Most patients with multiple defects of the cytochrome P450 system, which is largely responsible for metabolizing opioids, naturally gravitated toward an opioid regimen primarily metabolized through the cytochrome P450 3A4 enzyme or a non-cytochrome, metabolic pathway, a new study suggests.
Each patient in the study was initially referred for intractable pain therapy and had not responded to standard low doses of opioids. Results were presented in a scientific poster today at the 30th Annual Meeting of the American Academy of Pain Medicine.
The study's author said the major message is that "non-responsive" or "resistant" patients need P450 cytochrome testing.
"There is a general, misguided fright of opioids without realizing that proper selection of an opioid means lower dosage and less misuse," said Forest Tennant, MD, an internist and addictionologist who specializes in the research and treatment of intractable pain at the Veract Intractable Pain Clinics in West Covina, Calif.
"There is a sub-group of severe pain patients who go doctor-to-doctor and can't find relief. Many of these 'resistant' or 'non-responsive' patients have multiple metabolic defects and will only respond to some opioids," Dr. Tennant said. "Patients with multiple genetic defects may have to use injectable opioids."
Genetic factors contribute to how quickly and well individual patients metabolize the opioids given for pain, as shown in many scientific studies. Due to variability in the action of metabolizing enzymes, certain people eliminate drugs quickly and others do so more slowly. This, in turn, influences whether the drug is effective or whether it builds to a toxic level. Effective opioid regimens are generally developed clinically through trial and error, Dr. Tennant said, and the dose or medication choice that works for one patient may prove unsuccessful in another.
In the study, 49 patients were assayed for cytochrome P450, 2D6, 2C9 and 2C19 and had 2 or 3 cytochrome defects that might affect metabolism. A defect was defined as any indication of a poor, rapid or intermediate metabolizer, while an extensive metabolizer was considered normal.
In reviewing the opioid regimens found in the patient charts, Dr. Tennant found that 1 or more of the following opioids gave sufficient pain control to allow activities of daily living and maintenance of normal blood pressure and pulse rate:
• Fentanyl in 18 (30.7%) and oxycodone in 26 (53.1%) patients. Fentanyl and oxycodone are metabolized primarily through the CYP3A4 enzyme.*
• Morphine in 24 (49.0%) and hydromorphone in 26 (53.1%) patients. Both drugs are metabolized by phase 2 glucuronidation.*
• Hydrocodone in 5 (10.2%) and methadone in 9 (18.4%) of patients. The CYP2D6 enzyme is responsible for the metabolism of hydrocodone, while the metabolism of methadone is more complex, involving as many as 6 different enzymes.*
• Seven (14.3%) patients required injectable opioids because they did not respond to oral opioids, perhaps due to the large number of cytochrome P450 enzymes present in the intestine and liver.
Taken together, the results suggest patients showed a propensity to respond to opioids using metabolic pathways consistent with prior test results indicating cytochrome P450 function. The findings could inform future research and considerations for choosing the optimal opioid regimen when opioids are indicated for intractable pain. However, Dr. Tennant added, such clinical decision making is always based on many factors.
*Reference Smith HS. Opioid Metabolism. Mayo Clinic Proc 2009;84(7):613-24.
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