methadone in Cancer Pain. Current Opinion in Oncology, Vol 12,  2000. Pp 308-313

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

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

Clifford Gevirtz, Methadone’s Role in Pain Management: New Dangers Revealed, Topics in Pain Management, Vol 23, No 5, December 2007, Pp 1-5

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

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, Pp660-672