Observational,open-label,non-randomized study on the efficacy of onabotulinumtoxinA in the treatment of nummular headache: The pre-numabot study

Abstract

Background

Nummular headache is a primary headache characterised by superficial, coin-shaped pain. Superficial sensory fibre dysfunction might be involved in its pathophysiology. Considering the mechanism of action of onabotulinumtoxinA, it could be a reasonable option in treatment of nummular headache. The aim of the study was to evaluate the efficacy and tolerability of onabotulinumtoxinA in a series of nummular headache patients.

Patients and methods

This was an observational, prospective, non-randomized and open-label study. Nummular headache patients with at least 10 headache days in three preceding months were included. They were administered 25 units of onabotulinumtoxinA. The primary endpoint was the decrease of headache days per month, evaluated between weeks 20 to 24, compared with baseline. The secondary endpoints included reduction of intense headache days and acute treatment days evaluated between weeks 20–24 and weeks 8–12, compared with baseline. The 30%, 50% and 75% responder rates were determined, and tolerability described.

Results

We included 53 patients, 67.9% females, with a median age of 54 years. Preventive treatment had been used previously in 60.4% of patients. The median diameter of the nummular headache was 5 cm. At baseline, the number of headache days per month was 24.5 (7.3); the number of intense headache days was 12.5 (10.1), and the number of acute treatment days was 12.8 (7.8). After onabotulinumtoxinA, the mean number of headache days per month decreased to 6.9 (9.3) between weeks 20 and 24 (p < 0.001). Secondary endpoints concerning intense headache days per month and acute treatment days per month were also statistically significant (p < 0.001). The 50% responder rate, evaluated between weeks 20 and 24, was 77.4% and the 75% responder rate was 52.8%. Concerning tolerability, 26 patients (49.1%) experienced an adverse event (AE), the commonest being injection-site pain in 12 cases (22.6%). There were no moderate or severe AEs.

Conclusion

It was found that after injecting onabotulinumtoxinA, the number of headache days per month was reduced in nummular headache patients. The number of intense headache days per month and acute treatment days were also lowered. No serious adverse events occurred during treatment.

Keywords

Headache disorders botulinum toxins (onabotA)drug therapy nummular headache

Introduction

Nummular headache (NH) is an uncommon primary headache. It represents 4% of all patients evaluated for headache in headache-clinic based series (1). It is characterised by superficial pain, sharply contoured, with a fixed round or elliptical shape and size, which can range from 1–6 cm (2–3). Its pathophysiology suggested impairment of superficial sensory terminations, considering its superficial topography, precise location, and the frequent presence of circumscribed allodynia and trophic changes as a marker of superficial sensory fiber dysfunction (4 –7). Preventive treatment is required in two third of patients. Gabapentin is the first line treatment, whereas use of many other prophylactics drugs has been described, with inconsistent results and no randomised controlled trials (RCT) to date (4,8,9).

OnabotulinumtoxinA (onabotA) is a metalloprotease that binds to a receptor-specific presynaptic nerve terminal, internalised via endocytosis, leading to the enzymatic cleavage of intracellular synaptosomal-associated protein SNAP25 to an inactive form. This protein becomes unable to mediate neuroexocytosis and vesicular recycling, inhibiting neurotransmitter and neuropeptide release from nerve fibre endings, which affects important neurotransmitters involved in pain, such as substance P, glutamate and calcitonin-gene related peptide (CGRP) in the presynaptic endings of primary afferent neurons (10). Its effect in nociceptive transmission is primarily in the amyelinic C-fibers, but a possible effect in the Aδ fibers has been suggested by its modulation of CGRP secretion (11). This mechanism of action seems attractive considering NH pathophysiology.

