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`Pain Medicine 2010; 11: 1224–1238
`Wiley Periodicals, Inc.
`
`A Hypothesis for the Cause of Complex
`Regional Pain Syndrome-Type I (Reflex
`Sympathetic Dystrophy): Pain Due to
`Deep-Tissue Microvascular Pathologypme_911 1224..1238
`
`Terence J. Coderre, PhD,*†‡§¶** and
`Gary J. Bennett, PhD*†§¶
`
`Departments of *Anesthesia,
`
`†Neurology & Neurosurgery, and
`
`‡Psychology,
`
`§Faculty of Dentistry,
`
`¶the Alan Edwards Centre for Research on Pain,
`McGill University;
`
`**the McGill University Health Centre Research
`Institute, Montreal, Quebec, Canada
`
`Reprint requests to: Terence J. Coderre, PhD,
`Anesthesia Research Unit, McGill University, Room
`1203, McIntyre Bldg., 3655 Promenade Sir William
`Osler, Montreal, Quebec, Canada H3G 1Y6. Tel:
`514-398-5773; Fax: 514-398-8241; E-mail:
`terence.coderre@mcgill.ca.
`
`Abstract
`
`Complex regional pain syndrome-type I (CRPS-I;
`reflex sympathetic dystrophy) is a chronic pain con-
`dition that usually follows a deep-tissue injury such
`as fracture or sprain. The cause of the pain is
`unknown. We have developed an animal model
`(chronic post-ischemia pain) that creates CRPS-I-like
`symptomatology. The model is produced by occlud-
`ing the blood flow to one hind paw for 3 hours under
`general anesthesia. Following reperfusion,
`the
`treated hind paw exhibits an initial phase of hyper-
`emia and edema. This is followed by mechano-
`hyperalgesia, mechano-allodynia,
`and
`cold-
`allodynia that lasted for at least 1 month. Light
`microscopic analyses and electron microscopic
`analyses of the nerves at the site of the tourniquet
`show that the majority of these animals have no sign
`of
`injury to myelinated or unmyelinated axons.
`However, electron microscopy shows that
`the
`ischemia-reperfusion injury produces a microvascu-
`lar injury, slow-flow/no-reflow, in the capillaries of the
`
`1224
`
`hind paw muscle and digital nerves. We propose that
`the slow-flow/no-reflow phenomenon initiates and
`maintains deep-tissue ischemia and inflammation,
`leading to the activation of muscle nociceptors, and
`the ectopic activation of sensory afferent axons due
`to endoneurial ischemia and inflammation.
`
`These data, and a large body of clinical evidence,
`suggest that in at least a subset of CRPS-I patients,
`the fundamental cause of the abnormal pain sensa-
`tions is ischemia and inflammation due to microvas-
`cular pathology in deep tissues,
`leading to a
`combination of inflammatory and neuropathic pain
`processes. Moreover, we suggest a unifying idea
`that relates the pathogenesis of CRPS-I to that of
`CRPS-II. Lastly, our hypothesis suggests that the
`role of the sympathetic nervous system in CRPS-I is
`a factor that is not fundamentally causative, but may
`have an important contributory role in early-stage
`disease.
`
`Key Words. CRPS; RSD; Pain; Deep Tissue
`Microvascular Dysfunction
`
`Symptomatology of Complex Regional Pain
`Syndrome-Type I
`
`is a
`(CRPS-I)
`Complex regional pain syndrome-type I
`chronic pain syndrome that occurs following injuries such
`as sprains,
`fractures, and crush injuries that are not
`accompanied by a clinically verified nerve injury [1].
`CRPS-I
`is a relatively rare disorder, with an estimated
`incidence of 26.2 per 100,000 [2]. Nevertheless, this con-
`dition has fascinated, perplexed, and frustrated clinicians
`for well over a century. Symptoms of CRPS-I
`include
`spontaneous pain (“burning” pain referred to the skin
`and “aching” pain referred to deep tissues) and a
`variety of stimulus-evoked abnormal pain sensations,
`including mechano-hyperalgesia, mechano-allodynia,
`cold-allodynia, and sometimes heat hyperalgesia. Other
`symptoms include disorders of vasomotor and sudomotor
`regulation; trophic changes in the skin, hair, nails, and
`bone; and dystonia and other motor abnormalities [3–9].
