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REVIEW ARTICLE

Intradiscal Methylene Blue Injection for

Discogenic Low Back Pain: A Meta-Analysis

Xiaohui Guo, MD*,†; WenYuan Ding, MD*; LanZe Liu, BA†; SiDong Yang, MD*
*Department of Spinal Surgery, The Third Hospital of Hebei Medical University, Hebei
Shijiazhuang, Hebei; †Department of Spinal Surgery, The Second Hospital of TangShan, Hebei
TangShan, Hebei, China

& Abstract
Objectives: The purpose of this study was to assess the
effects of intradiscal methylene blue (MB) injection on
discogenic low back pain (DLBP).
Methods: We conducted an electronic search of the
PubMed, Ovid, Ovid MEDLINE and Embase databases using
the search terms “low back pain” and “methylene blue”; the
search was limited to English language articles from
database inception to October 2017. In addition, the
reference lists of all included studies were manually
searched. Two reviewers independently assessed the quality
of the studies, extracted data from the included studies, and
analyzed the data.
Results: Five studies were included. The results of the meta-
analysis indicated that the effects of intradiscal MB injection
between preoperation and postoperation on DLBP were
statistically significant based on the 3-month visual analog
scale (VAS) or numeric rating scale (NRS) (weighted mean
difference [WMD] = 3.61; 95% confidence interval [CI]: 2.46
to 4.76; P < 0.05) and Oswestry Disability Index (ODI)
(WMD = 24.64, 95% CI: 12.07 to 37.21, P < 0.05), the 6-
month VAS or NRS (WMD = 2.95; 95% CI: 1.20 to 4.71;
P < 0.05) and ODI (WMD = 23.21, 95% CI: 12.89 to 33.53,
P < 0.05), and the 12-month VAS or NRS (WMD = 3.19; 95%
Address correspondence and reprint requests to: WenYuan Ding, MD,
Department of Spinal Surgery, The Third Hospital of Hebei Medical
University, Hebei Shijiazhuang, No. 139, ZiQiang Road, ShiJiaZhuang, China.
E-mail: dingwyster@126.com.
Submitted: April 24, 2018; Revised July 11, 2018;
Revision accepted: July 12, 2018
DOI. 10.1111/papr.12725
© 2018 World Institute of Pain, 1530-7085/18/$15.00
Pain Practice, Volume 19, Issue 1, 2019 118–129
CI: 0.99 to 5.40; P < 0.05) and ODI (standard mean
difference = 29.51, 95% CI: 20.60 to 38.42, P < 0.05).
Conclusions: Intradiscal MB injection can reduce pain sever-
ity and improve the ODI score in individuals with discogenic
low back pain. Although intradiscal MB injection seems to be
a safe and effective treatment for discogenic low back pain,
the clinical benefits for patients with discogenic low back
pain need to be further appraised in larger samples and more
in-depth studies. &
Key Words: low back pain, discogenic back pain, methy-
lene blue injection, meta-analysis
INTRODUCTION
Low back pain has become a common worldwide health
problem and a prominent socioeconomic burden on
public health.1,2 Any pathological change to the lumbar
structures may cause low back pain, for example,
intervertebral discs, ligaments, fascia, muscles, facet
joints, sacroiliac joints, and nerve roots. The internal
disruption of intervertebral discs has been thought to be
the main cause of low back pain.3,4 For instance, it has
been reported that up to 42% of cases of low back pain
are associated with disrupted intervertebral discs.5 In
addition, intervertebral disc injuries have been reported
to be the most common cause (56%) of low back pain
caused by motor vehicle accidents.6 Of note, low back
pain originating from intervertebral discs has been
shown to be more common in younger patients.7 As its
name implies, discogenic low back pain (DLBP) is
defined as pain caused by an internal disturbance in the
intervertebral disc. The treatment of DLBP has been a