Since 2008, some observational studies have described the use of onabotA in NH patients. Four patients with no or mild response to gabapentin improved after the injection of 25 onabotA units (12). Three out of five patients with inadequate response to oral preventive drugs responded to 10–25 onabotA units (13). One patient refractory to gabapentin and duloxetine improved after onabotA (14). Eight patients with absent or partial response to 2–4 preventive prophylactics had partial (one case) or excellent (seven cases) response to 25–35 U of OnabotA (15). In those studies, no relevant adverse events were described. Moreover, local administration of small doses is unlikely to cause serious adverse events, and thus is an interesting option in patients with tolerability problems or interactions. Considering NH pathophysiology, the potential adverse effects of oral preventive drugs and the reported cases of patient improvement with the use of onabotA, we designed an observational study to evaluate whether onabotA is effective in improving headaches in a series of NH patients.

Patients and methods

An observational, prospective, non-randomized, open-label study evaluating the efficacy and safety of onabotA in the treatment of nummular headache was undertaken. The study was done according to the Strenghtening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines (16). We considered and adapted recommendations from IHS guidelines for preventive drug trials in migraine (17).

The study population consisted of NH patients that were evaluated in the headache clinic of the University Hospital of Valladolid, Spain, a third level hospital with a reference population of 280,000 patients and about 2,000 headache patient visits per year.

Inclusion criteria were: a) age over 18 years, b) definite NH diagnosis according to International Classification of Headache Disorders (ICHD) criteria operating at the moment (3,18), c) ability to give informed consent, d) at least 10 headache days per month in the preceding 3 months. Patients were excluded if: a) a secondary NH was diagnosed, b) the presence of another primary headache with a frequency of more than 10 headache days per month at the moment was identified, c) any other painful condition with more than 10 pain days per month was present, d) there had been drug abuse in the 12 prior months; e) they were pregnant or breastfeeding. Preventive drug use was allowed if it was stable in the prior 3 months with no expected changes during the first 3 months, and only in monotherapy. Use of acute treatment was not restricted. We tried to avoid selection bias through inclusion/exclusion criteria.

All patients underwent physical examination and imaging, either with cranial tomography or magnetic resonance in order to rule out a secondary form of nummular headache.

The study period was from 1 February 2017 to 21 May 2019. Recruitment was non-probabilistic by opportunism. All consecutive cases that fulfilled the inclusion and exclusion criteria were included, and the selection of patients and the reasons for non-inclusion or exclusion were detailed. The sample size was not estimated a priori. We did not anticipate any dropout rate, but the patients that discontinued the treatment and their reasons were detailed.

A specialized nurse prepared an onabotA solution diluted in 5 units per 0.1ml of isotonic saline. A trained headache specialist injected 25 units of onabotA divided over five points, creating a cross with a 30 gauge needle that included the largest diameter, and injecting 5 units per point. Treatment was given at week 0 and repeated at week 12.

Patients were instructed to keep a headache diary in which they detailed headache episodes, intensity of episodes on a 0–10 scale and need for symptomatic treatment. Participants registered their clinical situation during the 4 weeks before onabotA administration and daily during the first 24 weeks.

In the first visit, we registered demographic variables such as age, gender, and age of onset, as well as clinical variables such as months of evolution, diameter, intensity of baseline pain, topography, duration of episodes, presence and intensity of exacerbations, presence of allodynia, prior use of symptomatic or preventive drugs, and current preventive drugs. We considered intensity as stable if less than ± 1 VAS variations were described. We defined prior response to preventive drugs according to IHS guidelines (17), considering response to be a decrease of at least 50% compared with baseline, and partial response if the response was from 30–49%.

Information from the headache diary was also included, such as the number of headache days per month, the number of intense headache days per month, and the number of symptomatic treatment days and adverse events. A headache day was defined as the presence of pain in the nummular area that lasted at least 4 hours, or a day with a headache that was successfully treated by an acute medication. Intense headache days were defined as headache days in which the patient additionally reported pain intensity of 7 or more on a 0–10 scale. We allowed patients to spontaneously report adverse events (AEs) but we also actively evaluated the most frequently described AEs in trials using onabotA.

