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Appendix F

Methadone Dosing Recommendations for Treatment of Chronic Pain

Based on Methadone Dosing Recommendations for Treatment of Chronic Pain available at:

http://www.vapbm.org

Background
While methadone has gained increasing acceptance as an alternative to morphine for treatment of moderate to severe pain, a number of authors have cautioned clinicians about the complexities of dosing methadone or have suggested the drug be prescribed by practitioners with relevant experience in an adequately monitored setting.1-7 Significant toxicity has occurred particularly when dosage increments were made too frequently, conversion doses were too high, or dosing intervals were too close.5,8-10 Accruing experience, however, suggests that methadone can be safely used when initial doses are small, conversion ratios are adjusted to the previous opioid dose, and dosage is slowly titrated to patient response.2,3,5,6,9,11-15 The general principles of dosing methadone are similar to those of other opioids.

The pharmacokinetic and pharmacodynamic properties of methadone are complex and incompletely documented.16,17 Although methadone may have a long elimination half-life (range of mean/medians among studies: 3 to 128 h in healthy volunteers, opiate addicts, patients with chronic pain, and patients with acute pain),18-31 the elimination half-life does not necessarily reflect duration of analgesia.28,32 Patients may require dosing intervals of 6 hours to achieve adequate pain relief, although repeated oral administration of methadone for cancer pain may lead to progressively longer dosing intervals.33,34 As a result of the dissociation between half-life and analgesic duration, tissue accumulation of methadone can occur. Patients need to be reassessed more frequently (e.g., every few days) when methadone is initiated and when the dose is increased. However, once a stable dosing is established, follow-up can be as clinically indicated. With a 3-day phased conversion from morphine to methadone, the analgesic effects have taken a median of 5 days (range: 4 to 13 days) to stabilize.3

Summary

  • Methadone is a synthetic opioid analgesic with similar adverse effects to other opioids
  • Duration of action is usually 6 hours or longer
  • Methadone is the only long-acting opioid available as an oral solution
  • Long half-life and drug accumulation can lead to delayed toxicity (e.g., on days 2 to 5)
  • The analgesic effects of methadone may take about 1 to 2 weeks to stabilize
  • The equianalgesic dose of methadone in repetitive dosing is much smaller (1/5th to 1/10th) than that suggested by single-dose studies
  • Initial doses of methadone should be small and adjusted to the previous opioid dose, using smaller methadone–to–morphine-equivalent conversion ratios (%) the larger the previous morphine-equivalent dose
  • As with other opioids, methadone requires close patient monitoring for analgesic and adverse effects.
Table F1 Points to consider about equianalgesic conversion ratios
A number of equianalgesic dosing tables underestimate the potency of methadone.†
Conversion ratios in many equianalgesic dosing tables do not apply to repeated doses of opioids.
The morphine- or hydromorphone-to-methadone conversion ratio increases (i.e., the potency of methadone increases) as the previous dose of morphine or hydromorphone increases.‡
Conversion ratios may not be bi-directional (i.e., the morphine-to-methadone conversion ratio may not be the same as the methadone-to-morphine ratio).§
There may be large interpatient variability in the equianalgesic conversion ratio; a single ratio may not be applicable to all patients.§
The use of high but ineffective doses of previous opioid may result in overestimation of the equivalent dose of methadone.
The relative analgesic potency ratio of oral to parenteral methadone is 2:1; however, confidence intervals are wide.||
† Management of Cancer Pain, Clinical Practice Guidelines, AHCPR (1994)35; Cancer pain: a monograph on the management of cancer pain, Health & Welfare Canada (1984)36; Twycross (1990)37; Levy (1985)38
‡ The oral morphine to oral methadone conversion ratio may be unexpectedly much higher in patients who previously received very high doses of morphine.2-4,39
§ Bruera (1999)40
|| Estimated ratio based on single-dose, double-blind, double-dummy, cross-over studies in patients with moderate to severe cancer pain.1

The present dosing recommendations are provided to offer guidance on dosing methadone in the treatment of patients with chronic noncancer pain (CNCP) or chronic cancer pain, particularly when converting from another opioid to methadone. If in doubt, a practitioner should consult a pain management specialist, clinical pharmacist, or another practitioner who has the relevant knowledge.