complicated issue. There are many treatments available
for DLBP, including injection therapies, thermal annular
procedures, interbody fusion, and disc replacement.8–13
However, there is considerable controversy over the
efficacy of these therapies.
Freemont et al.14 and Coppes et al.15 discovered that
the pathogenesis of DLBP was associated with nerve
growth into the intervertebral disc; when the posterior
of the annulus fibrosus was torn as a result of injury or
degeneration, the extensive nerve ending extended from
the outer layer of the annulus fibrosus into the inner
parts of the disc along a torn fissure. Since it was first
synthesized in 1876, methylene blue (MB) has been used
in many different areas of clinical medicine.16 For
example, MB has been utilized as a neurotropic drug to
block nerve conduction or the damage to nerve endings;
it has been injected locally to treat many painful
ailments and idiopathic pruritus ani17–20; and recently,
it has been used for DLBP. Peng et al.21 first reported
that intradiscal MB injection was an effective and
minimally invasive intervention for the treatment of
DLBP. Subsequently, Peng et al.22 verified the efficacy of
intradiscal MB injection for DLBP in another double-
blind randomized controlled trial (RCT). However,
Schiltenwolf et al.23 openly questioned the very positive
outcome of this RCT. Kim et al.24 concluded that
intradiscal MB injection is an effective short-term
treatment but that it may lose its effectiveness over time
in their study. In a case series, Gupta et al.25 found
outcomes contrary to the results reported by Peng
et al.22 Nevertheless, Zhang et al.26 found that intradis-
cal MB injection might be an effective treatment for
DLBP in a short-term clinical observational study.
While the outcomes of the aforementioned studies are
controversial, several limitations should be noted,
including small sample sizes, inconsistent evaluation
criteria, and deficiencies in study design. Therefore, we
conducted a large-scale meta-analysis to assess the
effects of intradiscal MB injection treatment for DLBP.
METHODS
Search Strategy
This study complied with the recommendations pro-
posed by the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) guidelines.27
Based on the Cochrane Collaboration guidelines, we
conducted an electronic search of the PubMed, Ovid,
Ovid MEDLINE, and Embase databases from database
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Intradiscal Injection for Back Pain  119
inception to October 2017. The search process was
conducted as illustrated in Figure 1. We used the search
terms “low back pain” and “methylene blue” in
combination with the Boolean operator “AND”. In
addition, the reference lists of all included studies were
manually searched to identify articles that may have
been missed in the initial search. This search was limited
to English language articles. This study is a meta-
analysis that does not require approval by an ethics
committee or institutional review board.
Inclusion and Exclusion Criteria
An inclusion criterion was intradiscal MB injection
treatment for DLBP patients who were confirmed by the
standard pressure-controlled provocative discography.
Outcomes included changes in the pain score and
Oswestry Disability Index (ODI) from before to after
treatment. Exclusion criteria were unavailable or
unclear data and duplicate reports.
Study Selection
Once all relevant full-text papers had been gathered,
each paper was imported into EndNote (Thomson
Reuters ResearchSoft), which is a bibliographic database
manager, and duplicates were removed. Two reviewers
(LZ.L., SD.Y.) scrutinized the reference lists of each
eligible paper for any missed studies. All conflicts were
discussed and resolved with a third author (WY.D.).
Data Collection Process and Outcome Measures
Following selection of all relevant articles, two authors
(LZ.L., SD.Y.) extracted all data into a preconstructed
data table. The following data were extracted: author,
year published, age, sample size, pain duration, time of
preoperation, and visual analog scale (VAS) or numeric
rating scale (NRS) scores and ODI scores of preopera-
tion at follow-up times of 3, 6, and 12 months. For those
studies25,28,29 that met the inclusion criteria but data
was not readily available in the article, the authors
(LZ.L., SD.Y.) tried to contact the researchers via e-mail
for raw data.
Assessment of Risk for Bias
Quality assessment of risk for bias was evaluated using
the scale from “Assessing the Risk of Bias of Individual
Studies in Systematic Reviews of Health Care

