EA and COMT Val158Met 2023

Stimulated by Yang et al 2023.[1]

EA – electroacupuncture
AA – auricular acupuncture
COMT – catechol-o-methyltransferase
MSK – musculoskeletal
BFA – battlefield acupuncture (an AA protocol – See: Ears and the battlefield)
rs – reference SNP cluster ID
SNP – single nucleotide polymorphism
PFC – prefrontal cortex
AI – aromatase inhibitor
CBT-I – cognitive behaviour therapy for insomnia

key to acronyms

This paper was a surprise. It combines 2 things that I am interested in but never expected to see in the same paper. The research is part of the PEACE trial that I mentioned on here in 2021: EA or AA vs UC – the PEACE trial.[2]

The original trial, published in JAMA Oncology, included 360 patients with chronic MSK pain and a previous cancer diagnosis. They were randomised in a ratio of 2:2:1 to local EA, BFA, or UC.

325 of the original 360 randomised patients provided samples for genetic analysis. This paper performed a subgroup analysis of the trial results based on the distribution of the genetic variant rs4680 in the samples. The SNP (rs4680) is also known as COMT Val158Met. In simple terms, there is a genetic variant whereby one amino acid (valine) is replaced by another (methionine) in the protein COMT. This results from the substitution of a G (guanine) with an A (adenine) in the gene at codon 158.

COMT is an enzyme that degrades catecholamines (eg dopamine, epinephrine, norepinephrine), catecholestrogens, and other molecules with a catechol structure. In some regions of the brain, such as the PFC, COMT is the most important enzyme in the degradation of dopamine.

When valine is replaced by methionine in COMT (at the position encoded by codon 158 in the gene), the efficiency of dopamine degradation by the enzyme is reduced by a factor of 4. I am guessing that 4 times as much dopamine at a synapse in the reward pathway of the brain is going to be noticed; however, as the Met variant is already overexpressed in the brain, the increase is more like 40% than 400%. Still, that is only one aspect of the potential effects of changes to the efficiency of the COMT enzyme.

The highest quantity of COMT in the body is found in the liver, where presumably it helps to mop up any excess circulating epinephrine (‘adrenalin’). That reminds me of Professor Nutt’s description of the COMT polymorphism when he mentioned it in a presentation at a meeting on opioids some years ago. He said something like the Val Val types (ie homozygotes for the more stable valine variant of COMT) were adrenalin junkies, and the Met Met types were more sensitive. The true picture is much more complex and nuanced, but that summary gives you an idea from which to start that seems to make sense. If you have a very efficient pathway for degrading catecholamines (ie Val Val), you can probably cope with more of them circulating from time to time.

I spent some time searching PubMed for definite answers concerning the role of rs4680 in a variety of disorders, including schizophrenia, major depressive disorder, Alzheimer’s disease, and breast cancer, but none are definitive, and there can be different (even opposing) effects in men and women as well as different racial groups.

For this study, the key aspects are involved with pain perception and treatment. The Val158 allele is associated with better tolerance to pain and other stressors, and the Met158 allele with a lower pain threshold, a greater affective response to pain, a less active endogenous opioid response and more opioid receptors in the brain.

You will perhaps not be surprised to hear that EA was associated with a significantly higher analgesic response rate in patients carrying the Met158 allele. EA was effective in over 73% of this group compared with 50% in those that only carried the Val158 allele.

For the first time, this gives us a predictive measure of responsiveness to EA. Interestingly, rs4680 did not affect the response to auricular acupuncture (BFA in this case).

Well, I say ‘for the first time’, and then I discover that the same team has already published preliminary research on rs4680 from 2 other studies – one on EA for AI-induced joint pain (n=38)[3] and the other from a trial comparing acupuncture with CBT-I in insomnia (n=136).[4] rs4680 was associated with higher response rates to acupuncture in both samples but did not show any difference in response to CBT-I in the larger of the two.

The main publication of the comparative trial in insomnia has already featured here: CBT-I pips acupuncture in insomnia.[5]

References

1          Yang M, Baser RE, Khanin R, et al. COMT Val158Met Affects the Analgesic Response to Acupuncture Among Cancer Survivors with Chronic Pain. J Pain 2023;:S1526-5900(23)00417-0. doi:10.1016/j.jpain.2023.05.005

2          Mao JJ, Liou KT, Baser RE, et al. Effectiveness of Electroacupuncture or Auricular Acupuncture vs Usual Care for Chronic Musculoskeletal Pain Among Cancer Survivors: The PEACE Randomized Clinical Trial. JAMA Oncol 2021;7:720–7. doi:10.1001/jamaoncol.2021.0310

3          Genovese TJ, Mao JJ. Genetic Predictors of Response to Acupuncture for Aromatase Inhibitor-Associated Arthralgia Among Breast Cancer Survivors. Pain Med 2019;20:191–4. doi:10.1093/pm/pny067

4          Genovese TJ, Gehrman P, Yang M, et al. Genetic Predictors of Response to Acupuncture or Cognitive Behavioral Therapy for Insomnia in Cancer Survivors: An Exploratory Analysis. J Pain Symptom Manage 2021;62:e192–9. doi:10.1016/j.jpainsymman.2021.03.002

5          Garland SN, Xie SX, DuHamel K, et al. Acupuncture Versus Cognitive Behavioral Therapy for Insomnia in Cancer Survivors: A Randomized Clinical Trial. J Natl Cancer Inst 2019;111:1323–31. doi:10.1093/jnci/djz050

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Declarations of interest MC