Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - Fibromyalgia and Sleep Disorders Scientific Conference

Portland, Oregon / October 2-4, 2008

Fibromyalgia occurs in 2% to 4% of the general population. Dr. I. Jon Russell, Associate Professor of Medicine, Division of Clinical Immunology, University of Texas Health Science Center, San Antonio, noted that the prevalence increases with age, particularly past 40, and occurs in three times as many adult females as males, so that as many as 8% of women aged 61 to 70 years suffer from the condition.

Fibromyalgia Not Just Pain

There is a lot more to fibromyalgia than widespread pain and tender points, according to Dr. Harvey Moldofsky, Professor Emeritus, Faculty of Medicine, University of Toronto, Ontario. In 1975, Dr. Moldofsky identified an association between fibromyalgia pain and non-musculoskeletal symptoms such as unrefreshing sleep, emotional distress and autonomic disturbances. In a sleep deprivation study, he was able to induce a disruptive brain wave pattern consisting of alternating delta and alpha waves by arousing healthy volunteers during non-rapid-eye-movement (NREM) sleep. The pattern was similar to that seen in “fibrositis” patients (Moldofsky et al. Psychosom Med 1975;37:341-51). Furthermore, symptoms of fibromyalgia pain are seen in individuals subjected to this type of sleep deprivation.

Dr. Moldofsky cited a recent study in which 2596 fibromyalgia syndrome (FMS) patients ranked their own primary symptoms as morning stiffness, fatigue, poor sleep and pain (Bennett et al. BMC Musculoskelet Disord 2007;8:27). These were also reported as primary symptoms in a German study (Hauser et al. Schmerz 2008;22(2):176-83). The frequency of general and extra-musculoskeletal symptoms underlines that fibromyalgia is really a syndrome, with the pain and abnormal sleep components being very closely linked, confirmed Dr. Moldofsky. As further evidence of this, in a population of 600 FMS patients, 96% were found to have poor sleep quality (Bigatti et al. Arth Care Res 2008;59:951-67).

Dr. Andrew J. Holman, Associate Clinical Professor of Medicine, University of Washington, Seattle, agreed strongly with Dr. Moldofsky’s comments, and further proposed that fibromyalgia is actually caused by the inhibition of restorative sleep, which in turn results from autonomic dysregulation. Joint hypermobility syndrome (JHS), which is believed by some to be a disease of the connective tissue, appears to be a risk factor for dysautonomia. Dr. Holman cited a study which found symptoms of dysautonomia in 78% of patients with JHS, compared to only 10% of controls (Gazit et al. Am J Med 2003;114:33-40).

The Pain/Sleep Circle

It is well known that chronic pain and sleep disorders are mutually reinforcing, noted Dr. Maurice M. Ohayon, Professor of Psychiatry and Behavior Sciences, Stanford University, California. Of particular interest is the finding that NREM sleep deprivation provokes increases in both musculoskeletal pain and pressure pain sensitivity (Lentz et al. J Rheumatol 1999;26(7):1586-92, Older et al. J Rheumatol 1998;25(6):1180-6, Onen et al. J Sleep Res 2001;10(1):35-42). Dr. Ohayon conducted a survey of 18,980 people in Europe and found that 17.1% reported suffering from a chronic painful physical condition (CPPC). Of this group, 46% experienced nocturnal awakenings at least three nights per week, and 77% of these people attributed the awakenings to pain, compared to only 8.2% of pain-free individuals (Ohayon et al. J Clin Psychiatry 2004;65(suppl 12):5–9). “This is not a little thing, three nights per week,” emphasized Dr. Ohayon. “It means that, if they have a reduction of their sleep of only one hour, it will be enough that they will be totally non-restored in the morning when they awake.” This leads to sleepiness, reduced efficiency and increased irritability during the day, he indicated.

Of the 4% of respondents suffering from a major depressive disorder, nearly half also reported a CPPC. Based on further research, Dr. Ohayon concluded that 67% of people with insomnia also have chronic pain, as do 72% of those with mental disorders.

