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Emerging Concepts in the Neurobiology of Chronic Pain: Evidence of Abnormal Sensory Processing in Fibromyalgia

  • Robert M. Bennett
    Correspondence
    Individual reprints of this article are not available. Address correspondence to Dr. R. M. Bennett, Department of Medicine (L329A), Oregon Health Sciences University, Portland, OR 97201
    Affiliations
    Division of Arthritis and Rheumatic Diseases, Oregon Health Sciences University, Portland, Oregon.
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      Chronic pain often differs from acute pain. The correlation between tissue pathology and the perceived severity of the chronic pain experience is poor or even absent. Furthermore, the sharp spatial localization of acute pain is not a feature of chronic pain; chronic pain is more diffuse and often spreads to areas beyond the original site. Of importance, chronic pain seldom responds to the therapeutic measures that are successful in treating acute pain. Physicians who are unaware of these differences may label the patient with chronic pain as being neurotic or even a malingerer. During the past decade, an exponential growth has occurred in the scientific underpinnings of chronic pain states. In particular, the concept of nonnociceptive pain has been refined at a physiologic, structural, and molecular level. This review focuses on this new body of knowledge, with particular reference to the chronic pain state termed “fibromyalgia.”
      GH ( growth hormone), NMDA ( N-methyl-D-aspartate), NNP ( nonnociceptive pain), SLE ( systemic lupus erythematosus)
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      REFERENCES

        • Croft P
        • Rlgby AS
        • Boswell R
        • Scholium J
        • Silman A
        The prevalence of chronic widespread pain in the general population.
        J Rheumatol. 1993; 20: 710-713
        • Croft P
        • Scholium J
        • Silman A
        Population study of tender point counts and pain as evidence of fibromyalgia.
        BMJ. 1994; 309: 696-699
        • Wolfe F
        • Rosa K
        • Anderson J
        • Russell IJ
        • Hebert L
        The prevalence and characteristics of fibromyalgia in the general population.
        Arthritis Rheum. 1995; 38: 19-28
        • Anderason HI
        • Ejlertsson G
        • Leden I
        • Rosenberg C
        Chronic pain in a geographically defined general population: studies of differences in age, gender, social class, and pain localization.
        Clin J Pain. 1993; 9: 174-182
        • Gagllese L
        • Melzack R
        Chronic pain in elderly people.
        Pain. 1997; 70: 3-14
        • MacFariane GJ
        • Thomas E
        • Papageorgiou AC
        • Scholium J
        • Croft PR
        • Silman AJ
        The natural history of chronic pain in the community: a better prognosis than in the clinic?.
        J Rheumatol. 1996; 23: 1617-1620
        • Claim DJ
        Fibromyalgia; more than just a musculoskeletal disease [published erratum appears in Am Fam Physician 1996:54:1896; 1901-1902], 4m Fam.
        Physician. 1995; 52 (853-854): 843-851
      1. Merskey H Bogduk N Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 2nd ed. IASP Press, Seattle1994: 210-211
        • Campball SM
        • Clark S
        • Tindail EA
        • Forehand ME
        • Bennett RM
        Clinical characteristics of fibrositis. I, A “blinded,” controlled study of symptoms and tender points.
        Arthritis Rheum. 1983; 26: 817-824
        • Atkins CJ
        • Zieilnski A
        • Makoslnskl A
        Palpometry: a novel concept in pain measurement.
        Nat Med. 1995; 1: 1138-1139
        • Bendtsen L
        • Norregaard J
        • Jensen R
        • Olesen J
        Evidence of qualitatively altered nociception in patients with fibromyalgia.
        Arthritis Rheum. 1997; 40: 98-102
        • Foreman RD
        • Schmidt RF
        • Willis WD
        Effects of mechanical and chemical stimulation of fine muscle afférents upon primate spinothalamic tract cells-.
        J Physiol (Lond). 1979; 286: 215-231
        • Yu XM
        • Men S
        Response properties and descending control of rat dorsal horn neurons with deep receptive fields.
        Neuroscience. 1990; 39: 823-831
        • Kosek E
        • Ekholm J
        • Hansson P
        Sensory dysfunction in fibromyalgia patients with implications for pathogenic mechanisms.
        Pain. 1996; 68: 375-383
        • Dohrenbusch R
        • Sodhi H
        • Lamprecht J
        • Genth E
        Fibromyalgia as a disorder of perceptual organization? An analysis of acoustic stimulus processing in patients with widespread pain.
        Z Rheumatol. 1997; 56: 334-341
        • Pertovaara A
        • Kemppalnen P
        • Leppanen H
        Lowered cutaneous sensitivity to nonpainful electrical stimulation during isometric exercise in humans.
        Exp Brain Res. 1992; 89: 447-452
        • Kosek E
        • Ekholm J
        • Hansson P
        Modulation of pressure pain thresholds during and following isometric contraction in patients with fibromyalgia and in healthy controls.
        Pain. 1996; 64: 415-423
        • Melzack R
        • Wall PD
        Pam mechanisms: a new theory.
