B complex vitamins for analgesic therapy

BACKGROUND AND OBJECTIVES: The B complex vitamins have been used as single therapy or combined to other drugs, such as anti-inflammatory drugs, in different clinical situations, such as degenerative spinal diseases, rheumatologic diseases, polyneuropathies and in different postoperative situations. This study aimed at identifying in the scientific literature most recent evidences of the use of B complex vitamins as analgesic therapy and at describing clinical situations where their analgesic action could be observed. CONTENTS: A search was carried out in Pubmed, Medline, LILACS, Cochrane Library and Scielo databases, contemplating the last 10 years and titles in Portuguese, Spanish and English.


INTRODUCTION
B complex vitamins (Bvits) belong to the hydrosoluble group of vitamins, being made up of thiamine, riboflavin, niacin, niacinamide, pyridoxine, cobalamin, folic acid, pantothenic acid, biotin, choline, inositol and para-aminobenzoic acid (PABA).Among their major representatives to manage pain there are vitamins B1 (thiamine), B6 (pyridoxine) and B12 (cyanocobalamin) 1 .Bvits are important for nucleic acid and proteins synthesis, as well as for phosphatidylcholine synthesis.Phosphatidylcholine is a cell membrane phospholipid which is transformed in choline which shall be used for acetylcholine synthesis which is a major neurotransmitter [2][3][4] .Possible Bvits analgesic and anti-neuralgic mechanisms (especially vitamins B1 and B12) shown in experimental animal studies include: interaction with mediators caus-REVIEW ARTICLE DOI 10.5935/1806-0013.20160013ing pain in nociceptors, increasing availability and effectiveness of norepinephrine and 5-hydroxitriptamine in pain inhibitory descending pathway; regeneration of damaged nerve fibers; stabilization of electric nervous excitability inhibiting ectopic discharges; and improved axonal transport, increasing nervous conduction velocity [5][6][7] .For many years, Bvits have been used in monotherapy or combined with other drugs, such as anti-inflammatory drugs, in several clinical situations, such as degenerative spinal diseases, rheumatologic diseases, polyneuropathies (especially diabetic neuropathy) and in different postoperative periods [1][2][3][4] .Notwithstanding several animal studies showing positive evidences of Bvits both for inflammatory and neuropathic pain, few human clinical trials have shown the same effects, which made Bvits analgesic efficacy controversial 3,8 .Cochrane Library has published in 2008 a review with 13 peripheral alcoholic and diabetic neuropathy trials, in a total of 741 participants, with emphasis to just one study with benfotiamine (derivative of vitamin B1).This study has observed a possible benefit of benfotiamine with slight increment on vibratory perception as compared to placebo.The review has stressed that high doses of Bvits are more effective than low doses, but the use of other therapies as compared to vitamins is more effective in the short term.So, it was suggested that further studies should be carried out to confirm the possible effect of Bvits on peripheral neuropathies 9 .After Cochrane's publication, some studies were carried out to evaluate analgesic effects of Bvits in the management of nociceptive and neuropathic pain.So, due to more recent publica-tions and still with questions about the real role of Bvits in the clinical practice involving different pain situations, this review is intended to update information on the use of such vitamins to manage pain.This study aimed at identifying in the scientific literature most recent evidences of the use of Bvits as analgesic therapy and at describing clinical situations in which their analgesic action could be observed, both in monotherapy and in adjuvant therapy.

