Fibromyalgia Newsletter # 3/2

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Fibromyalgia Newsletter # 3/2 Friday, 12/14/2001

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This week's News Summary

16) Research: Overnight Sleep Loss Boosts 'Sleep Hormone'

17) Article : Update FM-program Cypress Bioscience

18) Research: A new take on psychoneuroimmunology

19) Message : A Tombstone for Sherryl

20) Article : Hypothetical

21) Research: Fibromyalgia (Critical Review)

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Full Stories Are Available Via Web Links

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16)

Subject: Overnight Sleep Loss Boosts 'Sleep Hormone' Source : realage.com Author : Alan Mozes URL :

http://www.realage.com/HB2/HB2.asp?wci=HArticle&cid=12643&sid=616

<quote>

NEW YORK, Jun 15 (Reuters Health) - Apparently a common feature of modern life--"late to bed, early to rise"--will definitely not make an individual "healthy and wise."

Researchers have found that overnight sleep loss provokes an almost immediate rise in sleep-inducing hormones, leaving the individual to wage a battle of will to stay awake against a rising wave of sleepiness.

(....)

Read the full article on the website.

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17)

Subject: Update FM-program Cypress Bioscience Source : Cypress Bioscience Inc Author :

URL: http://biz.yahoo.com/bw/011206/60091_1.html

PRESS RELEASE SOURCE: Cypress Bioscience Inc.

Cypress Files IND to Begin Clinical Testing of Drug Candidate For Treatment of Fibromyalgia Syndrome

SAN DIEGO--(BW HealthWire)--Dec. 6, 2001--Cypress Bioscience Inc.

(Nasdaq:CYPB - news) today announced that it recently filed an investigational new drug application (IND) with the U.S. Food and Drug Administration (FDA) to begin a Phase II clinical trial of milnacipran, its drug candidate for the treatment of fibromyalgia syndrome (FMS), a chronic pain disorder.

Pending normal FDA review, the company will commence clinical studies in the first half of 2002.

'The filing of an IND for milnacipran represents a significant achievement for Cypress in the development of therapies for the treatment for FMS,' said Jay D. Kranzler, M.D., Ph.D., chairman and CEO of Cypress. 'Milnacipran is a dual action drug that is distinguished in its ability to affect serotonin and norepinephrine - two neurotransmitters involved in modulating pain within the human body. As increasing evidence suggests that modulation of more than one transmitter is likely to be required for better efficacy in addressing the pain associated with FMS, we believe that milnacipran could significantly improve the treatment of this condition.'

FMS is a chronic and debilitating condition characterized by widespread pain and stiffness throughout the body, accompanied by severe fatigue and headache. It affects an estimated 2-4 percent of the population worldwide and is the second most common diagnosis by rheumatologists in the U.S. after osteoarthritis. Despite the high prevalence and severity of this syndrome, today there are no approved treatments for FMS.

'Currently, only about half of FMS patients are prescribed drugs for pain management, since most available treatments have proven largely ineffective,' said Dr. Daniel Clauw, chief of the Division of Rheumatology, the Chronic Pain and Fatigue Research Center at Georgetown. 'There have been few clinical trials performed for FMS -

which is why Cypress' efforts with milnacipran are so important.'

In August of this year Cypress licensed the North American rights to develop and market milnacipran for the treatment of FMS and related chronic pain syndromes. The license from Pierre Fabre Medicament (Pierre Fabre), the pharmaceutical division of bioMerieux Pierre Fabre of Paris, France also gives Cypress an option to expand the terms to include other indications.

About Cypress Bioscience Inc.

Cypress is committed to be the innovator and commercial leader in providing products that improve the diagnosis and treatment of patients with FMS. In January 2001, the company began a strategic initiative focusing on FMS. For more information about Cypress, please visit the company's Web site at http://www.cypressbio.com.

