Abstract
Aim:
This is a retrospective report of the efficacy of botulinum toxin-A, Botox® (Allergan), in intractable chronic migraine patients non-responsive to previous pharmacological management and with largely no pain-free time, including those with new onset daily persistent headache.
Methods:
Thirty-three patients, all with severe Headache Impact Test (HIT)-6 scores at baseline, received 3-monthly injections of Botox® as per Phase III REsearch Evaluating Migraine Prophylaxis Therapy (PRE-EMPT) protocol over a maximum 33-month period. Response criteria were a sustained reduction of HIT-6 scores below 60.
Results:
Four patients had headache on at least 20 days a month; the remaining patients had daily headache with no pain-free time, including nine patients with new onset persistent migraine. There was a significant reduction in HIT-6 scores following Botox® therapy (x̅ = −5.45, p = 0.000920). Twenty-one percent of the cohort exhibited a sustained reduction in HIT-6 scores below 60. The number of headache days and pain-free time did not change in five of the six responders, but disability improved. There was no difference between patients with episodic migraine evolving to chronic as opposed to those with chronic migraine from onset.
Conclusion:
This report suggests that Botox® treatment is efficacious in intractable chronic migraine without pain-free time. The HIT-6 is a reliable and practical parameter to assess disability in this patient group. Use of such validated parameters should be considered with greater weight in future International Classification of Headache Disorders (ICHD) guidelines for controlled clinical trials.
Keywords: Chronic migraine, intractable migraine, botulinum toxin-A, standardised disability, new daily persistent headache
Introduction
The current definition of chronic migraine (CM) is ‘headache, occurring on 15 or more days per month for more than 3 months, which has the features of migraine headache on at least 8 days per month’. 1 The population prevalence of CM is 2%, 2 and it is this patient group population which confers the most significant contribution to the global economic burden of migraine.3,4
Treatment of CM
Traditional first-line treatment for CM is with pharmacological agents. There is evidence for efficacy in migraine for amitriptyline, flunarizine (non-licenced in the United Kingdom), propranolol, sodium valproate and topiramate, 5 serendipitously discovered to have an effect in migraine prevention. However, migraine is notorious for being undertreated. 6 Given that almost a third of all migraine suffers will be experiencing more headache days than not, barely a tenth will be on a preventative for the specific purpose of treating the CM. This is compounded by poor persistence. Only 14% of patients in one large study had maintained prophylaxis at 1 year 7 with progressive worsening of compliance as patients cycle through the oral preventatives.
Botulinum toxin
Neurotoxins produced by the gram-positive anaerobe Clostridium botulinum are potent toxins. Botulinum toxin (BTX) acts by blocking the release of acetylcholine from the presynaptic terminal of the neuromuscular junction. Seven distinct antigenic BTXs (A–G) are produced by different strains of Clostridium botulinum, of which the human nervous system is susceptible to five serotypes (A, B, E, F and G). Ingestion of food contaminated with preformed neurotoxin A, B and E can cause botulism, characterised by motor and autonomic paralysis. 8 Commercially developed BTX type-A (BTX-A) preparations have been utilised to treat disorders where there is an increase in muscle or autonomic activity such as craniocervical dystonia, spasticity, detrusor instability, hyperhidrosis and hypersalivation. Treatment success was bolstered by the prolonged duration of action, such that therapeutic effects could last 3–6 months for dystonia and 6–12 months for hyperhidrosis. 9 It was, however, noted that the duration of pain relief neither correlated with the duration of muscle paralysis nor the associated distribution. 10 This suggested independent anti-nociceptive effects. Subsequent animal studies have shown that BTX-A inhibits release of neuropeptide transmitters from the sensory nerve terminals, such as substance P, calcitonin gene-related peptide (CGRP) and glutamate, 11 neurotransmitters implicated in nociception. Chronic pain has been attributed to a lowering of the threshold for nociceptor activation and increasing responsiveness to normally innocuous stimuli which are then perceived adversely, termed peripheral sensitisation. Sensory information to the spinal cord and trigeminal nucleus is amplified as a consequence, resulting in central sensitisation. 12
