Or: “ Can an Operation Cure My Fibromyaglia?”

Many Fibromyalgia Syndrome (FMS) patients have become aware of a neurologic condition termed “Chiari I malformation,” and the possibility of having a neurosurgical operation that could potentially reduce or even cure their FMS. This is an area that has generated considerable controversy and is a very serious matter that has even been considered by medical boards. 

Or: “What else could I possibly have?”

Physicians use the words “differential diagnosis” to mean other conditions that have to be considered when diagnosing the medical condition of interest. In the case of FMS this includes diseases that both resemble FMS in some aspects of their medical symptoms and also, in the past, were believed to have contributed to the condition of “secondary FMS.” Secondary FMS means FMS is not the medical condition that is primarily important, it is “secondary.” 

Mention the words psychiatry or psychiatrist to an individual with Fibromyalgia syndrome (FMS) and you’re bound to get some raised neck hairs.  However, even though some people may refuse to even mention the “P” word, psychiatrists and the field of psychiatry have made notable contributions to the study of FMS. This short report will review the psychiatric findings, the accompanying psychological conditions, and their relationship to FMS. 

In the first two parts of “The Pain the Brain” series the concept of descending inhibition has been mentioned. This refers to a very elegant part of the central nervous system that originates in the brain and travels down the spinal cord to actual inhibit pain signals that have yet to be transmitted up into the brain—hence its name of “descending inhibition.” It has colloquially been referred to as “pain inhibits pain,” and its complete medical name is diffuse noxious inhibitory control (DNIC). 

Part 1 of this series described the pain process in the central nervous system, primarily the phenomenon called windup and how it is created. Windup is the beginning of an important change in the central nervous system called central sensitization which is at the heart of the pain felt by patients with FMS. It was mentioned in Part 1 of this series that there is some bad news for FMS patients regarding windup. Here it is.

The International Association for the Study of Pain has defined pain as both an "unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage." There has been an extensive medical literature published on the multitude of mechanisms responsible for the primary complaint of FMS patients — pain. 

Part 3 - Vaccinations and Infections

     The National Fibromyalgia Association’s 2006 Internet survey of 2596 individuals found that 26.7% of those who could trace the origin of their FMS to a specific event reported that event to be an illness and 45% felt that infections worsened their FMS symptoms.  However, the reports in the scientific literature are conflicting.

     Only one study has been reported showing that chronic hepatitis B infection may increase the risk of FMS. In this study 25% of patients who had antibodies that were positive for Hepatitis B also had FMS.  Two studies with a total of 202 FMS patients have reported an association of hepatitis C virus infection and FMS.  Conversely, two studies with 267 FMS patients found no association to hepatitis C.  If such an association does exist, one possible pathological mechanism may involve hepatitis C induced changes in cytokines which affect the hypothalamic-pituitary-adrenal axis. 

     If you’re wondering just what are cytokines, then be sure to read the two short reports on cytokines and neuroendocrinology. Until you do here is an introduction to cytokines. They are cellular molecular messengers that the body uses primarily to regulate inflammatory responses. When you hear about cytokines, it will usually be in regard to arthritis but they will also appear in discussions about inflammatory bowel disease and interstitial cystitis – two other conditions that occur in FMS. Cytokines can be released by different types of cells into the circulation or into tissue and they will then bind to specific receptors on other cells and trigger responses in these cells – hence the messenger function. 

     HIV is another infection that has caught the attention of FMS researchers. Dr. Buskila, who is a dedicated Israeli FMS researcher, has found 15 of 51 patients (29%) diagnosed with HIV to also have FMS which was not associated with duration or stage of HIV infection. FMS has been found in 11% and 17% of HIV patients in two other studies.

     Everyone has heard about Lyme disease and it has generated some interesting findings in regard to FMS. A study in the Annuals of Internal Medicine published in 1992 suggested that Lyme disease may trigger FMS but antibiotic treatment was not effective in resolving symtptoms. The confusion of Lyme disease and fibromyalgia was, in part, responsible for one physician stating that approximately half of the 91 courses of antibiotics provided to 100 patients first seen at the Lyme Disease Center at the Robert Wood John Medical School were “probably unwarranted.”  This was most likely due to the infectious organism causing Lyme disease, Mycoplasma, creating symptoms similar to FMS. However, to date, no definitive association exists between FMS and Mycoplasma infection.

