Introduction

Introduction

Evidence based decision making is one of the best ways for an advanced practice nurse (APRN) to determine the most effective treatment for any patient. Chronic migraine is an area where the APRN can make a substantial difference in the treatment and overall quality of life for the chronic migraine patient. Current treatments and recommendations are important to remain abreast of in this area, as they are ever changing. Efficacy of treatments also varies greatly between patients, as an APRN knowing when to recommend a certain treatment or therapy based upon evidence is as important as the diagnosis itself.

Problem

Chronic migraine is a disease in which the patient experiences headaches 15 days per month for a period 3 months. These headaches will have the features of migraines 8 times per month. The condition differs from episodic migraine in the severity and frequency of migraine symptoms and the subsequently higher disability and negative effect on quality of life suffered by the chronic migraine patient (Blumenfeld, Stark, Freeman, Orejudos, Adams, 2018). In October of 2010, following the phase III PREEMPT trial, the FDA approved OnabotulinumtoxinA for the prophylactic treatment of chronic migraines. The PREEMPT trials were double blind randomized control trials that also studied the effect of placebo. Chronic migraine is often undertreated and of those that are treated 50% consistently take their preventive medications. These patients are more likely to suffer depression, anxiety, and chronic pain resulting in decreased quality of life (Khalil, Zafar, Quarshie, Ahmed, 2014). While there are many oral medications to interrupt a migraine, only Topiramate has been shown to have a prophylactic effect on chronic migraine (Matthew Jaffri, 2009). Because of the relatively high number of adverse effects in oral medications, and intolerability of the medications by many patients it is important that a prophylactic treatment that is well tolerated and effective be available to patients. OnabotulinumtoxinA was shown during the PREEMPT trials to have demonstrated efficacy in reducing the average number of headache days in both frequency and severity over a period of 24 weeks. OnabotulinumtoxinA was demonstrated in the trials to be well tolerated with very few adverse effects in comparison to oral medications. Healthcare providers are left to answer which of the treatments available are best offered to chronic migraine patients based upon the latest evidence-based practice and treatment recommendations.

PICO Question

In adults with chronic migraines, how does OnabotulinumtoxinA toxin injection compared to no OnabotulinumtoxinA therapy affect average number of headache days per month? (P=adults with chronic migraine diagnosis, I= prophylactic OnabotulinumtoxinA toxin injections, C=no OnabotulinumtoxinA injections, O=reduced number of headache days per month). Background

Chronic migraine affects approximately 1.4-2.2% of the adult population and includes migraine headaches 8 times per month with at least two of the following characteristics: unilateral location, pulsatile qualities, moderate to severe pain, increased intensity with activity and nausea, vomiting, photo or phonophobia (Chiang Starling, 2017). Even though chronic migraine is prevalent in the population, it is often not diagnosed accurately and so is often not treated appropriately. Chronic migraine is described as resulting from the pain centers in the brain being overly excitable, producing the sensation of pain even in the absence of an actual pain stimulus. This can lead to structural and functional brain alterations with sensitization of the trigeminovascular pathway (Whitcup, Turkel, DeGryse, Brin, 2013). CaMEO a study in the United States demonstrated that of 1254 participants meeting the eligibility criteria of chronic migraine, only 512 met with their healthcare provider about the headaches. Of those, only 126 received an accurate diagnosis of chronic migraine and then only 56 received both acute and preventative treatment (Chiang Starling, 2017). Possible reasons for this lack of effective treatment and diagnosis falls on the APRN or primary care physician (PCP). Patients generally meet with their APRN or PCP with a complaint of headache, seeking treatment and diagnosis. The APRN or PCP can refer the patient to a headache specialist but should remain involved in the patients care as prophylactic treatments can take 6-8 weeks to become effective. Primary care physicians and APRN’s can also assist the patients with modifiable risk factors for migraines such as: medication overuse, stress, psychiatric abnormalities and caffeine. A multi-disciplinary approach is best for the management of migraine because of the wide array of causes and difficulty in treatment, often requiring pharmacological and non-pharmacological treatments (Starling Dodick, 2015).

