review article methylcobalamin: a potential vitamin of...

Hindawi Publishing CorporationNeural PlasticityVolume 2013 Article ID 424651 6 pageshttpdxdoiorg1011552013424651

Review ArticleMethylcobalamin A Potential Vitamin of Pain Killer

Ming Zhang Wenjuan Han Sanjue Hu and Hui Xu

Institute of Neurosciences The Fourth Military Medical University Xirsquoan 710032 China

Correspondence should be addressed to Hui Xu xubzfmmueducn

Received 19 September 2013 Revised 6 November 2013 Accepted 12 November 2013

Academic Editor Sheng Tian Li

Copyright copy 2013 Ming Zhang et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Methylcobalamin (MeCbl) the activated form of vitamin B12 has been used to treat some nutritional diseases and other diseasesin clinic such as Alzheimerrsquos disease and rheumatoid arthritis As an auxiliary agent it exerts neuronal protection by promotingregeneration of injured nerves and antagonizing glutamate-induced neurotoxicity Recently several lines of evidence demonstratedthat MeCbl may have potential analgesic effects in experimental and clinical studies For example MeCbl alleviated pain behaviorsin diabetic neuropathy low back pain and neuralgia MeCbl improved nerve conduction promoted the regeneration of injurednerves and inhibited ectopic spontaneous discharges of injured primary sensory neurons This review aims to summarize theanalgesic effect and mechanisms of MeCbl at the present

1 Introduction

Vitamin B12 had been usually treated as sport nutrition andused to keep old people from getting anemic in past yearsVitamin B12 was regarded as painkilling vitamin in somecountries from 1950 Recently studies have shown that vita-min B12 played a key role in the normal functioning of thebrain and nervous system and the formation of blood Vita-min B12 is normally involved in several metabolisms suchas DNA synthesis and regulation fatty acid synthesis andenergy production Vitamin B12 has some analogs includingcyanocobalamin (CNCbl) methylcobalamin (MeCbl) hydr-oxocobalamin (OHCbl) and adenosylcobalamin (AdoCbl)In mammalian cells CNCbl and OHCbl are inactive formsand AdoCbl acts as a coenzyme of methylmalonyl Co-Amutase in mitochondria However vitamin B12 was not useddirectly in human body and it should be translated into acti-vating forms such as MeCbl or AdoCbl MeCbl differs fromvitamin B12 in that the cyanide is replaced by a methyl group(Figure 1) [1] It is a coenzyme of methionine synthase whichis required for the formation of methionine from homocys-teine in the methylation cycle which involves methylation ofDNAor proteins [2ndash5] Comparedwith other analogsMeCblis the most effective one in being uptaken by subcellularorganelles of neurons Therefore MeCbl may provide better

treatments for nervous disorders through effective systemicor local delivery

As an auxiliary agentMeCbl has been always used to treatmany diseases such as B12 deficiency andAlzheimerrsquos diseasesyndromes [6 7] L-methylfolate MeCbl and N-acetyl-cysteine improved memory emotional functions and com-munication with other people among Alzheimerrsquos patients [78] MeCbl also has neuronal protection including promotinginjured nerve and axonal regeneration [9 10] and confrontingagainst glutamate-induced neurotoxicity [9 11] In additionMeCbl improved nerve conduction in either patients of dia-betic neuropathy [12ndash14] or streptozotocin-diabetic rats [15]and experimental acrylamide neuropathy [16] MeCbl alsoimproved visual function [17] rheumatoid arthritis [18] Bellrsquospalsy and sleep-wake rhythm disorder [19 20] RecentlyMeCbl has been demonstrated to have potential analgesiceffects on neuropathic pain in experimental and clinicalstudies

2 The Analgesic Effect of MeCbl

MeCbl is one active form of vitamin B12 which can directlyparticipate in homocysteine metabolism More and more re-searches showed that MeCbl has beneficial effects on clinicaland experimental peripheral neuropathy

2 Neural Plasticity

Table 1 The analgesic effect of MeCbl or combined use with other drugs on patients with diabetic neuropathic pain

Effects of MeCbl Indices Measures of intervention Reference

Alleviation of neuropathic pain symptomsimproved nerve conduction velocity

Pain scale scores ofpatients measure of nerveconduction velocity

Oral administration of MeCbl for3 months Devathasan et al [12]

