This systematic literature review identified substantial variability across studies in definitions and methodologies used to identify insufficient efficacy and/or tolerability to triptans for acute treatment of migraine. |
Across studies, the most commonly used outcomes to measure efficacy were pain relief and pain freedom at 2 h. |
The totality of evidence suggests that a proportion of patients with insufficient efficacy and/or tolerability to one triptan may benefit from switching to a different triptan. |
Factors associated with increased risk of insufficient efficacy and/or tolerability to triptans include severe baseline headache severity, photophobia, phonophobia, nausea, and depression. |
Findings from this review suggest that a large unmet need remains for people with insufficient efficacy and/or tolerability to triptans, irrespective of the definitions or methodologies used to identify this population. |
Digital Features
Introduction
Methods
Data Sources and Searches
Study Selection
Screening Process and Data Extraction
Bias Assessment and Quality Control
Definitions for Pain Freedom and Pain Relief
Results
Overall Search Results
Study Characteristics and Objectives
Author, year | Study design | Population investigated/key response criteria for inclusion | Intervention investigated | Key results |
---|---|---|---|---|
Patients with historicala triptan insufficient efficacy and/or tolerability: subsequent response to different triptan or different triptan dose/formulation (n = 10) | ||||
Seeburger, 2011 [20] | Randomized, blinded, crossover | Previous insufficient efficacy and/or tolerability to sumatriptana Within-trial screening criteria for insufficient efficacy: non-response to sumatriptan 100 mg in one migraine attack eligible to enter double-blind treatment Within-trial screening results: sumatriptan non-responsive: n = 109/159; responsive: n = 44/159 | Rizatriptan Rizatriptan 10 mg vs. placebo was assessed over three migraine attacks; 109 patients randomized 1:1:1 to dosing schedule of rizatriptan/rizatriptan/placebo, rizatriptan/placebo/rizatriptan, or placebo/rizatriptan/rizatriptan; 102 participants treated at least one migraine attack, 98 treated all three attacks | Pain relief 2 h (across 3 attacks): rizatriptan: 51%, placebo: 20% Pain-free 2 h (across 3 attacks): rizatriptan: 22%, placebo: 12%. (Number of treated patients 102) |
Stark, 2000 [23] | Randomized, blinded, parallel | Previous insufficient efficacy and/or tolerability to sumatriptana Within-trial screening criteria for insufficient efficacy (single-blind assessment): non-responsive to oral administration of sumatriptan 50 mg assessed over one attack Within-trial screening results: sumatriptan non-responsive: n = 220/347; responsive: n = 124/347 | Naratriptan Oral administration of naratriptan 2.5 mg (n = 99) vs. placebo (107) assessed over one attack during double-blind period | Pain relief 2 h: naratriptan: 25%; placebo: 10% Pain-free 2 h: naratriptan: 6%; placebo: 3% Pain relief 4 h: naratriptan: 41%; placebo: 19% Pain-free 4 h: naratriptan: 22%; placebo: 10% |
Diener, 2005 [21] | Randomized, blinded, parallel | Previous insufficient efficacy and/or tolerability to sumatriptana Within-trial screening criteria for insufficient efficacy: non-response to sumatriptan 50 mg assessed over one attack Within-trial screening results: sumatriptan non-responsive: n = 221/302; responsive n = 57/302 | Almotriptan Almotriptan 12.5 mg (n = 99) vs. placebo (n = 99) assessed over one attack | Pain relief 2 h: almotriptan 12.5 mg: 48%, placebo: 23% Pain-free 2 h: almotriptan: 33%, placebo: 14% |
Farkkila, 2003 [22] | Randomized, blinded, parallel design | Previous insufficient efficacy and/or tolerability to sumatriptana | Eletriptan Eletriptan 40 mg (n = 179), eletriptan 80 mg (n = 167), vs. placebo (n = 81) assessed for treatment of up to 3 attacks | Pain relief 2 h: first attack: eletriptan 40 mg: 59%, eletriptan 80 mg: 70%, placebo: 30% Consistency of response (2/3 attacks): eletriptan 40 mg: 66%; eletriptan 80 mg: 72%; placebo: 15% Consistency of response (all 3 attacks): eletriptan 40 mg: 38%; eletriptan 80 mg: 41%; placebo: 6% Pain-free 2 h: first attack: eletriptan 40 mg: 35%, eletriptan 80 mg: 42%, placebo: 7% |
Goldstein, 2006 [27] | Open-label | Previous insufficient efficacy and/or tolerability to rizatriptana | Eletriptan Eletriptan 40 mg (n = 121) assessed for first attack | Pain relief 2 h: eletriptan 40 mg: 64%a (95% CI 55–73%) Pain-free 2 h: eletriptan 40 mg: 30% (95% CI 22–39%) |
