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Abstract

Background

A systematic and meta-analysis was conducted to examine the evidence of the effects of botulinum toxin A on chronic tension-type headache.

Methods

Cochrane, Embase, Ovid, ProQuest, PubMed, Scopus, Web-of-Science databases, and ClinicallTrials.gov registry were systematically searched for studies examining the effects of botulinum toxin A on tension-type headaches. The records were screened by two independent reviewers using pre-determined eligibility criteria. DerSimonian Liard random-effects meta-analyses were performed using the ‘meta’ package (5.2-0) in R (4.2.0). Risk of bias and quality of evidence were assessed using the Cochrane Collaboration’s Tool RoB 2 and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Clinical significance was determined using pre-defined minimal clinically important differences.

Results

Eleven controlled trials were included (390 botulinum toxin A, 297 controls). Botulinum toxin A was associated with significant improvements in standardized headache intensity (−0.502 standard deviations [−0.945, −0.058]), headache frequency (−2.830 days/month [−4.082, −1.578]), daily headache duration (−0.965 [−1.860, −0.069]) and the frequency of acute pain medication use (−2.200 days/month [−3.485, −0.915]) vs controls. Botulinum toxin A-associated improvements exceeded minimal clinically important differences for headache intensity, frequency, and acute pain medication use. A 79% (28%, 150%) greater response rate was observed for botulinum toxin A vs controls in improving chronic tension-type headache. Treatment of eight chronic tension-type headache patients was sufficient to elicit a therapeutic response in one patient.

Conclusions

Corroborating the current mechanistic evidence, our meta-analysis supports the utility of botulinum toxin A for managing chronic tension-type headaches. However, due to limitations in the quality of evidence, adequately-powered high-quality controlled trials examining the effects of Botulinum toxin A on chronic tension-type headache are warranted.

Registration

Protocol preregistered in PROSPERO International Prospective Register of Systematic Reviews (CRD42020178616)

Keywords

Tension-type headache prophylaxis botulinum toxin systematic review meta-analysis

Introduction

Tension-type headache (TTH) is the most prevalent type of primary headache disorder, affecting approximately 1.89 billion individuals (i.e., 26% of the global population) annually (1). Lifetime prevalence of TTH is estimated to be around 42% (2). TTH accounts for approximately 7.2 million years lived with disability (3). While being less prevalent compared to episodic TTH (2.2% vs 38.3%), chronic TTH (CTTH; i.e., TTH attacks for >15 days per month for >3 months) accounts for missed work among 11.8% and decreased productivity among 46.5% of the affected individuals (4). Furthermore, due to its higher prevalence, the direct cost of medical services and medications for TTH is estimated to be approximately 54% greater than that of migraine (5). Thus, TTH is an important cause of moderate disability, loss of productivity, increased healthcare-related costs, and reduced overall quality-of-life (6).

The pathophysiology of TTH remains to be fully understood (7). It has been hypothesized that patients with CTTH may have abnormal sensitivity of not only nociceptive A-δ and C fibers, causing hyperalgesia, but also mechanosensitive A-α and A-β fibers causing allodynia and pericranial muscle spasms (8). Needle electromyography (EMG) evidence suggests that these TTH-associated sustained contractions are localized to specific pericranial trigger points (9). Central mechanisms may also contribute to converting episodic TTH to CTTH (i.e., chronification). Patients with CTTH exhibit decreased pain thresholds (10). This increased central pain sensitization is likely brought about by nitric oxide-mediated (11) increased sensitization of central nociceptive pathways (12). Impaired descending pain modulatory systems, as well as decreased gray matter volumes in the insula and anterior cingulate cortex, may also be associated with chronification of TTH (13,14).

Symptomatic medications (e.g., acetaminophen, NSAIDS) remain the mainstay of management of TTH (15), yet, patients with CTTH often require prophylactic medications (16) (e.g., tricyclic antidepressants, SNRIs) along with complementary interventions (17) (e.g., acupuncture, biofeedback) aimed at decreasing headache frequency or intensity. However, due to limitations in understanding the pathophysiology of CTTH, increased co-occurrence of CTTH with medication overuse headache (18), and limited efficacy plus undue adverse effects of medications, pharmacological management of CTTH remains a challenge (19).