This press release, as well as Cypress' SEC filings and Web site at http://www.cypressbio.com, contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Actual results could vary materially from those described as a result of a number of factors, including those set forth in Cypress Annual Report on Form 10-K and any subsequent SEC filings. In addition, there is the risk that Cypress may not be able to successfully develop or market any products for the treatment of FMS under the Pierre Fabre agreement or at all; that the clinical development plan or timeline for milnacipran may not shortened; that we may not be able to obtain appropriate regulatory approvals to begin Phase II clinical trials of milnacipran in the first half of 2002; that milnacipran may not significantly improve the treatment of FMS, that Cypress will not be successful in identifying or developing products under the Georgetown agreement; that Fresenius may not be able to successfully market the PROSORBA column; that the sales of the PROSORBA column may decrease; and that Cypress may not receive any future royalties under its revised agreement with Fresenius. Cypress undertakes no obligation to revise or update these forward-looking statements to reflect events or circumstances after the date of this press release, except as required by law.

Contact:

Cypress Bioscience Inc.

Lisa Walters-Hoffert or Manda Hall

858/452-2323

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Subject: A new take on psychoneuroimmunology Source : Monitor on Psychology Author : Beth Azar URL : http://www.apa.org/monitor/anewtake.html

<quote>

Monitor on Psychology Volume 32, No. 11 December 2001

A new take on psychoneuroimmunology Research pointing to a circuit linking the immune system and brain connects illness, stress, mood and thought in a whole new way.

Even though doctors have all but rejected the idea that going out in the winter with wet hair causes colds, many mothers still insist it's a recipe for illness. Those moms may soon have data on their side from some new research linking stress and the immune system.

The research indicates that stress--maybe even the stress of being cold--appears to tap into the same immune system=ADnervous system loop that triggers symptoms of the common cold, according to Steven Maier, PhD, who gave the Neal Miller Lecture at APA's 2001 Annual Convention..

For more than a decade, researchers have known that behavioral and psychological events can influence the immune system. But now new research shows that the immune system sends signals to the brain "that potently alter neural activity and thereby alter everything that flows from neural activity, mainly behavior, thought and mood," said Maier, professor of psychology at the University of Colorado. "In a real, true sense, stress makes you physically sick," explained Maier. "In addition, many of the changes over time in mood and cognition from day to day are driven by events in the immune system of which we are unaware."

(....)

Read the full article on the website.

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Subject: A Tombstone for Sherryl Source : co-cure.org Author : Nancy Angsten URL :

Some of you recently may have learned of Sherryl Atkinson's death.

Sherryl and I 'met' through Roger Burns' ACTION FOR CFS/ME e-group in early 1999. Our friendship began initially because we both had extremely low white blood counts when we first became ill with CFS and were comparing our experiences, and blossomed because of her desperate attempts to get adequate health care, social security benefits and health insurance. She also was a warm, caring person with a great sense of humor and integrity. She was feisty.

For some reason which I will never understand, I saved the dozens and dozens of e-mails that Sherryl and I sent back and forth over the years.

We shared birthdays, advocacy efforts, anniversaries and holidays -

often with a mix of hope and despair. Re-reading them now is heartbreaking. They chronicle her incredible suffering; her despair in attempting to get Social Security benefits and decent health care, and our attempts through the Wisconsin CFS Association to find an experienced, dedicated disability attorney in California for her. We found an attorney for her, but Sherryl was too ill to make the trip from Sacramento to San Francisco to meet with her. Her last battle with an administrative law judge for Social Security benefits ended in defeat once again.

Sherryl and I worked together, along with Katherine Carrington, on the ill-fated "tombstone" advocacy project for May 12 Awareness Day. Our idea was for each person to create their own grieving message of loss due to this DD; to mount each message on small cardboard tombstones attached to wooden pickets so they could be displayed wherever and whenever May 12 awareness day activities were held. People, however, found the idea too morose, and the project was dropped.

Now, Sherryl has a real tombstone.

I have attached Sherryl's obituary to this post, courtesy of THE UNION newspaper of Nevada County, California.

Rest softly now, Sherryl. There are no tears in heaven.

OBITUARY: Sherryl Atkinson Saturday, November 10, 2001

Memorial services for Sherryl Smith Atkinson of Fair Oaks will be conducted at 11 a.m. today at the Fair Oaks Presbyterian Church, 11427 Fair Oaks Blvd. Mrs. Atkinson died Wednesday, Nov. 7. She was 50. She was a longtime resident of Fair Oaks and graduated from Del Campo High School. She was a former resident of Grass Valley. She is survived by her husband of 24 years, Mike Atkinson; daughter and son-in-law, Wendi and Daren Mitchell of Orangevale; son and daughter-in-law, Jason and Barbara Atkinson; stepdaughter and son-in-law, Autumn and Todd Schneider of Reno, parents Don and Wanda Smith; brothers and sisters-in-law Roger and Kathy Smith and Randy and Diane Smith; grandmother, Dollie Lowrie; grandchildren Josilyn, Chelsea, Benjamin, Michael, Bryan, Mackenzie and Jared; and numerous aunts, uncles, nieces and nephews.

