SEARCH

SEARCH BY CITATION

Keywords:

  • frequent episodic migraine;
  • preventive treatment;
  • acute treatment;
  • disease modification

Abstract

  1. Top of page
  2. Abstract
  3. Study Design
  4. Study Population
  5. Study Medication
  6. Study Procedures
  7. Results
  8. Discussion
  9. Conclusion
  10. Acknowledgment
  11. Statement of Authorship
  12. References

Objective

This pilot study explored the potential for 2 recognized acute migraine medications, 85 mg of sumatriptan plus 500 mg of naproxen sodium in a combination tablet (SumaRT/Nap) and 500 mg of naproxen sodium, to treat and modify the disease progression of migraine. In other words, can these medications both abort an acute attack of migraine and reduce the number of future migraine attacks?

Background

Patients suffering with moderate to severe attacks of migraine desire acute treatment. As migraine frequency increases, so does the need for more frequent relief of acute attacks. This may lead to medication overuse and potentially medication overuse headache (MOH). Ideally, acute medication would have the ability to abort an attack of migraine and reduce the likelihood of future attacks.

Study Design

The primary endpoint of this study was a reduction in migraine headache days from baseline through month 3 of the study. Subjects were randomized 1:1 to treat 14 or fewer migraines per month with SumaRT/Nap (Group A) or naproxen sodium (Group B) for 3 months. Subjects in group A utilized SumaRT/Nap were encouraged, but not required, to treat migraine headache within 1 hour of onset of headache when the pain was mild. They could re-treat if needed after 2 hours. Subjects in group B utilized the same treatment strategy with 500 mg of naproxen sodium. Tablets of study medication were identical for both groups. Subjects recorded headache days, migraine attacks, duration of attacks, treatment, and treatment results daily on paper diaries. Subjects took the Migraine Disability Assessment Test (MIDAS) at randomization and 3 months later at the end of study.

Results

Naproxen sodium was associated with a statistically significant reduction in migraine headache days at month 3 compared to baseline (P = .0002). SumaRT/Nap was also associated with a reduction of migraine headache days, but this decrease did not reach statistical significance (P = .2). In addition, subjects in the naproxen sodium group had a statistically significant reduction of migraine attacks in all 3 months of the study compared to baseline. A greater than 50% reduction in the number of migraine headache days at month 3 occurred in 43% (6/14) of subjects in group B compared to 17% (3/18) of subjects in group A. Consistent with large regulatory studies comparing the efficacy of SumaRT/Nap with naproxen sodium, SumaRT/Nap in this study was statistically superior to naproxen sodium at 2 hours in reducing headache severity during months 2 and 3. There was a reduction of acute medication used from baseline to month 3 and improvement in MIDAS scores for both groups.

Conclusion

Naproxen sodium, when used as a sole acute treatment early in attacks, appears to reduce the frequency of headache days and migraine attacks for a select number of subjects over a 3-month period. SumaRT/Nap is more effective at 2-hour headache reduction than naproxen sodium alone, but has less impact on reducing attack frequency or the number of headache days. Both treatments were well tolerated, and there was no convincing evidence that either medication led to MOH.

Abbreviations
ACE

angiotensin-converting enzyme

ANOVA

analysis of variance

ARB

angiotensin receptor blocker

DHE

dihydroergotamine

GI

gastrointestinal

HCP

health care professional

ICHD-2

International Classification of Headache Disorders, 2nd edition

MAOI

monoamine oxidase inhibitor

MIDAS

Migraine Disability Assessment

MO

medication overuse

MOH

medication overuse headache

NSAE

nonserious adverse event

NSAIDs

nonsteroidal anti-inflammatory drugs

OTC

over-the-counter

SumaRT/Nap

sumatriptan and naproxen sodium

Pharmacological treatments of migraine are generally divided into acute and prophylactic therapies. Acute medication is used to abort an attack, while prophylactic medications reduce attack frequency and thus modify migraine disease or susceptibility of the nervous system to migraine. Many migraine medications approved, as either an acute or prophylactic treatment, have demonstrated ability to function as both acute and prophylactic treatments.1-3

There has been little research on the use of acute migraine medications in populations with frequent episodic or chronic migraine. Yet these patient populations arguably have the greatest need for effective relief from episodes of migraine. While many acute medications have clinical efficacy as being effective at relieving headaches in patients with high-frequency episodic and chronic migraine, it is widely accepted that too frequent use of acute medications can result in medication overuse headache (MOH).[4] Efforts to control use of acute medication in high-need populations either by providers or pharmacy benefit plans are complicated by the fact that there are many acute migraine medications available over-the-counter (OTC). Consequently, many patients utilize a combination of prescription and OTC medications in an effort to adequately treat their pattern of frequent migraine. This makes the control of acute medication a challenging clinical dilemma. In addition, little is known about the risks and benefits of using these products in combination with one another.

Population-based epidemiological studies suggest that opioids, caffeine, and butalbital combination products carry the highest risk of transforming episodic to chronic migraine.[5] Triptans and nonsteroidal anti-inflammatory drugs (NSAIDs) carry less risk.[5] In fact, one epidemiological study found that NSAIDs appear to have a protective effect when used with a frequency of less than 10 days per month.[6] Yet, this study did not consider the use of multiple classes of acute pharmacological treatments in a single subject as a risk factor for migraine chronification. The possibility exists that different classes of acute medication, when used together, may interact and produce different levels of risk or benefit.

