B Vitamins and musculoskeletal disease

VITAMIN B

Sidney Erwin T. Manahan, MD FPCP FPRA

16 September 2016

In Musculoskeletal

Diseases

WHAT’S THE EVIDENCE?

Disclosures

Received grants and honoraria from Pfizer,

Roche, Ajanta Phils and Wyeth.

Prescriptions for Neuropathic Pain

Vitamin

B

complex

40%

Anti-

epileptics

31%

NSAIDs

16%

Analgesics

13%

IMS Philippines Data , June 2011

Vitamins

WATER SOLUBLE

Vitamin B • Thiamine (B1)

• Riboflavin (B2)

• Niacin (B3)

• Pantothenic Acid (B5)

• Pyridoxine (B6)

• Biotin (B7)

• Inositol (B8)

• Folic Acid (B9)

• Cobalamin (B12)

Vitamin C (Ascorbic Acid)

FAT SOLUBLE

• Vitamin A (Retinol)

• Vitamin D (Calciferol)

• Vitamin E (Tocopherol)

• Vitamin K (Phytonadione)

Schellack G, et al. B complex vitamin deficiency and supplementation. S Afr Pharm J 2015; 82 (4): 28-33

Physiologic Functions of Vitamin B

Vitamin B

Complex

Metabolic Effects Thiamine, Riboflavin

Niacin, Pantothenic Acid

Pyridoxine, Biotin

Inositol, Folic Acid

Cobalamin

Hematinic

Pyridoxine, Folic Acid

Cobalamin

Nervous System

Functions Thiamine, Niacin

Pyridoxine, Cobalamin

Homocysteine levels Folic acid, Pyridoxine

Cobalamin


Dietary Sources of Vitamin B

RECOMMENDED DAILY ALLOWANCE

Male Female

Thiamine (B1) 1.2 – 1.4 mg 1 – 1.1 mg

Riboflavin (B2) 1.4 – 1.7 mg 1.2 – 1.3 mg

Niacin (B3) 16 – 19 mg 13 – 14 mg

Pantothenic Acid (B5) 4-7 mg

Pyridoxine (B6) 2 – 2.2 mg 2 mg

Folic Acid (B9) 400 mcg

Cobalamin (B12) 3 mcg

DIETARY Vitamin B Deficiency

• A specific B vitamin deficiency is not likely to occur

in insolation.

• If at least one B vitamin is found to be deficient,

the full spectrum should be considered deficient,

unless proven otherwise.

• B vitamin supplementation only in deficiency states

in the presence of adequate nutrition.


Factors That Cause Vitamin B Deficiency

• Malnutrition

• Strictly Vegan Diets

• High intake of milled rice

• Chronic alcoholism

• Chronic dialysis

• Post-gastrectomy/ GI

surgery

• Intestinal parasitism

• Patients on TPN

• Anticonvulsants

• Steroids

• Theophylline

• Hydralazine, diuretics

• Estrogen pills

• Isoniazid

• Metformin

• Colchicine

• Proton-pump inhibitors

and H2 blockers

Differences in Presentation of

Vitamin B Neuropathies

Thiamine

Present initially as muscle cramps followed by distal

sensory loss; Left untreated, may result in ascending

weakness of the legs and sensorimotor neuropathy of the

hands

Pyridoxine

DEFICIENCY - Numbness, paresthesia and burning

sensation in the feet which ascends to the legs &

eventually the hands

TOXICITY - sensory ataxia, areflexia and impaired

cutaneous sensation (burning and paresthesias)

severe toxicity affects motor nerves as well

Cobalamin

Sensory symptoms appear first (“Numb Hand

Syndrome”); May involve upper and lower extremities;

may also present with myeloneuropathy (with

concomitant copper deficiency)

Hammond N, et al. Nutritional Neuropathies. Neurol Clin 2013; 31 (2): 477-89

Pyridoxine in Carpal Tunnel Syndrome

Pyridoxine 2mg/d improved symptoms but longer durations of Pyridoxine

100mg/d allowed patients to avoid hand surgery

Folkers K, et al. Biochemical evidence for a deficiency of vitamin B6 in CTS

based on a crossover clinical study. Proc Nat Acad Sci USA 1978; 75 (7): 3410-2

Rate of symptoms alleviation was higher (68% vs 14.3%) among those who

took pyridoxine 100mg BID than those who didn’t receive it

Kasdan M, et al. Carpal tunnel syndrome and vitamin B6. Plast Reconstr Surg 1987; 79: 456-8

In 14 supplementation trials, 8 studies supported vitamin B

supplementation. (None were RCTs and half of these were in patients

found to have vitamin B6 deficiency)

Aufiero E, et al. Pyridoxine treatment of Carpal Tunnel Syndrome. Nutr Rev 2004; 62(3): 96-104.

Ryan-Harshmann M, et al. Carpal tunnel syndrome and vitamin B6. Can Fam Phy 2007; 53: 1161-2.