CONTENTS
This is a study carried out by means of integrative literature review, following the stages recommended for studies of this nature.Literature review was carried out in Pubmed, LILACS and Scielo databases, looking for scientific articles published in the last 10 years, from 2005 to 2015, in English, Portuguese and Spanish.Descriptors were "pain", "B complex vitamins", "management", "vitamin B1", "vitamin B6", "vitamin B12", "thiamine", "pyridoxine" and "cyanocobalamin".It should be stressed that these same descriptors were identified in DEcS (Health Science Descriptors).Narrative reviews and systematic reviews, experience reports, case reports and clinical trials were included in this scientific search.Among 40 studies found, we have selected just musculoskeletal and neuropathic pain trials with human beings, in which Bvits were used as analgesic agents.We have selected 13 trials which have met herein established inclusion criteria.Table 1 is a summary of selected trials and their primary results.To evaluate vitamins B1, 6 and 12 for pain.Randomization to diclofenac (50mg) + pyridoxine (50mg) + thiamine (50mg) + cyanocobalamin (1mg) (GDB), and diclofenac alone (50mg) (GD), by oral route 2x/ day, for no longer than 7 days.GDB has more effectively improved pain after 3 days, (decrease of ≥20mm in VAS), and there has been personal satisfaction in this group.GDB was also better for functionality and mobility (p<0.05)Maladkar, Tekchandani, Dave 10 Open, exploratory, prospective, multicenter study
Major improvement of neuropathic symptoms already in the 4 th week.With 12 weeks there has been improvement in all symptoms (p<0.05):78% pain decrease, 92.1% in numbness, 96.9% in muscle weakness, 96% in tingling and 99.2% in burning.The efficacy and safety of vitamin B associations for peripheral neuropathies was confirmed.

patients aged between 19 and 92 years, with neuropathic pain of different origins
To evaluate the efficacy of vitamin B12 (3µg) associated to uridine monophosphate (50mg) and folic acid (400µg) simultaneously with regular use of analgesics (paracetamol, tramadol and anti-inflammatory drugs), O 1x/day, forr 60 days.
Significant pain improvement according to Pain Detect (from 17.5 to 8.8 points), and of analgesic consumption in 75.6% of patients.The conclusion was that the association of vitamin B12, uridine and folic acid was effective for pain and also has allowed lower analgesic consumption.
Continue... SC methylcobalamin has progressively decreased pain, with superiority of this route as compared to oral route or to lidocaine in continuous paroximal pain or alodynia.The conclusion was that SC methylcobalamin was potential choice for sub-acute post-herpetic neuralgia.
Xu et al. 15 Randomized There has been significant improvement in itching with thiamine, of pain with cobalamin and of both with the association of cobalamin and thiamine, in addition to improved DLA with cobalamin and cobalamin associated to thiamine.The conclusion was that thiamine had major anti-itching action, cobalamin analgesic action and the association of both had dual actions without synergy.