The local ethics committee board approved the study (PI: 17-533) and all patients signed the informed consent form and kept a copy.

End points

The primary end point of the study was the decrease of headache days per month evaluated at 24 weeks, including weeks 20–24, compared with headache days per month during the baseline period. Secondary endpoints were: a) Decrease of headache days per month evaluated at 12 weeks, including weeks 8–12 compared with baseline; b) decrease of intense headache days per month compared with baseline evaluated at 12 and 24 weeks, including the four preceding weeks each time; c) acute treatment use per month compared with baseline, evaluated at 12 and 24 weeks, assessed in the periods between weeks 8–12 and 20–24; d) 30%, 50% and 75% responder rate at 12 and 24 weeks. The presence of AEs in terms of absolute frequency and percentage of patients were also described. As exploratory endpoints, we tried to evaluate response predictors, trying to determine potential variables associated with a positive response or that were possible effect modifiers.

Statistics

Qualitative data are presented as frequency and percentage, and continuous data as mean and standard deviation or median and interquartile range [IQR] if the distribution does not fit normal distribution. In the primary end point, the null hypothesis was an equal number of headache days per month between the baseline and during weeks 20–24, and an alternative hypothesis was the difference in number of headache days. We analysed per protocol and per intention to treat. In the contrast to the hypothesis, we checked for normal distribution with the Kolmogorov-Smirnov (KS) test, in the case of non-normal distribution we used the Wilcoxon test, and if distribution was normal and variance was homogeneous according to the Levene test, we used a paired-t test and included degrees of freedom (df). In the case of secondary endpoints 1, 2 and 3, the same statistical analysis was undertaken. Multiple comparisons were compensated for by Bonferroni adjustment. In the primary endpoint and first three secondary endpoints, six comparisons were made in the intention-to-treat (ITT) analysis and six comparisons in the per protocol (PP) analysis, leading to a corrected α error of 0.41% (p = 0.0041). The responder rate was calculated as the percent reduction from baseline in the number of headache days in the preceding month compared with baseline, determined both at 12 and 24 weeks. We determined the 30% responder rate, 50% responder rate and 75% responder rate. For the exploratory analysis, we tried to evaluate which variables were associated with the presence of a 50% response rate at weeks 20–24. We analysed the following variables: Age, age of onset, months of NH, gender, mean intensity, diameter, presence of exacerbations, allodynia, prior preventive use, prior gabapentin use, headache days per month at baseline, intense headache days per month at baseline and acute medication days per month at baseline. Because of the small sample, we used Fisher's exact test in the contrast of qualitative variables and the Mann-Whitney test in the contrast of quantitative variables, considering exact signification. Those variables with a p value of 0.15 or less were included in a regression analysis. We created a summary table with all the variables and results. We conducted a linear regression analysis with those variables and the number of headache days reduced between weeks 20 to 24 compared with baseline. After adjusting for multiple comparisons, considering that we anticipated 13 multiple comparisons, the α error was set at 0.384% (p = 0.0038).

In the primary endpoint and secondary endpoints a) to c), missing data was handled by imputation, in case of a missing entry, the day was considered as a headache day. Patients were allowed to fill in the diary a day late. The number of patients with missing data is detailed. In the regression analysis, the missing data was managed by complete case analysis. In the case of a lost patient, baseline data was used in the intention-to-treat analysis.

Results

Study population

During the study period, 199 patients were screened. Inclusion criteria were not fulfilled in 141 cases: Two were younger than 18, and 139 had less than 10 headache days per month, 48 of them because of spontaneous remission and 91 after oral preventive treatment. Thirteen patients were excluded: Five because a secondary NH was diagnosed; seven due to another primary headache occurring over more than 10 days per month; there were three cases of chronic migraine and four of epicrania fugax; and one patient was excluded because of pregnancy. Finally, 53 patients fulfilled the inclusion and exclusion criteria. Six patients received onabotA only once because they considered their clinical response as optimal, but they were followed up during the whole study period and kept headache diaries. Two patients were missed after the first administration without any possible follow up and there was no information about their response.