     So far, as in most other studies on the causative factors for FMS, there are no clear-cut answers regarding infection or vaccination and FMS. More evidence that work still needs to be done.

Part 2 - Emotionally Traumatic Events

     Emotionally traumatic events have long been considered a cause of Fibromyalgia Syndrome (FMS). However, it has been difficult to attempt to do research in this area primarily because of a statistical peculiarity called Berkson’s bias. If you have read some of the other short reports you may have remembered reading about the odds ratio. The odds ratio is a number that simply tells you about the odds of having a disease or medical condition compared to something else. For example, if you smoke the odds ratio of developing a particular type of cancer may be 6.8 compared to someone not smoking. This simply means you are at almost seven times the risk of developing that cancer by smoking, or it appears at a frequency in smokers that is 700% greater than non-smokers – the numbers mean the same thing.

     Berkson’s bias applies to people with two or more separate medical conditions – say heart disease and diabetes. People with heart disease and diabetes will see their doctor more than someone with just one of those diseases simply because having both diseases usually means they have more problems with both diseases than if they had just one. Berkson’s bias can either falsely elevate or lower an odds ratio depending on whether two medical conditions influence medical care for the other. In the case of FMS, patients who also have a history of physical or sexual abuse or post-traumatic stress disorder may disproportionately seek more medical care. If you are a researcher seeing FMS patients, you may see those FMS patients with a history of physical or sexual abuse more frequently than patients without such a history – this would inflate the odds ratio. Given that the independent consequences of trauma, such as musculoskeletal pain, fatigue, and mood and sleep disturbances overlap with the major core symptoms of FMS, this can be an important bias that confuses the picture when researchers try to separate out cause and effect.

     Stress has also been associated with imbalances in hormones and how the autonomic nervous system functions. Remember, the autonomic nervous system is largely responsible for all the unconscious actions of your body – breathing, heart rate, digestion, etc. A group of FMS researchers has shown that childhood physical abuse and sexual abuse both predicted abnormal cortisol responses in adult patients with FMS. Cortisol is the stress hormone of the body. Likewise, in adults studied immediately after trauma, disrupted cortisol levels are predictive of the later development of PTSD. These findings suggest there may be a neuroendocrine link between trauma, abuse, and dysruptions in the neuroendocrine axis affecting cortisol that could possibly begin in childhood – and that link may be tied to FMS.

     Three notable studies have provided support for an association of sexual and physical abuse and FMS, while two have not. FMS symptoms, if they are going to manifest, can develop up to 18 months after a traumatic event. A group of FMS researchers,  in 1997, compared FMS patients to those with rheumatoid arthritis and noted those with FMS had significantly higher lifetime prevalence rates of all forms of childhood and adult victimization as well as combinations of adult and childhood trauma. The strongest relationship was shown by FMS patients who had been physically assaulted in adulthood. It was also found that the severity of trauma could be correlated to measures of physical disability, psychiatric distress, the ability to adjust to illness, and the quality of sleep in FMS patients; but not to any of these characteristics in those patients with rheumatoid arthritis.  A psychiatrist specializing in FMS, Dr. Boudewijn Van Houdenhove, has found in FMS patients significantly higher prevalences of emotional neglect and abuse and physical abuse; he also identified a subgroup having experienced lifelong victimization. 

     Another group of FMS researchers has conducted the first community-based study of psychosocial trauma in FMS. The use of a community sample reduces the effects of something called reporting bias which is a significant factor when you try to study an issue this sensitive. Reporting bias means that people are reluctant to discuss certain aspects of their history with another individual because they are embarrassed, ashamed or otherwise uncomfortable but they will do so in an anonymous survey. They found that with the exception of actual rape, no self-reported sexual or physical abuse was associated with FMS; women who had been raped were 3.1 times more likely to be diagnosed with FMS.

