Medication Pearls For Practice: Methadone In Cancer Pain Overview

METHADONE

History2:

• Methadone was developed in Germany (it is synthesized from 1,1-diphenylbutane-2-sulfonic acid and dimethylamino-2-chloropropane) in the late 1930s in anticipation of possible shortages of raw opium during the upcoming war and possible blockades by the enemy.
• The drug was given the trade name Dolophine from the Latin dolor meaning pain (Cf. Dipidolor for piritramide, Dolantin for pethidine, and the "-dol" or "-phine" ending in so many trade and chemical names for analgesics of all types in German, English, French, and other languages) and was not named either in honour of or personally by Adolf Hitler, despite what Tom Cruise and the Church Of Scientology will have you believe.

Class1: Opioid analgesic.

Indications1:

• Moderate–severe pain (an alternative in cases of intolerance to other strong opioids, morphine poorly-responsive pain)
• pain relief in severe renal failure
• cough
• Also treatment of opioid addiction.

Potential uses1,3:

• Neuropathic pain (refractory)
• painful mouth ulcers: It has been used effectively as a mouthwash
• Restless Leg Syndrome: methadone (5 to 20 mg) have been administered in divided doses, 1 to 2 hours prior to bedtime.3

Pharmacology/Pharmacodynamics1:

• Methadone is a synthetic strong opioid with mixed properties. Thus, it is a μ-opioid receptor agonist, possibly a -opioid receptor agonist, an NMDA-receptor-channel blocker, and a presynaptic blocker of serotonin re-uptake.1
• Methadone binds to Mu (μ), Kappa (κ), and Delta (δ) opioid receptors, producing analgesia as well as typical opioid side effects.6 (See Notes section at end of document for opioid receptor information.
• There is no predictable relationship between methadone plasmalevel and pain relief.
• Methadone is a racemic mixture; L-methadone is responsible for most of the analgesic effect, whereas D-methadone is antitussive.
• Methadone is a non-acidic and lipophilic drug which is absorbed well from all routes of administration.

• Partly because of its lipid-solubility methadone has a high volume of distribution with only about 1% of the drug in the blood.
• Methadone accumulates in tissues when given repeatedly, creating an extensive reservoir.

Pharmacokinetics1:

• While methadone can be administered by a number of routes: oral, rectal, intravenous, intramuscular, subcutaneous, epidural, and intrathecal – it is most commonly given orally in either tablets or solution.
• Oral methadone is readily absorbed and very long-acting.
• By comparison, its bioavailability is nearly 3 times that of morphine and its half-life is about 10 times greater than morphine.6

• Bio-availability 80% (range 40–100%) PO.
• Onset of action <30min PO, 15min IM.
• Time to peak plasma concentration 4h PO; 1h IM.
• Plasma halflife 8–75h; longer in older patients; acidifying the urine results in a shorter halflife (20h) and raising the pH with sodium bicarbonate a longer halflife (>40h).

*methadone has an extended terminal half-life, up to 190 hours. This half-life does not match the observed duration of analgesia (6-12 hours) after steady state is reached. This long half-life can lead to increased risk for sedation and respiratory depression, especially in the elderly or with rapid dose adjustments.5

• Duration of action 4–5h PO and 3–5h IM single dose; 8–12h repeated doses.

Cautions:

In 2006, after a review of deaths and life-threatening adverse events (e.g. respiratory depression, cardiac arrhythmia) associated with unintentional overdose, drug interactions, and prolongation of the QT interval, the FDA in the USA issued a safety warning about the use of methadone. This highlighted the need for:

• physicians to be fully aware of the pharmacology of methadone
• close monitoring of the patient when starting methadone, particularly when switching from a high dose of another opioid
• slow dose titration, and close monitoring of the patient when changing the dose of methadone
• warning the patient not to exceed the prescribed dose.

Palliativedrugs.comconsiders that cumulation to a variable extent is bound to occur, particularly in elderly patients, and recommends p.r.n. dose titration to minimize the associated risk

Dosage:

• Dose titration is different from morphine because of the wide interindividual variation in the pharmacokinetics of methadone. Several guidelines exist for switching from morphine to methadone.
• 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.6
• For detailed dosing guidelines: http://pain-topics.org/pdf/OralMethadoneDosing.pdf
• http://www.palliativedrugs.com/methadone.html#guidelines
• From Lexicomp4:

Acute pain (moderate-to-severe):

Opioid-naive: Oral: Initial: 2.5-10 mg every 8-12 hours; more frequent administration may be required during initiation to maintain adequate analgesia. Dosage interval may range from 4-12 hours, since duration of analgesia is relatively short during the first days of therapy, but increases substantially with continued administration.

