ANODYNE study: A double-blind randomized trial of greater occipital nerve block of methylprednisolone and lignocaine versus placebo as a transitional preventive treatment for episodic cluster headache

Abstract

Background

There is inadequate evidence of the efficacy of greater occipital nerve block (GONB) for the preventive treatment of cluster headaches. We assessed the efficacy and tolerability of GONB injections as a transitional preventive treatment for episodic cluster headaches (ECH).

Methods

This randomized, double-blind, placebo-controlled, parallel-group trial conducted at GB Pant Institute of Postgraduate Medical Education and Research, New Delhi, India, included ECH patients diagnosed by ICHD-3 criteria, aged 18–65, with one or more attacks per 24 h for seven days before randomization (baseline). ECH patients were either not on preventive medications or on stable doses for at least three months. ECH patients were randomized to receive active GONB (2 ml methylprednisolone (80 mg) and 2 ml lignocaine (2%)) and placebo (4 ml saline injections). Before giving GONB, lignocaine jelly was applied topically to mask the effect of numbness following the GONB. The primary efficacy endpoint was the mean change in weekly attack frequency from baseline to Week 4. Efficacy analyses were performed in a modified intention-to-treat population that included all patients who received at least one injection of GONB and had a follow-up for one week following GONB. The safety analysis included treatment-emergent adverse effects (TEAE) in all patients who received at least one dose of investigational product. The trial was registered with the Clinical Trials Registry of India (CTRI/2021/21/038397).

Results

Forty ECH patients were randomized between December 2021 and January 2023. Thirty-nine patients (19 in the active and 20 in the placebo groups) were available for efficacy analysis. The change in weekly attack frequency from baseline to Week 4 was −11.1 (95% CI: −8.5 to −4.4) for the active group compared to −7.7 (95% CI: −11.8 to −9.8) for placebo (mean difference −3.4 (95% CI: −5.2 to −1.7, p < 0.001). We noted TEAE in 18 (90%) of 20 patients who received the active drug and in 18 (90%) of 20 patients who received a placebo (p = 0.38). The common TEAE were local site bleeding and pain, which were mild and transient. No serious adverse events were reported.

Conclusion

This study found that GONB with methylprednisolone and lignocaine significantly reduced the weekly attack frequency from baseline to Week 1 through Week 4 in ECH patients compared to a placebo. GONB was well tolerated.

Graphical abstract

This is a visual representation of the abstract.

Keywords

cluster headache episodic cluster headache greater occipital nerve block transitional treatment methylprednisolone patient reported outcome

Introduction

Cluster headache (CH), an uncommon but highly disabling primary headache disorder, is characterized by attacks of severe, strictly unilateral pain, usually orbital, supraorbital, or temporal, lasting 15–180 min and occurring once every other day up to eight times daily. The attacks are associated with ipsilateral cranial autonomic symptoms (CAS), restlessness, or agitation (1,2). Episodic CH (ECH) attacks occur in bouts called cluster periods (CP) that usually last from two weeks to two months but may occasionally last longer and are separated by pain-free periods of at least three months. When these pain-free periods are absent or last less than three months, the patient is diagnosed as suffering from chronic CH (CCH) (1).

Medical management of CH comprises acute, preventive, and transitional therapies (3). Acute or abortive treatment is given at onset and is aimed at aborting the attack, while preventives reduce the intensity, duration, and frequency of future attacks. Transitional therapy is an intermediate option, allowing a short-term or bridging solution to control attacks while waiting for preventive medication to take effect. The most common transitional treatment used in clinical practice is oral corticosteroids. A placebo-controlled double-masked, randomized controlled trial (RCT) using oral prednisolone for 17 days in ECH patients showed superiority over placebo (mean 7.1 (SD 6.5) attacks within the first week compared with 9.5 (SD 6.0) attacks in the placebo group (difference −2.4 attacks, 95% CI −4.8 to −0.03; p = 0.002)) (4). Complete cessation of cluster headache attacks occurred in 35% of patients compared to 7% receiving placebo at the end of one week. Prednisolone was well tolerated. However, systolic blood pressure was elevated in the prednisone group at visit day 7 with a mean difference of 6.9 mm Hg compared with placebo (1.2 to 12.5, p = 0.017). Another problem with the oral corticosteroids is the occurrence of rebound headaches upon withdrawal (5).

