JAOA • Vol 105 • No 3_suppl • March 2005 • 18-21
Prescribing Methadone for Pain Management in End-of-Life Care
John F. Manfredonia, DO
Address correspondence to John F. Manfredonia, DO, FACOFP, VistaCare Regional
Medical Director, 6420 E Broadway Blvd, Suite B-200, Tucson, AZ 85710.E-mail:
john.manfredonia{at}vistacare.com
Methadone hydrochloride is an effective, inexpensive, and relatively safe
opioid to use in the treatment of patients with chronic pain. It is especially
effective in management of pain during the final stages of life, as it is the
only long-acting analgesic available in liquid form. However, because
methadone has a long half-life, individual wide variations, and potential for
accumulation and overdosage, physicians must judiciously and conscientiously
prescribe it. Also, they should closely monitor patients during the titration
phase and educate them with regard to basic pharmacologic properties and
potential side effects. A plan to start at low doses and proceed slowly is
applicable to methadone.
Chronic pain is one of the most common conditions for which people seek
medical treatment; it affects more than 85 million
Americans.1 In
end-of-life care, in which the primary focus is the reduction or elimination
of suffering, a significant number of patients still suffer with uncontrolled
pain. In recent years, healthcare consumers have become more sophisticated,
demanding better pain control. Therefore, physicians need to be familiar and
competent with the various treatment options and pharmacologic management of
their patients with chronic pain.
Although the primary responsibility of physicians is to nurture the
physical and psychological well-being of their patients, it is also important
that they serve as stewards of financial resources. In the past several years,
there has been resurgence in the understanding of the pharmacologic and
pharmacokinetic properties of methadone hydrochloride. This resurgence,
coupled with methadone's low cost, has led to increased use of this agent in
the treatment of chronic pain.
Methadone is a synthetic opioid agonist developed in the late 1940s.
Historically, it has been used in the treatment of patients with narcotic
addiction and heroin maintenance since the 1960s. Although substantial
information exists regarding such use of methadone, only limited data are
available with respect to pain management. It is only within the past decade
that there has been a renewed focus on its use in the treatment of patients
with chronic pain.
Initial interest in methadone for pain management emerged in the care of
terminally ill patients with cancer, but methadone recently has been gaining
recognition in management of nonmalignant pain. Methadone is achieving greater
acceptance in end-of-life care because of its unique characteristic as the
sole long-acting opioid in liquid form. Its wide spectrum of absorption and
formulations allows administration using every route available: oral,
sublingual, rectal, subcutaneous, intramuscular, intravenous, epidural,
intrathecal, and percutaneous endoscopic gastrostomy (PEG) tube.
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Formulations
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Methadone hydrochloride is available in the United States as Dolophine or
Methadose in multiple formulations, including 5-mg, 10-mg, and 40-mg scored
tablets; solution in concentrations of 5 mg/5 mL, 10 mg/5 mL, and 10 mg/mL for
oral administration, and a 10-mg/mL solution for parenteral
administration.
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Pharmacokinetics
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Methadone is a highly lipophilic drug that is rapidly absorbed with
extensive tissue
distribution.2
Unlike morphine sulfate, methadone has no active metabolites and hepatic
metabolism has no significant effect on methadone concentrations, clearance,
or clinical
disposition.3 It is
predominantly excreted in the feces; however, acidification of the urine will
increase renal excretion. It has a prolonged and variable elimination phase
with a plasma half-life that ranges between 4.2 hours and 190.0 hours,
depending on the literature that is
reviewed.2,4-6
The mean plasma half-life of methadone is probably 15 to 60
hours,4 though even
this range is extremely variable and dependent on single versus multiple
dosing, individual adipose stores, and protein binding. This wide variation in
half-life contributes to methadone's potential for toxic accumulation and has
created difficulty with appropriately and easily dosing this medication.
