Triptan non-response in a London tertiary headache centre: What can we learn? A retrospective study

Abstract

Background

Triptans revolutionized the acute treatment of migraine; however, varied responses to triptans, as a result of poor efficacy and tolerability, are reported. A standardized definition of triptan non-response was recently proposed by the European Headache Federation (EHF). There is currently limited data available on the prevalence of triptan non-response.

Methods

We used clinic letters over a two-year duration to evaluate the triptan response and triptan efficacy or tolerability failure, or both, in a London-based tertiary headache service.

Results

In total, 419 adult migraine patients (females: 83.8%, age: 46 ± 18 years, chronic migraine: 88.5%) were included in a service evaluation. In line with the EHF definitions, “triptan non-response” was seen in 63.8% of patients (264/414), whereas 37.7% of patients (156/414) had failed at least two triptans (EHF “triptan resistant”) and 4.6% of patients (19/414) had failed at least three triptans, including a subcutaneous formulation (EHF “triptan refractory”). Notably, 21.3% of patients (88/414) had failed at least three triptans inclusive and exclusive of subcutaneous triptan use. Advancing age (p < 0.001) and the presence of medication overuse (p = 0.006) increased the probability of triptan response, whereas an increased number of failed preventives (p < 0.001) and the use of calcitonin gene-related peptide monoclonal antibodies (p = 0.022) increased the probability of triptan non-response. The largest proportion of patients responded to eletriptan (49.5%), followed by nasal zolmitriptan (44.4%) and rizatriptan (35.7%).

Conclusions

Our findings highlight an alarming prevalence of triptan non-response among adult migraineurs receiving treatment in a London-based tertiary headache service. It is imperative for clinicians to explore methods to optimize acute medication efficacy, whether this comprises changing to a triptan with a superior response rate, advocating for early intervention or considering alternative acute medication classes, such as gepants or ditans.

Graphical abstract

This is a visual representation of the abstract.

Keywords

ditan gepant migraine triptan triptan non-responder triptan responder

Introduction

Triptans, serotonin 5-HT_1B/1D receptor agonists (1), revolutionized the acute treatment of migraine, providing generally good efficacy with modest side-effects (2,3). They are now considered a first-line treatment for an attack of moderate-to-severe migraine (4). However, varied responses to triptans, as a result of poor efficacy and tolerability, are seen in approximately 30–40% of patients who do not respond adequately to therapy (5). Further use is limited in patients with cardiovascular and cerebrovascular diseases, as well as in hemiplegic migraine and migraine associated with brainstem aura, because of the risk of vascular adverse events associated with vasoconstriction caused by the activation of 5-HT_1B receptors (2) and regulatory considerations, albeit clinical experience suggests that these risks are minimal (6). Given a proportion of patients do not benefit from triptans, new treatments, including gepants and ditans, have been developed for acute migraine therapy with reported efficacy in triptan non-responders (4,7 –10).

To understand which patients are “triptan non-responders”, the definition of a “triptan responder” is a useful starting point. The European Headache Federation (EHF) Consensus Panel defined a “triptan responder” as a patient who experiences effective attack treatment consistently, at least three out of four consecutive attacks, when treating with a triptan (11). Patients should be able to plan activities knowing that, if an attack occurs, it can be controlled with the given triptan. Conversely, triptan failure includes cases where the above definition is not met. There are four distinct categories of triptan failure described by the EHF including triptan non-responder, defined as failure of a single triptan; triptan-resistant, defined as failure of at least two different triptans; triptan refractory, defined as failure to at least three different triptans, including subcutaneous formulation; and triptan ineligibility, defined as the presence of an acknowledged contraindication to triptan use (11).

Currently, there are limited data available on the prevalence of triptan non-responders. A previous pooled analysis from the rimegepant studies reported that 35.2% of participants had an insufficient response to one triptan and 9.3% of participants were triptan-resistant, defined as an insufficient response to at least two triptans. Similarly, in the ubrogepant clinical trial program some 25% were classified as “triptan-insufficient” responders (10). Ruscheweyh et al. (12) have reported that 13.1% of clinic patients in specialized headache care in Germany have failed at least two triptans. Considering that an inadequate response to triptans is seen in approximately one-third of patients and contraindications occur in roughly one-fifth of patients (13), it is interesting to observe so few patients being deemed as “triptan-resistant”, especially in tertiary headache services where the rate of triptan non-response is likely to be higher as a result of a more severely affected patient cohort.