The PREEMPT trials were designed to test the prophylactic efficacy of OnabotulinumtoxinA in chronic migraine. In 1986 it was observed that OnabotulinumtoxinA had analgesic effects and the first evidence of its effects on migraines was documented while patients were being treated for hyper functional lines of the face. The PREEMPT trials built upon this knowledge and specifically tested for a reduction in the number of headache days per month for the chronic migraine patient. It is theorized that chronic migraine patients generally have tried and failed in at least 3 different treatment modalities. Many chronic migraine patients also have a problem with medication overuse. The PREEMPT trials provided recommendations for the 31 injection sites and dosages of 155 MU. The trials demonstrated that OnabotulinumtoxinA adverse effects (AEs) were generally limited to the injection itself and that systemic reactions are very rare (Escher, Paracka, Dressler, Kollewe, 2017).

Other prophylactic treatment modalities involve the use of Topiramate, an oral medication. Topiramate is taken by the patient and resulted in similar reductions in average headache days per month to OnabotulinumtoxinA. The primary difference was that Topiramate resulted in approximately 24% of study participants discontinuing the study due to AEs vs 7.7% in the OnabotulinumtoxinA group (Matthew Jaffri, 2009). There are many points to consider in any evidenced based health care decision including treatment cost, insurance/patient reimbursement, as well as patient preference and their ability to adhere to the treatment protocol. Healthcare providers must have a general understanding of the current practice guidelines and effectiveness of prophylactic treatment options in chronic migraine in order to provide the best care.

Conceptual Definitions

Chronic migraine in adults (ages 18-65) is defined as headache days more than 15 per month with a minimum of 8 being qualified as migraines per the International Classification of Headache Disorders, third edition (2013). Screening for chronic migraine is done using a patient’s headache diary or log and the HIT-6 the six-item headache impact test (Blumenfeld, Stark, Freeman, Orejudos, Adams, 2018). OnabotulinumtoxinA treatment is injected per the PREEMPT recommended 31 locations 155 MU every 12 weeks (Schaefer, Gottschalk, Jabbari, 2015). Successful prophylactic OnabotulinumtoxinA injection treatment will reduce the average number of headache days per month and increase healthcare quality of life. These items will be measured based upon the feedback in the patients headache logs/diaries and the HIT-6 test.

Method used for Literature Search

Literature search was performed using One Search feature on Cedarville’s Library home page. The overview of the search and delineation of resources is seen in Table 1. The primary search terms were entered as “migraine” and “Botox” and full text available articles as well as “non-duplicates” were limiters on the search. The initial return was for 1624 articles, the search was then further limited by adding “US peer reviewed scholarly articles” and English language. This brought the number of articles to 87, a 1537 article reduction. To further narrow the search “Chronic Migraine” and “Adults” were added to a full text search reducing the available articles to 13. Finally, a review of the data and the structure of the remaining articles resulted in 5 being removed for either not being research articles or not having relevant data.

 

Table 1: Literature Search Flowchart

 

After reviewing all of the resources found in the literature search the accompanying Outcome Synthesis Table was generated (Table 2). The outcome synthesis table with the eight resources used for the literature search demonstrates with either an up or down arrow if the article and research support that OnabotulinumtoxinA Injections effectively reduce frequency and intensity of Chronic Migraine. The levels of evidence sythesis table (Table 3) contains a reference to each of the literature and its associated research level. The keeper table (Table 4) includes the author, type of study, sample size, intervention, comparison, findings from the study, and limitations of the study.

Table 2

Outcome Synthesis Table

1 2 3 4 5 6 7 8

OnabotulinumtoxinA Injections effectively reduce frequency and intensity of Chronic Migraine

LEGEND

1. Blumenfeld, A. M., Stark, R. J., Freeman, M. C., Orejudos, A., Adams, A. M. (2018). Long-term study of the efficacy and safety of OnabotulinumtoxinA for the prevention of chronic migraine: COMPEL study. The Journal of Headache and Pain.