        Science. 1965; 150: 971-979
        • Mendell LM
        • Wall PD
        Responses of single dorsal cord cells to peripheral cutaneous unmyelinated fibres.
        Nature. 1965; 206: 97-99
        • Kramis RC
        • Roberts WJ
        • Gillette RG
        Non-nociceptive aspects of persistent musculoskeletal pain.
        J Orthop Sports Phys Ther. 1996; 24: 255-267
        • Wall PD
        • Woolf CJ
        Muscle but not cutaneous C-afferent input produces prolonged increases in the excitability of the flexion reflex in the rat.
        J Physiol (Lond). 1964; 356: 443-458
        • 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
        • Lorenz J
        • Grasedyck K
        • Bromm B
        Middle and long latency somato-sensory evoked potentials after painful laser stimulation in patients with fibromyalgia syndrome.
        Electroencephalogr Clin Neurophysiol. 1996; 100: 165-168
        • Gracely RH
        • Lynch SA
        • Bennett GJ
        Painful neuropathy: altered central processing maintained dynamically by peripheral input [published erratum appears in Pain 1993 52: 251–253].
        Pain. 1992; 51: 175-194
        • Campbell JN
        • Raja SN
        • Meyer RA
        • Mackinnon SE
        Myelinated afferents signal the hyperalgesia associated with nerve injury.
        Pain. 1988; 32: 89-94
        • Arroyo JF
        • Cohen ML
        Abnormal responses to electroculaneous stimulation in fibromyalgia.
        J Rheumatol. 1993; 20: 1925-1931
        • Koltzenburg M
        • Kress M
        • Reeh PW
        The nociceptor sensitization by bradykinin does not depend on sympathetic neurons.
        Neuroscience. 1992; 46: 465-473
        • Torebjork HE
        • Lundberg LER
        • LaMotte RH
        Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans.
        J Physiol (Lond). 1992; 448: 765-780
        • Foreman RD
        • Kenshalo Jr, DR
        • Schmidt RF
        • Will is WD
        Field potentials and excitation of primate spinothalamic neurones in reponse to volleys in muscle afferents.
        J Physiol (Lond). 1979; 286: 197-213
        • Guieu R
        • Serratrice G
        Identifying the afferents involved in movement-induced pain alleviation in man.
        Brain. 1992; 115: 10731079
        • Berié A
        Central pain: “new” syndromes and their evaluation.
        Muscle Nerve. 1993; 16: 1017-1024
        • Dubner R
        • Ruda MA
        Activity-dependent neuronal plasticity following tissue injury and inflammation.
        Trends Neurosci. 1992; 15: 96-103
        • Desbiens NA
        • Wu AW
        • Alzola C
        • Mueller-Rizner N
        • Wenger NS
        • Connors Jr, AF
        • SUPPORT Investlgators
        • et al.
        Pain during hospital-ization is associated with continued pain six months later in survivors of serious illness.
        Am J Med. 1997; 102: 269-276
        • Wallace MS
        • Wallace AM
        • Lee J
        • Dobke MK
        Pain after breast surgery: a survey of 282 women.
        Pain. 1996; 66: 195-205
        • Wolfe F
        • Cathey MA
        • Kleinheksel SM
        Fibrositis (fibromyalgia) in rheumatoid arthritis.
        J Rheumatol. 1984; 11: 814-818
        • Urrows S
        • Affleck G
        • Tennen H
        • Hlggins P
        Unique clinical and psychological correlates of fibromyalgia tender points and joint tenderness in rheumatoid arthritis.
        Arthritis Rheum. 1994; 37: 1513-1520
        • Borensteln D
        Prevalence and treatment outcome of primary and secondary fibromyalgia in patients with spinal pain.
        Spine. 1995; 20: 796-800
        • Lapossy E
        • Maleitzke R
        • Hrycaj P
        • Mennet W
        • Muller W
        The frequency of transition of chronic low back pain to fibromyalgia-.
        Scand J Rheumatol. 1995; 24: 29-33
        • Middleton GD
        • McFarlin JE
        • Lipsky PE
        The prevalence and clinical impact of fibromyalgia in systemic lupus erythematosus.
        Arthritis Rheum. 1994; 37: 1181-1188
        • Morand EF
        • Milter MH
        • Whxztilngham S
        • Littlejohn GO
        Fibromyalgia syndrome and disease activity in systemic lupus erythematosus.
        Lupus. 1994; 3: 187-191
        • Buskila O
        • Neumann L
        • Vaisberg G
        • Alkalay D
        • Wolfe F
        Increased rates of fibromyalgia following cervical spine injury: a controlled Study Of 161 cases of traumatic injury.
        Arthritis Rheum. 1997; 40: 446-452
        • Veale D
        • Kavanagh G
        • Fielding JF
        • Fitzgerald O
        Primary fibromyalgia and the irritable bowel syndrome: different expressions of a common pathogenetic process.
        Br J Rheumatol. 1991; 30: 220-222
        • Wallace DJ
        Genitourinary manifestations of fibrositis: an increased association with the female urethral syndrome.
