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Keywords:

  • chronic migraine;
  • episodic migraine;
  • preventive treatment;
  • acute treatment

Abstract

  1. Top of page
  2. Abstract
  3. Study Design and Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgment
  8. Statement of Authorship
  9. References

Objective

To compare the use of a combination of 85 mg sumatriptan plus 500 mg naproxen sodium in a combination tablet with 500 mg naproxen sodium in an identically appearing tablet when used as a daily preventative and acute treatment for 1 month and episodic acute treatment for an additional 2 months in patients with chronic migraine.

Background

To date, there has been minimal study of acute medications for patients with chronic migraine. Consequently, there is a paucity of study methodology or evidence-based guidance on the use of acute treatment medications in patients with chronic migraine.

Methods

This two-center, double-blind, randomized, parallel-group, comparator pilot trial of 28 subjects, 18 to 65 years of age, with ICHD-II defined chronic migraine, was designed to generate hypotheses about the efficacy of 2 established acute migraine medications used both as a daily preventive treatment (month 1) and episodic acute treatment (months 1, 2, and 3). Subjects were randomized 1:1 to treat daily with SumaRT/Nap (85 mg sumatriptan + 500 mg naproxen sodium) (group A) or naproxen sodium (500 mg) (group B) in a prophylactic strategy for 1 month followed by 2 months of the same medications used for episodic acute treatment.

Results

The combination of SumaRT/Nap used over a 3-month period did not appear to significantly reduce the number of migraine headache days. In the subset of subjects using naproxen sodium and completing the study per protocol, there was a marked reduction in migraine headache days (P < .02 vs 0.25, respectively). Duration of migraine from treatment to pain free decreased in both groups, but was more robust in group B from baseline to month 3. Subjects in group B completing the study per protocol reported a 56% reduction in headache days vs 8% for group A. Subjects in group A and group B completing the study per protocol had considerably better 2-hour headache relief than subjects withdrawing early from the study. More subjects in group B prematurely withdrew from the study because of lack of efficacy (5 vs 1, respectively). Despite using significant quantities of acute medication during month 1, there was a reduction of acute medication in month 2 and 3 vs baseline vs month 1, particularly in the naproxen group.

Conclusion

A combination of SumaRT/Nap (group A) did not appear to reduce migraine headache frequency over a 3-month period. Subjects using naproxen sodium (group B) alone and completing the study per protocol had a marked statistically significant reduction in migraine headache days. Both groups completing the study per protocol had experienced clinically meaningful 2-hour headache relief. This suggests there may be a subset of patients with chronic migraine that are responsive to high doses of naproxen as an acute intervention with a significant prophylactic benefit. Subjects randomized to SumaRT/Nap experience benefit, primarily as an acute intervention. This hypothesis may warrant future larger scale clinical trials. Frequent dosing of SumaRT/Nap or naproxen sodium was well tolerated in this study.

Abbreviations
ANOVA

analysis of variance

CDH

chronic daily headache

CM

Chronic migraine

DHE

dihydroergotamine

EM

episodic migraine

ICHD-II

International Classification of Headache Disorders, 2nd edition

IHS

International Headache Society

MIDAS

Migraine Disability Assessment

MO

medication overuse

MOH

medication overuse headache

NSAE

nonserious adverse event

NSAID

non-steroidal anti-inflammatory drug

OTC

over-the-counter

SAEs

serious adverse events

SumaRT/Nap

sumatriptan and naproxen sodium

Chronic migraine (CM) is a relatively new construct in the taxonomy of primary headache disorders.[1] Criteria for CM were first created in the 2004 International Classification of Headache Disorders, 2nd edition (ICHD-II classification),[2] but revised in an appendix definition in 2006.[3] In June of 2013, ICHD III was released for comments. It includes important revisions of CM and medication overuse headache (MOH)[4] and specifically permits dual diagnosis of CM and MOH. This means that in patients with a history of episodic migraine experiencing 15 or greater days of headache per month and treating with quantities of medication in excess of defined limits of medication overuse will be diagnosed with 1.3 chronic migraine and 8.2 medication overuse headache until the offending drug has been reduced or eliminated. While this is an important advancement, it also suggests that that these diagnoses continue to be both allusive and inconclusive.