`CRPS-II (causalgia) is similar in all respects except that a
`clinically verified nerve injury is present [3,4].
`
`Until recently, it has been generally accepted that most, if
`not all, the ancillary symptoms of CRPS-I are due to a
`
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`hyperactive sympathetic outflow to the painful region, and
`that the sympathetic outflow is somehow causally related
`to the pain. This belief gained credence from the thera-
`peutic benefit that is achieved in at least some patients
`following sympathectomy or local anesthetic block of the
`sympathetic ganglia [10]. However, it is well known that
`not all CRPS-I patients benefit from sympathetic interven-
`tions, and those that do sometimes receive only partial or
`temporary pain relief. Not surprisingly, the role of the sym-
`pathetic innervation in the CRPS-I syndrome is not well
`understood [11].
`
`It is believed that there may be a temporal progression of
`symptoms in CRPS-I, resulting in three broadly defined
`stages of disease. The first is typified by hyperemia and
`edema, the second by cold, hyperhidrosis and cyanosis,
`and the third by dystonia and dystrophic changes [5,9].
`There is some evidence that this temporal progression is
`not present in all patients [8]. Clinical experience and
`animal experiments suggest that the sympathetic innerva-
`tion may contribute in the early stage of CRPS-I, but that
`the underlying pathology evolves from sympathetically
`maintained pain (SMP)
`to sympathetically-independent
`pain (SIP) [5,10,12,13].
`
`A New Animal Model of CRPS-I
`
`(chronic post-
`We have developed an animal model
`ischemia pain; CPIP) that creates CRPS-I-like symptoma-
`tology [14]. The CPIP model
`is produced in rats under
`general anesthesia with a tourniquet placed around the
`ankle for 3 hours. Following reperfusion, the hind paw
`exhibits an initial phase of hyperemia and edema lasting
`for 2–12 hours, followed by neuropathic pain (mechano-
`hyperalgesia, mechano-allodynia, and cold-allodynia) that
`lasts for at least 1 month. Light microscopic analyses and
`electron microscopic analyses of the hind paw nerves
`from CPIP rats show that nearly all have no sign of nerve
`injury due to the tourniquet [15]. Some of the animals have
`a small number of degenerating myelinated axons, which
`would be difficult or impossible to verify if present in a
`human patient. In addition, there are no changes in con-
`duction velocity of the sural nerve at 5 and 7 days post-
`reperfusion [16]. However, there is a reduced density of
`the sensory fibers’ terminal arbors in the epidermis in the
`injured hind paw, as determined by PGP9.5 immunohis-
`tochemistry [16], similar
`to that observed in CRPS-I
`patients [17].
`
`the hind paw digital
`Electron microscopic analysis of
`muscle and digital nerves reveals microvascular pathology
`that is indicative of the capillary slow-flow/no-reflow phe-
`nomenon [15]—a well known consequence of ischemia-
`reperfusion (I-R) injury in cardiac and skeletal muscle. The
`hind paw muscle also exhibits poor perfusion and a
`reduced density of viable capillaries for a week following
`reperfusion [16]. Single fiber recordings from primary affer-
`ent axons in CPIP rats at intervals of 2–9 days after
`tourniquet release have found spontaneously discharging
`Ab, Ad, and C fibers in every case examined [15]. Normal
`sensory fibers have little or no spontaneous discharge.