2. Chiang, C.-C., Starling, A. J. (2017). OnabotulinumtoxinA in the treatment of patients with chronic migraine: clinical evidence and experience. Therapeutic Advances in Neurological Disorders, 397-406.

3. Escher, C. M., Paracka, L., Dressler, D., Kollewe, K. (2017). Botulinum toxin in the management of chronic migraine: clinical evidence and experience. Therapeutic Advances in Neurological Disorders, 127-135.

4. Khalil, M., Zafar, H., Quarshie, V., Ahmed, F. (2014). Prospective analysis of the use of OnabotulinumtoxinA (BOTOX) in the treatment of chronic migraine; real life data in 254 patients from Hull, UK. Journal of Headache and Pain.

5. Matthew, N. T., Jaffri, S. F. (2009). A Double-Blind Comparison of OnabotulinumtoxinA (BOTOX) and Topiramate (TOPAMAX) for the Prophylactic Treatment of Chronic Migraine: A Pilot Study. Headache: The Journal of Head and Face Pain.

6. Schaefer, S. M., Gottschalk, C. H., Jabbari, B. (2015). Treatment of Chronic Migraine with Focus on Botulinum Neurotoxins. Toxins, 2615-2628.

7. Starling, A. J., Dodick, D. W. (2015). Best Practices for Patients With Chronic Migraine: Burden, Diagnosis, and Management in Primary Care. Phoenix: Department of Neurology Mayo Clinic

8. Whitcup, S. M., Turkel, C. C., DeGryse, R. E., Brin, M. F. (2013). Development of onabotulinumtoxinA for chronic migraine. Annals of the New York Academy of Sciences: Pharmaceutical Science to Improve the Human Condition. 

Table 3

Levels of Evidence Synthesis Table

X (copy symbol as needed) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Level I: Systematic review

or meta-analysis X X X

Level II: Randomized controlled trial

Level III: Controlled trial

without randomization X

Level IV: Case-control or

cohort study X X

Level V: Systematic review

of qualitative or descriptive

studies

Level VI: Qualitative or

descriptive study (includes evidence implementation

projects) X

Level VII: Expert opinion

or consensus X

 

LEGEND

1. Blumenfeld, A. M., Stark, R. J., Freeman, M. C., Orejudos, A., Adams, A. M. (2018). Long-term study of the efficacy and safety of OnabotulinumtoxinA for the prevention of chronic migraine: COMPEL study. The Journal of Headache and Pain.

2. Chiang, C.-C., Starling, A. J. (2017). OnabotulinumtoxinA in the treatment of patients with chronic migraine: clinical evidence and experience. Therapeutic Advances in Neurological Disorders, 397-406.

3. Escher, C. M., Paracka, L., Dressler, D., Kollewe, K. (2017). Botulinum toxin in the management of chronic migraine: clinical evidence and experience. Therapeutic Advances in Neurological Disorders, 127-135.

4. Khalil, M., Zafar, H., Quarshie, V., Ahmed, F. (2014). Prospective analysis of the use of OnabotulinumtoxinA (BOTOX) in the treatment of chronic migraine; real life data in 254 patients from Hull, UK. Journal of Headache and Pain.

5. Matthew, N. T., Jaffri, S. F. (2009). A Double-Blind Comparison of OnabotulinumtoxinA (BOTOX) and Topiramate (TOPAMAX) for the Prophylactic Treatment of Chronic Migraine: A Pilot Study. Headache: The Journal of Head and Face Pain.

6. Schaefer, S. M., Gottschalk, C. H., Jabbari, B. (2015). Treatment of Chronic Migraine with Focus on Botulinum Neurotoxins. Toxins, 2615-2628.

7. Starling, A. J., Dodick, D. W. (2015). Best Practices for Patients With Chronic Migraine: Burden, Diagnosis, and Management in Primary Care. Phoenix: Department of Neurology Mayo Clinic.

