Computer Monitor, like mac with blank screen. OVERVIEWDIAGNOSISTREATMENTFM DVDsSTUDY SIGN-UP FIQR self-test
       Pain explainedMyofascial painHaving SurgeryYour weightLupus in FMSjögren's
       Herbal medsGrowth hormonePregnancyMindfulnessFM DisabilityFM literature
                                                             PPT Slides    Frida Kahlo            

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”.

 

      References   

       (1)    Campbell SM, Clark S, Tindall EA, Forehand ME, Bennett RM. Clinical characteristics of fibrositis.I.A "blinded,: controlled study of symptoms and tender points. Arth Rheum 1983; 26:817-824.

       (2)    Bendtsen L, Norregaard J, Jensen R, Olesen J. Evidence of qualitatively altered nociception in patients with fibromyalgia. Arthritis Rheum 1997; 40:98-102.

       (3)    Kosek E, Ekholm J, Hansson P. Sensory dysfunction in fibromyalgia patients with implications for pathogenic mechanisms. Pain 1996; 68:375-383.

       (4)    Geisser ME, Casey KL, Brucksch CB, Ribbens CM, Appleton BB, Crofford LJ. Perception of noxious and innocuous heat stimulation among healthy women and women with fibromyalgia: association with mood, somatic focus, and catastrophizing. Pain 2003; 102(3):243-250.

       (5)    Wall PD, Cronly-Dillon JR. Pain, itch and vibration. Archives of Neurology 1960; 2:365-375.

       (6)    Lautenbacher S, Rollman GB. Possible deficiencies of pain modulation in fibromyalgia. Clin J Pain 1997; 13(3):189-196.

       (7)    Staud R, Robinson ME, Vierck CJ, Price DD. Diffuse noxious inhibitory controls (DNIC) attenuate temporal summation of second pain in normal males but not in normal females or fibromyalgia patients. Pain 2003; 101(1-2):167-174.

       (8)    Mense S. Neurobiological concepts of fibromyalgia--the possible role of descending spinal tracts. Scand J Rheumatol Suppl 2000; 113:24-29.

       (9)    Gibson SJ, Littlejohn GO, Gorman MM, Helme RD, Granges G. Altered heat pain thresholds and cerebral event-related potentials following painful CO2 laser stimulation in subjects with fibromyalgia syndrome. Pain 1994; 58:185-193.

     (10)    Lorenz J, Grasedyck K, Bromm B. Middle and long latency somatosensory evoked potentials after painful laser stimulation in patients with fibromyalgia syndrome. Electroencephalogr Clin Neurophysiol 1996; 100:165-168.

     (11)    Magerl W, Wilk SH, Treede RD. Secondary hyperalgesia and perceptual wind-up following intradermal injection of capsaicin in humans. Pain 1998; 74(2-3):257-268.

     (12)    Arroyo JF, Cohen ML. Abnormal responses to electrocutaneous stimulation in fibromyalgia. J Rheumatol 1993; 20:1925-1931.

     (13)    Vaeroy H, Helle R, Forre O, Kass E, Terenius L. Elevated CSF levels of substance P and high incidence of Raynaud phenomenon in patients with fibromyalgia: new features for diagnosis. Pain 1988; 32:21-26.

     (14)    Liu Z, Welin M, Bragee B, Nyberg F. A high-recovery extraction procedure for quantitative analysis of substance P and opioid peptides in human cerebrospinal fluid. Peptides 2000; 21(6):853-860.

     (15)    Russell IJ, Orr MD, Littman B, Vipraio GA, Alboukrek D, Michalek JE et al. Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome. Arthritis Rheum 1994; 37(11):1593-1601.

     (16)    Abbadie C, Brown JL, Mantyh PW, Basbaum AI. Spinal cord substance P receptor immunoreactivity increases in both inflammatory and nerve injury models of persistent pain. Neuroscience 1996; 70(1):201-209.

     (17)    Giovengo SL, Russell IJ, Larson AA. Increased concentrations of nerve growth factor in cerebrospinal fluid of patients with fibromyalgia. J Rheumatol 1999; 26(7):1564-1569.

     (18)    Bennett DL. Neurotrophic factors: important regulators of nociceptive function. Neuroscientist 2001; 7(1):13-17.

     (19)    Sorensen J, Bengtsson A, Backman E, Henriksson KG, Bengtsson M. Pain analysis in patients with fibromyalgia: effects of intravenous morphine, lidocaine and ketamine. Scand J Rheumatol 1995; 24:360-365.

     (20)    Andersen OK, Felsby S, Nicolaisen L, Bjerring P, Jensen TS, Arendt-Nielsen L. The effect of ketamine on stimulation of primary and secondary hyperalgesic areas induced by capsaicin--a double-blind, placebo- controlled, human experimental study. Pain 1996; 66:51-62.

     (21)    Koltzenburg M, Torebjork HE, Wahren LK. Nociceptor modulated central sensitization causes mechanical hyperalgesia in acute chemogenic and chronic neuropathic pain. Brain 1994; 117(Pt 3):579-591.

     (22)    Staud R, Vierck CJ, Cannon RL, Mauderli AP, Price DD. Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. Pain 2001; 91(1-2):165-175.

     (23)    Sorensen J, Graven-Nielsen T, Henriksson KG, Bengtsson M, Arendt-Nielsen L. Hyperexcitability in fibromyalgia. J Rheumatol 1998; 25(1):152-155.

     (24)    Staud R, Cannon RC, Mauderli AP, Robinson ME, Price DD, Vierck CJ. Temporal summation of pain from mechanical stimulation of muscle tissue in normal controls and subjects with fibromyalgia syndrome. Pain 2003; 102(1-2):87-95.

     (25)    Littlejohn GO, Weinstein C, Helme RD. Increased neurogenic inflammation in fibrositis syndrome. J Rheumatol 1987; 14:1022-1025.

     (26)    Levine JD, Dardick SJ, Basbaum AI, Scipio E. Reflex neurogenic inflammation. I. Contribution of the peripheral nervous system to spatially remote inflammatory responses that follow injury. J Neurosci 1985; 5(5):1380-1386.

     (27)    Salemi S, Rethage J, Wollina U, Michel BA, Gay RE, Gay S et al. Detection of Interleukin 1beta (IL-1beta), IL-6, and Tumor Necrosis Factor-alpha in Skin of Patients with Fibromyalgia. J Rheumatol 2003; 30(1):146-150.

     (28)    Gracely RH, Petzke F, Wolf JM, Clauw DJ. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum 2002; 46(5):1333-1343.

     (29)    Sterling M, Jull G, Vicenzino B, Kenardy J. Sensory hypersensitivity occurs soon after whiplash injury and is associated with poor recovery. Pain 2003; 104(3):509-517.

     (30)    Borut Banica, Steen Petersen-Felixa, Ole K.Andersenb, Bogdan P.Radanovc, P.M.Villigerd, Lars Arendt-Nielsen et al. Evidence for spinal cord hypersensitivity in chronic pain after whiplash injury and in fibromyalgia. Pain 2004; 107:7-15.

 

                                      About us    Donations  Disclaimer