Table 1.

A summary of the findings of included trials.

Study [Reference]	Study Type	Cause of Pain	Intervention Assessed	Main Outcome	Limitations
Sil et al., 2018 [19]	RCT	Peripheral polyneuropathy	Intramuscular methylcobalamin of two different doses.	There was a significant reduction in pain measured by Leeds assessment of neuropathic signs and symptoms (LANSS) and Douleur Neuropathique 4 (DN4).	No placebo arm. Small population size.
Negrao et al., 2014 [20]	Single armed interventional	Peripheral polyneuropathy	Oral capsule containing uridine monophosphate, B12 and folic acid	There was a significant reduction in PainDETECT questionnaire (PDQ) and a reduction in analgesia use.	Open label study design. No placebo group.
Prabhoo et al., 2012 [21]	Post-marketing surveillance study	Peripheral polyneuropathy	Oral pregabalin plus methylcobalamin	Reduction in visual analogue scale (VAS) for pain and a reduction in concomitant analgesia use.	Observational study design. Short follow-up.
Dongre and Swami. 2013 [22]	Single armed interventional	Peripheral polyneuropathy	Oral pregabalin plus methylcobalamin	Significant reduction in pain measured by VAS and an improvement in sleep disturbance.	No placebo arm. Open label. Short follow-up.
Mimenza Alvarado and Navarro.2016 [23]	Non-randomised controlled study	Diabetic peripheral neuropathy	Oral gabapentin, thiamine and cyanocobalamin versus pregabalin alone.	Both groups showed a statistically significant improvement in pain measured by VAS. Both arms experienced less interrupted sleep. There was no difference between arms.	Did not include patients with severe neuropathy. Open label. Non-randomised. No placebo arm.
Vasudevan et al., 2014 [24]	RCT	Diabetic peripheral neuropathy	Oral pregabalin alone versus oral pregabalin plus alpha lipoic acid and methylcobalamin	There was a statistically significant reduction in pain measured on numerical rating scale (NRS) in both groups but there was not a difference between arms.	Open label. No placebo arm. Small population size.
Talaei et al., 2009 [25]	RCT	Diabetic peripheral neuropathy	Intramuscular B12 versus oral nortriptyline	Both groups showed significant reductions in pain measured by VAS. B12 was superior to nortriptyline.	Poor Jadad score. Open label. No placebo arm.
Maladkar et al., 2009 [26]	RCT	Diabetic peripheral neuropathy	Oral methylcobalamin versus epalrestat	There was a significant reduction in prevalence of pain in both groups. Epalrestat outperformed methylcobalamin.	No placebo. No validated quantifier of pain is used, only pain prevalence.
Trippe et al., 2016 [27]	Single armed interventional	Diabetic peripheral neuropathy	Oral L-methylfolate, methylcobalamin and pyridoxal-5-phosphate	There was a significant reduction in pain captured by VAS and NTSS6. There was an improved quality of life with a focus on pain.	No placebo group. Open label. Adverse events were not reported.
Kuwabara et al., 1999 [14]	Single armed interventional	Uraemic diabetic peripheral neuropathy	Intravenous B12	Neuropathic pain grading score was not improved to a significant degree.	Small study size. No placebo arm. Open label.
Han et al., 2017 [28]	RCT	Chemotherapy induced peripheral neuropathy	Acupuncture plus intramuscular methylcobalamin initially then oral methylcobalamin versus methylcobalamin intramuscularly then orally alone.	Both treatment groups showed a significant reduction in pain measured by VAS. Although improvement was greater in the acupuncture group, it was not significant.	Open label. No placebo arm. Poor Jadad score.
Schloss et al., 2017 [29]	RCT	Chemotherapy induced peripheral neuropathy	Placebo versus oral capsule of thiamine, riboflavin, niacin, pantothenic acid, pyridoxine, folate (B9), cyanocobalamin, biotin, choline and inositol	The vitamin capsule did not decrease the incidence of pain compared with placebo.	This study was underpowered. Small study size.