8. Whitcup, S. M., Turkel, C. C., DeGryse, R. E., Brin, M. F. (2013). Development of onabotulinumtoxinA for chronic migraine. Annals of the New York Academy of Sciences: Pharmaceutical Science to Improve the Human Condition.

 

Table 4

Keeper Table

Author/Date Research Design Sample/Setting Intervention Comparison Findings Limitations

1 Blumenfeld et al.

(2018)

Non-randomized open label study

Grade A 716 Adults with diagnosed chronic migraine over 112 week period. No previous use of Botox Injection of OnabotulinumtoxinA in 31 sites every 12 weeks 4 week Patient specific HIT and headache diary pre-study baseline period Statistically significant reduction in headache days per month with few adverse events reported No placebo or active comparator arm, unintentional bias, low persistency rates, concomitant medication changes

2 Chiang, C.-C., Starling, A. J. (2017) Systematic review of RCT

Grade B 38 Articles Injection of OnabotulinumtoxinA per recommended location and schedule Dependent on trial but HIT-6 and Headache logs OnabotulinumtoxinA is well tolerted with few adverse effects effective in the reduction of the average number of headache days per month in the migraine patient Review of research only, more studies which address long term use and efficacy of the treatments needed in the future

3 Escher, C. M., Paracka, L., Dressler, D., Kollewe, K. (2017) Systematic Review with meta-analysis

Grade B 72 articles

Injection of OnabotulinumtoxinA per recommended location and schedule HIT-6, headache logs. The prophylactic use of OnabotulinumtoxinA is supported for chronic migraine. Resulting in higher quality of life and reduced number of headache days per month Some authors were supported by for profit organizations;

4 Khalil, M., Zafar, H., Quarshie, V., Ahmed, F. (2014) Quasi-experimental non-randomized trial

Grade C 254 adults with chronic migraine and no previous Injection of OnabotulinumtoxinA Injection of 155 units of OnabotulinumtoxinA per PREEMPT location and schedule 4 week Patient specific HIT and headache diary pre-study baseline period In patients refractory to other prophylactic oral therapies OnabotulinumtoxinA significantly reduced number of headache days High placebo response effect, unable to compare Botox to other treatments

5 Matthew, N. T., Jaffri, S. F. (2009) Double Blind randomized prospective study

Grade A 60 randomized patients to either OnabotulinumtoxinA or topiramate in a single center OnabotulinumtoxinA injections with oral placebo Topiramate with Saline injection placebo Significant reduction in headache days with both therapies, OnabotulinumtoxinA reported significantly fewer adverse effects and had higher study completion rates Relatively short time frame and small sample size. Results were less significant than other similar trials, larger comparator studies needed.

6 Schaefer, S. M., Gottschalk, C. H., Jabbari, B. (2015) Systematic review with recommendations

Grade C 56 articles reviewed on all aspects of chronic migraine OnabotulinumtoxinA injection in three location protocols None Review of multiple articles, causes, and injection protocols for chronic migraine and OnabotulinumtoxinA results in similar positive reults Author of the article drew conclusions based upon his injection protocol without demonstrated research support.

7 Starling, A. J., Dodick, D. W. (2015) Expert opinion

Grade B Adults with chronic migraine OnabotulinumtoxinA injection in addition to oral treatment regimens None Proper diagnosis of chronic migraine and referral of patients to neurological specialties is essential to ensure effective treatment Paper is entirely based upon authors opinions of current practice and referenced articles. Some authors have interests identified in for profit agencies.