120  GUO ET AL.
Figure 1. Search flow chart.
Interventions.”30 The scale contains nine questions that
refer to selection, performance, attrition, detection, and
reporting bias. Risk for bias was independently assessed
by two authors (LZ.L., SD.Y.) for each study. Disagree-
ments were discussed and resolved with a third author
(WY.D.).
Statistical Analysis
Statistical analysis was performed using Stata/MP 14.0
software (College Station, TX, U.S.A.), and a P value of
< 0.05 was considered statistically significant. The
outcome measures of the included studies were the 10-
cm or 100-mm VAS or the 0- to 10-point NRS for pain
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assessment, and the 100-point ODI for assessment of
specific functions.31 Pain scores deviating from a linear 0
to 10 or 0 to 100 point scale were transformed to a 10-
point scale.32 Because pain intensity and back function
were continuous variables, we calculated the weighted
mean differences (WMDs) and the corresponding 95%
confidence intervals (CIs) based on the mean values
pretreatment and posttreatment. In accordance with the
current literature, an improvement in pain intensity of 2
points (0 to 10 points) was considered clinically signif-
icant.33 Heterogeneity of the mean differences across the
studies was assessed using the chi-squared test and I2
statistic. If the results were significant (P < 0.1 or
I2 > 50%), a random-effects model was used to estimate

the overall effect sizes, and we conducted subgroup
analysis to explore factors related to a decrease in pain
scores after intradiscal MB injection. Otherwise, a fixed-
effects model was adopted.
RESULTS
Study Characteristics
The initial search identified 284 articles; following
removal of duplicates, screening of titles and
abstracts identified 19 potential studies. After a detailed
review of full text of retrieved studies, eight
articles21,22,24–26,28,29,34 met the inclusion criteria and
five21,22,24,26,34 (Figure 1) of these were eligible for
inclusion in this meta-analysis. The most prevalent
reasons for exclusion were invalid reference, incomplete
data, and the absence of follow-up. The authors tried to
contact the researchers25,28,29 via e-mail for raw data,
but failed in the end. The five articles were published
from 2007 to 2016, and 121 patients were included.
One study26 was a clinical RCT, but we extracted the
data for the intradiscal MB injection group only.
Another study34 included 16 cases, but the follow-up
data were incomplete; thus, complete data were
extracted for only 8 cases. The characteristics of the
five studies are described in Table 1.
Clinical Outcomes
Decreased Pain Scores (NRS or VAS) After Treat-
ment. Five studies assessed pain scores after treatment
using a VAS, a 0 to 10 point NRS,21,24,26,34 or a 0 to 100
point NRS.22 The pooled mean differences in pain scores
from baseline to follow-up decreased by 3.61 points
(95% CI: 2.46 to 4.76, P < 0.05, I2 = 90.1%) at
3 months, decreased by 2.95 points (95% CI: 1.20 to
Table 1. Characteristics of Studies
Sample Patients’
Study Size Age (Mean or Range)
Peng et al. (2007)21 24 43.4 months
(22 to 67)
Zhang et al. (2016)26 33 46.5 years
(20 to 71)
Kim et al. (2012)24 20 45.6  11.1 months
Peng et al. (2010)22 36 42.06  13.74 months
Levi et al. (2014)34 8 31.38  14.37 months
NRS, numeric rating scale; ODI, Oswestry Disability Index.
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Intradiscal Injection for Back Pain  121
4.71, P < 0.05, I2 = 94.3%) at 6 months, and decreased
by 3.19 points (95% CI: 0.99 to 5.40, P < 0.05,
I2 = 97.7%) at 12 months (Figures 2–4). An improve-
ment in pain intensity of 2 points (0 to 10 points) was
considered clinically significant.33 Based on these crite-
ria, the effect of intradiscal MB injection on DBLP was
remarkable, with a success rate of at least 50%.
Reduced ODI Score After Treatment. Five studies
measured the ODI score (0 to 100) after treat-
ment.21,22,24,26,34 The ODI is an assessment scale that
is used to measure impairment and quality of life in a
patient (ie, how badly the pain has affected the patient’s
life). It is the gold standard of low back functional
outcome measures. The pooled mean differences in ODI
score from baseline to follow-up decreased by 24.64
points (95% CI: 12.07 to 37.21, P < 0.05, I2 = 94.5%)
at 3 months, decreased by 23.21 points (95% CI: 12.89
to 33.53, P < 0.05, I2 = 94.6%) at 6 months, and
decreased by 29.51 points (95% CI: 20.60 to 38.42,
P < 0.05, I2 = 91.6%) at 12 months (Figures 5–7). The
mean ODI scores at the 3-month, 6-month, and 12-
month follow-up times were significantly different from
the mean ODI scores pretreatment.
Subgroup Analyses. Because the study outcomes of
Peng et al.21,22 were too positive, we conducted sub-
group analysis excluding the outlying results of Peng
et al. The pooled mean differences in pain scores (NRS
or VAS) from baseline to follow-up decreased by 2.96
points (95% CI: 1.85 to 4.06, P < 0.05, I2 = 80.8%) at
1 month, decreased by 2.14 points (95% CI: 0.52 to
3.76, P < 0.05, I2 = 91.1%) at 6 months, and decreased
by 1.22 points (95% CI: 0.03 to 2.42, P < 0.05,
I2 = 88.3%) at 12 months; the pooled mean differences
in ODI from baseline to follow-up decreased by 18.05
points (95% CI: 1.49 to 34.61, P < 0.05, I2 = 95%) at
Pain Duration Follow-up Maine
(Mean or Range) (months) Valuation Index
64 months 3, 6, ≥ 12 VAS
(6 to 144) ODI
4.3 years 1, 3, 6, 12 NRS
(0.6 to 14) ODI
85.3  97.8 months 1, 3, 6, 12 VAS
ODI
3.5  1.6 years 6, 12, 24 NRS
ODI
1, 2, 6 VAS
ODI
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122  GUO ET AL.

