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Volume 2013 (2013), Article ID 424651, 6 pages
Methylcobalamin: A Potential Vitamin of Pain Killer
Institute of Neurosciences, The Fourth Military Medical University, Xi’an 710032, China
Received 19 September 2013; Revised 6 November 2013; Accepted 12 November 2013
Academic Editor: Sheng Tian Li
Copyright © 2013 Ming Zhang et al. This is an open access article distributed under the Creative Commons Attribution License, which 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 diseases in clinic, such as Alzheimer’s disease and rheumatoid arthritis. As an auxiliary agent, it exerts neuronal protection by promoting regeneration of injured nerves and antagonizing glutamate-induced neurotoxicity. Recently several lines of evidence demonstrated that MeCbl may have potential analgesic effects in experimental and clinical studies. For example, MeCbl alleviated pain behaviors in diabetic neuropathy, low back pain and neuralgia. MeCbl improved nerve conduction, promoted the regeneration of injured nerves, and inhibited ectopic spontaneous discharges of injured primary sensory neurons. This review aims to summarize the analgesic effect and mechanisms of MeCbl at the present.
Vitamin B12 had been usually treated as sport nutrition, and used to keep old people from getting anemic in past years. Vitamin B12 was regarded as painkilling vitamin in some countries from 1950. Recently studies have shown that vitamin B12 played a key role in the normal functioning of the brain and nervous system and the formation of blood. Vitamin B12 is normally involved in several metabolisms such as DNA synthesis and regulation, fatty acid synthesis, and energy production. Vitamin B12 has some analogs including cyanocobalamin (CNCbl), methylcobalamin (MeCbl), hydroxocobalamin (OHCbl), and adenosylcobalamin (AdoCbl). In mammalian cells, CNCbl and OHCbl are inactive forms and AdoCbl acts as a coenzyme of methylmalonyl Co-A mutase in mitochondria. However, vitamin B12 was not used directly in human body, and it should be translated into activating forms such as MeCbl or AdoCbl. MeCbl differs from vitamin B12 in that the cyanide is replaced by a methyl group (Figure 1) . It is a coenzyme of methionine synthase, which is required for the formation of methionine from homocysteine in the methylation cycle which involves methylation of DNA or proteins [2–5]. Compared with other analogs, MeCbl is the most effective one in being uptaken by subcellular organelles of neurons. Therefore, MeCbl may provide better treatments for nervous disorders through effective systemic or local delivery.
As an auxiliary agent, MeCbl has been always used to treat many diseases, such as B12 deficiency and Alzheimer’s disease syndromes [6, 7]. L-methylfolate, MeCbl, and N-acetylcysteine improved memory, emotional functions, and communication with other people among Alzheimer’s patients [7, 8]. MeCbl also has neuronal protection including promoting injured nerve and axonal regeneration [9, 10] and confronting against glutamate-induced neurotoxicity [9, 11]. In addition, MeCbl improved nerve conduction in either patients of diabetic neuropathy [12–14] or streptozotocin-diabetic rats  and experimental acrylamide neuropathy . MeCbl also improved visual function , rheumatoid arthritis , Bell’s palsy, and sleep-wake rhythm disorder [19, 20]. Recently, MeCbl has been demonstrated to have potential analgesic effects on neuropathic pain in experimental and clinical studies.
2. The Analgesic Effect of MeCbl
MeCbl is one active form of vitamin B12 which can directly participate in homocysteine metabolism. More and more researches showed that MeCbl has beneficial effects on clinical and experimental peripheral neuropathy.
2.1. Diabetic Peripheral Neuropathic Pain
Clinical symptoms in legs, such as paresthesia, burning pains, and spontaneous pain, were ameliorated by MeCbl [21, 22] (Table 1). The effects of single use of MeCbl or combined use with other drugs were reviewed in diabetic neuropathy pain [12, 23] (Table 1). Clinical evidence proved that MeCbl had the capacity to inhibit the neuropathic pain associated with diabetic neuropathy.
The intensity of the pain is variable and may be described as a hot, burning, cold, aching, or itching sensation with, at times, increased skin sensitivity. In clinics, it is still a challenge to treat diabetic neuropathic pain. Carbamazepine and dolantin were not able to relieve these symptoms. Similarly, therapeutic effects of aldose reductase inhibitors and nimodipine were not encouraging in clinic as much as basic studies showed. Fortunately, MeCbl may bring a glimmer of hope to treat diabetic neuropathic pain.