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Subject: Hypothetical Source : co-cure.org Author : Daisy Cutter URL :

A 39 year old woman enters the hospital emergency room. She had suffered from 2 months of unexplained fatigue, pain, confusion, and odd twitches, tingling and other symptoms she cannot keep up with. Right now, the problem is this cough that has persisted for weeks, and the fever and chills that grip her body at odd hours, usually at night.

The preceding night had been one of insomnia, a horrible night. Seeing that the family computer was eerily unmanned at 2 a.m., she decided to try and see if she could find any medical information that might shed some light on these frightening symptoms that she had fought to ignore for a long time, as she was a wife and mother with a full-time job. She had confidentially been telling a co-worker about her symptoms, and this friend suggested she look up chronic fatigue syndrome. She was quietly shocked and a bit angry at this suggestion, as she had thought that the syndrome was a psychological problem. After all, it was the subject of jokes at work, and it seemed to be about people copping out from their responsibilities. What she finally found on the internet confused her even more. Although the varying descriptions were identical to her symptoms, many of the websites talked about a new name for chronic fatigue syndrome. It sounded like a real disease. She jotted down notes.

Finally, 7 hours later in the emergency room, a young intern entered her cubicle. Obviously, this young man was fresh out of medical school, she thought, so he will know all about what I read last night. After initial introduction, she says matter-of-factly, "Dr. I have sins." The young man closes the chart and runs his hand through his already thinning hair. He then reaches over and touches the pale, perplexed woman, and says, " I understand, I have them, too. Perhaps you would like to speak to our hospital chaplain?"

The woman shakes her head, and says, "No, I don't need the chaplain, I need you to cure me of this condition or whatever this is. I feel awful.

I am suffering categories 3-7, I believe." The doctor opened the chart, and saw no indication of the woman having a fever, it was a little low.

He saw that the chest x-ray was normal, and that her blood work was fine, except for a cholesterol test. He realized he did not have any memory of encounters with hypochondriacs, or schizophrenics, and this woman was talking about sins. He was worried about his fading memory at such a young age. He paged the psychiatrist on call.

Looking back at the woman, he said, "All looks fine in your chart, everything is normal, except for cholesterol. Are you interested in a diet packet, that explains how to lower your blood cholesterol level and decrease risk of heart disease? I don't think I quite know what else to offer you, except suggest an over the counter cough syrup for this cough you describe." The woman was looking at him like he was insane, and he nervously looked at his watch, saying, "Just wait here, and another doctor will be in to see you."

Three hours later, a psychiatrist appeared in the woman's cubicle. Her chart mentioned hypochondria and possibly schizophrenia...some obsession with categories of her sin-filled world. She was now flat on the stretcher, and grimacing in pain, pointing to her legs. She moaned, "Dr.

please help me. I truly think I have sins, and that categories 3-7 apply to me. I am frightened, and I don't know if I will be able to walk out of here. I am soooo exhausted and weak, and when I sit straight up, I feel I may pass out." The psychiatrist thought of his wife and her complaining and then asked, "So, how are things, at home?"

The woman began to cry, and the doctor quickly penned the word 'depression' in her chart...She obviously needed therapy. Especially if she claims not to be able to stand or walk, he thought. But, lacking any mention of suicide, he determined that she would not be eligible for inpatient hospitalization. "May I suggest that you get some therapy, and particularly that of helping you recognize your abilities, not weaknesses. I also recommend a walking program, starting with 15 minutes of brisk walking, gradually increasing each day." He handed her a prescription for Prozac. He couldn't figure out why thoughts of his wife were distracting him.