Migraineurs with CM or chronic daily headache (CDH) were excluded from regulatory trials of acute migraine medications. Consequently, there is a paucity of scientific evidence on efficacy or safety of acute migraine medications in this patient population. Complicating the taxonomy and acute treatment of CM is its relationship to medication overuse (MO) and medication overuse headache (MOH). There are legitimate concerns within the headache community that the too frequent use of many if not most acute treatment medications can transform episodic migraine into persistent and intractable CM. This iatrogenic cause of CDH in turn, increases disability and poses potential safety concerns for this patient population. Further, MOH is a secondary headache disorder and technically CM cannot be diagnosed until MOH (and any other secondary headache disorder) has been ruled out or appropriately managed. Consequently, disability can be sustained for many months as the potentially offending medication(s) are withdrawn without a clear endpoint of when frequent headaches within the migraine spectrum are no longer considered secondary to MOH.

Complicating matters even further is the recent acknowledgment that several triptans that are historically considered acute interventions, have Class A and/or B evidence for efficacy when used as a (short-term) prophylactic medication.[5] Thus, consider the confusion of the following scenario: a patient with CM is utilizing a daily triptan at the earliest onset of a headache and rarely experiences a headache lasting more than 1 hour. In the diary record, the frequency of migraine headache days (>4 hours a day of headache) decreases from 25 to 6 days a month over the previous 3 months. Is the triptan being used as an abortive or preventive treatment? The patient is using a triptan on greater than 10 days a month, but her headache pattern is improved. Is she diagnosed with MO? Does she now have episodic migraine (EM)? Is she in MOH despite her headache pattern improving?

An ideal acute treatment in CM would provide both sustained 2-hour headache relief and protect the nervous system from future migraine attacks. Acute medications with these attributes could potentially reduce the risk of MOH and likely provide synergistic benefit with other pharmacological and non-pharmacological prophylactic interventions.

This pilot study attempts to generate hypotheses for future study of acute treatment in CM by comparing the use of a combination of sumatriptan (85 mg) plus naproxen sodium (500 mg) vs naproxen sodium (500 mg) used in a unique treatment paradigm. During the first month of this study, these medications were utilized both as a daily preventative and if needed, a second dose could be utilized as acute treatment. During the subsequent 2 months, the study medication was used as acute treatment for up to 14 days per month. The primary endpoint of this study was a change in migraine headache days from baseline to month 3 of the study.

Study Design and Methods

  1. Top of page
  2. Abstract
  3. Study Design and Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgment
  8. Statement of Authorship
  9. 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 registered at ClinicalTrials.gov (NCT01090050) and sponsored by a grant from GlaxoSmithKline, Research Triangle Park, NC.

This is a two-center, double-blind, randomized, parallel-group, comparator pilot trial of 28 subjects, 18 to 65 years of age, with the ICHD-II appendix definition of CM.[3] 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. Randomization of subjects was accomplished by a supervisory individual, not associated with the study subjects or visits, numbering study medication in such a way that the medication was blinded to subjects, coordinators, and investigators. Subjects were provided with identical tablets containing either a combination of 85 mg of sumatriptan plus 500 mg of naproxen sodium or 500 mg of naproxen sodium.

Baseline

During a 1-month baseline period, subjects treated acute exacerbations of migraine with their current preferred acute treatment. Subjects could not have a history of MOH in the 3 months prior to enrollment in the study and were monitored closely for evidence of MOH throughout the study. Subjects and coordinators were provided education prior to study initiation designed to assess potential MOH, and subjects watched an instructional DVD about self-management of migraine and received a copy of the DVD with a list of educational websites, such as http://www.headaches.org, to use as support during the study.

Month 1

Following the baseline period, 28 of 56 screened individuals met diagnostic criteria for CM per diary analysis and were randomized 1:1 to daily SumaRT/Nap (group A) or naproxen sodium (group B) for 1 month as a preventative. During month 1, if subjects experienced an escalation of headache in the subsequent 24-hour period, they could repeat dosing with the study medication as an acute treatment provided there were at least 2 hours between doses.