In phase 3, regulatory trials of a combination of sumatriptan 85 mg and naproxen sodium 500 mg (SumaRT/Nap) with subjects who experienced 2-6 migraine attacks per month, SumaRT/Nap was superior in 2-hour efficacy to sumatriptan or naproxen sodium alone.[7] In addition, there was less recurrence of migraine than with either component of this product used alone. In a 12-month safety study, SumaRT/Nap was well tolerated in subjects who treated an average of 5 migraine attacks with an average of 6 days between attacks.[8] Migraine attack frequency increased slightly over baseline for both 6 and 12 months completers (4.3 vs 5.0 vs 4.9, respectively), suggesting there was no prophylactic benefit from using SumaRT/Nap as an acute treatment at this dosing frequency.

In a study of subjects with high-frequency migraine exploring the role of topiramate to reduce the risk of transforming from frequent episodic to chronic migraine, topiramate with demonstrated efficacy for prophylaxis of frequent migraine, did not prevent chronification.[9] Subjects in the study were allowed to use their usual acute treatment. It is plausible that frequent acute treatment, a risk factor for chronification, negated the positive benefit of topiramate. Yet paradoxically, another study found that subjects who used only frovatriptan for very frequent chronic migraine on a daily basis had a reduction in their migraine frequency when followed over 3 months.[10]

The ideal acute treatment would rapidly abort a migraine attack without adverse events and increase the time to the next migraine attack. An unanswered question is whether certain acute treatments when used repeatedly over time provide preventive benefits. For this reason, the current study explored the use of frequent administration of two specific acute medications in a population with frequent episodic migraine to ascertain if there are both acute and preventive benefits to subjects over 3 months' time.

Study Design

  1. Top of page
  2. Abstract
  3. Study Design
  4. Study Population
  5. Study Medication
  6. Study Procedures
  7. Results
  8. Discussion
  9. Conclusion
  10. Acknowledgment
  11. Statement of Authorship
  12. References

Protocol Approvals, Registrations, and Patient Consents

This study was conducted in accordance with the Declaration of Helsinki, all relevant US federal regulations, and in compliance with the International Conference on Harmonization guideline for Good Clinical Practice. The study protocol, informed consent forms, and all other appropriate study-related documents were approved by the Sterling Institutional Review Board/Ethics Committee. Written informed consent was obtained from each patient prior to any protocol-related activities. The study was sponsored as an investigator initiated study through a grant from GlaxoSmithKline, Research Triangle Park, NC. Clinical trial registration number: NCT01300546 on clinicaltrials.gov.

This study was a two-center, randomized trial of 39 subjects, 18 to 65 years of age, with frequent episodic migraine with or without aura, as defined by International Classification of Headache Disorders, 2nd edition, ICHD-II, and with Stage 2 (3 to 8 headache days per month) or Stage 3 migraine (9 to 14 headache days per month).[11] As this was a pilot study aimed at exploring proposed hypotheses with no intention of establishing efficacy, a formal power analyses was not completed. The sample size was determined considering the study design.

At Visit 1 and following informed consent, a physical and neurological exam, vital signs, and electrocardiogram were completed. Medical, migraine, and medication history were collected. Eligible subjects were given a written 1-month baseline diary that recorded migraine frequency, number of headache (migraine) days, and quantity of medications being used.

During the baseline period, subjects treated migraine attacks with their current preferred acute treatment(s). Subjects were eligible for the active phase of the study if they had 6-14 migraine headache days and utilized acute treatment at least 6 days, but no more than 14 days, during baseline.

Subjects meeting eligibility criteria were randomized to either group A, treated subsequent migraine headaches with 85 mg sumatriptan plus 500 mg naproxen sodium in a single combination tablet (SumaRT/Nap) or group B, treated with 500 mg naproxen sodium in an identical appearing tablet over a 3-month period. Subjects watched an instructional DVD about self-management of migraine and received a copy of the DVD and a list of educational websites, such as http://headaches.org, to use as support during the study. Subjects were followed at monthly intervals for 3 months.

Study Population

  1. Top of page
  2. Abstract
  3. Study Design
  4. Study Population
  5. Study Medication
  6. Study Procedures
  7. Results
  8. Discussion
  9. Conclusion
  10. Acknowledgment
  11. Statement of Authorship
  12. References

Subjects were screened at headache specialty clinics and the general population. Subjects had to have a stable history of migraines for at least 3 months prior to enrollment. Subjects on migraine preventive medications were required to remain on a stable regimen of their preventive medications for the 30 days prior to randomization and throughout the study period.

Randomization of subjects was orchestrated by a supervisory individual, not associated with the study subjects or visits. The randomization scheme was generated using the website: (http://www.randomization.com). Forty subjects were randomized 1:1 into 2 blocks. The supervisory individual numbered and assigned study medication, based on the randomization plan, in a blinded fashion to subject, coordinator, and investigator.

