FDA "ADVISORY" AND MANUFACTURER’S “PATIENT INFORMATION” STATEMENT ON METHADONE FOR PAIN - FAR TOO LITTLE, FAR TOO LATE

On Nov. 27, 2006, FDA issued an "advisory" on methadone for the management of pain. It and the associated new "patient information" issued by Roxane Labs actually divert attention from the only major change that has recently been introduced: a marked reduction in "usual" starting dose from a maximum of 80mg to a maximum of 30 mg per day.

Neither the FDA Advisory nor the manufacturer's information sheet makes any reference to any specific dosages - let alone is there mention of the dramatic reduction in what is considered to be an appropriate "usual" starting dose. It's hard to imagine why, since this flurry of activity is clearly in response to the recognition that 80 mg on day one is potentially lethal. One would imagine banner headlines on both documents proclaiming 30 MG METHADONE IN FIRST 24 HOURS TOP OF THE RANGE FOR INITIATING TREATMENT FOR PAIN; HIGHER DOSES CAN HAVE FATAL OUTCOME. Sure, one would want to leave flexibility to the individual practitioner - but the generalization of high, potentially fatal, risk should have been highlighted and extreme caution urged before exceeding the “usual” range. Instead, as noted, dosages were not even mentioned! What did receive great attention, as reflected in the very title of the FDA advisory, are references to allegedly life-threatening "heart beat" irregularities, though we have been unable to identify a single report in the professional literature of any death attributed to methadone-induced cardiac effects.

So where does one find the dramatic new dosage references? Only on page 15 of a 17-page, very fine print, comprehensive, description of methadone (Dolophine, to be exact). There, under the heading "initiation of therapy in opioid non-tolerant patients,” is written: "...the usual oral methadone starting dose is 2.5 mg to 10 mg every 8-12 hours slowly titrated to effect." Until now, the same section read : 2.5-10 mg every THREE TO FOUR HOURS. Thus, the top of the range for initial management has been reduced from 80 mg to 30 mg – but no hint of this very substantial reduction is alluded to by either FDA or Roxane.

Clearly, the "advisory" and "patient information" notices are far too little in not spelling out up front precisely what new message must be heeded to protect patients. The notices are also far too late - certainly, too late for some of those patients who may have been prescribed the previously noted "usual" doses, and/or who relied on the FDA-approved "package inserts" that spelled out the same total day one range of 15-80 mg, and who may have suffered an overdose as a result. Note that a 2003 study (Ballesteros et al, JAMA, July 2, 2003) of deaths "due to methadone" in North Carolina, reported by CDC, found that of almost 100 patients for whom information was available "75% had been prescribed methadone by a physician." One can only speculate whether at least some of these deaths might have been avoided had the "usual" dosages specified by FDA and the manufacturer been consistent with what has been known for decades. Indeed, FDA itself puts a 30mg day one limit on starting doses of methadone for opioid-dependent (and thus opioid tolerant!) individuals beginning maintenance treatment (see, for example, the US Department of Health and Human Services “Treatment Improvement Protocol TIP 43," 2005, p. 67; and also the 1999 Federal Register, July 12, 1999, vol. 64, number 140, p 398401). The evidence regarding initial methadone dosages that are least likely to cause serious adverse effects is massive, consistent and worldwide; it was embodied years ago in the clear and concise Province of Ontario methadone maintenance guidelines: "START LOW, GO SLOW".