Months 2 and 3

During months 2 and 3, subjects were provided 28 doses of medication each month for acute treatment of migraine with instruction to treat no more than 14 days per month and when possible treat early in the escalation of headache intensity. Subjects were allowed to take an additional dose of medication after 2 hours if they had not obtained adequate benefit from the first dose of study medication. Additional medications could be approved for use as a rescue treatment at the discretion of the investigator.

Study Population

Subjects were screened at headache specialty clinics and the general community population in Springfield, MO, and San Antonio, TX. 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 Randomization.com (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. History of CM according to the criteria defined in the appendix definition of CM proposed by the Headache Classification Committee of the IHS.
  3. Onset of migraine before age 50.
  4. Able to differentiate migraine from any other headache they may experience (eg, tension-type headache).
  5. Not currently taking a migraine preventive or has been taking preventive for at least 30 days prior to screening and agrees to continue medication without stopping, or changing the medication or dosage during the study period.
  6. If female of childbearing potential has a negative urine pregnancy test at visits 2-5 and uses, or agrees to use, for the duration of the study, one of the following medically acceptable forms of contraception as determined by the investigator.
    1. 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).
    2. Surgically sterile (hysterectomy or tubal ligation or otherwise incapable of pregnancy).
    3. Sterilization of male partner.
    4. Intrauterine device with published data showing lowest expected failure rate is less than 1% per year.
    5. Double barrier method (ie, 2 physical barriers or 1 physical barrier plus spermicide) for at least 1 month prior to visit 1 and throughout study.
    6. Hormonal contraceptives for at least 3 months prior to visit 1 and throughout study.
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 or retinal migraine.
  4. History of MOH in the 3 months prior to study enrollment or during the baseline period.
  5. Has abused, in the opinion of the investigator, any of the following drugs, currently or within the past year:
    1. opioids
    2. alcohol
    3. barbiturates
    4. benzodiazepine
    5. cocaine
  6. Unstable neurological condition or a significantly abnormal neurological examination with focal signs or signs of increased intracranial pressure.
  7. Suffers from cardiovascular disease (ischemic heart disease, including angina pectoris, myocardial infarction, documented silent ischemia, or with Prinzmetal's angina); has symptoms of ischemic heart disease; has uncontrolled hypertension; has electrocardiogram (ECG) results outside normal limits for clinically stable patients as judged by the investigator.
  8. History of hypersensitivity, intolerance, or contraindication with the use of sumatriptan or naproxen, any of its components, or any other nonsteroidal anti-inflammatory drug (NSAID) including aspirin and COX-2 inhibiting agents or has asthma and/or nasal polyps.
  9. History of peptic ulcer disease requiring therapeutic intervention in the year prior to study enrollment 0.10. History of bleeding disorder.
  10. History of NSAID induced gastritis, esophagitis, or duodenitis.
  11. Suffers from a serious illness, or an unstable medical condition that could require hospitalization, or could increase the risk of adverse events.
  12. Significant (as determined by the investigator) cardiovascular risk factors that may include uncontrolled high blood pressure, post-menopausal women, males over 40 years old, hypercholesterolemia, obesity, diabetes mellitus, smoking, or a family history of cardiovascular disease in a first degree relative.
  13. A psychiatric condition, in the opinion of the investigator that may affect the interpretation of efficacy and safety data or contraindicates the subject's participation in the study.
  14. Currently taking a migraine prophylactic medication containing an ergotamine or ergot derivative such as dihydroergotamine (DHE) or methysergide, monoamine oxidase inhibitors or any investigational agent within 30 days prior to visit 1.

Glossary of Predefined Terms

Baseline

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

Migraine Headache Day

A migraine headache day is defined as a day (00:00 to 23:59) with 4 or more hours of moderate headache, per subject diary, or any day with headache of any duration that was treated with a migraine specific medication.

Migraine Duration

Migraine duration was calculated from the time of treatment to the time of being headache free. Subjects were required to have been pain free for a minimum of 48 hours between headache days in order for a headache to be considered a new migraine attack. Duration was determined for each migraine separately and each subject's mean migraine duration. Thus, this endpoint reflected the hours of time subjects were experiencing the headache of migraine.

Medication Overuse (MO)

Specific quantities of acute medication defined by ICHD-II criteria as medication overuse.[2]

Medication Overuse Headache (MOH)

Worsening of underlying headache pattern associated with increasing utilization of acute medications and quantities defined by Revised Criteria for MOH.[6] In this study, the determination was made by primary and/or sub-investigators.