An alternative option for transitional treatment is the greater occipital nerve block (GONB) using suboccipital injections of steroids, with or without local anesthetics (6). GONB is generally considered safe with minimal systemic side effects, easy to perform, and cost-effective (7). Only two randomized placebo-controlled studies are available that assessed the efficacy and safety of GONB in CH (8,9). However, they used different methodologies such as single shot treatment versus multiple injections. Also, the primary efficacy endpoint of change in the weekly attack frequency suggested by the International Headache Society (IHS) was not considered in either study (10). Further, both RCTs included a mix of ECH and CCH patients; hence, whether the results could be generalized for either group is still being determined. A systematic review and metanalysis highlighted these lacunae and suggested that more robust RCTs based on the recommendations of IHS are required (11). We, therefore, devised this study to assess the efficacy and safety of GONB as a transitional treatment for ECH following IHS recommendations. We hypothesized that GONB with methylprednisolone and lignocaine would be superior to placebo in reducing weekly CH frequency.

Methods

Study design and participants

This was a single-center, double-blind, randomized, placebo-controlled interventional trial conducted at GB Pant Institute of Post Graduate Medical Education and Research in Delhi, India, over 16 months. The Institutional Ethics Committee approved the study. The study was conducted according to the International Council for Harmonization Good Clinical Practice regulations and guidelines. The study follows the tenets of the Declaration of Helsinki. The trial was registered with the Clinical Trials Registry of India. (CTRI/2021/12/038397).

All patients provided written informed consent before enrolment in the study. Eligible patients were aged 18–65 years and had a history of ECH, according to the International Classification of Headache Disorders-3 (ICHD-3) (1). Patients had at least one CP before the current bout, with one or more cluster attack per 24 h in the seven days before inclusion. The duration of the CP prior to randomization had to be less than two weeks. Eligible patients were either not on preventive medication or had to be on stable doses of preventive medications for the last three months before inclusion.

The following were the exclusion criteria: secondary CH, CP always lasting less than two weeks, patients who were recently started on preventive treatment (within three months), history of receiving GONB in the last three months, pregnant females, patients on oral anticoagulants or with a known bleeding disorder, patients with a contraindication to lignocaine or methylprednisolone and those who were already on oral corticosteroids for any other systemic and skin diseases.

Patients could use their preferred acute attack treatment but were limited to high-flow oxygen, intranasal zolmitriptan (subcutaneous sumatriptan was not available in India at the time of the trial), and oral analgesics. The detailed study protocol, including all inclusion and exclusion criteria and the permitted/restricted medications, is available in the Supplemental Material document.

Randomization and masking

All enrolled and eligible patients were randomly assigned 1:1 to receive either GONB with 2 ml of 2% lignocaine and 2 ml (80 mg) of methylprednisolone or a sham GONB with 4 ml of 0.9% normal saline. Randomization was done using a computer-based block randomization chart using small blocks, and patients were allocated to groups A or B (1:1) by investigator 1 (D.C.). Sequentially numbered opaque sealed envelopes and 40 labels were prepared for each injection labeled A or B. The labels were put inside the envelopes numbered from 1 to 40 according to the randomization chart by investigator 1. On the outside of the envelopes only a randomization code was printed. Envelopes were attached to the patient's proforma. Patients were recruited sequentially and were given enrollment numbers starting from 1, which was mentioned on their outpatient cards by investigator 2 (S.R.K.). Proforma carrying the same number as the patient enrolment number was then opened, and the patients were assigned to receive injections A or B based on their randomization by investigator 3 (R.N.). Investigator 3 prepared injections A and B and handed them to Investigator 1. Investigator 1 performed the GONB per standardized procedure (12) and was blinded to the group allocation. Investigator 2, blinded to the group allocation, documented the baseline characteristics and outcome in subsequent visits.

Trial procedures

Patients fulfilling the inclusion criteria were screened and randomized. Screening (visit −7) and randomization (visit 0) could occur on the same day. Baseline headache parameters, including the past week's attack frequency (seven days preceding the first visit), were estimated retrospectively at the time of randomization based on the patient's history. For patients presenting within seven days of the onset of the current CP, the weekly attack frequency was estimated, prorating the average attack frequency of the days since the onset. The duration of the double-blind treatment phase (DBTP) was 28 days. Patients who had remission by Week 1 were only started on add-on preventives once they became symptomatic again. Those with persistence of attacks at the end of Week 1 had the option of preventive add-ons in the form of oral verapamil tablets or escalation of the verapamil dose (if they were on stable verapamil dose prior to randomization) following a standardized protocol (supportive document). Briefly, verapamil was initiated at 40 mg three times a day and increased by 40 mg every three days up to 720 mg/day. The efficacy and safety assessment for DBTP was done at the end of Week 4 after the GONB. In the open-label treatment phase (OLTP), patients in both groups who continued to have attacks were offered another GONB with methylprednisolone and lignocaine at the end of Week 4 and continued with oral verapamil. The efficacy and safety of the second GONB during the open-label phase were assessed at the end of Week 8 and Week 12. Patients were followed up to Week 52 (physically or telephonically), and the recurrence of CP, the treatment received, and the remission were recorded. Oral, intramuscular, or intravenous steroids were not allowed during the entire DBTP. The trial design is depicted in Figure 1. This paper only describes the results of the DBTP.