Dosing Strategies
Recommendations for the use of methadone in the management of chronic non-cancer pain are extrapolated from studies involving mostly patients with cancer pain.

Table F2. Dosing methadone for patients receiving codeine preparations or no previous opioids
Dosing strategy Initial MET dose Increments Comments
Gradual titration
(For CNCP and patients monitored less frequently) 44
2.5 mg q 8 h 2.5 mg q 8 h every 5 to 7 d As a general rule, start low and go slow.
Faster titration
(For cancer pain and patients monitored frequently) 		2.5 mg q 6 or 8 h 2.5 mg q 6 or 8 h as often as every day over about 4 d
The dosing recommendations for gradual titration were modified with permission from Evidence-Based Recommendations for Medical Management of Chronic Non-Malignant Pain, College of Physicians and Surgeons of Ontario, November 2000. All doses refer to oral administration.
CNCP = Chronic noncancer pain
MET = Methadone

 

Table F3 Dosing recommendations for patients previously receiving other opioids
Gradual Conversion (For CNCP and patients monitored less frequently) 44
MOR-E[mg/d] Calculated MET dose [mg /d] Initial MET dose Increment
< 200 15 mg 5 mg q 8 h Increase by calculated MET dose every 5–7 d
200 – 500 ~ 7% of MOR-E * Calculated MET dose given in divided doses q 8 h Increase by calculated MET dose every 5–7 d
>500 ~ 7% of MOR-E * 1/3rd of calculated MET dose given in divided doses q 8 h Add 1/3rd of calculated MET dose every 5 dDecrease previous opioid by 1/3rd every 5 d
(Complete conversion period = 15 days)

* Calculation of MET dose based on oral oral morphine-equivalent [MOR-E] doses:
Methadone            [MET]     2 mg           Examples:
Morphine               [MOR]  30 mg          250 mg/d MOR = 250 x 2 /30 = 17 mg/d MET ~ 5 mg q 8 h
Hydromorphone  [HMO]     8 mg            60 mg/d HMO =   60 x 2 /  8 = 15 mg/d MET = 5 mg q 8 h
Oxycodone             [OXY]   15 mg         120 mg/d OXY  = 120 x 2 /15 = 16 mg/d MET ~ 5 mg q 8 h
   

600 mg/d MOR = 600 x 2/30 = 40 mg/d MET
1/3rd of 40 mg/d = 13 mg/d or about 15 mg/d
Give:
      MET   5 mg q 8 h + MOR 400 mg/d (in divided doses) x 5 d
      MET 10 mg q 8 h + MOR 200 mg/d (in divided doses) x 5 d
      MET 15 mg q 8 h + discontinue MOR
Rapid Conversion (For cancer pain and patients monitored frequently) 2,3,5,11,12,45,46
MOR-E[mg/d] MET-to-MOR-ERatio [%] Initial MET dose Increment
< 200 10% - 30% Calculated daily MET dose in divided doses q 8 h
(up to a maximum 50 mg q 8 h)		 Phased Conversion:
Replace 1/3 of MOR-E dose with calculated dose of MET every day (complete conversion in 3 days)

 Rapid (Stop-and-Go): Discontinue MOR-E and start
calculated dose of MET on day 1

200 – 500 10% - 20%
500 – 1000 5% - 10%
> 1000 5% or less
Example:
                           600 mg/d MOR = 30 to 60 mg/d MET (or about 45 mg/d)
                             1/3rd of MET dose = 10 to 20 mg/d (or about 15 mg/d)
                                    Day 1: MET 5 mg q 8 h + MOR 400 mg/d (in divided doses)
                                    Day 2: MET 10 mg q 8 h + MOR 200 mg/d (in divided doses)
                                    Day 3: MET 15 mg q 8 h + discontinue MOR
  1. For the most conservative approach, use 5% MET/MOR-E (or less with very high MOR-E doses) to calculate the initial MET dose irrespective of the previous MOR-E dose
  2. Titrate MET day by day according to patient’s symptoms and the number of rescue doses administered
  3. Smaller MET-to-MOR-E conversion ratios(%) should be used the larger the previous MOR-E dose

CNCP = Chronic noncancer pain
HMO = Hydromorphone
MET = Methadone; MOR = Morphine
MOR-E = Morphine-equivalent
OXY = Oxycodone

It is important to note that various dosing methods have been used (including a patient-controlled regimen 6,47) and are still evolving. Two dosing strategies 2,11 have been prospectively studied, but no clinical trials comparing systematic dosing methods have been performed. A literature search (PubMed 1966 to 2001) identified only a small case series that discussed methadone dosing during the treatment of CNCP.48 The lack of prospective and comparative studies highlights the need to carefully individualize the dosing regimen of methadone, as is done with other opioids.