Mathew, 2000 [25] | Open-label, crossover design | Previous insufficient efficacy and/or tolerability to sumatriptan 50 mga | Zomitriptan and rizatriptan Group 1: zolmitriptan 5 mg for first 5 headaches and rizatriptan 10 mg for next 5; Group 2: rizatriptan 10 mg followed by zolmitriptan (n = 48 patients; 120 attacks) to treat 10 attacks in total | Pain relief 2 h (% of attacks): across 10 attacks: zolmitriptan: 73%; rizatriptan: 81% Consistency: 2 out of 3 attacks: zolmitriptan: 81% of attacks; rizatriptan: 80%; 3 out of 3 attacks: zolmitriptan: 72%; rizatriptan: 70% Pain-free 2 h (% of attacks): across 10 attacks: zolmitriptan: 45%; rizatriptan: 58% |
Newman, 2008 [26] | Open-label, prospective | Previous insufficient efficacy and/or tolerability to low-dose sumatriptana | Sumatriptan Oral administration of sumatriptan 100 mg (rapid release) early intervention (within 30 min of onset of mild pain); 4 consecutive attacks treated | Pain-free 2 h: range 53–61% across the 4 attacks |
Landy, 2004 [24] | Open-label, prospective in headache clinic | Previous insufficient efficacy and/or tolerability to sumatriptan 50 mga | Sumatriptan Sumatriptan 100 mg (n = 20 patients; 60 attacks) at the earliest sign of pain while still mild, in 3 subsequent attacks | Pain-free 2 h (% of attacks): 80% Sustained pain-free 2–24 h: 75% |
Mathew, 2009 [29] | Two identical studies: randomized, double-blind, placebo-controlled, crossover | Previous insufficient efficacy and/or tolerability to a short-acting triptana | Sumatriptan plus naproxen Sumatriptan 85 mg plus naproxen 500 mg vs. placebo (n: study 1: 144; study 2: 139); 2 attacks treated in each trial | Pain-free 2 h (across attacks): Study 1: sumatriptan + naproxen: 40%; placebo: 17% Study 2: sumatriptan + naproxen: 44%; placebo: 14% Sustained pain-free 2–24 h (across attacks): Study 1: sumatriptan + naproxen: 26%; placebo: 8%; Study 2: sumatriptan + naproxen: 31%; placebo: 8% |
Diamond, 2007 [28] | Open-label study in headache clinic | Previous insufficient efficacy and/or tolerability to any orally administered triptana | Sumatriptan 6 mg sumatriptan (SC) (n = 43) to treat 3 attacks | Pain relief 2 h: first attack: 91%; second attack: 82%; third attack: 72% Pain-free 2 h: first attack: 56%; second attack: 49%; third attack: 51% Sustained pain free 2–24 h: first attack: 32%; second attack: 32%; third attack: 35% |
Patients with historical triptan insufficient efficacy and/or tolerability: subgroup analyses with subsequent non-triptan oral acute treatments (n = 3) | ||||
Blumenfeld, 2019 [32] | Pooled subgroup analysis of two randomized, double-blinded, studies | Previous insufficient efficacy and/or tolerability to any triptana | Ubrogepant Ubrogepant 50 mg/100 mg (study 1) or ubrogepant 25 mg/50 mg (study 2) vs. placebo (1:1:1 ratio) were assessed over a single attack (mITT population: study 1: n = 1327; study 2: n = 1355). Baseline results: 23–27% had triptan insufficient response; 32–42% were triptan-naïve; 35–40% were triptan responders | Pain-free 2 h: response rates were higher for ubrogepant vs. placebo across the triptan subpopulations for treatment of a single attack |
Knievel, 2018 [33] | Post hoc analysis of two pooled randomized, blinded studies | Prior insufficient efficacy and/or tolerability to any triptana | Lasmiditan Lasmiditan 100, 200 mg vs. placebo assessed in good, poor, or non-responders | Pain-free 2 h: benefit with lasmiditan versus placebo was generally unaffected by prior triptan therapy response. Percentages of patients reporting pain freedom with lasmiditan and placebo were not reported in abstract |
Ho, 2011 [31] | Post hoc analysis of one randomized, blinded, parallel design study | Previous insufficient efficacy and/or tolerability to any triptana | Telcagepant and zolmitriptan Telcagepant 150 mg, telcagepant 300 mg, zolmitriptan 5 mg, and placebo (ratio 1:1:1:1) were assessed in patients with good historical triptan response (HTR) (n = 660), intermediate HTR (n = 248), and poor HTR/no use (n = 450) | Pain relief 2 h: Good HTR: zolmitriptan: 72%, telcagepant 300 mg: 52%; telcagepant 150 mg: 48%; placebo: 26%; intermediate HTR: zolmitriptan: 47%, telcagepant 300 mg: 58%; telcagepant: 58%, placebo: 29% Poor HTR/no use: zolmitriptan: 40%, telcagepant 300 mg: 57%; telcagepant 150 mg: 48%, placebo: 31% Pain-free 2 h: Good HTR: zolmitriptan: 44%, telcagepant 300 mg: 23%, telcagepant 150 mg: 18% placebo: 9% Intermediate HTR: zolmitriptan: 29%, telcagepant 300 mg: 34%; telcagepant 150 mg: 23%; placebo: 8% Poor HTR/no use: zolmitriptan: 14%, telcagepant 300 mg: 29%; telcagepant 150 mg: 13%, placebo: 12% |