Improved nerve conduction velocity Measure of nerveconduction velocity

Intravenous administration ofMeCbl Ishihara et al [14]

Improved the symptoms of paresthesiaburning pains and heavinessno effect on nerve conduction velocity

Pain symptoms measure ofnerve conduction velocity

Repeated intrathecal injection ofMeCbl at a high dose of25mg10mL

Ide et al [21]

Relieved spontaneous pain by 73

Likert-type pain intensityscale Patientsrsquo GlobalImpression of Change(PGIC) scale

Intramuscular injection ofMeCbl for four weeks followedby oral administration of MeCblfor additional eight weeks

Li [22]

Relieved pain and paresthesiaimproved motor and sensory nerveconduction velocity

Neurolgical disability scorefor the grades of pain andparesthesia

Intravenous injection of MeCblfor 6 weeks Kuwabara et al [13]

Reduced pain scores and good tolerance Visual analog scale andchemical safety

Oral administration ofimmediate-releasemethylcobalamin andsustained-release pregabalin for 2weeks

Dongre and Swami[23]

N

N

ONH2 NH2

NH2

NH2

H H

O

N

H

O N

O

N

H

O

H

O

H

O

H

PO

O

O

OHO

N

NH

H

OH

H

H

Co

CH3

Ominus

H2N

H2N

Figure 1 The chemical structure of MeCbl

21 Diabetic Peripheral Neuropathic Pain Clinical symptomsin legs such as paresthesia burning pains and spontaneouspain were ameliorated byMeCbl [21 22] (Table 1)The effectsof single use ofMeCbl or combined use with other drugs werereviewed in diabetic neuropathy pain [12 23] (Table 1) Clini-cal evidence proved thatMeCbl had the capacity to inhibit theneuropathic pain associated with diabetic neuropathy

The intensity of the pain is variable and may be describedas a hot burning cold aching or itching sensation with attimes increased skin sensitivity In clinics it is still a chal-lenge to treat diabetic neuropathic pain Carbamazepine anddolantin were not able to relieve these symptoms Similarlytherapeutic effects of aldose reductase inhibitors and nimo-dipinewere not encouraging in clinic asmuch as basic studiesshowed Fortunately MeCbl may bring a glimmer of hope totreat diabetic neuropathic pain

22 Low Back Pain Between 70 and 80 adults have experi-enced low back pain at some times in their life [24] Back painis one of the most common health complaints But the causesare extensive cancer infection inflammatory disordersstructural disorders of the spine itself and disk herniation aresomewhat more common and together account for backpain It is supposed that the MeCbl is becoming a decentchoice for the therapy to the chronic low back pain Neuro-genic claudication distance was improved significantly afterthe application of MeCbl [25] (Table 2) However Waikakulrsquosresearch demonstrated that MeCbl was not good for painon lumbar spinal stenosis [25] In a trial the analgesic effectof MeCbl has been investigated in nonspecific low backpain patients with intramuscular injection [26] (Table 2)Theinconsistent effect of MeCbl might be due to different causesof lumbar spinal stenosis and nonspecific low back pain Fur-ther studies are needed to determine the effect of MeCbl onlow back pain

23 Neck Pain Chronic neck pain is becoming a commonproblem in the adult population for the prevalence of 30ndash50 in 12 months [27 28] It was shown that spontaneouspain allodynia and paresthesia of patients with neck painwere improved significantly in theMeCbl group andwith theincrease of treatment time of MeCbl the analgesic effect wasmore obvious [29] (Table 2)

24 Neuralgia

241 Subacute Herpetic Neuralgia The treatment of MeCblsignificantly reduced continuous pain paroxysmal pain andallodynia in the subacute herpetic neuralgia (SHN) patients[30] (Table 3) Thus MeCbl may be an alternative candidatefor treating SHN

Neural Plasticity 3

Table 2 The analgesic effects of MeCbl on low back pain and neck pain in clinical trials

Effects of MeCbl Indices Measures of intervention ReferenceRelieved spontaneous pain allodynia andparesthesia Pain symptoms of patients with neck pain Oral administration of

MeCbl for 4 weeks Hanai et al [29]

Amelioration of neurogenic claudicationdistance no effect on pain improvement andneurological signs

Pain symptoms measure the neurogenicclaudication distance of patients withdegenerative lumbar spinal stenosis

Oral administration ofMeCbl as an adjuvantmedication for 6 months

W Waikakul and SWaikakul [25]

