National Pain Management Strategy Coordinating Committee

Pharmacy Workgroup

**Methadone Dosing and Safety Information Paper**

**Methadone is a potent synthetic opioid analgesic that is structurally
distinct from other opioid classes, is naturally long acting, and has
NMDA receptor antagonistic properties. These unique characteristics make
methadone a good option for patients who are allergic to other opioids,
help provide longer and more stable analgesia, and make it feasibly more
effective than other opioids in patients with neuropathic pain
syndromes. Clinicians may be reluctant to use methadone because there
have been reports of inadvertent overdoses or are unfamiliar with its
use. The principles of using methadone are similar to those of other
opioids, and is a safe and effective therapy for pain when used
judiciously. To promote the safe use of orally administered methadone,
this letter provides clinicians with important information on the unique
properties, recommendations on who should be treated with methadone for
pain, and how to dose methadone.**

**[Properties]{.underline}**

-   Synthetic opioid analgesic.

-   Weak N-methyl D-aspartase (NMDA) antagonist activity making it
    feasibly more effective for neuropathic pain compared to non-NMDA
    opiates and extending the time to which one would otherwise develop
    opioid tolerance.

-   Minimal cross-sensitivity with morphine and morphine derivatives due
    to unique chemical structure (methadone is a diphenylheptane,
    morphine is a phenanthrene).

-   Highly bioavailable upon oral administration by tablet; may be
    crushed and/or dissolved.

-   Onset of action ranges from 30 minutes to 2 hours.

-   Highly protein bound to alpha-glycoprotein and widely distributed
    into body tissue.

-   Long half-life requires careful titration with washout time compared
    to other opioids.

-   Equivalency ratios (although variable) are not bi-directional, since
    methadone remains behind for days, even after discontinuation.

-   Average clearance time is 20-22 hours

-   Elimination half-life is variable: range from 15-60, with reported
    cases up to 120 hours. However, the duration of analgesic effects is
    much shorter (e.g., 6 to 12 hours); therefore, drug may accumulate
    in the body; if dosage increments are made before drug levels reach
    steady-state, and potentially lead to toxicity.

-   Metabolized by the liver into inactive metabolites
    2-ethyl-1,5-dimethyl-3,3-diphenylpyrolinium (EDDP) and
    2-ethyl-5-methyl-3,3-diphenylpyraline (EMDP).

-   Eliminated by kidneys, minutely detectable in bile, feces and sweat.

-   FDA approved for (drug rehabilitation) therapy, and pain (malignant
    and non-malignant).

-   Not recommended to be used for breakthrough pain due to long
    half-life and resultant cumulative levels/effects.

## Methadone Dosing

As a general rule for dosing methadone, *start low and go slow*.

Additional information on different methods of dosing methadone can be
found in *Methadone Dosing Recommendations for Treatment of Chronic
Pain* available at:
[http://www.pbm.va.gov/monitoring/Methadone%20Dosing%20Final%20(Rev%20081103).pdf](http://www.pbm.va.gov/monitoring/Methadone Dosing Final (Rev 081103).pdf)
.

**[Opioid Naïve]{.underline}**

-   Initiate at 2.5 mg every eight hours, three times a day.

-   Increase dose every 5 to 7 days, titrating dose as tolerated and/or
    until desired analgesia.

-   If patient is elderly or has renal or hepatic impairment, start at
    2.5 mg every 12 hours or once daily.

-   Provide short acting opioids for breakthrough pain.

**[Opioid tolerant]{.underline}**

The table below is meant to serve as an initial conversion from opioids
[to methadone]{.underline} in healthy patients. The final dose must be
individualized to the patient.

The previously prescribed opioid can be tapered while methadone levels
approach steady state. How often should they be tapered?

It is recommended that short acting opioids be available for
breakthrough pain during the titration period.

**Methadone Conversion Ratios**

  ----------------------- ----------------------- -----------------------
  *Current daily oral     *Conversion ratio       *Conversion factor
  morphine equivalent     (morphine to            (approximate percentage
  dose*                   methadone)*             of morphine dose)*

  ≤ 100 mg                3 to 1                  33.3

  101 to 300 mg           5 to 1                  20.0

  301 to 600 mg           10 to 1                 10.0

  601 to 800 mg           12 to 1                 8.3

  801 to 1000 mg          15 to 1                 6.7

  ≥ 1,001 mg              20 to 1                 5.0
  ----------------------- ----------------------- -----------------------

Med J Aust 2000; 173: 536-40.

