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Scientific Evidence for Abnormal Pain Processing in FM Patients

Robert Bennett MD

There have been many sophisticated studies of fibromyalgia patients that provide overwhelming evidence for a neuropathophysiologic basis for their increased pain perception. There is still much to learn in terms of genetic predisposition, environmental triggers and the role of the psyche in modulating chronic pain states. But the fact that fibromyalgia patients have all the hallmarks of “central sensitization” has been pivotal in understanding why these patients have so many diverse symptoms (that have often been ascribed to hypochondriasis, hysteria, somatization or malingering). These studies are briefly described in the paragraphs below; for more detailed information please consult the references that are given at the end.

Qualitative differences in pain

An objective measure of applied force to a tender point can be obtained by dolorimetry (1). A study using an electronic dolorimeter recorded the subject’s assessment of pain intensity on a 0 to 10-cm visual analogue scale (VAS) at varying levels of applied force (2). Distinctly different response curves were obtained for controls and fibromyalgia patients.  Similar abnormalities of pain processing in fibromyalgia patients have also been reported for heat and cold (3;4). These studies are just a more sophisticated way of showing that fibromyalgia patients are more sensitive to pressure stimuli. 

Deficient pain modulation in response to repeated thermal stimuli

An improvement of pain threshold can be demonstrated in normal individuals by subjecting them to repeated non-noxious skin stimulation. The physiological basis for this effect is the inhibition of dorsal horn neuron excitability by persistent stimulation of type A myelinated axons (5). This effect, known as diffuse noxious inhibitory control (DNIC) has been examined in fibromyalgia patients (6;7). In these studies tonic thermal stimuli at painful and non-painful intensities were used to induce pain inhibition. Concurrent tonic thermal stimuli, at both painful and non-painful levels, significantly increased the electrical pain threshold in the healthy subjects but not in the fibromyalgia patients. It was concluded that DNIC was deficient in fibromyalgia patients, suggesting that they either had deficient pain modulation (8). These studies support the notion that fibromyalgia patients have defective processing of sensory signals. 

Hyper-responsive somatosensory induced potentials

Somatosensory induced potentials refer to the electrophysiological activity in the brain that can be measured by skull electrodes in response to peripheral sensory stimulation.  Gibson et al reported an increased late nociceptive (CO2-laser stimulation of skin) evoked somatosensory response in 10 fibromyalgia patients compared to 10 matched controls (9).  Lorenz et al (10) have reported increased amplitude of the N170 and P390 brain somatosensory potentials in fibromyalgia compared to controls evoked by laser stimulation of the skin.  Furthermore they observed a response in both hemispheres, whereas in controls the response was localized to one side of the brain.  These 2 studies provide objective evidence that fibromyalgia patients have an altered processing of painful stimuli in comparison to pain free controls. 

Secondary hyperalgesia on electrocutaneous stimulation

Primary hyperalgesia is the normal perception of pain from nociceptor stimulation in an injured tissue.  Secondary hyperalgesia refers to pain elicited from uninjured tissues (11). Arroyo and Cohen, while attempting to treat fibromyalgia patients with electrical nerve stimulation reported sensory phenomena characteristic of secondary hyperalgesia (12). This is a direct example of central sensitization in fibromyalgia patients.

 Elevated levels of substance P in the CSF

Substance P is an important nociceptive neurotransmitter.  There are 3 definitive studies that have shown a 3 fold increase of substance P in the CSF of fibromyalgia patients compared to controls (13-15). Animal models of hyperalgesia and hypoalgesia have implicated substance P as a major etiological factor in central sensitization and have highlighted the relevance of substance P in human pain states (16). This finding provides impressive evidence for an abnormal biochemistry of pain related molecules in fibromyalgia compared to healthy controls. 

Elevated levels of nerve growth factor

Nerve growth factor (NGF) is required for the normal development of sympathetic and sensory neurons. Giovengo has reported a 4 fold elevation of NGF in the CSF of patients with primary fibromyalgia compared with healthy controls and other pain patients (17). The intravenous administration of recombinant nerve growth factor in humans results in a muscle pain syndrome resembling fibromyalgia which lasts for up to a week after the initial injection. The mechanism whereby NGF causes hyperalgesia is hypothesized to be related to its stimulation of protein synthesis in the CNS (18). This finding provides more impressive evidence for an abnormal biochemistry of pain related molecules in fibromyalgia compared to healthy controls.