Primary Objectives

  1. Compare the percentage of change in the number of migraine headache days from baseline and the month 3 treatment period for subjects being treated with a combination of 85 mg sumatriptan/500 mg naproxen (SumaRT/Nap) (group A) or 500 mg naproxen sodium (group B).
  2. From baseline to month 1, the percentage of change in the number of migraine headache days using the study medications as a daily preventative treatment and acute intervention.

Secondary Objectives

  1. Change in the number of migraine headache days at each interim visit (treatment period months 1, 2, and 3) compared to baseline for group A and B.

    Baseline and Demographic Characteristics

    Number of PatientsTotalGroup AGroup B
    1. IHS = International Headache Society; CM = chronic migraine.

    First subject in 9/24/10   
    Screened56  
    Failed to meet inclusion/exclusion criteria8  
    Failed to meet IHS criteria for CM during baseline9  
    Lost to follow-up4  
    Withdrew due to personal issues, time requirement, did not want study med, sought other treatment6  
    Withdrew, reason unknown1  
    Randomized281612
    Did not complete study817
    Lost to follow-up1 1
    Lack of efficacy615
    Withdrew due to noncompliance1 1
    Completed study20155
    Last subject out 6/25/12   
  2. Change from baseline to months 2 and 3, the percentage of change in the number of migraine headache days using the study medications as an episodic acute treatment.
  3. Change in mean migraine duration from time of treatment to pain free comparing baseline to each study visit (treatment period months 1, 2, and 3) for groups A and B.
  4. Percent 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) for groups A and B.
  5. Change in total number of doses of acute treatment medications used at baseline to the number of doses of study medication used during months 1, 2, and 3 of the active phase of the study.
  6. Change in 2 hours headache relief scores for groups A and B.
  7. Compare mean Migraine Disability Assessment Test (MIDAS) scores at baseline (visit 2) and 3 months after baseline (visit 5) in groups A and B.
  8. Monitor the tolerability, adverse events, and safety of subjects enrolled in this study .

Statistical Analyses

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. The multiple phases of treatment, preventative and acute, also made it difficult to implement an intent-to-treatment model. A systematic way of adjusting for missing data such as last-observation-carried-forward or baseline-observation-carried-forward would have posed complications in addressing the various phases of treatment and decreased variability within the small sample size. Given the exploratory fashion, a per-protocol analysis was deemed appropriate and conducted to further minimize Type II error.

A mixed-design analysis of variance (ANOVA) with a within-subjects factor of month of treatment (baseline, month 1, month 2, and month 3) and a between-subject factor of treatment group (SumaRT/NAP, naproxen) was used to analyze data for statistical significance. Mean comparison of pairs was conducted by post-hoc analyses. Data were analyzed from the per-protocol population.

Results

  1. Top of page
  2. Abstract
  3. Study Design and Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgment
  8. Statement of Authorship
  9. References

Fifty-six subjects were screened for this study, satisfying the proposed sample size of 40 subjects. The study population consisted of 28 subjects who randomized per protocol; 6 males and 22 females with a mean age of 40.9 years and with a diagnosis of ICHD-II chronic migraine; 28 were Caucasian. During month 1 – preventative treatment phase, 20 subjects completed month 1 of the study: 15 in group A and 5 in group B. Two subjects withdrew during month 1 (one from group A and one from group B) both because of lack of efficacy. An additional 6 subjects in group B withdrew at visit 3 (the preventative phase of the study); 4 due to lack of efficacy, 1 lost to follow-up, and 1 due to lack of compliance. During months 2 and 3 – acute treatment phase, 20 subjects completed both months of the study; 15 of 16 in group A (SumaRT/Nap) and 5 of 12 in group B (naproxen sodium).

In both arms of the study, there was a reduction in headache days from baseline to month 1, 2, and 3. This reduction reached statistical significance for group A (SumaRT/Nap) only at month 1 for the per-protocol population. Statistical significance was observed for group B (naproxen sodium) for all 3 months compared to baseline and between groups, naproxen sodium was statistically superior to SumaRT/Nap for all 3 months for the per-protocol population (Fig. 1 —, Table 1). The duration of migraine from treatment to pain-free decreased in both treatment groups. In group B, there was a greater decrease in duration of migraine compared to those in group A (Fig. 2 —, Table 2).