`
`Deep-Tissue Microvascular Pathology in CRPS-I
`
`Slow flow/no-reflow in deep-tissue microvasculature
`would be expected to produce a persistent inflammatory
`state. Data from the CPIP animals is consistent with this
`idea. Malondialdehyde, a product of free radical-induced
`lipid peroxidation, was significantly elevated in the CPIP rat
`hind paw, and CPIP allodynia was dose dependently
`attenuated by the antioxidant N-acetyl-L-cysteine, and the
`free radical scavenger 4-hydroxy-2,2,6,6-tetramethyl-
`piperydine-1-oxyl, suggesting a key role of free radicals
`[16]. Furthermore, the pro-inflammatory cytokines, tumor
`necrosis factor alpha (TNFa),
`interleukin-1 (IL-1) and
`interleukin-6 (IL-6), and the related transcription factor,
`nuclear factor kappa B (NFkB), are all elevated in the CPIP
`rat hind paws early after reperfusion, and both an IL-1
`receptor antagonist and an NFkB inhibitor, pyrrolidine
`dithiocarbamate, dose dependently reduce CPIP allo-
`dynia, suggesting that an NFkB-dependent generation of
`pro-inflammatory cytokines plays a role in CPIP. Lactate is
`also increased in the muscle tissue of CPIP rat hind paws,
`and the levels of lactate are further elevated when the rats
`exercise. Exercise also decreases mechanical paw with-
`drawal thresholds in CPIP rats, and there is a direct cor-
`relation between mechanical allodynia and lactate levels in
`unexercised and exercised CPIP rats [16].
`
`CPIP rats also develop a hypersensitivity to norepineph-
`rine (NE), reflected by enhanced arterial responsiveness to
`NE, as well as enhanced painful responses to hind paw
`injections of NE [18]. Mice also develop CPIP after I-R
`injury, and CPIP mice have an upregulation of endothelin A
`(ET-A) receptors in their hind paw muscles. Accordingly,
`CPIP mice exhibit enhanced sustained nociceptive behav-
`iors following hind paw injections of endothelin-1 (ET-1)
`[19].
`
`A Hypothesis for the Pathogenesis CRPS-I
`
`Our findings in CPIP animals lead us to propose a hypoth-
`esis that we believe to be applicable to both the CPIP
`animals and to at least a subset of CRPS-I patients. We
`propose that the fundamental cause of the pain is a per-
`sistent deep-tissue (muscle, bone, and nerve) ischemia
`and consequent
`inflammatory reaction produced by
`microvascular pathology subsequent to an I-R injury. We
`propose that
`the following processes (summarized in
`Figure 1) are critical to the initiation, development, and
`maintenance of the CPIP and CRPS-I syndromes.
`
`CRPS-I is Initiated When an Inflammatory Response
`to a Deep-Tissue Injury Produces a Compartment-Like
`Syndrome that Impairs Blood Flow to Muscle, Nerve,
`and Bone
`
`At its onset, CRPS-I is often characterized by significant
`regional edema that
`is
`sometimes described as
`“exaggerated” [20–22]. Edema develops due to the
`extravasation and accumulation of plasma in the interstitial
`space [23]. In the early stage of CRPS-I, there is plasma
`extravasation [20], increased density of perfused vessels,
`and higher capillary filtration capacity (an index of microvas-
`cular permeability) [24,25].
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`Coderre and Bennett
`
`Deep tissue injury
`
`Acute inflammation with edema
`
`CPIP/
`CRPS-I
`
`Normal healing
`
`Compartment-like syndrome
`1
`Microvascular I-R injury
`
`2
`
`Vasospasm
`
`Slow flow/no-reflow
`
`Deep tissue ischemia
`
`Chronic inflammation
`
`Muscle/bone
`
`Nerve
`
`CRPS-II:
`Neurovascular
`bundle injury
`
`Critical events
`for initiation
`
`Critical events
`for maintenance
`
`1 2
`
`Nociceptor activation
`& sensitization
`
`Nociceptor ectopic
`discharge
`
`Central sensitization,
`Pain, Allodynia, Hyperalgesia
`
`Figure 1 Schematic of the hypothesized pathophysiological mechanisms in the chronic post-ischemia pain
`(CPIP) model and at least a subset of complex regional pain syndrome-type I (CRPS-I) patients. In CRPS-I
`patients, deep tissue injury leads to edema and a compartment-like syndrome. Reperfusion (release of the
`tourniquet in the animal model) leads to injury of the microvascular endothelial cells induced by free radicals.
`These events lead to arterial vasospasms and slow flow/no-reflow in deep tissue microvasculature, which
`produces persistent ischemia that both spreads the ischemia-reperfusion (I-R) injury, and causes chronic
`inflammation. In muscle and bone, the resulting ischemia and inflammation (including generation of lactate)
`activates and sensitizes nociceptors. In nerve, the ischemia and inflammation cause ectopic nociceptor
`discharge. Injury to a neurovascular bundle may also evoke arterial vasospasm, and this may initiate the same
`vicious cycle in patients with CRPS-II (causalgia).