        J Rheumatol. 1990; 17: 238-239
        • Yunui MB
        • Aldag JC
        Restless legs syndrome and leg cramps in fibromyalgia syndrome: a controlled study.
        BMJ. 1996; 312: 1339
        • Dinerman H
        • Steere AC
        Fibromyalgia following Lyme disease: association with neurologic involvement and lack of response to antibiotic therapy [abstract].
        Arthritis Rheum. 1990; 33: S136
        • Simms RW
        • Ferrante N
        • Craven DE
        • AIDS Clinical Research Team
        High prevalence of fibromyalgia syndrome (FMS) in human immunodeficiency virus type 1 (HIV) infected patients with poiyarthralgia [abstract].
        Arthritis Rheum. 1990; 33: S136
        • Rivera J
        • de Diego A
        • Trinchet M
        • Garcia Monforte A
        Fibromyalgia-associated hepatitis C virus infection.
        Br J Rheumatol. 1997; 36: 981-985
        • Barkhulzen A
        • Schoepflin GS
        • Bennett RM
        Fibromyalgia: a prominent feature in patients with musculoskeletal problems in chronic hepatitis C; a report of 12 patients.
        J Clin Rheumatol. 1996; 2: 180-184
        • Leventhal LJ
        • Naldee SJ
        • Freundlich B
        Fibromyalgia and parvovirus infection.
        Arthritis Rheum. 1991; 34: 1319-1324
        • Bennett R
        The concurrence of lupus and fibromyalgia: implications for diagnosis and management.
        Lupus. 1997; 6: 494-499
        • Watkina LR
        • Maler SF
        • Goehler LE
        Immune activation: the role of pro-inflammatory cytokines in inflammation, illness responses and pathological pain states.
        Pain. 1995; 63: 289-302
        • Wlertelak EP
        • Furness LE
        • Horan R
        • Martinez J
        • Maler SF
        • Watkins LR
        Subcutaneous formalin produces centrifugal hyperalgesia at a non-injected site via the NMDA-nitric oxide cascade.
        Brain Res. 1994; 649: 19-26
        • Wlertelak EP
        • Roemer B
        • Maler SF
        • Watkins LR
        Comparison of the effects of nucleus tractus solitarius and ventral medial medulla lesions on illness-induced and subcutaneous formalin-induced hyperalgesias.
        Brain Res. 1997; 748: 143-150
        • Wetklna LR
        • Wlertelak EP
        • Goehler LE
        • Mooney-Helberger K
        • Martinez J
        • Furness L
        • et al.
        Neurocircurtry of illness-induced hyperalgesia.
        Brain Res. 1994; 639: 283-299
        • DeLeo JA
        • Colburn RW
        • Nichols M
        • Malhotra A
        lnterleukin-6-mediated hyperalgesia/allodynia and increased spinal IL-6 expression in a rat mononeuropathy model.
        J Interleron Cytokine Res. 1996; 16: 695-700
        • Woolf CJ
        • Allchome A
        • Safleh-Garabedian B
        • Poole S
        Cytokines, nerve growth factor and inflammatory hyperalgesia: the contribution of tumour necrosis factor alpha.
        Br J Pharmacol. 1997; 121: 417-424
        • Busklla O
        • Neumann L
        • Hazanov I
        • Carrni R
        Familial aggregation in the fibromyalgia syndrome.
        Semin Arthritis Rheum. 1996; 26: 605-611
        • Buskila D
        • Neumann L
        Fibromyalgia syndrome (FM) and nonarticular tenderness in relatives of patients with FM.
        J Rheumatol. 1997; 24: 941-944
        • Dubner R
        Hyperalgesia and expanded receptive fields [editorial].
        Pain. 1992; 48: 3-4
        • Dickenson AH
        • Sullivan AF
        NMDA receptors and central hyperalgesic states [letter].
        Pain. 1991; 46: 344-346
        • Woolf CJ
        • Thompson SW
        The induction and maintenance of central sensitization is dependent on M-methyl-D-aspartic acid receptor activation: implications for the treatment of post-injury pain hypersensitivity states.
        Pain. 1991; 44: 293-299
        • Basbaum AI
        Memories of pain.
        Sci Med. 1996 Nov/Dec; 3: 22-31
        • De Felipe C
        • Herrero JF
        • O'Brien JA
        • Palmer JA
        • Doyle CA
        • Smith AJ
        • et al.
        Altered nociception, analgesia and aggression in mice lacking the receptor far substance P.
        Nature. 1998; 392: 394-397
        • Arnetz BB
        • FJeliner B
        Psychological predictors of neuroendocrine responses to mental stress.
        J Psychosom Res. 1986; 30: 297-305
        • Sastry BR
        Substance P effects on spinal nociceptive neurones.
        Life Sci. 1979; 24: 2169-2177
        • Coderre TJ
        • Katz J
        • Vaccarino AL
        • Melzack R
        Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence.