Table 1. Migraine Headache Days 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/Nap18.9 (5.1)14.4 (7.9)18.0 (5.7)16.9 (6.6)0.0112**0.47720.2522
Group B – Naproxen16.4 (1.9)6.2 (4.0)8.4 (4.2)6.6 (4.2)0.0074**0.0415**0.0234**
P value A vs B0.30110.040*0.0028*0.0045*   
figure

Figure 1 —. Migraine headache days per month. *Group A vs Group B P .05. #Month vs Baseline P .05.

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figure

Figure 2 —. Migraine duration – treatment to pain free. *Baseline vs Month P .05. #Group A vs Group B P .05.

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Table 2. Migraine Duration – Treatment to Pain Free – Mean (StdDev)
 Group A – SumaRT/NapGroup B – NaproxenP value A vs B
  1. *Baseline vs Month P ≤ .05; **Group A vs Group B P ≤ .05.

Baseline157.73 (197.73)113.88 (119.78)0.3875
Month 191.95 (169.84)26.78 (26.04)0.1332
Month 298.84 (145.32)29.94 (36.47)0.0278**
Month 372.94 (135.31)21.09 (42.86)0.0810
P value BL vs M10.20730.0013* 
P value BL vs M20.25600.0007* 
P value BL vs M30.0350*0.0002* 

In group A, 3 of 15 subjects experienced a greater than 50% reduction in migraine headache days during months 1 and 3. A single subject in group A had a greater than 50% reduction in headaches/month for 2 of the 3 months of active study and none for all 3 months of the study. In group B, 4 out of 5 subjects experienced a greater than 50% reduction in migraine headaches days during months 1 and 3. During month 2, 3 out of 5 had a greater than 50% reduction in migraine headache days. Three of the 5 subjects had a greater than 50% reduction in migraine headache days for all 3 months of the active phases of the study (Fig. 3 —).

figure

Figure 3 —. Percentage of subjects with ≥50% reduction in number of migraine headache days. *Month vs Baseline P .05.

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Subjects completing the study per protocol had improvement in 2-hour headache relief for both group A and B during month 1. There was a numerically superior benefit for subjects in group B vs group A at 2 hours and a statistically significant benefit in favor of naproxen sodium at 8 hours vs SumaRT/Nap during the first month of the study when subjects were taking their study medication daily as a preventative. Subjects who withdrew prematurely from the study did not experience significant relief of headache until 8 hours post-dose, and at 8 hours their level of relief was inferior to those subjects completing the study per protocol.

During months 2 and 3, SumaRT/Nap was statistically superior to naproxen sodium (Fig. 4 —).

figure

Figure 4 —. Efficacy of acute intervention. *Group A vs early withdrawal P ≤ .05. #Group B vs early withdrawal P ≤ .05. †Group A vs B P ≤ .05. $Group A month 1 vs month 2, 3 P ≤ .05. ††Group B month 1 vs month 2, 3 P ≤ .05.

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At baseline, all doses of acute medication used during the 1-month run-in period were recorded and compared to study medications used in months 1 through 3. During baseline, subjects used their usual preferred medications, and nearly all subjects used more than one acute medication during the baseline period. The most common medications used were triptans and NSAIDs. Of the subjects randomized into the study, 12/20 (60%) subjects were using a triptan greater than 10 days and 2/20 (10%) were using an NSAID greater than 15 days during the baseline period. These subjects were technically in MO, but not experiencing a worsening of migraine and thus not considered to be in MOH. One subject was using an opioid for 8 days during that month.

During month 1, subjects were required to take study medication daily as a preventative, which increased the number of doses of medication used compared to baseline. Per protocol, subjects were permitted to take a second dose of study medication as needed for acute treatment. Subjects in group A took a second dose of medication more often than those in group B. During months 2 and 3, there was a reduction in doses of acute medication for both groups compared to baseline and month 1. The reduction in acute medication for group B was superior to group A for months 2 and 3 for subjects completing the study per protocol (Fig. 5 —).

figure

Figure 5 —. Medication utilization. #Group A vs Group B P .05. *Months vs baseline P ≤ .05. †Months 2 and 3 vs month 1 P ≤ .05.