From our clinical experience in a London tertiary headache service, we considered that levels of triptan non-response are much higher in our cohort than published data. To understand our service, we reviewed data over a two-year duration to estimate the frequency of triptan non-response in adult migraineurs, and thus the need in our setting for new therapies.

Methods

Ethics

The data were compiled and analysed with the objective of carrying out a service evaluation, which does not require Research Ethics Committee review in the UK (http://www.hra-decisiontools.org.uk/research). Informed consent was not required for use of patient data for this study because the data were acquired from patient clinic letters as part of an evaluation process; therefore, only local hospital approval was needed.

Study conduct

This analysis was based on data collected from detailed clinic letters in a tertiary headache service over two years (February 2022–2024) to estimate the frequency of triptan non-response.

For all patients included in the service evaluation, the last available clinic appointment letter was analysed to maximize information and ensure the data was accurate and up-to-date. Initial appointments within the tertiary headache service last approximately one hour, allowing a detailed history to be taken. All healthcare professionals including physicians and nursing colleagues use the same structured template to ensure key information is not missed. Information regarding headache phenotype, associated symptoms, past medical history, medication history, including patient responses and the presence of adverse effects (if any) to current and previous acute and preventive medications, family history and social history were collected. Of particular relevance to this evaluation, patients had to indicate the reason for discontinuation of previous acute headache medication, mainly adverse effects, inefficacy, alternative medication offered, headache improvement, contraindication or other. Current acute headache medication was additionally checked to ensure that patients found medications both effective and tolerable in line with the EHF definition of a “triptan responder” (11). Medication history for both current and previous medications was checked at each appointment to confirm the accuracy of the reporting.

Participants

We included all adult migraineurs who had a diagnosis of migraine with or without aura in line with the International Classification of Headache Disorders, 3rd edition (14) who had at least one appointment with the King's College London tertiary headache team over the last two years (n = 419). Diagnoses of migraine were validated by a headache specialist through history and headache diary. Patients with other chronic primary or secondary headache disorders, significant psychiatric disease and probable diagnoses of migraine, as well as those who were pregnant, were excluded. Pregnant women were excluded subsequent to cautionary triptan use in this subpopulation.

Assessments

The primary outcome of the service evaluation was to estimate the frequency of triptan non-response, defined below, in a London-based tertiary headache service. In line with the EHF Consensus panel and previous studies, we defined a “triptan non-responder” as either (i) previous triptan use discontinued secondary to adverse effects and/or inefficacy or (ii) current triptan use (at the time of the appointment) limited by reduced efficacy and/or tolerability. A “triptan responder” was characterized as a patient who generally reported good efficacy to triptans with minimal, unbothersome adverse reactions. To help categorize patients into responders and non-responders, patients were asked (i) whether they thought their triptan medication was effective; (ii) whether they wanted to continue with the medication; and (iii) whether they had any adverse effects. If adverse effects were identified, patients were assessed to determine the seriousness and bothersome nature of adverse reactions. Adverse events categorized as serious and/or bothersome requiring cessation of the medication were defined as a non-response, whereas adverse events categorized as mild and/or unbothersome with the patient choosing to remain on triptan medication were defined as a response.

Statistical analysis

Descriptive statistics include the mean ± SD, as well as numbers and percentages as appropriate, to the data and its distribution.

A single ordinal logistic regression model with proportional odds using a cumulative logit link function was performed for group comparisons between triptan responders and different levels of non-response. Dichotomous variables included sex, the presence of chronic migraine, the presence of aura and the presence of medication overuse, whereas scale variables included age, headache days per month, severe headache days per month, the number of acute medication days per month, and the number of current and failed preventives. Age of onset, disease duration and family history were excluded from analysis as a result of missing data. Statistical analysis was performed using SPSS, version 29.0 (IBM Corp., Armonk, NY, USA). p < 0.05 was considered statistically significant.