`
`The pressure exerted by the interstitial accumulation of
`extravasated plasma within a relatively confined anatomi-
`cal space occludes the capillaries of adjacent tissues and
`causes a compartment syndrome [26,27]. Pressures
`within a myofascial compartment of as
`little as
`30–40 mm Hg will occlude all capillary flow [28,29]. Com-
`partment syndrome is a well-known complication of frac-
`tures, joint trauma, and joint surgery [26,30–32]. CRPS-I
`also often follows fractures, joint injuries, and wrist, elbow,
`and knee surgery [33,34]. We think that it is extremely
`important to note that CRPS-I nearly always follows injury
`to deep tissues (fractures, sprains, surgeries, crush inju-
`ries, etc.). CRPS-I initiated by a strictly cutaneous injury
`(e.g., a laceration or burn) is exceedingly rare [35]. Edema
`in the subcutaneous space does not lead to a compart-
`ment syndrome.
`
`In its most severe form, musculoskeletal compartment
`syndrome leads to ischemia that is severe enough to
`cause tissue necrosis, but subtotal or episodic (exertional)
`ischemia leads to compartment-like syndromes that do
`not progress to tissue necrosis [36–38]. We propose that
`in the CPIP animal, a compartment-like syndrome is
`created by the period of extensive edema that follows
`release of the tourniquet. In man, both compartment syn-
`drome and CRPS-I are known risks of excessive tourni-
`quet exposure [39,40].
`
`The Compartment Syndrome Leads to an I-R Injury
`and Persistent Deep-Tissue Microvascular Pathology
`
`While the proposed compartment-like syndrome does not
`produce tissue necrosis, it does produce microvascular
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`injury. Ischemic tissues accumulate oxidative enzymes,
`primarily xanthine oxidase and NADPH oxidase. Upon
`reperfusion, the accumulated oxidases reduce the return-
`ing molecular oxygen and the cells composing the
`microvessels are exposed to high levels of oxygen free
`radicals that damage both vascular endothelial and
`smooth muscle cells [41–48]. The onset of reperfusion is
`obviously well defined when a tourniquet is removed, but
`less clearly demarcated when the ischemia is due to a
`compartment-like syndrome. In the latter case, it is prob-
`able that reperfusion is episodic or partial, and may
`migrate from one part of the tissue’s capillary bed to
`another.
`
`I-R injury is a multifactorial phenomenon characterized by
`several pathological mechanisms affecting arterioles, cap-
`illaries, and venules [48–55]. These mechanisms interact
`and generally contribute to positive-feedback loops that
`perpetuate and worsen the I-R injury. Although most
`studied as a consequence of
`ischemic insult to heart
`muscle, I-R injury phenomena are also known to occur in
`the microvasculature of skeletal muscle [52,56]. We
`propose here that I-R injury also occurs in the microvas-
`culature of bone and peripheral nerve.
`
`I-R Injury, Arterioles, Vasospasm, and the Sympathetic
`Nervous System
`
`Following I-R injury, the arteriole’s endothelial cells release
`less nitric oxide and the reduced amount of nitric oxide
`that is released is converted to toxic nitrogen free radicals
`after interaction with oxygen free radicals. The result is a
`deficit in the nitric oxide-mediated vasodilatation that nor-
`mally modulates the vasoconstriction that is evoked by the
`sympathetic nervous system [49,57,58]. Recent data
`show that CRPS-I patients have abnormal vasodilatation
`responses after sympathetically evoked vasoconstriction
`[59], and decreased levels of nitric oxide have been found
`in blister fluid from the affected region [60]. ET-1 is a potent
`vasoconstrictor derived from vascular endothelial cells
`that produces its pressor effects by acting on ET-A recep-
`tors on vascular smooth muscle cells [61]. Following I-R
`injury, ET-1 production and release are increased, and so
`is the vasoconstrictor
`response that
`it evokes [62].
`Increased levels of ET-1 are found in blister fluid from the
`affected extremity in early-stage CRPS-I patients [60]. As
`we described above, CPIP mice have upregulated ET-A
`receptors in hind paw muscle, and show enhanced painful
`responses to intraplantar ET-1 injections [19].
