Monday, March 1, 2010

Opioids & Pain Relief, It’s in the Genes

GenesIt is well known that not all opioid analgesics are created equal; for certain patients one may work wonders while another in the same class fails miserably. Critical differences appear to rest with the genetic makeup of patients, which explains the otherwise mysterious variable effects but is presently unhelpful in guiding clinical therapy.

A recent article in Pain Medicine News discusses a postsurgical patient who had no pain relief from hydrocodone but did well on oxycodone at a comparable dose [Miller 2010]. The chemical difference between the two opioid analgesics is just two atoms, one hydroxyl group, yet one helped the patient and the other did not. The question is not whether opioids are effective, since a sufficiently high opioid dose will overcome any pain (but with subsequently proportional side effects); rather, how can individual responses to opioids be explained and predicted? According to the article, in laboratory experiments there can be 10-fold differences in responses to morphine between animals, and the variability is likely even greater in humans. A study that looked at 3,200 patients recovering from back surgery found that some patients required as much as 40 times more morphine than others.

It is becoming increasingly clear that genetic variations may play a significant role in how patients respond to analgesics. Some of these have been well established, such as how differences in the expression of CYP450 enzymes in the liver can significantly affect the metabolism of certain opioids. Analgesics that require these enzymes for bioactivation — like codeine, for example — can be rendered useless if a person is genetically a poor metabolizer. Furthermore, genetic mutations that affect P-glycoprotein (a substance that transports opioid molecules across cell membranes) can influence analgesic potency or, in some cases, cause unexpected overdose as opioid serum levels rise. Another genetic influence on analgesia comes from the COMT gene, which makes enzymes that degrade catecholamine neurotransmitters like dopamine, epinephrine, and norepinephrine, and also affects mu-opioid receptor binding. Finally, it is suspected that polymorphisms of the mu-opioid receptor gene itself may significantly affect opioid response.

Aside from analgesic-drug effects, writing in the journal Practical Pain Management Alyson Fincke, DO, describes how genetic variations influence sensitivity to pain, perceptions of pain, and risks of developing chronic pain [Fincke 2010]. Certain pain-related genotypes appear to be sex dependent (affecting more women than men), and pain conditions influenced by genetic factors include musculoskeletal pain, chronic fatigue/fibromyalgia, and low back pain. As another example, diminished activity of the COMT gene (noted above) may elevate catecholamine levels and, thereby, promote persistent pain states, increased pain sensitivity, and allodynia (pain caused by normally non-painful stimuli).

CLINICAL COMMENTS: As the above articles suggest, this is a complex and emerging field of study. However, clinical applications of new knowledge may eventually allow personalizing pain therapies based on a patient’s genetic makeup. For acute pain, a patient might be genotyped before a surgical procedure and postoperative analgesia could be based in part on pain-related genetic variations. For chronic pain, genetics would influence the selection and dosing of appropriate pain relievers. Further down the road, a better understanding of the genetics of pain and opioid metabolism might help to predict a patient’s risk for developing painful disease, the clinical course it might run, and even the patient’s risk for developing drug addiction.

All of this, of course, is in the future. Today, even though research does not translate into genotyping in the clinic as a guide for developing treatment plans, a general appreciation of possible genetic influences helps to explain why some patients respond much differently to pain-relieving interventions than others. Due to genetic makeup, certain patients may require many-fold greater doses of an opioid analgesic, and still be undermedicated because they are rapid metabolizers of the drug. And, even though their urine tests may be negative for the prescribed medication in such cases, it does not necessarily mean that they are diverting or selling their opioid drugs. Taking into account the possibility of still undefined genetic influences adds a whole new level of complexity that demands much greater flexibility and understanding in treating patients with pain.

RESEARCH ADDENDUM: Newly published research in the Proceedings of the National Academy of Sciences reports that persons with variations in a particular gene — designated SCN9A — experience greater pain sensitivity. Investigators found that having a particular DNA base at a specific location on the gene (an A instead of a G) facilitates sodium influx that spurs nerve cells to send pain signals to the brain that are stronger and of longer duration than normal. It is estimated that 10% to 30% of people have the ‘A version,’ which makes them susceptible to certain chronic pain syndromes. In extreme cases, mutations of SCN9A can influence the so-called “man on fire syndrome,” in which victims experience relentless, searing pain. See: Reimann F, Cox JJ, Belfer I. Pain perception is altered by a nucleotide polymorphism in SCN9A. PNAS. 2010(Mar 8). Online ahead of print [available here].

> Fincke A. Genetic influences on pain perception and treatment. Practical Pain Management. 2010;10(1):12-16.
> Miller G. Genetics of opioid prescribing: many questions, few answers. Pain Medicine News [online]. 2010(Feb);36(2) [
see article].