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      Efficacy and Tolerability of a Fixed Dose Combination of Methylcobalamin and Pregabalin in the Management of Painful Neuropathy

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          Abstract

          Pregabalin and Methylcobalamine are both capable reliving the symptoms of peripheral neuropathy but their effectiveness when used in a fixed dose combination still remains a subject of evaluation, especially in the orthopaedic setting. This post marketing surveillance study evaluates efficacy and tolerability of a fixed dose combination of Methylcobalamin 750 μg and Pregabalin 75 mg in the management of the same. The fixed dose combination of was prescribed for 4 weeks to the selected patients at 300 orthopaedic clinics all over India involving 1327 patients. Pain was assessed on a 10 point Numerical Pain Intensity Scale while physicians and patients overall assessment of efficacy and tolerability was done on a four-point scale. Results demonstrated a reduction in the pain which was evidenced by a visual analogue score of 38.87 and 73.99% at second and fourth week respectively. Eighty seven per-cent doctors and 88.11% patients expressed response to therapy as good to excellent. Tolerability was expressed as good to excellent by 81.48% of patients. Adverse events were of mild severity. Thus the fixed dose combination was efficacious and well tolerated in neuropathic pain with minimal adverse effects. This multi-centre open label, non-interventional observational, Phase IV (Post marketing surveillance) trial was planned to determine the efficacy and tolerability of a FDC of Methylcobalamine and Pregabalin in cases of painful peripheral neuropathy. The study was conducted in accordance with the Declaration of Helsinki and its subsequent revisions, with strict adherence to protocol which was approved by the independent ethic committee. Patients of either sex between the ages of 18-65 years with painful peripheral neuropathy were recruited in the study from the outpatient department of 300 orthopaedic clinics across India. The nature of the study was explained to them and informed consent was taken. The primary requirement for inclusion was neuropathic patients with a score of > 4 on neurogenic pain diagnostic questionnaire (NPDQ).[1] The main exclusion criteria included any contraindication to Methylcobalamin and Pregabalin, complex regional pain syndrome (type 1 and 2), pregnancy, lactating mothers and also women with no reliable history of contraception in childbearing age. Eligible patients consumed the FDC of Methylcobalamin and Pregabalin, orally, as prescribed by the treating physician for duration of 4 weeks. Medication for control of diabetes and those considered necessary for the patients well-being and which did not interfere with the study medication were prescribed at the discretion of treating investigator. Patients were screened during Visit 1. The efficacy and safety was assessed on two visits (on completion of second weeks) and third visit (on completion of fourth weeks). Pain was assessed on a 10 point Numerical Pain Intensity Scale or the visual analogue scale (VAS);[2] the patients were asked to rate their pain and the corresponding visual analogue score was recorded. The pain assessed during the first visit served as the baseline score. Physicians and Patients performed the overall assessment of efficacy and tolerability at the end of the study on a four-point scale of; Excellent, Good, Moderate and Poor. The nature and severity of the adverse events reported assessed was assessed at the end of the study. The primary outcome measure was the change in the pain level from the baseline on the VAS score. Secondary outcome measures included; (i) Adverse Events that were either spontaneously reported by the patient or noticed by the physician. (ii) Doctors Global Assessment of Response to Therapy (DGART), (iii) Patients Global Assessment of Response to Therapy (PGART) and (iii) Patients Global Assessment of Tolerability to Therapy (PGATT). Statistical analysis was done using IBM SPSS 19.0 (Statistical Package for the Social Sciences). Demographic data was presented as descriptive statistics and baseline and end of surveillance (EOS) characteristics were compared by using the t-test for quantitative variables. Paired t-test was performed to assess the statistical significance of the differences between baseline and surveillance visits, under each group separately. All analyses were prospectively planned and conducted on an intention-to-treat (ITT) basis. Patient data loss was kept to a minimum by defining ITT eligibility as any patient with at least one baseline and one follow-up visit. A total of 1525 patients were screened, of which 63.90% were males and 36.10% were females. The mean (±SD) age of patient recruited was 47.98 (±10.27) years. All patients data was included for safety analysis but since 198 scored <4 on the NPDQ,[Table 1] there were 1327 eligible patients for efficacy analysis. One patient dropped out due to early relief, 26 withdrew due to no relief while for five patients follow up data was not available. The baseline signs and symptom in patients with NPDQ score > 4 is summarized in Table 2. A total of 30.37% (n=403) reported use of concomitant medication at second weeks, whereas on completion of study only 8.29% (n=110) were taking additional drugs, this reduction was seen predominantly for pills that decreased pain or relaxed the muscles [Table 3] Participants that completed the trial remained compliant to study medication by adhering to the treatment as per study protocol. Table 1 Patients baseline Neuropathic pain diagnostic questionnaire (NPDQ) scores (n=1525) Table 2 Baseline clinical signs and symptom distribution in study population Table 3 Concomitant medication received by the patients The mean (±SD) VAS scores at baseline was 7.74 (±1.54). At second visit and end of study, a higher proportion of patients reported relief of pain from baseline which was shown by mean scores of 4.73 (±1.41) and 2.01 (±1.40) respectively . The reduction in the pain as evidenced by change form baseline in the mean VAS score for pain was 38.87% and 73.99% at second and fourth week respectively. Eighty eight per cent doctors and 88.11% patients expressed response to therapy as good to excellent. Tolerability to therapy was expressed as good to excellent by 81.48% of patients. Adverse events reported were of mild severity. Thirty one patients experienced a total of 33 adverse events. Only one participant reported severe vertigo and another dizziness which lead to study dropouts, the former was not related to study medication as confirmed by the investigator. There was also a report of severe giddiness after start of therapy which was adequately managed tablet Betahistine 8 mg . Dyspepsia related to the concomitant Non-Steroidal Anti-inflammatory Drugs use, was treated using a proton pump inhibitor. Giddiness and drowsiness in three patients resolved without any intervention [Table 4]. Table 4 Adverse events reported by the patients (n=1525) Pain, one of the cardinal symptoms of neuropathy, was reduced by the FDC of Methylcobalamin and Pregabalin and significant effect was seen from second week onwards to end of study. Majority of the physicians expressed that FDC of Methylcobalamin and Pregabalin clearly demonstrated good to excellent response to therapy. Patients were of similar opinion regarding the efficacy and tolerability to the study drug. Also, most of the adverse events that occurred did not warrant discontinuation of the treatment and the overall tolerability profile of the study medications was not affected. Pregabalin's anticonvulsant and analgesic action is by binding to the α2-δ protein subunit of voltage-gated calcium channels, thereby reducing excitatory neurotransmitter release. Pregabalin exhibits linear pharmacokinetics after oral administration, with low intersubject variability.[3] Pregabalin was effective in relieving central neuropathic pain, improving sleep, anxiety, and overall patient status in patients with spinal cord injury.[4] A Cochrane Systematic Review of various studies on Pregabalin has proven its efficacy in neuropathic pain conditions and fibromyalgia.[5] The neurologically active form of vitamin B12 is Methylcobalamin is.[6] In a four-month, double-blind, placebo-controlled trial of type 1 and 2 diabetics with neuropathy, it was found that Methylcobalamin (1500 mcg per day) significantly improved somatic and autonomic symptoms in the treatment group compared to placebo.[7] Systematic review of several controlled clinical trials on vitamin B12 concluded Methylcobalamin therapy benefits on autonomic symptoms were as consistent as its effects on pain and somatosensory symptoms and which were relatively reliable.[8] Clinical studies have also demonstrated that Vitamin B 12 is more effective than nortriptyline in improving painful diabetic neuropathy.[9 10] In the view of the finding of this study we conclude that a FDC of Methylcobalamin 750 μg and Pregabalin 75 mg is well tolerated and efficacious in treating the pain of neuropathic origin.