`
`I-R injury also evokes an upregulation of the expression
`of a-adrenoceptors on arterial smooth muscle cells,
`resulting in a threefold increase in the contractile
`response to NE [63]. As a result, arteries will spasm in
`response to normal
`levels of sympathetic discharge
`(vasoconstrictor “tone”), to the myriad of sympathetic
`reflexes that are evoked by daily activity, and perhaps to
`catecholamines (NE and epinephrine) that arrive via the
`circulation. As discussed above, CPIP rats exhibit
`enhanced arterial vasoconstrictor responses to NE. Both
`CRPS-I patients and CPIP rats display abnormal pain
`
`Deep-Tissue Microvascular Pathology in CRPS-I
`
`responses to intraplantar injections of NE [18,64]. There
`is clear evidence that there is dramatically reduced sym-
`pathetic reflex activity in early CRPS [65]. There is also
`evidence that
`this reduced sympathetic outflow itself
`results in a hypersensitivity of
`the smooth muscle
`adrenoceptors, that is, functional denervation supersen-
`sitivity [66]. There is evidence for
`increased vascular
`a-adrenoceptor
`responsiveness
`in CRPS-I patients
`[67–69]. The situation is likely to be very complex and
`variable from patient to patient, or from time to time in a
`vascular a-adrenoceptor
`given
`patient:
`increased
`responsiveness that might be driven by circulating cat-
`echolamines and/or the NE released in the context of
`decreased activity at
`the postganglionic sympathetic
`fiber’s synapse.
`In any case,
`the result
`is that
`sympathetic activity would be contributory, rather than
`fundamentally causative, and exacerbate ischemia,
`inflammation, and consequent pain.
`
`Nerve injury evokes sympathetic fiber sprouting in the
`dorsal root ganglion. However, there is evidence that this
`sprouting may not contribute to CRPS-II pain (and, by
`implication, CRPS-I pain)
`[70]. There is also evidence
`that nerve injury evokes the de novo expression of
`a-adrenoceptors on primary afferent nociceptors, which
`suggests a direct link between NE and epinephrine (via the
`circulation or via the sympathetic postganglionic synapse)
`and nociceptor activation [71]. The presence of such a
`mechanism is not incompatible with the hypothesis that
`we propose.
`
`Vasospasm in precapillary arterioles exacerbates the
`ischemia and leads to further I-R injury, and may contrib-
`ute to the spread of microvascular dysfunction. The result-
`ing vicious cycle contributes to the maintenance and
`worsening of the ischemic state. Such spreading dysfunc-
`tion may account for the “contiguous” spread of CRPS-I
`symptoms, that is, the tendency for edema and pain to
`gradually spread outward from the initially symptomatic
`region [72]. There is extensive evidence for such a spread-
`ing phenomenon in the case of ischemic heart disease
`[73]; we propose here that the same thing occurs in
`skeletal muscle. A long forgotten paper by Foisie [74]
`suggested that arterial vasospasm might contribute to
`causalgic-like pain after crush injuries and soft tissue inju-
`ries that did not injure a nerve (i.e., CRPS-I). Arterial vasos-
`pasm after I-R injury is sometimes relieved by a brief
`tourniquet application [75]. CRPS-I patients sometimes
`report temporary pain relief after brief tourniquet applica-
`tion [76,77].
`
`I-R Injury to Capillaries
`
`Free radicals also damage capillary endothelial cells
`and stimulate them to release various pro-inflammatory
`mediators. Free radicals increase the expression of selec-
`tins,
`intracellular and extracellular adhesion molecules
`[78], complement factors [79], leukotriene B4 [80,81], and
`platelet activating factor [82,83]. Many of these molecules
`are chemotaxic and recruit monocytes, leukocytes, and
`platelets which accumulate and occlude the capillary
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`Coderre and Bennett
`
`lumen, and release TNFa, IL-1, and IL-6, which produce
`toxic effects that might spread tissue injury to adjacent
`regions [84,85].
`
`Occlusion of capillaries generates the phenomenon
`known as slow-flow/no-reflow, which we believe to be a
`key feature of both the CRPS-I and CPIP syndromes.
