Deng Methylene Blue in Discogenic Pain Metaanalysis Neurol Surg A Cent Eur Neurosurg 2021
Deng Methylene Blue in Discogenic Pain Metaanalysis Neurol Surg A Cent Eur Neurosurg 2021
Deng Methylene Blue in Discogenic Pain Metaanalysis Neurol Surg A Cent Eur Neurosurg 2021
1 Department of Orthopedics, Renmin Hospital of Wuhan University, Address for correspondence Ping Xie, MD, Department of Chinese
Wuhan, Hubei Province, P. R. China Traditional Medicine, Tongren Hospital of Wuhan University, No. 241,
2 Department of Orthopedics, Hainan Provincial People’s Hospital, Peng Liu Yang Road, Wuchang District, Wuhan, Hubei Province, P. R.
Haikou, Hainan, P. R. China China (e-mail: 395460475@qq.com).
3 Department of Chinese Traditional Medicine, Tongren Hospital of
Wuhan University, Wuhan, Hubei Province, P. R. China
Several studies have documented the potential of intra- EBSCO, and Cochrane Library databases. The keywords for
diskal injection of methylene blue for discogenic back pain, electronic search strategy were discogenic back pain, and
but there were some conflicting results.17–19 This meta- methylene blue. The inclusive selection criteria were as
analysis aims to investigate intradiskal injection of methy- follows: (1) study design was randomized controlled trial
lene blue for pain control in patients with discogenic back (RCT); (2) patients were diagnosed with discogenic back
pain. pain; (3) intervention treatments were intradiskal injection
of methylene blue versus placebo (or ozone ablation).
Journal of Neurological Surgery—Part A Vol. 82 No. A2/2021 © 2021. Thieme. All rights reserved.
Methylene Blue for Back Pain Deng et al. 163
Quality Assessment in Individual Studies Among the three studies included here, two studies
Modified Jadad scale was used to assess the methodological reported pain scores at 3 months,17,18 three studies reported
quality of the included studies.21,22 There were three items pain scores at 6 months,17–19 two studies reported ODI at 4 to
for Jadad scale: randomization (0–2 points), blinding (0–2 6 weeks and at 3 months,17,19 and three studies reported ODI
points), and dropouts and withdrawals (0–1 points). The at 6 months.17–19 Jadad scores of the three included studies
score of Jadad scale varied from 0 to 5 points. Jadad score 3 varied from 4 to 5, and all three studies had high quality.
indicated high quality, while Jadad score 2 suggested low
quality.23 Primary Outcomes: Pain Scores at 3 and 6 Months
The random-effects model was used, and compared with the
Statistical Analysis control group for discogenic back pain, methylene blue injec-
We estimate the standard mean difference (MD) with 95% tion substantially decreased pain scores at 3 months (MD ¼ –-
confidence interval (CI) for all continuous outcomes. The 0.71; 95% CI ¼ –0.96 to –0.46; p < 0.00001), with no
random-effects model is used regardless of heterogeneity. heterogeneity among the studies (I2 ¼ 0%, heterogeneity
Heterogeneity was reported using the I2 statistic, and p ¼ 0.62; ►Fig. 2), and 6 months (MD ¼ –13.92; 95% CI ¼ –-
I2 > 50% indicated significant heterogeneity.24 We searched 22.31 to –5.54; p ¼ 001) with significant heterogeneity among
for potential sources of heterogeneity via omitting one study the studies (I2 ¼ 100%, heterogeneity p < 0.00001; ►Fig. 3).
in turn when encountering significant heterogeneity. Publi-
cation bias was not evaluated because of the limited number Sensitivity Analysis
(<10) of included studies. All statistical analyses were per- Significant heterogeneity was observed for pain scores at
formed using Review Manager Version 5.3 (the Cochrane 6 months. After excluding the study conducted by Peng,18 no
Collaboration, Software Update, Oxford, UK). heterogeneity remained (I2 ¼ 0%, heterogeneity p ¼ 0.94).
Methylene blue injection still resulted in the decrease in
pain scores at 6 months compared with the control group.