Figure 1.

Trial design.

All patients were evaluated using a detailed structured proforma covering demography and the clinical characteristics of headaches. If not previously done, relevant hematological and biochemical tests (hemogram, kidney, liver, and thyroid function) and MRI brain were also done to exclude secondary causes. Patients were asked to maintain a paper headache diary and note the following parameters: attack frequency, attack duration, attack severity, and the number of times the acute treatment was used throughout the trial period. Detailed assessments of CAS and restlessness during the attacks were made, including the presence or absence of CAS, types of CAS, and duration of CAS (by averaging the duration of each CAS). The persistence of CAS was extracted from the records across all attacks. Restlessness was graded on a scale of 1–4, with 1 being absent, 2 mild (rubbing or pressing repeatedly the ipsilateral head but able to lie down or sit still), 3 moderate (unable to lie or sit still or pacing around), and 4 severe (verbalizing, crying, continuously tossing, turning or moving and self-harming behavior such as hitting head against a wall). The headache impact was assessed by the Headache impact test (HIT6) (13), and headache-related disability was assessed by headache disability inventory (HDI) (14) and VAS (15) for the severity of the headache. The cluster headache quality of life scale (CHQOL) (16) was used to measure quality of life before and after the intervention. A simple verbal scale indicated patient satisfaction with treatment: poor, moderate, good, excellent. Complete remission was defined as the total absence of cluster attacks for the duration of DBTP.

GONB injection protocol

GONB was performed using a standardized method (12) by a single investigator (D.C.). The injection site was marked, i.e., approximately two-thirds of the distance on a line drawn from the center of the mastoid to the external occipital protuberance, only if these points exhibited conspicuous pain sensitivity to pressure. Before the injection of GONB, on the marked point and an area surrounding it with a 3 cm diameter, lignocaine jelly was applied topically to mask the effect of numbness following the GONB. Injection was given on the symptomatic side after 10 min of topical application of lignocaine. The patient was appropriately positioned by slight neck flexion. The injection site was cleaned with spirits to give GONB under aseptic precaution. One-third of the injection was injected in that area, one-third slightly medially, and one-third slightly laterally. 80 mg of methylprednisolone (2 ml) and 2 ml of 2% lignocaine were injected in group A patients, and 4 ml of 0.9% saline was injected into the patients in group B. Both the injections were identical and could not be differentiated from each other.

Outcomes

The primary endpoint was the mean change in weekly attack frequency from baseline to end of Week 4. Key secondary endpoints included the proportion of patients achieving complete remission of pain (disappearance of attacks) within four days to Week 1 (‘sustained attack- free day 4-Week 1’) and within four days to Week 2 (‘sustained attack- free day 4-Week 2’). Other secondary endpoints included mean change in weekly attack frequency from baseline to end of Week 1, 2 and 3; achievement of complete remission of pain (disappearance of attacks) within four days to Week 3 (‘sustained attack-free day 4-Week 3’), within four days to Week 4 (‘sustained attack-free day 4-Week 4); mean change in weekly attack severity and duration from baseline to end of Weeks 1, 2, 3 and 4; changes in the occurrence rates, duration, number and persistence of CAS, change in the severity of restlessness from baseline to Week 4, mean total number of attacks between day 1 and day 28; mean total number of attacks between day 1 and day 3; proportions of patients needing repeat GONB at Week 4; total number of times the specific acute treatment used during the entire DBTP; proportion of patients requiring additional verapamil treatment or escalation of the existing dose ; mean verapamil dose at Week 4; changes in HIT-6, HDI and CHQOL scores from baseline (at the time of randomization) to Week 4; total number and type of treatment-emergent adverse effects (TEAE) and serious adverse events and patient's satisfaction at the end of Week 4.

