Can This Gene Influence Your Sensitivity To Pain (COMT)?

The COMT gene codes for an enzyme called catechol-o-methyltransferase (also called COMT). As its name implies, COMT transfers a methyl group to catechol-containing compounds. COMT uses SAM-e as its methyl donor. Therefore, having either too little SAM-e, or too much S-adenosylhomocysteine (SAH) — which is formed when SAM-e loses its methyl group — results in inhibition of COMT [R, R].

The main function of COMT is to help break down catecholamines, a family of neurotransmitters that includes dopamine, norepinephrine (also known as noradrenaline), and epinephrine (also known as adrenaline) [R].

COMT is widely distributed throughout the body, including in regions associated with pain perception, such as the prefrontal cortex of the brain, the spinal cord, and peripheral nerves [R, R]. 

The COMT gene encodes an enzyme of the nervous system that breaks down the neurotransmitters dopamine, norepinephrine, and adrenaline by transferring a methyl group to them, from SAM-e.

COMT Function and Pain Perception

Studies in gene-edited mice have reported that mice which overproduced COMT enzymes had increased pain tolerance, whereas mice lacking this protein were more sensitive to acute pain. Interestingly, mice deficient in COMT, while more sensitive to pain in general, also showed increased pain relief in response to opioids [R, R, R].

Similarly, most COMT inhibitors increase pain sensitivity in mice and rats. The only exception is nitecapone, which seems to prevent the activation of certain nerve cells of the spinal cord that perceive pain [R, R, R].

Role of Catechol Neurotransmitters

There are several possible mechanisms by which reduced COMT activity may increase pain perception.

On the one hand, COMT inhibition results in higher norepinephrine and epinephrine levels. These neurotransmitters may increase pain sensitivity by activating receptors in the peripheral nerves. Moreover, the breakdown of these neurotransmitters produces a toxic chemical that may further worsen pain [R, R, R].

However, in certain situations, norepinephrine and epinephrine may also help relieve acute pain. For example, one study in rats reported that norepinephrine injections triggered the release of endorphins, which reduce pain by activating opioid receptors [R].

On the other hand, reduced COMT activity increases dopamine availability. Although dopamine inhibits pain, it also blocks the production of pain-relieving chemicals (enkephalins) in the brain. On the upside, it can increase the number of opioid receptors in certain brain areas, and may thus enhance the effectiveness of certain opiates [R, R].

Finally, carriers of underactive COMT variants showed increased activation of several brain regions responsible for perceiving pain (such as the anterior cingulate cortex, periaqueductal grey, lingual gyrus, cerebellum, hippocampus, and precuneus) in response to painful stimuli [R, R].

Reduced COMT activity is generally associated with increased pain sensitivity but also better response to opioids. The increased availability of neurotransmitters and activation of pain centers in the brain may account for these effects.

SNP Summary and Table

Primary SNP: COMT rs4680

• ‘G’ = Normal pain sensitivity
• ‘A’ = Increased pain sensitivity
• 41% of the world population has genotype ‘GG’ 
• In people with European ancestry, both alleles are equally frequent

Other Important SNPs 

COMT rs6269

• ‘A’ = Normal pain sensitivity
• ‘G’ = Increased pain from surgery and sickle cell disease
• Only 14% of the global population has genotype ‘GG’
• In people with a European background, the ‘A’ variant is slightly less common

COMT rs4633

• ‘C’ = Normal pain sensitivity
• ‘T’ = Increased pain from surgery and sickle cell disease
• The genotype distribution is very similar to that of rs4680 for all ethnicities

COMT rs4818

• ‘C’ = Normal pain sensitivity
• ‘G’ = Increased pain from surgery
• Globally, 1 out of 2 people has genotype ‘CC’
• The most common situation in European descendants is to carry one copy of each allele

COMT rs165599 

• ‘G’ = Normal pain sensitivity
• ‘A’ = Increased pain from sickle cell disease and experimental (heat) pain
• The ‘G’ allele is only slightly more frequent than ‘A’ in the global population
• In European descendants, ‘A’ is the most common allele

COMT rs165774 

• ‘G’ = Normal pain sensitivity
• ‘A’ = Reduced pain sensitivity
• Only 5% of the world population has genotype ‘AA’
• Allele ‘A’ is slightly more common in people of European ancestry (10% of ‘AA’)

COMT rs887200

• ‘T’ = Normal pain sensitivity
• ‘C’ = Reduced pain sensitivity
• Almost 43% of the world population has genotype ‘TT’ 
• In people with a European background, the percentage of ‘TT’ is increased to 76%

Rs4680

By far, rs4680 is the most widely-studied COMT gene variant. Its minor ‘A’ allele encodes a less-stable protein that results in reduced COMT levels and activity [R, R].

This variant has been associated with increased sensitivity to pain caused by heat and the injection of concentrated salt solution in experiments on healthy people [R, R, R].

In a study on fibromyalgia patients, carriers of this variant were more sensitive to experimental pain caused by cold temperatures and pressure [R].

Although the rs4680 polymorphism doesn’t influence the risk of chronic headaches (migraines and tension headaches), carrying two copies of the ‘A’ allele results in more severe attacks and increased sensitivity to pressure pain in adults and children [R, R, R, R].

The ‘A’ variant has also been associated with an increased incidence of acute pain crises in people with sickle cell disease [R].

As previously mentioned, low COMT activity may enhance the effectiveness of opiates. In line with this, people with cancer or postsurgical pain required lower morphine doses when they carried the ‘A’ variant [R, R, R].

A widely-investigated COMT underactive variant is associated with increased sensitivity to painful stimuli.

Other Variants

The contribution of the rs6269 polymorphism to COMT activity hasn’t been investigated. Its minor ‘G’ variant is associated with increased pain relief in response to morphine and decreased pain relief in response to butorphanol. This variant is also associated with increased pain from [R]:

• Surgery (tonsil removal, tooth removal, and orthopedic surgeries) [R, R, R]
• Sickle cell disease [R]

The minor ‘T’ allele of rs4633 increases COMT expression. This variant is associated with greater pain relief in response to butorphanol, as well as with increased pain from [R, R, R]:

• Surgery (tonsil removal, orthopedic surgery, and groin hernia repair) [R, R, R]
• Sickle cell disease [R]

The minor ‘G’ variant of rs4818 encodes a protein with reduced activity, and has been associated with increased pain after the surgical removal of the uterus and tonsils [R, R, R].

The minor ‘A’ allele of rs165599 reduces COMT expression in the brain. This variant has been associated with an increased number of severe episodes of pain in people with sickle cell disease and reduced the placebo effect of a fake TENS treatment, resulting in increased sensitivity to pain caused by heat [R, R, R].

The minor ‘A’ allele of rs165774 increases COMT gene expression, but encodes a COMT protein with reduced activity. This variant has been associated with reduced sensitivity to pain from heat and electric stimuli, possibly by increasing dopamine levels [R, R, R].

Another minor variant, ‘C’ at rs887200, has been reported to reduce sensitivity to pain caused by cold temperatures [R].

Several COMT variants may increase or reduce pain sensitivity.