Have Difficult-to-Treat Pain Patients? Try Genetic Testing

Pauline Anderson

March 02, 2016

PALM SPRINGS, California — A patient was in a motor vehicle accident that shattered his right leg. He started taking morphine extended-release tablets (MS Contin, Purdue Pharma) at a dose of 100 mg up to three times daily with escalating doses over 4 years, but he still had persistent back and leg pain that he rated a 10 on the 10-point Visual Acuity Scale.

Increasing the dose at that point would not be appropriate, said Ramesh M. Singa, MD, from the Anesthesiology Department at Saint Barnabas Medical Center, Livingston, New Jersey, in describing this case. "However, he had also tried numerous other medications over the past few years with little pain relief," Dr Singa said.

Dr Ramesh M. Singa

So he and his colleagues suggested genetic testing. The tests revealed that this patient was an ultrarapid metabolizer of the CYP allele 2D6, which metabolizes oxycodone. The medication was basically just going through his system too quickly to give him much relief.

The treatment team added gabapentin (Gralise, Depomed), an anticonvulsant sometimes used to treat neuropathic pain, and low-dose methadone, which is mainly metabolized by CYP 3A4, a different pathway than that which metabolizes morphine. Within about three visits, the patient's pain score dropped to 4.

"That's a dramatic decrease," said Dr Singa. It is patients like this one that led the researchers to take a closer look at the effect of genetic characterization of chronic pain on treatment outcomes.

Their report on the topic was featured in the late-breaking poster section of the American Academy of Pain Medicine (AAPM) 2016 Annual Meeting.

Drug Metabolism

Over a 2-year period, they looked at 70 pain patients (mean age, 54 years) with an average initial pain score of 8.6. All had genetic testing to determine their CYP composition.

Researchers looked at three CYP alleles (which are versions of a particular gene) that are involved in metabolizing drugs: 2D6 as well as 2C19 and 2C9.

For each allele, they determined the percentage of study patients who were poor, normal, intermediate, rapid or ultrarapid metabolizers of pain medications. Some medications are processed by more than one allele.

With CYP 2D6, only 6% of the study group were ultrarapid metabolizers (as was the car accident victim described above), while 3% were poor, 57% normal, and 34% rapid metabolizers.

For the CYP 2C9 allele, 6% of patients were poor, 53% normal, and 41% intermediate metabolizers. And for the CYP 2C19, 1% were poor, 34% normal, 26% intermediate, 33% rapid, and 6% ultrarapid metabolizers.

When pain medications were adjusted according to the patient's genetic profile, pain scores went down. There was an average decrease of 55% in pain scores.

"Our study shows that genetic testing is a very important adjunct in treating chronic pain patients and can certainly reduce their pain scores, and reduce side effects in patients as a corollary," said Dr Singa.

As it stands now, it's typically only those who have not shown clinically significant decreases in pain who have genetic testing performed. This, said Dr Singa, represents "a fairly small number of patients."

However, physicians in the field suggest that "it should be used for almost every person to improve outcomes and decrease side effects," he said.

Important Implications

Results of genetic testing have important implications for treatment decisions and could prevent costly interventions that won't do patients any good. Dr Singa pointed to one of his patients with chronic pain who also had end-stage renal disease and was about to get a kidney transplant.

But when transplant nephrologists went over her chart, which included genetic testing results, they determined that if this woman got the transplant, she wouldn't react to immunosuppressive drugs and would reject the kidney. She didn't get the transplant.

When another patient at Dr Singa's clinic had a kidney transplant, she rejected her new organ.

"She was tested retroactively, and we found that she had the same genetic profile as the woman who was told not to get a transplant."

The idea of having genetics-related prediction of analgesic response originated with research into reducing adverse effects of psychiatric drugs, said Dr Singa. In psychiatry, finding the right medication can involve a lot of trial and error, and the adverse effects of some these drugs can be serious, he said.

Although the current study looked at only three alleles — among the most common ones, he said — the company offering the tests has expanded the number of alleles that can be tested.

Way of the Future

According to some experts, genetic testing is the way of the future. Some even see it as something newborns will eventually get as a matter of course to determine what medications would be most appropriate to treat their various illnesses throughout life.

Asked to comment on this new research, Fred Davis, MD, president and co-founder, ProCare Systems Inc, Grand Rapids, Michigan, said such studies are important in the search for markers determining analgesic response to drugs.

"By definition, pain is a subjective experience; it's very emotional and very individualized, so it's hard to quantify," said Dr Davis, who is an anesthesiologist and pain medicine specialist.

"Having some quantitative markers, quantitative ways of assessing pain, predicting pain, and understanding pain, can be very important in our long-term treatment strategies."

However, the study represents "the tip of the iceberg" in terms of understanding pain medicine metabolism, said Dr Davis.

He's optimistic about learning more in the future. "I think there will be something that we can find that's a predictor or a marker for pain that we don't know yet. It may be a scan; it may be a chemical marker; it may be a genetic marker, but something is there because we know pain is real."

Dr Singa has disclosed no relevant financial relationships.

American Academy of Pain Medicine (AAPM) 2016 Annual Meeting. Late Breaking Poster 008.

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