Fibromyalgia and chronic pain: Why painkillers don't help

[David Baxter PhD]

Research discovers why painkillers don't alleviate fibromyalgic pain
September 30, 2001

New research from the University of Michigan Health System (U-M) has discovered why people with fibromyalgia often don't get pain relief from common painkillers. They were found to have reduced binding ability of a type of receptor in the brain that is the target of opioid drugs such as codeine and morphine.

Positron emission tomography (PET) scans of the brains of 17 female patients with fibromyalgia, and of an equal number of age-matched people without the condition revealed the fibromyalgia patients had reduced m?-opioid receptors (MOR) availability in regions of the brain which normally process and dampen pain signals - specifically, the nucleus accumbens, the anterior cingulate and the amygdala.

"The reduced availability of the receptor was associated with greater pain among people with fibromyalgia," says lead author Richard E. Harris, Ph.D., research investigator in the Division of Rheumatology at the U-M Medical School's Department of Internal Medicine and a researcher at the U-M Chronic Pain and Fatigue Research Center.

"These findings could explain why opioids are anecdotally thought to be ineffective in people with fibromyalgia," he notes. "The finding is significant because it has been difficult to determine the causes of pain in patients with fibromyalgia, to the point that acceptance of the condition by medical practitioners has been slow."

Opioid pain killers work by binding to opioid receptors in the brain and spinal cord. In addition to morphine, they include codeine, propoxyphene-containing medications such as Darvocet?, hydrocodone-containing medications such as Vicodin?, and oxycodone-containing medications such as Oxycontin?.

Based on their findings, the researchers theorize that with the lower availability of these receptors such painkillers may not be able to bind as well to the receptors as they can in the brains of people without the condition.

When the painkillers cannot bind to the receptors they cannot alleviate the patient's pain as effectively, Harris says. The reduced receptors availability could result from a reduced number of opioid receptors, or enhanced release of naturally produced endogenous opioids such as the endorphins, or both, Harris says.

The research team also found a possible link with depression. The PET scans showed that the fibromyalgia patients with more depressive symptoms had reductions of MOR binding potential in the amygdala, a region of the brain thought to modulate mood, the fear response, and the emotional dimension of pain.

Source: Harris RE, Clauw DJ, Scott DJ, et al. Decreased Central ?-Opioid Receptor Availability in Fibromyalgia. J Neurosci. 2007 Sep 12;27(37):10000-6. [Abstract]

 

[David Baxter PhD]

Fibromyalgia Study Provides Possible Explanation for Reduced Efficacy of Opioid Therapy
by Caroline Cassels

October 3, 2007 ? A new study indicates individuals with fibromyalgia (FM) have decreased opioid-receptor?binding ability, a finding that may explain a long-held anecdotal observation that treatment with opiates has reduced efficacy in this patient population.

Using positron emission tomography (PET), investigators at the University of Michigan Health System found that compared with healthy, matched controls, FM patients had reduced μ-opioid-receptor (MOR)?binding potential (BP) in the nucleus accumbens, the anterior cingulate, and the amygdala, areas of the brain known to play a role in pain modulation.

"We found that patients with fibromyalgia have lower receptor availability, also known as binding potential, within 3 structures of the central nervous system. In practical terms, this may indicate that exogenous opiates would not be able to bind to these receptors and therefore would not be able to alleviate the chronic pain that is characteristic of this condition," Richard Harris, PhD, the study's first author, told Medscape Neurology & Neurosurgery.

"I think this study gives us a little more information on what, mechanistically, is going on in the central nervous system of these patients. It looks as though the opioid system [of FM patients] is dysfunctional and not operating at the same level as it does in pain-free individuals. If the opioid system is dysfunctional, clinicians may want to reconsider using opioid therapy to treat fibromyalgia patients," Dr. Harris added.

The study is published in the September 12 issue of the Journal of Neuroscience.

Possible Mechanism
According to Dr. Harris, previous research by his group has demonstrated that patients with FM and those with chronic low back pain have increased levels of endogenous opioids in their cerebral spinal fluid (CSF) compared with pain-free individuals. This result, he said, suggests that endogenous pain-management mechanisms in such individuals are activated. This would be consistent with the reduced MOR-receptor availability previously observed by Dr. Harris and colleagues.

Part of a larger, ongoing study investigating the impact of acupuncture on FM, the current study sought to determine whether the previous observation of increased levels of endogenous opioids in the CSF of FM patients was associated with decreased MOR-receptor availability, possibly through receptor downregulation.

Secondary end points included an investigation of the association of MOR availability with both the affective and sensory dimensions of clinical pain. In addition, researchers examined the relationship between depressive symptoms in FM patients and MOR BP.

For the study, 17 right-handed female FM patients were examined with PET and compared with 17 right-handed, age- and sex-matched healthy controls.

All analyses were performed using data acquired before acupuncture treatment. Patients were between the ages of 18 and 75 years and met the American College of Rheumatology criteria for the diagnosis of FM for at least 1 year, had pain more than 50% of the time, and were willing to forgo the introduction of any new medications or other treatment for the duration of the study.

Depressive Symptoms
Patients' clinical pain was assessed immediately before the PET scan using the Short Form of the McGill Pain Questionnaire (SFMPQ). Patients' depressive symptoms were also assessed using the Center of Epidemiological Studies-Depression Scale.

PET imaging revealed FM patients had significant reductions in MOR BP compared with controls in the bilateral nucleus accumbens, the left amygdala, and the right dorsal anterior.

In addition, researchers found that, among FM patients, MOR BP was negatively correlated with clinical pain ratings in the affective, but not the sensory, dimension of pain. "We looked specifically at the ratio between the affective and the sensory dimensions of pain and found that those people who have more of the affective dimension of pain, which is a measure of the unpleasantness of the pain sensation, have lower binding potential, mostly in the cingulate regions," he said.

Finally, the study showed that patients with more depressive symptoms had greater reductions of MOR BP, particularly in the amygdala.

Need for Alternate Therapies
Dr. Harris said he was surprised to find reductions in receptor availability were local, rather than global.

"Based on a previous study, where we found elevated opioid levels in the CSF, I anticipated we would see reductions in receptor availability throughout the brain. However, what we observed was reduced receptor binding limited to very discrete and focal brain regions," he said.

To date, said Dr. Harris, there have been no randomized, controlled trials of exogenous opioids in FM. However, he added, the findings of the current study suggest the results of such a trial could be negative.

Future research by his team will focus on gaining a better understanding of the pain mechanisms in FM as well as the development of alternative, potentially more effective, therapies for these patients.

J Neurosci. 2007;27:10000 -10006. Abstract