Funding for 1996

Positron Emission Tomography (PET) in FMS and Pain-Free Controls

Principal Investigator: Muhammad Yunus, M.D.
University of Illinois College of Medicine at Peoria
Award: $30,000 - June 1996

The goal of this project was to investigate possible abnormalities in the brain by PET scanning patients with FMS and comparing them to pain-free healthy controls. PET can measure the rate of glucose metabolism in important centers in the brain that may be involved in producing the painful symptoms of FMS. Dr. Yunus and co-workers hypothesized that there would be abnormalities in the pain processing and transmission centers in the brains of FMS patients.

Elevated substance P in the spinal fluid and low serum serotonin levels (among other problems) suggest neurochemical dysfunctions in the brain of patients with FMS. What brain structures are really involved in such dysfunctions or abnormalities? Functional imaging of the brain by single-photon-emission computed tomography (SPECT) has already shown interesting abnormalities in the blood flow through various structures in the brain. More specifically, SPECT has identified those areas of the brain that are involved in pain perception, such as the caudate nucleus and the thalamus.

While SPECT studies in FMS and CFS are ongoing, PET is believed to be more sensitive at pinpointing brain abnormalities with a higher degree of accuracy. Although the FDA has yet to approve tracer drugs for tagging receptor sites of various neurotransmitters, such as serotonin, norepinephrine, substance P, and dopamine, the development of such tracers for PET remains hopeful.

Twelve FMS/CFS patients and seven normal pain-free healthy controls with a similar age distribution were evaluated by PET scan. The scan involves an intravenous injection of a radioactive chemical called 18-fluorodeoxyglucose (FDG) and scanning of the brain 30 minutes later to study glucose metabolism (i.e., the uptake of the FDG) in different regions of the brain.

Study Results - Presented at 1997 ACR

Dr. Yunus performed glucose evaluations while patients were at rest in a dark, quiet room. This tranquil state did not demonstrate a significant difference between FMS/CFS patients and healthy controls, however, it may still provide important clues as to what is happening in patients. Yunus' work may explain the phenomenon that you battle each day: if you take it easy, you may be able to reduce some of your symptoms. This may be why the PET scan didn't pick up anything abnormal in the tranquil state. Yet, the harder you function and the more you try to get accomplished during your day, the worse you feel.

Yunus adds that the PET scans of FMS/CFS patients were not characteristic of people with major depression.

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Melatonin in Patients with FMS and CFS

Principal Investigator: Leslie Crofford, M.D.
University of Michigan, Ann Arbor
Award: $30,000 - June 1996

There were two main goals of this project. One was to determine if the rhythm of production of melatonin (i.e., its circadian rhythm) is abnormal in FMS and CFS patients. The other was to measure the total 24-hour output of melatonin to determine if it differs from that of healthy age and sex-matched controls. Dr. Crofford and co-workers hypothesized that patients with FMS and CFS would display a disturbed melatonin secretory pattern. In addition, the total daily output of melatonin might also be abnormal.

Melatonin is a hormone produced by the pineal gland at the base of your brain. It is important for transmitting information that synchronizes the daily 24-hour circadian rhythms of your neuro-hormones. In other words, melatonin operates somewhat like an internal clock: its secretion cycle signals when certain brain hormones should be released or when they should be shut off.

Abnormalities in the pattern of melatonin secretion have been associated with fatigue, sleep disorders, and mood disturbances in conditions such as jet lag and shift work. Patients with FMS and CFS display similar symptoms, suggesting that there may be abnormalities of melatonin secretion. In addition to symptoms, there are other reasons to believe melatonin secretion may be disturbed in patients with FMS and CFS, such as:

1. melatonin is manufactured in the brain from tryptophan or serotonin, and both of these precursor molecules have been shown to be low in patients.
2. several abnormalities of the sympathetic nervous system (fight or flight responses) have been found, which directly stimulates melatonin synthesis and secretion.
3. disturbances in the circadian rhythms of other hormones such as cortisol have been found and this could reflect a generalized disruption of the body's natural circadian rhythms.

Blood was collected every hour over a 24-hour period from 20 patients with the diagnosis of FMS, CFS or both, and from 20 healthy controls. The pattern of secretion of melatonin (circadian rhythm) was determined along with the total 24-hour melatonin output from the pineal gland. This data was also correlated with the person's cortisol secretion. Comparison is important because increases in cortisol production are believed to inhibit the secretion of melatonin. In addition, symptoms of fatigue, pain, sleep disorder, and mood disturbance were correlated with the melatonin and cortisol findings.