`Slow-flow/no-reflow is characterized by the swelling of
`microvascular endothelial cells, platelet aggregation, and
`plugging of the capillary lumen by leukocytes and eryth-
`rocytes [45,48,49,51,52,55,86–95]. “Slow-flow” refers to
`the condition where the lumen is partly occluded; com-
`plete occlusion is “no-reflow.” In cardiac muscle, the onset
`of slow-flow/no-reflow is detectable immediately after rep-
`erfusion, but it worsens significantly during the following
`hours and days [55,96]. It is important to recall how easy
`it is to block capillary flow. The smallest capillaries are
`formed from a single endothelial cell, and their lumen
`diameters are nearly the same as the shortest diameter of
`a red blood cell. The lumens’ diameter is restricted further
`at the level of the endothelial cell’s nucleus. Red blood
`cells must deform and squeeze through the capillary
`lumen. The pain of a sickle cell crisis is due to ischemia
`that occurs because of an abnormality of the erythrocyte’s
`membrane that makes it too stiff to deform and squeeze
`through the capillary lumen.
`
`As well as occurring in skeletal muscle, we have evidence
`from the CPIP animals that slow-flow/no-reflow also
`occurs in the nerve’s capillaries, and we think it likely that
`it also occurs in periosteal and intramedullary bone capil-
`laries. There is no logical reason to suppose that slow-
`flow/no-reflow does not also occur
`in cutaneous
`capillaries. However, because of their important role in
`thermoregulation,
`the cutaneous capillary beds in the
`distal extremities of man are extremely dense and highly
`anastomotic; this renders the skin’s capillary bed relatively
`resistant to slow-flow/no-reflow [97].
`
`I-R Injury to Venules
`
`Free radical damage to the endothelial cells of venules
`resembles that seen in capillaries. However, venules have
`lumens that have a greater diameter than that of capillaries
`and venules are thus relatively resistant to slow-flow/no-
`reflow. However,
`I-R injury causes damage at post-
`capillary venules, which causes leakage of plasma
`through resultant gaps between adjacent endothelial cells
`[98].
`It is significant that plasma extravasation occurs
`mostly at the level of the venules, not the capillaries. Free
`radical damage to venules is thus the immediate cause of
`edema formation. As we discuss below, it is significant to
`note that a leaky venule has nothing to leak if its upstream
`capillary supply is blocked.
`
`Compensatory Reactions to Microvascular Pathology
`
`Although arterial vasospasm and slow flow/no-reflow
`would produce areas of
`tissue ischemia,
`the system
`responds with attempts to compensate via reactive hype-
`remia and arteriovenous shunting [52,56]. Limbs in early
`
`1228
`
`stages of CRPS-I often have high arterial flow, yet at the
`same time have elevated venous pressure and arterio-
`venous shunting [24,25]. These phenomena are likely to
`be due to slow-flow/no-reflow in the affected capillary
`bed. The alternation between ischemia and reperfusion
`provides a way to spare tissue from lethal injury, but it also
`creates a vicious cycle of
`I-R injury which maintains
`microvascular dysfunction.
`
`Microvascular Pathology Leads to Persistent Ischemia
`which in turn Leads to Persistent Inflammation
`
`We propose that microvascular pathology leads to an
`ischemic state that evokes persistent
`inflammatory
`responses.
`
`Microvascular Pathology and Ischemia
`
`Several observations are consistent with the presence of
`impaired blood flow in CRPS-I patients. Skin capillary
`is lowered and skin
`hemoglobin oxygenation (HbO2)
`lactate is increased in CRPS-I limbs, suggesting that there
`is both impaired nutritive blood flow and enhanced
`anaerobic glycolysis [99,100]. Nail bed capillary flow is
`decreased [101], and reactive hyperemia in the cutaneous
`vasculature is impaired in CRPS-I patients [66]. Addition-
`ally, there is an impairment of high-energy phosphate
`metabolism in CRPS-I muscles [21,102], consistent
`with an impaired blood supply. Experimentally-evoked
`plasma extravasation is exaggerated in CRPS-I patients
`[103,104].