As a general rule, smaller methadone-to-morphine conversion proportions (%) should be used the larger the previous morphine-equivalent dose, remembering that precise conversions from another opioid to methadone are impossible. Disproportionately smaller methadone doses may be required with the larger morphine doses. However, it is important to remember that the equianalgesic conversion ratio is only one part of the process of properly dosing methadone and other opioids.

For inadequately treated pain during titration, a short-acting opioid preparation (such as acetaminophen with codeine, oxycodone with or without acetaminophen, or immediate-release morphine) may be used as necessary. Keep in mind that the use of supplemental opioid medications in patients with CNCP is controversial. If opioid medications for breakthrough pain (BTP) are indicated following titration to a stable methadone dose in a patient with CNCP, they should be used sparingly.44 Methadone has been used for inadequately treated pain during titration (in doses 10% to 30% of the calculated daily methadone dose up to 3 to 8 doses per day as needed)6,11,46,47; however, the short-acting opioids are generally preferred to avoid drug accumulation.

Special patient populations
Patients 65 years and older may have a decreased clearance of methadone.30 In patients with stable chronic liver disease, no dosage adjustments appear to be necessary.49 Methadone and its metabolites do not accumulate in patients with renal failure.50 The two prospective studies on methadone dosing strategies excluded patients with liver or renal disease.2,11 Use extra caution when dosing any opioid in all of these patient populations.[a]

COMMENTS

  • Once a stable analgesic dose is reached, dosing intervals may be extended to 8 to 12 h or longer.
  • Provide careful dose titration until adequate pain relief is achieved or adverse effects limit further dose escalation.
  • Absence of a graded analgesic response (in CNCP) suggests that the patient’s pain may not be “opioid responsive.”
  • Patients should be closely monitored, at least once weekly during titration and at least once a month during maintenance.
  • Patients should be warned about potential adverse effects (drowsiness, respiratory depression) and the possibility that analgesic and adverse effects may continue to evolve during the week after each dose adjustment.
  • If drowsiness develops, patients (family member) should contact the provider to obtain advice about further dosing.
  • Use additional caution with elderly patients (65 years and older), patients with liver, renal, or pulmonary disease, debilitated patients, and patients previously receiving high doses of opioid. Patients who cannot be monitored at home may be considered for inpatient titration of methadone.

Patient education

  • Explain to patients that the initial dose may not provide optimum pain relief but that the starting dose is chosen in order to reduce the chance of adverse effects. A pain and pain medicine diary should be kept.
  • Reassure patients that the dose will be titrated to achieve adequate analgesia.
  • When applicable explain the reason for and how to use the short-acting opioid during methadone dose titration.
  • Advise patients that the effects of methadone will increase over at least one week following a dosage increment. Pain relief during the last few days of that week will be greater than at the first few days of the week.
  • Remind patients about the need for and the frequency of monitoring during the titration and maintenance periods. Provide patients with instructions on what to do if they develop increasing or intolerable adverse effects.
  • Advise patients to avoid abrupt discontinuation of their opioid medication without first consulting their physician. Educate patients about withdrawal symptoms.
  • Since patients may become concerned about the social stigma associated with the use of methadone for treatment of opioid dependence, reassure them that methadone is also an accepted pain medication and that they are not “addicts” because they are taking methadone for pain control. Explain the difference between addiction and dependence.[b]

[a] For patients with liver or renal disease, special consideration can be given locally to use an alternative opioid at the discretion of the care team or provider.

[b] For more information on the definitions of addiction and dependence, see the Web-based educational program for VA employees entitled Opioids in the Management of Acute and Chronic Pain; available at: http://vaww.sites.lrn.va.gov/pain/opioids/ or reference 51.

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