Statistical analysis

The statistical analyses were performed according to a prespecified plan. The analysis was done at the end of the DBTP. The descriptive statistics by each treatment group were tabulated at each visit. The sample size was calculated based on the estimates provided by a previous study that showed 95% of the patients receiving the GONB achieved a reduction in the mean number of attacks per day to two or fewer as compared to 55% of the placebo group (odds ratio 14.5, 95% CI 1.8–116.9; p = 0.012) (9). Using a two-sample t-test with a two-sided significance level of 0.05 and 80% power, the sample size was estimated to be 18 patients in each group. The planned sample size was 20 patients in each group assuming a 10% loss during follow-up. To maintain the overall type I error rate at a two-sided alpha level of 0.05 for the primary and key secondary endpoints, a prespecified hierarchical gatekeeping strategy was used in which the significance of the key secondary endpoints would be evaluated only if a significant treatment effect in the primary efficacy endpoint was achieved. If the key secondary endpoints were met, all other secondary endpoints were evaluated irrespective of the treatment effect.

Statistical analysis was done with SPSS version 25 and R statistical software (v 4.1.2; R core Team 2021). Categorical data was summarized as frequencies and percentages, and continuous data was summarized as mean and standard deviation.

Efficacy analysis

We performed efficacy analysis in a modified intention-to-treat (mITT) population that included all patients who received at least one injection of GONB in DBTP and had a follow-up for one week following GONB. For the primary and secondary endpoints, which were measured at various time points (Week1, 2, 3 and 4), a least-square-mean (LSM) change from baseline was calculated using a linear mixed-effects model for repeated-measures that included participants as a random effect, baseline weekly values (1-week pre-randomization) as covariates. The model included fixed categorical effects of the treatment group, sex (male or female), use of preventive medication during DBTP (yes or no), and week and week-by-treatment group interaction without any imputation for missing data. We reported the LSM change from baseline for each treatment group, treatment difference compared with placebo, 95% CI, and p values for pairwise comparison. The continuous secondary endpoints that were measured at baseline and the end of Week 4 such as HIT-6, HDI, CHQOL, number, duration and CAS persistence across attacks and severity of restlessness were analyzed using a generalized linear model with treatment group, sex (male or female); use of preventive medication during DBTP (yes or no) and the week-by-treatment group interaction as factors and baseline values (1-week pre-randomization) as covariates without imputing the missing data. For the secondary efficacy endpoints, such as the proportions of patients in each group having a sustained attack-free interval from Day4-Week1, Day4-Week2, Day4-Week3, and Day4-Week4, we used a Cochran Mantel-Haenszel test. We reported adjusted odds ratio (OR), 95% CI, and p values. The patients with missing data in Week 4 were considered non-responders. Other secondary endpoints such as dose of verapamil required per day and the proportions of patients requiring another GONB at Week 4 were analyzed by student-test and chi-square test (or Fisher's exact test) respectively. The level of significance was set at p < 0.05.

Results

Between 10 December 2021 and 10 January 2023, 46 consecutive episodic cluster headache patients in their current CP were screened. Six patients were excluded as they did not fulfill the inclusion criteria. Forty patients were enrolled in the study and assigned treatment after randomization. Twenty participants were randomized to receive GONB with 2 ml of 2% lignocaine and 80 mg methylprednisolone (2 ml) or placebo (4 ml of 0.9% normal saline). Thirty-nine participants were included in the mITT analysis (19 in the active and 20 in the placebo groups). The flow of the study is depicted in Figure 2. The trial groups were balanced concerning demographics and clinical characteristics (Table 1).

Figure 2.

Flow of the study.

Table 1.

Baseline characteristics of the study population.

	Active Group(GONB with MPS and lignocaine)(n = 20)	Placebo Group(GONB with normal saline)(n = 20)
Mean age (years)	39.4 (11.2)	34.5 (11.3)
Male	18 (90%)	17 (85%)
Female	2 (10%)	3 (15%)
Disease duration (years)	8.3 (7.3)	6.1 (5.0)
Delay in diagnosis (years)	5.6 (6.7)	5.0 (4.5)
Average duration of previous cluster periods (days)	37.2 (15.9)	34.7 (18.4)
Average duration of previous remission periods (months)	9.4 (2.1)	8.2 (2.6)
Number of cluster periods prior to current CP	6.4 (6.2)	5.2 (4.6)
Circumannual periodicity	15 (75%)	14 (70%)
Mean duration of current CP (days)	8.8 (1.6)	9.6 (2.2)
Mean weekly attack frequency	11.8 (3.9)	10.0 (3.5)
Mean attack duration (minutes)	71.4 (27.5)	61.1 (18.6)
Mean attack severity	9.9 (0.2)	9.6 (0.4)
Mean number of cranial autonomic symptoms/attack	2.3 (0.6)	2.8 (1.2)
Mean duration of cranial autonomic symptoms (minutes)	32.7 (11.8)	26.1 (9.4)
Mean percentage of attacks with cranial autonomic symptoms	71.3 (20.3)	69.5 (16.2)
HIT-6 score	69.9 (2.4)	68.6 (3.7)
HDI score	80.5 (4.8)	78.3 (9.3)
CHQOL score	85.3 (7.0)	83.0 (10.3)
Number of patients on verapamil	5 (25%)	5 (25%)

