Anne Louise Oaklander

Neuropathic pain following breast cancer surgery: proposed classification and research update

Chronic pain following surgical procedures for breast cancer was once thought to be rare. The results of recent studies, however, suggest that the incidence of chronic pain following breast cancer surgery may be over 50% (Tasmuth et al., 1995; Kwekkeboom, 1996; Fassoulaki et al., 2000). Post-operative sensations reported by patients can be transient or long-lasting, and can include pain, phantom sensations, and sensory loss or changes. Chronic pain can be a source of considerable disability and psychological distress. In patients undergoing diagnostic studies, surgical procedures, and other treatments for breast cancer, persisting pain is an additional burden for individuals already suffering from many psychosocial and medical stressors (Wyatt and Friedman, 1998; Velanovich and Szymanski, 1999; Kuehn et al., 2000). Chemotherapy and radiotherapy can be additional sources of pain and related symptoms and make diagnosis difficult. More patients are surviving breast cancer as a result of progress in diagnosis and treatment. The population at risk for chronic pain and other late complications can therefore be expected to increase in coming years. Although most surgical advances are less invasive and have fewer complications, the rapid pace of change in treatment complicates outcomes research. This article reviews the types of breast cancer surgery and research on the epidemiology and natural history, pathophysiologic mechanisms, treatment, and prevention of chronic pain following these procedures. We emphasize neuropathic pain because it is the most prevalent type, and propose a classification of chronic neuropathic pain following breast cancer surgery that takes into account recent advances in surgical procedures. This classification includes only chronic neuropathic pain syndromes that are a direct consequence of breast cancer surgery. There are other neuropathic pain syndromes that occur following breast cancer surgery that are a consequence of breast cancer and its non-surgical treatment. These syndromes, which include neuropathic pain caused by tumor recurrence and paraneoplastic processes, chemotherapy-associated neuropathy, and radiation plexitis and plexopathy, are beyond the scope of this article. Breast cancer occurs in men with a low incidence (Meguerditchian et al., 2002). Unfortunately, no studies have systematically compared chronic pain in men and women patients following breast cancer surgery; indeed, to our knowledge, only one study of chronic pain following breast cancer surgery has included men (Miaskowski and Dibble, 1995). The nature of the samples studied therefore limits our conclusions to women with breast cancer.

Evidence of focal small-fiber axonal degeneration in complex regional pain syndrome-I (reflex sympathetic dystrophy).

Abstract 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.

Congenital insensitivity to pain: an update

Elna M. Nagasako, Anne Louise Oaklander, Robert H. Dworkin* Washington University School of Medicine, St. Louis, MO, USA Nerve Injury Unit, Departments of Anesthesiology, Neurology, and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 604, Rochester, NY 14642, USA

Single-agent bortezomib in previously untreated multiple myeloma: efficacy, characterization of peripheral neuropathy, and molecular correlations with response and neuropathy.

PURPOSE To assess efficacy and safety of single-agent bortezomib in previously untreated patients with multiple myeloma, investigate prevalence of baseline and treatment-emergent polyneuropathy, and identify molecular markers associated with response and neuropathy. PATIENTS AND METHODS Patients received bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11, for up to eight 21-day cycles. A subset of patients underwent neurophysiologic evaluation pre- and post-treatment. Bone marrow aspirates were performed at baseline for exploratory whole-genome analyses. Results Among 64 patients, 41% had partial response or better, including 9% complete/near-complete responses; median duration of response was 8.4 months. Response rates did not differ in the presence or absence of adverse cytogenetics. After median follow-up of 29 months, median time to progression was 17.3 months. Median overall survival had not been reached; estimated 1-year survival was 92%. Thirty-two patients successfully underwent optional stem-cell transplantation. Bortezomib treatment was generally well tolerated. At baseline, 20% of patients had sensory polyneuropathy. Sensory polyneuropathy developed during treatment in 64% of patients (grade 3 in 3%), but proved manageable and resolved in 85% within a median of 98 days. Neurologic examination, neurophysiologic testing, and measurements of epidermal nerve fiber densities in 35 patients confirmed pretreatment sensory neuropathy in 20% and new or worsening neuropathy in 63%. Pharmacogenomic analyses identified molecular markers of response and treatment-emergent neuropathy, which will require future study. CONCLUSION Single-agent bortezomib is effective in previously untreated myeloma. Baseline myeloma-associated neuropathy seems more common than previously reported, and bortezomib-associated neuropathy, although a common toxicity, is reversible in most patients.

The density of remaining nerve endings in human skin with and without postherpetic neuralgia after shingles

&NA; The mechanisms of chronic neuropathic pain are not well understood. Postherpetic neuralgia (PHN), which occurs in some patients after shingles (herpes zoster), was used to investigate the neural determinants of chronic pain. Skin biopsies were obtained from 38 adults with or without PHN at least 3 months after healing of shingles on the torso. Vertical sections were immunolabeled against PGP9.5, a pan‐axonal marker, to measure the density of remaining nerve endings in skin previously affected by shingles. All axons that end in the epidermis are nociceptors, neurons that transmit pain messages. The densities ranged between 2 and 3976 neurites/mm2 skin surface, but the overlap between subjects and without PHN was small. Of 19 subjects without PHN, 17 had more than 670 neurites/mm2 skin surface area (mean±SEM=1569±230), and 18 of 19 subjects with PHN had 640 or fewer neurites/mm2 (mean±SEM=367±92). PHN may be a ‘phantom‐skin’ pain associated with loss of nociceptors. This threshold of approximately 650 neurites/mm2 skin surface was not detected in previous studies that used summary statistics. It implies that the absence of pain after shingles may require the preservation of a minimum density of primary nociceptive neurons, and that the density of epidermal innervation may provide an objective correlate for the presence or absence of PHN pain.