"Doctor, don't you think I should have some sort of a test, perhaps about category 5, the blood pressure thing?" She cried, noting his direction towards the curtain and away from helping her. The psychiatrist turned back around and opened the chart, noting a low but normal blood pressure. He said, "Your blood pressure is fine. You are fine, and you must get on with your life, and go to the doctor I wrote down for you." His private thoughts were on how detailed sounding her 'categories' or false health problems were. Amazing, he thought, as he left the cubicle. He could hear the woman beginning to argue with a nurse, trying to get her out of the much needed cubicle space. She didn't want to get up and leave, obviously.

The nurse was all too familiar with this type of patient. She thought to herself, they all come in here, thinking they are seriously sick, and there's not a thing wrong with them. I am burnt out, confused, and my legs are killing me....and these 12 hour shifts are leading to me feeling much worse. Why just yesterday, I, myself, had an anxiety attack at the mall! I think this job is stressing me out too much! Why am I working in this E.R.? She attempted again to discuss the discharge instructions, and somehow comfort this mentally ill woman. The woman transferred from the stretcher to the wheelchair, very unsteady on her feet. The nurse thought, boy, they really know how to look impaired!

"I just don't understand how I could get this type of treatment because of sins. It certainly doesn't matter whether I call it that or chronic fatigue syndrome!" The nurse retained her smile, and wheeled her out to the curb, wishing her well. When the nurse returned to the desk, she casually mentioned to the new doctor on staff that had seen this patient, "She thinks she has chronic fatigue syndrome, too, Doctor." The doctor turned and said, "Well, amazingly, she got the exact treatment for that, too! Don't you see what a genius I am?"

Laughing, they missed the code announcement overhead, that a body was 'down' in the parking lot. They both watched the nurses running with a stretcher towards the door. They both turned serious, and waited for a 'real' patient to be wheeled in, probably a heart attack or stroke patient, something to get their adrenaline going. After all, this was why they were both in medicine, to save lives..........

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21)

Subject: Fibromyalgia (Critical Review) Source : Haworth Press Author : Roberto Patarca-Montero, MD, PhD URL : http://www.HaworthPress.com

Journal: J of Chronic Fatigue Syndrome, Vol. 9(3/4) 2001, pp. 21-161

Affiliation: E. M. Papper Laboratory of Clinical Immunology, Departments of Medicine, Microbiology and Immunology, University of Miami School of Medicine, 1600 NW 10th Avenue, Miami, FL 33136.

ABSTRACT. Although much has been learned over the last decade about fibromyalgia, much remains to be learned about its causes, nosology, treatment, and overlap with a variety of rheumatic and nonrheumatic conditions. Advances in rheumatology, cardiovascular medicine, endocrinology, epidemiology, immunology, infectious diseases, neurology, psychiatry, and psychology have served as the basis for the formulation of new lines of research and novel therapeutic interventions. The purpose of this review is to summarize the knowledge gained and published mainly within the last decade.

KEYWORDS. Fibromyalgia, epidemiology, precipitating events, modulating factors, laboratory tests

[The the following excerpts are the first two sections of this 140 page article.]

DEFINITION

Fibromyalgia is a form of nonarticular, or soft tissue, rheumatism characterized by spontaneous widespread musculoskeletal aching, tenderness on palpation with multiple tender points (at least 11 out of 18 in defined locations) (hyperalgesia), decreased pain threshold (allodynia), fatigue, poor sleep, mood disturbances, and other systemic symptoms (Ang and Wilke, 1999; Bennett, 1998; Briggs, 1997; Celiker et al., 1997; Clauw, 1995; Coward, 1999; Fibromyalgia, 2000; Fibromyalgia syndrome-An Interdisciplinary Challenge of Basic and Clinical Science. International conference. Bad Nauheim, Germany, October 23-25, 1997; Fordyce, 2000; Gerster, 1999; Gordon and Morrison, 1998; Hadler, 1996; Healey, 1996; Leslie, 1999; Littlejohn, 1996; KrsnichShriwise, 1997; Lilleas, 1997; MacFarlane et al., 1996; Mailis, 1996; Nishikai, 1999; Parziale and Chen, 1996; Pasero, 1998; Proceedings of the International Fibromyalgia Conference. Bad Nauheim, Germany, October 1997, 1998; Rankin, 1999; Raspe and Croft, 1995; Reiffenberger and Amundson, 1996; Reveille, 1997; Reynolds, 1996; Romano, 1996; Siegmeth, 1999; Simms, 1996; Slavkin, 1997; Tabeeva et al., 2000; Unger, 1996; Van Santen-Hoeufft, 1996; Wallace, 1999; Wallace et al., 1999; Winfield, 1997; Wootton, 2000; Xie and Ye, 1997). The concept and diagnosis of fibromyalgia became popular, especially in North America, in the 1970s, after the seminal publications of Hugh Smythe in 1972 and Smythe and Moldofsky in 1977. It is noticeable that there does not appear to be an early case report as there is for instance for gout, rheumatoid arthritis or certain vasculitides. After Smythe and coworkers, operational definitions and classification criteria were given in 1989 by Yunus et al. (1998), Lautenschlager et al. (2000) and Wolfe and collaborators in 1990. The latter received the endorsement of the American College of Rheumatology and are now the most widely used.

