Experimental tissue acidosis leads to increased pain in complex regional pain syndrome (CRPS)

&NA; The aim of this study was to investigate the role of local acidosis in the generation of pain in complex regional pain syndrome (CRPS). We investigated ten patients with CRPS of the upper extremity with a mean duration of the disease of 43 weeks (range 4–280 weeks) and ten control subjects for sensitivity to infusion of fluids with low pH (pH 6.1). Another group of five CRPS patients and three healthy controls was investigated using the same protocol but neutral infusion fluid (pH 7.4). A motorized syringe pump was installed for a constant infusion of synthetic interstitial fluid (SIF, either acidified (pH 6.1) or neutral) into the skin at the back of the hands and, thereafter, into the interosseus I muscle on both sides. A flow rate of 30 ml/h was chosen for intradermal and 7.5 ml/h for intramuscular infusion over a period of 10 min. The magnitude of pain was rated on an electronic visual analogue scale. Patients were requested to give their ratings every 10 s during the whole stimulation period. The ratings were normalized as fractions of individual grand mean values. We found significantly increased pain perception during infusion of acidified SIF on the affected side in CRPS patients. Low pH fluid into the skin was significantly more painful between 4 and 6 min (ipsi 1.27 normalized rating (NR) (0.19–1.94), contra 0.31 NR (0.03–0.51), P<0.02) and between 8 and 10 min (ipsi 1.38 NR (0.19–1.94), contra 0.08 NR (0–0.27), P<0.03) on the affected side, while analysis over the whole stimulation period just failed to reach statistical significance (ipsi 281 area under the curve (AUC) (187–834), contra 87 AUC (28–293), P=0.059). Low pH infusion into the muscle was significantly more painful on the affected side during the whole infusion time (ipsi 861 AUC (308–1377), contra 190 AUC (96–528), P<0.01). The quality of the deep pain during infusion into the muscle was described by the patients as very similar to the CRPS‐related pain. In controls we found no side differences of pain intensity during low pH stimulation. Neutral SIF evoked no pain at all, neither in CRPS patients (ipsi 0 AUC, contra 0 AUC) nor in healthy controls. Our results suggest that hyperalgesia to protons is present in patients with CRPS. Further, we could demonstrate that pain is not only restricted to the skin but is also generated in deep somatic tissue of the affected limb.

[1]  P. Grafe,et al.  Hyperglycaemic hypoxia alters after‐potential and fast K+ conductance of rat axons by cytoplasmic acidification. , 1993, The Journal of physiology.

[2]  M. Bonfiglio Ischemia and Necrosis of Bone. , 1981 .

[3]  R. Meyer,et al.  Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain , 1991, Pain.

[4]  R. Schwartzman,et al.  Reflex sympathetic dystrophy. A review. , 1987, Archives of neurology.

[5]  M. Koltzenburg,et al.  Nociceptor modulated central sensitization causes mechanical hyperalgesia in acute chemogenic and chronic neuropathic pain. , 1994, Brain : a journal of neurology.

[6]  S. Bevan,et al.  Protons activate a cation conductance in a sub‐population of rat dorsal root ganglion neurones. , 1991, The Journal of physiology.

[7]  F. Gabreëls,et al.  Complex regional pain syndrome type I (RSD) , 1998, Neurology.

[8]  Noble Ja,et al.  Reflex sympathetic dystrophy. , 1949 .

[9]  R. Goris,et al.  Clinical signs and symptoms of acute reflex sympathetic dystrophy in one hindlimb of the rat, induced by infusion of a free-radical donor. , 1998, Acta orthopaedica Belgica.

[10]  D. Slaaf,et al.  Reflex sympathetic dystrophy: evolution of microcirculatory disturbances in time , 1995, Pain.

[11]  A. Basbaum,et al.  The Cloned Capsaicin Receptor Integrates Multiple Pain-Producing Stimuli , 1998, Neuron.

[12]  D. Julius,et al.  The capsaicin receptor: a heat-activated ion channel in the pain pathway , 1997, Nature.

[13]  P. Reeh,et al.  Pain due to tissue acidosis: a mechanism for inflammatory and ischemic myalgia? , 1996, Neuroscience Letters.

[14]  P. Reeh,et al.  Chapter 8. Tissue acidosis in nociception and pain , 1996 .

[15]  P. Reeh,et al.  A dominant role of acid pH in inflammatory excitation and sensitization of nociceptors in rat skin, in vitro , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[16]  Anthony H. Dickenson,et al.  Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat , 1979, PAIN.

[17]  P. Reeh,et al.  Topical acetylsalicylic, salicylic acid and indomethacin suppress pain from experimental tissue acidosis in human skin , 1995, Pain.

[18]  K. Davis,et al.  Systemic alpha-adrenergic blockade with phentolamine: a diagnostic test for sympathetically maintained pain. , 1991, Anesthesiology.

[19]  G. Schott An unsympathetic view of pain , 1995, The Lancet.

[20]  M. Rowbotham,et al.  The interpretation of pain relief and sensory changes following sympathetic blockade. , 1994, Brain : a journal of neurology.

[21]  C. France,et al.  A comparison of diffuse noxious inhibitory controls in men and women , 1999, Pain.

[22]  Richard Kijowski,et al.  Role of neuropeptides in pathogenesis of reflex sympathetic dystrophy. , 1998, Acta orthopaedica Belgica.