Pyridoxine in Carpal Tunnel Syndrome

Patient 46 Adult patients with clinical / EP diagnosis of carpal

tunnel syndrome

Intervention Pyridoxine 200 mg/d for 10-12 weeks

Methods 2 Randomized blinded controlled Trials

Results No significant improvement in symptoms, nocturnal

discomfort, hand coordination, Phalen’s test or Tinel’s

sign.

Improvement in finger swelling and movement

discomfort after 12 weeks of intervention.

O’Connor D, et al. Non-surgical treatment for carpal tunnel syndrome. Cochrane Database of Sys Rev 2003, Issue 1, Art No.

CD003219.

Cobalamin in Diabetic Neuropathy

Patients 336 Adult patients with diabetic neuropathy

Intervention Vitamin B12 or combination treatment (includes vitamin B) or

methylcobalamin given for 4-16 weeks

Methodology Systematic review of 7 randomized controlled trials

Results 6/6 trials showed significant improvement in pain or

somatosensory symptoms compared to placebo or BL; 3/4 trials

showed improvement in vibration perception threshold and

autonomic symptoms.

Only 1/4 clinical trials showed improvement with vitamin B

combination while 2/3 studies showed improvement with

methylcobalamin in electrophysiologic measures.

Methylcobalamin was better than conventional vitamin B12 in

improving somatosensory, autonomic symptoms and EP results

Sun Y, et al. Effectiveness of vitamin B12 in diabetic neuropathy: systematic review of clinical controlled trials. Acta Neurolo

Taiwan 2005; 14(2): 48-54.

Cobalamin in Diabetic Neuropathy

Patients 363 Adult patients with diabetic neuropathy

Intervention Various vitamin B12 interventions for 12-24 weeks


Results Only 1 trial showed more improvement in neuropathic symptoms

with vitamin B interventions compared to non-vitamin B

interventions, placebo

Only 1 trial showed improvement in EP changes with

intervention

In 1 trial, there was improvement in somatic, sensory and

autonomic symptoms with methylcobalamin after 4 months but

no comparison made to placebo

No clear advantage in using vitamin B12 in DM

neuropathy

Jayabalan B, et al. Vitamin B supplementation for diabetic peripheral neuropathy. Singapore Med J 2016; 57 (2): 55-9.

Alcoholic and Diabetic Neuropathy

Patients 741 Adult patients with either diabetic or alcoholic neuropathy

Intervention Vitamin B12 given for 2-8 weeks


Results Two trials showed no improvement in pain intensity

One trial showed a small improvement in vibration threshold

with benfotiamine versus placebo

Higher doses of vitamin B complex resulted in short term

reduction in pain and improvement in paresthesias, pain and

numbness.

Evidence for vitamin B in treating peripheral

neuropathy is limited and insufficient to determine

whether it is beneficial or harmful

Ang CD, et al. Vitamin B for treating peripheral neuropathy. Cochrane Database Sys Rev 2008, (3), CD004573.

Vitamin B for Peripheral Neuropathy

• Vitamin B appears to improve some of the symptoms in

peripheral neuropathy compared to placebo.

• Larger studies are needed before its efficacy in treating

patients who do not have a deficiency can be established

Onysko M, et al. Targeting neuropathic pain: consider these alternatives. J Fam Prac 2015; 64 (8): 470-5.

Beyond Supplements, Going Analgesic

• Interaction with pain mediators

• Increasing NE and 5-hydroxytriptamine in pain inhibitory

descending pathway

• Regeneration of damaged nerve fibers

• Stabilizing neurons – inhibiting ectopic discharges

• Improved axonal transport

• Increasing nerve conduction velocity

Gazoni FM, et al. B complex vitamins for analgesic therapy. Rev Dor Sao Paulo 2016; 17 (1): 52-6

Vitamin B in Acute Pain Author Patients / Interventions Results

Ponce-Monter

HA, et al 2012

122 patients with lower limb

fracture, initial VAS >50mm

Diclofenac + vitamin B IV versus

Diclofenac IV 2x/day1

>30 mm decreased in pain VAS

within 4 hours. More effective

analgesia with combination

therapy from 8 hours post

application & maintained for 48

hours

Mibielli MA, et

al 2009

372 patients with acute low

back pain (DOLOR Study)

Diclofenac + vitamin B PO

versus Diclofenac BID x 7 days2

More effective pain relief (>20

mm) after 3 days, better

functionality and mobility with

combination therapy.


