Mathematical Model For Methadone Conversion Examined
Opioid analgesics have long been the mainstay, both domestically and abroad, for treating moderate to severe pain from a variety of etiologies.1 Historically, morphine has been the first-line opioid agent. Today, it is the standard to which all other opioids are measured due to its ubiquity, availability for essentially every possible route of administration, and clinician familiarity. Morphine demonstrates those attributes most coveted in a drug therapy: it undergoes straightforward pharmacokinetics with two well-elucidated metabolites; is effective, inexpensive, and widely available; and it has been safely used for nearly 200 years in Western medicine. Although morphine once stood prominently at the center of the opioid analgesic toolkit, it is now beset by new opioid agents, reformulations of erstwhile agents, new non-opioid therapies, and new insights into the enigmatic world of pain management.
The importance of a broad and variable assortment of formulations, mechanisms, and pharmacokinetic profiles is clear to any pain management clinician. For although morphine may be the established gold standard, the majority of chronic pain patients with moderate to severe pain will not be controlled and maintained on their initial opioid analgesic, and often will receive medications with varying pharmacological mechanisms to maximize therapeutic benefit.2-4There is a considerable degree of inter-patient variability in response to opioid therapy and in an effort to maximize efficacy and reduce opioid-related toxicity and drug interactions, numerous agents are frequently tried before a patient reaches their pain management goals.5,6
The Role of Methadone
As clinicians and researchers attempt to expand their pain management repertoire to better treat the specific nuances of each patient, it is not just toward the future that they gaze. Methadone, a µ-opioid agonist with a unique N-methyl-D-aspartate (NMDA) receptor antagonist profile, was developed in Germany in 1937 and expropriated to the Allies following World War II. In 1947, Eli Lilly and Company purchased the rights to the compound for $1, and methadone became widely available in the United States.7 Perhaps to its detriment, methadone originally found its niche in the treatment of opioid dependence, a stigmatization that follows the drug to this day.8 Nonetheless, methadone has grown in popularity as a viable option for the treatment of moderate to severe chronic pain.9
The myriad benefits to methadone therapy for severe chronic pain are clear. It is relatively inexpensive, has excellent oral bioavailability, high potency, no known active metabolites, and a receptor activity profile unique enough to allow for effective analgesia in patients intolerant or unresponsive to many other opioids. Methadone has potent µ-opioid analgesia, but is unique for NMDA receptor antagonism and modest norepinephrine reuptake inhibition. The benefit of NMDA receptor antagonism in neuropathic pain has been well established, allowing methadone particular usefulness in chronic pain with neuropathic components.10
Unfortunately, these benefits must be weighed against an intimidating combination of concerns that limit methadone’s use among inexperienced practitioners. The elimination half-life of methadone is significantly longer than its analgesic effect, which may potentiate toxic drug accumulation with too frequent dosing or attempts at rapid escalation.11 Methadone requires slow dose escalation for several days or weeks to achieve optimal analgesic response. Even at unchanged doses, one may not realize benefit for several days because of the complex pharmacokinetics including high and variable volume of distribution, long half-life, and resultant time to steady state.12 Methadone is partially metabolized through the cytochrome-P450 enzyme system, which may cause a fluctuation in serum concentrations in response to concomitant inducers or inhibitors of the same enzymes.12 In addition, methadone is extensively protein-bound, with the active drug being free in the serum. Other extensively protein-bound drugs have the potential to displace methadone from its binding sites.12
Methadone may prolong the QTc interval in some patients, particularly those who are receiving high methadone doses combined with tricyclic antidepressants and/or other agents that may affect myocardium electroconductivity.13Compounding these concerns, perhaps the most pressing to inexperienced practitioners is accurate and safe dosing, or more specifically, how to convert from another opioid analgesic to methadone or from methadone to another opioid. Unfortunately, conversion to or from methadone is not bi-directional. After discontinuing methadone, it remains in the serum for several days. Therefore, an abrupt switch to an alternate opioid will result in double dosing even in the absence of further methadone doses.
There has been some contention regarding the equianalgesic dose ratio (EDR) between oral morphine and oral methadone within the literature.14 Different authors have reported three varying methadone conversion schematics, all of which have been based on small sample sizes.15-17 There is a great deal of genetic polymorphism resulting in broadly varying inter-patient variability both pharmacodynamically and pharmacokinetically with opioids, including methadone. For these reasons, no specific formula or methadone conversion guidelines are sanctioned due to lack of replicated data in larger-scale controlled studies for which a priori power analyses have been done. Notwithstanding, these schematics have been routinely employed by clinicians in an attempt to titrate methadone. Although the authors caution and discourage endorsing any specific methadone conversion strategy, each previous attempt may certainly provide tentative starting points.
The first of these conversion strategies was published by Ripamonti et al in 1998.15 Being one of the first widely distributed studies of morphine to methadone conversion, it provided useful guidance, but had several significant limitations. As of 1998, methadone’s use for analgesia was limited predominantly to cancer-related pain and heroin maintenance, the former of which is reflected in the investigators’ population. In addition, the sample size included only 38 patients. Despite this, the study offered a tentative starting point and clearly established that the equianalgesic dose ratio between morphine and methadone was significantly more capricious than previously thought. The median dose ratio was found to be 7.75:1, with a 1:1 ratio found to be inappropriate for any patient, regardless of previous morphine requirements. The findings from the investigators’ study are summarized in Table 1.