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Complex regional pain syndrome (CRPS) is the current consensus-derived name for a syndrome usually triggered by limb trauma. Required elements include prolonged, disproportionate distal-limb pain and microvascular dysregulation (e.g., edema or color changes) or altered sweating. CRPS-II (formerly "causalgia") describes patients with identified nerve injuries. CRPS-I (formerly "reflex sympathetic dystrophy") describes most patients who lack evidence of specific nerve injuries. Diagnosis is clinical and the pathophysiology involves combinations of small-fiber axonopathy, microvasculopathy, inflammation, and brain plasticity/sensitization. Females have much higher risk and workplace accidents are a well-recognized cause. Inflammation and dysimmunity, perhaps facilitated by injury to the blood-nerve barrier, may contribute. Most patients, particularly the young, recover gradually, but treatment can speed healing. Evidence of efficacy is strongest for rehabilitation therapies (e.g., graded-motor imagery), neuropathic pain medications, and electric stimulation of the spinal cord, injured nerve, or motor cortex. Investigational treatments include ketamine, botulinum toxin, immunoglobulins, and transcranial neuromodulation. Nonrecovering patients should be re-evaluated for neurosurgically treatable causal lesions (nerve entrapment, impingement, infections, or tumors) and treatable potentiating medical conditions, including polyneuropathy and circulatory insufficiency. Earlier impressions that CRPS represents malingering or psychosomatic illness have been replaced by evidence that CRPS is a rare complication of limb injury in biologically susceptible individuals., (© 2015 Elsevier B.V. All rights reserved.)

Unlabelled: Complex regional pain syndrome (CRPS) is a potentially debilitating chronic pain syndrome with a poorly understood but likely neuroimmune/multifactorial pathophysiology associated with axonal injury. Based on the potential contribution of proinflammatory cytokines to CRPS pathogenesis and prior research with thalidomide, we investigated lenalidomide, a thalidomide derivative, for CRPS treatment. We conducted a phase II, randomized, double-blind, placebo-controlled study to evaluate the efficacy of oral lenalidomide 10 mg once daily in consenting patients with unilateral or bilateral CRPS type 1. The study comprised 12 weeks of treatment followed by a long-term extension. The primary efficacy outcome was reduced pain in the index limb, defined as ≥30% improvement from baseline using an 11-point numeric rating scale. One hundred eighty-four subjects enrolled. The primary endpoint was not met because equal proportions of treated (16.1%) and control (16.1%) subjects achieved the outcome; however, lenalidomide was well tolerated, with no evidence of neuropathy or major adverse effects. This study is the largest controlled, blinded clinical trial in subjects with chronic CRPS using the Budapest research criteria. It demonstrates the feasibility of conducting high-quality clinical trials in CRPS type 1 and provides considerations for designing future trials., Perspective: This article reports an adequately powered, controlled clinical trial in subjects with CRPS. Treatment and placebo were equally effective, but the study demonstrated that lenalidomide treatment is feasible in this population. The study provides examples to consider in designing future CRPS trials., (Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Fibromyalgia is a common, disabling syndrome that includes chronic widespread pain plus diverse additional symptoms. No specific objective abnormalities have been identified, which precludes definitive testing, disease-modifying treatments, and identification of causes. In contrast, small-fiber polyneuropathy (SFPN), despite causing similar symptoms, is definitionally a disease caused by the dysfunction and degeneration of peripheral small-fiber neurons. SFPN has established causes, some diagnosable and definitively treatable, eg, diabetes. To evaluate the hypothesis that some patients labeled as having fibromyalgia have unrecognized SFPN that is causing their illness symptoms, we analyzed SFPN-associated symptoms, neurological examinations, and pathological and physiological markers in 27 patients with fibromyalgia and in 30 matched normal controls. Patients with fibromyalgia had to satisfy the 2010 American College of Rheumatology criteria plus present evidence of a physician's actual diagnosis of fibromyalgia. The study's instruments comprised the Michigan Neuropathy Screening Instrument (MNSI), the Utah Early Neuropathy Scale (UENS), distal-leg neurodiagnostic skin biopsies, plus autonomic-function testing (AFT). We found that 41% of skin biopsies from subjects with fibromyalgia vs 3% of biopsies from control subjects were diagnostic for SFPN, and MNSI and UENS scores were higher in patients with fibromyalgia than in control subjects (all P ≤ 0.001). Abnormal AFTs were equally prevalent, suggesting that fibromyalgia-associated SFPN is primarily somatic. Blood tests from subjects with fibromyalgia and SFPN-diagnostic skin biopsies provided insights into causes. All glucose tolerance tests were normal, but 8 subjects had dysimmune markers, 2 had hepatitis C serologies, and 1 family had apparent genetic causality. These findings suggest that some patients with chronic pain labeled as fibromyalgia have unrecognized SFPN, a distinct disease that can be tested for objectively and sometimes treated definitively., (Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Hypothesis: Suprascapular neuropathy (SSN) is considered a rare condition, and few studies have analyzed how commonly it is encountered in practice. Electrophysiologic studies are the gold standard for diagnosis; however, there is no consensus on diagnostic criteria. We hypothesized that SSN would be frequently diagnosed by electrophysiologic testing in a subset of patients with specific clinical and radiographic findings suggestive of the pathology. This study characterizes SSN in an academic shoulder referral practice and documents the electrodiagnostic findings that are currently being used to diagnose the condition., Materials and Methods: A retrospective review of a 1-year period was used to identify all patients who completed electrodiagnostic studies to evaluate the suprascapular nerve. Clinical exam findings and associated shoulder pathology was documented. The specific electromyography (EMG) and nerve conduction studies (NCS) findings were analyzed., Results: Electrodiagnostic results were available for 92 patients, and 40 (42%) had confirmed SSN. Patients with a massive rotator cuff tear were more likely to have an abnormal study than those without a tear (P = .006). The most common electrodiagnostic abnormalities were abnormal motor unit action potentials (88%), whereas only 33% had evidence of denervation. The average latency in studies reported as diagnostic of SSN was 2.90 ± 0.08 milliseconds for the supraspinatus and 3.78 ± 0.14 milliseconds for the infraspinatus., Discussion: An electrodiagnostically confirmed diagnosis of SSN was seen in 4.3% of all new patients and in 43% of patients with clinical or radiographic suspicion of SSN. Clinical evaluation may be difficult because other shoulder pathology can have overlapping symptoms., Conclusion: Shoulder surgeons should consider electrophysiologic evaluation of patients with clinical or radiographic signs of SSN and be cognizant of the parameters that constitute an abnormal study., (Copyright © 2011 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Mosby, Inc. All rights reserved.)

