Dr. Pellegrino is a leading fibromyalgia specialist and author who has had FM himself since childhood. His observations of familial fibromyalgia patterns and permutations such as "the aging threshold" reflect more than 20 years' experience treating patients at the Ohio Pain & Rehab Specialists Center. Basic knowledge to help genomic researchers sort things out as we move closer to understanding and control.
THE PROBABLE CAUSES OF FIBROMYALGIA
All of us involved in fibromyalgia, either by treating it or having it, have come to appreciate how complicated this condition is…. Most important, there is more than one way to get fibromyalgia; it is an “end point” condition with multiple ways leading to it.
One of my pet peeves is that I continue to read in the scientific literature statements such as “the cause of fibromyalgia is not currently known,” or "future research will hopefully discover the cause of biromyalgia." This implies that we don't know anything about the causes. I have had some doctors and attorneys suggest to me that if the cause is unknown, then perhaps we are not even sure that fibromyalgia exists.
I think we can say that a number of causes of fibromyalgia are known at the present time. And I think one of our problems is that we try to be too scientific, when we really need to be more practical and logical. One difficulty is determining the difference between cause and pathological mechanism. In fibromyalgia the cause would be WHY fibromyalgia developed. The pathologic mechanism would be HOW fibromyalgia developed.
I have compiled a list of probable causes of fibromyalgia.
This list is based on my experiences and understanding of the current literature. My opinions on these probable causes may not be shared by everyone. My list of probable causes is as follows:
3. connective tissue disease
5. Catastrophic stresses
6. Chemical exposure.
Probable FM Cause #1: GENETICS
These observations support the notion that fibromyalgia can be inherited, or at least the tendency to develop fibromyalgia is inherited:
• Physicians who see patients with fibromyalgia can recall a number of patients who are relatives.
• I have seen numerous family members,mother-daughter, sister-sister, sister-brother, etc., who have the typical symptoms and findings of fibromyalgia.
• Several members of my family have fibromyalgia through four generations!
• I also see numerous patients who tell me they have family members known to have it (their family history is positive for fibromyalgia).
• Many adult patients state they had pain as a child.
Several studies on the hereditary aspects of fibromyalgia have been published. Dr. George Waylonis and I published a study in 1989.(1)
We studied 17 families and as many first-degree relatives as we could gather up (sibling, parent, child), and concluded that:
• A number of family members had fibromyalgia in a pattern that suggested an autosomal dominant mode of inheritance. This means that if one parent has fibromyalgia, then 50% of the offspring have a chance of getting fibromyalgia, whether they are male or female.
• There also appeared to be a variable latent stage, which means that the fibromyalgia could develop at different ages in different offspring.
• There also appeared to be variable transmission (i.e., it could skip a generation).
My study found a high percentage of fibromyalgia in men with a positive family history, nearly equal to the women.
This is much different than the people who present to the doctor’s office, because among these people more than six times as many women as men will be diagnosed with Fibromyalgia. Men DO have Fibromyalgia, but they take a different course than women. Sometimes we have to go out and look for them because they do not tend to come to us to be diagnosed.
Dr. Dan Buskila from Israel performed a study looking at 60 children of 21 mothers with fibromyalgia.(2)
He found that 23% of the offspring, most of them female, have fibromyalgia. When he looked at the males with fibromyalgia, he found that the ones who were under 18 had fibromyalgia almost as frequently as the women under 18. He concluded that fibromyalgia had a major genetic component that possibly fit the autosomal dominant mode of inheritance (50% of children who have one parent with FM will have FM, whether male or female) – especially among males and females under age 18.
Dr. Buskila did another study looking at people with fibromyalgia, and many of their relatives.(3) He found that 45% of the relatives reported widespread musculoskeletal pain resembling fibromyalgia.
Other studies have supported an inherited pattern to fibromyalgia.
Dr. Muhammad Yunus performed Human Leukocyte Antigen (HLA) studies in fibromyalgia. HLAs are genetically determined molecules that are found in virtually all cells. HLA genes can be markers for certain diseases, and the results of Dr. Yunus’ HLA study suggests a genetic role in fibromyalgia.(4)
I believe that the literature, combined with accumulated clinical experience, supports a genetic cause of fibromyalgia.