`
`lines of evidence suggest that at least some
`Several
`CRPS-I patients have a persistent inflammatory condition.
`Necropsy studies of amputated limbs from patients with
`severe CRPS-I find lipofuscin deposits, atrophic fibers,
`and severely thickened capillary basal membranes in
`muscle and subcutaneous tissue [105,106], consistent
`with the presence of
`ischemia-evoked inflammation.
`Serum levels of calcitonin-gene related peptide and
`bradykinin are elevated in the venous drainage of CRPS-I
`limbs, consistent with the presence of an ongoing
`ischemic and inflammatory state in deep tissues
`[107,108].
`
`[109] have detected greatly elevated
`Eisenberg et al.
`levels of
`inflammatory by-products (e.g., malondialde-
`hyde) and cellular antioxidants in the serum and saliva of
`CRPS-I patients with typical disease. We suggest that
`these markers originate in tissues made ischemic and
`inflamed by slow-flow/no-reflow. There are several reports
`of
`increased levels of pro-inflammatory cytokines in
`CRPS-I patients [60,110–112], as would be expected if
`there was an ongoing inflammatory reaction. These find-
`ings are consistent with our results that malondialdehyde
`and pro-inflammatory cytokines are increased in the hind
`paw muscle of CPIP rats [16], as well as numerous reports
`that these mediators are elevated after skeletal I-R injury
`(see above).
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`The Ischemic and Inflammatory State in Muscle
`Results in Nociceptor Activation
`
`In muscle, an ischemic state would be expected to be a
`direct cause of nociceptor discharge and nociceptor sen-
`sitization due to acidosis [113]. It has long been known
`that
`tissue acidosis associated with increased lactate
`causes muscle pain in ischemic tissue [114]. It is signifi-
`cant that mechanical allodynia in CPIP rats is directly
`correlated with lactate levels in CPIP hind paw muscle
`[16]. These findings are consistent with the reports of
`CRPS-I patients that the pain produced by infusing a low
`pH solution into muscle in the affected limb is far more
`painful than the same infusion into a contralateral muscle
`[99]. Moreover, they report that the pain produced by an
`infusion into the normal, contralateral
`limb is qualitatively
`similar to their ipsilateral CRPS-I pain, that is, their CRPS-I
`pain feels like inflammatory muscle pain [99]. Differential
`activation of sympathetic vasoconstrictor reflex responses
`to muscle and skin shows that the response in muscle,
`rather than skin, causes the greatest pain [115], consis-
`tent with ischemic muscle being a primary cause of
`CRPS-I pain.
`
`Muscle lactate has also long been known to increase
`following exercise [116], so it is not surprising that lactate
`increases in exercised CPIP rats. Importantly, mechanical
`allodynia is also increased after exercise in CPIP rats, and
`mechanical allodynia is directly correlated with muscle
`lactate levels in CPIP rats [16]. This could explain the often
`reported phenomenon that
`the pain of CRPS-I
`is
`increased during exercise [20,117]. In sum, these mecha-
`nisms would be expected to cause a persistent deep,
`aching pain sensation. CRPS-I patients frequently
`(perhaps always) report the presence of a deep, aching
`pain, and they also commonly report
`that movement
`worsens their pain, as would be expected if their muscles
`were ischemic and inflamed.
`
`The Effects of an Ischemic and Inflammatory
`State in Bone
`
`Prolonged ischemia of bone has been shown to produce
`bone inflammation and injury [118,119]. Three-phase
`bone scans reveal that CRPS-I patients often have a late-
`phase periarticular accumulation of tracer [33], consistent
`with an I-R injury-induced injury to venules leading to
`intramedullary plasma extravasation. The abnormality may
`not be confined to periarticular bone, as is generally
`believed, but may affect the bone shafts as well [120].
`Using scintigraphic studies of CRPS-I patients over time
`reveals an early hyperperfusion of bone that is followed by
`later hypoperfusion [121].