Dr. Russell examined the neurological basis for the relationship between pain and sleep deprivation. Nociception is normally balanced between pro- and anti-nociception factors, he explained. An imbalance towards pro-nociception would result in pain, while one towards anti-nociception would lead to numbness. Pain, then, could result from either excessive pro-nociception or weak anti-nociception. “What we actually have is both,” stated Dr. Russell. “Pro-nociception is too strong neurochemically, anti-nociception is too weak. This has been determined by examining the concentrations of neurochemicals in the cerebrospinal fluid (CSF). For example, the pro-nociceptive neuromodulator substance P (SP) is significantly elevated in FMS.

Dr. Robert Bennett, Professor of Medicine and Nursing, Oregon Health Science University, Portland, commented that SP is elevated in a number of other conditions that have associations with FMS. These include some cases of depression; post-traumatic stress disorder with acute elevation on exposure to a related stressor; and osteoarthritis of hip and knee. Conversely, SP levels are reduced in neuropathic pain disorders.

A New Definition

Neuroimaging reveals both functional and structural differences in the brains of patients with FMS, mentioned Dr. Patrick B. Wood, Chief Medical Officer, Orange County, California (Angler Biomedical Technologies LLC). According to Dr. Wood, MRI studies show evidence of augmented pain processing (Gracely et al. Arthritis Rheum 2002;46(5):1333-43). Dr. Wood’s own work, as well as that of other researchers, has shown changes in grey matter density in patients with FMS. In addition, Dr. Wood has demonstrated decreased dopamine synthesis in the brainstem, thalamus and limbic cortex, correlated with increased visual analogue pain scores using PET imaging.

Dr. Wood has proposed the following definition for FMS: a chronic disorder characterized by abnormal somatosensory processing stemming from changes within the central nervous system (CNS), i.e. brain and spinal cord.

Fibromyalgia Treatment Strategies

The antiepileptic pregabalin has been shown to be safe and effective against pain in FMS (Arnold et al. APS 2007). Dr. Holman noted that pregabalin is approved in Europe and Canada for central and/or peripheral neuropathic pain, in contrast to the US, where it is approved for both neuropathic pain and fibromyalgia. In addition, noted Dr. Russell, pregabalin demonstrated significantly improved sleep quality in a placebo-controlled trial of 745 patients with FMS (Arnold et al. EULAR 2007). Dr. Russell commented that the therapeutic effect of pregabalin develops very rapidly, with significant improvements in pain and sleep quality evident after one week.

The antidepressant duloxetine has also been shown to be effective against two of the major symptoms of FMS, indicated Dr. Russell. A placebo-controlled study of 495 patients showed a significant reduction in the HAMD17 score at two weeks, and an approximately 3-point drop compared to placebo at seven and nine weeks (P<u><</u>0.005) (Brannan et al. J Psychiatr Res 2005; 39:161-72). As well as its antidepressant properties, Dr. Russell has also demonstrated significant reductions in BPI pain score at two doses in patients with FMS (n=444) (Russell et al. Pain 2008;136(3):432-44).

A placebo-controlled study of sodium oxybate (not approved for FMS) showed that it, too, is significantly effective against pain and sleep disturbances in patients with FMS (Russell et al. Arthritis Rheum 2008, in press). Sodium oxybate 4.5 g and 6 g produced similar improvements in pain visual analog score and in Jenkins sleep. Sleep quality improvements were correlated with improvements in fatigue, stiffness and tender point index.

The three primary symptoms seen in FMS are pain (100%), disturbed sleep (70% to 90%) and depression (approximately 30%), noted Dr. Russell. He indicated that “strategic polypharmacy” could be used to treat this primary FMS symptomatic triad. He suggested using pregabalin or sodium oxybate to treat the pain and insomnia, and possibly duloxetine or milnacipran when depressive symptoms require additional attention. “It’s interesting that pregabalin blocks the afferent signal, pro-nociception; it decreases SP levels, according to animal studies, while duloxetine facilitates descending inhibition,” he told the audience.

Summary

FMS appears to be a CNS disorder, accompanied by physical and functional changes within the brain. Its primary symptoms—pain, non-refreshing sleep and depression—are mutually reinforcing via neurochemical pathways. There is a strong rationale for treatment of these symptoms using stategies that are active against abnormalities in these CNS pathways.