 Beneficial response to an NMDA receptor antagonist

The excitatory amino acid glutamine reacting with NMDA (N-Methyl-D-Aspartic acid) receptors plays a central role in the generation of non-nociceptive pain. Two studies have reported that intravenous ketamine (an NMDA receptor antagonist) attenuates pain and increases pain threshold, as well as improving muscle endurance in fibromyalgia patients (19). The experimental induction of pain summation and referral by intramuscular hypertonic saline in fibromyalgia is attenuated by the use of ketamine (20). This study provides direct experimental evidence that the "biochemical signature" of central sensitization (i.e. activation of NMDA receptors) is present in fibromyalgia patients. 

Experimentally induced central hyperexcitability

Temporal summation of nociceptive impulses at the level of the spinal cord normally occurs when unmyelinated C fiber input exceeds a rate of one impulse every 2-3 seconds. There is good experimental evidence that this neurophysiological process is a critical event in the development of central sensitization (21). An amplification of temporal summation has been demonstrated after repetitive thermal stimulation of the palmar skin in fibromyalgia patients (22) and after intramuscular electrical stimulation of muscle (23).  A recent study reported increased temporal summation in fibromyalgia subjects compared to controls after direct repetitive mechanical stimulation of muscle (24).  These finding provides crucial confirmation that fibromyalgia patients amplify sensory impulses according to the concepts of “central sensitization”.

 Neurogenic Inflammation

“Tender skin” is a common complaint of fibromyalgia patients. There have been repeated observations going back nearly 25 years that fibromyalgia patients have an increased susceptibility to neurogenic inflammation (dermatographia) after scratching the skin (25). Neurogenic inflammation is now understood in terms of antidromic (i.e. retrograde) impulses in type C fibers evoking the release of histamine, substance P and inflammatory cytokines from nociceptors in the skin (26). A recent study has now demonstrated that fibromyalgia patients, in comparison to healthy controls, have increased levels of messenger RNA for inflammatory cytokines (IL-1, TNFa and IL-6) in their skin (27). This observation provides validation for another common symptom reported by fibromyalgia patients, namely increased skin tenderness.

 Functional MRI imaging

Functional MRI imaging (fMRI) is a technique for visualizing metabolic activity in the brain in “real time”.   A 2002 study confirmed that fibromyalgia patients have increased brain activity from a stimulus intensity that does not activate the brain of healthy controls (28). The authors’ concluded that their findings support the notion that fibromyalgia is characterized by cortical or subcortical augmentation of pain processing – i.e. “central sensitization”. This study validates the report of pain in fibromyalgia patients in terms of increased brain activity in locations that are known to be involved in the cortical and sub-cortical response to pain. In other words if a patient says they “have pain” that statement can be verified in this type of experimental setting.

 The Spinal Flexion Reflex

This reflex is an entirely objective response that evaluates the degree of central sensitization at the level of the spinal cord.  It is demonstrated by electrically stimulating a purely sensory nerve (the sural nerve that lies just below the lateral malleolus – the outside prominence of the ankle) and recording the electromyographic reflex contraction of the biceps femoris muscle (a hamstring muscle). In this test the amount of electrical current applied to the sural nerve is gradually increased (from 1 mA up to 100 mA) until a contraction is registered electromyographically in the biceps femoris muscle. The current at which this occurs is referred to as "the reflex threshold" (RT) There are two studies that have shown a facilitated RT in fibromyalgia subjects, and in one of these studies similar findings were found in patients with chronic pain after whiplash injuries.
In the first study Swiss investigators evaluated 85 patients with fibromyalgia compared to 40 healthy controls (29). The median RT threshold in patients with FM (22.7 mA]) was significantly decreased compared with that in healthy controls (33 mA). A cutoff value of <27.6 mA for the RT provided sensitivity of 73% and specificity of 80% for detecting central allodynia in the setting of fibromyalgia. In the second study. 
In the second study, Danish investigators evaluated 22 patients with fibromyalgia, 27 patients with chronic whiplash pain and 29 healthy controls (30). They found that RTs were significantly lower in both the whiplash and fibromyalgia subjects compared with the control subjects.  It was surmised that these results provided good objective evidence for spinal cord hyperexcitability in patients with chronic pain after whiplash injury and in fibromyalgia patients. The authors commented that "this spinal hypersensitivity may explain pain in the absence of detectable tissue damage, in both fibromyalgia and chronic pain following whiplash injuries".

These articles were summed up by a 2002 Editorial in Arthritis and Rheumatism (the leading journal of American Rheumatologists): “Taken together, the data on pain processing in fibromyalgia demonstrate that the central representation of pain correlates with patient reports of pain, and that purely behavioral or psychological factors are not primarily responsible for the pain and tenderness seen in fibromyalgia”.



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