According to the American College of Rheumatology, the diagnosis of fibromyalgia is based on criteria consisting entirely of clinical signs and symptoms (Alarcon, 1997; Barth, 1997; Bassetti, 1996; Brown, 1997; Garfin, 1995; Hart, 1998; Jacobsen, 2000; Kavanaugh, 1996; Kjaergaard,

1998; Maier, 1998; Pongratz and Sievers, 2000; Reinhold-Keller, 1997; Unraveling a mysterious cause of pain, 1998; Weber, 1998; Xie and Ye, 1997; Zborovskii and Babaeva, 1998). The American College of Rheumatology criteria, established in 1990, provide the primary care provider with definitive subjective and objective findings that have shown to be 88% accurate in their ability to diagnose patients with the syndrome (Smith, 1998). In the majority of fibromyalgia patients the generalized pain is preceded by localized or regional pain, usually in the musculoskeletal system. In many fibromyalgia patients there are findings compatible with tissue injury pain, with pain mechanisms involving both the primary afferent neuron and the nociceptive system in the central nervous system (Henriksson, 1999; Olin and Lidbeck, 1996).

The distinction between fibromyalgia (tender points) and myofascial pain syndrome (trigger points) is essential (Klineberg et al., 1998; Uppgaard, 2000) (see below). Also, macrophagic myofascitis, a recently identified inflammatory myopathy that can be detected by deltoid muscle biopsy and is manifested mainly in the lower limbs, can be differentiated from fibromyalgia and sarcoidosis by gallium-67 scintigraphy (Cherin et al., 2000). Fitzcharles and Esdaile (1997) reported that 11 women with spondyloarthritis had been incorrectly diagnosed as having fibromyalgia. Internal and neurological disorders as a primary cause of fibromyalgia have to be excluded (Olin and Lidbeck,

1996).

Although nearly all rheumatologists now accept fibromyalgia as a distinct diagnostic entity and it is also recognized by the World health Organization, the validity of fibromyalgia as a distinct clinical entity has been challenged for several reasons: the subjective nature of chronic pain; the subjectivity of the tender point examination; the failure to agree on the importance and biological nature of tenderness itself; the lack of a gold standard laboratory test; the absence of a clear pathogenic mechanism; the use of a syndromic description without a unifying concept; the relative nature of the pain-distress relationship in the rheumatology clinic; the apparently continuous relationship between tender points and somatic distress across a variety of clinical disorders; the failure to distinguish a clinical feature from a disease process; legal defenses of insurance carriers motivated by economic concerns; psychiatric dogma; uninformed posturing; suspicion of malingering; ignorance of nociceptive physiology; and occasionally honest misunderstanding (Buskila et al., 1997; Cathebras, 1998, 2000; Cohen, 1999; Finestone, 1997; Fitzcharles, 1999; Gamaz-Nava et al.,

1998; Goldenberg, 1999; Gordon, 1997; Hadler, 1996, 1997; Hamilton,

1998; Handler, 1998; Hantzschel and Boche, 1999; Helliwell, 1995; Hellstrom, 1995; Hilden, 1996; Holoweiko, 1996; Hudson, 1998; Hunt et al., 1998; Hyams, 1998; Jones, 1996; Kaden and Bubenzer, 1999; Katz et al., 1997; Kissel and Mahnig, 1998; Laser, 1998; Leonhardt, 2000; Lindberg and Lindberg, 2000; Makela, 1999; Marlowe, 1998; Matsumoto,

1999; Neeck, 1998; Neerinckx et al., 2000; Peloso, 1998; Quintner and Cohen, 1997, 1999; Raspe, 1996; Rau and Russell, 2000; Rekola et al.,

1997; Romano, 1998; Russell, 1999; Safran, 1998; Shojania, 2000; Smith,

1998; Solomon and Liang, 1997; Thorson, 1998; Wessely and Hotopf, 1999; White and Harth, 1998; Wigley, 1999; Wilke, 1996; Wolfe, 1997; Wolfe et al., 1997).