A “common sense” approach would be to recognize that fibromyalgia is so common in the general population of the entire world that there must be some type of common genetic make-up that leads to it. Another logical conclusion from all of the available information is that people are genetically predisposed to getting fibromyalgia.
I think a number of people are programmed genetically to develop fibromyalgia over time, probably independent of the environment. However, for a number of others, an environmental trigger must occur (i.e., the other causes listed here and perhaps others yet unknown) for the fibromyalgia to develop.
Who Is at Risk Genetically to Develop Fibromyalgia?
I think the following can be considered at risk:
1. A child with one or both parents with fibromyalgia.
2. A child of one or both parents with a connective tissue disorder such as rheumatoid arthritis or lupus.
3. A child with a sibling who has fibromyalgia.
4. A child with a first-degree relative (parent or sibling) who has fibromyalgia.
Just because someone is a risk does not mean he or she will automatically get fibromyalgia. The right “trigger” may never happen. If a child at risk does become symptomatic with fibromyalgia, there’s a lot that can be done. (See
"Fibromyalgia in Children and Teens – Risk Factors, Symptoms, and Treatment"). Don’t assume that someone will get fibromyalgia or that it will be bad if he or she does.
Genetics Play a Role in Pain Sensitivity
Dr. George Uhl (a neurologist at Johns Hopkins) found that differences in pain perception were due to variations on the surface of nerve cells, specifically on the molecule called the mu opiate receptor. The mu receptor works by bonding with natural chemicals called peptides that help diminish the sensation of pain. Individuals who have lots of these receptors (too few mu’s!) cannot diminish the pain as well, and even small stimuli can cause severe pain.
The number of these receptors is controlled by the action of the mu opiate receptor gene. Those with fibromyalgia, or at risk for it, may be genetically mu deficient.
I believe with additional research we will be able to further clarify specific genes causing pain, identify gene expression profiles of specific subtypes of fibromyalgia, and develop genetic-specific medicines to control pain and reduce the effects of fibromyalgia.
[Note: just weeks ago, a pioneering study involving whole genome sequencing of identical twins with a rare condition found that they had inherited a "double dose" of such a gene variant, one from each parent; a "dramatic manifestation" of what in single copies the researchers believe may explain a recognized pattern of fibromyalgia symptoms among other family members.(5)]
Genetics and the “Aging Threshold”
A common story I hear from patients is that their pains gradually developed without any obvious or precipitating event. We mentioned earlier that genetics may cause some people’s fibromyalgia to develop randomly at some point, and once the pain starts it’s always there and can get worse over time. But is this process random, programmed, or subject to environmental factors? Probably a combination is involved.
I see many children and teenagers with fibromyalgia, but I see more adults in their 30’s or older when they first developed fibromyalgia symptoms. If genetics were the only factor in developing fibromyalgia, I would expect more younger patients with chronic pain complaints.
Genetic expression of a condition may take years to happen, so some people who first develop FM symptoms in their 30’s or later may have programmed genes causing the delayed expression.
Although genetics are a factor, I think there might be additional factors causing the “delayed” development of fibromyalgia; factors that I refer to as the “aging threshold.”
The aging threshold implies that as a person gets older, the threshold is lower for developing fibromyalgia. The person may be more vulnerable to getting fibromyalgia from various causes in the [probable cause list], but the aging process is also a risk for getting fibromyalgia, especially in women.
• Both men and women are found to lose their ability to inhibit chronic pain signals as they get older, and normal women already have a “defective” pain inhibitory system to begin with. Thus, any vulnerable person (who inherited fibromyalgia genes) would be less able to inhibit pain signals as he or she aged, and would become more susceptible to developing amplified pain (women more than men).
• Also, wear and tear changes on the body over time may contribute to the aging threshold. As we age, inevitably our muscles, tendons, ligaments, discs and joints show signs of deterioration accumulated micro-trauma. These deteriorating tissues may form painful areas, i.e., pain-generation. In a vulnerable person, the development of painful areas may trigger the “amplified pain” cascade.