Subsequent attacks: different or same triptan results (n = 2) | ||||
Tietjen, 2005 [34] | Randomized, crossover design | Patients with no response (self-defined meaningful relief/satisfaction) to oral administration of naratriptan 2.5 mg during a migraine attack were screened for enrollment; 35/60 patients had no response | Naratriptan plus prochlorperazine Naratriptan 2.5 mg plus prochlorperazine 25 mg rectal suppository vs. naratriptan 2.5 mg plus placebo were assessed; subjects and investigators blinded to rectal suppository content; of 15 patients who enrolled in the study, 14 completed | Significant decreases in headache severity and disability at 2 h and 4 h were observed with both regimens; however, there were no differences between regimens |
Landy, 2014 [66] | Post hoc pooled analysis of 4 randomized, blinded, studies | Insufficient efficacy with eletriptan 40 mg in the first attack (intervention results reported on the basis of patients who did not achieve pain relief at 2 h with eletriptan 40 mg in attack 1) | Eletriptan Eletriptan 40 mg vs. placebo was assessed over 3 attacks. First attack screening results: no pain relief at 2 h: eletriptan 40 mg: 297/1299 patients, placebo 375/1299 patients. Patients with no 2 h pain relief with eletriptan in first attack and who treated all three attacks received eletriptan 40 mg (n = 170) or placebo (n = 193) in the 2nd and 3rd attacks | Pain relief 2 h: attack 2: eletriptan 49%; placebo 20%; attack 3: eletriptan: 37%; placebo 16% Pain free 2 h: attack 2: eletriptan 17%; placebo 4%; attack 3: eletriptan 19%; placebo 3% |
Same attack: second dose with same treatment (n = 2) | ||||
Scott, 1996 [64] | Randomized, blinded, parallel design (conducted in general practice centers) | Insufficient efficacy to the first dose of sumatriptan 100 mg (no pain relief at 4 h) | Sumatriptan Sumatriptan 100 mg (second dose) vs. placebo assessed in patients who did not respond to first dose First-dose screening results: lack of pain relief at 4 h with sumatriptan 100 mg in 30% of 1349 patients | Pain relief 4 h: after second dose (range over 3 treated attacks): sumatriptan 100 mg: 51–63%; placebo: 51–61% |
Spierings, 2009 [67] | Randomized, double-blinded | Insufficient efficacy to the first dose of frovatriptan 2.5 mg | Frovatriptan Frovatriptan 2.5 mg for first attack; frovatriptan 2.5 mg vs. placebo for second attack (n = 547 enrolled patients of which 486 treated moderate or severe headache) | In first attack, 63% of 486 patients with moderate or severe headache had no pain relief at 2 h after the first dose. Of 486 patients, 173 (36%) did not take a second dose of study medication at 2 h for non-response (rapid responders). Among rapid responders, 84% and 98% reported mild or no pain at 2 h and 4 h, respectively. Among rapid responders, 24-h recurrence rate was 6% Second attack results not provided |
Predictors of insufficient efficacy within a single attack (n = 2) | ||||
Cady, 2007 [35] | Two identical randomized, blinded studies Aim: assessment of patient-reported symptoms of cutaneous sensitivity (SCS) as a negative predictor of response | Patients with migraine with/without aura with history of attacks that were typically mild at onset | Rizatriptan Rizatriptan 10 mg or placebo with early treatment (within 1 h while pain still mild) was assessed over one attack Symptoms of SCS were present pre treatment in 22–29% of patients across the two studies Patient numbers were rizatriptan: n = 353 (study 1) and 331 (study 2); placebo: n = 177 (study 1) and 169 (study 2) | Pain-free 2 h: Baseline symptoms of SCS: rizatriptan 55–58%; placebo 24–35% No baseline symptoms of SCS: rizatriptan 58–59%; placebo 29–33% |
Diener, 2008 [45] | Pooled analysis of 10 randomized, blinded, parallel design studies | Patients with migraine with/without aura | Eletriptan Negative predictors of response with eletriptan 20 mg, eletriptan 40 mg, eletriptan 80 mg, or sumatriptan 100 mg vs. placebo were assessed (n = 8473 patients for first-attack data) | Pain free 2 h: eletriptan 20 mg: ~ 15%; eletriptan 40 mg: ~ 30%; eletriptan 80 mg: ~ 35%, sumatriptan 100 mg: ~ 25%; placebo: ~ 5% Multivariate regression analyses identified severe headache pain, presence of photophobia/phonophobia, and presence of nausea as significant baseline predictors of failure to achieve 2-h pain-free response. Time of dosing following headache onset did not show influence |