Chronic itch can be caused by dysfunctions of itch-sensing neurons that produce sensory hallucinations of pruritogenic stimuli. The cellular and molecular mechanisms are still unknown. All neurological disease categories have been implicated, and neurological causes should be considered for patients with otherwise-unexplained itch. The same neurological illnesses that cause neuropathic pain can also or instead cause itch. These include shingles (particularly of the head or neck), small-fiber polyneuropathies, radiculopathies (eg, notalgia paresthetica and brachioradial pruritis), and diverse lesions of the trigeminal nerve, root, and central tracts. Central nervous system lesions affecting sensory pathways, including strokes, multiple sclerosis, and cavernous hemangiomas, can cause central itch. Neuropathic itch is a potent trigger of reflex and volitional scratching although this provides only fleeting relief. Rare patients whose lesion causes sensory loss as well as neuropathic itch can scratch deeply enough to cause painless self-injury. The most common location is on the face (trigeminal trophic syndrome). Treating neuropathic itch is difficult; antihistamines, corticosteroids, and most pain medications are largely ineffective. Current treatment recommendations include local or systemic administration of inhibitors of neuronal excitability (especially local anesthetics) and barriers to reduce scratching., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Monophasic (one-time) nerve injuries heal without clinically significant residua in most cases, but rare individuals are left with neuropathic pain, even after seemingly minor lesions. The effects of lesion size on risk for chronic pain persistence are not well understood, particularly as concerns the complex regional pain syndrome, which is defined in part by pain "disproportionate" to the severity of the causative lesion, and extending outside the autonomous territory of a single nerve. To better clarify the expected prevalence of pain behaviors after nerve injury, we compared the effects in rats of different-sized axotomies on the prevalence and location of evoked pain behaviors. To highlight clinical relevance, we also describe a patient with iatrogenic tibial-nerve injury causing similar chronic neuralgia. Adult male Sprague-Dawley rats were anesthetized and had either 1/3, 2/3 or their entire left tibial nerves tightly ligated at two sites just below the sciatic trifurcation and the interposed nerve was cut. Unoperated rats provided controls. Sensory function in the tibial and sural-innervated territories of both plantar hindpaws was assessed for as long as 6 months postoperatively. Soon after surgery, evoked pain behavior developed in the ipsilesional sural-innervated site in a subset of axotomized rats and recovery was variable. The relationship between lesion size and prevalence and severity of hyperalgesia varied for different pain behaviors, with pinprick hyperalgesia clearly more likely after larger axotomies. In summary, partial tibial-nerve injury in rats models human disease and suggests that expectations of proportionality between lesion size and development of neuropathic pain may need revision., (© 2010 The Authors. Pain Practice © 2010 World Institute of Pain.)