Results

Patients

Table 1 summarizes the characteristics of patients in each study. The total number of adult migraineurs included within the two-year study period was 419. The mean age of patients included within the study was 46 years, and most patients were female (83.8%). The majority of patients had chronic migraine (88.5%). Aura was present in 43.1% of patients. In the sample, 58.4% (245/419) of patients were currently using triptans as acute medication, whereas 29.6% (124/419) of patients had previously used and discontinued triptan therapy. Fifty patients (11.9%) had never tried triptans as acute therapy, with just under half (42%) of these patients having a contraindication to triptan therapy. Contraindications included ischaemic heart disease, previous cerebrovascular accidents, previous myocardial infarctions, coronary artery disease, elderly age, brainstem aura and hemiplegic migraine. The median number (interquartile range) of triptans failed within the patient sample was 1 (1–2) triptans. Oral sumatriptan was the most commonly used triptan with 65.0% of the patients currently using or previously having used the tablet, followed by rizatriptan (37.9%). The most common triptan associated with poor response or intolerance was sumatriptan nasal spray (80.5%, 33/41) followed by oral zolmitriptan (78.9%, 71/89).

Table 1.

Characteristics of the study population (n = 419).

Demographics
Age (years)	46 ± 18
Sex
Female	351 (83.8%)
Headache characteristics
Diagnosis
Chronic migraine	371 (88.5%)
Episodic migraine	47 (11.2%)
Presence of aura	181 (43.2%)
Headache days per month	18 ± 11
Severe headache days per month	11 ± 9
Headache intensity [0–10]	7 ± 2
HIT-6 score (27)	69
Number of patients with medication overuse	113
Acute medication days per month	9 ± 11
Current preventive migraine medication	333 (79.5%)
Number of patients on CGRP monoclonal antibody therapy	196 (46.8%)
Number of previous failed preventive migraine medication	6 ± 4
Current or previous triptan use
Current or previous use of any triptan	369 (88.1%)
Contraindication to use of triptan	30 (7.2%)
Sumatriptan oral	240 (57.3% / 65.0^a%)
Sumatriptan nasal	41 (9.8% / 11.1^a%)
Sumatriptan subcutaneous	39 (9.3% / 10.6^a%)
Rizatriptan	140 (33.4% / 37.9^a%)
Naratriptan	42 (10.0% / 11.4^a%)
Zolmitriptan oral	89 (21.2% / 24.1^a%)
Zolmitriptan nasal	45 (10.7% / 12.2^a%)
Eletriptan	93 (22.2% / 25.2^a%)
Almotriptan	51 (12.2% / 13.8^a%)
Frovatriptan	52 (12.4% / 14.1^a%)

Values are the mean ± SD or numbers and percentages with respect to the total population (n = 419).

For single triptans, values represent the total number of times each triptan has been used. Percentages are given with respect to the total population (n = 419), followed by the population of current or previous triptan users, represented by the letter^a (n = 369).

CGRP: calcitonin gene-related peptide.

Triptan responders and triptan non-response

Figure 1 illustrates the numbers of patients with varying levels of triptan non-response (n = 414). It is important to note that five patients were excluded from the analysis because they could not remember the number of triptans they had previously tried. Triptan non-response (failure) was defined as current or previous triptan use limited by inefficacy and/or intolerance. In line with the EHF definitions given by the Consensus Panel (11), “triptan non-response” was seen in 63.8% of patients (264/414), whereas 37.7% of patients (156/414) had failed at least two triptans (EHF “triptan resistant”) and 4.6% of patients (19/414) had failed at least three triptans, including a subcutaneous formulation (EHF “triptan refractory”). Notably, 16.7% (69/414) had failed at least three triptans where one was not subcutaneous sumatriptan. A detailed overview according to the levels of triptan non-response is provided in the supplementary material (Table 1).

Figure 1.

Triptan failure and no failure subgroups. Total population = 419, included population = 414. Patients (n = 5) were unable to provide the number of triptans failed.

Comparison of patients with and without triptan non-response

Statistical comparisons comparing triptan responders and varying levels of triptan non-response were performed using a single ordinal logistic regression with proportional odds including all selected predictors. The deviance goodness-of-fit test indicated that the model was a good fit to the observed data (χ²₁₀₈₇= 942.852, p = 0.999), and the final model significantly predicted the dependent variable against the intercept-only model (χ²₁₁= 51.503, p < 0.001). Collinearity statistics showed that the variance inflation factor varied from 1.047–1.995 (minimum–maximum) for all predictors included within the model, indicating that multicollinearity was not observed between a given predictor variable and any other predictor variables in the model.