The use of BTX, in the treatment of headache, followed the observation of improvement seen in individuals with headache being treated cosmetically with BTX.13–15 The most optimal protocol was explored and developed for clinical trials in headache.15–17
Clinical trials with BTX in the treatment of migraine
A randomised-placebo-controlled study in episodic migraine used commercially available BTX-A, Botox® (Allergan) in 369 patients. The study showed that at least 50% of all patients in each group experienced a decrease from baseline of 50% or more migraine episodes, per 30-day period over 9 months. 18 The study was notable for (1) the high placebo-response rate, double that seen in oral preventative trials and (2) the comparative tolerability, with only 1.6% of patients discontinuing treatment due to adverse effects. The efficacy of Botox® in CM was shown in two randomised placebo-controlled phase 3 clinical trials, PRE-EMPT I and II.19,20
PRE-EMPT I was a 24-week, double-blind, parallel-group, placebo-controlled study followed by a 32-week open-label phase. Subjects were randomised to 12-weekly injections of Botox® (155U–195U) or placebo for two cycles. The primary endpoint was mean change from baseline in headache episode frequency at week 24. A headache episode was defined as an attack with continuous pain for at least 4 hours. There was no significant difference between the two groups for the primary endpoint. A significant difference for Botox® was observed for the secondary endpoints of headache days and migraine days. 19 The study protocol for PRE-EMPT II was identical to PRE-EMPT I. The primary endpoint was mean change in headache days per 28 days from baseline to weeks 21–24 post-treatment. The headache day was defined as a calendar day (00:00–23:59) during which the patient reported at least 4 hours of continuous headache. Botox® was statistically significantly more effective than placebo for the primary endpoint. 20
Pooled analysis for both studies included a total of 1384 adults randomised to Botox® (n = 688) or placebo (n = 696). Two-thirds had been overusing acute treatment during the 28-day baseline period. The analysis demonstrated a significant decrease from baseline in frequency of headache days by 2 days per month in the Botox® group at week 24 and at all other time points. 21 Significant differences favouring Botox® were observed for all secondary efficacy variables, with the exception of frequency of acute headache pain medication intake; a reduction in intake was seen in both Botox® and placebo arms. Sustained improvement (p < 0.001) in standardised disability ratings, such as the Headache Impact Test (HIT)-6, was seen across all time points from 12 to 24 weeks and similarly so for the cumulative total of headache hours on headache days. Adverse events occurred in 62.4% of Botox® patients and 51.7% of placebo patients. Discontinuation rates were Botox®, 3.8% and placebo, 1.2 %. The most common adverse effect was neck pain in 6.7% compared to placebo 2.2%.
BTX in the treatment in migraine with acute-relief medication overuse
The issue of acute-relief medication overuse in migraine has long compounded management. The estimated prevalence of migraine with medication overuse is 1%. Across reports of preventative treatment responses, the lack of full preventative efficacy is not seen until the acute-relief medication is withdrawn.22–24 Although purported efficacy for topiramate was reported, in fact the traditional endpoint of a 50% reduction in headache frequency was not achieved in the presence of medication overuse compared to the response without medication overuse.25,26 The results of the PRE-EMPT studies were thus encouraging in showing improvement despite continued use of acute-relief medication. There remain limited data on the comparative response of Botox® in medication overuse and without. One double-blind, placebo-controlled, randomised trial addressed whether add-on therapy with Botox® enhances efficacy of withdrawal in a cohort of 179 patients with acute-relief medication overuse. 27 All patients were withdrawn over 12 weeks. There was no significant difference between the Botox® and placebo arms in number of headache or migraine days, nor in disability or quality of life measures.