[23]  W. Jänig,et al.  Reflex sympathetic dystrophy : a reappraisal , 1996 .

[24]  H. Genant,et al.  The reflex sympathetic dystrophy syndrome. A comprehensive analysis using fine-detail radiography, photon absorptiometry, and bone and joint scintigraphy. , 1975, Radiology.

[25]  S. Hassenbusch,et al.  Reflex sympathetic dystrophy: changing concepts and taxonomy , 1995, Pain.

[26]  W. Magerl,et al.  Pain and vascular reflexes in man elicited by prolonged noxious mechano-stimulation , 1990, Pain.

[27]  H. Handwerker,et al.  Patterns of hyperalgesia in complex regional pain syndrome , 1999, Pain.

[28]  J. Calder,et al.  Evidence for Immune System Involvement in Reflex Sympathetic Dystrophy , 1998, Journal of hand surgery.

[29]  S. Ramamurthy,et al.  Intravenous Regional Guanethidine in the Treatment of Reflex Sympathetic Dystrophy/Causalgia: A Randomized, Double-Blind Study , 1995, Anesthesia and analgesia.

[30]  P. Reeh,et al.  Protons selectively induce lasting excitation and sensitization to mechanical stimulation of nociceptors in rat skin, in vitro , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[31]  P. Veldman,et al.  Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients , 1993, The Lancet.

[32]  D. Slaaf,et al.  The spinal component to skin blood flow abnormalities in reflex sympathetic dystrophy. , 1996, Archives of neurology.

[33]  P. Dijkstra,et al.  Relationship between impairments, disability and handicap in reflex sympathetic dystrophy patients: a long-term follow-up study , 1998, Clinical rehabilitation.

[34]  R. Baron,et al.  Reflex sympathetic dystrophy: Skin blood flow, sympathetic vasoconstrictor reflexes and pain before and after surgical sympathectomy , 1996, Pain.

[35]  E. Cooke,et al.  Vicious Circles in Reflex Sympathetic Dystrophy-A Hypothesis: Discussion Paper , 1990, Journal of the Royal Society of Medicine.

[36]  H. Blumberg,et al.  [Diagnosis of sympathetic reflex dystrophy. Comparison of ischemia test and modified guanethidine blockade]. , 1994, Der Nervenarzt.

[37]  R. Goris,et al.  Are toxic oxygen radicals involved in the pathogenesis of reflex sympathetic dystrophy? , 1987, Free radical research communications.

[38]  A. Bretag,et al.  Synthetic interstitial fluid for isolated mammalian tissue. , 1969, Life sciences.

[39]  P. Reeh,et al.  Sustained graded pain and hyperalgesia from harmless experimental tissue acidosis in human skin , 1993, Neuroscience Letters.

[40]  K. Davis,et al.  The plasticity of cutaneous hyperalgesia during sympathetic ganglion blockade in patients with neuropathic pain. , 1992, Brain : a journal of neurology.

[41]  J. Arendzen,et al.  Reflex sympathetic dystrophy: early treatment and psychological aspects. , 1994, Archives of physical medicine and rehabilitation.

[42]  R. Sittl,et al.  Sudomotor function in sympathetic reflex dystrophy , 1997, Pain.

[43]  A. Dickenson,et al.  Pharmacological evidence for the involvement of serotonergic mechanisms in diffuse noxious inhibitory controls (DNIC) , 1982, Brain Research.

[44]  J. Willer,et al.  Morphine blocks descending pain inhibitory controls in humans , 1992, Pain.

[45]  J. Bonica Causalgia and other reflex sympathetic dystrophies. , 1973, Postgraduate medicine.

[46]  L. C. Russell,et al.  Pain response to perineuromal injection of normal saline, epinephrine, and lidocaine in humans , 1992, Pain.

[47]  Anthony H. Dickenson,et al.  Diffuse noxious inhibitory controls (DNIC). II. Lack of effect on non-convergent neurones, supraspinal involvement and theoretical implications , 1979, PAIN.

[48]  L. Vyklický,et al.  Inflammatory mediators at acidic pH activate capsaicin receptors in cultured sensory neurons from newborn rats. , 1998, Journal of neurophysiology.

[49]  Arend Heerschap,et al.  Metabolic changes in reflex sympathetic dystrophy: A 31P NMR spectroscopy study , 1993, Muscle & nerve.

[50]  Wilfrid Jänig,et al.  Peripheral nerve injury triggers noradrenergic sprouting within dorsal root ganglia , 1993, Nature.

[51]  W. Kingery,et al.  A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes , 1997, Pain.

[52]  G. Wasner,et al.  Vascular abnormalities in acute reflex sympathetic dystrophy (CRPS I): complete inhibition of sympathetic nerve activity with recovery. , 1999, Archives of neurology.

[53]  A. Franco‐Cereceda,et al.  Capsazepine inhibits low pH- and lactic acid-evoked release of calcitonin gene-related peptide from sensory nerves in guinea-pig heart. , 1992, European journal of pharmacology.

[54]  C. Maggi,et al.  Low pH-induced release of calcitonin gene-related peptide from capsaicin-sensitive sensory nerves: Mechanism of action and biological response , 1991, Neuroscience.

[55]  Josef K. Wang Advances in Pain Research and Therapy , 1980 .