Inclusion Criteria:
1. Male or female, in otherwise good health, 18 to 65 years of age.
2. Established history of frequent episodic migraine (6-14 migraine days per month) (with or without aura) according to the ICHD-II for at least 3 months (Stage 2, frequent, or Stage 3, transforming migraine).[12]
3. Onset of episodic migraine before age 50.
4. Able to differentiate migraine from any other headache they may experience.
5. Stable history of headache at least 3 months prior to screening.
6. Not currently taking a migraine preventive or has been taking preventive for at least 30 days prior to screening and agrees to not start, stop, or change medication and/or dosage during the study period.
7. At least 50% of migraine attacks beginning at mild severity.
8. If female of childbearing potential, has a negative urine pregnancy test at visits 1-5 and uses, or agrees to use, for the duration of the study, a medically acceptable form of contraception as determined by the investigator.
A. Complete abstinence from intercourse from 2 weeks prior to administration of study drug throughout the study, and for a time interval after completion or premature discontinuation from the study to account for elimination of the study drug (a minimum of 7 days).
B. Surgically sterile (hysterectomy or tubal ligation or otherwise incapable of pregnancy).
C. Sterilization of male partner.
D. Intrauterine device with published data showing lowest expected failure rate is less than 1% per year.
E. Double barrier method (ie, 2 physical barriers or 1 physical barrier plus spermicide) for at least 1 month prior to visit 1 and throughout the study.
F. Hormonal contraceptives for at least 3 months prior to visit 1 and throughout the study.
9. Had ≥6 migraine treatment days in 1 month (baseline) prior to visit 2.
Exclusion Criteria:
1. Unable to understand the study requirements, the informed consent, or complete headache records as required per protocol.
2. Pregnant, actively trying to become pregnant, or breast-feeding.
3. Experienced the following migraine variants: basilar migraine, aura without headache, familial hemiplegic migraine, complicated migraine, ophthalmoplegic migraine and retinal migraine.
4. History of medication overuse headache in the 3 months prior to study enrollment or during the baseline phase.
6. Abuse, in the opinion of the investigator, of any of the following drugs, currently or within the past 1 year:
1. Opioids
2. Alcohol
3. Barbiturates
4. Benzodiazepine
5. Cocaine
7. History of significantly impaired hepatic or renal function that, in the investigator's opinion, contraindicates participation in this study.
8. Unstable neurological condition or a significantly abnormal neurological examination with focal signs or signs of increased intracranial pressure.
9. History of asthma and/or nasal polyps.
10. History of peptic ulcer disease requiring therapeutic intervention in the year prior to study enrollment.
11. Evidence or history of any gastrointestinal (GI) surgery or GI ulceration or perforation of the stomach or intestine in the past 6 months, gastrointestinal bleeding in the past year or evidence or history of inflammatory bowel disease or history of any other bleeding disorder, or has taken or plans to take any anticoagulant or any antiplatelet agent within the 2 weeks prior to screening through 48 hours post final study treatment.
12. History of nonsteroidal anti-inflammatory drug induced gastritis, esophagitis, or duodenitis.
15. Has in the opinion of the investigator a significant cardiovascular or cerebrovascular disease or risk profile.
16. Has a psychiatric condition, in the opinion of the investigator, which may affect the interpretation of efficacy and safety data or contraindicates the subject's participation in the study.
18. Has hypersensitivity, intolerance, or contraindication to the use of sumatriptan, any of its components, or any other 5-Ht1 agonist or naproxen sodium or other NSAIDs.
19. Is currently taking a migraine prophylactic medication containing an ergotamine or ergot derivative such as dihydroergotamine (DHE) or methysergide.
20. Has taken, or plans to take, a monoamine oxidase inhibitor (MAOI) including herbal preparations containing St. John's Wort (Hypericum perforatum), anytime within the 2 weeks prior to screening through 2 weeks post final study treatment.
21. Has taken or plans to take an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) anytime within the 2 weeks prior to screening through 48 hours post final study treatment.
22. Has received any investigational agents within 30 days prior to Visit 1.

Study Medication

  1. Top of page
  2. Abstract
  3. Study Design
  4. Study Population
  5. Study Medication
  6. Study Procedures
  7. Results
  8. Discussion
  9. Conclusion
  10. Acknowledgment
  11. Statement of Authorship
  12. References

Group A

At visit 2, subjects randomized to group A (SumaRT/Nap) were dispensed 14 tablets, composed of 85 mg of sumatriptan and 500 mg of naproxen sodium, to treat migraines acutely for a maximum of 14 days during the next month and an additional 14 tablets for treatment of nonresponse to the initial dose or recurrence within 2-24 hours. Two doses of study medication were not allowed within 2 hours of each other. Subjects were allowed to rescue with a medication other than a triptan or NSAID between 2 and 24 hours following the first dose at the discretion of the investigator. Subjects were instructed on how to take medication, dosage limitations (ie, not more than 2 tablets per day separated by at least 2 hours and to treat no more than 14 days per month), storage requirements, and to return all used/partially used/unused medication containers at the next office visit. An identical 1-month supply of 14 tablets for treatment and 14 tablets for rescue of study medication was dispensed at visits 3 and 4. Tablets were identical to those supplied to subjects in group B.