Advances in the understanding of the pathogenesis and epidemiology of herpes zoster.

The primary varicella zoster virus (VZV) infection results in chickenpox (varicella), which is transmitted via the airborne route. VZV is highly infectious, but in the USA the incidence of varicella has been reduced by 76-87% as a result of the varicella vaccine. The virus establishes latency in the dorsal root ganglia during varicella and, when reactivated, travels along the sensory nerve axons to cause shingles (herpes zoster [HZ]). There are over 1 million cases of HZ in the USA each year, with an estimated lifetime attack rate of 30%. The incidence of HZ, which causes significant morbidity, increases with age and reaches approximately 10 cases per 1,000 patient-years by age 80. Cell-mediated immunity (CMI) is known to decline with age as part of immunosenescence, and decreased CMI is associated with reactivation of VZV. This article provides an overview of our emerging understanding of the epidemiology and pathogenesis of varicella and HZ, in addition to exploring the current theories on latency and reactivation. Understanding the risk factors for developing HZ and the complications associated with infection, particularly in older people, is important for prompt diagnosis and management of HZ in primary care, and they are therefore also reviewed.

Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia.

Summary Comparing symptoms, examinations, skin biopsies, and autonomic functions in fibromyalgia as opposed to control subjects suggests that approximately half of fibromyalgia patients have previously unrecognized small‐fiber polyneuropathy. Abstract 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.

Is reflex sympathetic dystrophy/complex regional pain syndrome type I a small-fiber neuropathy?†

Neurologist S. Weir Mitchell first described “causalgia” following wartime nerve injury, with its persistent distal limb burning pain, swelling, and abnormal skin color, temperature, and sweating. Similar post‐traumatic symptoms were later identified in patients without overt nerve injuries after trauma. This was labeled reflex sympathetic dystrophy (RSD; now complex regional pain syndrome type I [CRPS‐I]). The pathophysiology of symptoms is unknown and treatment options are limited. We propose that persistent RSD/CRPS‐I is a post‐traumatic neuralgia associated with distal degeneration of small‐diameter peripheral axons. Small‐fiber lesions are easily missed on examination and are undetected by standard electrophysiological testing. Most CRPS features—spreading pain and skin hypersensitivity, vasomotor instability, osteopenia, edema, and abnormal sweating—are explicable by small‐fiber dysfunction. Small fibers sense pain and temperature but also regulate tissue function through neuroeffector actions. Indeed, small‐fiber–predominant polyneuropathies cause CRPS‐like abnormalities, and pathological studies of nerves from chronic CRPS‐I patients confirm small‐fiber–predominant pathology. Small distal nerve injuries in rodents reproduce many CRPS features, further supporting this hypothesis. CRPS symptoms likely reflect combined effects of axonal degeneration and plasticity, inappropriate firing and neurosecretion by residual axons, and denervation supersensitivity. The resulting tissue edema, hypoxia, and secondary central nervous system changes can exacerbate symptoms and perpetuate pathology. Restoring the interest of neurologists in RSD/CRPS should improve patient care and broaden our knowledge of small‐fiber functions. Ann Neurol 2009;65:629–638

Diagnosis and Assessment of Pain Associated With Herpes Zoster and Postherpetic Neuralgia

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.

Heterogenous patterns of sensory dysfunction in postherpetic neuralgia suggest multiple pathophysiologic mechanisms

Background: Postherpetic neuralgia (PHN) is considered by some investigators to be predominantly a deafferentation-type central pain syndrome; others suggest that activity of remaining peripheral nociceptors plays a critical role. The authors investigated the sensory dysfunction in subjects with PHN of varying duration and at different sites to gain further insight into the mechanisms responsible for the clinical features of neuropathic pain. In addition, the relationships between ongoing pain and pain evoked by mechanical and thermal stimuli were compared in patients with trigeminal and truncal PHN, to determine if the pathophysiologic mechanisms differed among subjects. Methods : In 63 subjects with PHN, quantitative sensory testing was performed in the region of maximum allodynia or ongoing pain and the corresponding contralateral site. The intensity of ongoing pain was recorded. Sensory thresholds for warmth, coolness, heat pain, and cold pain were determined. Pain induced by various mechanical stimuli (dynamic, static, punctate) was rated using a numerical rating scale of 0-10. Results: The mean rating of ongoing PHN pain was 7.3 ± 2.0 (mean ± SD). Allodynia induced by one or more mechanical stimuli was observed in 78% of subjects. A smaller subset (40%) had hyperalgesia to heat or cold stimuli. In subjects with duration of PHN of ≤ 1 yr duration, but not in those with duration of > 1 yr, the intensity of ongoing pain correlated with intensity of allodynia induced by dynamic stimuli. Deficits in thresholds for heat and cold pain were observed in the affected region of subjects with PHN in the thoracic dermatomes (P < 0.005), but not in the trigeminal distribution. No relationship was observed between the thermal deficits and ongoing pain or mechanical allodynia in the groups of subjects with either trigeminal or thoracic PHN. conclusion: Despite a common cause, the patterns of sensory abnormalities differ between subjects. Particular differences were noted between groups with facial or truncal PHN and between groups with recent or more chronic PHN. The observations suggest that the relative contributions of peripheral and central mechanisms to the pathophysiology of pain differ among subjects and may vary over the course of PHN.