Reduced pain

Oswestry disability index questionnaire(ODI) and visual analogue scale (VAS)pain score of patients with nonspecificlow back pain

Intramuscular injectionof MeCbl for 2 weeks Chiu et al [26]

Table 3 The analgesic effect of MeCbl or combined with other agents on neuralgia


Reduced or eliminated pain symptoms Pain scales in patients with trigeminalneuralgia

Intravenous injection ofMeCbl at a single dose of05mg

Teramoto [32]

Relieved overall pain continuousspontaneous pain paroxysmal pain andallodynia

Likert-type pain intensity scale PatientsrsquoGlobal Impression of Change (PGIC)scale

Local subcutaneousinjection of MeCbl for 4weeks

Xu et al [30]

Lowered pain intensities improved painrelief reduced pain interference with qualityof life

Numerical pain scale and brief paininventory of glossopharyngeal neuralgia

Oral administration ofgabapentin tramadoland MeCbl (05mg)

Singh et al [31]

242 Glossopharyngeal Neuralgia Glossopharyngeal neu-ralgia (GPN) is a common facial neuralgia in the pain clinicsIt was reported that the numerical pain scales were decreasedsubstantially with the treatment of MeCbl combined withgabapentin and tramadol in GPN patients [31] (Table 3) Anddegree of interference in quality of life includingmood inter-personal relationship and emotion was improved earlier [31]

243 Trigeminal Neuralgia Thepain of trigeminal neuralgia(TN) can be described as agonizing paroxysmal and lanci-nating which may be activated by small activities such aschewing speaking and swallowing A clinical trial provedthat the pain of TN patients was alleviated greatly in theMeCbl group and no recurrence of TN in pain symptomswasclosed to 64 [32] (Table 3)

25 Neuropathic Pain of AnimalModels The coapplication ofMeCbl and pioglitazone dramatically decreased allodyniaand hyperalgesia in diabetic rats [33] And the combinedapplication ofMeCbl and vitamin E alleviated thermal hyper-algesia in sciatic nerve crush injured rats [34] Our recentwork observed that tactile allodynia was markedly alleviatedfollowing a chronic treatment of MeCbl injection in chroniccompression of dorsal root ganglion (CCD) rats (Figure 2)

3 Mechanisms Underlyingthe Analgesic of MeCbl

For many years the B12 group of vitamins had been used totreat pain In some countries vitamin B12 was categorised asan analgesic drug It was suggested that vitamin B12 may in-

crease availability and effectiveness of noradrenaline and 5-hydroxytryptamine in the descending inhibitory nociceptivesystem [35] MeCbl exerted therapeutic effects on neuro-pathic pain in diabetics possibly through its neurosynthesisand neuroprotective actions [13 36] But the analgesic mech-anisms of MeCbl remained elusive till now

31 Improving Nerve Conduction Velocity Previous studiesshowed that high doses ofMeCbl improved nerve conductionin either patients with diabetic neuropathy [12ndash14] strep-tozotocin-diabetic rats [15] or experimental acrylamide neu-ropathy [16] Morphological and histological evidence con-firmed that a long-term administration of MeCbl promotedthe synthesis and regeneration ofmyelin [37]Thesemorpho-logical and histological recoveries of myelin may result inimproving nerve conduction velocity and neuronal functionin peripheral neuropathy

32 Promoting the Regeneration of Injured Nerves MeCbladvanced the incorporation of radioactive leucine into theprotein fraction of the crushed sciatic nerve in vivo As aresult the activity abilities of injured nerve were recovered[38] In this study the most terminals were degenerated inthe mutant mouse but the sprouts were more frequently ob-served in the MeCbl treatment group [39] MeCbl had theability to promote the injured nerves regeneration In theexperimental acrylamide neuropathy and sciatic nerve injurymodels the number of regenerations of motor fibers showedsignificant increase with high-dose methylcobalamin [16]And the combined use of L-methylfolate MeCbl and pyri-doxal 51015840-phosphate improved the calf muscle surface neuraldensity [40]

4 Neural Plasticity

Time after injection (d)

ControlMeCbl

Paw

with

draw

al th

resh

old

(g)

10

8

6

4

2

0

minus5 0 5 10 15 20 25 30

lowast

lowastlowast

lowastlowastlowast

lowastlowastlowast lowastlowastlowast

(a)


