Funding for 1997

A Double Blind, Placebo Controlled Study to Determine Whether Dextromethorphan is More Effective Than a Placebo in the Treatment of FMS Pain

Principal Investigator: Robert Bennett, M.D.
Oregon Health Sciences University, Portland
Award: $16,140 - July 1997
Award: $4,000 - July 1998 for modified design

The pain of FMS/CFS is thought to be caused by a "hypersensitized" central nervous system (CNS). A Swedish research team recently showed that three different drugs aimed at taming this hypersensitized state provided varying degrees of pain relief in 18 FMS patients (Journal of Rheumatology, August 1997). The three drugs used were morphine (an opioid), ketamine (an NMDA blocker that works to reduce pain amplification in the CNS), and lidocaine (an anesthetic that blocks the amount of noxious inputs going to the CNS). Intravenous ketamine provided the longest duration of pain relief--it lasted up to five days in some patients. Unfortunately, ketamine is not available in pill form and it has too many side effects to be administered on a routine basis.

Dextromethorphan is a commercially available NMDA blocker. It has less side effects than ketamine and can be compounded in pill form (it's in over-the-counter liquid form, Delsym, in 30 mg adult dosing but this can't be used in the study because it would unblind participants ... patients would know what they were getting). Dr. Bennett will be giving specially formulated dextromethorphan to FMS patients in increasing doses until they either obtain a significant relief of pain or experience unacceptable side effects.

Initially, Bennett began the first phase of the study by bringing patients up to the dose of dextromethorphan that eased the pain. However, after six patients had entered the study and they were taking greater than 200 mg daily doses of dextromethorphan, they indicated that while they had very little pain, they also were experiencing significant concentration difficulties. Dextromethorphan can block pain amplification in the spinal cord, but when it reaches the higher centers in the brain, it can interfere with one's ability to think. Dr. Bennett was kind enough to alert AFSA of this problem up front and suggested an alternative study design that includes the combination of Ultram with dextromethorphan.

Ultram (tramadal) is a weak opioid that can be easily prescribed by physicians (it's not a controlled substance). By using Ultram, a lower dose of dextromethorphan will likely be needed to reach a level of significant pain relief. In addition, the combination therapy should be superior than Ultram by itself. Therefore the original study has been changed to compare the effectiveness of Ultram versus the combination of Ultram plus dextromethorphan. Those patients obtaining sufficient pain relief will be randomized to continue on either dextromethorphan/Ultram combo or Ultram/Benadryl combo for 30 days (the Benadryl causes mild drowsiness similar to that of dextromethorphan and serves as an "active" placebo). Both the physician and patient will be blinded as to which pill is administered. The major end point will be whether the addition of dextromethorphan to Ultram results in a significant improvement in pain and other measures, compared to the use of Ultram alone. This study will also help determine the typical dose of dextromethorphan that is effective with the least amount of side effects.

The ground-breaking work of the Swedish team using ketamine in FMS patients shows promise for the effectiveness of NMDA receptor antagonists in the management of FMS pain (it also shows that opioids may be beneficial as well). Although ketamine has too many side effects, the use of high doses of a less potent NMDA receptor blocker, such as dextromethorphan, may be helpful for the treatment of chronic pain.

If the outcome of this study is positive, then this trial will allow for more sophisticated, long term studies using this combination drug therapy. It may also pave the way for testing other combination therapies that include dextromethorphan.

Project Update

At the October 2000 American College of Rheumatology (ACR) meeting, Drs. Bennett and Clark presented their findings to date on the use of dextromethorphan (DM) to boost the pain relieving action of Ultram (a weak opioid commonly prescribed for FMS).

This double-blind, placebo controlled study looked at the dropout rate of FMS patients who were initially taking both Ultram and DM, but were blindly switched to Ultram plus a placebo pill that was made to look just like the DM. The placebo used was Benadryl, so it had some mild side effects that were intended to help "blind" patients who were taken off of DM. Most patients on the placebo (but still taking Ultram) had dropped out at the time of the ACR meeting, implying that the pain reducing abilities of DM were very real for those who responded to it. (Bennett says the study is now complete and he plans to prepare the results for publication.)

