April 5, 2012 — Opioid rotation — switching from one opioid drug or route of administration to another to improve the outcome — is largely to blame for the growing number of unintentional deaths related to opioids, a new review suggests.
The review cites evidence of a link between opioid-related deaths and common opioid rotation practices, including the use of dose-conversion ratios published in equianalgesic tables.
Opioid rotation is flawed, said study coauthor Lynn R. Webster, MD, president elect of the American Academy of Pain Medicine and medical director and founder of Lifetree Clinical Research, Salt Lake City, Utah. Although using conversion tables is harmless in most cases, "this is an area where the harm has such devastating consequences — death — that we cannot accept even a 1% error," said Dr. Webster.
Along with his coauthor, Perry G. Fine, MD, Pain Research Center and Pain Management Center, University of Utah, Salt Lake City, Dr. Webster reviewed the literature and found several case reports of opioid-related deaths or "near misses."
The review was published online March 28 in Pain Medicine, the official journal of the American Academy of Pain Medicine.
In an accompanying article published at the same time in the same journal, Dr. Webster and Dr. Fine suggest a slower and potentially safer method for switching opioids.
Painkiller Overdoses
Almost 15,000 people die every year as a result of overdoses involving prescription painkillers, with that number exceeding deaths from heroine and cocaine combined, according to a Centers for Disease Control and Prevention report. The US Food and Drug Administration (FDA) found that opioids, including oxycodone, fentanyl, morphine, methadone, and acetaminophen/hydrocodone, accounted for 5 of the 15 drugs most frequently named in fatal outcomes.
According to the new review, most proposed protocols for opioid rotation involve the use of equianalgesic dosing tables to convert the dose of the original opioid to a putative equivalent dose of morphine. That dose is then converted to that for the new opioid, with a safety margin incorporated.
One of the problems is that the most widely accepted guideline for opioid rotation was developed many years ago. At the time, experts believed that the relative strength of one opioid compared with that of another in the chronic state would be the same as that in the acute state, said Dr. Webster. "In other words, we didn't take into account that people would develop a tolerance, and certainly until just recently, we never knew about the genetic issues."
Not only did most studies use a single dose or a limited range of doses, they also investigated only a specific route. Thus, the findings aren't generalizable to other routes. Further, the studies didn't account for responses based on ethnicity, advanced age, concomitant medication use, or comorbid conditions.
"The key issue is that every human being has a different sensitivity to every different opioid molecule," said Dr. Webster. "So the way you respond to morphine will be different to the way that I respond to morphine, even in the acute state."
The rotation protocol has never been formally validated for safety or efficacy, added Dr. Webster. "There has never been an attempt to determine what is an equal analgesic of 1 opioid over another for chronic use — for example, after someone has been on a drug for 6 months or a year or 2. There is no research that has demonstrated consistently, across the board, that these tables have any validity."
Relying on tables derived from single-dose studies is especially problematic with repeated dosing of methadone. The authors noted the FDA's public health advisory on deaths and life-threatening changes in breathing and heart rate in patients newly started on methadone.
Although prescribing a new pain reliever might be necessary because of loss of effectiveness or side effects, in many cases the switch is called for because an insurer no longer covers a particular drug, said Dr. Webster. "So doctors have been forced to move to less costly drugs, and the least costly is usually methadone."
Gambling With Life?
Contributing to the problem is that published equianalgesic tables have inconsistent and variable conversion ratios. In addition, dose conversion guidelines found in package inserts for opioids, particularly the newer extended-release opioids, are inconsistent and potentially dangerous, said Dr. Webster.
He used the example of hydromorphone (Exalgo, Mallinckrodt/Covidien); the language of the insert is such that the conversion would result in 1 of 3 options, he said: an underestimate of the amount of extended-release hydromorphone necessary for adequate analgesia, an overestimate of the necessary amount that could increase the risk for overdose, or a dose within a reasonable window.
This, said Dr. Webster, boils down to "guessing" or "gambling" on the part of the clinician. "When we're dealing with a life, we should not be gambling."
Prescribing competence is "shockingly inadequate," said the authors. Errors can stem from inadequate education, lack of attention to detail, and calculation errors.
Confusion can also contribute to the problem. A survey of 406 non–pain specialist physicians found that 59% had difficulty calculating opioid dosages when rotating. When asked to convert a daily dose of 60 mg oxycodone to the dose for a fentanyl patch, 41% of clinical specialists, 28% of general practitioners, and 17% of geriatric care physicians said they "don't know" how to do that.
Physicians may be lulled into believing that conversion tables are safe and appropriate. "We like to have things structured in medicine," said Dr. Webster. "These tables were established to some degree to provide some security and safety and guidance toward rotating, but the irony is that they've actually made it unsafe."
Research suggests that 50% to 80% of patients with chronic pain who respond poorly to one opioid improve after being rotated to another opioid.
In their second report, a clinical case also published in Pain Medicine, Dr. Webster and Dr. Fine suggest an alternative to using opioid-rotation tables.
The best approach, they suggest, is to decrease the first drug by 25% to 30% per week while introducing the new drug at a dose that would be given to an opioid-naive patient, increasing the dose according to the clinical response, said Dr. Webster. "In many instances, it may take 3 to 4 weeks to rotate from one opioid to another," he said.
If patients are experiencing pain during the switch, physicians should give an immediate-release opioid to help "bridge" inadequate dosing.
He cautioned that some patients may be sensitive to the new drug. "A new molecule may be highly effective at a very low dose."
Hold Next Dose
Seddon Savage, MD, medical director, Chronic Pain and Addiction Program, Silver Hill Hospital, New Canaan, Connecticut, and president of the American Pain Society, agrees with this slow rotation protocol.
She added that patients should be told that if they feel sedated they should hold their next opioid dose and call their physician.
Dr. Savage commented that the review paper does a good job of pointing out and documenting the problems related to opioid rotation and of making physicians more aware of the limitations of conversion tables.
"One of the points that the authors make is that there is a lot of variability in response to different opioids. If you take these opioid conversion tables as gospel, apply them indiscriminately to all people, and just do a mathematical conversion, you will end up with some people for whom the conversion aren't appropriate."
For a list of companies from which Dr. Webster has received funding, and for conflict of disclosures for Dr. Fine, please see original paper.
Pain Medicine. Both articles published online March 28, 2012. Abstract Abstract
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