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The percentage of subjects who fell under the definition of MO at the end of 3 months was 14/15 (93%) in group A (using a triptan 10 or more days per month) and 1/5 (20%) in group B (using a naproxen greater than 15 days per month).

Of the 26 subjects in the baseline population that were randomized, 3 had an increase in headache days in month 1 over baseline; 2 of these subjects decreased in headache days in months 2 and 3; the third persisted with daily headaches through baseline and all 3 months of active study and used study drug twice daily from randomization through month 3. The subject reported via diary that she was doing better and finding the medication helpful with her daily migraine. Post hoc review of this specific subject revealed use of any acute medication on only 4 days during baseline to treat daily CM. However, during the 3-month active phase of the study, this subject used SumaRT/Nap twice daily. The fact she had access to a medication that provided temporary headache relief likely accounted for her increased use rather than an abrupt escalation of her underlying migraine pattern. Other explanations such as stockpiling medications should also be considered. Given the definition of MOH is defined as escalation in migraine associated with increasing use of medication for greater than 3 months, it is difficult to define this patient as having MOH, but this diagnosis cannot be absolutely excluded either.

In terms of rescue medication beyond the study medication, during month 1, 7 subjects (2 in group A; 5 in group B) rescued with an antihistamine; 1 an over-the-counter (OTC) analgesic; 2 an opiate agonist. During month 2, 4 subjects (3 in group A; 1 in group B) rescued with an opiate agonist. During month 3, 5 subjects (4 in group A; 1 in group B) rescued with an OTC analgesic; 3 an opiate agonist; 1 a non-opioid analgesic. The same subject in group A used an opiate agonist as a rescue medication during all 3 months; 4 times in month 1; 6 times in month 2; and once in month 3.

There was substantial improvement in total overall MIDAS scores at baseline (visit 2) and at visit 5 for both groups in the per protocol population. The mean score for group A decreased from 76 to 56, whereas the mean score for group B decreased from 81 to 16 (Fig. 6 —).

figure

Figure 6 —. Migraine Disability Assessment Scores. *End of month 3 score vs end of baseline score P ≤ .05.

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There were 2 serious adverse events (SAEs) reported in this study, but neither was considered to be drug related (Table 3). In group B, one subject was hospitalized for cholecystitis, and another was hospitalized for menorrhagia. Each of the SAEs resolved and both subjects completed the study. Conceivably, menorrhagia could have been worsened by the use of high-dose naproxen sodium, but this was not felt to be the case by the investigator. Both active treatment medications used in the 2 groups were well tolerated. There was no significant difference in adverse events (AEs) between the groups.

Table 3. Nonserious Adverse Events
EventTotalGroup A – SumaRT/NapGroup B – Naproxen
No. of Subjects With EventNo. of Times Event ReportedNo. of Subjects With EventNo. of Times Event ReportedNo. of Subjects With EventNo. of Times Event Reported
Abdominal pain110011
Cholecystitis110011
Dizziness221111
Elevated blood pressure111100
Heartburn111100
Menorrhagia110011
Nausea with fatty foods111100
Right leg ulcer111100
Stomach burn110011

Non-Adverse Events

Total number affected by nonserious adverse event (NSAE) = 15 of 28 (54%)

Number affected by NSAE in group A = 9 of 16 (56%)

Number affected by NSAE in group B = 6 of 12 (50%)

Serious Adverse Events

Total number affected by SAE = 2 of 28 (7%)

Discussion

  1. Top of page
  2. Abstract
  3. Study Design and Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgment
  8. Statement of Authorship
  9. References

As a small exploratory pilot study, the results must be interpreted with caution and bear in mind the purpose of this study is to generate hypotheses for further study. It is also paramount to be cognizant of treatments deemed effective in EM cannot be assumed to be effective in CM. It is essential to understand that the evidence base for pharmacological treatment of CM is in its infancy.

