Variations in the COMT Gene: The Basis for Pain in Fibromyalgia?

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Variations in the COMT Gene:
The Basis of Pain in Fibromyalgia?

 February 24, 2003


 by Dr. John C. Lowe
Diplomate: American Academy of Pain Management
Director of Research: Fibromyalgia Research Foundation

19 Long Springs Place, The Woodlands, Texas 77283 USA
drlowe@FibromyalgiaResearch.org | www.drlowe.com | 603-391-6061

University of Michigan researchers recently identified a pain gene. It's called the "COMT gene." Based on their studies, they propose that variations in the gene are responsible in part for how sensitive people are to pain.[1]

Research Results: Cells use the COMT gene's code to produce a particular enzyme called "COMT." In our bodies, the COMT enzyme breaks down the nerve-transmitting chemical called dopamine. Dopamine suppresses the production of endorphins, which are morphine-like chemicals that powerfully suppress pain perception. When the COMT enzyme is working well, it lowers our dopamine level. When our dopamine level drops far enough, we produce endorphins. With more endorphins, we perceive less pain.

The COMT gene has two components: one inherited from one's father, the other from one's mother. Each of the two components carries a code. Each code tells the cell to incorporate a specific amino acid  into the COMT enzyme during its production.

The researchers found that in some people, both codes of the COMT gene dictate that cells incorporate the amino acid valine into the COMT enzyme. We can symbolize their two-component COMT gene like this: val/val. The people with the two valine codes had high pain tolerance. The study showed that the people's brains had high levels of endorphins. The assumption is that in these pain-tolerant people, the COMT enzyme (containing its two valine amino acids) rapidly breaks down dopamine. The reduced dopamine level allows the endorphin level to rise, and this renders the people fairly insensitive to pain.

The researchers also found that some people had a variation of the val/val COMT gene. In these people, one code of the COMT gene dictates that cells incorporate the amino acid valine into the enzyme. The other code, however, dictates that cells incorporate another amino acid, methionine, into the enzyme. We can symbolize their COMT gene this way: val/met. These people had moderate pain sensitivity—more than those with two valines in the enzyme. The COMT enzyme with a valine and a methionine in its structure was three-to-four times less active than the enzyme with two valines. Presumably, in these people with moderate pain, the COMT enzyme leaves more dopamine in the body. As a result, their endorphin levels remain lower, and they are more sensitive to pain.

The researchers found that in a third group of people, both codes of the COMT gene dictate that cells incorporate only the amino acid methionine into the enzyme. Symbolically, their gene looks like this: met/met. With two methionines incorporated into the COMT enzyme, its activity is extremely low. Dopamine levels in the body remain high, and endorphin levels low. The low endorphin levels make the people highly sensitive to pain.

It's important to note that the researchers aren't arguing that the gene is the only thing that determines pain sensitivity. They acknowledge that many other factors influence our pain sensitivity, and the gene is only one of the factors.

Relevance to Fibromyalgia: Lauran Neergaard of the Associated Press commented on the researchers' aim: It is to understand how genetics and other factors interact to make some people more susceptible to painful disorders—"like the joint-afflicting fibromyalgia that tends to strike women," she wrote.[2] Of course, fibromyalgia is not a "joint-afflicting" problem. In fact, we used to distinguish fibromyalgia from joint disorders by calling it "non-articular rheumatism." Regardless, a question naturally arises from this gene research: Do fibromyalgia patients have the val/met or met/met variation of the COMT gene? Is one of these variations the basis of fibromyalgia patients' chronic pain?

It will be fascinating to find what later research turns up. But at this point, the gene study results don't indicate that the COMT gene is involved in fibromyalgia. If the pain of fibromyalgia were due to a met/met code in the gene, fibromyalgia patients should have high dopamine and low endorphin levels.

Researchers have measured the breakdown product of dopamine in fibromyalgia patients' cerebrospinal fluid (the fluid in which the brain and spinal cord float). But they didn't find a high level. Instead, the level was low.[8]

In one study, fibromyalgia patients' blood endorphin levels were lower than in depressed patients.[3] But in two other studies, researchers found normal blood levels of endorphins in fibromyalgia patients.[4][5] A study of the endorphin levels in fibromyalgia patients' cerebrospinal fluid showed normal levels.[6] Other researchers found that rather than low endorphin levels in the fluid, fibromyalgia patients' levels were higher than normal. These researchers concluded that fibromyalgia patients' pain isn't caused by low endorphin levels.[7]

The available studies, then, don't show that fibromyalgia patients have the high dopamine and low endorphin levels dictated by the val/met or met/met variation of the COMT gene. Hence, it's unlikely that either of the gene variations is the basis of the chronic pain of fibromyalgia.

References

1. Zubieta, J.K., Heitzeg, M.M., Smith, Y.R., et al.: COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science, 299(5610):1240-1243, Feb. 21, 2003.

2. Neergaard, L.: Gene Helps Determine How Much You Hurt. Associated Press, Feb. 21, 2003.

3. Panerai, A.E., Vecchiet, J., Panzeri, P., et al.: Peripheral blood mononuclear cell beta-endorphin concentration is decreased in chronic fatigue syndrome and fibromyalgia but not in depression: preliminary report. Clin. J. Pain, 18(4):270-273, 2002.

4. Hamaty, D., Valentine, J.L., Howard, R., et al.: The plasma endorphin, prostaglandin and catecholamine profile of patients with fibrositis treated with cyclobenzaprine and placebo: a 5-month study. J. Rheumatol. Suppl., 19:164-168, 1989.

5. Yunus, M.B., Denko, C.W., and Masi, A.T.: Serum beta-endorphin in primary fibromyalgia syndrome: a controlled study. J. Rheumatol., 13(1):183-186, 1986.

6. Vaeroy, H., Nyberg, F., and Terenius, L.: No evidence for endorphin deficiency in fibromyalgia following investigation of cerebrospinal fluid (CSF) dynorphin A and Met-enkephalin-Arg6-Phe7. Pain, 46(2):139-143, 1991.

7. Vaeroy, H., Helle, R., Forre, O., et al.: Cerebrospinal fluid levels of beta-endorphin in patients with fibromyalgia (fibrositis syndrome). J. Rheumatol., 15(12):1804-1806, 1988.

8. Russell, I.J., Vaeroy, M., Jabors, M., and Nyberg, F.: Cerebrospinal fluid biogenic metabolites in fibromyalgia/ fibrositis syndrome and rheumatoid arthritis. Arthritis Rheum., 35:550-556, 1992.