BOSTON – In an ongoing study that is enrolling patients with highly refractory chronic pain, treatments selected on the basis of objective evidence of underlying genetic defects or other obstacles to pain control are yielding high rates of success, according to the director of the center where the study is underway.
In the 61 patients who underwent an evaluation of hormone activity, 80.3% had one or more abnormalities. For individual hormones tested, the rate of abnormalities was 27.3% for ATCH (adrenocorticotropic hormone), 20.8% for pregnenolone, 37.2% for DHEA (dehydroepiandrosterone), 37.2% for testosterone, 32.8% for cortisol, and 20.8% for progesterone. In most cases, the abnormality was reduced hormone level or activity, but about half of those with cortisol abnormalities had elevated activity.
In 80 patients tested for inflammatory markers, C-reactive protein was elevated in 32.5%, the erythrocyte sedimentation rate was elevated in 27.5%, and tumor necrosis factor–alpha was elevated in 25%. Two or more inflammatory biomarkers were elevated in 31.3%, according to Dr. Forest Tennant, director, Veract Intractable Pain Clinic, Los Angeles.
These findings provided the basis for analgesia selection. No test result assured that any single therapy would be effective, but the objective studies guided a rational approach that narrowed choices, according to Dr. Tennant.
“In our hands, we had to take each patient and find their own suit of clothes,” he said. He acknowledged that some of the analgesia regimens ultimately reached through these kinds of tests have been unorthodox, but the success rate in a very difficult population supports this approach.
“Rather than calling these people drug seekers or sending them on, the time has come to try to objectively evaluate the basis of their resistance to therapy,” Dr. Tennant said.
The strategy, although promising, needs to be clarified and reproduced in a broader number of settings, according to Dr. Gavril W. Pasternak, laboratory head, molecular pharmacology and chemistry, Memorial Sloan-Kettering Cancer Institute in New York. Of 101 patients enrolled since the study’s initiation in 2012, all but two or three have achieved improved pain control after therapies were adjusted on the basis of a series of objective studies that identified barriers to analgesic response, according to Dr. Tennant. He summarized the experience to date at the International Conference on Opioids.
The study has enrolled the hard cases, said Dr. Tennant. All were required to be pain treatment “failures,” defined as patients with an inability to maintain activities of daily living after treatment with multiple nonopioid therapies and an oral opioid dosage of at least 100 mg of morphine milligram equivalents.
Providing a flavor of the types of patients in this study, Dr. Tennant said that the first 40 enrolled had consulted 461 physicians, 172 pain specialists, and 104 mental health specialists. He said clinicians typically avoid this type of pain population and sometimes stigmatize such patients with terms such as “difficult” or “noncooperative.” All had centralized pain for at least 2 years and failure on one or more agents in every class of analgesic.
The research objective of the study was to develop a systematic and objective methodology for evaluating underlying defects leading to pain refractory to opioids in low or moderate doses. This included pharmacogenomics testing of CYP450 and Mu opioid receptor gene functions. It further included studies of hormone function, inflammatory activity, and metabolic biomarkers.
Abnormalities were common. Genetic defects in CYP2D6, CYP2C19, and CYP2C9, for example, were found in 90.1% of the 101 patients evaluated so far. Of these, 27.7% had defects in two and 7.9% had defects in all three, according to Dr. Tennant.
In the 45 patients who underwent pharmacodynamics genetic testing for OPRM1, 28.9% were found to have intermediate or low sensitivity, suggesting an impaired response. In the same patients, 62.2% had intermediate or high activity of catechol-o-methyltransferase activity, which is associated with an increased sensitivity to pain. In an interview after the presentation, Dr. Pasternak said he was intrigued but not fully convinced by the data presented.
According to Dr. Pasternak, the concept of evaluating refractory pain patients with a panel of tests looking at pharmacogenetics, hormones, and inflammatory markers is “interesting” and deserves further evaluation in well-validated studies, but he added, “let’s see if it leads anywhere.”