Pain, Palliative Care

Know thy Apps. Their role in Opioid Conversions!!

Methadone is still the opioid with which I am most cautious. Yesterday in clinic we were talking about its use, conversion and risks as we were seeing a woman who was on Methadone 20 mg tid with a diagnosis of cervical cancer.

Methadone is the opioid most commonly associated with opioid deaths in the US from the CDC data.  Lack of physician education about this drug and its pharmacology are one part of the problem, especially with its long  and variable half life.  There has also been considerable literature as to its conversion ratios from morphine and other opioids.  How accurate is your conversion ratio?

A true story.  Fourteen years ago, we converted a patient from 360 mg of oral morphine equivalents to methadone.  All of the conversion charts used at that time suggested the  conversion ratio of Morphine 30 mg = Methadone 20 mg.  So dutifully the oncology fellow and the pharmacist spent some time doing the conversion, yes methadone 240 mg daily written as 80 mg three times per day.  A few hours later the first dose, her respiratory rate dropped and she ended up ventilated in the ICU for two days…..  Iatrogenic methadone overdose because that conversion ratio is based on a single dose conversion and does not take into factors of drug accumulation.

What dose should this woman have got? We went to the literature and the colleagues from Italy were doing the most work on this and I continue to use the Ripamonti conversion.

  • <  90 mg morphine equivalent                       4:1

  • 90-300 mg morphine equivalent                   8:1

  • > 300 mg morphine equivalent                    12:1

So this woman should have received, 30 mg/day or 10 mg tid.  Our conversion charts have been corrected and significant education undertaken.  But perhaps we need to do that again.  Why? We went to a popular app that does opioid conversions (900,000 downloads as of last week).  The suggested dose in senario? 360 mg morphine = 240 mg Methadone.     WRONG!!!!   We did try another app that came up with 30 mg!!

Some call me a geek.  I love this technology stuff.  But they do not replace the factual knowledge.  Check the information and formulas that are being used.  Notify the builders.  Play your part in reducing the risk of opioids for your patients.  Not the only cause but this could be a factor contributing to deaths associated with opioids.

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Improving global pain relief by achieving balanced access to opioids worldwide


6 thoughts on “Know thy Apps. Their role in Opioid Conversions!!

  1. Could you share which apps you tried — and which apps had the correct conversion?

    Posted by Pamela Ressler | December 14, 2011, 10:06 PM
  2. Methadone is a synthetic μ opioid receptor agonist
    Schedule II medication; in addition to its opioid
    receptor activity, it is also an antagonist of the Nmethyl-
    D-aspartate (NMDA) receptor. Methadone is a
    racemic mixture of 2 enantiomers; the R form is more
    potent, with a 10-fold higher affinity for opioid receptors
    (which accounts for virtually all of its analgesic
    effect), while S-methadone is the NMDA antagonist.
    The inherent NMDA antagonistic effects make it potentially
    useful in severe neuropathic and “opioid-resistant”
    pain states. The S isomer also inhibits reuptake
    of serotonin and norepinephrine, which should
    be recognized when using SSRIs and TCAs. Although
    it has traditionally been used to treat heroin addicts,
    its flexibility in dosing, use in neuropathic pain, and
    cheap price has lead to a recent increase in its use. Unfortunately,
    a lack of awareness of its metabolism and
    potential drug interactions, as well as its long half-life,
    has lead to a dramatic increase in the deaths associated
    with this medication.
    Methadone is a unique synthetic opioid, unrelated
    to standard opioids (leading to its usefulness in
    patients with “true” morphine allergies). It is a basic
    and lipophilic drug with an excellent (though highly
    variable) oral bioavailability (from 40% to 100%). It
    can be crushed or dissolved to deliver down an NG
    tube and is also available in a liquid. Methadone is
    metabolized in the liver and intestines and excreted
    almost exclusively in feces, an advantage in patients
    with renal insufficiency or failure. Because of its high
    lipid solubility, it is redistributed to the fat tissues, and
    has a very long elimination phase, with a half-life of
    12 to 150 hours. It may also cause less constipation
    than morphine, and it is very inexpensive .
    The metabolism of methadone is always variable.
    Methadone is metabolized by CYP3A4 primarily and
    CYP2D6 secondarily; CYP2D6 preferentially metabolizes
    the R-methadone, while CYP3A4 and CYP1A2
    metabolize both enantiomers. CYP1B2 is possibly involved
    and a newly proposed enzyme CYP2B6 may
    be emerging as an important intermediary metabolic
    transformation . CYP3A4 expression can vary up
    to 30-fold, and there can be genetic polymorphism
    of CYP2D6, ranging from poor to rapid metabolism.
    The initiation of methadone therapy can induce the
    CYP3A4 enzyme for 5 to 7 days, leading to low blood
    levels initially, but unexpectedly high levels about a
    week later if the medication has been rapidly titrated
    upward, and an intestinal CYP3A4 transport enzyme
    may also be involved. A wide variety of substances can
    also induce or inhibit these enzymes (Tables 4 and 5).
    The potential differences in enzymatic metabolic
    conversion of methadone may explain the inconsistency
    of observed half-life. Methadone has no active metabolites,
    and therefore may result in less hyperalgia,
    myoclonus, and neurotoxicity than morphine. It may
    be unique in its lack of profound euphoria, but its analgesic
    action (4-8 hours) is significantly shorter than
    its elimination half-life (up to 150 hours), and patient
    self-directed redosing and a long half-life may lead to
    the potential of respiratory depression and death.
    Methadone also has the potential to initiate Torsades
    de Pointes, a potentially fatal arrhythmia caused
    by a lengthening of the QT interval. Congenital QT
    prolongation, high methadone levels (usually over 60
    mg per day), and conditions that increase QT prolongation
    (such as hypokalemia and hypomagnesemia)
    may increase that risk .
    There is an incomplete cross-tolerance between
    methadone and other opioids. Even when prescribed
    in low doses, and used appropriately by individuals
    experienced with opioids, the long half-life of methadone
    may be underestimated while dosing is titrated
    to analgesic effect. In general, better relief is observed
    with methadone doses that are 10% of the calculated
    equianalgesic doses of conventional opioids.
    Additional interactions may be seen with venlafaxine
    (a known CYP3A4 inhibitor).

    Posted by Mark S. Barletta | December 15, 2011, 6:08 PM
  3. So if I was taking 240 of morphine oral…..2 of 75mgs tid and 1 of 90 tid…..I shud take only 30mgs tid…..right

    Posted by javier cervantes | February 12, 2012, 4:33 PM
  4. MedCalc (the medical calculator featured implicitly in your piece) has been updated and now contains a fix that calculates methadone equivalence (with the Ripamonti conversion). Please test it and see if it fits your needs.

    Posted by Mathias Tschopp | October 14, 2012, 9:12 AM

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