Accepted Manuscript

Title: The efficacy of greater occipital nerve block for the

treatment of migraine: A systematic review and meta-analysis

Authors: Shuzhi Wu, Xiaokai Yang, Yijun Lin, Linglong

Chen, Hua Ye

PII: S0303-8467(17)30370-0
DOI: https://doi.org/10.1016/j.clineuro.2017.12.026
Reference: CLINEU 4871

To appear in: Clinical Neurology and Neurosurgery

Received date: 8-7-2017

Revised date: 5-11-2017
Accepted date: 28-12-2017

Please cite this article as: Wu S, Yang X, Lin Y, Chen L, Ye H, The

efficacy of greater occipital nerve block for the treatment of migraine: A
systematic review and meta-analysis, Clinical Neurology and Neurosurgery (2010),
https://doi.org/10.1016/j.clineuro.2017.12.026

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The efficacy of greater occipital nerve block for the treatment of

migraine: a systematic review and meta-analysis

Running title: Greater occipital nerve block for migraine;

Shuzhi Wu, Xiaokai Yang, Yijun Lin, Linglong Chen, Hua Ye*

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Department of Neurology, Wenzhou People hospital, Wenzhou, Zhejiang Province, P.R. China;

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*Address
correspondence to: Hua Ye

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Email: yhwzzz23@sina.com;

Telephone: 0086057788059907;

Fax number: 0086057788059907;

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Postal address: NO.57 Canghou Street, Wenzhou, Zhejiang Province,P.R.China 325000;
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Shuzhi Wu: wushuzhi999@126.com;
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Xiaokai Yang: yakeworld@126.com;
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Yijun Lin: gm1101@163.com;

Linglong Chen: 77587332@qq.com；

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Hua Ye: yhwzzz23@sina.com;

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Highlights
 Seven RCTs are included in the meta-analysis.
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 GON block intervention significantly reduces pain intensity and analgesic

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medication consumption in migraine patients.

 GON block has no remarkable impact on head duration and adverse events for
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migraine.

Abstract
Greater occipital nerve (GON) block has some potential in treating migraine. We
conduct a systematic review and meta-analysis to investigate the impact of GON block
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on pain management of migraine. We have systematically searched randomized
controlled trials (RCTs) assessing the efficacy of GON block versus placebo for
migraine in various databases including PubMed, EMbase, Web of science, EBSCO,
and Cochrane library databases. The primary outcome is pain intensity. Meta-analysis
is performed using the random-effect model. Seven RCTs are included in the meta-
analysis. Compared with control intervention in migraine patients, GON block
intervention can significantly reduce pain intensity (Mean difference=-1.24; 95% CI=-

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1.98 to -0.49; P=0.001) and analgesic medication consumption (Mean difference=-1.10;

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95% CI=-2.07 to -0.14; P=0.02), but has no remarkable impact on head duration (Mean

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difference=-6.96; 95% CI=-14.09 to 0.18; P=0.0.06) and adverse events (RR=0.93; 95%

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CI=0.52 to 1.65; P=0.80). GON block intervention is able to significantly reduce pain
intensity and analgesic medication consumption in migraine patients.

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Key words: greater occipital nerve block (GON), migraine, pain management,
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systematic review, meta-analysis.
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Introduction
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Migraine is known as a common neurological disease, and these patients have a high
risk of recurrence. Migraine headaches are painful and incapacitating, and result in poor
quality of life and high economic impact [1-3]. Treatment options for migraine mainly
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include antidepressants, antiepileptics, beta-blockers, and calcium channel blockers,

cognitive behavioral therapy and botulinum toxin [4-6]. However, current treatments
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still have insufficient efficacy in migraine patients [7, 8].

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Greater occipital nerve (GON) is the primary sensory nerve of the occipital region
and derived from C2 dorsal root [9]. GON block with lidocaine has been reported for
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immediate pain relief for migraine [10], and also demonstrates some potential in the
diagnosis and treatment of primary headaches [10-13]. GON blockade with local
anesthetics is an effective treatment for pain relief of migraine, cervicogenic headache,
cluster headache, and occipital neuralgia [10, 12, 14]. One randomized controlled trial
(RCT) has demonstrated that GON blockade with bupivacaine is capable to effectively
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reduce pain intensity and headache days in chronic migraine [15].
In contrast, some relevant RCTs has showed that GON block with local anesthetics
has no substantial impact on pain intensity, headache duration, and analgesic
medication consumption in migraine patients [16, 17]. Considering these inconsistent
effects, we therefore conduct a systematic review and meta-analysis of RCTs to
investigate the efficacy of GON block with local anesthetics for migraine patients.
Materials and methods

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We conduct this meta-analysis based on the guidance of the Preferred Reporting

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Items for Systematic Reviews and Meta-analysis statement [18] and the Cochrane

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Handbook for Systematic Reviews of Interventions [19].