Chronic pain (opioid-tolerant): Conversion from oral morphine to oral methadone:

• Daily oral morphine dose <100 mg: Estimated daily oral methadone dose*: 20% to 30% of total daily morphine dose
• Daily oral morphine dose 100-300 mg: Estimated daily oral methadone dose: 10% to 20% of total daily morphine dose
• Daily oral morphine dose 300-600 mg: Estimated daily oral methadone dose: 8% to 12% of total daily morphine dose
• Daily oral morphine dose 600-1000 mg: Estimated daily oral methadone dose: 5% to 10% of total daily morphine dose.
• Daily oral morphine dose >1000 mg: Estimated daily oral methadone dose: <5% of total daily morphine dose.
• *in divided doses (commonly q12h, q8h or q6h)

• Subsequent switching from methadone to other opioids can be difficult. In one series 12/13 patients experienced increased pain±dysphoria.1

Conversion:

• See: http://pain-topics.org/pdf/OralMethadoneDosing.pdf
• See: http://www.palliativedrugs.com/methadone.html#guidelines

Dose Adjustments1,6:

• Renal and hepatic impairment do not affect methadone clearance.
• When considering the use of methadone, the difficulty of subsequently switching from methadone to another opioid should also be borne in mind.
• Methadone is an alternative strong opioid for patients with chronic renal failure who would be at risk of excessive drowsiness±delirium with morphine because of cumulation of morphine-6-glucuronide.2
• Methadone is poorly removed by haemodialysis.30 However, for moribund patients, alfentanil is probably a better choice.
• Unlike morphine or meperidine, the metabolism of methadone produces no active or toxic metabolites.
• Only a minor fraction of methadone is cleared by the kidneys. Except in end-stage renal failure, it is usually unnecessary to adjust the dose of methadone because of renal disease.
• For patients with severe chronic liver disease, the elimination half-life of methadone increases. However, mean plasma concentrations and dose-adjusted mean plasma concentration do not significantly differ from patients with mild or moderate liver disease (Säwe, 1986), and no dose adjustments are typically required for this degree of hepatic failure (Eap, 2002).

Monitor:

• sedation
• confusion
• respiratory depression

Other Side Effects:

• lightheadedness, weakness
• dry mouth, urinary retention, constipation
• sleep apnea (see http://onco-prn.blogspot.com/2009/10/medication-pearls-for-practice.html )

Interactions1:

• Methadone is principally metabolized by CYP3A4
• CYP2D6, CYP2C9, CYP2C19 and CYP1A2 may play minor roles
• MAOIs may prolong and enhance the respiratory depressant effects of methadone.
• Carbamazepine, phenobarbital, phenytoin and rifampicin increase the metabolism of methadone
• amitriptyline, cimetidine, ciprofloxacin, fluconazole and SSRIs decrease its metabolism
• Methadone increases plasma zidovudine concentration.
• Efavirenz, lopinavir-ritonavir, nelfinavir, nevirapine and ritonavir (all antiretroviral agents) may reduce plasma methadone concentrations.
• Other medications, especially the benzodiazepines, may act synergistically with methadone, increasing the apparent effect of methadone and likelihood for life threatening adverse events.
• Certain medications may potentially influence the concentration of methadone indirectly. For example, topiramate is a carbonic anhydrase inhibitor and increases urinary pH alkalinization; Topamax PI 2007). Alkalinization of urine has been shown to increase the half-life of methadone to an average of 42 hours (Baselt 2004). Therefore, when used concomitantly with topiramate, methadone may reach higher plasma levels.
• Check: http://pain-topics.org/pdf/OralMethadoneDosing.pdf
• Always check reliable drug interaction sources such as Lexicomp and Micromedex

Patient Handout:

• Great patient information (print page 4-5 of the document)

http://pain-topics.org/pdf/MethadoneHandout.pdf

Advantages:

• Inexpensive
• can use in patients with morphine allergy
• ok with renal patients
• generally less constipating
• more effective for neuropathic pain in comparison with other opioids
• suited for the management of difficult pain syndromes, particularly where activation of the NMDA recptors has resulted in CNS sensitization - hyperanalgesia and allodynia {Note: Without the d-isomer [racemic d- & l-isomer used in North America ] less impressive results may be observed.}

Interesting…

• 9th on list of most abused drugs in U.S. see: http://www.drugabuseclinic.org/methadone-abuse.html

Sources/References:

1. http://www.palliativedrugs.com/methadone.html
2. http://en.wikipedia.org/wiki/Methadone
3. Micromedex Online
4. Lexicomp Online
5. http://www.eperc.mcw.edu/FastFactPDF/Concept%20075.pdf
6. http://pain-topics.org/pdf/OralMethadoneDosing.pdf
7. Pallium Palliative Handbook 2008 www.pallium.ca

inical Effects

*NOTES:

Receptor > Clinical Effects:

• Mu (μ): Analgesia, Euphoria, Respiratory depression, Physical dependence, Miosis, Decreased gastric motility
• Kappa (κ ): Analgesia, Sedation, Respiratory depression
• Delta (δ): Analgesia, Dysphoria, Hallucinations

*Adapted from: Warfield and Fausett, 2002

*(one pt - I.R. – took 90 mg qid + 60 mg q2h for over 700 mg/day – max we’ve seen)