Unlabelled: Central nervous system lesions cause peripheral dysfunctions currently attributed to central cell death that compromises function of intact peripheral nerves. Injecting quisqualate (QUIS) into the rat spinal cord models spinal cord injury (SCI) and causes at-level scratching and self-injury. Such overgrooming was interpreted to model pain until patients with self-injurious scratching after SCI reported itch motivated scratching that was painless because of sensory loss. Because self-injurious scratching is difficult to explain by central mechanisms alone, we hypothesized that QUIS injections damage peripheral axons of at-level afferents. QUIS was injected into thoracic spinal cords of 18 Long-Evans rats. Animals were killed 3 days after overgrooming began or 14 days after injection. Spinal cord lesions were localized and DRG-immunolabeled for ATF-3. At-level and control skin samples were PGP9.5-immunabeled to quantify axons. Eighty-four percent of QUIS rats overgroomed. Skin in these regions had lost two-thirds of epidermal innervation as compared with controls (P < .001). Rats that overgroomed had 47% less axon-length than nongrooming rats (P = .006). The presence of ATF-3 immunolabeled neurons within diagnosis-related groups of QUIS rats indicated death of afferent cell bodies. Overgrooming after QUIS injections may not be due entirely to central changes. As in humans, self-injurious neuropathic scratching appeared to require loss of protective pain sensations in addition to peripheral denervation., Perspective: This study suggests that intramedullary injection of quisqualic acid in rats causes death of at-level peripheral as well as central neurons. Self-injurious dermatomal scratching that develops in spinal-injured rats may reflect neuropathic itch and loss of protective pain sensations.

Unlabelled: Accurate evaluation of pain plays a critical role in identifying new interventions for the treatment and prevention of herpes zoster and postherpetic neuralgia (PHN). Different types of pain and other sensory symptoms are found in patients with herpes zoster, and these vary greatly with respect to their presence, location, duration, intensity, and quality. The results of recent studies of herpes zoster and PHN and the development of new methods for assessing neuropathic pain provide a foundation for diagnosing and assessing the pain associated with herpes zoster. We review the results of recent research to identify the essential components that must be considered in developing an evidence-based description of pain associated with herpes zoster and PHN., Perspective: Comprehensive assessments of pain are necessary for clinical research on the epidemiology, natural history, pathophysiologic mechanisms, treatment, and prevention of pain in herpes zoster and PHN.