ControlMeCbl

Paw

with

draw

al th

resh

old

(g)

10

8

6

4

2

0

minus5 0 5 10 15 20 25 30

lowastlowastlowastlowast

lowastlowastlowastlowastlowastlowast lowastlowastlowast

(b)

Figure 2 An anti-allodynic effect ofMeCblMeCbl was successivelyreceived by intraperitoneal injections from the 3rd postoperativeday (line segment) Bilateral paw withdrawal thresholds to vonFrey filaments were decreased following a long-term application ofMeCb1 (a) Ipsilateral side and (b) contralateral side (lowast119875 lt 005lowastlowast119875 lt 001 lowastlowastlowast119875 lt 0001 multivariate analysis of variance)

33 Inhibiting Ectopic Spontaneous Discharge Ectopic spon-taneous discharges are likely to initiate spontaneous painhyperalgesia and allodynia [41ndash45] It was reported thatMeCbl suppressed the ectopic firing induced by chemicalmaterials in the dog dorsal root [46] Our recent work de-monstrated that MeCbl markedly inhibited the ectopic spon-taneous discharges of dorsal root ganglion neurons in CCDrats (Figure 3) Our results suggested thatMeCbl exhibited itsanti-allodynic effect by inhibiting peripheral pain signals

0

20

30

10

700 1400 2100

Time (s)

(A)

(B)

(C)

Freq

uenc

y (H

z)

(a)

(A)

(B)

(C)

20120583V03 s

(b)

Figure 3 Inhibitory effect of MeCbl on ectopic spontaneousdischarges of dorsal root (a) Time histogram showing that localapplication of the MeCbl (300 120583molL) decreased the basal firingrate of dorsal roots (b) Three traces in right panel show firingpatterns before (A) during (B) and wash out (C) the applicationof MeCbl

4 Conclusions

MeCbl or its combined usewith other agents has the potentialanalgesic effect in specific patients and animal models forexample nonspecific low back pain neck pain diabetic neu-ropathic pain subacute herpetic neuralgia glossopharyngealneuralgia and trigeminal neuralgia However its mecha-nisms underlying the analgesic effect were poorly under-stood On the basis of recent work the possible mechanismscan be considered as follows (1) MeCbl improved nerve con-duction velocity (2) MeCbl promoted injured nerve regener-ation recovering the neuromuscular functions in peripheralhyperalgesia and allodynia and (3) MeCbl inhibited theectopic spontaneous discharges fromperipheral primary sen-sory neurons in neuropathic pain states As a vitamin MeCblmay be a potential candidate for treating peripheral neuropa-thy with good safety

Neural Plasticity 5

Acknowledgments

Thisworkwas supported byGrants from theNationalNaturalScience Foundation of China (nos 30870830 and 31371120 toDr Hui Xu) and the Ministry of Education Foundation forreturned overseas students (HG3503 to Dr Hui Xu)

References

[1] L RMcDowellVitamins inAnimal andHumanNutrition JohnWiley amp Sons 2008

[2] R Banerjee and SW Ragsdale ldquoThemany faces of vitamin B12catalysis by cobalamin-dependent enzymesrdquo Annual Review ofBiochemistry vol 72 pp 209ndash247 2003

[3] S K Ghosh N Rawal S K Syed W K Paik and S D KimldquoEnzymic methylation of myelin basic protein in myelinrdquo Bio-chemical Journal vol 275 part 2 pp 381ndash387 1991

[4] A Pfohl-Leszkowicz G Keith and G Dirheimer ldquoEffect of co-balamin derivatives on in vitro enzymatic DNA methylationmethylcobalamin can act as a methyl donorrdquo Biochemistry vol30 no 32 pp 8045ndash8051 1991

[5] J I Toohey ldquoVitamin B12 and methionine synthesis a criticalreview Is naturersquosmost beautiful cofactormisunderstoodrdquoBio-Factors vol 26 no 1 pp 45ndash57 2006

[6] Y Takahashi S Usui and Y Honda ldquoEffect of vitamin B12(mecobalamin) on the circadian rhythm of rat behaviorrdquo Clin-ical Neuropharmacology vol 15 supplement 1 part A pp 46Andash47A 1992

[7] A McCaddon and P R Hudson ldquoL-methylfolate methylcobal-amin and N-acetylcysteine in the treatment of Alzheimerrsquos dis-ease-related cognitive declinerdquo CNS Spectrums vol 15 supple-ment 1 no 1 pp 2ndash6 2010

