Nancy A. Melville

September 25, 2012

September 25, 2012 (Phoenix, Arizona) — Patients with chronic pain who require high doses of opioids to achieve pain relief show exceptionally high rates of defects of the cytochrome P450 (CYP450) enzyme system compared with the general population.

The CYP450 enzyme system is known to play an important role in the metabolism of opioids, and recent advances in genetic testing allow for the easy detection of defects to the enzymes.

"We've known for years that among patients with the exact same pain conditions one may need 500 mg of morphine a day while the other may need only 50 mg, but we've always wondered why," lead author Forest Tennant, MD, told Medscape Medical News.

"It turns out that among high-dose patients, about 85% have these defects in 1 or more of their CYP450 enzymes." In the general population, only about 20% to 30% of people have CYP450 defects, he said.

His findings were presented here at the American Academy of Pain Management (AAPM) 23rd Annual Clinical Meeting.

Emerging Frontier

To evaluate patterns among his own patients with intractable pain, Dr. Tennant tested 66 patients attending his clinic in West Covina, California, who required more than 150 mg equivalence of morphine a day for pain relief.

The patients were tested specifically for the CYP2D6, CYP2C9, and CYP2C19 enzymes. The results showed that 55 (83.3%) of the 66 patients had 1 or more CYP450 defects, 21 (31.8%) had 2 defects, and 6 (9.1%) had 3 defects.

According to chronic pain management expert Gary M. Reisfield, MD, genetic research is poised to reveal expansive new insights into the mechanisms of why some patients respond to medications whereas others don't.

"Pharmacogenomics represents the emerging frontier for understanding interindividual variability in opioid efficacy and toxicity, and in guiding safe and effective opioid pharmacotherapy," said Dr. Reisfield, an assistant professor and chief of Pain Management Services in the University of Florida College of Medicine's Divisions of Addiction Medicine and Forensic Psychiatry and Department of Psychiatry in Gainesville, Florida.

"With regard to opioid response, the mu-opioid receptor, the ATP [adenosine triphosphate]-binding cassette subfamily B, and other genes are believed to play significant roles," he explained.

With CYP450, a "superfamily" of enzymes responsible for the metabolism of most opioids, various polymorphisms and variables in activity can have clinical significance.

The enzymes, for instance, have been implicated as playing a role in the overactive metabolism of codeine. In a recent case, the US Food and Drug Administration (FDA) in fact issued a warning about the risks associated with codeine after 3 children died and a fourth child nearly died after having been administered codeine following tonsillectomy and adenoidectomy.

"Once in the body, codeine is converted to morphine in the liver by an enzyme called cytochrome P450 isoenzyme 2D6 (CYP2D6) (and) some people metabolize codeine much faster and more completely than others," the FDA wrote in a statement.

"These people, known as ultra-rapid metabolizers, are likely to have higher-than-normal levels of morphine in their blood after taking codeine. These high levels can lead to overdose and death," the agency said. "The three children who died after taking codeine exhibited evidence of being ultra-rapid metabolizers."

Conversely, some people are "poor" metabolizers of codeine, meaning that they have few, one, or no copies of the gene or CYP2D6, Dr. Reisfield added.

"Such individuals are incapable of metabolizing codeine morphine, and thus incapable of deriving analgesia from administration of the medication.  Both genetic defects would be detected through CYP2D6 genotyping."

Drug Seeker or Higher Requirement?

That being said, Dr. Reisfield suggested that the new study's findings, although intriguing, leave many unanswered questions.

"The study adds to a nascent literature on pharmacogenomics in opioid therapy," Dr. Reisfield said. "Dr. Tennant demonstrates an association between CYP 'defects' and requirements for high opioid dosages. He has not, however, established a causal association."

The study's limitations include that "the most frequent defects were in CYP2C19, which plays an inconsequential role in methadone metabolism, but plays no role in the metabolism of other opioids," Dr. Reisfield said.

Meanwhile, CYP3A4, an important enzyme for the metabolism of most opioids, was not genotyped in the study, Dr. Reisfield said.

In addition, the specific opioids used were not identified, which is important because some opioids, including hydromorphone, oxymorphone, and morphine, are not metabolized by CYPs, he added.

It's not known whether subjects were receiving other medications that could have affected CYP metabolic activity.

Dr. Tennant acknowledged that the study would have benefited from more information from a control group of patients with chronic pain who did not require the high doses.

No one should be called a drug-seeker these days until you've done the CYP450 testing.

"It is unknown just how prevalent severe intractable pain patients with CYP 450 defects who require high dose opioid therapy may be compared to the general, chronic pain population, but it is probably a small percentage," he wrote.

"This study makes it clear, however, that some severe chronic pain patients have major CYP defects that affect opioid metabolism and dosage."

At the very least, the findings suggest that CYP450 testing can represent an important starting point for evaluation when high doses of opioids are required, Dr. Tennant asserted.

"No one should be called a drug-seeker these days until you've done the CYP450 testing to see if that patient simply needs an awful lot more medication than someone else."

Dr. Tennant and Dr. Reisfield have disclosed no relevant financial relationships.

American Academy of Pain Management (AAPM) 23rd Annual Clinical Meeting. Abstract 5. Presented September 21, 2012.

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