Group B

At visit 2, subjects randomized to group B (naproxen sodium) were dispensed 14 tablets of naproxen sodium 500 mg for acute treatment and 14 tablets for treatment of nonresponse to initial treatment or recurrence of an attack of migraine within 2 to 24 hours of initial dosing. Tablets were identical to those provided to group A. Subjects were instructed on how to take medication, dosage limitations (ie, not more than 2 tablets per day separated by at least 2 hours and to treat no more than 14 days per month), storage requirements, and to return all used/partially used/unused medication containers at the next office visit. An additional 14-day supply of naproxen sodium 500 mg for acute treatment and 14 tablets for rescue was dispensed at visits 3 and 4. When needed, rescue medication could be taken at the discretion of the investigator for both study groups. All subjects were encouraged, but not required, to treat within 1 hour of migraine headache onset and during mild headache.

Study Procedures

  1. Top of page
  2. Abstract
  3. Study Design
  4. Study Population
  5. Study Medication
  6. Study Procedures
  7. Results
  8. Discussion
  9. Conclusion
  10. Acknowledgment
  11. Statement of Authorship
  12. References
 Visit 1Visit 2Visit 3Visit 4Visit 5
Informed consentX    
Physical/Neurological examX    
12-lead ECGX    
Vital signsXXXXX
Verify inclusion/exclusionXX   
Subject randomization X   
Medical historyX    
Migraine historyX    
Medication historyX    
Update medications XXXX
Pregnancy testXXXXX
View/Dispense educational DVD X   
Review contents of DVD with patient X   
Administer patient questionnaireXXXXX
Dispense patient questionnaire XXX 
Dispense study medication XXX 
Collect/Drug accountability  XXX
Dispense diaryXXXX 
Collect/Review diary XXXX
Collect adverse events XXXX
Administer MIDAS X  X

Primary Objective

Change from baseline in the number of migraine headache days reported in the month 3 treatment period diary in the SumaRT/Nap arm (group A) vs the naproxen sodium arm (group B).

Secondary Objectives

  1. Change (percentage reduction) in the number of migraine headache days at each interim visit compared to baseline in group A vs group B.
  2. Change in the number of migraine attacks at each interim visit (treatment period months 1, 2, and 3) compared to baseline between group A and B.
  3. Change in number of subjects with at least a 50% reduction in number of migraine headache days comparing baseline to each visit (treatment period months 1, 2, and 3) in the SumaRT/Nap arm vs the naproxen sodium arm.
  4. Change in 2-hour migraine headache relief scores between group A and B.
  5. Change in total number of doses of acute medication taken per month comparing baseline to each study visit.
  6. Adverse events in the SumaRT/Nap arm vs the naproxen sodium arm.
  7. Changes in MIDAS scores at randomization vs 3 months for group A vs group B.

Glossary

Baseline

Headache history collected by daily diary during the 30-day baseline period between visit 1 and visit 2 for both groups.

Migraine Headache Day

A migraine day is defined as a day (00:00 to 23:59) with 4 or more hours of headache of at least moderate pain intensity per subject diary, or any day with headache of any duration that has been treated.

Migraine Attack

A migraine attack is defined as a migraine headache lasting at least 4 hours or treated with study medication with a 48-hour pain-free interval between headaches.

Medication Overuse (MO)

Specific quantities of acute medication defined by ICHD-II criteria as medication overuse.[11]

Medication Overuse Headache (MOH)

Worsening of underlying headache pattern associated with increasing utilization of acute medications and quantities defined by Revised Criteria for MOH.[13] In this study, the determination was made by primary and/or sub-investigators.

Statistical Analysis

Data were statistically analyzed for changes between groups and across time via a 2-tailed repeated measures analysis of variance (ANOVA) and t-tests with individual means comparisons compared within and between group differences on reported number of migraine headache days and attacks per month for the 2 groups. In this analysis, the within-subjects factor consisted of all sample time points, while the between-subjects factor consisted of 2 levels (Group A and Group B). Data were analyzed from the per-protocol population. An intent-to-treat analysis was considered, but rejected, as the main objective of this study was exploratory in nature and any type of adjusting for missing data would have decreased variability within the small sample size as well.

Results

  1. Top of page
  2. Abstract
  3. Study Design
  4. Study Population
  5. Study Medication
  6. Study Procedures
  7. Results
  8. Discussion
  9. Conclusion
  10. Acknowledgment
  11. Statement of Authorship
  12. References

Fifty-nine subjects were screened for this study, satisfying the proposed sample size of 40 subjects. The study population consisted of 39 subjects who randomized per protocol; 3 males and 36 females with a mean age of 39.5 years with a range of 24-57 years with a diagnosis of frequent ICHD-II episodic migraine; 35 were Caucasian, 3 Asian, and 1 Hispanic. Nineteen subjects were randomized to group A (SumaRT/Nap) and 20 to group B (naproxen sodium). Seven subjects did not complete the study; 1 in group A and 6 in group B. The reason for withdrawal from group A was “too busy” to continue. Withdrawals from group B included 3 for lack of efficacy, and 3 lost to follow-up. Those subjects withdrawing for lack of efficacy all withdrew after visit 2 or at visit 3 of the study, ie, the first month of active treatment. The resulting sample size of 32 subjects was used for all statistical analyses (group A = 18, group B = 14) (Table 1). The demographics were similar for both groups.

