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Methadone: Biological Mechanisms, Surgical Applications, and Side Effects

By April 17, 2020 No Comments

Methadone (also known as Dolophine), is a synthetic opioid that is commonly used during cases of opioid dependence as well as for other chronic pain therapy. Developed in the late 1930s in Germany, it was approved for usage in the US in 1947. Since then, methadone quickly became the analgesic drug of choice for opioid detoxification and maintenance of patient groups dependent on opioids (particularly heroin)1. Pharmacologically, methadone works in a similar manner as morphine.1 As a mu-opioid receptor antagonist, it mimics the activity of endogenous opioids/enkephalins/endorphins and affects neurotransmitter release (acetylcholine, norepinephrine, substance P, and dopamine).1 Furthermore, methadone is a strong N-methyl-D-aspartate (NMDA) receptor antagonist.2,3 In the racemic mixture of the R and S enantiomers, R-methadone is responsible for most (if not all) of the analgesic effects.4 R-methadone has been found to have around ten times higher affinity for the mu 1, 2, receptors, as well as the delta receptor in comparison to S-methadone.4 This binding profile of the R-specific enantiomer resembles that of morphine, except for a lower kappa receptor affinity.4  

Administration of methadone can be achieved through oral or parenteral routes.5 A common application of methadone is as maintenance therapy for heroin addicts. By substituting heroin, which has a high risk of morbidity and mortality, with the legal methadone, patients are able to circumvent opiate withdrawal symptoms and heroin cravings5. Methadone can also be used in the treatment of chronic pain.2 Due to the shorter analgesic period (4-6 hours) of methadone relative to its half-life when given in a smaller dosage (5-10 mg), chronic pain treatment requires more frequent dosing. In terms of intraoperative usages, methadone has been shown to significantly reduce postoperative analgesic requirements, in comparison to shorter-acting opioids5. For example, with dosages of 20 mg or more, the half-life length can be favorably compared to the clinical effect (around 35 hours).5 Through an intravenous administration, methadone equilibrates in the central nervous system rapidly, causing a rapid onset of analgesia. Major surgeries (spin, open abdominal, thoracic) require higher dosages (20 mg) of methadone, while moderate surgeries (laparoscopic procedures) require around 10 mg of methadone.5 Generally, a single dose of methadone, administered at induction, is sufficient to provide analgesic effects.1  

Side effects of methadone through long-term use include sweating, constipation, disturbance of appetite leading to weight gain, sexual dysfunction, sedation, insomnia, and hypoventilation, among others.1 Most severe side effects include apnea, respiratory failure, hypoxia, and subsequent coma/seizures/death.1 However, these consequences are predominantly caused by high doses of methadone. However, due to the fact that methadone acts on central opioid receptors, respiratory depression is a potent consequence that should be carefully monitored.6 Toxicity can also occur from incorrect dosing (more frequent dosing), due to the long half-life of the drug and accumulation.5  

Drug usage can also interfere with methadone efficiency, particularly in regards to drugs that impact liver enzymatic metabolism.5 In contrast, binge alcohol drinking can prevent sufficient metabolism of methadone, leading to increased risk of respiratory depression.5 Tapering of methadone can minimize withdrawal symptoms, with tapering not exceeding 1 mg per day.1 Opioid withdrawal effects can be mitigated through symptomatic treatments.1 

Methadone is an important analgesic that has analgesic applications in the intra-operative and post-operative space. Safe and effective use of this drug requires understanding of its pharmacokinetic profile, potential side effects, and possible drug interactions to reduce any possible risk.  

References: 

1.Anderson, I. & Kearney, T. Use of methadone. West J Med 172, 43–46 (2000). 

2.Brown, R. Methadone: applied pharmacology and use as adjunctive treatment in chronic pain. Postgraduate Medical Journal 80, 654–659 (2004). 

3.Doi, S. et al. Characterization of methadone as a β-arrestin-biased μ-opioid receptor agonist. Molecular Pain 12, 174480691665414 (2016). 

4.Kristensen, K., Christensen, C. B. & Christrup, L. L. THE MU~,MU2, DELTA, KAPPA OPIOID RECEPTOR BINDING PROFILES OF METHADONE STEREOISOMERS AND MORPHINE. 56, 6 (1995). 

5.Murphy, G. S. & Szokol, J. W. Intraoperative Methadone in Surgical Patients: A Review of Clinical Investigations. Anesthesiology 131, 678–692 (2019). 

6.Hunt, G. & Bruera, E. Respiratory depression in a patient receiving oral methadone for cancer pain. Journal of Pain and Symptom Management 10, 401–404 (1995).