NASS “Best Paper” finds link between genes and pain associated with degenerative disk disease

“It may be possible to draw a blood sample or a buccal swab from a patient, run a quick gene sequencing test, and provide the patient with very specific probabilities regarding the outcome following surgical treatment,” Dr. Kim said. “In fact, a rapidly growing body of scientific and clinical evidence suggests that we are not far from being able to do just that.”

Dr. Kim emphasized that, as promising as these findings are, they also pose some ethical challenges.

The genetic connection
“Increasing evidence suggests that the experience of pain symptoms related to lumbar degenerative disk disease (DDD) is genetically determined,” said Dr. Kim.

Two genes that can confer a propensity for chronic pain are the catecholoamine-O-methyltransferase gene (COMT) and the GTP cyclohydrolase 1 gene (GCH1). “Both genes modulate pain sensitivity in humans,” he said.

COMT codes for a critical enzyme in the metabolism of catecholamine (a neural transmitter). It also regulates the neurotransmitter chemicals dopamine, epinephrine and norepinephrine as well as the µ-opioid system response.

COMT occurs in multiple allelic forms, resulting in enzymes with different levels of activity. The lower the enzymatic activity, the higher an individual’s pain sensitivity appears to be.

“GCH1 codes for the rate-limiting enzyme in synthesis of tetrahydrobiopterin and similarly affects levels of critical neurotransmitter proteins. Human studies have demonstrated that common functional genetic polymorphisms in both genes affect the response to sustained pain,” explained Dr. Kim.

“Individuals who inherit the low pain sensitivity form of GCH1 appear to be protected from developing chronic pain from DDD or, based on previous studies, chronic postoperative pain following diskectomy,” he noted.

The patient connection
The 100 patients in this prospective study had moderate to severe lower back pain for at least 6 months and had evidence of DDD in 1 to 2 vertebral levels on magnetic resonance imaging. Nonsurgical treatment—activity modification, nonsteroidal anti-inflammatory drugs, physical therapy, and/or epidural injections—had been ineffective in reducing pain.

A venous blood sample was drawn from each patient, genomic DNA was extracted, and a DNA sequence analysis was performed for both COMT and GCH1.

Based on the analysis of those blood samples, Dr. Kim and his colleagues found that “DDD patients differed significantly from the general population with the prevalence of the pain sensitivity genes COMT and GCH1. Not only did they have significantly higher rates of the genetic forms associated with vulnerability to chronic pain (COMT), they also had lower rates of the genetic forms that may protect against chronic pain (GCH1).”

Although investigation is ongoing, the researchers have also found that genetic analysis of COMT appears to predict outcome following surgical treatment of DDD. Specifically, patients with the “pain-sensitive” form of COMT demonstrated more than twice the failure rate after surgery compared to patients without this form.

“This is a significant epidemiologic finding with clear implications regarding the pathogenesis of this highly controversial condition. A more detailed understanding of these genetic differences could be used to greatly improve overall success rates in treating chronic low back pain,” concluded Dr. Kim.

The authors reported no potential conflicts of interest related to this study.

Annie Hayashi is the senior science writer for AAOS Now. She can be reached at hayashi@aaos.org