Table 1. Baseline and Demographic Characteristics
Number of PatientsTotalGroup AGroup B
First subject in 12/20/2010   
Screened59  
Randomized391920
Did not complete study716
Lost to follow-up3 3
Lack of efficacy3 3
Withdrew due to “too busy”11 
Completed study321814
Last subject out 3/26/2012   

The primary endpoint of the study was a reduction of migraine headache days at month 3 of active treatment. Group B (naproxen sodium) experienced a statistically significant reduction of 3.2 migraine headache days, whereas group A (SumaRT/Nap) had a reduction of 1.3 days. (P = .002, .20, respectively) (Fig. 1 —, Table 2). There was also a statistically significant reduction in migraine attacks for group B at months 1, 2, and 3. At month 3, migraine attacks were reduced from 5.4 per month to 3.4 per month for group B (P = .004). There was a nonstatistically significant numerical reduction for group A at month 3 of 0.7 migraine attacks per month (P = .15) (Fig. 2 —, Table 3).

figure

Figure 1 —. Migraine headache days per month. *Month vs baseline P ≤ .05.

Download figure to PowerPoint

figure

Figure 2 —. Migraine attacks per month. *Group A vs Group B P ≤ .05. #Month vs baseline P ≤ .05.

Download figure to PowerPoint

figure

Figure 3 —. Percentage of subjects with >50% reduction in number of migraine headache days.

Download figure to PowerPoint

Table 2. Migraine Headache Days per Month – Mean (StdDev)
 BaselineMonth 1Month 2Month 3P value BL vs M1P value BL vs M2P value BL vs M3
  1. *Month vs baseline P ≤ .05.

Group A – SumaRT/Nap9.39 (2.50)8.83 (2.64)8.61 (3.99)8.06 (3.99).3121.4581.2042
Group B – Naproxen9.29 (3.01)6.79 (3.26)7.29 (3.75)6.00 (4.21).1503.2045.0002*
P – value A vs B0.91760.05890.34620.1683   
Table 3. Migraine Attacks per Month – Mean (StdDev)
 BaselineMonth 1Month 2Month 3P value BL vs M1P value BL vs M2P value BL vs M3
  1. *Group A vs group B P ≤ .05; **Month vs baseline P ≤ .05.

Group A – SumaRT/Nap5.61 (1.14)5.11 (1.41)5.22 (1.73)4.94 (1.83).4031.4267.1498
Group B – Naproxen5.43 (1.50)4.86 (1.99)4.93 (1.82)3.36 (1.82).0019**.0222**.0036**
P value A vs B0.69920.67590.64500.0209*   

The number of subjects in group B vs group A with a greater than 50% reduction in migraine headache days at month 1 was 21% vs 6%; in month 2, 21% vs 11%; and month 3, 43% vs 17%, respectively (Fig. 3 —).

Two-hour headache relief was statistically superior for SumaRT/Nap for months 2 and 3 vs naproxen sodium (Fig. 4 —). SumaRT/Nap was not statistically superior in month 1 vs naproxen sodium, although the trend was still consistent with months 2 and 3.

figure

Figure 4 —. Migraine severity treatment vs 2 hours. *Time of treatment vs 2 hours post-treatment pain severity P ≤ .05. #Group A vs Group B – time of treatment vs 2 hours post-treatment P ≤ .05.

Download figure to PowerPoint

Medication usage decreased throughout the active study phase and was statistically significant for both groups during all active phases (Table 4). During the 1-month baseline period, subjects used their customary acute treatments. Those randomized to group A used an average of 18 doses of acute medication; an average of 4.5 of which were treated with a triptan. Subjects randomized to group B used an average of 15.6 doses of acute medication, an average of 6 doses treated with an NSAID. During month 1, medication usage for group A dropped to 11.6 vs 10.6 for group B. During month 2, both groups used acute medication 10.6 times. During month 3, group A used acute medication 10.3 times vs 9.1 times for group B. Subjects in both groups utilized a second dose of study medication on 8% of treatment days (Fig. 5 —). Non-study rescue medications were used on <0.4% of days for group A and 3% for group B.

Table 4. Adverse Events
EventTotalGroup AGroup B
# Subjects with Event# of Times Event Reported# Subjects with Event# of Times Event Reported# Subjects with Event# of Times Event Reported
Allodynia *2 hours after each administration of study drug18218200
Back pain110011
Diarrhea111100
Insomnia111100
Kidney stone pain flare110011
Neck pain120012
Right chest wall pain110011
Stiffness in neck111100
Vomiting110011
figure

Figure 5 —. Medication utilization. *Treatment months compared against Baseline P ≤ .05.

Download figure to PowerPoint

No subject was determined by the investigators to be in MOH at the end of the study, but one subject in a post hoc analysis of individual subjects did experience an increased number of headache days per diary record and increased medication usage in months 2 and 3 of the study. This subject was randomized to group A, treated migraine 12 days with non-triptan acute interventions through baseline and with 12 doses of SumaRT/Nap during month 1. During month 2, she treated migraine with 17 doses and during month 3, treated with 19 doses of SumaRT/Nap, although the number of doses were increased, it was documented she wanted to continue in the study because she felt the study medication was improving her migraines. The investigator did not think this subject was in MOH.