BTX in the treatment in patients with daily migraine
Of 641 patients with CM, the Chronic Migraine OnabotulinuMtoxinA Prolonged Efficacy open Label (COMPEL) study compared responses to Botox® in 138 patients with daily headache and 503 without. The primary endpoint was a change in headache days from baseline per 28-day period over nine cycles (108 weeks). The definition for headache day was as per PRE-EMPT II and 63.7% of the total cohort were overusing acute-relief medication. 28 The proportion overusing in each group was not given. There was a slightly higher discontinuation rate in the daily headache group (56.5%) compared to those without daily headache (45%). 29 The mean headache days in the group without daily headache was 20.3. Both groups had a significant reduction in frequency of headache days at weeks 24, 60 and 108. There was a significant between-group difference in change in headache-day frequency at weeks 24 (p < 0.001) and 60 (p = 0.004) but not week 108 (p = 0.132). Seventeen percent with daily headache at baseline had a ⩾50% reduction in headache frequency at week 24 and 39.6% at week 108. Similarly, Botox® significantly reduced mean moderate to severe headache days in patients with and without daily headache at all time points (p < 0.001 for within-group comparisons). There was no significant between-group difference in the change from baseline at any time point. The HIT-6 scores were significantly reduced at each time point in both groups from baseline (65.6 and 64.6, respectively) to 60 or less; p < 0.001 for all within-group time points but no between-group difference from week 24 onwards.
We report on the outcome of Botox® treatment in 33 patients with intractable CM from a single site. The majority experienced daily pain without pain-free time and in all, but one patient, the absence of acute-relief medication overuse. This group of patients poses the most difficult challenge in treating CM. To date, there has been no report of responses in this particular patient group.
Methodology
Patient group
Retrospective data for 33 patients were examined; all patients met International Classification of Headache Disorders (ICHD)-3 diagnostic criteria for CM. All 33 patients at baseline consistently had HIT-6 scores greater than 60, and hence, they were classified as having significant disability. 30 All patients had failed to respond to previous trials of pharmacological management; treatment with Botox® was seen as a final attempt to improve the quality of the patients’ symptoms. In line with guidelines of the Health Research Authority (http://www.hra-decisiontools.org.uk/research/), the work was classed as audit, and therefore, ethics was not required.
Treatment administration
Patients received 155U of Botox® (Allergan) via injections to 31 sites across seven areas as per PRE-EMPT protocol.19,20 Patients received doses in 3-monthly intervals while simultaneously having their HIT-6 scores recorded as a measurement of improvement. Patients were also asked to keep a daily headache diary. Treatment was stopped if the patient’s HIT-6 scores failed to reduce after two consecutive doses; one patient had a third treatment following two initial failed responses. Treatment was stopped immediately if severe adverse reactions were experienced. Response criteria were a sustained reduction of HIT-6 scores equal to or less than 60, and therefore, no longer having a severe impact in terms of disability.
Statistical analysis
Mean values for the change in each patient’s HIT-6 scores from baseline were calculated. Wilcoxon signed-rank tests were then performed and probability values were then calculated. A reduction in HIT-6 scores across the cohort was evaluated with a confidence threshold of 99.9%.
Results
Demographics
Table 1 shows the demographics of the patient group and comparison between responders and non-responders. All patients met diagnostic criteria for CM as per ICHD-3 and fulfilled criteria for comorbid primary headache diagnoses (Table 2). In nine patients, the onset of the headache was new daily and persistent, but the clinical syndrome was otherwise consistent with CM. This group was included based on the previously presented descriptive cohort of such patients (which included the nine in the current cohort) suggesting that the entity of new daily persistent headache is a mode of onset rather than a distinct disorder. 31 Clinically, there was no difference in this patient group to those patients with CM evolving from an episodic manner. Only four patients had some headache-free days (range = 3–5 days) and the remainder had no pain-free time. Only one patient had acute-relief medication overuse of daily naproxen taken for joint pain because of intolerability to amitriptyline, gabapentin and pregabalin. One patient had a mild post-traumatic exacerbation of a pre-existing migraine disorder.
Table 1.
