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Treatment of inflammatory neuropathy with dexamethasone plus B-vitamins: a clinical evaluation
Tratamento de neuropatia inflamatória com a associação de dexametasona e vitaminas B: uma avaliação clínica


Henrique Goldberg
Head of the Neurosurgery Service - HUPE. Master in Neurology - UFRJ. Professor and Coordinator of Neurosurgery - FCM-UERJ.
Carlos Pereira Nunes
Associate Professor of Internal Medicine - UNIFESO. Associate Professor - IPGMCC.
Carlos Alfredo Franco Cardoso
Professor and Chairman of Biochemistry - UNIFESO. Coordinator of Biological Sciences - UNIFESO.
Flavia de Paoli
Professor and Chairman of Pharmacology - UNIFESO.
Márcia Gonçalves Ribeiro
Associate Professor - UFRJ.
Rafael Higashi
Neurology - INDC-UFRJ. Training in Pain Management - NYU Pain Center.
Mauro Geller
Professor and Chairman of Immunology - UNIFESO. Professor and Chairman of Clinical Immunology - IPGMCC.

Lisa Oliveira
Researcher in Microbiology and Immunology - UNIFESO.

Cristiane Marques
Staff Physician - Hospital Municipal Miguel Couto.

Address for correspondence:
Departamento de Imunologia e Microbiologia - UNIFESO
Prof. Mauro Geller
Av. Alberto Torres, 111
CEP 25964-004 - Teresópolis - RJ
E-mail: microbiologia@feso.br

Recebido para publicação em 05/2009.
Aceito em 05/2009.

© Copyright Moreira Jr. Editora.
Todos os direitos reservados.

Indexado na Lilacs Virtual sob nº LLXP: S0034-72642009002100005

Unitermos: Inflammatory neuropathy, dexamethasone sodium phosphate, thiamine hydrochloride, pyridoxine hydrochloride, cyanocobalamin
Unterms: neuropatia inflamatória, fosfato dissódico de dexametasona, cloridrato de tiamina, cloridrato de piridoxina, cianocobalamina

Numeração de páginas na revista impressa: 169 à 173

Summary


We evaluated the use of a combination of vitamins B1, B6, and B12 with dexamethasone in the treatment of the signs and symptoms of inflammatory neuropathy of the upper and lower limbs, in an open-label clinical trial. Patients were submitted to a 9-day treatment period with three doses of study medication at three day intervals, and a series of clinical and laboratory assessments, prior to the first dose of study medication and at each of the following three visits to the study center. Efficacy evaluations at each study visit included a 100mm VAS pain scale and global and satisfaction surveys completed by the patient and the investigating physician.

Safety evaluations included a comparison of changes in laboratory evaluations at each visit and the incidence, severity, duration, and outcome of adverse events. A total of sixty-one patients were enrolled in the trial. A clinically significant improvement in all of the efficacy measures was observed from the pre-treatment to end-of-study evaluations. No clinically significant alterations in clinical assessments were observed during the treatment period. Based on the results of this clinical study, we conclude that the combination of dexamethasone with the B-vitamins is safe and effective in the treatment of the signs and symptoms of inflammatory neuropathy.

Introduction

The predominant pathological characteristics of neuropathies are axonal degradation or paranodal/segmental demyelinization. Neuropathies are characterized based on the primarily affected anatomical structure(1,2). Neuropathies are commonly grouped into two categories: mononeuropathies, which lead to a motor and/or sensory deficit, that is restricted to the area of the affected nerve and polyneuropathies, in which the deficit is predominantly distal and symmetric(3).

The inflammatory neuropathies are a group of conditions sharing a common pathological characteristic of inflammation surrounding the nerve fibers(2,3). These conditions may arise from various sources including autoimmune, infectious, paraneoplasic, granulomatous, or paraproteinemic factors(1). Neuropathic pain may be induced either by injury or nervous system disease resulting in abnormalities of structural lesions in the peripheral or central nervous system, and may present a significant impact on quality of life(1-4).

A careful medical history, evaluation of mode of onset, and identification of the predominant clinical manifestations may be used to pinpoint the cause of the inflammatory neuropathy. The following signs and symptoms should be evaluated by a physician when inflammatory neuropathy is suspected(4):

· Weakness, sensory disturbances, or both at the extremities
· Frequent pain
· Depressed or absent tendon reflexes
· Family history of neuropathy
· History of systemic disease or toxic exposure.

Management of neuropathic pain may pose a challenge for healthcare providers in terms of patient satisfaction. The standard therapeutic approach to treatment of neuropathic pain is pharmacotherapy, including use of antidepressants and antiepileptics(2,3).

Vitamins B1, B6, and B12 have been shown in numerous clinical and pre-clinical studies to have antinociceptive and anti-inflammatory properties(5-8), the effects of which may be observed with single or combined administration of these vitamins in the treatment of pain disorders related or not to vitamin deficiency(9-13). Additionally, the combination of these B vitamins enhances the anti-inflammatory and analgesic effect of conventional drugs in both animal models and human patients. This effect permits lower drug dosing regimens and shortened treatment duration(14-19).