Botulinum toxin A (BTX-A) is well-established for its efficacy in managing dystonias and spasticity due to potent skeletal muscle relaxation brought about via cleavage of a SNARE protein (i.e., SNAP-25) essential for acetylcholine release at the neuromuscular junctions (20). Furthermore, the utility of BTX-A for managing chronic migraine has been established in several high-quality controlled trials and meta-analyses (21,22). BTX-A also inhibits several pathophysiological mechanisms leading to CTTH. For instance, BTX-A decreases ion channel insertion into nociceptive nerve endings, decreasing the sensitivity of unmyelinated C fibers (23). BTX-A, a potent skeletal muscle relaxant, could also cause relaxation of cervico-facial trigger points. Moreover, BTX-A decreases the activation of wide-dynamic range neurons in the dorsal gray horns, possibly inhibiting central sensitization (24).

Thus, mechanistically, BTX-A seems to be a promising agent for CTTH prophylaxis. Accordingly, several case reports and subsequent controlled trials have suggested that BTX-A may effectively decrease the intensity and frequency of CTTH. Yet, a systematic review and meta-analysis examining the effects of BTX-A on the frequency of CTTH as part of a more extensive study did not find a beneficial effect (25). Little research has been done on this topic since this conclusion was made a decade ago, even though this study did not consider the effects of BTX-A on CTTH intensity or remission rates. We aimed to address this limitation in the literature in a systematic review and meta-analysis of clinical trials examining the potential effects of BTX-A on headache intensity, frequency, and response rates among patients with CTTH. We further aimed to examine the socio-demographic and treatment protocol-specific moderators of the potential effects of BTX-A on CTTH.

Methods

All procedures were performed per the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and the Cochrane handbook (26,27). The protocol was pre-registered in the PROSPERO International Prospective Register of Systematic Reviews (CRD 42020178616).

Search strategy

ProQuest, PubMed, Scopus, and Web-of-Science databases were searched on 1 May 2020, for peer-reviewed publications of clinical trials examining the effects of BTX-A injections for the management of TTH using a pre-determined keyword combination (Online Supplemental Table S1). While not included in the initial PROSPERO protocol, Cochrane, Embase, and Ovid databases and ClinicallTrials.gov registry were searched using the same keywords. The search was not restricted by language or publication year. Records obtained in the initial search were pooled, and the duplicates were removed using an in-house pipeline. Titles and abstracts of the records were screened by two independent screeners (DP and JYC) using pre-determined criteria (Figure 1, online Supplementary Table S2). Discrepancies in judgment of screeners (i.e., instances that lacked unanimous agreement for inclusion/exclusion) were resolved by a senior tie-breaker (CSD). References of eligible articles and relevant systematic reviews (i.e., captured during the initial search) were examined for additional studies per Cochrane methodology. Full-text manuscripts of eligible records were re-examined by the two screeners (DP and JYC) for eligibility, and discrepancies were resolved (CSD) to identify eligible articles considered for data synthesis.

Figure 1.

PRISMA flow chart showing publication selection.

Data extraction

Data were extracted from eligible manuscripts into a spreadsheet with pre-determined data fields. Pre- and post-intervention means and standard deviations of headache intensity and the number of headache days per month (i.e., frequency) in intervention and control groups were extracted. In addition, pre-and post-intervention means and standard deviations of days of acute pain medication use per month and hours of headache per day were extracted as secondary outcomes. Response rates (i.e., rates of significant improvements in headache intensity or frequency based on study-specific thresholds) were extracted as a secondary outcome. When other forms of central tendency (e.g., median) and dispersion (e.g., 95% CI, standard errors, inter-quartile range) were reported, such statistics were used to calculate or impute means and standard deviations. When reported, the mean post- vs pre-intervention changes and the corresponding standard deviations were extracted. When only the standard deviations of marginal means were available, the standard deviations of post- vs pre-intervention mean differences were imputed, assuming a linear correlation of 0.5 between pre- vs post-intervention data (27). When data from multiple study arms subjected to different doses of BTX-A were reported, the summary statistics of intervention groups were pooled to represent one study arm (27). Year of publication, the mean age of intervention-group participants, the proportion of females in the intervention groups, the mean BTX-A dose, and the duration of follow-up before post-intervention measurements were collected to include as moderators in exploratory meta-regression analyses.