1 Thiamine 100mg + Pyridoxine 100 mg + cyanocobalamin 1 mg

2 Thiamine 50 mg + Pyridoxine 50 mg + cyanocobalamin 1 mg

Vitamin B in Knee Osteoarthritis

Author Patients / Interventions Results

Garg S, et al

2013

30 patients with Knee OA

Benfotiamine+pyridoxine+methy

lcobalamn TID vs placebo for 24

weeks

Significant improvement in pain,

improved functionality and joint

mobility with vitamin B complex

Magana-Villa

MC et al 2013

48 patients with severe knee OA

in the pre-arthroplasty period

Diclofenac + vitamin B1versus

Diclofenac IM 48 hours prior to

OR and evaluated 12 hours later

Superiority of analgesia and

increased analgesic duration

with combination treatment


1 Thiamine 100mg + Pyridoxine 100 mg + cyanocobalamin 5 mg

Vitamin B in Knee Osteoarthritis


Dehghan M

2015

120 patients with Knee OA

Diclofenac + Vitamin B vs

Diclofenac + Vitamin E vs

Diclofenac

*Diclofenac 50 mg BID

** No dose of vitamin B and E

specified.

All groups had significant

improvement in parameters 3

weeks after initiating therapy.

Decrease in pain, improvement

in function was (statistically)

greater in those who received

vitamin B. More satisfaction

from patients on vitamin B but

not statistically significant.

Dehghan M. Comparative Effectiveness of B and E vitamins with diclofenac in reducing pain

due to osteoarthritis of the knee. Med Arh 2015; 69 (2): 103-106.

Vitamin B in Post Herpetic Neuralgia


Xu G et al

2014

98 patients with subacute

moderate to severe PHN of 120

days duration

Methylcobalamin SC vs

Methylcobalamin PO vs

lidocaine SC for 4 weeks

SC methylcobalamin

progressively reduced pain

(including paroxysms and

allodynia) compared to other

arms.

Xu G et al

2014

90 patients with PHN of 120

days in dermatomes T6-10

TENS+lidocaine SC vs

TENS+cobalamin SC vs triple tx

for 8 weeks

Significant improvement in pain

with TENS+cobalamin and triple

therapy. There was no

improvement with

TENS+lidocaine


ADD ON Vitamin B in Diabetic PN


Fonseca VA et

al 2013

214 Type 2 DM with neuropathy

documented as abnormal VPT

Pyridoxine 35 mg +

Methylcobalamin 2000 mcg +

methylfolate 3 mg BID vs

Placebo as ADD ON to

pregabalin, gabapentin or

duloxetine x 24 weeks

More patients receiving add on

vitamin B complex experienced

reduction in pain symptoms

(26% vs 15%) beginning Week

16 and sustained until week 24.

However no improvement in

VPT.

Improvement was greatest in

patients with low levels of

vitamin B6 and B12 and those

receiving metformin


Methylcobalamin in Low Back Pain

• 120 Adults with non-specific low

back pain of 6 months duration

• Randomized Double Blind Placebo

Controlled Trial

• S1: Methylcobalamin 1000 mg IM

OD for 2 weeks

• S2: Methylcobalamin 500 mcg

3x/week for 2 weeks

Mauro GL, et al. Eur Rev Med Pharmacol Sci 2000; 4: 53-58

Chiu CK, et al. The efficacy and safety of IM methylcobalamin in patients with chronic non-specific

low back pain. Sing J Med 2011; 52 (12): 868-73


75.53 70.63

56 54.8

9.53

36.83 38.6

51.5

MCbl Placebo MCbl Placebo

Mauro GL et al 2000 Chiu CK et al 2011

Pain VAS (in mm)

Pre-tx Post-tx

Mauro GL, et al. Eur Rev Med Pharmacol Sci 2000; 4: 53-58. Chiu CK, et al. The efficacy and safety of IM

methylcobalamin in patients with chronic non-specific low back pain. Sing J Med 2011; 52 (12): 868-73


13.27

11.53

2.43

5.8

MCbl Placebo

Disability

Pre-tx Post-tx

64 60.5

47

55.3

MCbl Placebo

Disability Index

Pre-tx Post-tx




LOWER mean paracetamol use in

patients who received cobalamin

• Mauro GL 2000: B12 9.9 + 8.04 tabs/

15 days versus Placebo 28.9 + 11.32

tabs/15 days

• Chiu CK 2011: B12 65.7 + 75.2 g

versus Placebo 87.6 + 57.3 g



Comparison of Available Vitamin B

Complex Preparations

Preparation Thiamine (mg) Pyridoxine (mg) Cobalamin

(mcg)

Brand N 100 200 200

Brand P 500 500 250 1000

Brand M 300 300 100 100

Brand M 1000 500 250 1000

Brand NE 300 100 1000

Brand Ph 100 5 50

Brand Rh 10 1 2

Polyneuropathy 10-30 50-100 1000-2000

MIMS Philippines Drug Reference 2016 Issue 1


Summary

• Non-dietary factors contribute to vitamin B deficiency despite adequate dietary intake

• Some symptoms in peripheral neuropathy improve with vitamin B administration

• There are small trials suggesting a potential role for vitamin B in acute pain, osteoarthritis, back pain and as add on to anticonvulsants in DPN

• Larger trials are needed to establish efficacy in patients without deficiency state

Health & Medicine

B Vitamins and musculoskeletal disease