        Pain. 1993; 52: 259-285
        • Liu H
        • Mahtyh PW
        • Basbaum AI
        NMDA-receptor regulation of substance P release from primary afferent nociceptors.
        Nature. 1997; 386: 721-724
        • Mantyh PW
        • DeMaster E
        • Malhotra A
        • Ghllardi JR
        • Rogers SD
        • Mantyh CR
        • et al.
        Receptor endocytosis and dendrite reshaping in spinal neurons after somatosensory stimulation.
        Science. 1995; 268: 1629-1632
        • Uu H
        • Brown JL
        • Jasmin L
        • Maggio JE
        • Vigna SR
        • Mantyh PW
        • et al.
        Synaptic relationship between substance P and the substance P receptor: light and electron microscopic characterization of the mismatch between neuropeptides and their receptors.
        Proc Natl AcadSei USA. 1994; 91: 1009-1013
        • Tslgos C
        • Dlemel LT
        • White A
        • Tomlinson DR
        • Young RJ
        Cerebro-spinal fluid levels of substance P and caicitonin-gene related peptide: correlation with sural nerve levels and neuropathic signs in sensory diabetic polyneuropathy.
        Clin Sci (Colch). 1993; 84: 305-311
        • 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
        • Russell IJ
        • Orr MD
        • Littman B
        • Vlpraio GA
        • Alboukrek D
        • Michalak JE
        • et al.
        Elevated cerebrospinal fluid levels of substance P in patients with ths fibromyalgia syndrome.
        Arthritis Rheum. 1994; 37: 1593-1601
        • Watkins LR
        • Wiertelak EP
        • Fumessh LE
        • Maler SF
        llness-induced hyperalgesia is mediated by spinal neuropeptides and excitatory amino acids.
        Brain Res. 1994; 664: 17-24
        • Fields HL
        • Basbaum AI
        Central nervous system mechanisms of pain modulation.
        in: Wall PD Melzack Ft Textbook of Pain. 3rd ed. Churchill Livingstone, Edinburgh1994: 245-257
        • Hohelael U
        • Menae S
        Response behaviour of cat dorsal horn neurones receiving input from skeletal muscle and other deep so matic tissues.
        J Physiol (Lond). 1990; 426: 265-280
        • Basbaum AI
        • Fields HL
        Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry.
        Annu Rev Neurosci. 1984; 7: 309-338
        • Wall PD
        • Cronly-Dlllon JR
        Pain, itch, and vibration.
        Arch Neurol. 1960; 2: 365-375
        • Lautenbacher S
        • Rollman GB
        Possible deficiencies of pain modulation in fibromyalgia.
        Clin J Pain. 1997; 13: 189-196
        • Lenz FA
        • Gracely RH
        • Romanoski AJ
        • Hope EJ
        • Rowland LH
        • Dougherty PM
        Stimulation in the human somatosensory thalamus can reproduce both the affective and sensory dimensions of previously experienced pain.
        Nat Med. 1995; 1: 910-913
        • Davis KD
        • Kiss ZH
        • Luo L
        • Tasker RR
        • Lozano AM
        • Dostrovsky JO
        Phantom sensations generated by thalamic microstimulation.
        Nature. 1998; 391: 385-387
        • Pillay PK
        • Hassenbusch SJ
        Bilateral MRI-guided stereolactic cingulotomy for intractable pain.
        Stereotact funct Neurosurg. 1992; 59: 33-38
        • Foltz EL
        • White Jr, LE
        Pain relief by frontal cingulumotomy.
        J Neurosurg. 1962; 19: 89-100
        • Rainville P
        • Duncan GH
        • Price DD
        • Carrier B
        • Bushneil MC
        Pain affect encoded in human anterior cingulate but not somatosensory cortex.
        Science. 1997; 277: 968-971
        • Devlnaky O
        • Morrell MJ
        • Vogt BA
        Contributions of anterior cingulate cortex to behaviour.
        Brain. 1995; 118: 27-306
        • Hsleh JC
        • Belfrage M
        • Stone-Elander S
        • Hansson P
        • Ingvar M
        Central representation of chronic ongoing neuropathic pain studied by positron emission tomography.
        Pain. 1995; 63: 225-236
        • Davis KD
        • Taylor SJ
        • Crawley AP
        • Wood ML
        • Mlkulis DJ
        Functional MRI of pain and attention-related activations in the human cingulate cortex.
        J Neurophysiol. 1997; 77: 3370-3380
        • Davis KD
        • Wood ML
        • Crawley AP
        • Mikulls DJ
        fMRI of human somatosensory and cingulate cortex during painful electrical nerve stimulation.
        Neuroreport. 1995; 7: 321-325
        • Jones AK
        Pain, its perception, and imaging.
        IASP Newslett. 1997 May/Jun; : 3-5
        • Bowsher D
        Central pain: clinical and physiological characteristics.
        J Neurol Neurosurg Psychiatry. 1996; 61: 62-69
        • Cralg AD
        A new version of the thalamic disinhibition hypothesis of central pain.