Risk of bias and quality of evidence

The risk of bias was assessed within individual studies by two independent raters (CSD and DP) using the Cochrane Collaboration’s Tool RoB 2: A revised Cochrane risk-of-bias tool for randomized trials (28), and discrepancies were resolved by (CNK). The quality of evidence of each outcome was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology for risk of bias, inconsistency, indirectness, imprecision, and publication bias, and ultimately summarized using the GRADE Profiler (GRADEpro, version 3.6) (29).

Data analysis

DerSimonian-Laird random-effects meta-analyses were performed using the ‘meta’ package (version 5.2-0) in R statistical software (version 4.2.0) to examine the effects of BTX-A vs placebo on the following outcomes: standardized CTTH intensity (primary), days suffered from CTTH per month (i.e., CTTH frequency; primary), duration of headaches per day (secondary), and the number of days requiring acute pain medications per month (secondary) (30). Two additional meta-analyses were performed on the response ratio and absolute response rates to treatment with BTX-A vs control interventions. The absolute response rate was used to compute the number needed to be treated with BTX-A to achieve a sufficient response in at least one patient. Leave-one-out sensitivity analyses confirmed the consistency of the findings. The likelihood of publication bias was explored using funnel plots, and the effect-sizes of missing (i.e., unpublished/unreported) studies were imputed via the trim-and-fill method (31). Heterogeneity of effect-sizes was quantified by calculating the tau-squared and Higgins’ I² statistic (27). Although we aimed to explain the between-study heterogeneity in each meta-analysis using potential moderators, meta-regression analyses could not be considered because fewer than ten studies were included in all performed meta-analyses (32). To address this limitation, all studies reporting each outcome in at least one BTX-A intervention arm were pooled, and exploratory univariate meta-regression analyses were performed using each potential moderator.

Clinical significance

A standardized BTX-A vs control group difference of 0.5 was considered as the minimal clinically important difference (MCID) for the post- vs pre-intervention improvement of headache intensity (33,34). A decrease by at least one day per month was considered as the MCID for the headache frequency and the number of days requiring acute pain medications (35,36). A treatment-associated decrease in the daily headache duration by ≥ 2 hours was required for clinical significance (37,38).

Results

Results of the initial database search, duplicate removal, and eligibility screening are summarized in the PRISMA flowchart (Figure 1). Articles that were excluded in the full-text screening are summarized in online Supplementary Table S3. Twenty-two interventional trials on the effects of BTX-A on CTTH met eligibility and were included (39 –60). The studies collectively exposed 652 patients with CTTH to BTX-A. Eleven randomized controlled trials (39 –49) were included in meta-analyses to examine the therapeutic effects of BTX-A in preventing CTTH (390 patients treated with BTX-A, 297 controls). The included studies' statistics and detailed summaries are presented in Table 1 and online Supplementary Table S4.

Table 1.

Summary statistics of all studies included in the qualitative synthesis and subsequent meta-regression analyses.

Variable	Randomized controlled trials^a(N = 390)	Single-arm pre-post interventions^a(N = 262)	All studies†(N = 652)
Studies	11	11	22
Sample size	35 [10–143]	25 [3–60]	31 [3–143]
Mean age (years)	42.81 [36.29–49.60]	37.85 [28.50–57.00]	41.12 [28.50–57.00]
Female (%)	60 [42–80]	73 [53–100]	65 [42–100]
Botox A dose (U)	178 [20–500]	58 [21–200]	139 [20–500]
Follow-up (weeks)	12 [ 8–24]	12 [4–24]	12 [4–24]

^aThe data of the BTX-A intervention arms are presented as mean [range].