Unlabelled: Study of humans with shingles or postherpetic neuralgia (PHN) is providing insights into pain mechanisms. Shingles pain is a combination of normal and neuropathic pain that reflects acute tissue and neural injury. PHN pain, which lasts after tissues have healed, is caused by persistent neural injuries. Spontaneous C-nociceptor activity has been documented in painful polyneuropathies and probably occurs in shingles as well, although there are no microneurographic studies of either shingles or PHN. It is uncertain if this persists in PHN since pathological examination of PHN-affected nerves and ganglia show chronic neuronal loss and quiescent scarring without inflammation. Skin-biopsy study has correlated the presence of PHN with the severity of persistent distal nociceptive axon loss, and autopsy has correlated pain persistence with segmental atrophy of the spinal cord dorsal horn, highlighting the importance of central responses to nerve injury. Pathological studies of tissues from patients with trigeminal neuralgia suggest that brief lancinating pains reflect ephaptic neurotransmission between adjacent denuded axons. The mechanisms of chronic spontaneous pain and mechanical allodynia remain uncertain despite considerable indirect evidence from animal models. Postherpetic itch is presumably caused by unprovoked firing of the peripheral and/or central neurons that mediate itch. If it occurs in neurons innervating skin left severely deafferented from shingles ("numb"), patients can give themselves painless injuries from scratching. Further human study, by electrophysiological recording, by structural and functional imaging, and by autopsy, should continue to provide much-needed insights., Perspective: Many patients continue to have chronic pain and/or itch after shingles that is unrelieved by current treatments. Many will gladly volunteer for clinical studies, including autopsy, to try and improve understanding of these common and disabling conditions. Their prevalence makes highly powered studies feasible. Funding and organization are the current bottlenecks.

CRPS-I consists of post-traumatic limb pain and autonomic abnormalities that continue despite apparent healing of inciting injuries. The cause of symptoms is unknown and objective findings are few, making diagnosis and treatment controversial, and research difficult. We tested the hypotheses that CRPS-I is caused by persistent minimal distal nerve injury (MDNI), specifically distal degeneration of small-diameter axons. These subserve pain and autonomic function. We studied 18 adults with IASP-defined CRPS-I affecting their arms or legs. We studied three sites on subjects' CRPS-affected and matching contralateral limb; the CRPS-affected site, and nearby unaffected ipsilateral and matching contralateral control sites. We performed quantitative mechanical and thermal sensory testing (QST) followed by quantitation of epidermal neurite densities within PGP9.5-immunolabeled skin biopsies. Seven adults with chronic leg pain, edema, disuse, and prior surgeries from trauma or osteoarthritis provided symptom-matched controls. CRPS-I subjects had representative histories and symptoms. Medical procedures were unexpectedly frequently associated with CRPS onset. QST revealed mechanical allodynia (P<0.03) and heat-pain hyperalgesia (P<0.04) at the CRPS-affected site. Axonal densities were highly correlated between subjects' ipsilateral and contralateral control sites (r=0.97), but were diminished at the CRPS-affected sites of 17/18 subjects, on average by 29% (P<0.001). Overall, control subjects had no painful-site neurite reductions (P=1.00), suggesting that pain, disuse, or prior surgeries alone do not explain CRPS-associated neurite losses. These results support the hypothesis that CRPS-I is specifically associated with post-traumatic focal MDNI affecting nociceptive small-fibers. This type of nerve injury will remain undetected in most clinical settings.

It is useful for dermatologists to know about the innervation of the skin because dysfunction of cutaneous neurons can cause symptoms--such as itching, pain, and paresthesias--that are evaluated by dermatologists. We review the innervation of the skin and update readers about recent neuroscientific discoveries.

Complex regional pain syndrome consists of pain and other symptoms that are unexpectedly severe or protracted after an injury. In type II complex regional pain syndrome, major nerve injury, often with motor involvement, is the cause; in complex regional pain syndrome I, the culprit is a more occult lesion, often a lesser injury that predominantly affects unmyelinated axons. In florid form, disturbances of vasoregulation (eg, edema) and abnormalities of other innervated tissues (skin, muscle, bone) can appear. Because of these various symptoms and the difficulty in identifying causative lesions, complex regional pain syndrome is difficult to treat or cure. Complex regional pain syndrome has not been systematically investigated; there are few controlled treatment trials for established complex regional pain syndrome. This article reviews the existing studies (even if preliminary) to direct clinicians toward the best options. Treatments for other neuropathic pain syndromes that may be efficacious for complex regional pain syndrome also are discussed. Some common treatments (eg, local anesthetic blockade of sympathetic ganglia) are not supported by the aggregate of published studies and should be used less frequently. Other treatments with encouraging published results (eg, neural stimulators) are not used often enough. We hope to encourage clinicians to rely more on evidence-supported treatments for complex regional pain syndrome.