Of the eleven predictors, four variables were statistically significant: age, the number of failed preventives, medication overuse and the use of calcitonin gene-related peptide (CGRP) monoclonal antibodies (Table 2). Increasing age (odds ratio (OR) = 0.976, 95% confidence interval (CI) = 0.963–0.989, χ²= 12.223, d.f. = 1, p < 0.001) and the presence of medication overuse (OR = 0.430, 95% CI = 0.236–0.785, χ²= 7.550, d.f. = 1, p = 0.006) was associated with a decreased likelihood of triptan non-response, whereas an increased number of failed preventives (OR = 1.125, 95% CI = 1.069–1.184, χ²= 20.235, d.f. = 1, p < 0.001) and the use of CGRP monoclonal antibodies (OR 1.642, 95% CI = 1.074–2.510, χ²= 5.238, d.f. = 1, p = 0.022), typically prescribed after the failure of three different migraine preventive medication classes, was associated with an increased likelihood of triptan non-response, respectively.

Table 2.

Characteristics of triptan responder and failure categories.

	B	SE	Wald	d.f.	p	Odds ratio	95% confidence interval for odds ratio
	B	SE	Wald	d.f.	p	Odds ratio	Lower	Upper
Age	−0.024	0.0069	12.223	1	<0.001*	0.976	0.963	0.989
Female sex	0.107	0.2639	0.164	1	0.685	1.113	0.663	1.867
Presence of chronic migraine	−0.141	0.3535	0.160	1	0.689	0.868	0.434	1.736
Presence of aura	0.191	−0.200	0.921	1	0.337	1.211	0.819	1.791
Headache days per month	0.002	−0.020	0.036	1	0.849	1.002	0.980	1.024
Severe headache days per month	−0.005	−0.032	0.127	1	0.722	0.994	0.969	1.022
Acute medication days per month	0.005	−0.020	0.170	1	0.680	1.005	0.981	1.031
Presence of medication overuse	−0.844	0.3071	7.550	1	0.006*	0.430	0.236	0.785
Number of current preventives	0.073	−0.157	0.390	1	0.532	1.076	0.855	1.354
Number of failed preventives	0.118	0.066	20.235	1	<0.001*	1.125	1.069	1.184
Use of CGRP antibody therapy	0.496	0.071	5.238	1	0.022*	1.642	1.074	2.510

Statistical comparison between groups were performed using a single ordinal logistic regression model with proportional odds. *p ≤ 0.05.

CGRP: calcitonin gene-related peptide.

Different triptans and formulations

Table 3 illustrates the rates of triptan response versus non-response in respect to the number of times the medication was used. Of the included 419 adult migraine patients, the most frequently used triptans in our sample were oral sumatriptan (57.3%), rizatriptan (33.4%) and eletriptan (22.2%). Subcutaneous sumatriptan was used in 9.3% of patients, often with patients favouring the use of oral triptan medications. In patients who had failed a single triptan, the next triptans tried was rizatriptan (+15.4%) and oral zolmitriptan (+15.0%). Similarly, in patients who had failed two triptans, the next triptans tried were oral zolmitriptan (+7.6%), subcutaneous sumatriptan (+7.9%) and rizatriptan (+9.9%). Among those who had tried at least three triptans, parenteral triptans were commonly used to a lesser extent than oral formulations (25.0% for nasal zolmitriptan, 27.3% for subcutaneous sumatriptan, 23.9% for nasal sumatriptan). Naratriptan (25.0%) and nasal sumatriptan (23.9%) were the least used triptans in those who had tried at least three different triptans (see supplementary material, Table 2).

Table 3.

Individual triptan response and non-response rates from a cohort of 369 patients who currently or previously have used triptans.