2.2. Low Back Pain
Between 70 and 80% adults have experienced low back pain at some times in their life . Back pain is one of the most common health complaints. But the causes are extensive, cancer, infection, inflammatory disorders, structural disorders of the spine itself, and disk herniation, are somewhat more common, and together account for back pain. It is supposed that the MeCbl is becoming a decent choice for the therapy to the chronic low back pain. Neurogenic claudication distance was improved significantly after the application of MeCbl  (Table 2). However Waikakul’s research demonstrated that MeCbl was not good for pain on lumbar spinal stenosis . In a trial, the analgesic effect of MeCbl has been investigated in nonspecific low back pain patients with intramuscular injection  (Table 2). The inconsistent effect of MeCbl might be due to different causes of lumbar spinal stenosis and nonspecific low back pain. Further studies are needed to determine the effect of MeCbl on low back pain.
2.3. Neck Pain
Chronic neck pain is becoming a common problem in the adult population, for the prevalence of 30%–50% in 12 months [27, 28]. It was shown that spontaneous pain, allodynia, and paresthesia of patients with neck pain were improved significantly in the MeCbl group, and with the increase of treatment time of MeCbl, the analgesic effect was more obvious  (Table 2).
2.4.1. Subacute Herpetic Neuralgia
The treatment of MeCbl significantly reduced continuous pain, paroxysmal pain, and allodynia in the subacute herpetic neuralgia (SHN) patients  (Table 3). Thus, MeCbl may be an alternative candidate for treating SHN.
2.4.2. Glossopharyngeal Neuralgia
Glossopharyngeal neuralgia (GPN) is a common facial neuralgia in the pain clinics. It was reported that the numerical pain scales were decreased substantially with the treatment of MeCbl combined with gabapentin and tramadol in GPN patients  (Table 3). And degree of interference in quality of life including mood, interpersonal relationship, and emotion was improved earlier .
2.4.3. Trigeminal Neuralgia
The pain of trigeminal neuralgia (TN) can be described as agonizing, paroxysmal and lancinating which may be activated by small activities such as chewing, speaking, and swallowing. A clinical trial proved that the pain of TN patients was alleviated greatly in the MeCbl group, and no recurrence of TN in pain symptoms was closed to 64%  (Table 3).
2.5. Neuropathic Pain of Animal Models
The coapplication of MeCbl and pioglitazone dramatically decreased allodynia and hyperalgesia in diabetic rats . And the combined application of MeCbl and vitamin E alleviated thermal hyperalgesia in sciatic nerve crush injured rats . Our recent work observed that tactile allodynia was markedly alleviated following a chronic treatment of MeCbl injection in chronic compression of dorsal root ganglion (CCD) rats (Figure 2).
3. Mechanisms Underlying the Analgesic of MeCbl
For many years, the B12 group of vitamins had been used to treat pain. In some countries, vitamin B12 was categorised as an analgesic drug. It was suggested that vitamin B12 may increase availability and effectiveness of noradrenaline and 5-hydroxytryptamine in the descending inhibitory nociceptive system . MeCbl exerted therapeutic effects on neuropathic pain in diabetics, possibly through its neurosynthesis and neuroprotective actions [13, 36]. But the analgesic mechanisms of MeCbl remained elusive till now.
3.1. Improving Nerve Conduction Velocity
Previous studies showed that high doses of MeCbl improved nerve conduction in either patients with diabetic neuropathy [12–14], streptozotocin-diabetic rats , or experimental acrylamide neuropathy . Morphological and histological evidence confirmed that a long-term administration of MeCbl promoted the synthesis and regeneration of myelin . These morphological and histological recoveries of myelin may result in improving nerve conduction velocity and neuronal function in peripheral neuropathy.
3.2. Promoting the Regeneration of Injured Nerves
MeCbl advanced the incorporation of radioactive leucine into the protein fraction of the crushed sciatic nerve in vivo. As a result, the activity abilities of injured nerve were recovered . In this study, the most terminals were degenerated in the mutant mouse, but the sprouts were more frequently observed in the MeCbl treatment group . MeCbl had the ability to promote the injured nerves regeneration. In the experimental acrylamide neuropathy and sciatic nerve injury models, the number of regenerations of motor fibers showed significant increase with high-dose methylcobalamin . And the combined use of L-methylfolate, MeCbl, and pyridoxal 5′-phosphate improved the calf muscle surface neural density .