        Pain Forum. 1998 Spring; 7: 1-14
        • Head H
        • Holmes G
        Sensory disturbances from cerebral lesions.
        Brain 1911-. 1912; 34: 102-254
        • Di Piero V
        • Fiaceo F
        • Tombari D
        • Pantano P
        Tonic pain: a SPET study in normal subjects and cluster headache patients.
        Pain. 1997; 70: 185-191
        • Pagni CA
        • Cansvero S
        Functional thalamic depression in a case of reversible central pain due to a spinal intramedullary cyst: case report.
        JNeurosurg. 1995; 83: 163-165
        • Hirato M
        • Watanabe K
        • Takahashi A
        • Hayase N
        • Horikoshi S
        • Shibasaki T
        • et al.
        Pathophysiology of central (thalamic) pain: combined change of sensory thalamus with cerebral cortex around central sulcus.
        Stereotact Funct Neurosurg. 1994; 62: 300-303
        • Mountz JM
        • Bradley LA
        • Modell JG
        • Alexander RW
        • Triana-Alexander M
        • Aaron LA
        • et al.
        Fibromyalgia in women: abnormalities of regional cerebral blood flow in the thalamus and the caudate nucleus are associated with low pain threshold levels.
        Arthritis Rheum. 1995; 38: 926-938
        • Sakiyama Y
        • Sato A
        • Senda M
        • lshi Wata K
        • Toyama H
        • Schmidt RF
        Positron emission tomography reveals changes in global and regional cerebral blood flow during noxious stimulation of normal and inflamed elbow joints in anesthetized cats.
        Exp Brain Res. 1998; 118: 439-446
        • Xu X
        • Fukuyama H
        • Yazawa S
        • Mima T
        • Hanakawa T
        • Magata Y
        • et al.
        Functional localization of pain perception in the human brain studied by PET.
        Neuroreport. 1997; 8: 555-559
        • Jones AK
        • Brown WD
        • Friston KJ
        • QI LY
        • Frackowlak RS
        Cortical and subcortical localization of response to pain in man using positron emission tomography.
        Proc R Soc Land B Biol Sci. 1991; 244: 39-44
        • Ladarola MJ
        • Max MB
        • Barman KF
        • Byas-Smfth MG
        • Coghill RC
        • Gracely RH
        • et al.
        Unilateral decrease in thalamic activity observed with positron emission tomography in patients with chronic neuropathic pain.
        Pain. 1995; 63: 55-64
        • Turk DC
        • OkifuJi A
        • Sinclair JD
        • Starz TW
        Pain, disability, and physical functioning in subgroups of patients with fibromyalgia.
        J Rheumatol. 1996; 23: 1255-1262
        • Toomey TC
        • Seville JL
        • Mann JD
        • Abashlan SW
        • Grant JR
        Relationship of sexual and physical abuse to pain description, coping, psychological distress, and health-care utilization in a chronic pain sample.
        Clin J Pain. 1995; 11: 307-315
        • Turk DC
        • Okifuji A
        • Starz TW
        • Sinclair JD
        Effects of type of symptom onset on psychological distress and disability in fibromyalgia syndrome patients.
        Pain. 1996; 68: 423-430
        • Bandura A
        Self-efficacy mechanism in physiological activation and health-promoting behavior.
        in: Madden JIV Matthysse S Earchas J Adaption, Learning and Affect. Raven Press, New York1986
        • Amir M
        • Kaplan Z
        • Neumann U
        • Sharabanl R
        • Shani N
        • Buskila D
        Posttraumatic stress disorder, tenderness and fibromyalgia.
        J Psychosom Res. 1997; 42: 607-613
        • Sigai LH
        Illness behavior and the biomédical model.
        Bull Rheum Dis. 1997 Feb; 46: 1-4
        • Affleck G
        • Urrows S
        • Tennen H
        • Hlgglns P
        • Abeles M
        Sequential daily relations of sleep, pain intensity, and attention to pain among women with fibromyalgia.
        Pam. 1996; 68: 363-368
        • Moldofsky H
        • Sculibrlck P
        • England R
        • Smythe H
        Musculoskelelal symptoms and non REM sleep disturbance in patients with “fibrositis syndrome” and healthy subjects.
        Psychosom /Wed. 1975; 37: 341-351
        • Moldofsky M
        • Scarlsbrtck P
        Induction of neurasthenic musculoskel-etal pain syndrome by selective sleep stage deprivation.
        Psychosom Med. 1976; 38: 3-44
        • Eccleston C
        • Crombez G
        • Aldrleh S
        • Stannard C
        Attention and somatic awareness in chronic pain.
        Pain. 1997; 72: 209-215
        • Moldofsky H
        Rheumatic pain modulation syndrome: the interrelationships between sleep, central nervous system serotonin, and pain.
        AdvNeurol. 1982; 33: 51-57
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders. 4th ed. American Psychiatric Association, Washington (DC)1994: 445-469
        • Matsuda S
        • Peng H
        • Yoshimura H
        • Wen TC
        • Fukuda T
        • Sakanaka M
        Persistent c-fos expression in the brains of mice with chronic social stress.