Distribution of patient demographics and characteristics between patients who did and did not respond to Botox® treatment. Mean change in HIT-6 scores, W test statistic and probability values are also shown.
| All patients (total N = 29) | Responders a (total N = 6) | Non-responders (total N = 23) | |
|---|---|---|---|
| Mean age at baseline, years (SEM) | 44.4 (2.09) | 43.8 (4.45) | 44.6 (2.41) |
| % Female | 65.5 | 83.3 | 60.9 |
| % Employed | 34.5 | 33.3 | 34.8 |
| Mean CM duration, years (SEM) | 16.9 (1.93) | 18.8 (5.61) | 16.4 (2.01) |
| % Previously received treatments | 100 | 100 | 100 |
| Mean N previous treatments (SEM) | 8.52 (0.635) | 9.00 (1.18) | 8.39 (0.75) |
| % Receiving treatments at baseline | 79.3 | 100 | 73.9 |
| Mean N treatments at baseline (SEM) | 1.93 (0.280) | 2.17 (0.477) | 1.87 (0.334) |
| % Severe b HIT-6 at baseline | 100 | 100 | 100 |
| Mean HIT-6 at baseline (SEM) | 68.6 (0.870) | 69.3 (2.28) | 68.4 (0.949) |
| Mean change in HIT-6 (SEM) | −5.45 (1.55) | −16.0 (2.91) | −2.70 (1.30) |
| W (critical W for p < 0.001) | 59 (63) | * (*) | 59 (32) |
| p-value | 0.000920 | * | 0.255 |
CM: chronic migraine; HIT: Headache Impact Test.
Responders were patients whose HIT-6 scores fell and stayed below 60.
HIT-6 scores ⩾60 are severe.
N was too small to calculate an accurate value.
Table 2.
Distribution of comorbid headache disorders between patients who did and did not respond to Botox® treatment.
| Headache classification a | All patients (total N = 29) | Responders b (total N = 6) | Non-responders (total N = 23) | |||
|---|---|---|---|---|---|---|
| N | % | N | % | N | % | |
| Chronic migraine | 29 | 100 | 6 | 100 | 23 | 100 |
| Migraine with typical aura | 7 | 24.1 | 1 | 16.7 | 6 | 26.1 |
| Migraine with brainstem aura | 10 | 34.5 | 3 | 50 | 7 | 30.4 |
| New daily persistent headache | 9 | 31.0 | 2 | 33.3 | 7 | 30.4 |
| Primary stabbing headache | 7 | 24.1 | 1 | 16.7 | 6 | 26.1 |
| Primary thunderclap headache | 3 | 10.3 | 1 | 16.7 | 2 | 8.7 |
| Medication overuse headache | 2 | 6.9 | 0 | 0 | 2 | 8.7 |
| Chronic cluster headache | 1 | 3.4 | 0 | 0 | 1 | 4.3 |
| Post-traumatic headache | 1 | 3.4 | 0 | 0 | 1 | 4.3 |
| Primary cough headache | 1 | 3.4 | 1 | 16.7 | 0 | 0 |
| Primary exercise headache | 1 | 3.4 | 0 | 0 | 1 | 4.3 |
Headache classification was performed as per ICHD-III diagnostic criteria. Those who had experienced aura with their migraine disorder were also given the ICHD diagnosis of migraine with the aura experienced.
Responders were patients whose HIT-6 scores fell and stayed below 60.
The responder and non-responder groups also showed no significant differences in age, employment, duration of CM, mean HIT-6 scores at baseline, mean number of total prior treatments received nor mean number of treatments at baseline. Although mean number of treatments at baseline did not show a difference between the two groups, all responders were on additional preventative treatments at baseline compared to 73.9% of non-responders, most commonly topiramate, flunarizine and nortriptyline (Table 3). A greater proportion of the responder group was female (83.3%) compared to the non-responder group (60.9%).
Table 3.