3.3. Inhibiting Ectopic Spontaneous Discharge
Ectopic spontaneous discharges are likely to initiate spontaneous pain, hyperalgesia, and allodynia [41–45]. It was reported that MeCbl suppressed the ectopic firing induced by chemical materials in the dog dorsal root . Our recent work demonstrated that MeCbl markedly inhibited the ectopic spontaneous discharges of dorsal root ganglion neurons in CCD rats (Figure 3). Our results suggested that MeCbl exhibited its anti-allodynic effect by inhibiting peripheral pain signals.
MeCbl or its combined use with other agents has the potential analgesic effect in specific patients and animal models, for example, nonspecific low back pain; neck pain; diabetic neuropathic pain, subacute herpetic neuralgia, glossopharyngeal neuralgia, and trigeminal neuralgia. However, its mechanisms underlying the analgesic effect were poorly understood. On the basis of recent work, the possible mechanisms can be considered as follows. (1) MeCbl improved nerve conduction velocity; (2) MeCbl promoted injured nerve regeneration, recovering the neuromuscular functions in peripheral hyperalgesia and allodynia; and (3) MeCbl inhibited the ectopic spontaneous discharges from peripheral primary sensory neurons in neuropathic pain states. As a vitamin, MeCbl may be a potential candidate for treating peripheral neuropathy with good safety.
This work was supported by Grants from the National Natural Science Foundation of China (nos. 30870830 and 31371120 to Dr. Hui Xu) and the Ministry of Education Foundation for returned overseas students (HG3503 to Dr. Hui Xu).
- L. R. McDowell, Vitamins in Animal and Human Nutrition, John Wiley & Sons, 2008.
- R. Banerjee and S. W. Ragsdale, “The many faces of vitamin B12: catalysis by cobalamin-dependent enzymes,” Annual Review of Biochemistry, vol. 72, pp. 209–247, 2003.
- S. K. Ghosh, N. Rawal, S. K. Syed, W. K. Paik, and S. D. Kim, “Enzymic methylation of myelin basic protein in myelin,” Biochemical Journal, vol. 275, part 2, pp. 381–387, 1991.
- A. Pfohl-Leszkowicz, G. Keith, and G. Dirheimer, “Effect of cobalamin derivatives on in vitro enzymatic DNA methylation: methylcobalamin can act as a methyl donor,” Biochemistry, vol. 30, no. 32, pp. 8045–8051, 1991.
- J. I. Toohey, “Vitamin B12 and methionine synthesis: a critical review. Is nature's most beautiful cofactor misunderstood?” BioFactors, vol. 26, no. 1, pp. 45–57, 2006.
- Y. Takahashi, S. Usui, and Y. Honda, “Effect of vitamin B12 (mecobalamin) on the circadian rhythm of rat behavior,” Clinical Neuropharmacology, vol. 15, supplement 1, part A, pp. 46A–47A, 1992.
- A. McCaddon and P. R. Hudson, “L-methylfolate, methylcobalamin, and N-acetylcysteine in the treatment of Alzheimer's disease-related cognitive decline,” CNS Spectrums, vol. 15, supplement 1, no. 1, pp. 2–6, 2010.
- T. Ikeda, K. Yamamoto, K. Takahashi et al., “Treatment of Alzheimer-type dementia with intravenous mecobalamin,” Clinical Therapeutics, vol. 14, no. 3, pp. 426–437, 1992.
- M. Kikuchi, S. Kashii, Y. Honda, Y. Tamura, K. Kaneda, and A. Akaike, “Protective effects of methylcobalamin, a vitamin B12 analog, against glutamate-induced neurotoxicity in retinal cell culture,” Investigative Ophthalmology and Visual Science, vol. 38, no. 5, pp. 848–854, 1997.
- X. Kong, X. Sun, and J. Zhang, “The protective role of Mecobalamin following optic nerve crush in adult rats,” Yan Ke Xue Bao, vol. 20, no. 3, pp. 171–177, 2004.
- A. Akaike, Y. Tamura, Y. Sato, and T. Yokota, “Protective effects of a vitamin B12 analog, methylcobalamin, against glutamate cytotoxicity in cultured cortical neurons,” European Journal of Pharmacology, vol. 241, no. 1, pp. 1–6, 1993.
- G. Devathasan, W. L. Teo, and A. Mylvaganam, “Methylcobalamin in chronic diabetic neuropathy. A double-blind clinical and electrophysiological study,” Clinical Trials Journal, vol. 23, no. 2, pp. 130–140, 1986.