Repeated attacks insufficient efficacy (n = 1) | ||||
Miljkovic, 2018 [70] | Randomized, blinded, parallel design | Patients with migraine without aura | Ergot-based formulation vs. sumatriptan Ergot-based formulation (Nomigren®) vs. sumatriptan (dose unspecified) was assessed (n = 201 patients) | Pain-free 2 h: Nomigren®: 51%; sumatriptan: 34%; Pain-free 2 h: repeat attacks only: Nomigren®: 51%, sumatriptan: 24% |
Menstrual migraine (n = 2) | ||||
Brandes, 2009 [63] | Randomized, blinded, parallel design | Patients with difficult-to-treat menstrual migraine and historical insufficient efficacy and/or tolerability to any triptana | Frovatriptan Frovatriptan 2.5 mg (loading dose: 5 mg) vs. placebo was assessed for short-term prevention of migraine. Two dosing regimens (qd or bid) were studied. A 6-day regimen (starting 2 days prior to anticipated migraine) was used (n = 410) | Headache-free peri-menstrual periods (mean number of per patient): frovatriptan qd: 0.69; frovatriptan bid: 0.92; placebo: 0.42 Severity and incidence of difficult-to-treat menstrual migraine were significantly reduced in both frovatriptan arms |
Cady, 2014 [65] | Randomized, blinded, parallel design | Patients with menstrual migraine Single menstrual migraine episode | Sumatriptan plus naproxen Sumatriptan 85 mg + naproxen 500 mg (Treximet) (n = 21) vs. placebo (n = 20) were to be taken at onset of menstrual migraine episode | Migraine recurrence within 24 h post treatment occurred in 2/14 patients treated with Treximet and 0/11 placebo-treated patients Mean time to pain-free was: Treximet: 3.9 h (n = 14); placebo: 7.64 h (n = 10) |
Author, year | Study design | Patient population; characteristics investigated | Study description or intervention | Results (key relevant findings) |
---|---|---|---|---|
Characteristics investigated in triptan insufficient efficacy and/or tolerability | ||||
Sheftell, 2010 [42] | 6-month observational study using data recorded in e-diaries | Patients with migraine who were prescribed any triptan | Any triptan Headache return with any triptan including sumatriptan, rizatriptan, eletriptan, zolmitriptan, almotriptan, sumatriptan injection, triptan nasal spray (n = 359 patients who treated 2168 attacks) | Pain freedom or pain relief at 2 h: 66% of attacks Headache returned by 48 h: 19% of attacks, across 320 patients Factors associated with increased likelihood of headache return: more severe baseline headache, short duration since diagnosis of migraine, female gender |
Terrazzino, 2010 [43] | Cohort study | Patients with migraine with/without aura | Any triptan Specific genetic markers predictive of consistency in headache response to any triptan including eletriptan, rizatriptan, almotriptan, frovatriptan, sumatriptan, and zolmitriptan were assessed | Consistent response to triptans was observed in 67% of patients with migraine (87/130); 33% (43/130) of patients did not consistently respond. Consistent responders to each triptan (n): eletriptan: 33; rizatriptan: 29; sumatriptan: 20; frovatriptan: 18; almotriptan: 21; zolmitriptan: 9 Patients who had undergone preventive treatment versus who had not appeared to, responded more consistently to triptan therapy Results support role of STin2 VNTR polymorphism of serotonin transporter gene in conferring higher risk of inconsistent response to triptans |
Munjal, 2016 [36] | Cohort study | Patients with episodic migraine | Any triptan Impact of allodynia on triptan (any) response | Pain-free 2 h: overall: 44% (n = 3621) No pain-free 2 h: triptan users with allodynia: 50%; triptan users without allodynia: 36%; non-triptan use with allodynia: 65%; non-triptan use without allodynia: 51% Inadequate response to medication more likely in the presence of allodynia among triptan and non-triptan users |
