Genetic Discovery Could Change The Way Pain Is Treated

In a genomewide association study of some 500 subjects, Japanese scientists have identified a snip of genetic material that appears to influence both pain sensitivity and susceptibility to substance dependence.

It appears to be the most potent snip of genetic material associated with human opioid sensitivity that has been identified to date, the scientists said in their research report published online November 27, 2012, in Molecular Psychiatry. The lead scientist was Kazutaka Ikeda, Ph.D., project leader of the Addictive Substance Project at the Tokyo Metropolitan Institute of Medical Science.

The snip of genetic material is a single nucleotide polymorphism (SNP) called rs2952768. It is located on chromosome 2 and includes a gene called CREB1 and one called METTL21A. The CREB1 gene makes CREB-1, a protein that induces transcription of genes in response to hormonal stimulation of the cAMP pathway. The METTL21A gene makes METTL21A, an unknown protein probably related to methylation.

Those subjects who had the C variant of rs2952768, especially two copies of it, needed more analgesia after cosmetic surgery than did subjects who had the T variant. The same applied to subjects who needed analgesia after abdominal surgery. Thus subjects who had the C variant seemed to be less sensitive to opioid medications than were those who possessed the T variant.

Moreover, a cohort of some 900 individuals with alcohol dependence, other substance dependence, or eating disorders were genotyped to see whether they possessed the C variant or the T variant of rs2952768. Those carrying the T variant (and who were presumably more sensitive to opioids) were found to be more at risk of serious substance dependence than were those with the C variant.

Finally, in another arm of this study, approximately 500 healthy subjects who had been genotyped for rs2952768 were given a personality questionnaire. Those who possessed the T variant of rs2952768 (and thus expected to be more at risk of serious substance dependence) scored higher on “reward dependence” than did those who possessed the C variant.

Altogether the results suggest that rs2952768 influences both pain sensitivity and the risk of substance dependence, the researchers said.

They are also attempting to harness these discoveries to create personalized treatment for pain. As Ikeda explained to Psychiatric News, they are recruiting 200 subjects who are about to undergo surgery to take part in a randomized, double-blind, placebo-controlled study. Half will receive conventional pain medications (opioid analgesics) after surgery. So will the other half, but in the latter group, the amount of opioid analgesics given will be partially determined by the variant of rs2952768 that the subjects possess. That is, subjects with the C variant, who are presumably less sensitive to opioids, will get more medication than those with the T variant. The researchers will then compare the outcomes of the two groups to evaluate whether the personalized treatment is more effective than the conventional one in countering postsurgical pain.

Ikeda said that, to his knowledge, he and his colleagues are among the first to attempt to use variations in psychiatric-related genes or SNPs for treatment purposes. “A polymorphism in the gene encoding aldehyde dehydrogenase 2 (ALDH2) is useful for predicting vulnerability to alcoholism,” he said. “But I do not know whether clinicians are using such knowledge in their practices.”

The study was funded by the Japanese Ministry of Education, Culture, Sports, Science, and Technology; the Japanese Ministry of Health, Labor, and Welfare; and the Smoking Research Foundation. ■