- S. Kuwabara, R. Nakazawa, N. Azuma et al., “Intravenous methylcobalamin treatment for uremic and diabetic neuropathy in chronic hemodialysis patients,” Internal Medicine, vol. 38, no. 6, pp. 472–475, 1999.
- H. Ishihara, M. Yoneda, W. Yamamoto, et al., “Efficacy of intravenous administration of methycobalamin for diabetic peripheral neuropathy,” Med Consult N Remedies, vol. 29, no. 1, pp. 1720–1725, 1992.
- M. Sonobe, H. Yasuda, I. Hatanaka et al., “Methylcobalamin improves nerve conduction in streptozotocin-diabetic rats without affecting sorbitol and myo-inositol contents of sciatic nerve,” Hormone and Metabolic Research, vol. 20, no. 11, pp. 717–718, 1988.
- T. Watanabe, R. Kaji, N. Oka, W. Bara, and J. Kimura, “Ultra-high dose methylcobalamin promotes nerve regeneration in experimental acrylamide neuropathy,” Journal of the Neurological Sciences, vol. 122, no. 2, pp. 140–143, 1994.
- T. Iwasaki and S. Kurimoto, “Effect of methylcobalamin in accommodative dysfunction of eye by visual load,” Journal of UOEH, vol. 9, no. 2, pp. 127–132, 1987.
- M. Yamashiki, A. Nishimura, and Y. Kosaka, “Effects of methylcobalamin (vitamin B12) on in vitro cytokine production of peripheral blood mononuclear cells,” Journal of Clinical and Laboratory Immunology, vol. 37, no. 4, pp. 173–182, 1992.
- M. Ikeda, M. Asai, T. Moriya, M. Sagara, S. Inoué, and S. Shibata, “Methylcobalamin amplifies melatonin-induced circadian phase shifts by facilitation of melatonin synthesis in the rat pineal gland,” Brain Research, vol. 795, no. 1-2, pp. 98–104, 1998.
- K. Takahashi, M. Okawa, M. Matsumoto et al., “Double-blind test on the efficacy of methylcobalamin on sleep-wake rhythm disorders,” Psychiatry and Clinical Neurosciences, vol. 53, no. 2, pp. 211–213, 1999.
- H. Ide, S. Fujiya, Y. Asanuma, M. Tsuji, H. Sakai, and Y. Agishi, “Clinical usefulness of intrathecal injection of methylcobalamin in patients with diabetic neuropathy,” Clinical Therapeutics, vol. 9, no. 2, pp. 183–192, 1987.
- G. Li, “Effect of mecobalamin on diabetic neuropathies. Beijing Methycobal Clinical Trial Collaborative Group,” Zhonghua Nei Ke Za Zhi, vol. 38, no. 1, pp. 14–17, 1999.
- Y. U. Dongre and O. C. Swami, “Sustained-release pregabalin with methylcobalamin in neuropathic pain: an Indian real-life experience,” International Journal of General Medicine, vol. 6, pp. 413–417, 2013.
- J. W. Frymoyer, “Back pain and sciatica,” The New England Journal of Medicine, vol. 318, no. 5, pp. 291–300, 1988.
- W. Waikakul and S. Waikakul, “Methylcobalamin as an adjuvant medication in conservative treatment of lumbar spinal stenosis,” Journal of the Medical Association of Thailand, vol. 83, no. 8, pp. 825–831, 2000.
- C. K. Chiu, T. H. Low, Y. S. Tey, V. A. Singh, and H. K. Shong, “The efficacy and safety of intramuscular injections of methylcobalamin in patients with chronic nonspecific low back pain: a randomised controlled trial,” Singapore Medical Journal, vol. 52, no. 12, pp. 868–873, 2011.
- L. Manchikanti, E. E. Dunbar, B. W. Wargo, R. V. Shah, R. Derby, and S. P. Cohen, “Systematic review of cervical discography as a diagnostic test for chronic spinal pain,” Pain Physician, vol. 12, no. 2, pp. 305–321, 2009.
- L. Manchikanti, S. Abdi, S. Atluri, et al., “American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: part I—evidence assessment,” Pain Physician, vol. 15, no. 3, pp. S1–S65, 2012.
- I. Y. Hanai, M. K'Yatsume, et al., “Clinical study of methylcobalamin on cervicales,” Drug Therapy, vol. 13, no. 4, p. 29, 1980.