        NeuroSciRes. 1996; 26: 157-170
        • Hunt SP
        • PInl A
        • Evan G
        Induction of c-fos-like protein in spinal cord neurons following sensory stimulation.
        Mature. 1987; 328: 632-634
        • Abbadl C
        • Season JM
        C-fos expression in rat lumbar spinal cord following peripheral stimulation in adjuvant-induced arthritic and normal rats.
        Brain Res. 1993; 607: 195-204
        • Elliott KJ
        • Brodsky M
        • Hynansky AD
        • Foley KM
        • Inturrfsi CE
        Dextromethorphan suppresses both formalin-induced nociceptive behavior and the formalin-induced increase in spinal cord cfos mRNA.
        Pain. 1995; 61: 401-409
        • Bobbins JM
        • Kirmayer U
        • Hemaml S
        Latent variable models of functional somatic distress.
        J Nerv Ment Dis. 1997; 185: 606-615
        • Turk DC
        • Okifuji A
        • Scharff L
        Chronic pain and depression: role of perceived impact and perceived control in different age cohorts.
        Pain. 1995; 61: 93-101
        • Krause SJ
        • Wiener RL
        • Tait RC
        Depression and pain behavior in patients with chronic pain.
        Clin J Pain. 1994; 10: 122-127
        • McWhliney IR
        • Epstein RM
        • Freeman TR
        Rethinking somatization.
        Ann Intern Med. 1997; 126: 747-750
        • King SA
        Review: DSM-IV and pain.
        ClinJ Pain. 1995; 11: 171-176
        • Bennett RM
        Confounding features of the fibromyalgia syndrome: a current perspective of differential diagnosis.
        J Rheumatol Suppl. 1989; 19: 58-61
        • Wolfe F
        • Smythe HA
        • Yunus MB
        • Bennett RM
        • Bombardier C
        • Goldenberg DL
        • et al.
        The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia: report of the Multicenter Criteria Committee.
        Arthritis Rheum. 1990; 33: 160-172
        • Deodhar AA
        • Fisher RA
        • Blacker CVR
        • Woolf AD
        Fluid retention syndrome and fibromyalgia.
        BrJ Rheumatol. 1994; 33: 576-582
        • Weiss DJ
        • Kreck T
        • Albert RK
        Dyspnea resulting from fibromyalgia.
        Criest. 1998; 113: 246-249
        • Plesh O
        • Wolfe F
        • Lane N
        The relationship between fibromyalgia and temporomandibular disorders: prevalence and symptom severity.
        J Rheumatol. 1996; 23: 1948-1952
        • Pellegrino MJ
        Atypical chest pain as an initial presentation of primary fibromyalgia.
        Arch Phys Med Rehabil. 1990; 71: 526-528
        • Caidahl K
        • Lurie M
        • Bake B
        • Johansson G
        • Wetterqvist H
        Dyspnoea in chronic primary fibromyalgia.
        J Intern Med. 1989; 226: 265-270
        • Blasberg B
        • Chalmers A
        Temporomandibular pain and dysfunction syndrome associated with generalized musculoskeletal pain: a retrospective study.
        J Rheumatol Suppl. 1989; 19: 87-90
        • Dinerman H
        • Goldenberg DL
        • Felson DT
        A prospective evaluation of 118 patients with the fibromyalgia syndrome: prevalence of Raynaud's phenomenon, sicca symptoms, ANA, low complement, and Ig deposition at the dermal-epidermal junction.
        J Rheumatol. 1986; 13: 368-373
        • Gerster JC
        • HadJ-Djilani A
        Hearing and vestibular abnormalities in primary fibrositis syndrome.
        J Rheumatol. 1984; 11: 678-680
        • Burckhardt CS
        • O'Reilly CA
        • Wiens AN
        • Clark SR
        • Campbell SM
        • Bennett RM
        Assessing depression in fibromyalgia patients.
        Arthrits Care Res. 1994; 7: 35-39
        • Yunus M
        • Masi AT
        • Calabro JJ
        • Miller KA
        • Feigenbaum SL
        Primary fibromyalgia (fibrositis): clinical study of 50 patients with matched normal controls.
        Semn Arthritis Rheum. 1981; 11: 151-171
        • Bennett RM
        • Clark SR
        • Campbell SM
        • Ingram SB
        • Burckhardt CS
        • Nelson DL
        • et al.
        Symptoms of Raynaud's syndrome in patients with fibromyalgia: a study utilizing the Nielsen test, digital photoplethys-mography, and measurements of platelet alpha 2-adrenergic receptors.
        Arthritis Rheum. 1991; 34: 264-269
        • Sivri A
        • Cindas A
        • Dlncer F
        • Sivrl B
        Bowel dysfunction and irritable bowel syndrome in fibromyalgia patients.
        Clin Rheumatol. 1996; 15: 283-286
        • Palra SO
        Fibromyalgia associated with female urethral syndrome.
