An Underused Alternative in Pain Management

 

Introduction

Methadone can be a good choice for the management of cancer pain and chronic non-cancer pain both as a first-line medication and as a replacement opioid. Due to methadone’s unique pharmacokinetics and pharmacodynamics, caution must be observed. Milligram for milligram methadone is much more powerful than morphine, although there is significant interindividual variability in the response to methadone. When initiated, careful day-to-day monitoring is essential. Methadone can interact with numerous medications, so, drug interactions must be considered when deciding to use it. Compared with other opioids, methadone can offer a very significant cost-savings advantage.

 

How it works in the body

Methadone is an opioid narcotic analgesic which binds to mu, kappa, and delta opioid receptors, producing analgesia. It mimics the actions of endogenous opioid compounds at 2 of the 3 major opioid receptors, with strongest affinity for the mu receptor but also appreciable affinity for the delta receptor. Most opioids only act at the mu receptor. The clinical effectiveness of methadone increases with chronic dosing. Methadone also acts as an N-methyl-D-aspartate (NMDA) receptor antagonist which can help prevent central sensitization and reduce opioid tolerance. Methadone non-competitively blocks these receptors, thereby decreasing pain. Frequent or large methadone dose changes are not usually necessary after the initial titration phase.

 

What are the pharmacokinetic principles to know?

Methadone is well absorbed from all routes of administration and can be administered orally, rectally, intravenous, intramuscular, subcutaneous, epidural, and intrathecal. It is highly lipophilic and is quickly distributed to tissues. Between doses, plasma concentrations are maintained by this tissue reservoir.  This reservoir ultimately allows for longer administration intervals. It is highly protein bound with only 1% of the drug remaining in the blood.

 

The interpatient variability in tissue accumulation and half-life makes standardized dosing difficult and increase the potential for toxicity. However with careful dosing and monitoring during the initial absorption phase, steady state concentration can be achieved successfully and potential toxicity problems can be avoided.

 

Methadone’s bioavailability is nearly 3 times that of morphine and its half-life is about 10 times greater than morphine. Peak plasma concentration occurs on average 2.5-4 hours following ingestion. While the half-life of methadone may be 30 hours, the duration of analgesia is much shorter. The mismatch of half-life and duration of analgesia is potentially life threatening if patients start out using methadone every 4 to 6 hours like other opioids. Because of its long half-life, plasma levels of methadone may take up to 10 days to stabilize. There must be a cautious balance between inadequate analgesia due to insufficient dosing and systemic toxicity due to excessive dose during the titration phase. Patients should be advised of methadone’s slow onset of action and gradual enhancement of analgesia over time.

 

What are the advantages?

·       Incomplete cross-tolerance with other mµ-opioid agonist, so provides relief when tolerance to other opioids has developed.

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·       Lower incidence of side effects, such as nausea, sedation and constipation

·       Metabolized to inactive metabolites, therefore no routine dose adjustment are necessary in pts with renal or hepatic impairment

·       Useful for neuropathic pain, due to its activity at the NMDA receptors, where other opioids are not effective

·       Once steady state is reached, it has a long duration of action allowing for longer administration intervals and the only long-acting opioid in liquid form

·       Excellent oral and rectal bioavailability

·       Various dosage forms and routes of administration

·       Low cost

 

Methadone Dosing: Opioid-Naïve Patients

 The general rule is to “Start Low and Go Slow.” It is recommended starting at a dose of 2.5mg po every 8 hours. This is a conservative and typically safe starting dose, for a frail or elderly patient an initial dose of 2.5mg po once daily might be necessary.

 

Acceptable guidelines for methadone titration are lacking, so increases should be based on the patient’s response. An increase of 2.5mg per dose every 5 to 7 days has been recommended in the VA/DoD Clinical Practice Guideline for the Management of Opioid Therapy for Chronic Pain.

 

Methadone Dosing: Opioid-Tolerant Patients

Most equianalgesic tables indicate that a 15mg oral dose of morphine is approximately equivalent to a 10mg oral dose of methadone. For a single dose, this may be true, but, with repeated dosing methadone may have a much greater analgesic effect. If one relies on these “single dose tables” to transition a patient to methadone from one or more other opioids can result in a substantial methadone overmedication, possibly overdose, that may not be apparent for a number of days.

