Methadone in the ED

[Feature image via WeeMikey]

In my current practise environment, a LOT of my patients are on long term methadone replacement. Indeed such is the unique nature of our local population that there’s quite a lot of research into intravenous drug use and even HIV. In a few years if my smart colleague gets all the data together,  we’ll hopefully be able to tell you exactly what proportion of people are on methadone attending the ED.

It’s so ubiquitous amongst our patients that most don’t even consider it a medication. When you ask someone one if they take any regular medication, people will frequently not mention the fact that they take the OCP. The same goes for methadone, and even LMWH which a lot of our patients receive daily for their IDU (injecting drug use) associated VTE (venous thromboembolism).

Methadone is a fascinating little drug, both in regular use and in overdose so here’s a summary:

History

• developed in Germany during world war II as a synthetic alternative to morphine as morphine was hard to obtain
• used for opioid treatment programs, chronic pain, and palliative care.

Use in opioid treatment programs

• usually provided as a directly observed medication in  a pharmacy or drug clinic. In our part of the world it’s green like fairy liquid. The concentration can be altered so that even when receiving the same volume a bigger does is given.
• The aim is usually long term rather than a short term detox. To come off methadone is normally a process that is meant to take months-years.
• There is  good evidence of effect on reduced relapse and possibly even mortality

Mechanism

• mu opioid receptor agonist
• NMDA receptor antagonist. The NMDA part is thought to attenuate opioid tolerance

Pharmacokinetics/dynamics

• Volume of distrubution 4 L/kg. This is realatively large and all you need to know is that is widely distributed in the tissues. This is one of the reasons for its long half life as it leaks back into the circulation from the tissues over time.
• Elimination: mainly by oxidative biotransformation – which means it’s coverted into lots of metabolites, some active, some inactive. The metabolites and indeed methadone itself mainly leave in the wee wee.
  • of note there are, as usual, some problems with the urine testing. Some urine tox kits will test methadone separately from other metabolites. This is obviously a good way to monitor abstinence from illicit opioids. But like all urine testing – you need to know your test characteristics.
• Half-life ranges from 5-130 hrs (which is a massive range) though the mean is around 30 hrs. There are a lot of issues with dosing in the early stages and can lead to significant accumulation and it has been noted in several papers that numerous death have occurred in the first week of methadone therapy.

Interactions

• CYP3A4 inducers will increase methadone metabolism and reduced clinical effect
  • eg carbamazepine, phenytoin and some anti-virals
• CYP3A4 inhibitors will reduce metabolism and increase clinical effect (where the real harm happens, either from resp depression or prolonged QT)
  • these include fluconazole, a bunch of HIV drugs and erythromycin

Chronic Side Effects

• constipation
• diaphoresis
• drowsiness
• Prolonged QT
  • a lot of people on methadone will have a prolonged QT. Like a lot of long QTs we find it’s likely meaningless. The risk probably comes with interactions with other drugs. If someone is on methadone and we add a drug that is also know to prolong the QT then there might be problems. Personally I doubt there’s an epidemic of torsades happening out there related to methadone and prolonged QT but it’s worth thinking about. [UPDATE ToxTalk thinks the QTc prolongation might be a real and important thing]
  • the mechanism is related to hERG K+ channel. I know – that’s just changed your whole world right there hasn’t it?…

In overdose

• as always with toxicology studies, it’s a mish mash of autopsy, animals and chart reviews. Not exactly the highest standard of evidence
• Methadone is commonly found in fatal ingestions and is most commonly found with benzos. Bottom line – benzos and methadone in an OD are a bad combo.
• Onset appears to usually be within the first few hours and one chart review found that everyone who got sick did so within the first 24 hrs
  • as a result it has been frequently recommended to me that methadone ingestions warrant admission for at least 24 hr observation (ToxBase recommend this for all symptomatic patients) unlike standard heroin toxicity, where people are normally fit for discharge fairly quickly.
  • the other recommendation is not to be too reassured by response to naloxone. Naloxone will indeed reverse some of the opioid effects, maybe just enough to allow them to abscond from the department just in time for the naloxone to wear off and the methadone to kick back in and they collapse and die in a corner. This happens. In general the best way to titrate your naloxone is breathing but still mainly unconscious.
• just like heroin, non-cardiogenic pulmonary oedema can occur

Comments or corrections welcome as ever.

References:

Miscellaneous Methadone Facts James R Roberts Emergency Medicine News March 2009

Opioid Treatment of Opioid Addiction. McDonough, Michael. Australian Prescriber (June 2013): 1–5.

Lugo, Ralph, Kristin Satterfield, and Steven Kern. “Pharmacokinetics of Methadone.” Journal of Pain & Palliative Care Pharmacotherapy 19, no. 4 (January 6, 2005): 13–24. doi:10.1300/J354v19n04_05. PMID 16431829

EM:RAP June 2012 Bouncebacks

Moody, David E. “Metabolic and Toxicological Considerations of the Opioid Replacement Therapy and Analgesic Drugs: Methadone and Buprenorphine.” Expert Opinion on Drug Metabolism & Toxicology 9, no. 6 (June 2013): 675–697. doi:10.1517/17425255.2013.783567. PMID 23537174 [WARNING – lots of complicated chemical structures and biochem in this one]

LoVecchio, Frank, Anthony Pizon, Brad Riley, Azadeh Sami, and Carmella D’Incognito. “Onset of Symptoms After Methadone Overdose.” The American Journal of Emergency Medicine 25, no. 1 (January 2007): 57–59. doi:10.1016/j.ajem.2006.07.006. PMID 17157684

ToxBase 

Gruber, Valerie A, and Elinore F McCance-Katz. “Methadone, Buprenorphine, and Street Drug Interactions with Antiretroviral Medications..” Current HIV/AIDS Reports 7, no. 3 (August 2010): 152–160. doi:10.1007/s11904-010-0048-2. PMCID 2892618 [Open Access]

Methadone’s Cardiotoxicity. Notes from Dr RW