Dexamethasone belongs to the synthetic glucocorticoid family, and is used as an anti-inflammatory agent in the treatment of symptoms of various disorders, specifically those presenting inflammatory or immunological components such as arthritis, infections, and tissue and muscle disorders, as well as respiratory, renal, and neurologic disorders(20). Advantages of dexamethasone use include a strong anti-inflammatory response at low doses, and a lower effect on electrolyte metabolism compared to other anti-inflammatory drugs. In equipotent anti-inflammatory doses, dexamethasone is almost completely exempt of the sodium-retaining properties of hydrocortisones, which make it suitable for use in cases where water retention is a concern. In a manner similar to that of other glucocorticoids, dexamethasone may trigger a variety of metabolic effects and modify the organism’s immune response to various stimuli(20,21).

The combination of the B-vitamins with dexamethasone has been evaluated in several studies using animal models. The analgesic activity of dexamethasone was significantly increased with concomitant administration of vitamin B6 in the pain-induced inflammatory model in rats(22). The combination of the B-vitamins with dexamethasone reportedly resulted in a synergistic interaction which reduced tactile allodymia(23). In a rat model of neuropathic pain, the combination of B-vitamins with dexamethasone resulted in complete pain relief in the animals, who had undergone spinal nerve ligation(24).
The addition of the B-vitamins to dexamethasone therapy has also been evaluated in clinical trials, with encouraging results(25). In patients with uncomplicated low back pain, Medina-Santillan et al. (2000) reported a superior efficacy of the combination of dexamethasone plus B-vitamins compared to treatment with dexamethasone alone, suggesting that this combination improves functional disability by means of anti-inflammatory and antineuritic actions(26).

In this study, we evaluated the effect of the combination of dexamethasone with vitamins B1, B6 and B12 on the signs and symptoms of patients presenting inflammatory neuropathies.

Materials and methods

This was an open-label clinical trial evaluating the efficacy and safety of the parenteral administration of a combination of dexamethasone and the B-vitamins on the signs and symptoms of inflammatory neuropathy. We recruited patients of both genders, ranging in age from 18-65, with a clinical presentation of limb inflammatory neuropathy of the upper or lower limbs. The study protocol was evaluated and approved by the Ethical Committee (no. 005/2004). The efficacy evaluation included the response to treatment as assessed by the patient and by the investigating physician, while the safety evaluation took into account changes in laboratory values from pretreatment as well as adverse event occurrence, duration, and severity.

Following informed consent, screened patients presenting inflammatory neuropathy of the upper or lower limbs and who met all inclusion criteria were included in the study. Patients were evaluated prior to the first dose of study medication with a complete physical examination, medical history, and laboratory evaluations. Patients were asked to specify which limb presented the inflammatory neuropathy. In case more than one limb was affected, the investigating physician identified the one with the most severe symptoms as the study index limb.

The treatment regimen was established in accordance with the widely accepted recommendations, of one intramuscular injection every three days. Enrolled subjects received three intramuscular injections of the study medication, with a total treatment period of 9 days. Each dose of the study medication included:

· 4.370 mg dexamethasone sodium phosphate
· 100 mg thiamine hydrochloride
· 100 mg pyridoxine hydrochloride
· 5 mg cyanocobalamin.

No dose changes to the study drug medication were allowed. Patients were submitted to four study visits: Pretreatment, Visit 2 (three days following the previous visit), Visit 3 (three days following the previous visit) and Final Visit (one to three days following previous visit). At each study visit, complete physical examinations, laboratory evaluations, concomitant medication and adverse event monitoring, and study patient and physician evaluations were performed.

Efficacy assessments were conducted at each study visit. The Physician’s Satisfaction Assessment and the Patient’s Satisfaction Assessment of Pain and Mobility consisted of 10-point questionnaires responded by the physician or patient, respectively, that were used to grade the performance of the study medication on the index limb, ranging from 1 (“very unsatisfied”) to 10 (“very satisfied”). For statistical analysis, a score ranging from 1-7 points was considered unsatisfactory, while scores from 8-10 were considered positive.

The Physician’s Global Evaluation and the Patient’s Global Evaluation evaluated the degree of interference of the inflammatory neuropathy with performance of normal activities. The questionnaire scores ranged from 1 point (“very good”), with no limitation of normal activities, to 5 points (“very poor”), in which the patients’ neuropathic condition severely interfered with carrying out normal activities. For statistical analysis, a score of 1-2 points was considered positive, while those ranging from 3-5 points were considered unsatisfactory.

The Patient’s Assessment of Pain consisted of a 100mm visual analog scale (VAS). The patient was asked to place a vertical mark along a 100mm line, between 0mm (“no pain”) on the left side of the line and 100mm (“most severe pain”) on the right side of the line, based on the current condition of the index limb. The distance in mm from the left side of the line to the patient’s mark was measured and recorded.

Safety evaluations were based on incidence, severity, duration and outcome of adverse events, as well as any clinically significant alteration from pretreatment to the final study visit in the patient’s physical and laboratory evaluations.
All study evaluations were based on the intent-to-treat population, including all patients who were enrolled in the study and who had received at least one dose of the study medication. Statistical analysis was performed using the GraphPad Prism 5 software. Categorical variables were analyzed using the chi-square test, and continuous variables were analyzed using the repeated measures ANOVA.