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Role of the Limbic Brain System in Abnormal Pain Perception in FMS

Principal Investigator: Laurence Bradley, Ph.D.
University of Alabama, Birmingham
Award: $30,000 - June 1997

Dr. Bradley is measuring changes in the brain blood flow when mild electrical stimulus is applied to several body sites on people with and without FMS. This will provide researchers more insight as to what happens in the brain of patients as they receive new stimuli that may produce unpleasant or even painful sensations.

In addition to just looking at the thalamus and the caudate nucleus, two pain processing centers that are already known to have low blood flow levels when patients are at rest, there are other important structures within the limbic system that are involved in pain perception and stress response mechanisms. Bradley is using SPECT (single-photon-emission computed tomography) in combination with MRI to analyze the blood flow in three other brain limbic structures to shed more light on what other areas of the brain could be functioning abnormally in patients. One structure in particular that is being assessed is the locus coeruleus, which is involved not only in the regulation of pain, but also that of sleep and stress response mechanisms.

The hypersensitivity that FMS patients display to a variety of stimuli is poorly understood and is often viewed as a psychological phenomenon. If Dr. Bradley's study is successful, it may provide evidence for a physiological basis for the perception of pain among FMS patients in response to low intensity stimuli that are generally not painful or unpleasant to healthy people. It may also clarify the role of the interactions between abnormal functional brain activity and abnormal hypothalamic-pituitary-adrenal function, as well as lead to the development of improved drug therapies.

Research Update

Laurence Bradley, Ph.D., presented his first AFSA-funded study at the October 2000 ACR meeting. Then at the April 2001 American Pain Society meeting (pictured at right), he presented the preliminary findings of his second project. Here are the highlights of his two brain imaging studies involving the use of SPECT scans:

• The heightened pain sensitivity to painful stimuli is not an imagined phenomenon. The mere suggestion of giving a painful stimulus to FMS patients who are already burdenedby pain-related anxieties causes an increased blood flow or "activation" in pain control centers in the brain. Both drug and non-drug therapies for anxieties—often brought on by past painful experiences—may help minimize FMS pain.

• People with depression have a normal pain threshold and their brain imaging response to a painful stimulus closely resembles that of healthy people. Both of these findings are different for FMS patients. (Bradley will present more details at the November 2001 ACR.)

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Sensitization in FMS and CFS - with and without Chemical Intolerance

Principal Investigator: Iris Bell, M.D., Ph.D.
University of Arizona, Tucson
Award: $29,957 - June 1997

Chemical sensitivity studies by Dr. Bell suggest that chemical intolerance may be a measurable indicator of your brain's ability to amplify symptoms (including pain) or sensations, such as that of odors that may not be noxious to other people. Airborne chemicals and infectious agents are not the only factors believed to lead to or aggravate chemical sensitivities. High levels of body chemicals such as substance P (which is known to be extremely elevated in FMS patients) can also cause your brain to become sensitized and produce amplification of symptoms due to a malfunctioning of the brain.

If chemical intolerance is present, then repeat exposure to various substances will likely lead to further amplification of the brain's abnormal response. One part of the brain controlling this amplification is the limbic system, which is also involved in the development of craving for drugs such as stimulants and foods such as sugar. These substances give the individual a short-lived boost of energy. This same area of the brain responds to substance P as though it, too, were a rewarding drug-like substance. It's known that FMS patients have increased levels of substance P released in their central nervous system and that people with chemical intolerance often crave sweets even though they feel ill after consuming them. These, along with other abnormalities, may form a biochemical link between FMS/CFS and chemical intolerance.

Many different substances can cross-sensitize with one another in the body. What this means is that one substance can cause the same amplified effect that a high level exposure to some other substance has previously triggered into motion. This cross-sensitization may allow many different substances that are abnormally produced or present in patients to then create amplified symptoms that were initially set off by another substance or stressor. These amplified symptoms may include pain, fatigue and other problems that FMS/CFS patients have.

Dr. Bell hypothesizes that FMS/CFS and chemical intolerance patients suffer from increased susceptibility to sensitization from internal factors like substance P and also from environmental factors, such as foods and airborne chemicals or pollutants. If this is so, FMS/CFS patients may have sensitization to certain foods like sugar.

A series of repeat exposure to a common stimulus will be used to test the study hypotheses. Data collection will employ: symptom checklist, health history questionnaires, examinations, and repeated laboratory tests that measure brain waves, heart rate, and blood pressure.

