Maria Melanson

A treatment algorithm for neuropathic pain

BACKGROUND Neuropathic pain is a chronic pain syndrome caused by drug-, disease-, or injury-induced damage or destruction of sensory neurons within the dorsal root ganglia of the peripheral nervous system. Characteristic clinical symptoms include the feeling of pins and needles; burning, shooting, and/or stabbing pain with or without throbbing; and numbness. Neuronal hyperexcitability represents the hallmark cellular mechanism involved in the underlying pathophysiology of neuropathic pain. Although the primary goal is to alleviate pain, clinicians recognize that even the most appropriate treatment strategy may be, at best, only able to reduce pain to a more tolerable level. OBJECTIVE The purpose of this review is to propose a treatment algorithm for neuropathic pain that health care professionals can logically follow and adapt to the specific needs of each patient. The algorithm is intended to serve as a general guide to assist clinicians in optimizing available therapeutic options. METHODS A comprehensive review of the literature using the PubMed, MEDLINE, Cochrane, and Toxnet databases was conducted to design and develop a novel treatment algorithm for neuropathic pain that encompasses agents from several drug classes, including antidepressants, antiepileptic drugs, topical antineuralgic agents, narcotics, and analgesics, as well as various treatment options for refractory cases. RESULTS Any of the agents in the first-line drug classes (tricyclic antidepressants, antiepileptic drugs, topical antineuralgics, analgesics) may be used as a starting point in the treatment of neuropathic pain. If a patient does not respond to treatment with at least 3 different agents within a drug class, agents from a second drug class may be tried. When all first-line options have been exhausted, narcotic analgesics or refractory treatment options may provide some benefit. Patients who do not respond to monotherapy with any of the first- or second-line agents may respond to combination therapy or may be candidates for referral to a pain clinic. Because the techniques used at pain clinics tend to be invasive, referrals to these clinics should be reserved for patients who are truly refractory to all forms of pharmacotherapy. CONCLUSIONS Neuropathic pain continues to be one of the most difficult pain conditions to treat. With the proposed algorithm, clinicians will have a framework from which to design a pain treatment protocol appropriate for each patient. The algorithm will also help streamline referrals to specialized pain clinics, thereby reducing waiting list times for patients who are truly refractory to traditional pharmacotherapy.

CYFIP2 is highly abundant in CD4+ cells from multiple sclerosis patients and is involved in T cell adhesion

DNA microarray profiling of CD4+ and CD8+ cells from non‐treated relapsing and remitting multiple sclerosis (MS) patients determined that the cytoplasmic binding partner of fragile X protein (CYFIP2, also called PIR121) was increased significantly compared to healthy controls. Western analysis confirmed that CYFIP2 protein was increased approximately fourfold in CD4+ cells from MS compared to inflammatory bowel disorder (IBD) patients or healthy controls. Because CYFIP2 acts as part of a tetrameric complex that regulates WAVE1 activation we hypothesized that high levels of CYFIP2 facilitate T cell adhesion, which is elevated in MS patients. Several findings indicated that increased levels of CYFIP2 facilitated adhesion. First, adenoviral‐mediated overexpression of CYFIP2 in Jurkat cells increased fibronectin‐mediated adhesion. Secondly, CYFIP2 knock‐down experiments using antisense oligodeoxynucleotides reduced fibronectin‐mediated binding in Jurkat and CD4+ cells. Thirdly, inhibition of Rac‐1, a physical partner with CYFIP2 and regulator of WAVE1 activity, reduced fibronectin‐mediated adhesion in Jurkat and CD4+ cells. Finally, inhibition of Rac‐1 or reduction of CYFIP2 protein decreased fibronectin‐mediated adhesion in CD4+ cells from MS patients to levels similar to controls. These studies suggest that overabndance of CYFIP2 protein facilitates increased adhesion properties of T cells from MS patients.