Figure 2. Decreased pain score (numeric rating scale and visual analog scale, 0 to 10) after 3 months of treatment. CI, confidence
interval; WMD, weighted mean difference.

Figure 3. Decreased pain score (numeric rating scale and visual analog scale, 0 to 10) after 6 months of treatment. CI, confidence
interval; WMD, weighted mean difference.

Figure 4. Decreased pain score (numeric rating scale and visual analog scale, 0 to 10) after 12 months of treatment. CI, confidence
interval; WMD, weighted mean difference.

1 month and decreased by 16.48 points (95% CI: 2.28 relieving effect was remarkable, with a success rate of at
to 35.24, P > 0.05, I2 = 96.4%) at 6 months (Fig- least 50% at 6 months; however, the success rate was
ures 8–12). Based on the clinical criteria,33 the pain- below 50% at 12 months and the mean ODI score at the

Figure 5. Decreased Oswestry Disability Index (0 to 100) after 3 months of treatment. CI, confidence interval; WMD, weighted mean
difference.
Figure 6. Decreased Oswestry Disability Index (0 to 100) after 6 months of treatment. CI, confidence interval; WMD, weighted mean
difference.
6-month follow-up time was not significantly different
from the mean ODI score pretreatment.
We also conducted subgroup analysis to explore the
sources of heterogeneity in pain scores with respect to
patient age (greater than 45 years vs. less than 45 years)
and duration of pain prior to the operation (greater than
5 years vs. less than 5 years). The analysis demonstrated
that there were no differences in pain scores according to
these conditions (Table 2).
Safety. No serious complications related to MB inter-
vention were reported in any of the included studies.
Risk for Bias
Quality assessment of risk for bias was evaluated using a
scale that contains 9 questions referring to selection,
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Intradiscal Injection for Back Pain  123
performance, attrition, detection, and reporting bias. Risk
for bias values for each study are presented in Table 3.
DISCUSSION
Low back pain is a common health problem worldwide
and has a significant socioeconomic burden on public
health.1,2 It has been reported that up to 42% of cases of
low back pain are associated with disruption of inter-
vertebral discs.5 While the exact pathogenesis of DLBP
is very complicated, a widely accepted hypothesis is that
the pain is caused by nociceptive nerves growing deeply
into the nucleus pulposus along the torn fissure in the
posterior part of the annulus fibrosis.14,15 One possible
mechanism by which intradiscal MB injection relieves
pain in cases of DLBP is via denervation of the small
nociceptive fibers that grow into the inner layer of the
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124  GUO ET AL.

Figure 7. Decreased Oswestry Disability Index (0 to 100) after 12 months of treatment. CI, confidence interval; WMD, weighted mean
difference.

Figure 8. Subgroup of decreased pain score (numeric rating scale and visual analog scale, 0 to 10) after 1 month of treatment. CI,
confidence interval; WMD, weighted mean difference.