Quality ratings of the controlled clinical trials included in the meta-analyses are depicted in online Supplementary Figure S1, and their GRADE evidence profiles are presented in online Supplementary Table S5. The GRADE levels of evidence were moderate for headache frequency, frequency of acute pain medication intake, and response rates. In contrast, the GRADE levels of evidence were low for headache intensity and the duration of headache per day.

Headache intensity

BTX-A significantly decreased the standardized headache intensity among patients with CTTH vs control interventions (Δ = −0.502 standard deviations [−0.945, −0.058], p = 0.027; Figure 2A). The observed BTX-A-associated improvement in standardized headache intensity also exceeded the MCID of 0.5 (33,34). Leave-one-out sensitivity analyses did not significantly change the pooled estimates (online Supplementary Table S6). Similarly, subgroup sensitivity analyses performed after grouping the studies based on the risk of bias did not reveal significant deviations in the pooled outcomes (online Supplementary Figure S3A). A funnel plot created to examine for publication bias is shown in online Supplementary Figure S4A. While Egger’s test did not reveal publication bias (p = 0.111), trim-and-fill analysis imputed one additional effect. Re-analyzing the data, including this imputed effect-size decreased the pooled effect size (Δ = −0.337 standard deviations [−0.952, 0.278], p = 0.282). Significant between-study heterogeneity was observed (τ² = 0.275, I² = 66%, p = 0.004). However, meta-regression analyses were not attempted.

Figure 2.

Results of random-effects meta-analysis examining the effects of BTX-A vs control interventions on CTTH.

A separate exploratory meta-analysis was performed using the BTX-A intervention arms of both controlled trials and single-arm pre-post interventional studies to address the limited number of studies. This meta-analysis revealed a pooled pre-post difference of −1.380 standard deviations [−2.001, −0.753] in standardized headache intensity with BTX-A (online Supplementary Figure S5A). Univariate meta-regression analyses to explore the moderator effects revealed that as the age of patients with CTTH increases, the BTX-A-associated reduction in standardized headache intensity seems to become less marked (β = 0.084, SE = 0.041, p = 0.003; Table S7). All other explored moderators were not significant.

Headache frequency

BTX-A significantly decreased the frequency of CTTH (Δ = −2.830 days per month [−4.082, −1.578] vs control interventions (Figure 2B). This reduction in headache frequency was superior to the MCID of ≥ 1 day per month (35,36). This effect remained robust in leave-one-out sensitivity analyses (online Supplementary Table S6) and when sensitivity analyses were performed after grouping the studies based on the risk of bias (online Supplementary Figure S3B). The funnel plot was asymmetric (online Supplementary Figure S4B)—possibly due to the limited number of studies; however, Egger’s test was not significant (p = 0.090). Trim-and-fill analysis imputed three additional effect-sizes. Re-analyzing the data, including these imputed effect-sizes, revealed a much larger effect-size in favor of BTX-A vs control interventions (Δ = −3.670 days per month [−4.931, −2.409], p < 0.001). Between-study heterogeneity was not a concern (τ² = 0.0327, I² = 0%, p = 0.467).

An exploratory meta-analysis of 12 intervention arms that examined pre-post changes in headache frequency following BTX-A treatment revealed a significant effect-size (Δ = −4.092 [−7.230, −0.914]; online Supplementary Figure S5B). Effect-sizes included in this meta-analysis were also heterogenous (τ² = 29.574, I² = 98%, p < 0.001). However, univariate meta-regression analyses using potential study-level variables did not reveal significant moderators (online Supplementary Table S7).

Duration of headache per day

Duration of headache per day is not a reliable indicator of a response as there is substantial variability. Nonetheless, we included this measure mainly as an imperfect surrogate for the quality-of-life and loss of productivity. Only three controlled trials (39,42,49) reported data regarding the effects of BTX-A on the duration of CTTH headaches per day. On a random-effects meta-analysis of these three studies, BTX-A decreased the daily headache duration by almost one hour (Δ = −0.965 [−1.860, −0.069], p = 0.035; Figure 2C). However, this estimate was inferior to the MCID of ≥2 hours per day (37,38). This finding remained consistent in leave-one-out sensitivity analyses (online Supplementary Table S6), and the between-study heterogeneity was negligible (τ² = 0.000, I² = 0%, p = 0.932). Thus, meta-regressions could not be performed. We did not test for publication bias or conduct sensitivity analyses based on the risk of bias due to the limited number of studies.