- G. Xu, Z. W. Lv, Y. Feng, W. Z. Tang, and G. X. Xu, “A single-center randomized controlled trial of local methylcobalamin injection for subacute herpetic neuralgia,” Pain Medicine, vol. 14, no. 6, pp. 884–894, 2013.
- P. M. Singh, M. Dehran, V. K. Mohan, A. Trikha, and M. Kaur, “Analgesic efficacy and safety of medical therapy alone vs combined medical therapy and extraoral glossopharyngeal nerve block in glossopharyngeal neuralgia,” Pain Medicine, vol. 14, pp. 93–102, 2013.
- J. Teramoto, “Effects of Methylcobalamin on neuralgia,” Neurological Therapeutics, vol. 1, no. 2, p. 315, 1984.
- A. S. Morani and S. L. Bodhankar, “Neuroprotecive effect of early treatment with pioglitasone and methylcobalamin in alloxan induced diabetes in rats,” Pharmacologyonline, vol. 3, pp. 282–293, 2007.
- A. S. Morani and S. L. Bodhankar, “Early co-administration of vitamin E acetate and methylcobalamin improves thermal hyperalgesia and motor nerve conduction velocity following sciatic nerve crush injury in rats,” Pharmacological Reports, vol. 62, no. 2, pp. 405–409, 2010.
- I. Jurna, “Analgesic and analgesia-potentiating action of B vitamins,” Schmerz, vol. 12, no. 2, pp. 136–141, 1998.
- Y. Sun, M. S. Lai, and C. J. Lu, “Effectiveness of vitamin B12 on diabetic neuropathy: systematic review of clinical controlled trials,” Acta Neurologica Taiwanica, vol. 14, no. 2, pp. 48–54, 2005.
- K. Okada, H. Tanaka, K. Temporin et al., “Methylcobalamin increases Erk1/2 and Akt activities through the methylation cycle and promotes nerve regeneration in a rat sciatic nerve injury model,” Experimental Neurology, vol. 222, no. 2, pp. 191–203, 2010.
- K. Yamatsu, Y. Yamanishi, T. Kaneko, and I. Ohkawa, “Pharmacological studies on degeneration and regeneration of peripheral nerves. (II). Effects of methylcobalamin on mitosis of Schwann cells and incorporation of radio active leucine into protein fraction of crushed sciatic nerve in rats,” Folia Pharmacologica Japonica, vol. 72, no. 2, pp. 269–278, 1976 (Japanese).
- K. Yamazaki, K. Oda, C. Endo, T. Kikuchi, and T. Wakabayashi, “Methylcobalamin (methyl-B12) promotes regeneration of motor nerve terminals degenerating in anterior gracile muscle of gracile axonal dystrophy (GAD) mutant mouse,” Neuroscience Letters, vol. 170, no. 1, pp. 195–197, 1994.
- A. M. Jacobs and D. Cheng, “Management of diabetic small-fiber neuropathy with combination L-methylfolate, methylcobalamin, and pyridoxal 5′-phosphate,” Reviews in Neurological Diseases, vol. 8, no. 1-2, pp. 39–47, 2011.
- W.-H. Xiao and G. J. Bennett, “Synthetic ω-conopeptides applied to the site of nerve injury suppress neuropathic pains in rats,” Journal of Pharmacology and Experimental Therapeutics, vol. 274, no. 2, pp. 666–672, 1995.
- Y. W. Yoon, H. S. Na, and J. M. Chung, “Contributions of injured and intact afferents to neuropathic pain in an experimental rat model,” Pain, vol. 64, no. 1, pp. 27–36, 1996.
- Y. S. Lyu, S. K. Park, K. Chung, and J. M. Chung, “Low dose of tetrodotoxin reduces neuropathic pain behaviors in an animal model,” Brain Research, vol. 871, no. 1, pp. 98–103, 2000.
- J. Lai, M. S. Gold, C. S. Kim et al., “Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8,” Pain, vol. 95, no. 1-2, pp. 143–152, 2002.
- S. R. Chaplan, H.-Q. Guo, D. H. Lee et al., “Neuronal hyperpolarization-activated pacemaker channels drive neuropathic pain,” The Journal of Neuroscience, vol. 23, no. 4, pp. 1169–1178, 2003.
- I. T. Atsuta Y, O. Sugawara, T. Muramoto, T. Watakabe, and Y. Takemitsu, “The study of generating and suppressive factors of ectopic firing in the lumbar dorsal root using an in vitro model,” Rinsho Seikei Geka, vol. 29, pp. 441–446, 1994.