Silberstein, 2019 [37] | Case–control study | Patients with migraine | Any triptan Opioid use, rebound headache, and healthcare resource utilization with any triptan were analyzed using data from electronic medical records, and patient and physician surveys | Triptan insufficient responders were 3 times more likely than responders to suffer from rebound headaches, 3 times more likely to be admitted to a hospital in the past year, 13 times more likely to receive an opioid, and had 37% more visits to a healthcare professional in the past year |
Peng, 2016 [40] | Cohort study in headache clinic | Patients with migraine using/recently prescribed sumatriptan | Sumatriptan Patients were asked for effectiveness and AE of sumatriptan 50 mg for their migraine attacks (n = 1024 patients); demographics and comorbidity characteristics assessed | Overall effectiveness (definition unspecified) rate of treatment with one tablet sumatriptan 50 mg: 61.3% Responders to sumatriptan, compared to non-responders, were older (mean 40.6 vs. 37.2 years), had milder headache intensity (mean 6.4 vs. 6.7 on 0–10 scale), had lower scores in Beck Depression Inventory (mean 10.6 vs. 12.1), and have regular coffee intake |
Wang, 2017 [44] | Cohort study in headache clinic | Patients with migraine prescribed with sumatriptan | Sumatriptan Sumatriptan 50 mg tablet (n = 1499 enrolled patients) | Pain relief 2 h (in at least 2 out of 3) attacks: 69% Regular coffee consumption positively associated with effectiveness of sumatriptan. Compared to non-responders, responders had lower psychiatric measures (Beck Depression Inventory: mean 10.5 vs. 11.8) and lower baseline headache frequency (mean 9.8 vs. 11.6 days per month) |
Patrick, 2000 [39] | Long-term (1 year) observational cohort study | Patients with migraine who had participated in zolmitriptan trials | Zolmitriptan Quality of life associated with oral administration of zolmitriptan 5 mg (n = 1383) | A significantly greater improvement in MSQOL score was observed in patients who had pain relief at 2 h and pain freedom at 2 h, compared with non-responders Post treatment, responders had MSQOL scores approximately 5 points higher than those of non-responders Non-responders had lower baseline MSQOL scores (by approximately 4 to 7 points) than responders |
Sarchielli, 2006 [38] | Cohort study across 3 headache centers | Triptan-naïve patients with migraine without aura | Rizatriptan Clinical and biochemical correlates associated with rizatriptan responders and non-responders (n = 20, 10 each for responders and non-responders). Response was defined as achieving pain relief at 2 h (without 48 h recurrence) to rizatriptan 10 mg in at least 3 consecutive attacks | CGRP and NKA levels measured at baseline were significantly higher in those with baseline sufficient efficacy vs. those with insufficient efficacy 1 h after rizatriptan administration, a decrease in CGRP and NKA levels was evident in those with sufficient efficacy, and this corresponded to significant pain relief and alleviation of accompanying symptoms. Those with insufficient efficacy had less significant variations in CGRP and NKA levels at all time points Insufficient efficacy appeared to be correlated with a lesser degree of trigeminal activation, lower variations of trigeminal neuropeptides after triptan administration, and no evidence of parasympathetic activation at baseline |
Seo, 2016 [41] | Observational case–control study in headache clinic | Triptan-naïve patients with migraine | Frovatriptan Patients were instructed to take frovatriptan 2.5 mg as early as possible after migraine attack. Demographic, clinical, and psychiatric variables were investigated (n = 128 patients) | No pain relief 4 h in at least 1 out of 2 consecutive attacks in 22% of patients. In patients with major depressive disorder (MDD), 50% had no pain relief (4 h); MDD was identified as a risk factor Pain relief 4 h in at least 1 out of 2 consecutive attacks in 78% of patients; 92% of responder patients, achieved response in first attack and responded in second attack as well |
Specific populations | ||||
al Deeb, 1997 [69] | Prospective cohort study in 2 hospitals | Patients with migraine in Saudi Arabia | Sumatriptan Orally administered sumatriptan 100 mg to be taken as soon as possible and maximally within 2 h after each of two attacks (n = 63 patients). Better response of two attacks reported. Neurologist assessed efficacy on a 4-point scale on the basis pain diminution along a pain severity scale (severe: 3; moderate: 2; mild: 1; none: 0) | 3-point drop 4 h: 33% 2-point drop 4 h (better of 2 treated attacks): 33% 1-point drop 4 h (better of 2 treated attacks): 14% No drop 4 h in either attack: 19% |