Barsky and Borus (1999), among other authors (Ford, 1997; Masi, 1998; Robbins et al., 1997; Walker et al., 1997), have applied the term functional somatic syndromes to several related syndromes characterized more by symptoms, suffering, and disability than by consistently demonstrable tissue abnormality. These syndromes include multiple chemical sensitivity, the sick building syndrome, repetition stress injury, the side effects of silicone breast implants, the Gulf War syndrome, chronic whiplash, the chronic fatigue syndrome, the irritable bowel syndrome, and fibromyalgia. Barsky and Borus (1999) purport that although discrete pathophysiologic causes may ultimately be found in some patients with functional somatic syndromes, the suffering of these patients is exacerbated by a self-perpetuating, self-validating cycle in which common, endemic, somatic symptoms are incorrectly attributed to serious abnormality, reinforcing the patient's belief that he or she has a serious disease. Ford (1997) considers these syndromes a "fashionable" way to hide the diagnosis of hysteria.

Despite the professionals who question the existence of fibromyalgia as a distinct physiopathological entity, in the United States, fibromyalgia is the third or fourth most common reason for rheumatology referral (Celiker et al., 1997; Gomez-Nava et al., 1998; Wallace, 1997), and several websites are dedicated to this condition (Armstrong, 2000; Jahn and Klenke, 1999). MartinezLavin et al. (2000) reported on the influence of fibromyalgia in Frida Kahlo's life and art. The two great pianists Clara Wieck Schumann (1819-1896) and Sergei Vassilievich Rachmaninov (1873-1943) suffered from chronic pain, and a report by Hingtgen (1999) discusses the pain syndromes that plagued these great musicians and the effect of chronic illness on their music. It is important for the physician to differentiate fibromyalgia from the pain, sensory loss and lack of coordination that may result from the physical demands of performing on musical instruments (Potter and Jones, 1995).

Fibromyalgia patients journey along a continuum from experiencing symptoms, through seeking a diagnosis, to coping with the illness.

Experiencing symptoms usually entails pain, a precipitating event, associated symptoms, and modulating factors. Seeking a diagnosis is associated with frustration and social isolation. Confirmation of diagnosis brings relief but anxiety about the future. After diagnosis, several steps lead to creation of adaptive coping strategies (Mannerkorpi et al., 1999; Raymond and Brown, 2000; Thorson, 1999).

EPIDEMIOLOGY

In 1995, an estimated 15% (40 million) of Americans had some form of musculoskeletal pain disorder including fibromyalgia, and by the year 2020, an estimated 18.2% (59.4 million) will be affected (Lawrence et al., 1998). Pain syndromes can be divided anatomically into those which cause generalized pain, such as fibromyalgia syndrome and myofascial pain syndromes, and those which are confined to one regional anatomical area. The latter group comprise those of the neck, shoulder, elbow, wrist/hand, hip, knee and ankle/foot (Linaker et al., 1999).

Fibromyalgia can also be secondary to other rheumatologic disorders (Karaaslan et al., 1999).

It is estimated that fibromyalgia affects up to six million patients worldwide (Gordon and Morrison, 1998; Smith, 1998). The prevalence of fibromyalgia in the United States general population was found to be 2% and it increased with age (Goldenberg, 1996). Extrapolation of a survey of 4027 general practitioners by Bazelmans et al. (1997) indicates that in 1997 there were at least 24,000 primary fibromyalgia patients in the Netherlands. A population survey of 2498 females living in South Norway yielded a calculated annual incidence of fibromyalgia of 583/100,000 (Forseth, 1997; Forseth et al., 1997). Major problems associated with interpreting and comparing epidemiologic studies on pain syndromes in adults and children include the diversity of classification criteria and selection bias (Gare, 1996). The prevalence of fibromyalgia in a study of 548 schoolchildren by Clark et al. (1988) was 1.2%, a figure that is 5-fold lower than a previous report. This variance may be due to (1) racial and sociocultural differences between populations; and (2) differences in methodological approach. However, Sardini et al. (1996) found the same incidence of fibromyalgia of 1.2% in students of the schools of Castiglione delle Stiviere (Mantova, Italy).