[8] T Ikeda K Yamamoto K Takahashi et al ldquoTreatment ofAlzheimer-type dementia with intravenous mecobalaminrdquoClinical Therapeutics vol 14 no 3 pp 426ndash437 1992

[9] M Kikuchi S Kashii Y Honda Y Tamura K Kaneda and AAkaike ldquoProtective effects of methylcobalamin a vitamin B12analog against glutamate-induced neurotoxicity in retinal cellculturerdquo Investigative Ophthalmology andVisual Science vol 38no 5 pp 848ndash854 1997

[10] X Kong X Sun and J Zhang ldquoThe protective role of Mecobal-amin following optic nerve crush in adult ratsrdquo Yan Ke Xue Baovol 20 no 3 pp 171ndash177 2004

[11] A Akaike Y Tamura Y Sato and T Yokota ldquoProtective effectsof a vitamin B12 analog methylcobalamin against glutamatecytotoxicity in cultured cortical neuronsrdquo European Journal ofPharmacology vol 241 no 1 pp 1ndash6 1993

[12] G Devathasan W L Teo and A Mylvaganam ldquoMethylcobal-amin in chronic diabetic neuropathy A double-blind clinicaland electrophysiological studyrdquo Clinical Trials Journal vol 23no 2 pp 130ndash140 1986

[13] S Kuwabara R Nakazawa N Azuma et al ldquoIntravenousmeth-ylcobalamin treatment for uremic and diabetic neuropathy inchronic hemodialysis patientsrdquo Internal Medicine vol 38 no 6pp 472ndash475 1999

[14] H Ishihara M Yoneda and W Yamamoto ldquoEfficacy of intra-venous administration of methycobalamin for diabetic periph-eral neuropathyrdquo Med Consult N Remedies vol 29 no 1 pp1720ndash1725 1992

[15] M Sonobe H Yasuda I Hatanaka et al ldquoMethylcobalamin im-proves nerve conduction in streptozotocin-diabetic ratswithout

affecting sorbitol and myo-inositol contents of sciatic nerverdquoHormone and Metabolic Research vol 20 no 11 pp 717ndash7181988

[16] T Watanabe R Kaji N Oka W Bara and J Kimura ldquoUltra-high dosemethylcobalamin promotes nerve regeneration in ex-perimental acrylamide neuropathyrdquo Journal of the NeurologicalSciences vol 122 no 2 pp 140ndash143 1994

[17] T Iwasaki and S Kurimoto ldquoEffect of methylcobalamin inaccommodative dysfunction of eye by visual loadrdquo Journal ofUOEH vol 9 no 2 pp 127ndash132 1987

[18] M Yamashiki A Nishimura and Y Kosaka ldquoEffects of methyl-cobalamin (vitamin B12) on in vitro cytokine production ofperipheral blood mononuclear cellsrdquo Journal of Clinical andLaboratory Immunology vol 37 no 4 pp 173ndash182 1992

[19] M IkedaMAsai TMoriyaM Sagara S Inoue and S ShibataldquoMethylcobalamin amplifies melatonin-induced circadianphase shifts by facilitation of melatonin synthesis in the rat pin-eal glandrdquo Brain Research vol 795 no 1-2 pp 98ndash104 1998

[20] K Takahashi M Okawa M Matsumoto et al ldquoDouble-blindtest on the efficacy of methylcobalamin on sleep-wake rhythmdisordersrdquo Psychiatry and Clinical Neurosciences vol 53 no 2pp 211ndash213 1999

[21] H Ide S Fujiya Y Asanuma M Tsuji H Sakai and Y AgishildquoClinical usefulness of intrathecal injection ofmethylcobalaminin patients with diabetic neuropathyrdquo Clinical Therapeutics vol9 no 2 pp 183ndash192 1987

[22] G Li ldquoEffect of mecobalamin on diabetic neuropathies BeijingMethycobal Clinical Trial Collaborative Grouprdquo Zhonghua NeiKe Za Zhi vol 38 no 1 pp 14ndash17 1999

[23] Y U Dongre and O C Swami ldquoSustained-release pregabalinwith methylcobalamin in neuropathic pain an Indian real-lifeexperiencerdquo International Journal of General Medicine vol 6pp 413ndash417 2013