Melatonin levels can be manipulated by supplementation, psychoactive medications, sympathetic nervous system blockade, or by bright light. However, it is only by rigorous investigation of the secretory characteristics of melatonin in individuals with FMS and CFS that one can predict the therapeutic impact of manipulation of melatonin levels.

Preliminary Results - Presented at the 1997 ACR

Dr. Crofford found that the nighttime plasma melatonin levels in patients were significantly higher than in healthy controls. The large burst of melatonin secretion occurred at the right time of night, but when it was compared to the peak production time of cortisol, it was delayed by 76 minutes. Melatonin is supposed to set your body clock, but Crofford's findings indicate that this internal clock may not be working right. Dr. Crofford has already used the data collected by this study to obtain an NIH grant to further her work in this area as well as attempt to relate these findings to disturbances in pain control mechanisms. She is also submitting the study for medical journal publication.

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Neuroendocrine Therapies for FMS and CFS

Principal Investigator: Robert McMurray, M.D.
University of Mississippi, Jackson
Award: $29,704 - June 1996

Dr. McMurray's project goal was to conduct a double-blind, placebo-controlled study of two different therapies taken at night for FMS: 6 mg of melatonin or 2.5 mg of bromocriptine. Multiple neuroendocrine abnormalities may occur in FMS patients and these therapies may help correct them. Dr. McMurray suspects that FMS is a circadian rhythm disease that alters the function of important neuro-hormones. His hypothesis is that patients will have decreased pain, improved sleep, and increased function in response to one or both of the medications tested.

Serotonin abnormalities are thought to exist in FMS and may hamper the body's natural production of melatonin in the pineal gland. Supplementation with melatonin may directly improve symptoms in patients or may even reduce some symptoms by increasing the amount of available serotonin because less will be needed in the brain for making melatonin.

Bromocriptine acts like the neurotransmitter dopamine, and also reduces the production of a pituitary hormone called prolactin. The spinal fluid level of the dopamine metabolite, homovanillic acid, has been shown in one study to be significantly low in FMS patients. Low homovanillic acid is a good indicator that dopamine in the central nervous system might be low as well.

The most common disease characterized by low dopamine levels is Parkinson's disease in which movement disorders occur (such as uncontrollable tremors). Other movement disorders like restless legs syndrome, bruxism (teeth grinding or clinching), and periodic limb movements during sleep (PLMS or nocturnal myoclonus) occur in at least 20% of FMS patients. Low dopamine levels may be at the root of these problems as well.

What about bromocriptine's effect on reducing prolactin secretion? By suppressing prolactin secretion, bromocriptine is thought to relieve anxiety and stress--both of which may reduce the HPA system abnormalities. This drug has also been shown to be useful in the treatment of premenstrual syndrome.

A small pilot study by Dr. McMurray (published in Journal of Rheumatology, November 1995) indicated that the use of bromocriptine in lupus patients actually reduced many symptoms that are also found in FMS: fatigue, cognitive dysfunction, depression, muscle pain and headaches. In addition, the drug was found to be well tolerated.

Thirty-five FMS/CFS patients were to be enrolled in this study that was completed in 1998. Each patient was randomly placed in a series of three treatments each lasting four months: melatonin, bromocriptine and placebo. There were placebo "washout" periods between the two drugs, melatonin and bromocriptine, so that the effects of one drug would not carry over into the other trial. None of the patients knew what they were getting--all pills were specially formulated to look the same. With this study design, patients functioned as their own control during the placebo phase of the drug trial.

Throughout the trial period, the investigators assessed the patient's symptoms and drew blood each month to test for the following: melatonin, prolactin and cortisol. Other tests to determine how the brain-pituitary system is working were done as well. Therefore, this is much more than just a standard drug trial that tells whether or not a particular therapy reduces the symptoms. This study is designed to also determine why and how melatonin and/or bromocriptine work in patients with FMS/CFS. This is a crucial element of the project because one therapy may not be as helpful for all patients and at least the investigators will be left with a few clues as to why this might be so.

Although some treatments for FMS have been transiently effective, 66% of FMS patients still have significant symptoms no matter what therapies they try. As stated above, this is no ordinary drug trial; it can have a high impact on our current understanding of this devastating disease. Dr. McMurray completed the trial in February of 1999 and is in the process of analyzing the study results.