     This was recently substantiated by a 2010 review that also found that two types of traumatic experiences, sexual assault and physical abuse, were associated with fibromyalgia. This study also looked at males with FMS.  Men with FMS experienced more life-threatening trauma while women had suffered more sexual assaults and abuse. No association was seen for other major life stresses, life threatening trauma, or emotional abuse and neglect.

     The first study examining post-traumatic stress disorder and FMS was published in 1997 and reported FMS in 21% of a group of 29 PTSD patients seen for care at a mental health clinic compared to normal control patients.  However, those PTSD patients with FMS were quite affected by the syndrome, much more so than other FMS patients, suffering pain, poorer quality of life, higher functional impairment, and psychological distress.

     In a 2000 study 56% of 93 FMS patients consecutively referred to a pain management center were found to have significant levels of PTSD-like symptoms.  As before, patients with both PTSD and FMS had significantly greater levels of pain, emotional distress, life interference, and disability with over 85% having significant disability. A separate study found PTSD symptoms in a similar percentage of patients – 57% of 77 FMS patients (40 women and 37 men).  In this study, FMS patients reported the single most important trauma to be the death of a loved one; this characteristic is similar to PTSD patients in general. 

     In regard to irritable bowel syndrome (IBS) and gastrointestinal reflux disease (GERD), both of which are frequently found in FMS patients, women with a history of sexual or physical abuse show a higher prevalence of gastrointestinal disorders. One study has shown abuse to be significantly more prevalent among those with GERD (92%) and IBS (82%). However, this study originated from an academic center and may reflect biases of more severe cases being sent to this center.

     Rather than PTSD being a risk factor for FMS, one FMS researcher, Dr. Karen Raphael and her group from the New Jersey Medical School, have proposed that women with FMS are at risk for PTSD not because they are exposed to more traumatic events compared to other women but because their biological nature makes them more susceptible to developing PTSD. They had the opportunity to test this hypothesis through a natural experiment that began with a community based study of family and psychiatric factors among women with FMS they conducted by telephone surveys. They contacted over 9,000 women in the Manhattan and nearby New Jersey area prior to September 11, 2001.

     After the attack, 2,026 of these participants were randomly contacted and assessed for pain and FMS like symptoms as well as PTSD symptoms. There was no significant increase in symptoms consistent with FMS.  However, after 9/11 the odds of probable PTSD were more than three times greater in women with FMS-like symptoms which were not reduced by controlling for FMS-like symptoms before 9/11. In other words, if a woman had FMS her risk of developing PTSD would be three times greater than a woman without FMS as a result of the 9/11 incident.

     Several studies have addressed the relationship between FMS and soldiers who served in the Gulf War but only two have shown an association. The Canadian Forces Personnel Health Study did not calculate prevalences but reported an odds ratio of 1.81.  The odds ratio of 1.81 means that Canadian soldiers who served in the Gulf War were almost twice as likely to develop FMS as those who did not.  The Iowa Persian Gulf Study found FMS prevalences of 19.2% in deployed veterans compared to 9.6% in non-deployed veterans using a telephone interview. Interestingly, PTSD was identified in only 1.9% of the combat veterans. Remember, the prevalence of FMS in the general population is about 3% - 4%; with 3% in females and 0.5% in males. You would say these numbers are exceptionally high and you would be correct. However, this was a telephone survey and did not include a physical exam. Consequently, there is a high risk for what are called, “false positives,” meaning individuals who test incorrectly positive for the criteria used over the phone for FMS.

     A much more extensive study was done by Dr. Bourdette and his group at the Portland Veteran Affairs Medical Center. They conducted a mail survey of 2022 veterans in the northwest U.S. From that mail survey they selected 443 individuals who agreed to come into their office for a clinic visit and then conducted a FMS examination on 241 patients randomly selected from this group. They calculated what are called minimum prevalence estimates, which means they assumed none of the control population would have FMS, so this would significantly underestimate their numbers. It would be like comparing a new anti-smoking product in a population that smoked to a reference population assuming none of that population smoked.