Drug	Route	Total	Triptan response	Triptan failure	Reasons for failure
Drug	Route	Total	Triptan response	Triptan failure	Discontinued for other reason	Efficacy failure	Tolerability failure
Sumatriptan	Oral	241	60 (24.9%)	181 (75.1%)	1 (0.4%)	131 (54.4%)	49 (20.4%)
	Nasal	41	8 (19.5%)	33 (80.5%)	0	26 (63.4%)	7 (17.1%)
	SC	39	13 (33.3%)	26 (66.7%)	0	15 (38.5%)	11 (28.2%)
Rizatriptan	Oral	140	50 (35.7%)	90 (64.3%)	1 (0.7%)	68 (48.6%)	21 (15.0%)
Naratriptan	Oral	42	11 (26.2%)	31 (73.8%)	1 (2.4%)	22 (52.4%)	7 (16.7%)
Zolmitriptan	Oral	90	19 (21.3%)	71 (78.9%)	1 (1.1%)	58 (64.4%)	12 (13.5%)
Zolmitriptan	Nasal	45	20 (44.4%)	25 (55.6%)	1 (2.2%)	19 (42.2%)	4 (8.9%)
Eletriptan	Oral	93	46 (49.5%)	47 (50.5%)	0	36 (38.7%)	11 (11.8%)
Almotriptan	Oral	51	18 (35.3%)	33 (64.7%)	0	26 (51.0%)	6 (11.8%)
Frovatriptan	Oral	52	13 (25.0%)	39 (75.0%)	0	35 (67.3%)	4 (7.7%)

Values represented as numbers and percentages in respect to the total number times the medication was used.

Note that, within the cohort, most patients had trialled multiple triptans. If a patient had both efficacy and tolerability failure, priority was given to the tolerability and adverse effects experienced. Discontinuation for other reasons includes: formulation issues, not required because of headache improvement, discontinuation advised by physician, other.

Triptan responders and non-responders

Figure 2 illustrates the percentage of patients characterized as “triptan responders” who show good efficacy and minimal adverse effects to their given triptan in respect to the number of times the medication was used. The largest proportion of patients responded to eletriptan (49.5%), followed by nasal zolmitriptan (44.4%) and rizatriptan (35.7%). Oral sumatriptan was the most frequently used triptan; however, only one-quarter of patients (24.9%) reported a triptan response. Subcutaneous sumatriptan exhibited a marginally higher response rate of 33.3%; however, it was limited by an elevated tolerability failure rate of 28.2%, surpassing that of other triptans by a considerable margin. By contrast, our study found the highest triptan non-response rates associated with nasal sumatriptan (80.5%) and oral zolmitriptan (78.9%). Similarly, long-acting triptans, such as frovatriptan and naratriptan, equally had reduced response rates, reported as 75.0% and 73.8%, respectively.

Figure 2.

Proportion (%) of patients who met the definition of “triptan response” characterized as generally good efficacy and well-tolerated.

Reasons for triptan non-response

Figure 3 demonstrates the reasons for triptan non-response comparing efficacy failure against tolerability failure. In our sample, efficacy failure outweighed tolerability failure for every triptan. Efficacy failure was most associated with frovatriptan (67.3%), oral zolmitriptan (64.4%) and nasal sumatriptan (63.4%), whereas tolerability failure was most associated with subcutaneous sumatriptan (28.2%), oral sumatriptan (20.4%) and nasal sumatriptan (17.1%).

Figure 3.

Reasons for triptan failure. Proportion (%) of patients who reported efficacy failure, shown in blue, and tolerability failure, shown in orange. Note that, if a patient had both efficacy and tolerability failure, priority was given to the tolerability and adverse effects experienced. Discontinuation for other reasons is shown in Table 2.

Discussion

Similar to other published studies (12), triptan non-response was defined as either (i) previous triptan use discontinued secondary to adverse effects and/or inefficacy or (ii) current triptan use (at the time of the appointment) limited by reduced efficacy and/or serious adverse events (categorized as serious and/or bothersome). This was similar to the novel definition set by the EHF Consensus Panel, which defined triptan failure as ineffective acute attack treatment in more than one out of four migraine attacks (11). Failure may be further characterized by at least one of the following: (i) limited headache improvement; (ii) limited improvement in migraine related non-pain symptoms, such as photophobia, nausea and phonophobia, and/or (iii) the presence of drug-related adverse effects (11). Dependent on the number of triptans failed, different definitions of failure may be applied: a “triptan non-responder” is defined as failure of a single triptan not matching the definition of a triptan responder, whereas failure of at least two different triptans is defined as “triptan-resistant” and failure of at least three different triptans, including subcutaneous formulation, is defined as “triptan refractory”. Notably, it must be acknowledged that the complete EHF criteria for triptan failure could not be completely reproduced from the present data because this would require information from single attacks, the number of treated attacks, and separate information on pain intensity, intervention approach (early/late) and non-pain symptoms (11).

