Nancy A. Melville

October 04, 2012

October 4, 2012 (Phoenix, Arizona) — Abnormal serum concentrations of cortisol and corticotropin (ACTH) may help identify patients with severe pain who are likely to require high opioid dosages, a new study suggests.

The findings were presented here at the American Academy of Pain Management (AAPM) 23rd Annual Clinical Meeting.

Severe pain is linked to the hypothalamic-pituitary-adrenal axis, but diagnostic testing has only recently allowed such imbalances to be assessed according to serum concentrations of cortisol and ACTH, the researchers point out.

"We know that severe pain activates the pituitary gland and makes ACTH go up," said pain specialist Forest Tennant, MD. "It is the body's natural mechanism to control stress and pain and the immune system."

To evaluate the serum levels among his own intractable pain patients, Dr. Tennant, a physician with the Veract Intractable Pain Clinic in West Covina, California, evaluated 22 patients who were referred by primary pain physicians because of a failure to achieve relief with standard opioid dosages, defined as less than 80 mg equivalence of morphine a day.

The patients' serum ACTH and cortisol concentrations were taken at baseline, and opioid dosages were titrated upward over 6 weeks until patients achieved satisfactory pain relief and had no impairment of daily activities, such as dressing, ambulation, and socialization.

Fifteen of the 22 patients showed abnormal ACTH serum levels, including 6 with high levels and 4 low. Seven of the 15 patients had high cortisol levels and 3 had low levels.

The 15 patients with abnormal levels all required daily morphine equivalence doses of more than 150 mg. Meanwhile, only 1 of the 7 patients with normal serum ACTH and cortisol concentrations required the high dosage.

"If pain is severe, the hypothalamus and pituitary gland overreact trying to control the pain, and corticotrophin goes up in the blood and can be measured," Dr. Tennant told Medscape Medical News. "Therefore practitioners can tell with the test that the pain is out of control."

Dr. Tennant added that the ACTH levels that are abnormally low may be an even more ominous sign, suggesting that levels had been abnormal for an extended period of time.

"The pain depletes the ability of the pituitary and adrenal gland to keep up," he said. "So a very low level suggests the patient has gone on for a long time and may have even sustained damage to their immune system or mental health, etc."

Importantly, the neuroendocrine levels can also provide some objective measures when patients indicate that pain medications aren't working.

"The monitoring of hormone levels can help gauge whether a pain management treatment is effective and appropriate," Dr. Tennant said. "They can represent an objective means of separating a severe patient from a drug seeker or drug addict."

That can ultimately result in reductions in opioid prescriptions. "When you do start the hormones you don't use nearly as many opioid drugs because you know what you're trying to get at," Dr. Tennant added.

Nonspecific Markers

Pain specialist Gary Reisfield, MD, noted that the study has several limitations, including apparently not being blinded, having no control group, and no apparent consideration of other variables.

"Abnormalities in these markers of neuroendocrine function are nonspecific and are just as likely due to other factors, such as comorbid depression or chronic opioid therapy," asserted Dr. Reisfield, an assistant professor and chief of Pain Management Services in the University of Florida College of Medicine's Divisions of Addiction Medicine and Forensic Psychiatry and Department of Psychiatry in Gainesville, Florida.

Abnormalities in these markers of neuroendocrine function are nonspecific and are just as likely due to other factors, such as comorbid depression or chronic opioid therapy.

Dr. Tennant acknowledged there are many unanswered questions regarding the ACTH-corticotropin relationship with pain, such as what kind of pain the levels suggest, but he said that the measures can indeed offer important insights on a patient's pain status.

"While we can't determine things like what kind of pain is going on, we are prepared to say at this time if you have really severe pain, the ACTH-corticotropin blood levels are the best way to get an objective lab measure of pain severity."

He added that patients tend to respond well to having something besides a doctors' opinion regarding their pain levels.

"When the patient knows you have objective measurements, they are much more compliant and cooperative, Dr. Tennant said.

"We Americans are taught to look at our cholesterol and our glucose, our PSA [prostate-specific antigen] — we're a diagnostic society. Doctors may have this and that opinion, but hormone tests in the blood are objective."

Lynn R. Webster, MD, an expert on prescription drug abuse and overdose, commended the research as offering important insights into an area of pain management that has generated much interest.

"Dr. Tennant has really led the way in exploring this relationship with pain opioids and the endocrine effect," said Dr. Webster, medical director of Lifetree Clinical Research in Salt Lake City, Utah.

"I think he has a concept that really needs to be developed more. There is a tremendous stress response to pain and the opioids have an effect on the stress response as well."

"That relationship is not entirely clear to me or in the literature, but there does appear to be a significant relationship."

The study received support from the Tennant Foundation and the Yum Brands Foundation Inc. Dr. Tennant and Dr. Reisfield have disclosed no relevant financial relationships. Dr. Webster reports that he receives consulting fees from Boston Scientific Corporation, Covidien, Iroko Pharmaceuticals, Medtronic, Nektar Therapeutics, Pfizer Inc, and Salix Pharmaceuticals.

American Academy of Pain Management (AAPM) 23rd Annual Clinical Meeting. Poster abstract 6. Presented September 21, 2012.