Methadone has a rapid onset of action, with analgesic effects occurring
within 30 to 60 minutes and an analgesic peak between 2.5 and 4.0 hours. Its
oral bioavailability, though variable, generally exceeds 80%. It binds with
mu, delta and to a lesser extent kappa opioid receptor sites.
Figure
17
categorizes the opioid family.
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Figure 1. Opioid family categories. (Source: Killion K, ed. Drug Facts and
Comparisons. 54th ed. St Louis, Mo: Facts and Comparisons;
2000:784-797.)
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Drug Interaction
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Cytochrome P450 is the main isoenzyme involved in methadone
biotransformation.2
Physicians must be sensitive to co-administration of other drugs that could
result in either an increase or a reduction of methadone levels.
Table
12
reflects examples of some of those medications.
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Clinical Advantages
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Although initially used in cancer patients, methadone is being increasingly
used in the end-of-life care setting for patients with nonmalignant pain
syndromes. As the only long-acting opioid liquid formulation, methadone
provides an attractive alternative to the expensive transdermal fentanyl patch
in patients with debilitating states of advanced dementia, in patients with
arthritis, and in deconditioned bedridden individuals with adult failure to
thrive who have generalized pain or allodynia and when patients can no longer
swallow pills. Methadone's high bioavailability and long duration of action
with rectal administration make it a potential alternative to intravenous
administration.7
Whereas methadone and fentanyl have been shown to be safe in patients with
renal failure,3
morphine and codeine with their active metabolites should be avoided and
hydromorphone and oxycodone should be used with caution. An additional
advantage of methadone is its property as an
N-methyl-D-aspartate (NMDA) receptor antagonist. This
property contributes to a reduced propensity to develop opioid tolerance as
compared with morphine and a greater efficacy in treating patients with
neuropathic
pain.2,3,5
Figure 2 summarizes
the advantages and disadvantages associated with the use of methadone.
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Figure 2. Advantages and disadvantages associated with the use of methadone.
(*Ripamonti C, Bianchi M. The use of methadone for cancer pain. Hematol
Oncol Clin North Am. 2002;16:543-555.  Bruera E, Sweeney C.
Methadone use in cancer patients with pain: a review. J Palliat Med.
2002;(1):127-138.)
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Prescribing Methadone
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Equianalgesic dosing of methadone is more complex than it is for other
opioids. Unlike morphine, methadone exhibits wide variations in half-life
among patients and must be cautiously prescribed, especially in individuals
currently medicated with an opioid.
There are several approaches to prescribing methadone. In end-of-life care
where some patients have noncancer pain syndromes and debilitated elderly have
moderate pain, a reasonable approach is to start at 5 mg every 12 hours.
Additional increases are determined based on the frequency and amount of
short-acting opioid used for breakthrough or incidental pain and titrated
accordingly every 3 to 5 days. The following examples demonstrate some of the
established
protocols8 for both
initiating and converting to methadone.
New Start: Opioid-Naïve Patients
This is the easiest method for initiating treatment with methadone in
opioid-naïve patients:
- Start methadone 5 mg every 6 to 12 hours.
- Titrate every 3 to 5 days until adequate analgesia is achieved.
- When steady state is achieved, switch to every 8- to 12-hour dosing
schedule.
- Use methadone or a short-acting opioid as needed for breakthrough or
incidental pain. Provide 10% to 15% of the total 24-hour dose every 2 hours as
needed.
Conversion From Morphine to Methadone
Table
28
provides the conversion ratio of oral morphine to methadone.
- Start dosing every 6 hours for four to six doses; then, decrease frequency
to every 8 to 12 hours.
- Use an immediate-release opioid as rescue dosing.
Switching From Another Opioid to Methadone
The process of switching from another opioid to methadone, especially when
high doses are being used, is much more complex. Several conversion protocols
are
available.8-10
One example follows:
- Discontinue current opioid.