Baseline data were estimated retrospectively based on the patient's history for 7 days preceding randomization. Data are n (%), mean (SD); GONB: greater occipital nerve block; MPS: methylprednisolone; HIT-6-headache impact test; HDI-headache disability inventory; CHQOL-cluster headache quality of life

With respect to the primary endpoint, the change in weekly attack frequency from baseline to the end of 4 weeks was −11.1 (95% CI: −8.5 to −4.4) for the active group compared to −7.7 (95% CI: −11.8 to −9.8) for placebo. The mean difference between the two groups was −3.4 (95% CI: −5.2 to −1.7, p < 0.001) (Table 2). The weekly attack frequency from baseline to the end of Weeks 1, 2, and 3 also showed a significantly greater reduction in the active group than in the placebo group (Figure 3).

Figure 3.

Change in weekly attack frequency.

Table 2.

Primary and key secondary outcomes.

	Active Group(GONB with MPS and lidocaine)(n = 19)	Placebo Group(GONB with normal saline)(n = 20)	Mean difference (95% CI)Or Odd's Ratio(95% CI)	p-value
Primary end point
Change in mean weekly attack frequency from baseline to Week 4	−11.1 (−13.3 to −9.0)	−7.7 (−11.8 to −9.8)	−3.4 (−5.2 to −1.5)	<0.001
Key secondary endpoints
Proportion of patients with sustained attack-free period between Day 4 – Week 1	10 (52.6%)	4 (20%)	4.4 (1.1 to 18.4)	0.039
Proportion of patients with sustained attack-free period between Day 4 – Week 2	14 (73.7%)	6 (30%)	6.5 (1.6 to 26.5)	0.009

GONB: greater occipital nerve block; MPS: methylprednisolone.

The key secondary endpoints were also met. A significant difference was found between the active and the placebo groups in the proportion of patients achieving complete remission of pain from Day 4-Week 1 and Week 2. Ten patients (52.6%) from the active group achieved complete remission in the first week compared to four patients (20%) in the placebo group (OR = 4.4, 95% CI = 1.1–18.4, p = 0.039). Fourteen patients in the active group (73.7%) achieved complete remission in Week 2 compared to six patients (30%) in the placebo group (OR = 6.5, 95% CI = 1.6–26.5, p = 0.009) (Table 2). However, there was no significant difference in the complete remission rates between the groups in Week 3 and Week 4 (Figure 4). Regarding the use of verapamil, five patients each in active and the placebo group were on low doses of verapamil [88(±17.9) and 104(±21.9) mg respectively] at baseline. After Week 1, an additional seven and twelve patients in the active and the placebo group, respectively, required verapamil. By the end of Week 4, twenty-nine patients (twelve in the active and seventeen in the placebo group) were receiving verapamil. There was no statistically significant difference in the mean daily doses of verapamil used by the patients in the active and the placebo groups at Week 4 (186.7 ± 105.8 mg/day versus 237.3 ± 123.3 mg/day; p = 0.869). At Week 4, 34 patients completed the DBTP (16 in the active treatment group and 18 in the placebo group). None of the patients in the active group needed another GONB compared to five in the placebo group (p = 0.046). The other secondary endpoints are summarized in Table 3. At the end of Week 4, 80% of patients receiving active treatment and 65% receiving placebo reported overall satisfaction as good or excellent.

Figure 4.

Proportion of patients achieving complete remission.

Table 3.

Other secondary endpoints.