[24] J W Frymoyer ldquoBack pain and sciaticardquoTheNew England Jour-nal of Medicine vol 318 no 5 pp 291ndash300 1988

[25] WWaikakul and SWaikakul ldquoMethylcobalamin as an adjuvantmedication in conservative treatment of lumbar spinal stenosisrdquoJournal of the Medical Association of Thailand vol 83 no 8 pp825ndash831 2000

[26] C K Chiu T H Low Y S Tey V A Singh and H K ShongldquoThe efficacy and safety of intramuscular injections of methyl-cobalamin in patients with chronic nonspecific low back pain arandomised controlled trialrdquo Singapore Medical Journal vol 52no 12 pp 868ndash873 2011

[27] LManchikanti E E Dunbar BWWargo R V Shah R Derbyand S P Cohen ldquoSystematic review of cervical discography as adiagnostic test for chronic spinal painrdquo Pain Physician vol 12no 2 pp 305ndash321 2009

[28] L Manchikanti S Abdi S Atluri et al ldquoAmerican Society ofInterventional Pain Physicians (ASIPP) guidelines for responsi-ble opioid prescribing in chronic non-cancer pain part Imdashevid-ence assessmentrdquo Pain Physician vol 15 no 3 pp S1ndashS65 2012

[29] I Y Hanai M KrsquoYatsume et al ldquoClinical study of methylcobal-amin on cervicalesrdquo Drug Therapy vol 13 no 4 p 29 1980

[30] G Xu ZW Lv Y FengW Z Tang andG X Xu ldquoA single-cen-ter randomized controlled trial of local methylcobalamin injec-tion for subacute herpetic neuralgiardquo Pain Medicine vol 14 no6 pp 884ndash894 2013

[31] P M Singh M Dehran V K Mohan A Trikha and M KaurldquoAnalgesic efficacy and safety of medical therapy alone vs com-bined medical therapy and extraoral glossopharyngeal nerve

6 Neural Plasticity

block in glossopharyngeal neuralgiardquo PainMedicine vol 14 pp93ndash102 2013

[32] J Teramoto ldquoEffects of Methylcobalamin on neuralgiardquo Neuro-logical Therapeutics vol 1 no 2 p 315 1984

[33] A S Morani and S L Bodhankar ldquoNeuroprotecive effect ofearly treatment with pioglitasone and methylcobalamin in al-loxan induced diabetes in ratsrdquo Pharmacologyonline vol 3 pp282ndash293 2007

[34] A S Morani and S L Bodhankar ldquoEarly co-administration ofvitamin E acetate and methylcobalamin improves thermal hy-peralgesia and motor nerve conduction velocity following sci-atic nerve crush injury in ratsrdquo Pharmacological Reports vol 62no 2 pp 405ndash409 2010

[35] I Jurna ldquoAnalgesic and analgesia-potentiating action of B vita-minsrdquo Schmerz vol 12 no 2 pp 136ndash141 1998

[36] Y Sun M S Lai and C J Lu ldquoEffectiveness of vitamin B12 ondiabetic neuropathy systematic review of clinical controlled tri-alsrdquo Acta Neurologica Taiwanica vol 14 no 2 pp 48ndash54 2005

[37] K Okada H Tanaka K Temporin et al ldquoMethylcobalamin in-creases Erk12 and Akt activities through the methylation cycleand promotes nerve regeneration in a rat sciatic nerve injurymodelrdquo Experimental Neurology vol 222 no 2 pp 191ndash2032010

[38] K Yamatsu Y Yamanishi T Kaneko and I Ohkawa ldquoPharma-cological studies on degeneration and regeneration of periph-eral nerves (II) Effects of methylcobalamin on mitosis ofSchwann cells and incorporation of radio active leucine intoprotein fraction of crushed sciatic nerve in ratsrdquo Folia Pharma-cologica Japonica vol 72 no 2 pp 269ndash278 1976 (Japanese)

[39] K Yamazaki K Oda C Endo T Kikuchi and T Wakabay-ashi ldquoMethylcobalamin (methyl-B12) promotes regeneration ofmotor nerve terminals degenerating in anterior gracile muscleof gracile axonal dystrophy (GAD) mutant mouserdquo Neurosci-ence Letters vol 170 no 1 pp 195ndash197 1994