The median age of patients was 54 years (IQR 41–72), with a range between 23 and 86 years. At the moment of access, patients had experienced NH for 11 months, median (IQR 6–33), and 67.9% were female. Six patients had a prior medical history of episodic migraine, three had infrequent epicrania fugax, and one patient had episodic tension-type headache.

Preventive treatment had been previously used by 32 patients (60.4%), the most common drug being gabapentin (25 patients, 47.2%), followed by topiramate (nine patients, 17%), amitriptyline (eight patients, 15.1%), pregabalin (four patients, 7.5%) and topiramate (two cases, 3.8%). Among the treated patients, 13 (40.6%) had previously used several preventive drugs. Response was absent in 14 treated patients (43.8% of those treated), between 30 and 50% in seven patients (21.8%) and positive in 11 cases (34.4% of those treated), which had previously been discontinued because of side effects.

NH pain at baseline

The median intensity of pain was 6 (IQR 5–7). Pain was constant and stable in intensity in 90.6% of patients and 9.4% reported fluctuations in its intensity, 58.3% as < 60 sec exacerbations and 41.7% as increases of pain intensity within 1–30 min. The median intensity of exacerbations was 8 (IQR 8-9). Median NH diameter was 5 cm (IQR 4-5) and the shape was round in 81.1%. The most frequent location of NH was parietal (27 patients, 50.9%), followed by occipital (nine patients, 17%), upper-frontal (eight patients, 15.1%), and vertex (three patients, 5.7%); temporal, temporo-parietal and fronto-temporal locations were each present in two cases (3.8%) and one patient (1.9%) described the location as parieto-occipital.

Table 1 summarises headache frequency per month, intense headache frequency per month and acute treatment days per month at baseline between weeks 8–12 and weeks 20–24.

Table 1.

Headache days per month, intense headache frequency per month and acute treatment days per month at baseline, between weeks 8 and 12 and between weeks 20 and 24.

	Headache days per month		Intense headache days per month		Acute treatment days per month
	Mean (SD)	Median [IQR]	Mean (SD)	Median [IQR]	Mean (SD)	Median [IQR]
Baseline (n = 53)	24.5 (7.3)	30 [17.5–30]	12.5 (10.1)	10 [5–20]	12.8 (7.6)	10 [6.5–20]
Weeks 8–12 (n = 53)	10.6 (10.6)	8 [0–20]	3.8 (7.3)	0 [0–5]	5.6 (8.0)	2 [0–10]
Weeks 20–24 (n = 51)	6.9 (9.3)	2 [2–10]	2.6 (4.7)	0 [0–4.5]	3.2 (5.7)	0 [0–5]

SD: standard deviation, IQR: inter-quartile range.

Two patients presented missing data in their diaries over 4 and 5 days respectively, which were considered as headache days in the analysis.

Primary endpoint

Decrease of headache days between weeks 20–24

The distribution of headache days per month was not normal at baseline (KS, p < 0.001). In the intention-to-treat analysis, the number of headache days per month was significantly lower between weeks 20–24 than at baseline (24.5 vs. 6.9 days; Wilcoxon, p < 0.001). In the per-protocol analysis, it was also significantly lower (24.7 vs. 7.5 days; Wilcoxon, p < 0.001).

Secondary endpoints

Decrease in headache days between weeks 8–12

Headache days per month were also lower between weeks 8–12 than at baseline both in the ITT analysis (24.5 vs. 10.6 days; Wilcoxon, p < 0.001) and PP analysis (24.7 vs. 12.0 days; Wilcoxon, p < 0.001).