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Literature search and selection criteria
PubMed, EMbase, Web of science, EBSCO, and the Cochrane library are

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systematically searched from inception to July 2017, with the following keywords:
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GON block, and migraine. Titles/abstracts or even full texts are screened until no
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additional eligible studies are added. The inclusion criteria include: (1) study population
are patients with migraine, (2) intervention treatments are GON block versus GON
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injection, (3) and study design is RCT.

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Data extraction and outcome measures

We have extracted the following information from the included RCTs: first author,
publication year, sample size, baseline characteristics of patients, intervention of GON
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block, intervention of control, study design. The authors are contacted to acquire the
data when necessary. The primary outcome is pain intensity. Secondary outcomes
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include headache duration (day), analgesic medication consumption (day), and adverse
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events.
Quality assessment in individual studies
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Methodological quality of the included studies has been independently evaluated

using the modified Jadad scale [20]. There are 3 items to evaluate the Jadad scale:
randomization (0-2 points), blinding (0-2 points), dropouts and withdrawals (0-1
points). The score of Jadad Scale varies from 0 to 5 points. An article with Jadad score

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≤2 is considered to be of low quality. If the Jadad score≥3, the study is thought to be
of high quality [21].
Statistical analysis
Mean differences (MDs) with 95% confidence intervals (CIs) for continuous
outcomes (pain intensity, headache duration, and analgesic medication consumption)
and risk ratios (RRs) with 95% CIs for dichotomous outcomes (adverse events) are used
to calculate the estimated pooled difference. The random-effects model with

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DerSimonian and Laird weights is used in all analysis. Heterogeneity is tested by the I2

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statistic and is considered to be low (I2 less than 50%), or significant (I2 more than 50%).

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Sensitivity analysis is performed to detect the influence of a single study on the overall

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estimate via omitting one study in turn for significant heterogeneity. Publication bias is
not assessed because of the limited number (<10) of included studies. P value less than

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0.05 indicates a statistical significance. Review Manager Version 5.3 (The Cochrane
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Collaboration, Software Update, Oxford, UK) was used for all statistical analysis.
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Results
Literature search, study characteristics and quality assessment
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Figure 1 demonstrates the flow chart for the selection process and detailed
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identification. 625 publications are identified through the initial search of databases.
428 papers are excluded after reading the titles and abstract. Seven RCTs are included
in the meta-analysis [15-17, 22-25].
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The baseline characteristics of the seven eligible RCTs in the meta-analysis are
summarized in Table 1. The four studies are published between 2008 and 2017, and
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sample sizes range from 23 to 72 with a total number of 323. There are similar baseline
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characteristics of patients in GON block group and control group. Four RCTs report
that intervention treatments are GON block with bupivacaine versus GON injection
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with saline [15, 22, 23, 25]. The intervention treatments are GON block with
corticosteroids, bupivacaine or (and) lidocaine versus GON injection with bupivacaine
or (and) lidocaine in the remaining three RCTs [16, 17, 24]. Jadad scores of the seven
included studies vary from 3 to 5, and all seven studies are considered to be high-quality
ones according to quality assessment.
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Primary outcome: pain intensity
This outcome data is analyzed with the random-effect model, and the pooled estimate
of the five included RCTs suggests that compared to control group in migraine patients,
GON block intervention significantly reduces pain intensity (MD=-1.24; 95% CI=-1.98
to -0.49; P=0.001), with significant heterogeneity among the studies (I2=63%,
heterogeneity P=0.03) (Figure 2).
Sensitivity analysis

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Significant heterogeneity is observed among the included studies for the pain

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intensity. As shown in Figure 2, one RCT shows the result that is almost out of range

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of the others and probably contributes to the heterogeneity [25]. After excluding this

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study, the results suggest that GON block is associated with significantly reduced pain
intensity (MD=-0.89; 95% CI=-1.38 to -0.39; P=0.0005). The remaining studies

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demonstrate no heterogeneity (I2=0%, heterogeneity P=0.39).
Secondary outcomes
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Compared with control intervention in migraine patients, GON block intervention
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shows no notable influence on head duration (MD=-6.96; 95% CI=-14.09 to 0.18;
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P=0.0.06; Figure 3), but results in substantially decreased analgesic medication

consumption (MD=-1.10; 95% CI=-2.07 to -0.14; P=0.02; Figure 4). There is no
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significant increase in adverse events following GON block intervention compared to

control group (RR=0.93; 95% CI=0.52 to 1.65; P=0.80; Figure 5).
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Discussion
GON block has been reported to be promising to treat headaches [22, 26]. The
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efficacy of GON blockade has been assessed in a number of studies for the treatment
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of various types of headache [27-31]. For instance, 150 consecutive patients with
cervicogenic chronic migraine result in positive treatment response in 78 patients and
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better headache disorder in 90 patients after the treatment of suboccipital nerve

blockade [28]. Our meta-analysis suggests that compared to control intervention in
migraine patients, GON block intervention significantly decreases pain intensity and
analgesic medication consumption, but has no significant impact on headache duration.
The mechanisms of GON block may include the changes in brain nociceptive

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pathways and the diffuse noxious inhibitory control [32, 33]. It is well known that the
trigeminocervical complex is connected to the nucleus salivatorius with raphe nucleus,
locus coeruleus, and hypothalamus. Painful stimulus of cranial structures is transmitted
through trigeminal nerve and superior cervical nerve to the trigeminocervical complex
and then upper centers [25, 34]. There is important functional connection between the
sensory occipital segments and the trigeminal nociceptive system in humans. Thus,
GON blockade is an effective treatment option in migraine patients, and protects the

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patients from serious complications [35].