[40] A M Jacobs and D Cheng ldquoManagement of diabetic small-fiber neuropathy with combination L-methylfolate methylco-balamin and pyridoxal 51015840-phosphaterdquo Reviews in NeurologicalDiseases vol 8 no 1-2 pp 39ndash47 2011

[41] W-H Xiao and G J Bennett ldquoSynthetic 120596-conopeptidesapplied to the site of nerve injury suppress neuropathic pains inratsrdquo Journal of Pharmacology and Experimental Therapeuticsvol 274 no 2 pp 666ndash672 1995

[42] YW YoonH S Na and JM Chung ldquoContributions of injuredand intact afferents to neuropathic pain in an experimental ratmodelrdquo Pain vol 64 no 1 pp 27ndash36 1996

[43] Y S Lyu S K Park K Chung and J M Chung ldquoLow dose oftetrodotoxin reduces neuropathic pain behaviors in an animalmodelrdquo Brain Research vol 871 no 1 pp 98ndash103 2000

[44] J Lai M S Gold C S Kim et al ldquoInhibition of neuropathicpain by decreased expression of the tetrodotoxin-resistant sod-ium channel NaV18rdquo Pain vol 95 no 1-2 pp 143ndash152 2002

[45] S R Chaplan H-Q Guo D H Lee et al ldquoNeuronal hyper-polarization-activated pacemaker channels drive neuropathicpainrdquo The Journal of Neuroscience vol 23 no 4 pp 1169ndash11782003

[46] I T Atsuta Y O Sugawara T Muramoto T Watakabe and YTakemitsu ldquoThe study of generating and suppressive factors ofectopic firing in the lumbar dorsal root using an in vitromodelrdquoRinsho Seikei Geka vol 29 pp 441ndash446 1994

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Neural Plasticity


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Research and TreatmentAutism

Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


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Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


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Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

2 Neural Plasticity

Table 1 The analgesic effect of MeCbl or combined use with other drugs on patients with diabetic neuropathic pain


Alleviation of neuropathic pain symptomsimproved nerve conduction velocity

Pain scale scores ofpatients measure of nerveconduction velocity

Oral administration of MeCbl for3 months Devathasan et al [12]

Improved nerve conduction velocity Measure of nerveconduction velocity

Intravenous administration ofMeCbl Ishihara et al [14]

Improved the symptoms of paresthesiaburning pains and heavinessno effect on nerve conduction velocity

Pain symptoms measure ofnerve conduction velocity

Repeated intrathecal injection ofMeCbl at a high dose of25mg10mL

Ide et al [21]

Relieved spontaneous pain by 73

Likert-type pain intensityscale Patientsrsquo GlobalImpression of Change(PGIC) scale

Intramuscular injection ofMeCbl for four weeks followedby oral administration of MeCblfor additional eight weeks

Li [22]

Relieved pain and paresthesiaimproved motor and sensory nerveconduction velocity

Neurolgical disability scorefor the grades of pain andparesthesia

Intravenous injection of MeCblfor 6 weeks Kuwabara et al [13]

Reduced pain scores and good tolerance Visual analog scale andchemical safety

Oral administration ofimmediate-releasemethylcobalamin andsustained-release pregabalin for 2weeks

Dongre and Swami[23]

N

N

ONH2 NH2

NH2

NH2

H H

O

N

H

O N

O

N

H

O

H

O

H

O

H

PO

O

O

OHO

N

NH

H

OH

H

H

Co

CH3

Ominus

H2N

H2N

Figure 1 The chemical structure of MeCbl

21 Diabetic Peripheral Neuropathic Pain Clinical symptomsin legs such as paresthesia burning pains and spontaneouspain were ameliorated byMeCbl [21 22] (Table 1)The effectsof single use ofMeCbl or combined use with other drugs werereviewed in diabetic neuropathy pain [12 23] (Table 1) Clini-cal evidence proved thatMeCbl had the capacity to inhibit theneuropathic pain associated with diabetic neuropathy

The intensity of the pain is variable and may be describedas a hot burning cold aching or itching sensation with attimes increased skin sensitivity In clinics it is still a chal-lenge to treat diabetic neuropathic pain Carbamazepine anddolantin were not able to relieve these symptoms Similarlytherapeutic effects of aldose reductase inhibitors and nimo-dipinewere not encouraging in clinic asmuch as basic studiesshowed Fortunately MeCbl may bring a glimmer of hope totreat diabetic neuropathic pain