8 Whitcup, S. M., Turkel, C. C., DeGryse, R. E., Brin, M. F. (2013) Systematic Review of RCT’s with meta-analysis

Grade B Multiple large RCT’s including double blind and open label studies Injection of 155 units of OnabotulinumtoxinA per PREEMPT location and schedule Dependent on study being reviewed OnabotulinumtoxinA injected per PREEMPT location and schedule effectively reduces number of headache days in a safe and effective manner Need for longer term studies to determine effectiveness of OnabotulinumtoxinA. Authors are all employees of Allergan, manufacturer of OnabotulinumtoxinA

Results

Literature reviewed unanimously supported the efficacy of OnabotulinumtoxinA in the prophylactic treatment of chronic migraine. There were three level I sources all of which primarily reference the Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) trials. These trials represent the impetus for FDA approval of OnabotulinumtoxinA in the treatment of chronic migraine. Chiang and Starling (2017), stated that OnabotulinumtoxinA is recommended for chronic migraine of all types and includes the use of OnabotulinumtoxinA for chronic migraine in association with medication overuse headache. Health related qulaity of life (HRQoL) is found to be improved in chronic migraine patients by reducing overall headache days per month by -7 and increasing headache free days per month by +7 and a coinciding reduction of 9 units in the HIT-6 scores. This was further reinforced by the Chronic Migraine OnabotulinumtoxinA Prolonged Efficacy Open Label (COMPEL) trial. In this trial the long term efficacy and safety of OnabotulinumtoxinA was tested at a period of 108 weeks including 9 injection treatments. It was determined that there were very few adverse effects in relation to OnabotulinumtoxinA. The significant and maintained reduction in headache days began at 8-12 weeks following injection, with sustained improvement 3 months after treatment (Chiang Starling, 2017). Doses and injection sites were set forth as recommendations in the PREEMPT trials and included 31 sites around the head and neck area. Generally, a total of 150 MU was injected in the sites resulting in a myorelaxant and analgesic effect (Escher, Paracka, Dressler, Kollewe, 2017). The effects of the OnabotulinumtoxinA injection are long lasting but need repeated at the recommended 12 week interval. OnabotulinumtoxinA works by inhibiting hyper excitation of sensory receptors and preventing maladaptive pain responses inducing migraines (Whitcup, Turkel, DeGryse, Brin, 2013). Whticup et al. (2013) also examined the effect of OnabotulinumtoxinA in relation to placebo. The authors reviewed the data from the PREEMPT trials and determined that in both of the PREEMPT trials OnabotulinumtoxinA resulted in a greater reduction of headache days and greater mean change (2.4) in the HIT-6 scores.

There was one level III source reviewed, Matthew and Jaffri (2009), this was a pilot study and looked at the efficacy and safety of OnabotulinumtoxinA versus Topiramate in a non-randomized double blind study with placebo. The authors found that of the 60 patients randomized to the treatments that both OnabotulinumtoxinA and Topiramte had similar efficacy for the prophylaxis of chronic migraine. Their study lasted nine months and found that OnabotulinumtoxinA patients receiving oral palacebo for Topiramate had an adverse effect loss rate of 25%, whereas Topiramate patients with OnabotulinumtoxinA placebo had an adverse effect loss rate of 53.3% (Matthew Jaffri, 2009).

There are two level IV studies that were included in the review. Khalil et al. (2014) involved 254 patients and sought to determine the efficacy of OnabotulinumtoxinA and the cost effectiveness of the treatment. The authors discovered similar to other literature reviewed that there was a statistically significant reduction in the average number of headache days (-44% severe headache days, -16% mild headache days) and a 75% reduction in days off work following OnabotulinumtoxinA treatment. The authors also determined that it would be cost beneficial to offer OnabotulinumtoxinA injection treatments based upon efficacy prior to more costly procedures such as nerve block or stimulation. Equivalent results were discovered by Blumenfeld et al. (2018) in which the average number of headache days was reduced by approximately 10 days per month with very few adverse effects. Similar 10 point reductions were noted in the HIT-6 test in the 108 week trial period.