Both treatments regiments were well tolerated. There were no serious adverse events in either group. MIDAS scores modestly decreased for both groups. For group A, the decrease was from 28.7 to 22.6, and for group B 27.9 to 24.1.

Adverse Events

Adverse Events Collected for 39 Randomized Subjects

Total number affected by NSAE = 11 of 39 (28%)

Number affected by NSAE in Group A = 5 of 19 (26%)

Number affected by NSAE in Group B = 6 of 20 (30%)

Discussion

  1. Top of page
  2. Abstract
  3. Study Design
  4. Study Population
  5. Study Medication
  6. Study Procedures
  7. Results
  8. Discussion
  9. Conclusion
  10. Acknowledgment
  11. Statement of Authorship
  12. References

These data suggest that there may be clinically meaningful differences between SumaRT/Nap and naproxen sodium when used frequently for acute treatment in subjects with frequent episodic migraine. Those subjects completing per protocol utilizing naproxen sodium had a significant decrease in the number of headache days and migraine attacks suggesting a role for naproxen sodium as having both an acute and preventive benefit. Those subjects in the SumaRT/Nap group experienced a more robust pain reduction at 2 hours post-dose, but despite having the same dose of naproxen sodium in the product, there was minimal evidence of disease modification. Conversely, there was no indication of increasing migraine frequency with SumaRT/Nap during this study as might be expected with a triptan used alone at this high frequency for treatment of acute migraine.

One possible explanation for this difference is that there may be an inhibitory interaction between sumatriptan and naproxen sodium that prevents the reduction of migraine headache days and attack frequency observed with naproxen sodium alone. Given that sumatriptan is associated with MOH, and animal studies suggest that with frequent exposure to triptans there are neural adaptations leading to triptan-induced latent sensitization of sensory afferents,[14] it is plausible that while the combination of sumatriptan plus naproxen does not reduce migraine headache days, neither is it associated with an increase of migraine headache days. Despite frequent use of both SumaRT/Nap and naproxen, there was no clear evidence of MOH in either study group. Conceivably, naproxen sodium may have a protective benefit when used alone and a beneficial effect when used in combination with sumatriptan in lessening the risk of MOH that might be attributable to sumatriptan when used at this frequency as an acute abortive. This hypothesis clearly requires further study before any definitive statement can be made.

Another possible explanation for this observation is that subjects entering the study were actually in unrecognized medication overuse headache due to combinations of acute medications rather than a single medication. That appears unlikely as throughout baseline, only 2 subjects utilized more than 10 doses of a triptan, and only one took more than 15 doses of an NSAID. While many subjects, particularly in group A, used quantities of study medication breaching the threshold of MO, most had improvement in their migraine pattern. It is likely the increased quantity of triptan medication was in part related to not having access to other medications as described in the study protocol.

Another interesting observation is that during baseline, subjects had similar 2-hour headache relief with their acute treatment regimens. Most subjects (97%) of the total population were using a combination of triptans and NSAIDs either to treat different attacks or together as treatment of a single attack. However, in the active phase of the study, SumaRT/Nap subjects consistently reported superior 2-hour headache relief over all 3 active months of the study when only a single drug was used for acute treatment. Given the clinical value attached to acute treatments that provide rapid relief, it is understandable that a reduction in migraine frequency may not be as readily appreciated as an attribute of treatment as relief at 2 hours. Over the long term, however, overreliance on this expectation of acute therapy may be central to understanding the dynamic of MO and MOH.

MOH has been observed for decades, but clinical awareness increased through the 1980s and 1990s. Initially the offending medications were most often butalbital, opioids, ergotamines, and caffeine.[11] With the advent of triptans, there was an alternative to these medications, and triptans rapidly became the “gold standard” for acute treatment. In 1996, Göbel published the first report of MOH resulting from triptans, and since that time, other reports have been published.15-17 Today, MOH has become well entrenched in the lexicon of health care professionals (HCP) caring for migraine patients. Undoubtedly, this is due largely to the establishment of criteria for MO and MOH. Given that triptans have superb 2-hour efficacy as a migraine abortive, they are also associated with MOH. While a causal relationship between sumatriptan and MOH has not been fully established, failure of triptans to positively alter migraine frequency may be an important factor in the progression of migraine disease. Patients and HCPs may be overly reliant on the 2-hour benefits of triptans in deference to preventive treatments. While this study cannot make a definitive statement regarding triptans and MOH, it can serve to raise awareness of the importance of disease modification through the use of preventive treatment or potentially acute treatments that alter disease frequency.[5, 18] Alternatively, given that SumaRT/Nap is superior to naproxen sodium as an acute treatment and associated with fewer early study withdrawals, one might argue that the lack of an increase in migraine frequency is a favorable attribute of this combination vs sumatriptan used alone in a frequent acute treatment paradigm. These hypotheses may warrant further study as it may be an important dynamic of medication overuse and medication overuse headache.