Decrease in intense headache days

Intense headache days per month had a normal distribution (KS, p = 0.21). The number of intense headache days was lower at weeks 20–24 than at baseline, both in the ITT analysis (12.5 vs. 2.65 days; paired t-test, p < 0.001, 52 df), and in PP analysis (13.2 vs. 2.8 days; paired t-test, p < 0.001, 44 df). It was also reduced when weeks 8–12 and baseline were compared, both in the ITT analysis (12.5 vs. 3.8 days; paired t-test, p < 0.001, 48 df) and PP analysis (13.2 vs. 4.31 days; paired t-test, p < 0.001, 42 df).

Decrease of acute medication days

Acute medication days per month did not have a normal distribution (KS, p = 0.008). The number of acute medication days was lower between weeks 20 and 24 than at baseline, both in the ITT analysis (12.8 vs. 3.2 days; Wilcoxon, p < 0.001) and in the PP analysis (12.9 vs. 3.5 days; Wilcoxon, p < 0.001). The number of acute medication days was also lower between weeks 8–12 than at baseline, both in the ITT analysis (12.8 vs. 5.6 days; Wilcoxon, p < 0.001) and in the PP analysis (12.9 vs. 6.3 days; Wilcoxon, p < 0.001).

Figure 1 shows the number of headache days, intense headache days and acute medication days per month at baseline, weeks 8–12 and weeks 20–24, with standard error of mean.

Figure 1.

Mean number of headache days (blue), intense headache days (red) and acute treatment days (green) per month at baseline, between weeks 8 and 12 and between weeks 20 and 24, including standard error of mean bars.

Responder rate

Figure 2 shows 30%, 50% and 75% responder rates at 12 and 24 weeks, both in the intention-to-treat and per protocol analysis.

Figure 2.

30%, 50% and 75% responder rate between weeks 8 and 12, orange in the intention-to-treat analysis and red in the per protocol analysis; and between weeks 20 and 24, light blue in the ITT analysis and dark blue in the PP analysis.

Tolerability and adverse events

Table 2 summarises frequency of AEs. No patients presented severe AEs.

Table 2.

Procedure-related adverse events related by any patient during the study. Frequency and percentage of all the participants.

Adverse event	Frequency (n = 53) n (%) ITT	Frequency (n = 51) n (%) PP
Injection-site pain	12 (22.6)	12 (23.5)
Musculoskeletal pain	5 (9.4)	5 (9.8)
Local bleeding	4 (7.5)	4 (7.8)
Muscle tightness	3 (5.6)	3 (5.9)
Headache	2 (3.8)	2 (3.9)
Total	26 (49.1)	26 (51.0)

ITT: intention-to-treat; PP: per protocol.

Response predictors

Table 3 shows the comparison of demographical and clinical variables in patients with 50% response between weeks 20–24. We included in the final analysis female gender, NH duration in months, diameter, presence of allodynia, prior preventive use and number of headache days per month at baseline. The only variable that was close to statistical significance was the number of headache days at baseline, showing that for every headache day at baseline, the number of headache days between weeks 20 and 24 decreased 0.62 days more (0.24–1.00) (p = 0.002, linear regression, 47 df). Supplemental Table 1 shows all the variables included in the regression analysis.

Table 3.

Comparisons of demographical and clinical variables between patients with 50% response at 20–24 weeks and non-responders.

	Responders (n = 35)	Non- responders (n = 8)	p-value
Age	57.5 (17.2)	56.9 (21.5)	0.97
Age of onset	53.2 (19.3)	56.1 (21.4)	0.67
Months of NH	20.8 (16.5)	11.8 (10.7)	0.24
Female gender	71.4%	37.5%	0.10
Mean intensity	6.0 (1.6)	5.7 (1.8)	0.71
Diameter	4.6 (1.8)	5.1 (0.4)	0.07
Exacerbations	40.0%	50.0%	0.70
Allodynia	68.6%	37.5%	0.12
Prior preventive use	68.6%	37.5%	0.12
Prior gabapentin use	63.3%	66.7%	1.00
Headache days at baseline	23.6 (7.8)	28.1 (3.7)	0.17
Intense headache days at baseline	12.7 (9.7)	16.0 (13.1)	0.57
Acute treatment days at baseline	13.0 (6.5)	14.7 (10.8)	0.63

Note: Data are provided as mean and standard deviation or percentage. Fisher's Exact test and Mann-Whitney U test with Exact test. Data in parenthesis is provided as Mean and standard deviation.