Half of the 30 FMS/CFS patients to be tested will also have chemical intolerance. A normal, healthy control group will undergo the same testing.

This study could lead to increased understanding of how the brain might contribute to the long term symptoms of FMS/CFS. The outcome of this study may favorably influence treatment rationales for preventing and/or reversing the abnormal brain function in patients.

Dr. Bell has finished this study and will be presenting her data at a medical conference in March of 1999. Once her data become public, we will discuss them further in the AFSA Update.

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The Role of Zinc in FMS

Principal Investigator: I. Jon Russell, M.D., Ph.D.
University of Texas, San Antonio
Award: $22,000 - June 1997

I. Jon Russell, M.D., Ph.D. has discovered that the serotonin storage in the platelets in the blood of FMS patients is decreased as opposed to people without FMS. Serotonin plays a number of roles in the body, such as regulating sleep and reducing pain sensations. As for the platelets, they are the cells in the blood that clump together to help stop bleeding at the site of an injury. This clumping process may not be working properly. In this study, Dr. Russell hypothesizes that many of the blood abnormalities might be related to zinc.

Zinc is needed for certain immune system functions and is also involved in the growth hormone-induced release of IGF-1 from the platelets into the serum. IGF-1 helps repair cells and has been found to be low in the serum of FMS patients. Zinc is concentrated in the central nervous system in areas that may be involved in pain inhibition. Russell suspects that zinc might reduce the pain-producing effects of high substance P and nerve growth factor (meaning that low zinc stores could be a problem).

Thirty FMS/CFS patients and age/sex matched healthy controls will have their blood drawn for zinc analysis on the first day of the study. They will be evaluated in terms of pain scores and many other symptom measures, as well as a dietary assessment. The blood assays and symptom assessments will serve as the baseline scores for each individual. FMS patients and healthy controls will be instructed to take coded tablets that either contain a placebo or zinc supplement. After a few days, the subjects will return to Dr. Russell's laboratory where the tests will be repeated.

Dr. Russell does not recommend that patients increase zinc supplementation before the results of this study are known. There is a potential risk of upsetting the body's copper/zinc balance when too much zinc is ingested. However, if a zinc abnormality can be found, then the next step for researchers would be to determine how to solve this problem.

Dr. Russell has finished this study and is analyzing his data for formal publication.

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Pain Induced Changes in Basal Ganglia and Limbic System Function Among Patients with FMS, CFS, and Healthy Controls versus People with Major Depression

Principal Investigator: Laurence Bradley, Ph.D.
University of Alabama, Birmingham
Award: $29,773 - October 1997

Tag-on Project to Ongoing NIH Study

Dr. Bradley's team has indicated that FMS patients at rest have abnormally low cerebral blood flow levels in their caudate nucleus and a tendency toward reduced blood flow in the thalamus. These structures are located in the basal ganglia and work to inhibit pain. The processing of stressors, emotions, and one's perceptions of pain and other stimuli, are all accomplished in the limbic system of the brain. This system has a network of connections to a multitude of other regions in the brain and is responsible for making sense out of the incoming signals and developing an appropriate response.

We can only speculate what happens to cerebral blood flow when a painful stimulus is given to people with FMS, CFS, and major depression as opposed to healthy controls. Fortunately, these questions are being addressed by an NIH grant, except for the part about testing individuals with major depression. AFSA has given Dr. Bradley the opportunity to answer this question.

All too often, findings in FMS and CFS are attributed to depression. Addressing this problem, Bradley writes: "It's important to determine whether FMS and CFS are associated with functional abnormalities in the basal ganglia or limbic system structures independently of effects of depression."

After an initial baseline scan, here is what Bradley is proposing will happen on the second SPECT scan performed when FMS patients are subjected to pressure pain stimulus on the right side of their body:

l The increase in blood to the pain processing areas (basal ganglia) will be significantly less in FMS patients than depressed or healthy control subjects.

l Both FMS and depressed people will have higher levels of blood flow to the limbic structures as compared to healthy controls. This is because painful stimulus to these two patient groups will understandably elicit more distress. Elevated levels of distress may be the primary physiological link between FMS and major depression.

Bradley's team is attempting to demonstrate that FMS and CFS are distinct neurosomatosensory processing disorders. In other words, they don't represent a form of depression.