Frequency of acute pain medication intake

Only four controlled trials (39,42,45,49) reported data regarding the effects of BTX-A on the frequency of acute pain medication intake. Data on acute pain medication intake were converted to the number of days requiring acute pain medications per month before including in the meta-analysis. Unfortunately, the studies did not report data on the cumulative use of acute pain medications. BTX-A decreased the frequency of medication intake by approximately two days per month (Δ = −2.200 [−3.485, −0.915], p < 0.001; Figure 2D). This pooled estimate was greater than the MCID of ≥ 1 day per month (35,36). Between-study heterogeneity was negligible (τ² = 0.000, I² = 0%, p = 0.949). The observed pooled estimate remained consistent in leave-one-out sensitivity analyses (Table S6). Due to the limited number of clinical trials, publication bias or the effects of risk of bias could not be estimated.

Response rates

A random-effects meta-analysis examining the risk ratio of response rates based on study-specific definitions (e.g., >50% improvement in headache intensity, >25% improvement in mean headache days per month) revealed that BTX-A is likely to yield a 79% greater response rate vs control interventions (RR = 1.792 [1.281, 2.504], p < 0.001; Figure 3A). Subgroup analyses based on the definition of response rates (i.e., intensity vs mean headache days per month) revealed that patients with CTTH treated with BTX-A are 92% more likely to experience an improvement in headache intensity and 68% more likely to experience an improvement in mean headache days per month (RR = 1.923 [1.190, 3.107], p = 0.008 and RR = 1.675 [1.049, 2.674], p = 0.031 respectively). The risk ratio remained significant in leave-one-out sensitivity analyses (online Supplementary Table S6), and the funnel plots (online Supplementary Figure S4C), as well as Egger’s and Peter’s tests, did not suggest publication bias (p = 0.940 and p = 0.749). Accordingly, the trim-and-fill analysis failed to impute additional studies. Between-study heterogeneity was negligible (τ² = 0.000, I² = 0%, p = 0.767). Four studies (39,42,45,48) used definitions based on improvements in headache intensity vs baseline. Three studies (46,47,49) defined the response rates based on reductions in headache days per month vs baseline. However, these three studies used different thresholds (i.e., >25% reduction, >50% reduction, and 100% reduction in headache days per month).

Figure 3.

Results of random-effects meta-analysis examining the effects of BTX-A vs control interventions on study-specific response rates among patients with CTTH.

A random-effects meta-analysis including the same studies on response rates revealed a 12% improvement in absolute response rates with BTX-A treatment (ARR = 0.124 [0.031, 0.217], p = 0.009; Figure 3B), indicating that treatment of approximately eight CTTH patients with BTX-A will be sufficient to improve headache in one patient (NNT = 8 [5, 32]). Subgroup analyses revealed a significant 21% absolute response rate in decreasing headache intensity (ARR = 0.213 [0.074, 0.352], p = 0.003), yet, the absolute improvement in reducing headache frequency was not significant (ARR = 0.079 [−0.044, 0.203], p = 0.208). The pooled outcomes minimally changed in leave-one-out sensitivity analyses (online Supplementary Table S6), and Egger’s and Peter’s tests did not reveal significant publication bias (p = 0.091 and p = 0.125). A funnel plot created using the effect-sizes was asymmetric (online Supplementary Figure S4D). The findings remained significant on re-analysis of the data, including three additional effect-sizes imputed via trim-and-fill analysis (ARR = 0.085 [0.004, 0.165], p = 0.038).

