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Practical Guide to the Safe Use of Methadone

Methadone is an inexpensive, long-acting opioid that may be particularly beneficial in patients with neuropathic pain or opioid-induced hyperalgesia. However, methadone is challenging to use. This guide describes Methadone’s unique characteristics.
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Methadone’s unique pharmacokinetic and pharmacodynamic properties render it distinguishable from other opioids. While methadone can be more challenging than other opioids to use clinically, it also is potentially more helpful. Methadone’s pharmacokinetics and mechanism of action are more complex than those of other opioids. In addition, it carries risks, such as the potential for prolongation of the QTc interval, that are not associated with other opioids.

On the other hand, methadone’s low cost and unique mechanism of action make it more accessible, and potentially more beneficial, to patients. These characteristics enable methadone to be used in cases in which other opioids fail, whether due to patient allergy and intolerance, or lack of efficacy.

Why is Methadone Dosing So Challenging?

Methadone’s complex pharmacokinetics require close attention to detail to allow appropriate patient selection, initial dosing and titration, and monitoring. However, an understanding of these pharmacokinetics can allow practitioners to use methadone safely and take advantage of its therapeutic potential. Perhaps the most challenging aspect of methadone’s pharmacokinetics is its long and variable half-life.1-4 The half-life of methadone typically is between 15 and 60 hours, although it has been reported to be as long as 120 hours in some patients.1,3 Other pharmacokinetic considerations for methadone include its absorption, distribution, metabolism, and elimination.

Conversions from other opioids to methadone are non-linear, and patients who are stable on a dose of another opioid often show incomplete tolerance to methadone.3 Methadone also has the potential to interact with many other medications, so patients’ medication regimens must be reviewed carefully before and during methadone therapy.

Lastly, methadone is associated with potential cardiac toxicity. Specifically, methadone can cause prolongation of the QTc interval, which can lead to Torsades de pointes, a potentially fatal cardiac arrhythmia.1-3,5,6 Since 2000, methadone has been second to dofetilide in cases of drug-related arrhythmia reported to the US FDA Adverse Event Reporting System.1

Is It Worth It? The Benefits of Safe Methadone Use

Like all other opioids, methadone is an agonist at the µ opioid receptor, making it a strong analgesic through modulation of the perception of pain. In addition to modulating pain via the µ opioid receptor, methadone also exerts analgesia by blocking the reuptake of the neurotransmitters serotonin and norepinephrine in the synaptic cleft.7 Increasing the availability of serotonin and norepinephrine in the central nervous system (CNS) has been proposed as a mechanism of providing analgesia, particularly for neuropathic pain.7 Methadone also acts as an antagonist at the N-methyl-D-aspartate (NMDA) receptor.2-4,7 Activation of the NMDA receptor has been implicated in the development of opioid-induced hyperalgesia and central sensitization, both of which perpetuate chronic neuropathic pain.2,4,7,8 Methadone’s complex mechanism of action makes it particularly useful in patients with neuropathic pain or opioid-induced hyperalgesia.

While challenging to use in practice, methadone has great potential to relieve pain. Methadone’s low cost and long duration of action make it a therapeutic option for patients without access to other, more expensive, long-acting opioids formulations.4,7-10 As a synthetic opioid with a distinct chemical structure, methadone is also safe for use in patients with a true allergy to morphine and other phenanthrenes.2 Methadone is available in oral tablets, oral solution, and intravenous formulations.2,7 It is the only long-acting opioid available as an oral solution, including a highly concentrated (10 mg/mL) oral solution; this formulation makes long-acting therapy available to patients unable to use tablets or capsules.2,7

Compared to other opioids, methadone has been proposed to have a lower incidence of some adverse events (AEs), including myoclonus, constipation, and nausea.7,8 In patients with renal failure, methadone is considered one of the safest opioids, because only about 20% of a dose is eliminated unchanged by the kidneys and it does not have active metabolites.2,4,7

How to Use Methadone Safely

To use methadone safely, a clinician must have a thorough understanding of all its unique characteristics. To ensure patients receive maximum benefit with minimum risk of harm, clinicians must identify appropriate candidates for methadone therapy and monitor patients diligently.

Patient Selection

Methadone’s unique characteristics make it potentially beneficial for many patients, particularly patients who have a true morphine allergy or have experienced intolerable AEs with other opioids, as well as patients with neuropathic pain, pain that is not controlled with other opioids, and renal insufficiency or failure.2 Methadone also is a good option for patients who need low cost, long-acting opioid therapy.2 However, due to methadone’s long half-life and the resulting prolonged time to maximal therapeutic efficacy, patients with a very limited life expectancy
(ie, <1 week), may not receive the full therapeutic benefit of methadone.

Methadone’s unique pharmacokinetics also require patients to take their medications reliably, without self-adjusting their doses. Patients with questionable adherence to therapy or lacking social support are at greater risk of methadone AEs, and, therefore, are not good candidates for methadone therapy.1,2 When considering prescribing any opioid, clinicians should assess patients for their risk of substance misuse, abuse, and addiction.1,11 In addition, patients who take interacting drugs or other QTc-prolonging agents, or who have a history of syncope or cardiac arrhythmias, also are at greater risk of methadone-associated AEs.2

Last updated on: April 14, 2015
First published on: March 1, 2015