Figure 9. Subgroup of decreased pain score (numeric rating scale and visual analog scale, 0 to 10) after 6 months of treatment. CI,
confidence interval; WMD, weighted mean difference.

annulus fibrosis or nucleus pulposus. Another possible synthesis of nitric oxide, which plays an important role
mechanism is that MB may alleviate inflammatory in the inflammatory processes of intervertebral disc
processes underlying pain by directly inhibiting degeneration and DLBP.14,35
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Intradiscal Injection for Back Pain  125

Figure 10. Subgroup of decreased pain score (numeric rating scale and visual analog scale, 0 to 10) after 12 months of treatment. CI,
confidence interval; WMD, weighted mean difference.

Figure 11. Subgroup of decreased Oswestry Disability Index (0 to 100) after 1 month of treatment. CI, confidence interval; WMD,
weighted mean difference.

Figure 12. Subgroup of decreased Oswestry Disability Index (0 to 100) after 6 months of treatment. CI, confidence interval; WMD,
weighted mean difference.

In this study, we retrieved eight articles about et al.21 in 2007 conducted a trial of intradiscal MB
intradiscal MB injection that met the inclusion criteria, injection for the treatment of DLBP, in which they
each of which had different clinical outcome. Peng examined the effect of intradiscal MB injection in 24
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126  GUO ET AL.

patients with intractable DBLP for whom conservative
treatment had been minimally effective. They found a
remarkable improvement in pain (defined as a minimum
of a 2-point reduction in pain intensity on the VAS
compared with pain intensity pretreatment) in 87% of
the patients. Based on the VAS and ODI, there was no
difference in pain intensity between 3 and 12 months (or
more) postoperation for all the patients. In 2010, Peng
et al.22 demonstrated the efficacy and safety of intradis-
cal MB injection in 72 patients with DLBP through a
double-blind randomized trial. In this study, patients
who received intradiscal MB injections showed a 52.5-
point reduction in mean NRS score and a 35.6-point
reduction in ODI score. The overall success rate
following treatment was 89%, with 47% of the patients
reporting complete relief of pain at the 6-month follow-
Table 2. Subgroup Analysis to Explore the Source of
Heterogeneity on Changes of Oswestry Disability Index
Subgroup Mean Difference (95% CI)
Age
> 45 years 17.07 ( 6.57 to 40.70)
< 45 years 30.4 (23.80 to 36.29)
Pain duration of preoperation
> 5 years 18.36 ( 8.12 to 44.84)
< 5 years 30.46 (27.12 to 33.80)
CI, confidence interval.
up and a 91.6% satisfaction rate at 24 months after
treatment. In a similar study in 2012, Kim et al.24
reported that the average VAS score decreased signifi-
cantly from 5.1 at baseline to 3.2 at 3 months after
intradiscal MB injection and that the ODI score
decreased significantly from 38.0 at baseline to 10.2 at
3 months after intradiscal MB injection in patients with
DBLP; however, at the 12-month follow-up time, the
mean VAS score dropped to 4.5 (not significantly
different from the pretreatment scores), and the success
rate decreased from 55% at 3 months to 20% at
12 months after treatment. Based on these findings,
the authors concluded that intradiscal MB injection is an
effective short-term treatment but that it may lose its
effectiveness over time. In the same year, Gupta et al.25
reported a clinical trial with a cohort of eight patients
with mental health issues, and their results revealed a
success rate of only 13%, in contrast to the outcomes
reported by Peng et al.21,22 In 2014, Levi et al.34 defined
success as improvement of at least 30% on the VAS
I2 (%) accompanied by improvement of at least 30% on the
ODI, and they found that the success rate was only 19%,
98.2 21%, and 25% for the 1-, 2-, and 6-month follow-up
55.3 times, respectively. Kallewaard et al.28 found that 40%
97.5 of the patients who responded to this treatment accord-
38.2 ing to the VAS and ODI improved by at least 30%.
However, in a recent study by Zhang et al.26 (2016),

Table 3. Risk for Bias Detail of Each Study

Peng et al. Zhang et al. Kim et al. Peng et al. Levi et al.
Risk for Bias Criterion (2007)21 (2016)26 (2012)24 (2010)22 (2014)34