     Their minimum prevalence estimates of FMS, (remember - calculated assuming none of the non-responders would have FMS), were 2.47% total and 7.4% female and 1.8% male. These prevalence figures are similar to general community estimates of 2.8%.  A very large study conducted by physicians who worked for the Department of Defense looked at all hospitalizations in the Department of Defense medical facilities from October 1988 through July 1997. Gulf War veterans were found to be at a slightly greater risk for FMS, approximately 1.2 times greater. However, the researchers then looked at the conditions the soldiers had before they went into the war, which was possible because the Department of Defense keeps very good medical records on soldiers. Then there was no association. They did find the FMS was three times more common in females than males. Overall, it seems that even though studies show higher rates of PTSD in veterans there is no evidence of also having FMS.

     However, just like in non-soldiers, FMS exacerbates the symptoms of PTSD.  When the symptoms in individuals with both FMS and combat related PTSD were examined it was found those individuals with PTSD had more severe PTSD symptoms than veterans without FMS.  A recent 2010 study describes a chronic musculoskeletal pain syndrome in veterans where those afflicted, similar to FMS patients, reported naturally occurring exercised induced muscle pain as more intense. These individuals were also more sensitive to experimentally applied heat stimulation before and after acute exercise compared to normal control individuals.
The latter finding reflects a phenomenon termed exercised-induced hypoalgesia, in which exercise in healthy individuals renders them less sensitive to experimental pain. In other words, after people exercise heavily they tend to me more tolerant of painful stimulation. This is thought to be due to the natural release of endorphins. In patients with FMS, the opposite is found and patients become more sensitive to pain during and after exercise.

     Perhaps the ultimate test of PTSD is that of the Holocaust. A study by a group of FMS researchers has identified a significantly increased prevalence of FMS among Holocaust survivors who have now lived over six decades after the end of World War II. In survivors of the Nazi Holocaust 24% have developed FMS compared to age matched controls not exposed to Nazi occupation. A rather remarkable finding, and perhaps the best test to date regarding exposure to a traumatic situation and FMS.

Part 1 - Physically Traumatic Events

     The role of physical trauma in the development of Fibromyalgia Syndrome (FMS) continues to be deliberated in the literature. A major difficulty has been the reliance on someone’s ability to recall events that may have occurred thirty years prior. Post-traumatic fibromyalgia is also known as reactive fibromyalgia syndrome and the first paper on the subject was published in 1992. Those researchers reported that 23% of 127 FMS patients reported a specific event – trauma, surgery, or medical illness preceded their FMS. Patients in this group were significantly more affected with 70% losing their job, 34% receiving disability, and 45% having reduced physical activity. Shortly thereafter, in 1994, another study reported a follow-up of 176 FMS patients; 61% reported symptoms after a motor vehicle accident, 12.5% after a work injury, 7% after surgery, 5% after a sports related injury, and 14% after some other type of traumatic injury.

     A 2002 case-control study was published, which is a type of study where people with FMS are matched to healthy, normal individuals in as many characteristics as possible except for their disease, FMS. Then researchers try to find out what was different about people who had developed FMS. When the 136 FMS patients in this study were examined it was found that 39% had evidence of significant trauma within the 6 months prior to the onset of their FMS. The three most frequent types of trauma were surgery (38%), work injuries (14.7%), and childbirth (11.8%). A rather famous and experienced pain researcher, Dr. Dennis Turk, has found that compared to FMS without a known cause, post-traumatic FMS was associated with significantly higher degrees of pain, disability, life interference, affective distress, and lower levels of activity. Post-traumatic patients in his study were also more likely to be receiving opioid pain medications and to have more extensive treatment histories with nerve blocks, physical therapies, and modalities.