Discussion

In the present study, onabotA reduced headache frequency per month both at 20–24 weeks and between weeks 8–12 in patients with NH. It also decreased the number of intense headache days per month and acute medication days per month in the same periods. About two thirds of patients had a 50% responder rate and half of the patients had a 75% response rate. We also found that 9.5% of patients that did not respond to the first procedure responded after the second. A similar phenomenon was described in chronic migraine (CM) studies, in which 11.3% and 10.3% of non-responder patients responded to the second and third administration, respectively (19). We used the same dose as most authors had previously reported (12 –15).Nevertheless, due to the exploratory nature of our study, we did not evaluate either the potential benefit of an increase in dose in non-responder patients, as pivotal CM trials did (20), or the use of a higher concentration of onabotA.

The 50% responder rate between weeks 20 and 24 was higher in NH than in the reported CM studies, 81.6% vs. 48.2% in pivotal studies (20) and 66.2% in real-life studies (21). This fact could be related to NH pathophysiology, with onabotA acting directly subcutaneously on superficial sensory fibers (5–6) through blocking presynaptic transmission (4), targeting the primary origin of pain.

To date, no randomised controlled trials exist in NH. Gabapentin is the most frequently studied preventive drug. Observational open label studies set its efficacy at around 60% (22). Studies evaluating predictors of onabotA efficacy in CM stated that prior use of preventive drugs was associated with a lower percentage of response (21). In our study, we did not find a worse response in previously treated patients; indeed, the responder group had been treated to a higher percentage than the non-responder group, although the difference was not statistically significant.

Also, a more prolonged duration of CM has been associated with a lower probability of onabotA response (21). We could not replicate this in our NH patients. Nevertheless, NH was not differentiated in this study into episodic or chronic patients as is typically done in migraine. Future trials should try to address whether this fact is associated with responsiveness. On the other hand, only patients that had maintained at least 10 headache days per month in the previous 3 months were treated, so infrequent episodic patients were excluded from the study.

When we tried to ascertain which factors better predicted response, we could not replicate some of the findings that other authors have reported in the case of migraine, such as a unilateral headache, imploding pain, ocular topography or shorter disease duration (21,23,24). In the regression analysis, only a higher frequency of headache days per month at baseline was associated with a higher reduction in headache days between weeks 20 and 24; nevertheless, this is not a surprising finding, it could be expected in advance and it could also be a confounder, so we recommend that it be anticipated in future studies. Allodynia was more frequent in responders than in non-responders (68.6 vs. 37.5%), albeit this was not statistically significant, which could support onabotA's effect on the sensitized superficial sensory fibers (4 –7). Other variables such as prior preventive use or gender showed numerically different percentages, but statistical signification was not reached; this should be taken into account in future studies to see if the clinical response differs in those groups. Future studies will have to determine the role of other possible predictors such as serological biomarkers (CGRP, VIP, PTX3) (25 –27), haemodynamic changes measured by ultrasound (28) or asymmetrical cortical thickness in some cranial regions (29,30), and specific response predictors should be determined for NH.

The placebo effect was particularly high in The Phase III REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) studies (19,20). It has been described that the more invasive a treatment is, the greater the placebo effect. In the case of NH, existing evidence does not support an invasive procedure such as anesthetic blocks being beneficial (1,12,13,15,31,32). Due to the fact that this was an open label study without a control arm we cannot determine which part of the effect was attributable to onabotA, as we did not control for the placebo effect. On one hand, a finding that would support a real onabotA effect is the high percentage of 75% responders, which reached 52.8%, while placebo is supposed to be lower. On the other hand, spontaneous remissions for a limited time, or definitively, have been described in the natural history of NH in up to 19.4% of patients (1,4,33 –35), so some of our patients could have improved spontaneously. These facts highlight the need for a controlled trial to determine the real efficacy of onaboA in NH.