	Active Group(GONB with MPS and lignocaine)(n = 19)	Placebo Group(GONB with normal saline)(n = 20)	Mean difference (95% CI)	p-value
Change in mean weekly attack frequency
Baseline to Week 2	−9.8 (−11.9 to −7.7)	−4.7 (−6.8 to −2.7)	−5.1 (−6.8 to −3.3)	<0.001
Baseline to Week 3	−10.6 (−12.7 to −8.5)	−6.5 (−8.5 to −4.4)	−4.1 (−5.9 to −2.3)	<0.001
Baseline to Week 4	−11.1 (−13.3 to −9.0)	−7.7 (−11.8 to −9.8)	−3.4 (−5.2 to −1.5)	<0.001
Proportion of patients with sustained attack-free period
Day 4 – Week 3	15 (78.9%)	11 (55%)	3.1 (0.7 to 12.6)	0.120
Day 4 – Week 4	16 (84.2%)	13 (65%)	2.9 (0.6 to 13.4)	0.179
Change in mean attack duration
Baseline to Week 1	−40.7 (−53.1 to −28.3)	−28.1 (−40.1 to −16.0)	−12.6 (−23.1 to −2.1)	0.022
Baseline to Week 2	−61.0 (−73.5 to −48.4)	−41.1 (−53.5 to −28.7)	−19.8 (−30.5 to −9.0)	<0.001
Baseline to Week 3	−66.4 (−79.1 to −53.6)	−47.2 (−59.6 to −34.8)	−19.2 (−30.0 to −8.4)	<0.001
Baseline to Week 4	−70.9 (−84.0 to −57.9)	−52.2 (−64.6 to −39.8)	−18.8 (−29.7 to −7.9)	0.001
Change in mean attack severity
Baseline to Week 1	−1.2 (−3.3 to 0.8)	−1.0 (−3.0 to 1.0)	−0.2 (−2.0 to 1.5)	0.819
Baseline to Week 2	−6.4 (−8.5 to −4.3)	−3.1 (−5.2 to −1.0)	−3.3 (−5.1 to −1.5)	<0.001
Baseline to Week 3	−8.4 (−10.5 to −6.2)	−4.8 (−6.9 to −2.7)	−3.6 (−5.3 to −1.7)	<0.001
Baseline to Week 4	−9.2 (−11.4 to −7.0)	−6.9 (−9.0 to −4.8)	−2.3 (−4.1 to −0.4)	0.019
Total number of attacks
Day 1–28	7.9 ± 3.4	19.0 ± 3.4	−11.0 (−18.4 to −3.7)	0.004
Day 1–3	2.6 ± 0.4	3.5 ± 0.4	−0.9 (−1.7 to −0.09)	0.030
Change in cranial autonomic symptoms and restlessness from baseline to Week 4
Number of CAS/attacks	−2.1 (−2.8 to −1.4)	−1.5 (−2.2 to −0.9)	−0.6 (−1.3 to 0.1)	0.107
Mean duration of CAS (minutes)	−32.8 (−38.0 to −27.7)	−22.3 (−27.2 to −17.4)	−10.5 (−15.9 to −5.1)	<0.001
Percentage of CAS/attack	−70.4 (−81.9 to −58.9)	−57.3 (−68.3 to −46.3)	−13.1 (−25.2 to 0.9)	0.039
Severity of restlessness	−2.5 (−2.9 to −2.2)	−2.1 (−2.5 to −1.8)	−0.4 (−0.7 to −0.03)	0.036
Change in headache impact scores from baseline to Week 4
HIT-6 score	−30.3 (−32.7 to −27.9)	−20.1 (−22.4 to −17.8)	−10.2 (−12.7 to −7.7)	<0.001
HDI score	−52.2 (−58.2 to −46.2)	−38.9 (−44.6 to −33.2)	−13.3 (−9.6 to −7.0)	<0.001
Change in quality of life from baseline to Week 4
CHQOL score	−56.2 (−61.4 to −51.0)	−45.1 (−50.1 to −40.2)	−11.1 (−16.6 to −5.6)	<0.001

GONB: greater occipital nerve block; MPS: methylprednisolone; CAS: cranial autonomic symptoms; HIT-6: headache impact test; HDI: headache disability inventory; CHQOL: cluster headache quality of life.

Safety

GONB with both the active drug and placebo was well tolerated, and only minor and transient adverse effects were noted. We recorded 18 TEAE in each group, and the mean number of TEAE following GONB injection was similar in both groups. The most common TEAE observed were local site reactions with local site bleeding (35%) and pain at the injection site (30%) (Table 4). No serious adverse events (SAE) were reported.

Table 4.

Adverse events.

Adverse Events	Active Group(GONB with MPS and lidocaine)(n = 20)	Placebo Group(GONB with normal saline)(n = 20)
At least one adverse event	18 (90%)	18 (90%)
At least one adverse event related to the trial regimen	17 (85%)	17 (85%)
At least one serious adverse event	0	0
Any adverse event leading to the discontinuation of the trial	0	0
Death	0	0
Adverse events reported by the patients
Local site bleeding	8 (40%)	6 (30%)
Local site pain	7 (35%)	5 (25%)
Local site swelling	3 (15%)	8 (45%)
Local site numbness	2 (10%)	4 (10%)
Dizziness	2 (10%)	0
Syncope	0	1 (5%)
Local site restricted alopecia	1 (5%)	1 (5%)
Local site pruritis	1 (5%)	0

Discussion

This study showed that a single GONB with 2 ml of methylprednisolone (80 mg) and 2 ml of 2% lignocaine was superior to placebo (GONB with 4 ml of 0.9% saline) in reducing the weekly CH attacks in ECH patients. GONB was safe and well tolerated.