     The single event that has received the most attention is whiplash injury which has generated a number of studies and anecdotal reports. One of the more famous accounts is a family of 6 (2 parents and 4 children) who shared a complex of multiple constitutional and psychological symptoms who were evaluated 6 and 8 years after a minor car accident and all found to have FMS.  The major prospective studies, meaning studies that were conducted on people after their accident and followed forward in time, have been conducted by different Israeli researchers and they have reached opposite conclusions.
The first report of 161 cases, published in 1997 by Dr. Buskila and his colleagues suggested that FMS was 13 times more frequent following neck injuries than lower extremity injuries. FMS developed in 21.6% of individuals within 1 year after a motor vehicle accident compared to 1 individual with a lower extremity injury. This generated a number of critical letters to the editor with doctors suggesting possible confounding factors ranging from increased anxiety and sleep disturbances to biases introduced simply because there are more tender points in the upper body around the sites of neck injuries (10 of 18 tender points are in the neck and shoulder region).

     Of the 161 cases identified in 1997, 78 were able to be followed-up 3 years later. Even though 60% still had FMS all of the original cases were able to return to work. Of note, an additional 2009 study by Dr. Buskila found 15% of the survivors of a major train crash in Israel met the American College of Rheumatology’s criteria for FMS 3 years after the event.

     The findings of Dr. Buskila regarding whiplash and FMS remained the only prospective studies in the literature until another group of Israeli researchers, Dr. Tishler and colleagues, published two reports based on 153 patients presenting to the emergency department after whiplash injuries. The first in 2006 provided a mean follow-up of 14.5 months and found no association between injury and FMS with only one patient developing FMS.  A second report in 2010, was able to provide a 3 year follow-up of 126 of these 153 patients and confirmed the results of the authors’ earlier study showing that whiplash injury and FMS were not associated; only three patients in the study group had developed FMS in the intervening time.

     Why such discrepancies exist is still a matter of debate. Some researchers have proposed the potential role of interactions between genetics, prior experience, stress response systems, and central neurobiological pain processing systems as well as cultural differences. There will be a set of future short reports on the central neurobiological pain processing changes in FMS patients. Two studies on the development of chronic widespread pain and motor vehicle accidents suggest that the greatest predictors of persistent pain are related to pre-collision psychological and physiological health.

     Factors that influence if neck or back pain becomes chronic include the severity of pain, being female, having a history of abuse, a family history of chronic widespread pain, and the presence of additional diseases such as irritable bowel syndrome, restless leg syndrome, or migraines. It will be interesting to see how this debate unfolds using the new 2010 American College of Rheumatology criteria. However, until the debate is settled, it is probably best to avoid any whiplash injuries.
 

Or, Cyto-What?

     Cytokines are small molecules that do not stay around very long in the body before they are either taken up or degraded. They act as chemical messengers to affect immune responses, tissue repair, or cell growth.  Their production is influenced by both the central nervous system and the immune system. The sympathetic nervous system, through the secretion of catecholamines, will activate the hypothalamic-pituitary-adrenal axis (HPA) and stimulate the release of cytokines. If you don’t know about HPA axis then read the two short reports on “The Neuroendocrine Theories Behind Fibromyalgia.” Catecholamines are the “fight or flight” hormones produced by the adrenal glands – epinephrine and norepinephrine and they primarily act through the sympathetic nervous system. For more information about epinephrine and norepinephrine you can read the short reports on “Dysautonomia, ”and the two-part series on ‘The Neuroendocrine Theories of Fibromyalgia.”

     The most common cytokines are “interleukins,” and they are abbreviated and numbered, e.g. IL-1, IL-6, IL-8, and so on. IL-8 is a key cytokine that plays a role in inflammation. It is released by macrophages, cells that are activated in response to tissue injury.  They help promote pain in laboratory animals and will cause pain in a dose dependent manner, meaning the higher the concentration of IL-8, the greater the pain the animal will experience.  The secretion of IL-8 by macrophages can also be induced by substance P, which is a major nerve transmitter that you will read quite a bit about in the sections on pain in fibromyalgia syndrome (FMS) that are coming up in the near future. IL-8 is of particular importance because it also activates the sympathetic nervous system. IL-6 and another cytokine called tumor necrosis factor-alpha (TNF-alpha) are also major inflammatory cytokines and have been implicated in the generation of a particular type of pain called neuropathic pain.

