Friday, July 4, 2008

Methadone, methadone, methadone

Three recent methadone-related reviews, two by the same group, are well worth the reading. The first two, on conversion ratios and drug-drug interactions, respectively, are the long-awaited published versions of presentations made at the AAHPM/HPNA conference in Salt Lake City in 2007. They are among the most thorough and well-organized reviews on any topic that I have read in recent years. The third is a consensus guideline on parenteral methadone in palliative care.

Methadone conversion ratios:
The authors reviewed clinical trials, retrospective analyses, case reports, and case series published from 1996 to 2006; reviews were excluded. A total of 41 papers (22 studies, 19 case reports; N = 730) were reviewed. None of the studies were deemed to be of high value. Not surprisingly, they identified the heterogeneity of studies as the biggest challenge in their analysis. Not only were different methods and populations used, as well as different descriptive statistics and outcome definitions, but different conversion values and tables for non-methadone opioids were used. While most suggested conversion procedures recommend converting all opioids to morphine equivalents, some use oral equivalents and some use parenteral equivalents. Rather than just throwing up their hands in frustration, the authors recalculated many of the formulas presented, using consistent values.

It should be well known by now that there is not a simple ratio of morphine to methadone that works at all dose levels. Most studies stratified patients according to the pre-rotation morphine-equivalent dose because of the “dynamic inverse potency relationship between methadone and other opioids.” The most common ratios reported were 4:1 and 10:1; the review authors estimate that 30% of all patients were converted using one of these ratios. However, the reported range was 4:1 to 37.5:1.

Using scatter plots, the authors sought to determine the correlation between prerotation morphine dose and the morphine: methadone ratio. They identify a “strong, positive linear relationship between the prerotation morphine dose and the postrotation methadone dose,” but the dose ratio is not constant in relation to the previous morphine dose. When attempting to apply these findings to individual patients, there is confounding due to large interindividual pharmacokinetics with methadone. They emphasize that the “care process” or conversion procedure as well as the calculation of dose ratios varies considerably across studies. “It may be less important to determine an exact opioid ratio . . . than to be sure that the patient is an appropriate candidate for methadone rotation, the switch is carried out over a time period consistent with the therapeutic goals, and that the patient is monitored closely by medical staff throughout the process.” They note that there is no consensus regarding the various published methods of conversion, but that the majority of patients are successfully rotated in all settings regardless of method employed and ratio used.

There is also acknowledgement that conversion ratios are not bidirectional and that there is almost no guidance in the literature for conversion from methadone to another opioid.

Finally, there is a long discussion of the deficits in the research literature and suggestions for the future direction of research.

I’m not sure that anyone already experienced in methadone conversions will change his/her clinical practice because of this paper, but it may well provide rationales for teaching and encouragement for reseach.

Weschules DJ, Bain KT. A Systematic Review of Opioid Conversion Ratios Used with Methadone for the Treatment of Pain. Pain Med. 2008 Jun 18. [Epub ahead of print] DOI:10.1111/j.1526-4637.2006.00289.x

Methadone drug-drug interactions:
This is an advanced primer in the clinical science of managing patients on multiple drugs, especially when one of them is methadone. It should be in everyone’s teaching and reference files. The paper includes:

  • Eye-opening dissertation on just how complex methadone metabolism is
  • Good description of the cytochrome-P 450 (CYP450) enzyme system in drug metabolism
  • Other mechanisms—including some that are pretty esoteric—that can affect how methadone is absorbed, metabolized or eliminated, including the effect of changes in urine pH
  • The important effect of the order in which drugs are added—or removed—from a regimen
  • Theoretical vs clinically observed interactions
  • Class-by-class descriptions of actual or potential interactions
  • Limitations of the evidence base
  • The fact that pharmacy drug-drug interaction checkers can pick up an interaction when a drug is added but not when it is removed from a regimen

Weschules DJ, Bain KT, Richeimer S. Actual and potential drug interactions associated with methadone. Pain Med. 2008 Apr;9(3):315-44. DOI:10.1111/j.1526-4637.2008.00461.x

Parenteral methadone use:
The consensus panel are almost all very well-known pain and/or palliative care clinicians. They review the very limited literature specific to parenteral methadone, then suggest clinical approaches to optimize it’s use. The paper includes a pretty extensive discussion of the implications for QTc interval changes and the risk of torsades de pointes. This paper doesn’t compare in thoroughness to the other two, but it is a useful review and probably unique in its focus specifically on parenteral methadone.

Shaiova L, Berger A, Blinderman CD, Bruera E, Davis MP, Derby S, Inturrisi C, Kalman J, Mehta D, Pappagallo M, Perlov E. Consensus guideline on parenteral methadone use in pain and palliative care. Palliat Support Care. 2008 Jun;6(2):165-76.