Some clinicians consider NH as a mild condition because of its small size, but in our sample the mean intensity was moderate and patients required symptomatic treatment for 12.8 days per month mean, reflecting that it is associated with significant impairment. Use of symptomatic treatment decreased to 3.2 days between weeks 20 and 24, and the number of intense headache days decreased to less than 3 after onabotA.

Concerning safety, we did not find any moderate or severe AE. Local pain, transient mild bleeding at the infiltration point and muscular pain were the main reported AEs. The most delicate area of the head is the frontal area, in which aesthetic effects might occur. We only had five patients with frontal pain and none of them described it in the lower frontal area. In the case of lower frontal pain, a possible solution could be infiltrating the contralateral side with the same or a lower dose to avoid facial asymmetry (36).

Mean age of onset of NH is around 50 (1,4) and mean age of onabotA administration was over 60 in our sample, so side effects and contraindications seem to be particularly important. The main oral preventive drugs used in NH patients could be associated with dizziness, gait disturbance, somnolence, peripheral edema or anticholinergic effects (37,38).

As we previously mentioned, our study had some limitations. It is an open-label study, without a control arm, so the magnitude of the placebo effect or spontaneous remissions cannot be accurately estimated. Concerning the study endpoints, we did not include patient-reported outcome measurements, which we recommend for future studies. We did not analyse headache duration per day or average headache intensity specifically as end points, so we recommend future studies to include and analyse them additionally. We evaluated allodynia by anamnesis and examination, but no specific questionnaires were used. The study was performed in a single centre. We did not examine the effect of increased onabotA doses in refractory patients. An important question to be solved is the long-term effectiveness and duration of treatment. Our results should encourage other researchers to conduct randomised multicentre controlled trials.

Conclusion

OnabotA decreased the number of headache days per month between weeks 20 and 24 compared with baseline. The number of intense headache days and acute medication days also decreased between weeks 20 and 24 and between weeks 8 and 12. Response was optimal in more than half of the treated patients. No moderate or severe adverse events occurred. Randomized controlled trials are needed in order to truly estimate the efficacy of onabotA in NH.

Supplemental Material

Supplemental material for Observational, open-label, non-randomized study on the efficacy of onabotulinumtoxinA in the treatment of nummular headache: The pre-numabot study

Supplemental Material for Observational, open-label, non-randomized study on the efficacy of onabotulinumtoxinA in the treatment of nummular headache: The pre-numabot study by David García-Azorín, Javier Trigo-López, Álvaro Sierra, Laura Blanco-García, Enrique Martínez-Pías, Blanca Martínez, Blanca Talavera and Ángel L Guerrero in Cephalalgia

Footnotes

Clinical implications

Headache days decreased after onabotA treatment from 24.5 days per month at baseline to 6.9 between weeks 20 and 24.

More than half of the patients had an optimal response (75%) after onabotA administration.

Both intense headache days and acute treatment days decreased significantly at 8–12 and 20–24 weeks.

OnabotulinumtoxinA was safe and well tolerated in nummular headache.

Abbreviations

NH: Nummular headache; RCT: randomized controlled trial; OnabotA: onabotulinumtoxinA; CGRP: calcitonin-gene related peptide; ICHD: International Classification of Headache Disorders; ITT: intention-to-treat; PP: per protocol; df: degrees of freedom; AE: adverse events; IQR: interquartile range; CM: chronic migraine.

Approvals

The Clinical Research Ethics Committee of East Valladolid Area approved the study. All the patients read and signed informed consent. The present work has been partially presented at the Athens 2019 EHF congress.

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.

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