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
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.
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:
- melatonin is manufactured in the brain from tryptophan
or serotonin, and both of these precursor molecules have been shown to be
low in patients.
- several abnormalities of the sympathetic nervous system
(fight or flight responses) have been found, which directly stimulates melatonin
synthesis and secretion.
- 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
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.
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.