The results of this study compared the effectiveness of two acute medications used daily and preventively for 1 month followed by using the same 2 acute medications to abort attacks for 2 months. In month 1, when the study medication was used as a daily preventive and, if needed, additionally as an acute intervention, there was a decrease in migraine headache days for both group A and B. The reduction in migraine headache days in the small number of subjects completing per protocol in group B was more robust than group A. In months 2 and 3, there was no evidence that the combination of SumaRT/Nap (group A) significantly decreased or increased the frequency of migraine days. However, a small group of subjects utilizing naproxen sodium alone (group B) and completing the study per protocol had a statistical significant reduction in migraine headache days that was profound and sustained. Group B also responded well to naproxen sodium as an acute treatment. The efficacy of naproxen sodium as a preventative was also supported by a decreased duration of migraine, reduction in migraine attacks, and a substantial reduction in MIDAS scores. Similar improvements were not observed in the SumaRT/Nap group.

Four of the 5 subjects in the naproxen sodium group completing the study per protocol reverted to treatable EM; the fifth subject had only 6 headache days during month 1 but returned to CM during months 2 and 3. Ironically, 5 of 12 subjects in group B withdrew due to lack of efficacy, and all did so in or at the month 1 visit. The group of subjects withdrawing early because of lack of efficacy did not respond well to naproxen sodium as an acute treatment (Fig. 4 —). This suggests the withdrawal for lack of efficacy was primary related to poor 2-hour headache relief. It may also suggest that the responder and poor responder populations might be separated from one another, early in an empirical trial of naproxen sodium.

Interestingly, during month 1, subjects taking a daily dose of study medications preventively appeared to respond to acute interventions better at 2 and 8 hours post treatment than subjects initiating acute treatment at the onset of headache escalation during month 2 and 3. This may suggest that a daily dose of study medication improves response to acute treatment, at least for those subjects completing the study per protocol.

Group B experienced superior outcomes at 2 and 8 hours vs group A during month 1. However, during months 2 and 3, SumaRT/Nap provided better 2-hour headache relief than naproxen sodium. Subjects in groups A and B had a statistically superior response to acute interventions at 2 and 8 hours during month 1 than subjects withdrawing early from the study. This may in part account for their early withdrawal from the study.

A curious question arising from these data is why a subset of subjects in group A did not experience similar efficacy to that observed in group B despite both groups using similar quantities of naproxen sodium. The explanation for this observation is unclear. However, it is well accepted that when sumatriptan is used as a migraine abortive, it is associated with the transformation of EM into CM. Further, when it is used too frequently in patients with CM, they become more intractable to treatment.[7, 8] In addition, repetitive exposure to triptans in rats has been observed to induce neural adaptations resulting in a state of latent sensitization in dural afferents.[9] NSAIDs on the other hand have been associated with a decreased risk of MOH when used up to 10 days per month.[10] In other neuro-inflammatory disease states such as Alzheimer's and Parkinson's disease, NSAIDs have been demonstrated to have a neuroprotective role.[11, 12]

Perhaps in subjects with CM, sumatriptan inhibits the potential benefit of naproxen sodium to decrease migraine headache frequency at least for some subjects. Conversely, one might argue that the inclusion of naproxen sodium with sumatriptan may inhibit further migraine chronification associated with frequent triptan use when used as a single abortive agent. If these observations are confirmed, they may have implications for the prevention and treatment of CM.[13]

Another important consideration in this study is that despite subjects provided sufficient quantities of acute medications that exceeded the defined limits of MO, there was little indication of transformation to MOH. In the entire study population, 2 of the 3 subjects in group A utilized their allotted monthly quantities of acute medications in month 1, but then decreased medication usage in months 2 and 3. As described earlier, only a single subject used all the study medication throughout months 1, 2, and 3 of the study. In group B, no subject utilized their allotted monthly quantity of naproxen sodium through all 3 months of the study.