- Start methadone at a fixed oral dose every 3 hours as needed: Administer a
fixed dose of methadone that equals 10% of prior daily oral morphine sulfate
equivalent with a maximum dose of 30
mg.9,10
- Example—If prior daily opioid dose equals 150 mg of oral
morphine sulfate equivalent per day; then, use 15 mg of methadone
hydrochloride every 3 hours as needed. (Note: This is not a 1:10
ratio, unless only one dose is given in 24 hours: 1:10 ratio would be 15 mg/d,
not 15 mg per dose.)
On day 6, calculate total amount of methadone taken during previous 48
hours and convert to twice-daily methadone dose. If the patient actually took
the 15 mg dose every 3 hours on days 4 and 5, then the correct dosing would be
60 g every 12 hours.
- Example—Patient is taking 600 mg of oral morphine sulfate
equivalent per day. Because the oral morphine equivalent is greater than 300
mg/d, use 30 mg of methadone hydrochloride as initial fixed dose and give 30
mg of methadone hydrochloride every 3 hours as needed. If patient has taken
eight doses of 30 mg over 2 days on days 4 and 5, for a total of 240 mg in 48
hours, or 120 mg of oral methadone hydrochloride per day, then, on day 6,
adjust methadone dose to 40 mg taken orally every 8 hours or 60 mg every 12
hours.9,10
Table 3 provides a
cost comparison of methadone with equivalent medication doses of other
opioids.11
Figure 3 provides a
list of additional print and Web site resources.
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Comment
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Methadone is gaining recognition in the arsenal of pain management. With
knowledge and initial cautious titration, physicians can readily manage and
consider methadone with the other extended-release opioids of morphine,
oxycodone, hydromorphone, and fentanyl. Methadone's efficacy, long-acting
liquid formulations, multiple routes of administration, and low cost make it a
noteworthy contender in the treatment of patients with chronic pain.
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Footnotes
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This continuing medical education publication supported by an
unrestricted educational grant from Purdue Pharma LP
Dr Manfredonia is board certified in Hospice and Palliative
Medicine.
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References
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1. Moskowitz M. Advances in understanding chronic pain.
Neurology.2002; 59(5 Suppl 2):S1
.[Free Full Text]
2. Ripamonti C, Bianchi M. The use of methadone for cancer pain.
Hematol Oncol Clin North Am.2002; 16:543
-555.[Medline]
3. Dean M. Opioids in renal failure and dialysis patients. Abstract
Review. J Pain Symptom Manage. 2004;28:497-504. From NIH/NLM MEDLINE
Available
at:http://www.das/journal/view/45309477-2N/15183529?source=MI.
Accessed January 15, 2005.
4. Doyle D, Hanks GW,Cherny N. Oxford Textbook of
Palliative Medicine. 3rd ed. New York, NY: Oxford University
Press; 2004: 324-325.
5. Bruera E, Sweeney C. Methadone use in cancer patients with pain: a
review. J Palliat Med. 2002;(1):127
-138.
6. McCaffery M, Pasero C. Pain Clinical
Manual. 2nd ed. St Louis, Mo: Mosby; 1999:185
-186.
7. Killion K, ed. Drug Facts and Comparisons.
54th ed. St Louis, Mo: Facts and Comparisons; 2000:784
-797.
8. Gazelle G, Fine P. Fast facts and concepts #75 Methadone for the
treatment of pain. September 2002. End-of-Life Physician Education Resource
Center. Available at
http://www.eperc.mcw.edu.
Accessed January 15, 2005.
9. Morley JS, Makin MK. The use of methadone in cancer pain poorly
responsive to other opioids. Pain Rev.1998; 5:51
-58.
10. Texas Academy of Palliative Medicine. Available at:
http://www.tapm.org/vault/Converting_to_Methadone.pdf.
Accessed January 15, 2005.
11. Fleming T, ed. 2004 Drug Topic Red Book..
108th ed. Montvale, NJ: Thomson Healthcare; 2004.
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