Case definitions and overlap between different syndromes affect the results of the different epidemiological studies. For example, of 32 individuals with chronic fatigue syndrome identified in a random sample of 18,675 Chicago residents, 40.6% met criteria for multiple chemical sensitivity and 15.6% met criteria for fibromyalgia (Jason et al., 2000). Referral practices and primary care physician's perceptions of fibromyalgia (Bellamy et al., 1998) also affect epidemiological estimates. For instance, Gran and Nordvag (2000) found that the annual incidence of referrals of new patients to a rheumatology clinic was 423 per 100,000. The main cause of referral was diagnosis, and more than half of the diagnoses suggested were changed at the visit. Few of the referred patients had severe disease. In a study of 100 confirmed fibromyalgia cases, 76 widespread pain controls, and 135 general controls in a random community survey of 3395 noninstitutionalized adults living in London, Ontario, White et al.\ (1999c) found that, adults who meet the American College of Rheumatology definition of fibromyalgia appear to have 4 distinct features compared to those with chronic widespread pain who do not meet criteria, namely pain severity, severe fatigue lasting 24 h after minimal activity, weakness, and self-reported swelling of neck glands. In a different report from the same study, White et al. (1999b) reported that female sex, middle age, less education, lower household income, being divorced, and being disabled are associated with increased odds of having fibromyalgia.

White et al. (1999c) also determined that fibromyalgia has a major effect on direct health care costs. The latter is particular relevant since fibromyalgia is prevalent among lower income people. In a study of 1997 Pakistani adults distributed evenly between poor rural and poor urban communities and relatively affluent urban people, Farooqi and Gibson (1998) found that there was significantly more soft-tissue rheumatism and back pain in the rural population compared with those in the city. Fibromyalgia was almost completely absent from the urban affluent, but osteoarthritis of the knee was significantly more common in this community, perhaps due to relative obesity. In contrast with the latter results, no chronic widespread pain was identified in a survey of Pima Indians, a finding that suggests that this population has different pain perception or different patterns of risk factors for these disorders (Jacobsen et al., 1996).

The heterogeneous group of diseases that causes chronic arthralgia and arthritis is the most common cause of activity limitation and disability among middle age and older women (Holtedahl, 1999; Stormorken and Brosstad, 1999). For reasons that remain poorly understood this group of diseases affects women substantially more frequently than men (Belilos and Carsons, 1998; Forseth et al., 1999; Meisler, 1999). In particular, the prevalence rates of the most common causes of arthralgia and arthritis, osteoarthritis and rheumatoid arthritis, and the prevalence rates of less common diseases that cause arthralgia, including systemic lupus erythematosus, systemic sclerosis, and fibromyalgia, are between two and 10 times higher in women (Buckwalter and Lappin, 2000; Burckhardt and Bjelle, 1996). Forseth et al. (1997) estimated an annual incidence of fibromyalgia in women of 583/100,000. Because many women with these conditions seek medical care from orthopaedists, orthopaedic residency education and continuing medical education should place emphasis on early diagnosis and nonoperative treatment of patients with arthralgia and arthritis, and, when appropriate, early referral to rheumatologists (Schaefer, 1997).

A study by Buskila et al. (2000) comparing 40 men and 40 women with fibromyalgia concluded that although fibromyalgia is uncommon in men, its health outcome is worse than in women (more severe symptoms, decreased physical function, and lower quality of life in men despite similar mean point tender counts). In contrast to the latter study, Yunus et al. (2000) in a comparative study of 67 men and 469 women with fibromyalgia found that male fibromyalgia patients had fewer symptoms and fewer tender points, and less common "hurt all over" complaints, fatigue, morning fatigue, and irritable bowel syndrome, compared with female patients. Further gender comparison studies are needed.