The clinical importance of neutralizing antibodies in relapsing-remitting multiple sclerosis

ABSTRACT Background: Neutralizing antibodies (NAbs) develop in patients receiving interferon beta (IFN-β) for multiple sclerosis (MS). Debate continues concerning the relevance of NAb development on treatment efficacy. Objective: To determine the incidence and clinical importance of NAbs in patients with relapsing-remitting MS (RRMS). Methods: A comprehensive literature review was conducted using PubMed (accessed from 1983 to June 2005), Cochrane MS Group trials register (accessed June 2005), MEDLINE (accessed 1983 to June 2005), and Toxnet (accessed June 2005) databases. NAb-induced changes in clinical efficacy and disease progression were evaluated according to the clinical guidelines established by the American Academy of Neurology. Results: Currently, there is no standardized assay to comparatively assess NAbs among different treatments. NAbs develop independent of age, sex, disease duration and progression index at the onset of treatment. The occurrence of NAbs varies from 2–45% depending on the treatment initiated. NAb+ patients demonstrate accelerated disease progression as confirmed by an approximate 1‐point increase in the Expanded Disability Status Scale score. The odds of relapse during a NAb+ period are between 1.51 and 1.58 ( p < 0.03) with the time to first relapse being shortened by an average of 244 days after 12 months of IFN‐β therapy. NAb+ patients experience an approximately four-fold increase ( p = 0.009) in the median number of active T2 magnetic resonance imaging (MRI) lesions compared to NAb-negative patients (1.4 vs. 0.3 respectively, p < 0.01). Conclusion: The induction of NAbs in IFN‐β treated patients reduce clinical effect and accelerate disease progression.

Staphylococcus aureus harbouring Enterotoxin A as a possible risk factor for multiple sclerosis exacerbations

Background: Staphylococcus aureus may produce superantigens that can non-specifically activate CD4+ cells to potentially target the myelin basic protein. Objective: This study examined the association between individuals with multiple sclerosis (MS) and colonization with S. aureus harbouring superantigens. Methods: Nasal swabs were collected from non-MS subjects and patients with MS who had not experienced a relapse in the past six months (MS stable group) and who had suffered a relapse within 30 days of study recruitment (MS exacerbation group). S. aureus was isolated from the anterior nares of participants following standard procedures and staphylococcal superantigen genes (sea, seb, and tsst-1) were detected using standard laboratory PCR techniques. Results: The study enrolled 204 patients, 80 in the non-MS and MS stable groups and 44 patients in the MS exacerbation group. Overall, 27.0% of patients were colonized with S. aureus with no significant differences identified between study groups. Amongst individuals colonized with S. aureus, the prevalence of sea was significantly greater in the MS exacerbation versus non-MS study group (p < 0.05; odds ratio 7.9; 95% confidence interval 1.2–49.5). Conclusions: The ability to rapidly screen patients for the presence of S. aureus producing sea may serve as a useful marker of a potential MS exacerbation.

Examining the evidence: complementary adjunctive therapies for multiple sclerosis

Abstract Objective: The purpose of this article is to provide a comprehensive overview of the most frequently encountered non-conventional approaches trialed for use in multiple sclerosis (MS). The efficacy and safety of non-conventional approaches ranging from bee venom therapy (BVT) to an array of vitamins and herbal products were discussed and evaluated. Methods: Relevant English-language articles were identified through searches of MEDLINE (1990–2006), PubMed (1999–2006), Cochrane (1995–2006) and Toxnet (2000–2006). Classification of available literature was conducted according to the evidence based guidelines established by the American Academy of Neurology (AAN). However, due to the non-conventional nature of these treatment approaches, most available literature was derived from anecdotal reports and suboptimal clinical studies, lacking the rigor of evidence-based practice. Results: There is presently only marginal supportive evidence for BVT in MS treatment. The inability to identify and quantify the active component of BVT combined with the associated risk of anaphylaxis has deterred its widespread use. The most promising evidence comes from prophylactic daily supplementation with vitamin D. Despite beneficial reports regarding non-herbal supplements such as alpha-lipoic acid (ALA), luteolin, evening primrose oil and vitamins such as B12, the lack of evidence does not support their prophylactic use. Discussion: Based on available evidence, the prophylactic use of vitamin D is a viable option as an adjunct to conventional medicine. Although there is a lack of conclusive evidence to support the use of other non-conventional treatments, patients are still opting to trial and bare the risks of these products which are accessible without the intervention of a healthcare professional. Controlled, evidence-based trials are essential for healthcare professionals to competently intervene and recommend these products.

