What is the answer for pain?

Individual genetic differences in drug metabolism in pain medication can lead to severe toxicity or therapeutic failure.

The International Association for the Study of Pain (IASP) defines pain as an “unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.” The current analgesic strategies for treating chronic pain and cancer pain are based on the World Health Organization’s (WHO) 1990 analgesic ladder, in which nonsteroidal anti-inflammatory drugs (NSAIDs) or other nonopioid (non-synthetic) analgesics are used first, then followed by a stepwise progression to centrally acting analgesics. But is this general approach to care the best approach? The answer may be as individual as one’s genetics and metabolism.
A New Study Underway

A new study is now underway that explores the relationship between pain and selected medications. It is entitled, “Is Pharmacogenetics the Answer for Pain Management?; Evaluation of the Clinical Efficacy of Genotyping CYP2D6 Variant Alleles for Chronic Pain Patients on Analgesic Therapy, and Monitoring of Plasma Drug Concentrations.” The status of the research will be presented by the primary investigator, Paul Jannetto, Ph.D., Medical College of Wisconsin, Milwaukee, WI. Dr. Jannetto will make his remarks during the 55th Annual Meeting of the American Association for Clinical Chemistry (AACC) in Philadelphia, PA July 20-24, 2003. More than 16,000 are expected to attend.

Background

Pain is clinically divided into various types: nociceptive, involving tissue injury as with osteoarthritis; neuropathic or nerve injury, such as diabetic neuropathy; and combination pain, such as cancer or chronic lower back pain. There are also several approaches to treating pain: pharmacotherapy, which uses drugs either alone or in combination; invasive procedures, such as nerve blocks and steroid injections; and adjunct therapies, such as acupuncture, physical therapy and psychotherapy.

Pharmacogenetics is the study of the linkage between an individual’s genetic make-up and that individual’s ability to metabolize a foreign compound. Most therapeutic drugs are metabolized to some extent and the metabolism of these drugs results in either the detoxification and elimination of the drug or the activation of the prodrug to its biologically active form.

Cytochrome P450 enzymes are an important superfamily of proteins that are involved in phase I drug metabolism. Consequently, mutations in cytochrome P450 (CYP) genes, such as CYP2D6, can cause alterations in the way a drug is metabolized. In humans, CYP2D6 affects the metabolism of several clinically important drugs, such as oxycodone, amitriptyline and tramadol, all essential for pain management therapy.

The genetic differences in drug metabolism can therefore lead to severe toxicity or therapeutic failure by altering the relation between the dose and blood concentration of the pharmacologically active drug. Since up to ten percent of Caucasians and up to four percent of most other ethnic groups have decreased CYP2D6 activities (poor metabolizers), they may risk toxic effects if they receive the routine clinical dose of a drug inactivated by CYP2D6.

Objective and Methodology

Accordingly, the study now underway examines the clinical efficacy of genotyping chronic pain patients on analgesic therapy. They have begun by genotyping new and existing patients at the Pain Management Clinic at the Zablocki VA Medical Center and the Froedtert Hospital, both in Milwaukee, WI.

Dr. Jannetto and his colleagues hypothesize that poor drug metabolizers taking analgesics metabolized by CYP2D6 will have higher plasma concentrations and therefore be more likely to experience adverse effects. To test the hypothesis, they will determine the genotype of chronic pain patients being treated with medications metabolized by CYP2D6. The genotype will then be correlated with the plasma concentrations of the various analgesics after steady state levels have been reached. They will also clinically evaluate the patients for adverse reactions as well as the efficacy of the pain management therapy, using verbal and/or visual analogue scales, clinical indices relevant to function and assessments of the use of breakthrough medication.

Significance of This Research

Overall, the results from this study can be used to predict the clinical usefulness of genotyping patients in an attempt to determine the appropriate drug therapy. This is important since prior knowledge of the genotype and drug metabolism could potentially predict the outcome and allow for appropriate adjustment of the dose to prevent adverse reactions from occurring.