• Additionally, hormonal changes over time can increase the risk for developing pain. For example, early menopausal women are more likely to report increased fibromyalgia pain.
If we combine these different factors, we can appreciate how the pain / fibromyalgia threshold lowers as one ages, and it appears that by the 4th or 5th decade (30’s and 40’s) the aging threshold has reached a “predictable” level – where fibromyalgia can take hold. Hence the increased frequency of fibromyalgia complaints in this age range.
Once the pain threshold drops below the body’s ability to inhibit potential / random chronic pain signals, the threshold is “breached.” Now, chronic pain signals have a better chance of propagating the amplified pain cascade of changes and lead to Fibromyalgia. (To read more on this cascade of changes, see “Fibromyalgia – Ultimately a Disease of Amplified Pain.")
Probable FM Cause # 2: TRAUMA
Probable FM Cause # 3: CONNECTIVE TISSUE DISEASE
Many people get fibromyalgia associated with another disease, particularly rheumatic and connective tissue diseases. After genetics and trauma, I believe this type of disease is the most common cause of Fibromyalgia. Conditions in this category that can lead to reactive fibromyalgia include rheumatoid arthritis, lupus, polymyalgia rheumatica, and autoimmune disorders such as thyroiditis and Sjogren’s syndrome. Fibromyalgia does not turn into rheumatoid arthritis, lupus, or other inflammatory conditions, however.
Probable FM Cause # 4: INFECTION
Probable FM Cause # 5: CATASTROPHIC STRESSES
These are synonymous with emotional trauma. These are not your everyday stresses. Rather they represent more severe stresses which can cause fibromyalgia. The mechanism is probably very similar to a physical trauma, only instead of a tissue injury, there is a stress injury that may disrupt the hypothalamic-pituitary-adrenal hormone regulation (the stress hormones).
Probable FM Cause # 6: CHEMICAL EXPOSURE
I’ve seen a number of patients who have developed fibromyalgia after chemical exposure. Usually they have inhaled fumes from offending chemicals which include petroleum oils, paint thinners, cleaning solvents, dyes, or gasses/fumes from burning products. Most of the time these patients are treated at the hospital, but have lingering symptoms and ultimately develop fibromyalgia. The mechanism whereby these chemical exposures cause fibromyalgia appears to be an allergic and/or autoimmune response that escalates and sets off the fibromyalgia cascade. Many people with fibromyalgia are sensitive to chemicals, drugs, and environmental allergens like pollen, dust and molds. A condition known as chemical sensitivity syndrome occurs when one becomes chronically fatigued and ill from exposures to various substances.
We may not know the specific cause for a particular individual, but every single person with fibromyalgia has a cause, and ongoing funding and research of this complicated condition will result in further understanding. Future research will continue to shed light on these factors:
1. More specific identification of Fibromyalgia subgroups and better delineation of the overall Fibromyalgia Spectrum (See “The Fibromyalgia Spectrum – Part of the Big Picture in Understanding Fibromyalgia.")
2. Better understanding of the actual pathological mechanism, and learning what specifically triggers fibromyalgia from a microscopic or cellular level.
3. The ability to predict who will get fibromyalgia and what happens over time, and to understand the risks.
4. Additional genetic research to identify specific gene markers or specific neurobiological factors that contribute to fibromyalgia. Genetic research could also identify healing factors or specific gene therapy.
1. "Familial occurrence of primary fibromyalgia," Archives of Physical Medicine and Rehabilitation, Jan 1989.
2. "Mechanisms of Disease: Genetics of Fibromyalgia," Nature Clinical Practice, Rheumatology, 2006.
4. "Genetic linkage analysis of multicase families with fibromyalgia syndrome," Journal of Rheumatology, 1999.
* Note: This article is excerpted with kind permission from Dr. Pellegrino’s book, Fibromyalgia, Up Close & Personal © Anadem Publishing, Inc. and Mark Pellegrino, MD, 2005. You may purchase a copy of this highly recommended book by contacting Dr. Pellegrino's office at the Ohio Pain & Rehab Specialists Center (Phone: 330-498-9865, Toll-Free: 800-529-7500).