Data are n or means (± SD).


Data are means (±SD) or repeated-measures ANOVA

Results

Sixty-one patients were enrolled in this study. The demographic data of the patient population is summarized in Table 1. Of the total patients, 50 (81.97%) reported previous treatment of the inflammatory neuropathy, while 11 (18.03%) reported no previous treatment.

Table 2 summarizes the results of the safety evaluations. There were no clinically significant changes from Pretreatment to the Final Visit in the physical evaluations performed (weight, pulse, and blood pressure). The adverse events (AEs) recorded during the study are presented in Table 3. A total of 29 patients (47.54%) presented 86 AEs during the study. Of these, 6 patients (20.69%) presented 1 AE, 8 (27.59%) patients presented 2 AEs, 5 (17.24%) patients presented 3 AEs, 5 (17.24%) patients presented 4 AEs, while 1 (3.45%) patient presented 5 AE, and 4 (13.79%) patients presented 6 AEs. Of the total adverse events, 81 (94.2%) were resolved before the Final Visit, and 5 (5.8%%) were ongoing at the end of the study.

Of the total adverse events reported, 64 (74.4%) were directly related the intramuscular administration of the study medication. The majority of the adverse events were classified as mild, and lasted less than ten minutes. The five AEs classified as “severe” related to pain at the injection site of the study medication, none of which lasted longer than 3 minutes. One patient was withdrawn from the study due to worsening of a previously existing condition (intraocular hypertension). The alterations in laboratory exams observed in 2 patients were not considered clinically significant.
The results of the efficacy evaluations are presented in Table 4. We observed clinically significant improvements from the Pretreatment assessment to the Final Visit in all of the efficacy evaluations performed.

Discussion

The results of this study confirm the efficacy and safety of the use of the combination of dexamethasone and the B-vitamins in terms of significant pain relief and anti-inflammatory activity.
Although a large number of adverse events were recorded during this study, most were directly related to the intramuscular administration of the study medication. Those that were not directly related to the study drug administration were mild or moderate in severity, and were resolved by the end of the study. The safety profile and risks of adverse reactions to the glucocorticoids, including dexamethasone, is well known. The adverse effects reported during the study could be attributed to the dexamethasone component of the study medication(21). While there are reports of adverse events associated with B-vitamin use in the literature, the B vitamins used in this study are considered safe at the doses employed(27).




The findings of this study are in conformity with those in the literature regarding the therapeutic benefit of the combination of dexamethasone with the B-vitamins, although the mechanism by which these effects are exerted remains unclear(22-26). The results of this study mirrored those of a previously reported trial of a similar drug combination and trial design(28). The addition of thiamine, pyridoxine, and cyanocobalamin to dexamethasone could enable administration of lower concentrations of dexamethasone in the treatment of neuropathic pain.

The results of the efficacy evaluations carried out during the study demonstrated clinically significant improvement in pain and mobility in the treated patient population. These results are encouraging in light of the challenge faced by healthcare providers in the treatment and management of neuropathic pain.

Conclusion

Based on the results of this study, we conclude that the combination of dexamethasone with thiamine, pyridoxine, and cyanocobalamin at the doses employed in this study, is both safe and effective in the treatment of the signs and symptoms of inflammatory neuropathy.

Acknowledgements

The authors would like to thank Evolution Consultancy for clinical protocol development and statistical evaluations. Thanks also to Luiza Lisboa Carramenha and Filipe Augusto Carvalho de Paula, Breno Lorch, and Flavia Kuperman for CRF handling and for clinical review.

Resumo

Foi realizada uma avaliação da combinação das vitaminas B1, B6, e B12 com a dexametasona no tratamento dos sinais e sintomas de neuropatia inflamatória dos membros superiores e inferiores, em um estudo clínico aberto. Os pacientes foram submetidos a um período de tratamento de 9 dias com três doses do medicamento do estudo em intervalos de três dias, junto com uma série de avaliações clínicas e laboratoriais, antes da primeira dose do medicamento do estudo e em cada uma das seguintes três visitas ao centro do estudo. As avaliações de eficácia em cada visita do estudo incluíram uma escala de dor de 100mm e questionários da condição global e da satisfação realizadas pelo paciente e o médico investigador.

As avaliações de eficácia incluíram uma comparação de alterações aos exames laboratoriais em cada visita, bem como a incidência, severidade, duração e resultado de eventos adversos. Foi incluído na pesquisa um total de sessenta e um pacientes. Uma melhora clinicamente significativa foi observada em todas as medidas de eficácia utilizadas, do pré-tratamento até as avaliações de final de estudo.

Não foram observadas alterações clinicamente significativas nas avaliações clínicas realizadas durante o período de tratamento. Com base nos resultados desta pesquisa clínica, concluímos que a combinação de dexametasona com as vitaminas B é segura e eficaz no tratamento dos sinais e sintomas de neuropatia inflamatória.




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