By contrast to other studies (9,10,12), our study found much higher rates of triptan non-response, with 63.8% of patients having failed at least one triptan, 37.7% having failed at least two triptans and 21.3% having failed at least three triptans, necessitating the need for new acute treatments for migraine (Table 4). Eletriptan was associated with the best overall responder rates (49.5%) followed by nasal zolmitriptan (44.4%), rizatriptan (35.7%) and almotriptan (35.3%), where a response required the triptan to be both tolerable and effective. Conversely, nasal sumatriptan (19.5%) and oral zolmitriptan (21.3%) were most commonly associated with triptan non-response.

Table 4.

Comparison of the different levels of triptan failure amongst three studies investigating the prevalence of triptan failure (9,12).

Study	Failure of ≥ 1 triptan (%)	Failure of ≥ 2 triptans (%)	Failure of ≥ 3 triptans (%)
Present data	63.8	37.7	21.4
Lipton et al. (9)	35.2	9.3
Ruscheweyh et al. (12)	42.5	13.1	3.9

Frequency of triptan non-response

Previous literature estimates triptan non-response in approximately 25–42.5% of patients (9,10,12). By contrast, our results of triptan non-response were much higher, with 63.8% of patients having failed at least one triptan (Figure 1). Values of triptan non-response were calculated in respect to the total included study population (n = 414) and included patients who were triptan naïve, accounting for 12% of patients (n = 50). Of the triptan naïve patients, the majority of patients preferred to use simple non-opioid analgesics, such as paracetamol and ibuprofen, over triptan medication. Remarkably few patients used sumatriptan by injection; this may represent practice bias where the injections are relatively expensive and thus less often prescribed. The differences in rates of triptan non-response observed in our study may be partially explained by differences in the demographics of the included study cohorts. Compared with both the German and rimegepant studies (9,12), our study population reported a higher number of severe headache days per month and a greater proportion of patients utilized migraine preventive medication, possibly representing a more severely affected migraine population. Moreover, further differences emerged when comparing our patient cohort with the German study alone. In our sample, more patients had a diagnosis of chronic migraine, were typically older and reported higher headache intensity with a greater number of acute medication days, which may partially account for the higher results of non-response seen (12).

More severe migraine may be associated with poor responses to triptans

In our study, patients characterized as “triptan non-responders” showed greater differences for age, medication overuse, the number of failed preventives and the use of CGRP monoclonal antibodies. Advancing age and the presence of medication overuse was associated with a reduction in the likelihood of triptan non-response, whereas an increased number of failed preventives and the use of CGRP monoclonal antibodies was associated with an increased likelihood of triptan non-response. These findings may possibly suggest that individuals with more severe and refractory migraine profiles may be predisposed to triptan non-response, as evidenced by their history of increased failed preventives and reliance on CGRP monoclonal antibodies, typically prescribed after the failure of three different migraine preventive medication classes. Importantly, the number of headache days and the number of migraine days per month between triptan responders and non-responders was not significant.

The association between medication overuse and the increased probability of triptan response warrants consideration. Although excessive acute medication usage is typically associated with increased frequency of headache (15), our data suggest that medication overuse increases triptan response. There are a number of plausible suggestions to account for this finding. First, patients who overuse triptans may initially experience a more pronounced therapeutic effect. This phenomenon has been previously observed by Oh et al. (16) who found that, in patients who excessively use triptans, fewer headache days (21.0 (20.0–30.0) vs. 30.0 (20.5–30.0) days per month, p = 0.008) and fewer severe headache days (7.0 (4.0–10.0) vs. 10.0 (5.0–15.0) days per month, p = 0.017) were reported compared to those who overused non-opioid analgesics. Additionally, patients who respond well to triptans and have highly frequent headache may be more prone to medication overuse as a way of reducing headache frequency and severity. Second, the combined efficacy of multiple medications from different drug classes, such as non-steroidal anti-inflammatory drugs, paracetamol and opioid-containing medications, may contribute to enhanced headache relief, potentially boosting triptan response rates. Lastly, it is important to acknowledge that patients who overuse medication may inadvertently potentiate the placebo effect. Patients who overuse medication may associate this with greater therapeutic effects, leading to an augmented perception of triptan response.