Although fibromyalgia is predominant in middle-aged women, it has also been reported in elderly individuals and in the pediatric population (Borenstein, 1996; Buskila,1999; Cathebras et al., 1998; Holland and Gonzalez, 1998). The prevalence of fibromyalgia increases with age (Buckwalter and Lappin, 2000; Goldenberg, 1996). Neck pain, joint pain, and fibromyalgia all appear to increase with age in both genders, whereas abdominal pain and tension-type headaches decrease with age, and migraine headache and temporomandibular disorder appear to peak in the reproductive years (Meisler, 1999).

Fibromyalgia and polymyalgia rheumatica are the most common diffuse pain syndromes in the elderly (Belilos and Carsons, 1998; Gowin, 2000).

Fibromyalgia may be primary or a secondary phenomenon of other diffuse pain syndromes associated with inflammatory, endocrine or neoplastic diseases (Gowin, 2000). The initial manifestations of fibromyalgia and other rheumatologic disorders in elderly patients may differ from the typical findings in younger patients. Geriatric patients may have nonspecific complaints, a decline in physical function, or even confusion. Common soft tissue problems encountered in older adults, including fibromyalgia, selected bursitis/tendinitis syndromes, nerve entrapment syndromes, and miscellaneous manifestations such as Dupuytren's contractures, trigger fingers, palmar fascitis, and reflex-sympathetic dystrophy are generally diagnosed as arthritis or normal age-related problems but need to be distinguished clinically (Holland and Gonzalez, 1998). In the selection of optimal pharmacologic and nonpharmacologic therapeutic modalities in the geriatric population, clinicians should focus on maintaining or improving the patient's quality of life and level of independent function (Michet et al., 1995).

In the other extreme of age, it should be noted that the frequency of chronic pain syndromes in pediatric rheumatology has increased over the past 25 years. Diagnosis is complex: underlying organic illness, somatization, and growing pains are all possibilities (Cassidy, 1998).

Fibromyalgia has also been recognized in children and adolescents as juvenile fibromyalgia (JF) (Buskila, 1996; Kulig, 1991; Sherry, 1997; Tayag-Kier et al., 2000). Juvenile rheumatoid arthritis (JRA) and juvenile fibromyalgia can coexist (Schikler, 2000). For the patient with an initial diagnosis of either JRA or JF whose clinical response to therapy is not in keeping with expectations or physical examination findings or whose clinical course worsens without explanation, reevaluation to determine if JF in the JRA patient has developed or JRA in the JF patient has emerged is warranted.

The clinical spectrum of fibromyalgia in children (diffuse aching, headaches, sleep disturbances, and less commonly stiffness, subjective joint swelling, fatigue, abdominal pain, joint hypermobility, dizziness, and depression) is similar to that of adults but with better outcomes (Gedalia et al., 2000; Mikkelsson et al., 1997a,b; Mikkelsson, 1999; Rusy et al., 1999; Sieb et al., 1997; Siegel et al., 1998). Tayag-Kier et al. (2000) also demonstrated, in 16 children and adolescents with JF, abnormalities in sleep architecture, including periodic limb movement in sleep, similar to those seen in adult fibromyalgia patients. However, Breau et al. (1999) consider that fibromyalgia and chronic fatigue syndrome may be related in children and may not be duplicates of the adult disorders; that psychological and psychosocial factors are unlikely contributors to the etiology of these disorders; and that the evidence is increasingly pointing to a role for genetic factors in their etiology. Roizenblatt et al. (1997) reported a significant concordance of fibromyalgia diagnosis, and significant correlations between polysomnographic indexes, sleep anomalies, and pain manifestations in children and their mothers.

Gedalia et al. (2000) reported that active exercise programs seem to correlate with better outcomes in JF. Kujala et al. (1999) point out that, in addition to its likely long term health benefits, vigorous physical activity causes musculoskeletal pains during adolescence, which should be considered as a confounder in epidemiological studies on fibromyalgia and related issues. In terms of other factors that affect JF symptomatology, Schanberg et al. (1998) found that family environment and parental pain history may be related to how children cope with JF.

Behavioral interventions targeting the family may improve the long-term functional status of children with JF (Haavet and Grunfeld, 1997; Schanberg et al., 1996). In this respect, Reid et al. (1997) point out that disability among children with fibromyalgia or JRA is a function of the children's psychological adjustment and physical state, and of the parents' physical state and method of coping with pain.

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