 

The following table of EDR (Equianalgesic Dose Ratios) correlates with the total daily opioid dose before switching to methadone. However, this EDR is not without fault and is only a predicted value, where the actual EDR may be quite different.

 

Using the above table, 300mg, 600mg, and 900mg of oral morphine will each predict a 60mg dose of methadone. Existing opioid analgesia is typically discontinued the evening before starting methadone. Methadone is usually started in the morning to help gauge its effects during the day.

 

Guidelines for dosing methadone: Revised Morley-Makin Method

1.     Calculate the 24-hr morphine equivalent dose

2.     If morphine equivalent is <300mg/day, the fixed methadone dose should be one-tenth of the calculated 24-hour morphine equivalent dose.

3.     If the morphine equivalent is >300mg/day, the fixed methadone dose should be 30mg

4.     Discontinue all other opioids before starting methadone therapy (do not recommend a gradual weaning “weaning off”)

5.     The calculated fixed dose (steps 2 or 3) should be initiated orally every 12 hours and may eventually be dosed up to every 4 hours (worsening of pain should not occur, but warn patients that it may take 24-48 hours for significant pain relief to be achieved). Methadone should not be used for breakthrough pain upon initiation. Use another opioid, such as MSIR, OxyIR, or Lortab for breakthrough pain. Half-life is anywhere from 22-190 hours- do not increase dose more often than every 4 days. Duration of analgesia after steady state is 6-12 hours.

6.     A decrease in methadone requirements is usually seen within 2-3 days and steady state is reached on days 4-5.

7.     On day 6, divide the total dose of previous 48 hours (day 4-5) by four and use this dose as the new BID daily dosage regimen.

8.     If further adjustments in dose are needed once the BID steady dose is reached, incremental escalation by 50% is recommended.

9.     Once the appropriate BID regimen is achieved, breakthrough therapy is recommended as 10% of the total daily dose given every 3 hours as needed.

10.   Careful monitoring is required, especially during the initial dosing phase to reach steady state, to decrease the potential for toxicity problems due to drug accumulation

 

 

How to Titrate & Monitor

Dosing increases should not be made more frequently than every 5-7 days. Patients must be monitored for side effects during the transition to methadone, particularly respiratory depression. Methadone’s peak respiratory depressant effects typically occur later, and persist longer than the peak analgesic effects, particularly in the early dosing period. Even correctly calculated doses of methadone may be too high in some patients.

 

Monitoring parameters include pain control, respiratory depression, CNS depression (sedation, confusion), miosis (pin-point pupils), constipation, blood pressure, heart rate and hypothermia. Patients should be monitored daily when starting methadone.

 

Side Effects

Most side effects are transient. The most common side effects, as with other opioids, are respiratory depression and sedation. Constipation and stomach upset may also develop, but to a lesser extent than with other opioids.

 

 

Potential Drug Interactions

·       Barbiturates, phenytoin or other hydantoins (Dilantin®), carbamazepine (Tegretol®), primodone, rifampin, pentazocine (Talwin®) can decrease the effects of methadone, leading to inadequate pain control and possibly, withdrawal symptoms.

·       The –azole antifungals (fluconazole, itraconazole, ketoconazole), cimetidine (Tagamet®), ciprofloxacin, fluvoxamine and fluoxetine are examples of drugs that may increase serum levels and/or toxicity of methadone.

·       An interaction is also seen with amitriptyline, nortriptyline, and other tricyclic antidepressants, which may increase methadone levels.

 

 

What patient is most likely to benefit?

·       If the patient is experiencing inadequate analgesia despite dose escalations and use of adjuvant therapies

·       If the patient has developed intolerable side effects or tolerance to current opioid therapy

·       If the patient is suffering from pain of neuropathic origin

·       If the patient requires >300mg of oral morphine equivalent daily

·       In pts who can no longer swallow pills, methadone offers the only long acting opioid available in liquid formation, once the drug has reached steady state.

·       If the patient has renal or hepatic impairment

·       If the patient has >3 week prognosis

·       If the patient has a true allergy to morphine

 

**Methadone does not relieve general anxiety. When anxiety is present which may be due to ineffective pain control, do not titrate dose for Methadone. You must add an anxiolytic and may increase Methadone dose every 4 days.

 

- Digi Graham, D.Ph


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