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          Most cited references9

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          Pregabalin for acute and chronic pain in adults.

          Antiepileptic drugs have been used in pain management since the 1960s. Pregabalin is a recently developed antiepileptic drug also used in management of chronic neuropathic pain conditions. To assess analgesic efficacy and associated adverse events of pregabalin in acute and chronic pain. We searched MEDLINE, EMBASE, and CENTRAL to May 2009 for randomised controlled trials (RCTs). Additional studies were identified from the reference lists of retrieved papers and on-line clinical trial databases. Randomised, double blind trials reporting on the analgesic effect of pregabalin, with subjective pain assessment by the patient as either the primary or a secondary outcome. Two independent review authors extracted data and assessed trial quality. Numbers-needed-to-treat-to-benefit (NNTs) were calculated, where possible, from dichotomous data for effectiveness, adverse events and study withdrawals. There was no clear evidence of beneficial effects of pregabalin in established acute postoperative pain. No studies evaluated pregabalin in chronic nociceptive pain, like arthritis.Pregabalin at doses of 300 mg, 450 mg, and 600 mg daily was effective in patients with postherpetic neuralgia, painful diabetic neuropathy, central neuropathic pain, and fibromyalgia (19 studies, 7003 participants). Pregabalin at 150 mg daily was generally ineffective. Efficacy was demonstrated for dichotomous outcomes equating to moderate or substantial pain relief, alongside lower rates for lack of efficacy discontinuations with increasing dose. The best (lowest) NNT for each condition for at least 50% pain relief over baseline (substantial benefit) for 600 mg pregabalin daily compared with placebo were 3.9 (95% confidence interval 3.1 to 5.1) for postherpetic neuralgia, 5.0 (4.0 to 6.6) for painful diabetic neuropathy, 5.6 (3.5 to 14) for central neuropathic pain, and 11 (7.1 to 21) for fibromyalgia.With 600 mg pregabalin daily somnolence typically occurred in 15% to 25% and dizziness occurred in 27% to 46%. Treatment was discontinued due to adverse events in 18 to 28%. The proportion of participants reporting at least one adverse event was not affected by dose, nor was the number with a serious adverse event, which was not more than with placebo.Higher rates of substantial benefit were found in postherpetic neuralgia and painful diabetic neuropathy than in central neuropathic pain and fibromyalgia. For moderate and substantial benefit on any outcome NNTs for the former were generally six and below for 300 mg and 600 mg daily; for fibromyalgia NNTs were much higher, and generally seven and above. Pregabalin has proven efficacy in neuropathic pain conditions and fibromyalgia. A minority of patients will have substantial benefit with pregabalin, and more will have moderate benefit. Many will have no or trivial benefit, or will discontinue because of adverse events. Individualisation of treatment is needed to maximise pain relief and minimise adverse events. There is no evidence to support the use of pregabalin in acute pain scenarios.
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            Pregabalin in patients with central neuropathic pain: a randomized, double-blind, placebo-controlled trial of a flexible-dose regimen.