Linder, 1996 [71] | Cohort study | Pediatric patients with migraine | Sumatriptan (SC) Subcutaneously administered sumatriptan 0.06 mg/kg (n = 50 children) | Pain relief reported in 78% of patients; 22% had no or suboptimal response Migraine with episodic tension-type headaches/chronic tension-type headaches was much more frequent in the female patients and, in general, was more difficult to treat |
Switching or discontinuation of triptans | ||||
Sheftell, 2004 [68] | Retrospective cohort study | Patients with migraine with current use of triptans | Any triptan Any triptan including sumatriptan (subcutaneous, nasal, oral), zolmitriptan, rizatriptan, naratriptan and, almotriptan was allowed | Incomplete or no relief as reason for switching a triptan, n (%): sumatriptan 25 mg: 89 (70.1); sumatriptan 50 mg: 105 (33.3); sumatriptan 100 mg: 62 (27.2); sumatriptan nasal spray: 17 (37.7); sumatriptan SC: 10 (12.2); zolmitriptan: 69 (28.9); rizatriptan: 52 (26.7); naratriptan: 54 (39.4) “Incomplete or no relief were most common most frequent switches in 6 out of the 8 assessed formulations. Side effects were the most frequent cause leading to switches in the remaining two (sumatriptan 100 mg and sumatriptan SC)” “Patients using sumatriptan 25 mg were more likely to report that the other triptans they used to be better, while patients using sumatriptan SC were less likely to do so. For all the other triptan/formulations, patients were equally likely, from a statistical perspective, to report that other triptan they had used was better. More patients who used sumatriptan 50 or 100 mg as the initial triptan were likely to switch back to it” |
Alam, 2018 [72] | Cohort study: Web-based survey | Respondents using acute prescription migraine medications | Any triptan Overall triptan use and discontinuation with oral/nasal/injectable triptan | Discontinuation rates were highest for injectables (81.5%), nasal sprays (66.5%), and oral medications (55.2%) Lack of efficacy and side effects were the main reasons for discontinuation |
Study | Terminology | Definition |
---|---|---|
Previous insufficient efficacy and/or tolerability to triptans | ||
Inadequate/unsatisfactory response | ||
Stark, 2000 [23] | Patients who “respond poorly” to oral administration of sumatriptan | Patients described themselves as experiencing an unsatisfactory response to sumatriptan |
Goldstein, 2006 [27] | Patients with previous “unsatisfactory response” to rizatriptan | Patients who were dissatisfied with their previous treatment response to rizatriptan within the past 12 months, due to inadequate relief from migraine headache pain; slow onset of migraine pain relief; inadequate relief from associated migraine symptoms (nausea, vomiting, phonophobia, photophobia, etc.); recurrence of migraine headache and/or needed to take multiple doses of medication to keep the pain away; delayed return to normal function; lack of consistent response; troublesome side effects |
Newman, 2008 [26] | Patients previously “dissatisfied” with sumatriptan in any formulation at a dose lower than 100 mg, and had not received treatment with sumatriptan at the 100 mg dose prior to start of study | Satisfaction was measured by a single-item question with a 7-point response scale. Subjects who were dissatisfied with previous sumatriptan and were less than very satisfied with their current treatment were included in the study |
Brandes, 2009 [63] | “Difficult-to-treat” menstrual migraine | Difficult-to-treat menstrual migraine was defined as having previous exposure to non-triptan therapy for the treatment of menstrual migraine and an inadequate response to triptan therapy for the acute treatment of menstrual migraine over ≥ 2 menstrual cycles An inadequate response to triptan therapy was determined by the investigator using the Migraine Medication History Questionnaire and defined as a lack of efficacy or poor tolerability, triptan dose in excess of the maximum recommended amount, the need to use rescue medication, recurrence of headache (within 48 h), or partial response |
Seeburger, 2011 [20] | Sumatriptan “non-responders” | Eligible participants reported that they did not respond to treatment with sumatriptan and, at a minimum, that they have demonstrated a ≥ 50% unsatisfactory response (e.g., no pain relief at 2 h post dose) to sumatriptan across their total migraine history (including failure to respond to at least 2 administrations of sumatriptan) |