Distribution of previous preventative treatments tried by patients who did and did not respond to Botox® treatment. Range of MTD is shown. Average MTD’s could not be calculated for the patient cohort as some patients were only known to have tried certain medications but the previous doses tried were unclear.
| MTD range (mg) | All patients (total N = 29) | Responders a (total N = 6) | Non-responders (total N = 23) | |
|---|---|---|---|---|
| Greater occipital nerve block | UK | 28 (96.6%) | 6 (100%) | 22 (95.7%) |
| Topiramate | 25–800 | 27 (93.1%) | 5 (83.3%) | 22 (95.7%) |
| Amitriptyline | 10–200 | 25 (86.2%) | 6 (100%) | 19 (82.6%) |
| Valproate | 200–4500 | 24 (82.8%) | 6 (100%) | 18 (78.3%) |
| Propranolol | 10–360 | 22 (75.9%) | 5 (83.3%) | 17 (73.9%) |
| Gabapentin | 300–3600 | 20 (69.0%) | 4 (66.7%) | 16 (69.6%) |
| Dihydroergotamine | UK | 18 (62.1%) | 4 (66.7%) | 14 (60.9%) |
| Flunarizine | 5–20 | 15 (51.7%) | 3 (50.0%) | 12 (52.2%) |
| Pizotifen | 0.5–4.5 | 14 (48.3%) | 2 (33.3%) | 12 (52.2%) |
| Dosulepin | 25–225 | 13 (44.8%) | 5 (83.3%) | 8 (34.8%) |
| Nortriptyline | 10–160 | 13 (44.8%) | 2 (33.3%) | 11 (47.8%) |
| Pregabalin | 100–600 | 12 (41.4%) | 4 (66.7%) | 8 (34.8%) |
| Candesartan | 8–16 | 6 (20.7%) | 1 (16.7%) | 5 (21.7%) |
| External vagal nerve stimulator | n/a | 6 (20.7%) | 0 (0%) | 6 (26.1%) |
| Venlafaxine | 75–150 | 5 (17.2%) | 1 (16.7%) | 4 (17.4%) |
| Acupuncture | n/a | 2 (6.9%) | 0 (0%) | 2 (8.7%) |
| Methysergide | UK | 2 (6.9%) | 1 (16.7%) | 1 (4.3%) |
| Metoprolol | UK | 2 (6.9%) | 1 (16.7%) | 1 (4.3%) |
| Atenolol | 50 | 1 (3.4%) | 0 (0%) | 1 (4.3%) |
| I.V. lidocaine | UK | 1 (3.4%) | 0 (0%) | 1 (4.3%) |
| Patent foramen ovale closure | n/a | 1 (3.4%) | 0 (0%) | 1 (4.3%) |
| Trimipramine | UK | 1 (3.4%) | 0 (0%) | 1 (4.3%) |
MTD: maximum tolerated dose; UK: unknown; n/a: not applicable.
Responders were patients whose HIT-6 scores fell and stayed below 60.
Four patients were lost to follow-up for the following reasons: pregnancy, injury, bereavement and non-attendance (DNA). These patients lost to follow-up were excluded from any further data analysis.
Response to treatment
As the W test statistic is below the critical value, with 99.9% confidence, there was a statistically significant reduction in HIT-6 scores across the 29-patient cohort of −5.45 from baseline (p = 0.000920). These data are summarised in Table 1.
When analysing the two subgroups of the cohort, the full impact of Botox® can be seen. Within the responder group, there was a reduction in HIT-6 scores of −16.0 from baseline. However, as this group has a relatively low sample size of six, we were unable to accurately calculate a W test statistic and probability values; therefore, we cannot conclude whether or not this difference is statistically significant.
Across the non-responder group there was a reduction in scores of −2.70 from baseline (p = 0.255), although this fell outside the 99.9% confidence margins and therefore was not seen as significant. At baseline (T0), the mean HIT-6 score of the 33 patients was 68.4 with a standard error of the mean (SEM) of 0.772. This reduced throughout the course of treatment, to a minimum at T11 of 57.0 (SEM = 0.246). The percentage of patients with severe HIT-6 scores (values above 60) also reduced throughout the study, with a maximum at T0 of 100% and a minimum at T11 of 0%. These data are summarised in Table 4.
Table 4.