Comparison between different triptans and formulations

It is widely acknowledged that failure with one triptan does not necessarily predict the failure with another (17 –21). Physicians should actively advocate for patients to explore alternative triptans following initial treatment failure, aiming to mitigate migraine pain and optimize acute pain relief. In our study, oral sumatriptan was the most frequently used triptan. Subsequent to initial triptan non-response, rizatriptan or eletriptan were frequently chosen next, consistent with recent meta-analysis findings indicating their superior efficacy among oral triptans (22,23).

Our analysis of responder rates and factors contributing to triptan non-response generally concurs with both clinical trial data and the recent study conducted by Ruscheweyh et al. (12), as shown in Figures 2 and 3. In our sample, oral sumatriptan was the most frequently prescribed triptan and of those who were currently using or had previously used sumatriptan, approximately one-quarter of patients (24.9%) reported a positive response. Of the patients who discontinued sumatriptan, over half of the patients (54.4%) reported that this was a result of efficacy failure and roughly one-fifth of patients reported tolerability failure (20.4%). Eletriptan had the overall largest responder rates and was well-tolerated, with only 11.8% of patients discontinuing eletriptan therapy as a result of adverse effects, consistent with its clinical trial results (24). This was equal to the tolerability failure rate observed for almotriptan, a triptan known for its remarkably low adverse effect profile (2). In addition, eletriptan had greater response rates than subcutaneous sumatriptan and nasal zolmitriptan, both of which are fast-acting parenteral triptans, suggesting its superiority as a monotherapy. Notably, oral formulations of rizatriptan and almotriptan also ranked above subcutaneous sumatriptan for triptan response in our study population. This may be partially explained by the high tolerability failure rates observed in the subcutaneous sumatriptan group (28.2%), compared to that of rizatriptan (15.0%) and almotriptan (11.8%), respectively. Subcutaneous sumatriptan was generally more effective than both rizatriptan and almotriptan (efficacy: sumatriptan SC 61.5% > rizatriptan 51.4%, almotriptan 49.0%). Similar to the German study (12), nasal sumatriptan had the lowest responder rates, as a result of an efficacy failure rate of 63.4% and a tolerability failure rate of 17.1%. This is unexpected given that randomized, masked, multicentre studies report that 62–64% of patients using 20 mg sumatriptan nasal spray experience headache reduction two hours post-dose which was significant to placebo (25–35%, p < 0.05) (25,26). In addition, sumatriptan nasal spray is widely reported as tolerable, aside from complaints of its unpleasant taste (25,26).

Limitations

Our study reported the frequency of triptan non-response amongst adult migraineurs seen within a London-based tertiary headache centre using information collected from retrospective clinic letters. Definition of a “triptan responder” and “triptan failure” were standardized in line with the EHF Consensus panel definitions. The higher rates of triptan non-response observed in our results must be interpreted in the context of a more severely affected migraine population. Migraineurs were recruited from a tertiary headache service, often presenting with a greater number of headache days per month, migraine days per month and a larger number of failed medication regimes compared to other migraineurs seen in primary and secondary care services. In addition, healthcare professionals working within the tertiary service also have greater access to a diverse range of acute medications, including triptans, which may further encourage patients to swap triptans or try a new treatment approach, such as gepants or ditans. Equally, patients who experienced triptan failure may not be offered, nor choose not to try a second triptan, which may further affect the results of triptan efficacy. Moreover, patients attending the service were likely to have already failed the most frequently used triptans, such as oral sumatriptan, oral zolmitriptan and oral rizatriptan, which may have affected the response rates of these medications. Given that the data was collected in a retrospective fashion, the increased risk of recall bias must be acknowledged, with particular reference to the broad definition of triptan non-response characterized by poor efficacy and/or tolerability (11). Subsequently, the retrospective study design may increase the risk of misclassification and offer an inferior level of evidence compared with prospective studies. Furthermore, in light of the retrospective design, the study may also be further subject to confounding whereby other non-measured risk factors, such as differences in availability, price and reimbursement of triptans, may affect the final result of triptan non-response.