The mechanisms of preventive medications are poorly understood, so it is challenging to propose any mechanism by which a 5-HT 1B/1D receptor agonist might inhibit the preventive benefit observed in this study with naproxen sodium. This is particularly true given a number of studies demonstrating a prophylactic benefit from short-term daily use of several triptans including sumatriptan.[19, 20] Also, there are reports of patients successfully using daily triptans to control chronic migraine.[18, 21] Studies in rats suggested that sustained or repeated administration of triptans elicited cutaneous tactile allodynia and increased labeling for calcitonin gene-related peptide in trigeminal afferents. This leads to latent sensitization of trigeminal afferents induced by triptans and may be an important mechanism leading to MOH. Possibly, this might explain a lack of prophylactic benefit for the SumaRT/Nap group. Conversely, in animal studies, NSAIDs have been observed to provide neuroprotection in several inflammatory central nervous system diseases and prevent neuronal recruitment via glia mechanisms.[22, 23] These may serve as potential mechanisms for NSAIDs as migraine preventives or as being protective of MOH. They also may serve to explain the prophylactic benefit of naproxen sodium observed in group B.

It is interesting to note that transformation of frequent episodic migraine to chronic migraine did not seem to occur in the naproxen sodium group, with the possible exception of a single subject, and did not occur with SumaRT/Nap. This observation is consistent with studies by Manack et al that estimated 26% of subjects “relapse from episodic to chronic migraine” during the clinical trials.[24] In another study, Diener suggested that the time required for MOH to develop with triptans is 1-2 years, and this patient was not using triptans during the baseline period.[25] Though the lack of MOH in both study groups is interesting, no definitive statement about either study drug being associated with or without MOH can be made from this study. It is, however, a hypothesis worthy of further study.

There are several limitations to this study. Most importantly are the small sample size and the short duration of study. Clearly, the hypotheses drawn from this study require larger more rigorous clinical trials. In addition, as with all studies on prevention, there are operational challenges in determining causality of changes in migraine frequency. In clinical practice, it is widely observed that a patient's migraine frequency changes for better or worse because of numerous factors. Obviously not all factors affecting migraine frequency can be controlled.

Conclusion

  1. Top of page
  2. Abstract
  3. Study Design
  4. Study Population
  5. Study Medication
  6. Study Procedures
  7. Results
  8. Discussion
  9. Conclusion
  10. Acknowledgment
  11. Statement of Authorship
  12. References

This study suggests that naproxen sodium used as frequent therapy can reduce the number of migraine days and be beneficial in acute migraine attacks. SumaRT/Nap is a superior acute intervention for reducing headache severity at 2 hours (Fig. 4 —, Table 5). The reason that naproxen sodium, but not SumaRT/Nap, modifies migraine frequency despite both groups using the same amount of naproxen sodium is unknown. There may be an inhibition occurring when sumatriptan is used frequently in conjunction with naproxen sodium or that naproxen is protective while sumatriptan can increase migraine frequency. When used as a combination, the effects may offset or balance each other. If true, this has important clinical implications in managing patients with frequent episodic migraine. Both medications were well tolerated, and there was little evidence that either product resulted in MOH.

Table 5. Migraine Severity – Treatment vs 2 Hours
 Group A – SumaRT/NapGroup B – NaproxenGroup A vs Group B
Treatment2 HoursP valueTreatment2 HoursP valueP value
  1. *Time of treatment vs 2 hours post-treatment pain severity P ≤ .05; **Group A vs group B – time of treatment vs 2 hours post-treatment P ≤ .05.

Baseline1.871.16.0008*1.791.21.0013*.4843
Month 11.860.96.0004*1.581.19.1069.1131
Month 21.810.79.0001*1.521.05.0038*.0331**
Month 31.800.64<.0001*1.621.20.0829.0100**

Statement of Authorship

  1. Top of page
  2. Abstract
  3. Study Design
  4. Study Population
  5. Study Medication
  6. Study Procedures
  7. Results
  8. Discussion
  9. Conclusion
  10. Acknowledgment
  11. Statement of Authorship
  12. References

Category 1

  • (a)
    Conception and Design
    Roger Cady, Fred Freitag, Phillip O'Carroll
  • (b)
    Acquisition of Data
    Roger Cady, Phillip O'Carroll, Fred Freitag, Kent Dexter
  • (c)
    Analysis and Interpretation of Data
    Roger Cady, Fred Freitag, Candace Shade

Category 2

  • (a)
    Drafting the Manuscript
    Roger Cady, Fred Freitag, Kent Dexter
  • (b)
    Revising It for Intellectual Content
    Roger Cady, Fred Freitag, Kent Dexter, Phillip O'Carroll, Candace Shade

Category 3

  • (a)
    Final Approval of the Completed Manuscript
    Roger Cady, Phillip O'Carroll, Kent Dexter, Fred Freitag, Candace Shade