Efficacy of Botox® in reducing HIT-6 scores in 33 chronic migraine patients over a 33-month period of eleven 3-monthly intervals.
| T0 | T1 | T2 | T3 | T4 | T5 | T6 | T7 | T8 | T9 | T10 | T11 | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| N | 33 | 33 | 26 | 13 a | 11 | 8 | 8 | 8 | 6 | 5 | 2 | 2 |
| Mean HIT-6 (SEM) | 68.4 | 65.7 | 64.7 | 63.6 | 63.8 | 62.1 | 60.9 | 59.6 | 59.5 | 59.4 | 58.5 | 57.0 |
| (0.772) | (0.942) | (1.10) | (0.952) | (1.12) | (0.775) | (0.613) | (0.756) | (0.502) | (0.585) | (0.123) | (0.246) | |
| Change in mean HIT-6 from T0 | – | −2.7 | −3.7 | −4.8 | −4.6 | −6.3 | −7.5 | −8.8 | −8.9 | −9.0 | −9.9 | −11.4 |
| % Severe b HIT-6 | 100 | 90.9 | 88.5 | 92.3 | 72.7 | 62.5 | 75 | 75 | 50 | 40 | 0 | 0 |
| Cumulative N with any reduction in HIT-6 scores | – | 20 | 24 | 25 | 25 | 25 | 25 | 25 | 25 | 25 | 25 | 25 |
| Cumulative N responders c | – | – | 2 | 2 | 2 | 3 | 3 | 3 | 4 | 5 | 6 | 6 |
SEM: standard error of the mean; HIT-6: Headache Impact Test.
Indicates time interval where a continuing patient failed to attend their appointment.
Headache Impact Test (HIT)-6 scores ⩾60 indicate a severe impact.
Responders were patients whose HIT-6 scores fell and stayed below 60.
Twenty-five of the patients experienced a reduction in their HIT-6 scores, as shown in Figure 1. Nine patients’ scores reduced below 60, and of these, six patients exhibited a sustained reduction below 60, thus identified as responders. Sub-60 reductions in HIT-6 scores were observed on average after 3.1 doses. The most commonly reported adverse effects were head and, or, facial pain, 7 neck stiffness, 5 neck pain, 4 ptosis, 4 eye pain 2 and bouts of presyncope. 2
Figure 1.
Graph showing change in HIT-6 scores for 33 patients after receiving 3-monthly Botox® injections over a maximum of 33 months.
Three patients showed an initial decrease in their HIT-6 scores sub-60 before returning to their baseline values. The response was thus interpreted as a likely placebo response and the patients hence classed as non-responders.
Longer-term outcome of responders
All responders remain on one or more preventative treatments. Two responders had 3–5 pain-free days per month at the start of treatment. Four had no pain-free time. One of the latter groups, having maintained HIT-6 below 60 after 12 treatments experienced constant daily headache but without disability. Over subsequent months, the patient gradually developed pain-free time and ultimately after 5 years is pain free with 2 headache days a month on nortriptyline prevention. Any attempt to withdraw the nortriptyline has resulted in exacerbation of the disorder. Two patients continued to have daily pain without disability. One was re-referred with recurrence of CM 3 years after she had stopped treatment; the patient did not attend her scheduled appointment. The other withdrew all preventatives but developed recurrent disability coinciding with a number of stressful life events. The fourth patient has had two treatments but sustained HIT-6 below 60 despite no pain-free time and in the presence of daily naproxen for joint pain. Treatment was temporarily stopped because of the COVID-19 pandemic. Of the two patients who responded and had had a few pain-free days a month, one continued to have a similar number of headache days but without the disability. The other has developed episodic migraine but can have some months with up to 15 headache days yet still without HIT-6 rising above 60.
Discussion
The data from this cohort showed a percentage reduction in severe HIT-6 scores of 6 out of 29 (21%) patients, similar to the 26.2% attained by PRE-EMPT II. Reductions in HIT-6 scores across the cohort (x̅ = −5.45) were similar to those seen after two 12-weekly doses in PRE-EMPT II (x̅ = −4.5).
This is a retrospective observational report. The sample size is small, but it is a single site of patients managed by the same consultant team throughout, thus ensuring consistency of care. Although the sample size of this cohort is small, the COMPEL study was able to identify only 16% of the initial 700 patients, from multiple international sites, with daily headache. Although four of our patients did not have daily headache, similar to the COMPEL group of at least 20 days a month, the remainder had constant daily pain without pain-free time. This group in COMPEL was not identified and analysed separately as a subset of patients with daily headache.