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Regarding the sensitivity analysis, there is significant heterogeneity for the meta-

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analysis of pain intensity. No heterogeneity is observed for the analysis of remaining

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included RCTs after excluding one study [25], and the results indicate that GON block
is able to significantly reduce pain intensity compared to control group for migraine

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patients. Several factors may account for this heterogeneity, including different types
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and dosages of local anesthetics, and different time and methods of applying GON
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block. There are very few adverse events following GON block, such as injection site
pain, abdominal distension, paresthesia, and fat redistribution. No increase in adverse
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events is found based on the results of our meta-analysis. Only one serious adverse
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event, benign intracranial hypertension, is reported six days after GON injection and
this patient is diagnosed as migraine and pseudotumor cerebri [17].
There may be several limitations. Firstly, our analysis is based on only seven RCTs,
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and they all have a relatively small sample size (n<100). Overestimation of the
treatment effect occurs more frequently in smaller trials. The types and dosages of local
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anesthetic, time and methods of application in the included studies are different and
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have some influence on the pooled results. Next, the follow-up time is relatively short
after applying local anesthetics, and the extended observation period should be
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performed.
Conclusion
GON block intervention is found to substantially reduce pain intensity and analgesic
medication consumption for migraine patients, with no increase in adverse events. GON
block intervention should be recommended to be administrated in migraine patients.
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Compliance with Ethical Standards

Declaration of conflict of interest: None.

Disclosure of potential conflicts of interest

The authors declare no conflict of interest.

Research involving human participants and/or animals

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Not applicable.

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Acknowledgements

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This research was supported by the Science and Technology Major Project of Wenzhou，
china ( Grant No.ZS2017020) and a grant from the Science and Technology Foudation
of Wenzhou, China ( Grant No. Y20160286).
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Figure legends
Figure. 1 Flow diagram of study searching and selection process.

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Figure. 2 Forest plot for the meta-analysis of pain intensity.

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Figure. 3 Forest plot for the meta-analysis of headache duration (day).

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Figure. 4 Forest plot for the meta-analysis of analgesic medication consumption (day).

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Figure. 5 Forest plot for the meta-analysis of adverse events.

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Table 1 Characteristics of included studies
GON block group Control group Jada
score
s
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Author Age Femal BMI, Age (years) Femal BMI, Methods
.
Numbe (years) e No. kg/m2 or Numbe e No. kg/m2 or

r weight, kg Methods r weight, kg

38.8 20 - Bilateral GON 37.9 19 - Sham 4

block with 1.5 mL GON block

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of 0.5%
1 Gul 2017 22 22
bupivacaine

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diluted in 1 mL of
saline
35.7±8.6 - 25.8±6.8 Bilateral GON 35.9±13.4 - 23.6±4.2 Sham 4

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Cuadrado
2 18 kg/m2 block with 18 kg/m2 GON block
2016

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bupivacaine 0.5%
39.00±9.6 10 26.65±6.6 GON block with 39.08±11.4 11 25.75±5.6 Sham 3
Palamar 7 7 kg/m2 local anesthetic 2 7 kg/m2 GON
3 11 12
2015 (bupivacaine 0.5% block.9%

37.3±8.8 34
1.5 mL)
68.2±15.7 GON block four
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1.5 mL)
68.2±15.0 Sham 5
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kg times (once per kg GON block
4 Inan 2015 39 33
week) with
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bupivacaine
44±11 30 26.2±6.6 GON block with 42 ±16 25 25.1±7.4 GON 3
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kg/m2 2.5 ml 0.5% kg/m2 injection

bupivacaine plus with 2.75
0.5 ml (20 mg) ml normal
methylprednisolon saline plus
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5 Dilli 2015 33 e over the 30 0.25 ml 1%

ipsilateral lidocaine
(unilateral without
headache) or epinephrin
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bilateral (bilateral e
headache)
37.00±4.4 21 - GON block with 37.04±9.93 22 - GON 4
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1 1.0 mL lidocaine injection

2%, 0.5 mL with 1.0
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Kashipazh
6 24 triamcinolone 24 mL
a 2014
lidocaine
2%, 0.5 mL
saline
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40.3±8.9 17 - GON block with 41.9±11.3 14 - GON 3

lidocaine 2% and injection
bupivacaine 0.5% with
Ashkenazi plus triamcinolone lidocaine
7 19 18
2008 40 mg 2% and
bupivacain
e 0.5% plus
saline
GON: greater occipital nerve.
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