Woelk et al., 1998 [30]	RCT	Alcohol-related polyneuropathy	Three treatment groups of capsules containing (A) B1, (B) B1, B6 and B12, (C) placebo	There was a significant improvement in pain assessed using McGill pain questionnaire in all three groups, with no differences between arms.	This is a high-quality study with few limitations. It does not assess B12 monotherapy.
Peters et al., 2006 [31]	RCT	Alcohol-related polyneuropathy	Three treatment arms: (A) B1, B2, B6, B12; (B) Regimen A plus folate; (C) Placebo	Groups A and B showed a greater reduction in pain measured by McGill pain questionnaire than with placebo. There is no additional benefit with addition of folate.	This is a high-quality study with few limitations. It does not assess B12 monotherapy.
Goldberg et al., 2017 [32]	RCT	Degenerative orthopaedic alteration with neural compression	Oral cytidine monophosphate disodium uridine triphosphate trisodium and hydroxocobalamin versus oral hydroxocobalamin alone.	Both arms had a statistically significant reduction in pain measured by VAS, but the improvement was greater in the arm inclusive of nucleosides.	Short follow-up. No placebo arm.
Negrao et al., 2016 [33]	Single armed interventional	Peripheral entrapment neuropathy	Oral uridine monophosphate, folic acid and vitamin B12	There was a significant reduction in pain assessed by PDQ score and a reduction in concomitant use of analgesics.	No placebo arm. Open label. Did not include severe neuropathies. A very small dose of B12 is used. Small study size.
Huang et al., 2019 [12]	Single armed interventional	Piriformis syndrome	Intravenous mannitol plus oral B1, B2 and B12	There was a significant reduction in pain evaluated by NRS and LRS.	Small study size. No placebo arm. Open label.
Singh et al., 2013 [34]	RCT	Glossopharyngeal neuropathy	Standard medical therapy (combination of oral methylcobalamin, tramadol and gabapentin) versus standard medical therapy plus extraoral glossopharyngeal nerve block	Pain measured by numerical pain scale and brief pain inventory significantly reduced in both groups. There were no significant differences between groups at the end of follow-up.	Poor Jadad score. No placebo group. Open label.
Xu et al., 2013 [13]	Post-herpetic neuralgia	RCT	Subcutaneous methylcobalamin versus subcutaneous lidocaine versus oral methylcobalamin	Pain intensity measured on NRS was improved in both methylcobalamin arms, but significantly more so in the subcutaneous methylcobalamin arm. The impact of pain upon quality of life was reduced in the subcutaneous methylcobalamin group but not in the other arms.	Small study size. No placebo arm. Short follow-up.
Xu et al., 2014 [35]	Post-herpetic neuralgia	RCT	Subcutaneous thiamine versus subcutaneous cobalamin versus a combination of the two and finally a group receiving subcutaneous lidocaine.	Pain measured by zoster brief pain inventory was significantly reduced only in the arms containing cobalamin.	Small study size. Short follow-up. No placebo group.
Xu et al., 2014 [36]	Post-herpetic neuralgia	RCT	Transcutaneous electrical nerve stimulation and cobalamin injection versus transcutaneous electrical nerve stimulation plus lidocaine injection.	No significant differences were identified between the two groups. Both groups showed a significantly improved quality of life and reduced pain measured by zoster brief pain inventory.	Small study size. No placebo arm.
Xu et al., 2016 [37]	Acute ophthalmic herpetic neuralgia	RCT	Lidocaine and methylcobalamin subcutaneously locally versus intramuscularly	Whilst the intramuscular group showed a statistically significant reduction in pain measured by NRS, this was short-lived and tapered off after 14 days. The subcutaneous locally delivered treatment showed a decrease in pain severity a year later.	No placebo arm. Small study size.
Xu et al., 2015 [38]	Truncal post-herpetic neuralgia	RCT	Lidocaine and methylcobalamin subcutaneously locally versus intramuscularly	There was a more significant reduction in pain measured by NRS and improvement in quality of life in those receiving local subcutaneous injection over the intramuscular group.	No placebo arm.