Discontinuation reasons | ||
Farkkila, 2003 [22] | Patients with previous “poor response/tolerance” to oral administration of sumatriptan | Patients who had discontinued therapy with orally administered sumatriptan between 2 weeks and 2 years prior to the screening visit. Subjects had been in the practices of the investigators for a significant period and their lack of enough response to sumatriptan was documented in the patient notes. Patients were asked to give one of the following reasons for stopping treatment with sumatriptan: slow onset of action; inconsistent response; poor overall efficacy; recurrence; tolerability |
Mathew, 2009 [29] | “Poor responders” intolerance to short-acting triptans | Poor response was defined as patient-reported discontinuation of treatment with a triptan for reasons related but not limited to slow onset of efficacy, inconsistent efficacy, poor overall efficacy, or poor sustained efficacy through 24 h or longer Intolerance was defined as discontinuation of treatment with a triptan for any reason other than poor response, hypersensitivity, or allergic reaction |
Considered consistency of response | ||
Mathew, 2000 [25] | Oral administration of sumatriptan “non-responders” | Defined as lack of response in at least 3/5 attacks having taken the medication early in the headache phasea |
Landy, 2004 [24] | Patients with a history of “non-response” to sumatriptan 50 mg | Patients had a documented history of non-response to 50 mg sumatriptan tablets at 2 h after dosing in the early, mild-pain phase of 2/3 migraine attacksa |
Diener, 2005 [21] | Patients with previous “poor response” to sumatriptan 50 mg | Patients describing themselves as experiencing an unsatisfactory response to sumatriptan on ≥ 2 prior occasionsa |
Diamond, 2007 [28] | Patients who historically “fail to respond” to orally administered triptans | Patients with migraine who historically had failed to achieve relief from an orally administered triptan in 2/3 attacks. Relief was defined as reduction of pain severity from mild, moderate, or severe pain to no pain, or from moderate or severe pain to mild pain |
Other | ||
Ho, 2011 [31] | Patients with self-reported historical triptan response of “poor/no use”b | Patients completed a migraine history questionnaire, which included the following question to determine whether patients had insufficient efficacy to triptans: “On average, how often did your moderate or severe migraine headaches respond to triptan medications?” Patients had to select from 75–100% of the migraine attacks (good triptan historical response subgroup); 50–74% of the migraine attacks; 25–49% of the migraine attacks (intermediate triptan historical response subgroup); < 25% of the migraine attacks; you do not take triptans (poor/no historical triptan response subgroup); take triptans but do not know the frequency of response (excluded) |
Knievel, 2018 [33] | “Non-responders” to triptan therapy | At baseline, patients rated themselves as good, poor, or non-responders to prior triptan therapya |
Blumenfeld, 2019 [32] | Triptan “insufficient responder” | Patients were categorized on the basis of historical experience as a triptan-responder, triptan-insufficient responder, or triptan-naïve. Reasons for categorization as insufficient considered efficacy, tolerability, and contraindications or warningsa |
Insufficient efficacy and/or tolerability to triptans in a general population of patients with migraine | ||
Cady, 2007 [35] | “Lack of response”, “non-responders” | Non-responders failed to meet endpoints “freedom from pain” at 2 h post dose, and 24 h “sustained freedom from pain”, and were permitted to use rescue medication 2 h post dose |
Cady, 2014 [65] | “Non-responders” | Non-responders failed to meet the endpoint “mild or no pain 2 h post dose” without the use of a rescue medication or an increase in pain level within 24 h of treatment |
Diener, 2008 [45] | High risk of “non-response” | Patients at high risk of non-response were identified on the basis of a logistic regression analysis, using 3 predictors of not achieving a 2 h pain-free response: severe baseline headache pain; photophobia/phonophobia; nausea |