There was one source at level VI and one at Level VII. The level VI study involved a basic review of OnabotulinumtoxinA, its mechanism of action and its efficacy in three injection placement profiles PREEMPT 2003, PREEMPT 2010, Yale 2015 (Schaefer, Gottschalk, Jabbari, 2015). The level VII source allowed for the expert opinion of Starling and Dodick (2015), in their paper they discussed the definition and the burden of chronic migarine. The authors spoke to the importance of a multidisciplinary approach to the treatment of chronic migraine as well as the proper diagnosis. They state that only 20% of patients with chronic migraine are actually diagnosed with the disorder. Primary care physicians play an important role in managing the modifiable risk factors associated with headache and the ongoing management of the chronic migraine patient’s health (Starling Dodick, 2015). Recommendations

Based upon the data provided in all levels of the research reviewed, it is recommended that patients be encouraged to seek appropriate healthcare for their headache. Chronic migraine has been determined to be underdiagnosed and undertreated (Chiang Starling, 2017). Patients first reporting to an APRN or PCP should receive a comprehensive review of symptoms and based upon history referred to a headache specialist for comprehensive treatment. Patients with chronic migraine require a multimodal and multidisciplinary approach for their treatment. Monitoring for medication overuse, contributing and complicating factors of headache, and adherence to treatment protocol is paramount to successful treatment. Treatments are divided into abortive, those that interrupt a headache or migraine, and prophylactic those that prevent their occurrence. OnabotulinumtoxinA has been determined through multiple trials to be safe and effective in the prophylactic treatment of chronic migraine. Initial trials were short term in nature, where as the more recent trials are over two years in length. All the trials and articles reviewed determined that the injection of approximately 150 MU in 31 sites around the head and neck of OnabotulinumtoxinA at a frequency of 12 weeks resulted in decreased number of headache days and increased HCQoL. Adult chronic migraine patients must be monitored for treatment compliance and if cost feasible OnabotulinumtoxinA injections should be offered as a prophylactic for chronic migraine.

Discussion

Chronic migraine is a condition that has been proven difficult to treat over the years. Multiple oral medications have been approved to interrupt the ongoing migraine headache. Many of these medications are minimally effective, and as such are proven to lead to medication overuse and subsequent increases in the frequency of headaches. Only two medications have demonstrated the ability to prophylactically treat chronic migraine. Topiramate and OnabotulinumtoxinA injections have both been studied multiple times and are also the subject of comparative studies such as Matthew and Jaffri (2009) in which both were found to be similarly effective in the prophylactic treatment of chronic migraine. The primary difference being the significantly higher potential for serious adverse effects with Topiramate in comparison to OnabotulinumtoxinA. The data from all of the research reviewed demonstrates the safety and efficacy of OnabotulinumtoxinA in reducing the number of headache days per month in both short and long term use.

Access to appropriate healthcare is important to the chronic migraine patient, with only 20% of the patients being diagnosed and less than 50% consistently taking their preventative medications (Khalil, Zafar, Quarshie, Ahmed, 2014). OnabotulinumtoxinA allows for a low risk, high return alternative to patients only taking minimally effective oral medications designed primarily to interrupt ongoing migraines not prevent them. OnabotulinumtoxinA reduces not only the average number of headache days per month but also increases the healthcare quality of life by increasing headache free days and a 75% reduction in days off work. Scores on the headache impact test were reduced by an average of 10 points in all the research reviewed. While the cost of OnabotulinumtoxinA injections is higher than oral medications available today, the benefit is substantial for the chronic migraine patient.

Education of primary care physicians and patients is key to the success of any chronic migraine treatment plan. Headache specialists may be more in tune with the latest recommendations for OnabotulinumtoxinA injection placement and treatment, but APRN’s and PCP’s need to be informed as to the benefits and treatment regimens for the patients. Patients need to be aware of the importance of following the treatment regimen established by their healthcare team. Based on the review of relevant research literature I recommend that OnabotulinumtoxinA should be made available to chronic migraine patients immediately following an accurate diagnosis to reduce the impact on the patients life and increase quality of life. Chronic migraine patients should receive treatment with OnabotulinumtoxinA injections for prophylactic treatment and a combibation of medications for intervention in an active migraine. Patients should also be educated in modifiable risk factors to reduce potential for increasing the frequency or severity of their headaches. All of these factors combine to effectively reduce the severity and frequency of chronic migraines and associated disability, while improving the overall health and quality of life for the patient.