Keywords
methylene blue - intradiskal injection - discogenic back pain - randomized controlled trials - meta-analysis
Introduction
Discogenic back pain is one of the most common types of low back pain, accounting for 28 to 43% of the patients with low back pain.[1]
[2]
[3] Discogenic back pain is mainly caused by internal disk disruption and vascularized granulation tissue containing nociceptive nerves.[4]
[5]
[6] Reduction of inflammation and/or ablation of the nociceptive nerves in the outer annulus are beneficial to alleviate discogenic back pain.[7]
[8] Current treatment methods include anti-inflammation strategy and invasive procedures.[9]
Methylene blue is a low–molecular weight, partially liposoluble vital dye.[10]
[11] It is widely used for destruction of free nociceptive nerve endings for the relief of pain, inhibition of nitric oxide synthesis, and neuroprotective effect.[10]
[12]
[13]
[14]
[15] Its promotion to pain control is derived from inhibition of free radical generation, deactivation of xanthine oxidase, and inhibition of the production of nitric oxide.[16]
Several studies have documented the potential of intradiskal injection of methylene blue for discogenic back pain, but there were some conflicting results.[17]
[18]
[19] This meta-analysis aims to investigate intradiskal injection of methylene blue for pain control in patients with discogenic back pain.
Materials and Methods
This was a systematic review and meta-analysis of previously published studies, and no ethical approval and patient consent were required. This meta-analysis was performed based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).[20]
Search Strategy and Study Selection
Two investigators searched the following databases (inception to November 2019): PubMed, EMbase, Web of Science, EBSCO, and Cochrane Library databases. The keywords for electronic search strategy were discogenic back pain, and methylene blue. The inclusive selection criteria were as follows: (1) study design was randomized controlled trial (RCT); (2) patients were diagnosed with discogenic back pain; (3) intervention treatments were intradiskal injection of methylene blue versus placebo (or ozone ablation).
Data Extraction and Outcome Measures
We have extracted the following information: author, number of patients, age, male, pain duration, and detail methods in each group, etc. Data have been extracted independently by two investigators, and discrepancies are resolved by consensus. We also contacted the corresponding author to obtain the data when necessary.
The primary outcomes are pain scores at 3 and 6 months. Secondary outcomes include Oswestry Disability Index (ODI) at 4 to 6 weeks, 3 months, and 6 months.
Quality Assessment in Individual Studies
Modified Jadad scale was used to assess the methodological quality of the included studies.[21]
[22] There were three items for Jadad scale: randomization (0–2 points), blinding (0–2 points), and dropouts and withdrawals (0–1 points). The score of Jadad scale varied from 0 to 5 points. Jadad score ≥3 indicated high quality, while Jadad score ≤2 suggested low quality.[23]
Statistical Analysis
We estimate the standard mean difference (MD) with 95% confidence interval (CI) for all continuous outcomes. The random-effects model is used regardless of heterogeneity. Heterogeneity was reported using the I
2 statistic, and I
2 > 50% indicated significant heterogeneity.[24] We searched for potential sources of heterogeneity via omitting one study in turn when encountering significant heterogeneity. Publication bias was not evaluated because of the limited number (<10) of included studies. All statistical analyses were performed using Review Manager Version 5.3 (the Cochrane Collaboration, Software Update, Oxford, UK).
Results
Literature Search, Study Characteristics, and Quality Assessment
[Fig. 1] demonstrates the flowchart of the search and selection result. Four hundred and thirty-three potentially relevant articles were identified initially, and three RCTs were finally included in the meta-analysis.[17]
[18]
[19]
Fig. 1 Flow diagram of study searching and selection process.
The baseline characteristics of the three eligible RCTs in the meta-analysis are summarized in [Table 1]. The three studies were published between 2010 and 2019, and the total sample size was 263. Two RCTs compared methylene blue with placebo,[17]
[19] and the remaining RCT compared methylene blue with ozone ablation.[18] One RCT was published in Chinese.
Table 1
Characteristics of included studies
|
No.
|
Author
|
Methylene blue group
|
Control group
|
Jada scores
|
|
No.
|
Age (y)
|
Male (n)
|
Pain duration (y)
|
Methods
|
No.