            The effective treatment of patients suffering from central neuropathic pain remains a clinical challenge, despite a standard pharmacological approach in combination with anticonvulsants and antidepressants. A randomized, double-blinded, placebo-controlled trial evaluated the effects of pregabalin on pain relief, tolerability, health status, and quality of life in patients with central neuropathic pain caused by brain or spinal cord injuries. At baseline and 4 weeks after the start of treatment subjects were evaluated with standard measures of efficacy: pain intensity measured by visual analog scale, health status (Pain Disability Index and EQ-5D) and quality of life (SF-36). Forty patients received escalating doses of either pregabalin (150, 300, and 600mg/day) or matching placebo capsules. In both groups, patients started with 1 capsule per day (either 150mg of pregabalin or placebo). If pain relief was insufficient, patients were titrated to a higher dose. There was a statistically significant decrease in mean pain score at endpoint for pregabalin treatment, compared with placebo (P=0.016). Follow-up observation showed no significant difference in Pain Disability Index scores between the two groups. The pregabalin group, however, showed a statistically significant improvement for the EQ-5D. Pregabalin treatment led to a significant improvement in the bodily pain domain of the SF36. In the other domains, more favorable scores were reported without reaching statistical significance. Pregabalin, in a flexible-dose regime, produced clinically significant reductions in pain, as well as improvements in health status in patients suffering from severe central neuropathic pain.
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              Effectiveness of vitamin B12 on diabetic neuropathy: systematic review of clinical controlled trials.

              The clinical effectiveness of vitamin B12 and its active coenzyme form on diabetic neuropathy is uncertain. Therefore, we searched the English- and non-English-language literature on this topic by using MEDLINE (Ovid, PubMed), the Cochrane Controlled Trials Register, and related papers. We identified seven randomized controlled trials from June 1954 to July 2004 and reviewed them for the clinical effectiveness of vitamin B12 according to the following parameters: Measurement scales of somatic and autonomic symptoms or signs; vibrometer-detected thresholds of vibration perception; and, electrophysiologic measures such as nerve conduction velocities and evoked potentials. Three studies involved the use of vitamin B complex (including B12) as the active drug, and four used methylcobalamin. Two studies were of fairly good quality (Jadad score = 3/5), and five were of poor quality (Jadad score < or = 2/5). Both the vitamin B12 combination and pure methylcobalamin had beneficial effects on somatic symptoms, such as pain and paresthesia. In three studies, methylcobalamin therapy improved autonomic symptoms. Effects on vibration perception and electrophysiological measures were not consistent. With both the vitamin B12 combination and pure methylcobalamin, symptomatic relief was greater than changes in electrophysiological results. However, more high-quality, double-blind randomized controlled trials are needed to confirm the effects of vitamin B12 on diabetic neuropathy.
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                Author and article information

                Journal
                N Am J Med Sci
                N Am J Med Sci
                NAJMS
                North American Journal of Medical Sciences
                Medknow Publications & Media Pvt Ltd (India )
                2250-1541
                1947-2714
                November 2012
                : 4
                : 11
                : 605-607
                Affiliations
                [1] Department of Orthopedics, Mukund Hospital, Mumbai, India.
                [1 ] Department of Orthopedics, Sanjeevani Hospital, Mumbai, India.
                [2 ] Department of Pharmacology, Padmashree Dr. D.Y. Patil Medical College, Pimpri, Pune, India. E-mail: drpavitra@ 123456gmail.com
                [3 ] Department of Pharmacology, Medical Services, Mumbai, India.
                [4 ] Department of Orthopedics, Mukund Hospital, Mumbai, India.
                [5 ] Department of Pharmacology, Head Medical Services, India.
                Article
                NAJMS-4-605
                10.4103/1947-2714.103336
                3503385
                23181238
                3377be14-47b3-49ce-b74f-fa78c4fb2e7f
                Copyright: © North American Journal of Medical Sciences

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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