22 Low Back Pain Between 70 and 80 adults have experi-enced low back pain at some times in their life [24] Back painis one of the most common health complaints But the causesare extensive cancer infection inflammatory disordersstructural disorders of the spine itself and disk herniation aresomewhat more common and together account for backpain It is supposed that the MeCbl is becoming a decentchoice for the therapy to the chronic low back pain Neuro-genic claudication distance was improved significantly afterthe application of MeCbl [25] (Table 2) However Waikakulrsquosresearch demonstrated that MeCbl was not good for painon lumbar spinal stenosis [25] In a trial the analgesic effectof MeCbl has been investigated in nonspecific low backpain patients with intramuscular injection [26] (Table 2)Theinconsistent effect of MeCbl might be due to different causesof lumbar spinal stenosis and nonspecific low back pain Fur-ther studies are needed to determine the effect of MeCbl onlow back pain

23 Neck Pain Chronic neck pain is becoming a commonproblem in the adult population for the prevalence of 30ndash50 in 12 months [27 28] It was shown that spontaneouspain allodynia and paresthesia of patients with neck painwere improved significantly in theMeCbl group andwith theincrease of treatment time of MeCbl the analgesic effect wasmore obvious [29] (Table 2)

24 Neuralgia

241 Subacute Herpetic Neuralgia The treatment of MeCblsignificantly reduced continuous pain paroxysmal pain andallodynia in the subacute herpetic neuralgia (SHN) patients[30] (Table 3) Thus MeCbl may be an alternative candidatefor treating SHN

Neural Plasticity 3








Reduced pain







Teramoto [32]




Xu et al [30]




Singh et al [31]









4 Neural Plasticity


ControlMeCbl

Paw

with

draw

al th

resh

old

(g)

10

8

6

4

2

0

minus5 0 5 10 15 20 25 30

lowast

lowastlowast

lowastlowastlowast


(a)


ControlMeCbl

Paw

with

draw

al th

resh

old

(g)

10

8

6

4

2

0

minus5 0 5 10 15 20 25 30



(b)



0

20

30

10

700 1400 2100

Time (s)

(A)

(B)

(C)

Freq

uenc

y (H

z)

(a)

(A)

(B)

(C)

20120583V03 s

(b)


4 Conclusions


Neural Plasticity 5

Acknowledgments


References

































6 Neural Plasticity





























Neural Plasticity










Psychiatry Journal









Journal of


Neural Plasticity 3








Reduced pain







Teramoto [32]




Xu et al [30]




Singh et al [31]









4 Neural Plasticity


ControlMeCbl

Paw

with

draw

al th

resh

old

(g)

10

8

6

4

2

0

minus5 0 5 10 15 20 25 30

lowast

lowastlowast

lowastlowastlowast


(a)


ControlMeCbl

Paw

with

draw

al th

resh

old

(g)

10

8

6

4

2

0

minus5 0 5 10 15 20 25 30



(b)



0

20

30

10

700 1400 2100

Time (s)

(A)

(B)

(C)

Freq

uenc

y (H

z)

(a)

(A)

(B)

(C)

20120583V03 s

(b)


4 Conclusions


Neural Plasticity 5

Acknowledgments


References

































6 Neural Plasticity





























Neural Plasticity










Psychiatry Journal









Journal of


4 Neural Plasticity


ControlMeCbl

Paw

with

draw

al th

resh

old

(g)

10

8

6

4

2

0

minus5 0 5 10 15 20 25 30

lowast

lowastlowast

lowastlowastlowast


(a)


ControlMeCbl

Paw

with

draw

al th

resh

old

(g)

10

8

6

4

2

0

minus5 0 5 10 15 20 25 30



(b)



0

20

30

10

700 1400 2100

Time (s)

(A)

(B)

(C)

Freq

uenc

y (H

z)

(a)

(A)

(B)

(C)

20120583V03 s

(b)


4 Conclusions


Neural Plasticity 5

Acknowledgments


References

































6 Neural Plasticity





























Neural Plasticity










Psychiatry Journal









Journal of


Neural Plasticity 5

Acknowledgments


References

































6 Neural Plasticity





























Neural Plasticity










Psychiatry Journal









Journal of


6 Neural Plasticity





























Neural Plasticity










Psychiatry Journal









Journal of














Neural Plasticity










Psychiatry Journal









Journal of


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