Due to the limited number of studies reporting response rates (k = 6) and minimal between-study heterogeneity, meta-regression analyses could not be performed. An exploratory random-effects meta-analysis, including all studies reporting response rates of at least a BTX-A intervention arm, revealed a pooled response rate of 43% [28, 60] in improving CTTH following treatment with BTX-A (online Supplementary Figure S6). Subgroup analyses revealed nearly similar response rates for studies defining responsiveness based on decreased headache frequency and intensity (42% [17, 71] and 45% [35, 55], respectively). Meta-regression analyses performed to explore the between-study heterogeneity (τ² = 1.138, I² = 84%, p < 0.001) revealed a significant negative moderator effect for the BTX-A dose (β = −0.005, SE = 0.002, p = 0.005; online Supplementary Table S7).

Quality-of-life

Only two of the included controlled trials (39,45) reported sufficient data to compute post- vs pre-intervention changes in quality-of-life with BTX-A among patients with TTH. However, these two studies utilized two different scales (i.e., Human Development Index and West Haven-Yale Multidimensional Pain Inventory). Given that evidence regarding the agreement between these two scales was non-existent, a meta-analysis was not attempted.

Discussion

While at least two prior meta-analyses (25,61) and two additional systematic reviews (62,63) have attempted to address the effects of BTX-A on CTTH, to our knowledge, this is the first comprehensive meta-analysis to examine the topic using multiple response indicators. We observed both statistically and clinically significant improvements in mean headache intensity, frequency, and acute pain medication requirement among patients with CTTH. Furthermore, treatment of CTTH with BTX-A was associated with a statistically significant, yet, clinically less than ideal improvement (by approximately one hour) of the mean daily headache duration. We also observed an overall 79% greater response rate following treatment with BTX-A vs control interventions, and injection of BTX-A to eight patients with CTTH was deemed sufficient to observe a favorable response in at least one patient.

The status quo as it pertains to the effects of BTX-A on CTTH was established primarily by a systematic review and meta-analysis published a decade ago (25). In this study, as part of a broader systematic review and meta-analysis, the authors examined the effects of BTX-A on CTTH frequency as well as responsiveness to treatment defined based on improvements in headache frequency. The authors concluded that despite decreasing the headache frequency by 1.43 days per month among patients with CTTH, BTX-A is not statistically superior to the control treatment. This negative finding may have contributed to diminishing the interest, and little work has been done on this topic after this meta-analysis. However, examining almost entirely the same literature, we observed that BTX-A significantly decreases headache frequency among patients with CTTH by nearly twice the effect size observed in the prior meta-analysis (25). A few methodological differences between the two meta-analyses are noteworthy. First, the meta-analysis conducted by Jackson et al. (25) compared post-intervention headache frequency between the intervention and control groups. In contrast, we compared the post- vs pre-intervention differences in headache frequency between the intervention vs control groups. Second, the headache frequency data of one study (47), which indicated an improvement in mean headache frequency with BTX-A vs placebo, seems to have been coded or interpreted incorrectly (25). We could not include this study due to the inability to compute standard deviations of post- vs pre-intervention differences using the reported data. Third, we included one additional study (44) that has not been considered by Jackson et al. (25). Sensitivity analyses performed after omitting this additional study further enhanced the pooled effect in favor of BTX-A. Fourth, our meta-analysis substantiated the superiority of BTX-A over placebo in multiple facets, in addition to headache frequency. Thus, we believe our findings will be an eye-opener for clinicians and clinical researchers to re-consider the potential of BTX-A as a treatment modality for CTTH, as suggested by two fairly recent systematic reviews (62,63).