DISCUSSÃO
This study has reviewed recent publications and also published after a major Cochrane's systematic review from 2008 about the role of Bvits to manage peripheral neuropathies, time when available information were insufficient to determine the real clinical benefit of those vitamins as analgesics.
We have found different results with more recent studies.It was observed that Bvits had significant analgesic effects in polyneuropathies, low back pain, osteoarthritis (OA) and post-herpetic neuralgias, both as adjuvant drugs and as monotherapy.In addition, Bvits had anti-inflammatory and anti-itching action, the latter in post-herpetic neuralgia patients and have also improved functionality.When those vitamins were associated to conventional acute or chronic pain management, they have decreased time for analgesic and antiinflammatory drugs consumption, thus contributing to less deleterious adverse effects in some individuals 1,7,[10][11][12][13][14][15][16][17][18][19][20] .
The review of publications on Bvits for neuropathic pain, a total of 6 studies, point to beneficial effects, but with different doses and administration routes.Maladkar, Tekchandani and Dave 10 , studying peripheral neuropathic pain patients, have shown that after 12 weeks of Bvits administration (1500 µg methylcobalamin, 200mg alpha-folic acid, 5mg folic acid, 5mg biotin, 50mg benfotiamine and 5mg vitamin B6), there has been significant improvement of neuropathic symptoms.Negrão et al. 11 have also shown improved neuropathic pain after 60 days of daily use of vitamin B12 (3 µg) associated to uridine monophosphate (50mg) and folic acid (400mg), Talei et al. 12 , using this same vitamin but in a dose of muscular 2000µg, twice a week for three months, have shown better efficacy of vitamin B12 as compared to nortriptyline (10mg) in diabetic polyneuropathy patients 12 .Stracke et al. 13 , using benfotiamine (600 or 300mg, orally, once a day during six weeks) for diabetic neuropathy, have observed significant analgesic results, especially when higher doses were used.Other three studies, now addressing postherpetic neuralgias, have shown that local subcutaneous cobalamin (1000µg once a day for 4 weeks) was superior to lidocaine to improve pain [14][15][16] .So, it is suggested that the association of vitamins B12, B6 and B1, respectively and especially, in the doses of 1500µg (orally and daily) or 2000µg (muscular twice a week), of 50mg and of 300mg (both orally and daily), are effective as analgesic drugs for neuropathic pain.
As to publications about Bvits for nociceptive pain, 7 articles in total have also shown its analgesic effects.Chiu et al. 17 have shown in chronic low back pain patients that vitamin B12 (500µg muscular, three times a week for two months) has improved pain and associated functional incapacity.Also, Mibielli et al. 7 have shown that vitamins B12, B6 and B1 (50mg pyridoxine, 50mg thiamine, 1mg cyanocobalamin) associated to anti-inflammatory drugs (50mg diclofenac) have more effectively improved acute low back pain as compared to anti-inflammatory drug alone.And these same authors in a different study, now involving acute lumbar, cervical and hip pain 18 , have shown that nucleotides (1.5mg uridine and 2.5mg cytidine) orally administered during 10 days, in association with vitamin B12 (1000µg) were effective in 51.23% of patients versus 87.5% when an antiinflammatory drug (diclofenac) was associated to the same nucleotides; however, associations with anti-inflammatory drugs are related to further risk of adverse effects.So, vitamin B12 as analgesic adjuvant could be an alternative for acute back, cervical and hip pain when there are higher risks for the use of anti-inflammatory drugs.In other nociceptive pains such as knee OA and pain after limb fracture, Bvits have also shown analgesic effects 1,19,20 , both alone and in association with anti-inflammatory drugs, in addition to benefits for inflammation (decreased C-reactive protein serum levels in monotherapy) and functional capacity 19,20 .
Although observing a role of Bvits as analgesics in nociceptive pain, it was not possible to establish most effective doses, as it also was the case for neuropathic pain, because formulations and doses of studied trials were quite different.However, it seems that muscular associations in single doses of thiamine (100mg), pyridoxine (100mg) and cyanocobalamin (5000µg), or just the weekly use of methylcobalamin (1500µg) are good options, as well as benfotiamine (150mg), pyridoxamine (150mg) and methylcobalamin (1500µg) formulations, orally during 180 days.
In light of the above, there is still the need for further studies and better standardization to try to establish most effective doses, best administration routes and Bvits administration time for nociceptive and neuropathic pain syndromes.
To date, it is suggested that higher doses for longer periods lead to better results.

CONCLUSION
Our review has counted on recent, however very heterogeneous studies, pointing to analgesic effects of Bvits in different neuropathic or nociceptive pain syndromes, as adjuvant or as monotherapy.So, Bvits, that are considered safe and have low cost, could be good options for pain management in Brazil.
t r o l l e d , d o u b l e -b l i n d study 48 patients, between 59 and 68 years of age, with severe knee AO (pain NS >7) in the preoperative period of arthroplasty To evaluate efficacy and safety of diclofenac associated to vitamins B1, 6 and 12 (diclofenac 75mg, thiamine 100mg, pyridoxine 100mg and cyanocobalamin 5mg) compared to diclofenac (75mg) alone.Single muscular application 48h before surgery and pain evaluation for 12h Analgesic superiority of the association of vitamins B1, 6 and 12 to diclofenac.There has also been increased analgesic duration for diclofenac in the preoperative period of arthroplasty (p<0.05)VAS = visual analog scale; O = orally; IM = intramuscular; SC = subcutaneous; NS = numeric scale; TENS = transcutaneous electric nerve stimulation; DLA = daily life activity; OA = osteoarthritis; CRP = C-reactive protein.

Table 1 .
Clinical trials with vitamin B in musculoskeletal and neuropathic pain Decreased pain in the first 4h (VAS >30mm) in both groups.With association of vitamin B there has been further effectiveness as from 8h of the first application, being superiority maintained for 48h (p<0.05).Conclusion was that the association of vitamin B to diclofenac has increased its analgesic efficacy.

Table 1 .
Clinical trials with vitamin B in musculoskeletal and neuropathic pain -continuation