# 

# **Warning, Precautions and Patient Monitoring**

-   Start with lower doses and titrate to effect/tolerability for
    patients who are elderly or who have renal or hepatic impairment.

-   Observe for latent opioid adverse effects or toxicities, varying
    from one-half hour to 7 days due to methadone's highly variable
    elimination half-life in patients.

    -   Somnolence

    -   Sedation

    -   Constipation

    -   Delirium

    -   Myoclonic jerking

    -   Hypertension

    -   Bradypnea

    -   Bradycardia

-   Can be taken with food, crushed, dissolved in liquid, or
    administered in commercially available solution.

-   Can cause \[an insignificant\] QT prolongation in patients at high
    doses, but precaution with patients with concomitant
    cardioarrhythmic medications such as tricyclic antidepressants.

-   Caution with cytochrome P450 (CYP) inducers which may reduce
    methadone serum levels and/or analgesia, such as phenobarbital,
    phenytoin, carbamazepine, neveripine.

-   Caution with CYP inhibitors which may increase methadone serum
    levels, analgesia and/or toxicity, such as erythromycin,
    ketoconazole, itraconazole.

-   Caution with other central nervous system depressing
    medications/substances, such as benzodiazepines, alcohol,
    concomitant opioids.

-   Methadone cannot be abruptly stopped when discontinuing opioid
    therapy but should be slowly tapered depending on the clinical
    situation.

-   Methadone can be abruptly stopped when rapidly crossing over to a
    different opioid

-   Previously prescribed opioid may be tapered down while slowly
    escalating the methadone dose.

# **Patient Education**

-   Allay the stigma associated with substance addiction.

-   Do not suddenly stop taking if patient has taken methadone for
    greater than two weeks.

-   Be aware of opioid adverse effects, most commonly somnolence, and
    constipation.

-   Explain to patient the differences between addiction, physical
    dependence, and tolerance.

-   Can be beneficial for those also suffering from neuropathic pain.

# References

Toombs, JD, Kral LA. Methadone Treatment for Pain States. American
Family Physician, April 2005, Vol 71, No. 7

Oda Y, Kharasch ED. Metabolism of Methadone and Levo-α- Acetylmethadol
(LAAM) by Human Intestinal Cytochrome P450 3A4 (CYP3A4): Potential
Contribution of Intestinal Metabolism to Presystemic Clearance and
Bioactivation. The Journal of Pharmacology and Experimental
Therapeutics. 2001, Volume 298, No.3

Krantz MJ, Lowery CM, Martell BA, Gourevitch MN, Arnsten JH. Effects of
Methadone on QT-Interval Dispersion. Pharmacotherapy. 2005 Volume 25,
No. 11

VA National Guidelines: Methadone Dosing Recommendations for Treatment
of Chronic Pain, Goodman F, Jones WN, and Glassman P
(http://www.pbm.va.gov/monitoring/Methadone%20Dosing%20Final%20(Rev%20081103).pdf)

AHFS Drug Information, 2004, pp 2046-2049

Methadone. Drug Information \[database on the internet\] Clinical
Pharmacology. Tampa (FL): Gold Standard. c2006) updated August 8, 2006.
Cited September 21, 2006.

Fudin J, Palmer J. Opioid Pharmacokinetics and Expected Metabolites
(updated June 2005)
(http://www.paindr.com/06-2005%20Opioid%20Metabolite%20Chart.pdf) cited
September 21, 2006

Elsayem, A, Bruera E. Methadone-Induced Respiratory Depression in a
Patient with a history of Alcoholism. Journal of Palliative Medicine.
2005. Volume 8, No. 5

Mercadante S, Ferrera P, Villari P, Casuccio A. Rapid Switching Between
Transdermal Fentanyl and Methadone in Cancer Patients. Journal of
Clinical Oncology. 2005, Volume 23, No. 22.

Cytochrome P450 Drug-Interaction Table. Indiana Univeristy Department of
Medicine; Division of Clinical Pharmacology. Updated May 16, 2006.
(<http://medicine.iupui.edu/flockhart/table.htm>) Cited September 22,
2006

Cytochrome P450 Drug-Interaction Table (Abbreviated table). Indiana
University Department of Medicine; Division of Clinical Pharmacology.
(<http://medicine.iupui.edu/flockhart/clinlist.htm>) Cited September 22,
2006.

Ayonrinde OT, Bridge DT. The rediscovery of methadone for cancer pain
management. Med J Aust 2000; 173: 536-40.

Prepared by Wen Gao Huang, Pharmacy Intern/Pharm.D. Candidate

Reviewed and edited by Jeffrey Fudin, B.S., Pharm.D., DAAPM