Selection bias Does the design or analysis control account for important Yes Yes Yes Yes Yes
confounding and modifying variables through matching,
stratification, multivariable analysis, or other approaches?
Performance bias Did researchers rule out any impact from a concurrent Yes Yes Yes Yes Yes
intervention or an unintended exposure that might bias
results?
Did the study maintain fidelity to the intervention protocol? Yes Yes Yes Yes Yes
Attrition bias If attrition (overall or differential nonresponse, dropout, loss to Yes Yes Yes Yes Yes
follow-up, or exclusion of participants) was a concern, were
missing data handled appropriately (eg, intention-to-treat
analysis and imputation)?
Detection bias Were the outcome assessor blinded to the intervention or No No Yes No No
exposure status of participants?
Were interventions/exposures assessed/defined using valid and Yes Yes Yes Yes Yes
reliable measures implemented consistently across all study
participants?
Were outcomes assessed/defined using valid and reliable Yes Yes Yes Yes Yes
measures implemented consistently across all study
participants?
Were confounding variables assessed using valid and reliable Yes Yes Yes Yes Yes
measures implemented consistently across all study
participants?
Reporting bias Were the potential outcomes prespecified by the researchers? Yes Yes Yes Yes Yes
Are all prespecified outcomes reported?

which defined successful outcome as at least 50%
improvement on the ODI and 2-point reduction in
NRS scores, the clinical success rates were 81%, 75%,
and 63% at the 1-, 3-, and 6-month follow-up times
after treatment, respectively. At 12 months after treat-
ment, only 54% of the patients showed a successful
clinical outcome; therefore, the efficacy of MB injection
for DLBP may not persist. Another triple-blind, ran-
domized placebo-controlled trial conducted by Farrokhi
et al.29 examined the effects of MB injection on post-
operative low back pain and functional outcomes after
lumbar open discectomy and showed that the group of
MB-treated patients had significantly less low back pain
than the control group at 24 hours and 3 months after
surgery, consistent with the findings of Peng et al.21,22
Thus, we conducted the present meta-analysis including
all published studies to precisely estimate the effects of
intradiscal MB injection.
No serious complications related to MB intervention
were reported in the studies included in this review.
However, some serious complications related to inter-
vertebral disc injection were often reported in the
literature, such as discitis (infection or inflamma-
tory),36–39 disc herniation,40 and nerve or vascular
injury.41–43 These complications should be taken into
account in the procedure of intradiscal treatment.
The overall results of this meta-analysis were posi-
tive, although the subgroup analyses were different. The
pain relieving effect was remarkable, with a success rate
of at least 50% at 6 months; however, the success rate
was below 50% at 12 months, and the mean ODI score
at the 6-month follow-up time was not significantly
different from the mean pretreatment ODI score.
According to the subgroup analysis data, the long-term
effect of intradiscal MB injection was not good.
Our study has several limitations. Although we
conducted a comprehensive search in four databases,
only five studies were included in this meta-analysis.
Three studies25,28,29 met the inclusion criteria, but data
were not readily available in the article; we tried to
contact the researchers via e-mail for raw data, but
failed in the end. The small number of studies and
patients included limit our confidence in the findings. A
considerable degree of heterogeneity was still observed
among the included trials despite the subgroup analysis.
This might be due to differences in patient characteris-
tics, such as the cause of pain, the pain severity at
baseline, and the treatment protocols, or otherwise
unknown biases in those studies. In addition, the 12-
month follow-up period was not long enough. The
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Intradiscal Injection for Back Pain  127
clinical benefits of intradiscal MB injection for patients
with DLBP require further investigation and should be
further evaluated in large cohorts through multicenter
studies and RCTs.
CONCLUSION
In summary, the findings of this meta-analysis suggest
that intradiscal MB injection can reduce the pain
severity and improve the ODI scores of patients with
DLBP. Although intradiscal MB injection seems to be a
safe and effective treatment for DLBP, its clinical
benefits for patients with DLBP must be further studied
in larger cohorts and in greater detail. On the basis of the
literature to date, the precise success rate remains
unclear. At present, intradiscal MB injection is not a
standard treatment for discogenic pain. However, for
patients who have responded poorly to traditional
treatments, intradiscal MB injection could be a promis-
ing treatment.
CONFLICTS OF INTEREST
The authors have declared no conflicts of interest.
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