Fatigue and Cognition in Patients with Relapsing Multiple Sclerosis Treated with Interferon Beta

ABSTRACT Introduction: Fatigue and cognitive deficits are common symptoms affecting patients with multiple sclerosis. Methods: The effects of interferon beta on fatigue and cognitive deficits were assessed in 50 patients with relapsing multiple sclerosis (recruited at a single center). The pre-treatment assessments were performed on visits 1 and 2 (Months 0 and 3). Patients started treatment with subcutaneous interferon beta-1a or beta-1b, or intramuscular interferon beta-1a at Month 3, with reassessment at visits 3 and 4 (6 and 12 months, respectively). Co-primary endpoints were change in fatigue (Modified Fatigue Impact Scale) and change in cognition (Brief Repeatable Battery of Neuropsychological Tests) from pre-treatment to visits 3 and 4. Follow-up data were obtained for 40 patients. Results: The pre-treatment demographic and disease characteristics did not differ between groups. Improvements in fatigue levels were reported for patients receiving subcutaneous interferon beta-1a versus patients in the intramuscular interferon beta-1a group (p = .04) and in the interferon beta-1b group (p = .09). Improvements were also reported in five out of 17 cognitive indices for all the treatment groups. Conclusion: The data suggest that interferon beta may reduce fatigue and cognitive deficits in patients with relapsing multiple sclerosis. Larger, randomized, and controlled studies are required to confirm our findings.

Axotomy-induced up-regulation of tumor necrosis factor-alpha in the dorsal root ganglia.

Abstract Objectives: Neuropathic pain is a chronic pain syndrome associated with drug, injury or disease-induced damage or destruction of sensory afferent fibers of the dorsal root ganglia (DRG). Although the exact underlying pathologic mechanisms are not known, pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) are recognized as potential modulators of peripheral and central nervous system inflammatory responses. They play a crucial role in injury and the pathologic development of chronic pain syndromes such as neuropathic pain. Methods: Twenty-four rats were divided into a naive control (n=6), sham (surgery exposing sciatic nerve, n=6), and peripheral nerve lesion group (unilateral axotomy of sciatic nerve, n=12). Results: The results of this study demonstrate a transient up-regulation of TNF-α expression within ipsi- and contralateral DRG following complete unilateral sciatic nerve axotomy as confirmed by immunohistochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR) and real-time PCR. Elevated expression of TNF-α was noted to occur within the first 7 days post-axotomy, which subsequently normalized to baseline levels by day 14. This transient up-regulation was also associated with a switch in cellular source from predominant satellite cell expression at baseline to that involving satellite cells and abundant numbers of sensory neurons. Discussion: These results support the role of TNF-α in the upstream cascade of cellular events involved in the underlying pathogenesis of neuropathic pain. Strategies targeting the early attenuation of TNF-α within the DRG during the first week post-injury may have significant clinical impact in preventing the downstream cascade of events involved in the underlying cellular pathology of neuropathic pain.

Corticosteroids and Multiple Sclerosis: To Treat or Not to Treat? Pharmacists Can Be the Front-Line Resource for MS Patients

Although a rare disease, multiple sclerosis (MS) has a high prevalence rate in Canada and affects many Canadians and their families. An autoimmune disease of the central nervous system, it results in the destruction of the myelin sheath that surrounds the nerve axons. High-dose IV steroid therapy is often used to treat an acute exacerbation in MS. Steroids have immunosuppressant effects that work to decrease the autoimmune pathology component of the disease and to reduce the inflammation around the nerve axon, thereby promoting closer contact of the damaged myelin and subsequently partially restoring adequate electrical nerve conduction to reduce symptoms. The high prevalence rate of MS in Canada makes it vital for pharmacists to become more aware of the different aspects of the disease and how these relate to therapy. The pharmacist should be aware of the adverse effects and impact of high-dose IV steroids in MS patients. The purpose of this review is threefold: 1) to provide a better understanding of MS pathology; 2) to contribute a systematic review of steroids; and 3) to assist in the clinical decision-making process and in the counselling requirements for patients on high-dose steroids.

Managing Migraines: Options for Acute Abortive Treatment

Introduction Triptans, ergotamine derivatives and nonsteroidal anti-inflammatory drugs are front-line agents used in the acute abortive therapy of migraines. In this article, these medications are reviewed and a treatment algorithm suggested. Methods A comprehensive review of the literature from 1990 to 2008 was conducted using PubMed, MEDLINE and The Cochrane Library to explore the underlying pathophysiology of migraines and comparatively assess the acute and chronic treatment options available in their management. The information obtained from all literature searches was further categorized as level 1, 2 or 3 based on pre-defined peer-reviewed criteria. Conclusion: This review is able to present a relatively preliminary but practical migraine treatment algorithm. Although there is no standard universal treatment strategy to manage migraine headaches in all patients, this review has been put forth to serve as a clinical guideline to assist health professionals in deciding the most appropriate treatment for migraine headaches.