Results
Literature Search, Study Characteristics, and Quality Secondary Outcomes
Assessment Methylene blue injection significantly reduced ODI at 4 to
►Fig. 1 demonstrates the flowchart of the search and selec- 6 weeks (MD ¼ –10.39; 95% CI ¼ –16.95 to –3.83; p ¼ 0.002;
tion result. Four hundred and thirty-three potentially rele- ►Fig. 4) and ODI at 3 months (MD ¼ –3.66; 95% CI ¼ –4.85 to
vant articles were identified initially, and three RCTs were –2.48; p < 0.00001; ►Fig. 5) compared with control interven-
finally included in the meta-analysis.17–19 tion for discogenic back pain, but not ODI at 6 months (MD ¼ –
The baseline characteristics of the three eligible RCTs in the 11.76; 95% CI ¼ –33.33 to 9.80; p ¼ 0.28; ►Fig. 6).
meta-analysis are summarized in ►Table 1. The three studies
were published between 2010 and 2019, and the total sample
Discussion
size was 263. Two RCTs compared methylene blue with place-
bo,17,19 and the remaining RCT compared methylene blue with Methylene blue is a potent reversible inhibitor of mono-
ozone ablation.18 One RCT was published in Chinese. amine oxidase A, and has some association with 5-
Journal of Neurological Surgery—Part A Vol. 82 No. A2/2021 © 2021. Thieme. All rights reserved.
164 Methylene Blue for Back Pain Deng et al.
Fig. 5 Forest plot for the meta-analysis of Oswestry Disability Index (ODI) at 3 months.
Fig. 6 Forest plot for the meta-analysis of Oswestry Disability Index (ODI) at 6 months.
hydroxytryptamine (5-HT or serotonin) levels.25 Serotonin radicular pain, as well as improve functional out-
(5-HT) may produce some analgesic effects and modulation comes.19,30 The follow-up of 2 to 3 months is important
in the central nervous system depending on the site of action to evaluate the safety and efficacy of methylene blue for
and the receptor subtype.26,27 Methylene blue shows the postoperative pain, and 6 months may be sufficient to
neurolytic effect and benefits to various painful conditions assess the pain. Intradiskal methylene blue injection was
and idiopathic pruritus ani.28 In patients with open lumbar found to relief at least 30% of pain in 40% of the patients
diskectomy, the anti-inflammatory method proved to reduce with discogenic low back pain at 6 months.31 However,
the low back pain after the surgery.29 another trial revealed no significant pain relief at 6 months
With the anti-inflammatory effect, methylene blue was after intradiskal methylene blue injection for discogenic
reported to significantly decrease low back pain and low back pain.32
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Methylene Blue for Back Pain Deng et al. 165
This meta-analysis concludes that intradiskal methylene blue 13 Vaccaro A, Patten SA, Ciura S, et al. Methylene blue protects
injection is associated with substantially reduced pain scores at against TDP-43 and FUS neuronal toxicity in C. elegans and D.
3 and 6 months, ODI at 4 to 6 weeks and 3 months compared to rerio. PLoS One 2012;7(07):e42117
14 Volke V, Wegener G, Vasar E, Rosenberg R. Methylene blue inhibits
control intervention in patients with discogenic low back pain,
hippocampal nitric oxide synthase activity in vivo. Brain Res
but there is no statistical difference of ODI at 6 months. There is 1999;826(02):303–305
significant heterogeneity for pain scores at 6 months, and this 15 Aneese AM, Ghaith G, Cannon ME, Manuballa V, Cappell MS. EUS-
heterogeneity may be caused by different combination of drugs, guided methylene blue injection to facilitate endoscopic cannu-
control intervention, and patient populations. lation of an obscured pancreatic duct orifice after ampullectomy.
Am J Gastroenterol 2018;113(05):782–783
Injection of methylene blue into the disk is widely accept-
16 Cohen SP, Williams KA, Kurihara C, et al. Multicenter, randomized,
ed as a safe and effective method for the treatment of
comparative cost-effectiveness study comparing 0, 1, and 2
discogenic low back pain.17,19 Several potential limitations diagnostic medial branch (facet joint nerve) block treatment
may exist in this meta-analysis. First, our analysis is based on paradigms before lumbar facet radiofrequency denervation.
only three RCTs and two of them have a relatively small Anesthesiology 2010;113(02):395–405
sample size (n < 100). There is significant heterogeneity, 17 Kallewaard JW, Wintraecken VM, Geurts JW, et al. A multicenter
randomized controlled trial on the efficacy of intradiscal methy-
which may be caused by different combination of drugs,
lene blue injection for chronic discogenic low back pain: the IMBI
control intervention, and patient populations, all of which study. Pain 2019;160(04):945–953
may have an influence on the pooling results. Finally, some 18 Zhang L. Effect of methylene blue injection on lumbar function
unpublished and missing data may lead to some bias. and pain in patients with discogenic low back pain. J Nat Med
Journal of Neurological Surgery—Part A Vol. 82 No. A2/2021 © 2021. Thieme. All rights reserved.