In this study, the patients randomized into the active and placebo groups were balanced at baseline and had a weekly attack frequency of 11.8 ± 3.9 and 10.0 ± 3.5, respectively. The patients receiving the active treatment had a significantly greater reduction of 3.4 attacks per week (95% CI: −5.2 to −1.7, p < 0.001) compared with those receiving the placebo at the end of Week 4. Further, the change in weekly attack frequency from baseline to the end of Week 1, 2, and 3 was also significantly superior for the active group compared with placebo. The mean difference in weekly attack frequency between the two groups was −3.4, −5.1, and −4.1 at the end of Week 1, 2, and 3, respectively. Thus, the superior efficacy of GONB as a transitional preventive treatment for ECH patients compared with placebo was evident as early as Week 1 and was sustained until Week 4. The previous double-blind RCTs did not assess the change in weekly attack frequency (8,9). However, the RCT using oral prednisolone as the transitional treatment in ECH patients reported a mean reduction of 2.4 attacks at the end of Week 1. The total CH attacks decreased by −4.7 from baseline to day 28 (4). Therefore, in the current study, the efficacy of GONB as a transitional preventive in patients with ECH for reducing CH attack frequency seems comparable to oral prednisolone. It is possible, however, that by Week 4, some of the patients in both the groups had spontaneous remissions and the results should be interpreted with caution. The patients in our study, however, received active and sham treatments within 8.8(±1.6) and 9.6(±2.2) days of the start of current CP. Based on history, the patients in the active and sham group had a mean duration of previous CPs of 37.2(±15.9) and 34.7(±18.4) days respectively. Hence, we believe that most patients had the observed outcomes due to the interventions received.

At the end of Weeks 1 and 2, a significantly higher proportion of patients receiving the active drug (52.6% and 73.3%) achieved complete remission compared with 20% and 30% in the placebo group, respectively. This finding is important because it suggests that a single GONB with methylprednisolone and lignocaine can induce complete remission of CH attacks in more than two-thirds of patients by Week 2. This beneficial effect could partly be due to spontaneous remission and the effect of the verapamil. However, the patients included in this study had, on average, more than one month of CH attacks in their previous cluster periods and were recruited within an average of less than ten days of their current CP onset. Also, verapamil was initiated only after Week 1 with a lower dose. Hence, verapamil is unlikely to impact remission by the end of Week 2 significantly. Additionally, for the efficacy analysis, we used a linear mixed-effects model for repeated-measures that adjusted for use of verapamil. The high complete remission rates during the early weeks following GONB, thus make it an attractive option as a transitional preventive for ECH patients. The differences between the two groups, however, became non-significant, possibly due to the escalation of verapamil dose by Weeks 3 and 4 and the spontaneous remissions that could have happened. Ambrosini et al. (8) reported a remission within the first 72 h of GONB sustained up to four weeks in 61% of patients who received the active drug compared with none receiving the placebo. Leroux et al. (9) reported that 76% of patients in the active group were in remission at Week 4 following GONB, compared with 59% in the placebo group. We found a comparable but slightly better remission rate of 84.2% at Week 4 in the active group versus 65% of those receiving placebo.

Among the other secondary endpoints, there was a significant reduction in attack duration and severity for the patients receiving the active GONB. A few open-label studies have shown a similar reduction in attack duration and severity following GONB in CH patients (17,18). The total number of attacks between days 1–3 and 1–28 in patients receiving the active treatment was significantly less (0.9 and 11 attacks, respectively) than those receiving placebo. Contrary to the belief that the effect of GONB usually becomes evident only about three days after the injection (8,9), the results of this study show that the effect of GONB in reducing the attack frequency starts early and is sustained till Week 4. The mean difference in the number of attacks between the active and the placebo group in the RCT conducted by Leroux et al. (9) was even higher, −19.7 for Days 1–15. However, the patients in this RCT reported a much higher daily average attack frequency at baseline (3.6 and 4.7 attacks per day in the active and placebo groups, respectively) and had multiple GONBs.

Patients receiving active GONB had a significantly greater reduction in the mean duration of CAS per attack and the persistence of CAS across attacks at Week 4 compared with baseline. There was, however, no significant change in the number of CAS per attack between the two groups. Despite being included in the diagnostic criteria, previous studies have not studied the effect of GONB on CAS and restlessness in CH patients. CAS can be very distressing for the patients, and hence, a reduction in the duration and their persistence across attacks by GONB could be clinically meaningful. Similarly, a significant reduction in the intensity of restlessness in patients receiving active GONB could be an important factor in reducing the attack-related disability.