`
`Some CRPS-I patients also have radiographic evidence of
`osteoporosis, although this may be transient and migra-
`tory [33,120,122–126]. Osteoporosis is an expected con-
`sequence of impaired medullary perfusion. Clinical reports
`of pain relief in at least some CRPS-I patients treated with
`bisphosphonates or calcitonin are consistent with the idea
`of pain arising from ischemic and inflamed bone [127–
`
`Deep-Tissue Microvascular Pathology in CRPS-I
`
`130]. The bone pathology of CRPS-I was originally
`attributed to an inflammatory process [122]. All of the
`observations noted above are likely results of edema,
`ischemia, and inflammation secondary to slow-flow/no-
`reflow in periosteal and intramedullary microvessels.
`Ischemia in bone would cause deep, aching pain. It is our
`experience that CRPS-I patients often insist that their
`bones hurt.
`
`The Effects of an Ischemic and Inflammatory State in
`Peripheral Nerves
`
`There is no reason to doubt that endoneurial capillaries are
`also prone to the slow-flow/no-reflow phenomenon.
`Small, distal nerves would be especially vulnerable, simply
`because they have few capillaries. We have shown evi-
`dence of slow-flow/no-reflow in endoneurial microvessels
`in hind paw digital nerves in CPIP rats [15]. An ischemic
`and inflammatory state within a peripheral nerve should
`produce spontaneous ectopic discharge in sensory fibers.
`We have shown that ectopic discharge is present in
`A-fibers and C-fibers in CPIP rats [15].
`
`Oaklander et al. [17] have shown degeneration of intraepi-
`dermal nerve fibers (IENF)
`in CRPS-I patients, and we
`have shown similar reduction of IENF density in the skin of
`CPIP rats [16]. No-flow in the capillaries of small, distal
`nerves might account for such degeneration.
`
`Endoneurial ischemia and inflammation would be associ-
`ated with increased levels of pro-inflammatory cytokines
`that are known to produce neuropathic (“neuritic”) pain
`[131,132]. Ectopic discharge in nociceptors due to endo-
`neurial microvascular pathology would cause spontane-
`ous pain referred to the tissue innervated by the
`nociceptors within the nerve. Such pain is properly cat-
`egorized as neuropathic, while the pain from ischemic and
`inflamed muscle and bone is not. We thus propose that
`both inflammatory and neuropathic pain mechanisms are
`present in CRPS-I.
`
`Nociceptor Activation Leads to Central Sensitization
`
`Deep-tissue C-fiber nociceptor discharge and the
`ectopic discharge of C-fibers traveling within ischemic
`and inflamed nerves will
`initiate and maintain N-methyl-
`D-aspartate
`receptor-mediated
`central
`sensitization
`[133]. Importantly, input from muscle C-fiber nociceptors
`is a much more potent initiator of central sensitization
`than input
`from cutaneous C-fiber nociceptors [134].
`Also, while injecting inflammatory agents into skin pro-
`duces allodynia that lasts at most hours, the same injec-
`tions into muscle induce central sensitization and
`cutaneous allodynia lasting up to several weeks
`[135,136].
`
`We hypothesize that the central sensitization evoked by
`deep-tissue nociceptor discharge is the primary cause of
`cutaneous allodynia and hyperalgesia. The presence or
`absence, severity, and spatial extent of cutaneous hyper-
`sensitivity might thus be expected to vary from patient to
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`Coderre and Bennett
`
`patient and from time to time, depending on fluctuations
`in the intensity of deep-tissue pain. Fluctuating cutane-
`ous hypersensitivity is a common observation in CRPS-I
`patients [137,138], and cutaneous allodynia can be sup-
`pressed with the persistence of ongoing deep-tissue
`pain [12,139]. Cutaneous allodynia and hyperalgesia
`might thus be categorized as epiphenomena.
`
`The Role of the Sympathetic Nervous System and
`the Stages of CRPS-I May Depend on a
`Progression from Slow-Flow to No-Reflow
`
`The duration of the initial, edematous stage of CRPS-I is
`highly variable. Some patients remain in this state, have
`episodes of exacerbated edema, or progress to a non-
`edematous stage characterized by cyanosis and/or
`atrophy of subcutaneous tissue. Patients with slow-flow
`would be expected to exhibit edema, but there can be no
`plasma extravasation from leaky venules if
`there is
`no-reflow in their upstream capillaries. Thus, at later times,
`when no-reflow predominates, the patient would be in the
`cyanotic/atrophic phase.
`
`We Propose that the Progre