        Clin Rheumatol. 1994; 13: 88-89
        • Alagiri M
        • Chottiner S
        • Ratner V
        • Slade O
        • Hanno PM
        Interstitial cystitis: unexplained associations with other chronic disease and pain syndromes.
        Urology. 1997; 49: 52-57
        • Ciauw DJ
        • Schmidt M
        • Radulovic D
        • Singer A
        • Katz P
        • Brisetta J
        The relationship between fibromyalgia and interstitial cystitis.
        J PsychiatrRes. 1997; 31: 125-131
        • Bou-Holalgah I
        • Calkins H
        • Flynn JA
        • Tunin C
        • Chang HC
        • Kan JS
        • et al.
        Provocation of hypotension and pain during upright tilt table testing in adults with fibromyalgia.
        Clin Exp Rheumatol. 1997; 15: 239-246
        • McDermid AJ
        • Rollman GB
        • McCain GA
        Generalized hypervigilance in fibromyalgia: evidence of perceptual amplification.
        Pain. 1996; 66: 133-144
        • Aaron LA
        • Bradley LA
        • Alarcon GS
        • Alexander RW
        • Triana-Alexander M
        • Martin MY
        • et al.
        Psychiatric diagnoses in patients with fibromyalgia are related to health care-seeking behavior rather than to illness.
        Arthritis Rheum. 1996; 39: 436-445
        • Goldenberg DL
        An overview of psychologic studies in fibromyalgia.
        J Rheumatol Suppl. 1989; 19: 12-14
        • Katz RS
        • Kravitz HM
        Fibromyalgia, depression, and alcoholism; a family history study, J.
        Rheumato). 1996; 23: 149-154
        • krmayer U
        • Robbins JM
        • Kapusta MA
        Somatization and depression in fibromyalgia syndrome.
        Am J Psychiatry. 1988; 145: 950-954
        • Hudson JT
        • Pope Jr, HG
        Fibromyalgia and psychopathology: is fibromyalgia a form of “affective spectrum disorder?”.
        J Rheumatol Suppl. 1989; 19: 15-22
        • Snow-Turek AL
        • Norris MP
        • Tan G
        Active and passive coping strategies in chronic pain patients.
        Pain. 1996; 64: 455-462
        • Rosenstlel AK
        • Keefe FJ
        The use of coping strategies in chronic low back pain Patients: relationship to patient characteristics and current adjustment.
        Pain. 1983; 17: 33-44
        • Nlcassio PM
        • Schoenfeld-Smith K
        • Radojevi V
        • Schuman C
        Pain coping mechanisms in fibromyalgia: relationship To pain and functional outcomes.
        J Rheumatol. 1995; 22: 1552-1558
        • Lisse JR
        Rheumatic disorders in adults under 50: guidelines for differential diagnosis.
        Postgrad Med. 1988 0ct; 84 (119-121): 113-114
        • Pillemer SR
        • Bradley LA
        • Crofford U
        • Moldofsky H
        • Chrousos GP
        The neuroscience and endocrinology of fibromyalgia.
        Arthritis Rheum. 1997; 40: 1928-1939
        • Crofford U
        • Pillemer SR
        • Kalogeras KT
        • Cash JM
        • Mlchelson D
        • Kline MA
        • et al.
        Hypothalamic-piluitary-adrenal axis perturbations in patients with fibromyalgia.
        Arthritis Rheum. 1994; 37: 1583-1592
        • Griep EN
        • Boersma JW
        • de Kloet ER
        Altered reactivity of the hypothalamic-piturtary-adrenal axis in the primary fibromyalgia syndrome.
        J Rheumatol. 1993; 20: 469474
        • Bennett RM
        • Clark SR
        • Campbell SM
        • Burekhardt CS
        Low levels of somatomedin C in patients with the fibromyalgia syndrome: a possible link between sleep and muscle pain.
        Arthritis Rheum. 1992; 35: 1113-1116
        • Bennett RM
        • Cook DM
        • Clark SR
        • Burekhardt CS
        • Campbell SM
        Hypothalamic-pituitary-insulin-like growih factor-l axis dysfunction in patients with fibromyalgia.
        J Rheumatol. 1997; 24: 1384-1389
        • Cuneo RC
        • Salomon F
        • McGauley GA
        • Sonksen PH
        The growth hormone deficiency syndrome in adults.
        Clin Endocrinol (Oxf). 1992; 37: 387-397
        • Wallymahmed ME
        • Baker GA
        • Humphris G
        • Dewey M
        • MacFarlane IA
        The development, reliability and validity of a disease specific quality of life model for adults with growth hormone deficiency.
        Clin Endocrinol (Oxf). 1996; 44: 403-411
        • Cuneo RC
        • Salomon F
        • Wllmshurst P
        • Byrne C
        • Wiles CM
        • Hesp R
        • et al.
        Cardiovascular effects of growth hormone treatment in growlrv-hormone-deficient adults: stimulation of the renin-aldosterone system.