Our study aimed to mitigate the risk of recall bias and incomplete reporting through the use of structured clinic letters that prompted healthcare professionals to confirm current and previous acute medication history, including efficacy responses and the presence of side effects. The minimum time between patient appointments with the headache team was approximately three months, allowing the study population to test their response to triptans consistently throughout this period, noting its effectiveness of attack relief and any side effects whilst taking the medication. It must be acknowledged that our study did not strictly collect data regarding triptan response for each individual migraine attack throughout this period. Similar to other studies, our study did not examine how patients were using triptans and whether they were following an early treatment paradigm which may influence the responsiveness of triptans. The presence of medication overuse was a significant predictor of a decreased likelihood of triptan non-response. Our study collected the presence of medication overuse as a binary data variable; therefore, we were unable to observe medication classes that may have contributed to this result. This may reduce the understanding of the association, as well as the underlying factors associated with them. To provide a direct comparison to the study conducted by Ruscheweyh et al. (12), we chose not to include the dosages of triptans which may influence triptan efficacy and tolerability. In addition, the study conducted by Ruscheweyh et al. (12), considered reporting dosing subgroups, however, reported that the numbers were too small to perform analysis. This would have also been a challenge in our study considering the smaller sample size.

Conclusions

Our findings highlight an alarming prevalence of triptan non-response among adult migraineurs receiving treatment in a London-based tertiary headache service. Triptan non-response was associated with an increased number of failed preventives and the use of CGRP monoclonal antibody therapy, whereas advancing age and the presence of medication overuse exhibited a paradoxical association with reduced triptan non-response rates. Considering the proportion of patients affected by triptan non-response, it is imperative for clinicians to explore methods to optimize acute medication efficacy, whether this comprises changing to a triptan with a superior response rate, advocating for early intervention or considering alternative acute medication classes, such as gepants or ditans. Moving forward, our study highlights the need for access to new acute medications in tertiary headache settings to mitigate the disability attendant triptan non-response. Further research should prioritize identifying predictive markers, if any, for triptan non-response, thereby attenuating non-responsiveness and advancing acute migraine care. Clinical implications

Previous estimates of the prevalence of triptan non-response vary between 9.3% and 35.2%.

We report that the prevalence of the “triptan non-response” is much higher, affecting 63.8% of patients (264/414), whereas 37.7% of patients (156/414) had failed at least two triptans (EHF “triptan resistant”) and 4.6% of patients (19/414) had failed at least three triptans, including a subcutaneous formulation (EHF “triptan refractory”).

An increased number of failed preventives and the use of CGRP monoclonal antibodies increased the probability of a triptan non-response.

Supplemental Material

sj-docx-1-cep-10.1177_03331024241278911 - Supplemental material for Triptan non-response in a London tertiary headache centre: What can we learn? A retrospective study

Supplemental material, sj-docx-1-cep-10.1177_03331024241278911 for Triptan non-response in a London tertiary headache centre: What can we learn? A retrospective study by Robyn-Jenia Wilcha and Peter J. Goadsby in Cephalalgia

Footnotes

Declaration of conflicting interests

RW has nothing to declare. PJG reports, over the last 36 months, grant from Kallyope, and personal fees from Aeon Biopharma, Abbvie, Aurene, CoolTech LLC, Dr Reddy's, Eli-Lilly and Company, Linpharma, Lundbeck, Pfizer, PureTech Health LLC, Satsuma, Shiratronics, Teva Pharmaceuticals, Tremeau, and Vial.

Funding

The work was supported in part National Institute for Health and Care Research (NIHR) King's Clinical Research Facilcity and Biomedical Research Centre at South London and Maudsley NHS Foundation Trust.

Ethical statement

The study did not require Research Ethics Committee review in the UK. Informed consent was not required for use of patient data for this study.

ORCID iDs

Robyn-Jenia Wilcha

Peter J. Goadsby

Supplemental material

Supplemental material for this article is available online.

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