References

  1. Top of page
  2. Abstract
  3. Study Design
  4. Study Population
  5. Study Medication
  6. Study Procedures
  7. Results
  8. Discussion
  9. Conclusion
  10. Acknowledgment
  11. Statement of Authorship
  12. References
  • 1
    Goadsby PJ, Ramadan NM. Potential new drugs for acute and prophylactic treatment of migraines. In: Olesen J , Goadsby PJ , Ramadan NM , Tfelt-Hansen P , Welch KMA , eds. The Headaches, 3rd edn. Philadelphia, PA: Lippincott, Williams & Wilkins; 2006:569-576.
  • 2
    Mathew NT, Kailasam J, Meadors L, Chernyschev O, Gentry P. Intravenous valproate sodium (Depacon) aborts migraine rapidly: A preliminary report. Headache. 2000;40:720-723.
  • 3
    Silberstein SD. Practice parameter: Evidence-based guidelines for migraine headache (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;55:754-762.
  • 4
    Silberstein SD. Migraine and medication overuse. In: Schoenen J , Dodick DW , Sandor PS , eds. Comorbidity in Migraine. Sussex, UK: Wiley-Blackwell; 2011:96-111.
  • 5
    Scher AI, Lipton RB, Stewart WF, Bigal M. Patterns of medication use by chronic and episodic headache sufferers in the general population: Results from the frequent headache epidemiology study. Cephalalgia. 2010;30:321-328.
  • 6
    Bigal ME, Serrano D, Buse D, Scher A, Stewart WF, Lipton RB. Acute migraine medications and evolution from episodic to chronic migraine: A longitudinal population based study. Headache. 2008;48:1157-1168.
  • 7
    Brandes JL, Kudrow D, Stark SR, et al. Sumatriptan-naproxen for acute treatment of migraine: A randomized trial. JAMA. 2007;297:1443-1454.
  • 8
    Winner P, Cady RK, Ruoff GE, et al. Twelve-month tolerability and safety of sumatriptan-naproxen sodium for the treatment of acute migraine. Mayo Clin Proc. 2007;82:61-68.
  • 9
    Lipton RB, Silberstein S, Dodick D, et al. Topiramate intervention to prevent transformation of episodic migraine: The topiramate INTREPID study. Cephalalgia. 2011;31:18-30.
  • 10
    Diamond S, Freitag FG, Diamond ML. Open-label trial of frovatriptan 2.5mg oral tablets in subjects with high frequency of migraine. Headache. 2008;48(Suppl 1):S50. Abstract#S27.
  • 11
    Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders. Cephalalgia. 2004;24(Suppl. 1):8-160.
  • 12
    Lipton RB, Cady RK, Farmer K. Bigal ME. Managing Migraine: A Healthcare Professional's Guide to Collaborative Migraine Care. Hamilton, ON: Baxter Publishing Inc.; 2008:26-27.
  • 13
    Silberstein SD, Olesen J, Bousser MG, et al; International Headache Society. The International Classification of Headache Disorders, 2nd Edition (ICHD-II)-revision of criteria for 8.2 Medication-overuse headache. Cephalalgia. 2005;25:460-465.
  • 14
    DeFelice M, Ossipov MH, Wang R, et al. Triptan-induced latent sensitization: A possible basis for medication overuse headache. Ann Neurol. 2010;67:325-337.
  • 15
    Göbel H, Stolze H, Heinze A Dworschak M. Easy therapeutic management of sumatriptan-induced daily headache. Neurology. 1996;47:297-298.
  • 16
    Bigal ME, Rapoport AM, Sheftell FD, Tepper SJ, Lipton RB. Transformed migraine and medication overuse in a tertiary headache centre-clinical characteristics and treatment outcomes. Cephalalgia. 2004;24:483-490.
  • 17
    Radat F, Creac'h C, Guegan-Massardier E, et al. Behavioral dependence in patients with medication overuse headache: A cross-sectional study in consulting patients using the DSM-IV criteria. Headache. 2008;48:1026-1036.
  • 18
    Holland S, Silberstein SD, Freitag F, et al; Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78:1346-1353.
  • 19
    Sheftell FD, Rapoport AM, Tepper SJ, Bigal ME. Naratriptan in the preventive treatment of refractory transformed migraine: A prospective pilot study. Headache. 2005;45:1400-1406.
  • 20
    Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E, Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Evidence-based guideline update: Pharmacologic treatment for episodic migraine prevention in adults: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78:1337-1345.
  • 21
    Rapoport AM, Bigal ME, Volcy M, et al. Naratriptan in the preventive treatment of refractory chronic migraine: A review of 27 cases. Headache. 2003;43:482-489.
  • 22
    Tzeng SF, Hsiao HY, Mak OT. Prostaglandins and cyclooxygenases in glial cells during brain inflammation. Curr Drug Targets Inflamm Allergy. 2005;4:335-340.
  • 23
    Klegeris A, McGeer PL. Non-steroidal anti-inflammatory drugs (NSAIDs) and other anti-inflammatory agents in the treatment of neurodegenerative disease. Curr Alzheimer Res. 2005;2:355-365.
  • 24
    Manack A, Buse DC, Serrano D, Turkel CC, Lipton RB. Rates, predictors, and consequences of remission from chronic migraine to episodic migraine. Neurology. 2011;76:711-718.
  • 25
    Diener HC, Limmroth V. Medication-overuse headache: A worldwide problem. Lancet Neurol. 2004;3:475-483.