|
Age (y)
|
Male (n)
|
Pain duration (y)
|
Methods
|
|
|
1
|
Kallewaard et al 2019
|
40
|
41.2 (9.6)
|
11
|
10.2 (8.8)
|
a mixture of 1-mL methylene blue (10 mg/mL), 0.5-mL lidocaine hydrochloride 2%, and 0.5-mL contrast dye was injected into the disk
|
41
|
42.6 (10.2)
|
12
|
8.5 (7.1)
|
placebo
|
5
|
|
2
|
Zhang 2018
|
55
|
38.45(4.96)
|
34
|
3.91(1.45)
|
1 ml of methylene blue solution at a concentration of 1% for disk injection
|
55
|
38.52(4.93)
|
33
|
3.95(1.46)
|
ozone ablation
|
4
|
|
3
|
Peng et al 2010
|
36
|
42.06(13.74)
|
21
|
3.5 (1.6)
|
1 ml of 1% methylene blue (10 mg) was injected into the discogram-proven diseased disk
|
36
|
41.28(12.84)
|
20
|
3.2(1.7)
|
placebo
|
4
|
Among the three studies included here, two studies reported pain scores at 3 months,[17]
[18] three studies reported pain scores at 6 months,[17]
[18]
[19] two studies reported ODI at 4 to 6 weeks and at 3 months,[17]
[19] and three studies reported ODI at 6 months.[17]
[18]
[19] Jadad scores of the three included studies varied from 4 to 5, and all three studies had high quality.
Primary Outcomes: Pain Scores at 3 and 6 Months
The random-effects model was used, and compared with the control group for discogenic back pain, methylene blue injection substantially decreased pain scores at 3 months (MD = –0.71; 95% CI = –0.96 to –0.46; p < 0.00001), with no heterogeneity among the studies (I
2 = 0%, heterogeneity p = 0.62; [Fig. 2]), and 6 months (MD = –13.92; 95% CI = –22.31 to –5.54; p = 001) with significant heterogeneity among the studies (I
2 = 100%, heterogeneity p < 0.00001; [Fig. 3]).
Fig. 2 Forest plot for the meta-analysis of pain scores at 3 months.
Fig. 3 Forest plot for the meta-analysis of pain scores at 6 months.
Sensitivity Analysis
Significant heterogeneity was observed for pain scores at 6 months. After excluding the study conducted by Peng,[18] no heterogeneity remained (I
2 = 0%, heterogeneity p = 0.94). Methylene blue injection still resulted in the decrease in pain scores at 6 months compared with the control group.
Secondary Outcomes
Methylene blue injection significantly reduced ODI at 4 to 6 weeks (MD = –10.39; 95% CI = –16.95 to –3.83; p = 0.002; [Fig. 4]) and ODI at 3 months (MD = –3.66; 95% CI = –4.85 to –2.48; p < 0.00001; [Fig. 5]) compared with control intervention for discogenic back pain, but not ODI at 6 months (MD = –11.76; 95% CI = –33.33 to 9.80; p = 0.28; [Fig. 6]).
Fig. 4 Forest plot for the meta-analysis of Oswestry Disability Index (ODI) at 4 to 6 weeks.
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.
Discussion
Methylene blue is a potent reversible inhibitor of monoamine oxidase A, and has some association with 5-hydroxytryptamine (5-HT or serotonin) levels.[25] Serotonin (5-HT) may produce some analgesic effects and modulation in the central nervous system depending on the site of action and the receptor subtype.[26]
[27] Methylene blue shows the neurolytic effect and benefits to various painful conditions and idiopathic pruritus ani.[28] In patients with open lumbar diskectomy, the anti-inflammatory method proved to reduce the low back pain after the surgery.[29]
With the anti-inflammatory effect, methylene blue was reported to significantly decrease low back pain and radicular pain, as well as improve functional outcomes.[19]
[30] The follow-up of 2 to 3 months is important to evaluate the safety and efficacy of methylene blue for postoperative pain, and 6 months may be sufficient to assess the pain. Intradiskal methylene blue injection was found to relief at least 30% of pain in 40% of the patients with discogenic low back pain at 6 months.[31] However, another trial revealed no significant pain relief at 6 months after intradiskal methylene blue injection for discogenic low back pain.[32]
This meta-analysis concludes that intradiskal methylene blue injection is associated with substantially reduced pain scores at 3 and 6 months, ODI at 4 to 6 weeks and 3 months compared to control intervention in patients with discogenic low back pain, but there is no statistical difference of ODI at 6 months. There is significant heterogeneity for pain scores at 6 months, and this heterogeneity may be caused by different combination of drugs, control intervention, and patient populations.
Injection of methylene blue into the disk is widely accepted as a safe and effective method for the treatment of discogenic low back pain.[17]
[19] Several potential limitations may exist in this meta-analysis. First, our analysis is based on only three RCTs and two of them have a relatively small sample size (n < 100). There is significant heterogeneity, which may be caused by different combination of drugs, control intervention, and patient populations, all of which may have an influence on the pooling results. Finally, some unpublished and missing data may lead to some bias.
Conclusion
Intradiskal methylene blue injection has beneficial effects on pain alleviation and functional improvement in patients with discogenic low back pain.