Landy, 2014 [66] | Headache “non-responders”, pain-free non-responders | Headache non-response at 2 h or sustained at 24 h, defined by failing to experience a 2-point reduction in a 4-point scale of pain intensity at 2 h or 24 h, respectively Pain-free non-response at 2 h or sustained at 24 h, defined by failing to achieve intensity of “no pain” |
Miljkovic, 2018 [70] | “Failure” of therapy | Patients who failed to achieve complete reduction of migraine pain 2 h post dose |
Scott, 1996 [64] | “Non-responders” | Patients failed to meet the endpoint “headache relief/freedom” in response to sumatriptan within 4 h of taking second dose |
Spierings, 2009 [67] | “Non-response” | Patients who did not respond to frovatriptan treatment within 2–24 h post dose |
Tietjen, 2005 [34] | “Inadequate relief”, “not satisfied” | Patients who had achieved (self-defined) meaningful relief and whether they were satisfied with naratriptan 2.5 mg |
Study | Terminology | Definition |
---|---|---|
Historical insufficient efficacy and/or tolerability to triptans | ||
Inadequate/unsatisfactory response | ||
Sarchielli, 2006 [38] | “Non-responders” to rizatriptan | Patients were selected on the basis of a poor response to rizatriptan. Inefficacy was verified in the treatment of at least 3 consecutive attacks using the following definition: failure to achieve a reduction in pain from severe or moderate to mild or absence of pain within 2 h after rizatriptan administration, without a recurrence in the next 48 h |
Discontinuation reasons | ||
Sheftell, 2004 [68] | Patients who were currently using a triptan as acute treatment medication for migraine and who had previously used at least one other triptan or a different triptan formulation | For each triptan/formulation used, information regarding patients’ satisfaction and reasons for discontinuation were summarized in following categories: to determine if another triptan is better; recurrence; incomplete/no relief; side effects; rebound; another triptan/formulation used was better; time to relief; other |
Other | ||
Silberstein, 2019 [37] | Triptan “insufficient responder” | Patients currently prescribed triptans/had received triptans in the past 6 months and failed to achieve pain freedom at 2 h, or discontinued because of lack of efficacy/side effects |
Insufficient efficacy and/or tolerability to triptans in a general population | ||
Alam, 2018 [72] | Discontinued triptan users | Assessed reasons for discontinuation from a pre-coded list of side effects and triptan sensations |
al Deeb, 1997 [69] | “Poor or nil response” (and poor efficacy) | A poor response to sumatriptan was characterized by a drop of no points, operationalized on the basis of pain diminution along a pain severity scale |
Linder, 1996 [71] | No response or “suboptimal response” | Lack of efficacy defined by failing to meet the endpoint “headache relief” |
Munjal, 2016 [36] | “Inadequate pain response” | Patients who responded “never, rarely and less than half the time” when asked if they achieved the endpoint “pain freedom” at 2 h and “24 h sustained relief” |
Patrick, 2000[39] | “Non-responders” | Treatment response to the initial zolmitriptan dose was assessed at 2 h using the following endpoints: headache response, pain-free response, and improvement in impairment of normal activity. Patients also recorded whether they had obtained meaningful migraine relief, a subjective global evaluation of treatment response incorporating all migraine symptoms, within 2 h of dose administration. Non-responders were defined as patients with a response rate of 0–10% |
Peng, 2016[40] | “Non-responders” | Patients were asked the effectiveness and AEs of one sumatriptan tablet for their migraine attack; however, non-response was not defined by the authors |
Seo, 2016[41] | Frovatriptan “inefficiency” | Patients failed to meet the endpoint “pain relief or absence” 4 h post dose in 1 of 2 successive migraine attacks |
Sheftell, 2010[42] | “Dissatisfied”, non-responding headaches | Secondary treatment failure was defined as a return of pain to any level following initially successful treatment |
Terrazzino, 2010[43] | “Inconsistent response” | Patients who did not experience a ≥ 2-point reduction in a 4-point scale of pain intensity 2 h post dose in at least 2 out of 3 attacks |
Wang, 2017[44] | “Non-responders” | Patients who reported no response/effectiveness based on the endpoint “freedom from pain, or reduction to mild intensity in headache severity” within 2 h post dose in at least 2 of 3 migraine attacks |