     A group of researchers  first proposed a link between cytokines and FMS when they observed that patients given IL-2 cell therapy for melanoma or terminal renal cell carcinoma developed FMS-like symptoms such as myalgia, cognitive impairment, and tender points. The IL-2 therapy was part of the treatment for these cancers. Since that time, there have been numerous studies that have attempted to correlate the role of cytokines to clinical manifestations of FMS based, in part, between their relationships with the HPA axis and the sympathetic nervous system. If you haven’t done so, it’s definitely time to read the two part series on the “Neuroendocrine Theories Behind Fibromyalgia.”

     Part of the interest is driven by what is known by psychiatrists as the “sickness behaviour” noted in FMS – pain, fatigue, cognitive changes, and depression that tends to match those signs seen with activation of the immune response system as a result of an infection. Remember, people with FMS will tend to say they feel like they have the “flu” all the time, that’s been one of the best ways used to describe FMS to other people. Psychiatrists are doctors, they like to have more medical ways to say things, so they called that common way of expressing FMS, “sickness behaviour.”

     Although patterns have tended to emerge, there are some subtle differences. The discordant results may reflect the small sample sizes used in the studies, differences in patients’ conditions, the amount of adipose tissue (which affect how cytokines are produced), as well as dissimilarities in laboratory techniques; no two studies were exactly alike.

     If you’re ready – here’s a rundown on what’s been found so far (take a deep breath).  One group of researchers have published two studies that found significantly elevated levels of IL-8 that correlated to pain intensity as measured by tender points.  Another group has also found high levels of IL-8 in FMS patients, but not IL-10 or TNF-alpha. On the other hand, different researchers noted high levels of IL-8 as well as IL-10 and TNF-alpha.  Then some other folks found elevated IL-8 and TNF-alpha but not IL-10. Wait a minute, here’s a group that reported no differences in IL-10 or TNF-alpha but now this fellow found decreased levels of TNF-alpha.  Another common inflammatory cytokine, IL-6, was not found to be higher in four studies of FMS patients, including a major report from the National Institute of Health, although a major FMS researcher group noted higher levels in patients, provided they had symptoms for more than two years. Confused? So is everyone else.

     This could be a reason - in a study of healthy adults a researcher found that after the application of an acute painful stimulus, pain catastrophizing was strongly related to IL-6 reactivity which means that emotional responses may influence cytokine responses. Here’s another reason - a 2010 study found higher levels of IL-6 and IL-8 in a group that showed a defective growth hormone response to heavy exercise. What are you thinking? That there are a lot of factors that influence cytokines? Well, you’re right.

     A group of researchers published in 2008 the first study that looked at cytokine levels in FMS patients while they were receiving 6 months of multidisciplinary pain therapy.  TNF-alpha and IL-8 at baseline were significantly higher compared to controls and both were reduced with therapy. Similar to earlier findings, IL-8 levels were correlated to pain intensity. Because of its design in following patients, this study also suggested that .3while TNF-alpha and IL-8 may contribute to contributing to FMS, neither could be the direct cause of FMS pain as it was only near the end of the study that levels correlated to pain intensity; both levels remained high earlier in the study while the patients reported their pain was decreasing.

     An often neglected effect of cytokines is their behavior manifestations, we mentioned this earlier – “sickness behavior.” These non-specific symptoms attributed to cytokines include weakness, malaise, concentration difficulties, anhedonia (generally feeling the ‘blues’), depression, and fatigue. People with FMS aren’t alone. These have been observed in people who have suffered a myocardial infarction and who also have diabetes, and cancer. Remember, they can also be brought on by therapy with cytokines. If you’re wondering why this would have ever been the case think about it from an evolutionary perspective.  Evolutionarily, this response would have been regarded as adaptive by promoting inactivity and rest but in chronic conditions these manifestations are now maladaptive, just like FMS is maladaptive.

     Cytokines are reflective of the general “state of the union” in someone who has FMS. They appear to contribute to the disease through a myriad of ways which manifest both in behaviour and physiologic characteristics. The good news is, they don’t seem to be a permanent fixture and as treatment progresses their influence becomes less and less.