Five patients in each the active and the placebo group were on stable low doses of verapamil at the time of randomization. It is not uncommon for ECH patients to continue verapamil in low doses despite the end of their cluster period because of the fear of recurrence. Both the previous RCTs included some patients with a stable dose of verapamil at baseline and prescribed verapamil either at the start of the trial (Leroux et al. (9)) or after Week 1 (Ambrosini et al. (8)), with the provision of escalating the dose over four weeks. This approach is justified from an ethical point of view of not depriving patients of an established preventive treatment and aiming to assess the transitional efficacy of GONB, a bridging treatment, until the preventive treatment takes effect. We also followed a similar approach. At Week 4, the mean dose of verapamil for the active group (186.7 ± 105.8 mg/day) was lower compared to the placebo group (237.3 ± 123.3 mg/day) but did not reach statistical significance (p = 0.869). Leroux et al. however, reported that patients who received GONB with cortivazol required a lower dose of verapamil compared to those who received placebo at four weeks (9). None of the patients receiving the active GONB required a repeat injection at Week 4 compared with 27.8% of patients who received placebo, again demonstrating the superior efficacy of GONB compared with placebo.

This study found that patients receiving the active treatment had significantly greater improvements in patient-reported outcome measures (PROM) such as headache impact (HIT-6), headache disability (HDI), and quality of life (CHQOL) compared with those in the placebo group. PROM has been sparsely studied in CH patients, and to the best of our knowledge, this double-blind trial is the only RCT that assessed the changes in PROM following a GONB.

Both groups reported mild and transient adverse effects equally. There were no serious adverse effects, and none of the patients in either group discontinued the study due to adverse effects. All discontinuations in both groups occurred due to the continuation of CH attacks despite the interventions. The two previous RCTs also reported good tolerability of GONB in CH patients (8,9).

This study has strengths and limitations. Strengths include robust study design using IHS-recommended outcome measures, local lignocaine jelly application before GONB for masking, and inclusion of CAS, restlessness and various PROM in the secondary outcomes. Local application of lignocaine at the injection site though could have potentially provided a very small but possible effect on efficacy. Limitations include using verapamil as a preventive, relatively small sample size, and single-center experience. Despite these limitations, the findings of this study underscore the utility of GONB with methylprednisolone and lignocaine as a transitional preventive for patients with ECH. A head-to-head study comparing GONB with oral prednisolone may shed further light on their relative effectiveness in ECH patients.

Clinical implications

A single GONB with 2 ml of methylprednisolone (80 mg) and 2 ml of 2% lignocaine significantly reduced the weekly attack frequency compared with a placebo in patients with ECH.

About half and two-thirds of the patients receiving active GONB had complete remission of cluster headache attacks starting from Day 4 to the end of Weeks 1 and 2 respectively.

GONB was well tolerated except for a few minor and transient adverse effects.

GONB with methylprednisolone and lignocaine seems to be a good alternative to oral steroid treatment for patients with ECH.

Supplemental Material

sj-pdf-1-cep-10.1177_03331024241291597 - Supplemental material for ANODYNE study: A double-blind randomized trial of greater occipital nerve block of methylprednisolone and lignocaine versus placebo as a transitional preventive treatment for episodic cluster headache

Supplemental material, sj-pdf-1-cep-10.1177_03331024241291597 for ANODYNE study: A double-blind randomized trial of greater occipital nerve block of methylprednisolone and lignocaine versus placebo as a transitional preventive treatment for episodic cluster headache by Debashish Chowdhury, Sanjay Rao Kordcal, Rahul Nagane and Ashish Duggal in Cephalalgia

Footnotes

Acknowledgements

We thank Debanjan Chowdhury, Heidelberg University, Germany for his invaluable suggestions and inputs. Some of the results of this trial were presented as late breaking abstract during the International Headache Congress at Seoul in 2023

Author contributors

D.C. conceptualized the design of the trial. D.C., S.R.K., R.N. and A.D. organized the study. S.R.K. acquired the data. D.C. analyzed the data and performed the statistical analysis. D.C. and S.R.K. wrote the first draft of the manuscript and interpreted the findings. R.N. and A.D. critically reviewed the manuscript. All authors provided their input to the manuscript.

Data sharing

The ANODYNE study trial data will be made available on request, from the time of publication of the article after approval of a formal written request. The corresponding author needs to be contacted for access to trial data.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Debashish Chowdhury

Sanjay Rao Kordcal

Supplemental Material

All supplemental material mentioned in the text is available in the online version of the journal.

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Supplementary Material

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