        Clin Sci (Colch). 1991; 81: 587-592
        • Rutherford OM
        • Beshyah SA
        • Schott J
        • Watkina Y
        • Johnston DG
        Contractile properties of the quadriceps muscle in growth hormone-deficient hypopituitary adults.
        Clin Sci (Colch). 1995; 88: 67-71
        • McGauley GA
        • Cuneo RC
        • Salomon F
        • Sonksen PH
        Psychological well-being before and after growth hormone treatment in adults with growth hormone deficiency.
        Horm Res. 1990; 33: 52-54
        • Salomon F
        • Cuneo RC
        • Hesp R
        • Sonksen PH
        The effects of treatment with recombinant human growth hormone on body composition and metabolism m adults with growth hormone deficiency.
        N Engl J Med. 1989; 321: 1797-1803
        • Florini JR
        Hormonal control of muscle growth.
        Muscle Nerve. 1987; 10: 577-598
        • Bennett RM
        The contribution of muscle to the generation of fibromyalgia symptomatology.
        J Musculoskeletal Pain. 1996; 4: 35-59
        • Bennett RM
        • Clark SC
        • Walczyk J
        A randomized, double-blind, placebr controlled study of growth hormone in the treatment of fibromyalgia.
        Am J Med. 1998; 104: 227-231
        • Clauw DJ
        • Chrornic GP
        Chrome pain and fatigue syndromes: overlapping clinical and neuroendocrine features and potential pathogenic mechanisms.
        Neuroimmunomodulation. 1997; 4: 134-153
        • Skuse D
        • Albanese A
        • Stanhope R
        • Gllmour J
        • Voss L
        A new stress related syndrome of growth failure and hyperphagia in children, associated with reversibility of growth-hormone insufficiency.
        Lancet. 1996; 348: 353-358
        • Portenoy RK
        Opioid therapy for chronic nonmalignant pain: a review of the critical issues.
        J Pain Symptom Manage. 1996; 11: 203-217
        • Friedman DP
        Perspectives on the medical use of drugs of abuse.
        J Pain Symptom Manage. 1990; 5: S2S5
        • Portenoy RK
        • Dole V
        • Joseph H
        • Lowinson J
        • Rice C
        • Segal S
        • et al.
        Pain management and chemical dependency; evolving perspectives.
        JAMA. 1997; 278: 592-593
        • Melzack R
        The tragedy of needless pain.
        Sei Am. 1990 Feb; 262: 27-33
        • Wall PD
        The generation of yet another myth on the use of narcotics [editorial].
        Pain. 1997; 73: 121-122
        • Welssman DE
        • Haddox JD
        Opioid pseudoaddiction: an iatrogenic syndrome.
        Pain. 1989; 36: 363-366
        • Aronson MD
        Nonsteroidal anti-inflammatory drugs, traditional opi-oids, and tramadol: contrasting therapies for the treatment of chronic pain.
        Clin Ther. 1997; 19: 420-432
        • Russell IJ
        • Kamin M
        • Säger D
        • Bennett RM
        • Schnitzer T
        • Green JA
        • et al.
        Efficacy of Ultrarn(tm) [tramadol HCL] treatment of fibromyalgia syndrome: preliminary analysis of a multi-center, randomized, placebo-controlled stuOy [abstract).
        Arthritis Rheum. 1997; 40: S117
        • Roth SH
        Efficacy and safety of tramadol HCI in breakthrough musculoskeletal pain attnbuted to osteoarthritis.
        J Rheumatol. 1998; 25: 1358-1363
        • Radbruch L
        • Grond S
        • Lehmann KA
        A risk-benefit assessment or tramadol in the management of pain.
        Drug Sa(. 1996; 15: 8-29
        • Blasl G
        • Manca S
        • Manganelll S
        • Marcolongo R
        Tramadol in the fibromyalgia syndrome: a controlled clinical trial versus placebo.
        Int J Clin Pharmacol Res. 1998; 18: 13-19
        • Haratl V
        • Gooch C
        • Swenson M
        • Edelman S
        • Greene D
        • Raskin P
        • et al.
        Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy.
        Neurology. 1998; 50: 1842-1846
        • Bennett RM
        Multidisciplinary group programs to treat fibromyalgia patients.
        Rheum Dis Clin North Am. 1996 May; 22: 351-367
        • Sorensen J
        • Bengtsson A
        • Backman E
        • Henrlksson KG
        • Bengtsson M
        Pain analysis in patients with fibromyalgia: effects of intravenous morphine, lidocaine, and ketamine.
        Scand J Rheumatol. 1995; 24: 360-365
        • Sorensen J
        • Bengtsson A
        • Ahlner J
        • Henrlksson KG
        • Eksellus L
        • Bengtsson M
        Fibromyalgia-are there different mechanisms in the processing of pain? A double blind crossover comparison of analgesic drugs.
        J Rheumatol. 1997; 24: 1615-1621
        • Woolf CJ
        A new strategy for the treatment of inflammatory pain: prevention or elimination of central sensitization.
        Drugs. 1994; 47: 1-9