Current clinical trial recommendations from the International Headache Society advise ‘the primary endpoint in controlled trials of preventive treatment of chronic migraine should be either change in migraine days; change in moderate to severe headache days; or responder rate’. From these three endpoints, the two not selected as the primary endpoint should be considered as secondary endpoints. Evaluations of efficacy should be based on information obtained from headache diaries:
The responder rate is calculated as a percent reduction from baseline in the number of migraine days or number of moderate or severe headache days in each treatment period. Responder rates in chronic migraine trials have traditionally been defined as at least a 50% reduction from baseline. 32
The HIT-6 questionnaire has previously been shown to be a reliable tool to measure the impact of headaches on the daily life of CM patients and a useful and simple tool to assess headache disability.30,33,34 The majority of our cohort had no pain-free time at baseline; thus, the frequency of days is irrelevant. The variation in endpoints of the two PRE-EMPT studies and outcome are exemplary of the confounding attributes of using such endpoints as surrogates to assess disability. The primary endpoint in PRE-EMPT I using ‘headache episodes’ was not achieved yet, the secondary endpoint of change in HIT-6 achieved significance (p < 0.001) as was the case on redefining the primary endpoints in the pooled data. 21
Of our responders, all but one had no change in headache days but marked improvement in disability using the HIT-6. The patients’ global impression was consistent with their HIT-6 scores except two who did not respond. Both patients felt that they had responded while the HIT-6 scores did not improve from baseline. Patients with new daily persistent headache with clinical syndrome consistent with ICHD CM did not show any difference in response to those with CM evolving from an episodic pattern; the small number in the cohort and implications on the analysis of data is acknowledged.
Conclusion
The results of this study suggest that Botox® treatment is an efficacious therapeutic option for one in five CM patients with largely zero headache-free time who have been previously unresponsive to pharmacological management. This includes patients with new daily persistent onset headache. This subgroup has yet to be reported separately to those patients with daily headache but with pain-free time.
The responders remain on preventative treatments but are not disabled by their condition, with maintained HIT-6 responses ≦60. Use of the HIT-6 remains a reliable measure of disability in patients with CM and daily constant headache. Given the difficulties that continue to arise using more traditional endpoints, as exemplified by PRE-EMPT I, the use of parameters such as the HIT-6 should be considered with greater weight in future ICHD guidelines for controlled clinical trials.
Clinical implications
Treatment with Botox® as per PRE-EMPT protocol can be effective in a fifth of patients with intractable migraine with no pain-free time.
This is the first published cohort of patients with no pain-free time, from a single centre and team, thus having had uniform prior treatment strategies.
Patients with new daily persistent onset migraine show a similar response to those with episodic migraine evolving to chronic.
HIT-6 disability <60 was maintained despite no change in number of headache days nor pain-free time.
Consistently validated and practical disability parameters, such as the HIT-6, should be considered with greater weight in future ICHD guidelines for controlled clinical trials.
Footnotes
Author note: Anish Bahra has participated in fee-based services on advisory boards and lecturing for Teva, Eli Lilly and Novartis Pharmaceuticals.
Conflict of interest: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.
Contributorship: The idea of the study was conceived by A.B. All patients were assessed by A.B. and R.I. D.A. and R.I. contributed to acquisition of data. D.A. contributed to data analysis and with A.B. interpretation of data. D.A. drafted the manuscript. A.B. revised the manuscript critically for important intellectual content. A.B. and D.A. contributed to final approval of the version submitted.
Ethical approval: In line with guidelines of the Health Research Authority (http://www.hra-decisiontools.org.uk/research/), the work was registered as service evaluation as part of normal medical care.
Funding: The author(s) received no financial support for the research, authorship and/or publication of this article.
Guarantor: A.B. is the guarantor of this study.
ORCID iDs: Dominic Atraszkiewicz 
https://orcid.org/0000-0002-5881-5275
Anish Bahra
https://orcid.org/0000-0002-9495-9006
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