CTTH, a chronic daily headache, shares common pathophysiological mechanisms with other chronic headache syndromes (e.g., chronic migraine), especially regarding chronification (10,12 –14). BTX-A is hypothesized to act on peripheral as well as central pain regulatory mechanisms to hinder the chronification of pain (23,64). Accordingly, our findings are consistent with prior meta-analyses on the effects of BTX-A on chronic migraine (21,22,25). For instance, in a Cochrane systematic review and meta-analysis of controlled trials, Herd et al. (21) observed that treatment with BTX-A seems to decrease migraine frequency by 3.07 days per month (vs the improvement of CTTH by 2.8 days per month in our meta-analysis). Herd et al. (21) also observed a significant decrease in headache intensity by 2.7 on a 10 mm visual analog scale. While BTX-A is currently approved for migraine prophylaxis based on the included studies (particularly PREEMPT1 and 2 trials) (65,66), before the publication of these high-quality studies, evidence regarding the efficacy of BTX-A on the management of migraine was ambiguous (62). Based on our evaluation of the quality of evidence, the current state of the literature regarding BTX-A on CTTH is not entirely different from the state of the literature regarding BTX-A on chronic migraine before the PREEMPT trials. As such, while re-iterating the potential of BTX-A for use in prophylaxis of CTTH, we emphasize the need to conduct high-quality randomized clinical trials with repeated administration of BTX-A at regular intervals and longer follow-up durations. Moreover, future clinical trials should aim to identify patient phenotypes who are more responsive to BTX-A (e.g., younger patients based on our meta-regression) as well as ideal treatment protocols (e.g., optimal doses). It is promising to see at least one well-designed phase three clinical trial being conducted currently to answer at least some of these questions (67).

Our meta-analysis had some notable limitations. First, only a small number of studies met eligibility to be included in the meta-analyses. Several studies had to be excluded due to the unavailability of variance estimates of effect sizes. Specifically, the meta-analyses of the duration of headache and acute pain medication use were grossly limited due to very few studies meeting eligibility for inclusion. Second, the evidence was of low-moderate quality. Third, despite the minimal between-study heterogeneity observed in the meta-analyses, the study protocols (e.g., injection sites and techniques, BTX-A doses, formulations of BTX-A, handling of missing data) were substantially heterogeneous. Finally, while we attempted to explore the between-study heterogeneity by performing meta-regression analyses of BTX-A intervention groups of single-arm and controlled clinical trials, this approach was not ideal because it ignored the effects observed in control arms, and only two significant moderator effects were identified.

Conclusion

Taken together, current limited mechanistic and clinical evidence suggests the potential of BTX-A for use as CTTH prophylaxis. Our systematic review and meta-analysis of the limited available evidence suggest that injection of BTX-A seems to have statistically and clinically significant effects in decreasing TTH intensity, the number of headache episodes per month, and acute pain medication use. Furthermore, BTX-A seems to significantly decrease daily headache duration and exhibit higher response rates to treatment vs placebo. These observed beneficial effects seem to decrease with the increasing age of patients and the use of high BTX-A doses. However, due to the low-quality evidence and a small number of patients included in each of the considered studies, we emphasize the need to establish the effects of BTX-A on CTTH in adequately-powered high-quality randomized controlled trials. Furthermore, we underscore the importance of conducting studies to identify phenotypes of CTTH patients who are more likely to respond to BTX-A and optimize the treatment protocols. Given the well-established safety of BTX-A and the evidence we have summarized, BTX-A could be recommended for off-label use for CTTH, at least for patients who remain unresponsive to currently approved prophylactic measures.

Article highlights

Our meta-analysis supports the utility of Botulinum toxin A for managing chronic tension-type headaches.

Headache intensity, frequency, and daily headache duration were improved with Botulinum toxin A.

Supplemental Material

sj-pdf-1-cep-10.1177_03331024221150231 - Supplemental material for The effectiveness of botulinum toxin for chronic tension-type headache prophylaxis: A systematic review and meta-analysis

Supplemental material, sj-pdf-1-cep-10.1177_03331024221150231 for The effectiveness of botulinum toxin for chronic tension-type headache prophylaxis: A systematic review and meta-analysis by Chathurika S Dhanasekara, Daniel Payberah, Joanna Y Chyu, Chwan-Li Shen and Chanaka N Kahathuduwa in Cephalalgia

Footnotes

Author contributions

CSD, CLS and CNK designed the study; DP, JYC, and CSD collected the data; CLS and CNK supervised data collection; CSD and CNK extracted and analyzed the data; CSD and CNK wrote the manuscript; all authors read, revised and helped finalize the manuscript. All authors accept full responsibility for all aspects of to the work described.

Data availability statement

The datasets generated during and analyzed during the current study are available from the corresponding author upon reasonable request.

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 disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was funded in-part by the Medical Student Summer Research Project of the School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX.

ORCID iD

Chathurika S Dhanasekara

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