Historically, the value of acute therapy has been measured in headache relief in 2 hours, while the value of prophylactic medications is measured over months in a reduction of migraine frequency. Anticipation of clinical outcome may bias the meaningful attributes of treatment especially when pejorative outcomes such as MO or MOH are linked to medications defined as acute therapies. Ironically, if a prophylactic medication provided an initial positive response for a patient, but later the patient's migraine frequency worsened despite increasing the dosage of that specific prophylactic medication, most headache specialists would consider this as a medication failure not MOH. However, if an acute medication is being used more frequently to provide relief of frequent migraine, clinicians clinically often consider it as the “causative” factor for MOH (though causation is in ICHD-II standards). Further, some studies have suggested that frequent acute medications improve headache outcome,[14] and others have suggested NSAIDs have a protective benefit and reduce the risk of chronification when used at a frequency up to 12 days per week. However, the ICHD-III defines MOH secondary to NSAIDs with a frequency of greater than 15 days per month. This ICHD-III definition is defined by consensus and not evidence. Further, it should be noted the quantity limits provided by the epidemiological study by Bigal et al did not account for concomitant use of triptans and NSAIDs. Thus, there may be a need to better define the role of NSAIDs in MOH and protection from migraine chronification. Perhaps consideration of an adaptive clinical strategy using NSAIDs daily as a daily initial treatment for a month to reduce headache frequency and then adding triptans secondarily as episodic acute treatment to capitalize on improved 2-hour efficacy in subsequent months might be considered in future studies. Clearly, furthermore rigorous studies are required to understand the appropriate use of acute interventions in CM.

There are numerous and significant limitations to this study. The most obvious is the small sample size of subjects completing the study per protocol and the high dropout rate in group B (naproxen sodium group). Another potential limitation is the fact that patients were not naive to the study medications, which may have compromised the blinding of the study medication, and this too could have been a possible factor in the high dropout rate for naproxen sodium. In this study, subjects were surveyed at discharge and 45% (9/20) correctly identified the medication they were taking, which is close to random guessing. However, assuming this did unblind the study and might in part explain the high early dropout rate in group B, it is not a likely explanation for the efficacy in those subjects completing the study per protocol. Regardless, blinding will be an issue for future studies of acute medications in CM, as subjects will undoubtedly have tried most acute treatments before evolving into a diagnosis of CM. Another limitation might be that patients entering the study were overusing acute medications prior to and during the baseline period and were in unrecognized MOH. When randomized to the active phase of the study, those in group B eliminated triptans, and this may have improved their migraine frequency. In the naproxen sodium group (group B), 4 out of 5 subjects (80%) used more than 10 doses of triptans during baseline. In the group randomized to SumaRT/Nap (group A), 53% (8/15) were taking triptans during baseline more than 10 days per month.

It is possible that stopping triptan usage in group B was a factor in the observed reduction in migraine frequency and the continuation of a triptan in group A largely nullified the benefit of naproxen sodium. It should be noted that subjects were not judged as being in MOH prior to randomization, and response to naproxen sodium was early in month 1 and without evidence of “rebound headache” or a temporary worsening of underlying migraine.

Conclusion

  1. Top of page
  2. Abstract
  3. Study Design and Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgment
  8. Statement of Authorship
  9. References

Small underpowered studies and even case reports have often provided insights and solutions for patients seeking relief of migraine. While it is unwarranted to suggest this study will do either, it is warranted to suggest these data support a hypothesis that there might be a differential response for naproxen sodium and SumaRT/Nap in treatment attributes as described in this study for subjects with CM. Numerous questions for future investigations are raised:

  1. Why didn't subjects using SumaRT/Nap and receiving essentially the same dose of naproxen sodium have as meaningful a benefit in reducing migraine headache days as the group using naproxen sodium only?
  2. Is there a subpopulation of chronic migraineurs that responds in a unique and positive manner to high doses of naproxen sodium?
  3. Why was MOH not more readily apparent when subjects had access to significant quantities of acute medication?

If this study has one conclusion it is how little we actually know and what a wonderful opportunity exists to advance the field of CM. Hopefully this study might support further research and understanding of acute treatment in CM.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Study Design and Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgment
  8. Statement of Authorship
  9. References

The authors wish to acknowledge Rebecca Browning for her statistical input.

Statement of Authorship

  1. Top of page
  2. Abstract
  3. Study Design and Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgment
  8. Statement of Authorship
  9. References

Category 1

  • (a)
    Conception and Design
    Roger Cady, Fred Freitag
  • (b)
    Acquisition of Data
    Roger Cady, Kent Dexter, Robert Nett, M.E. Beach
  • (c)
    Analysis and Interpretation of Data
    Roger Cady, Fred Freitag, M.E. Beach, Heather Manley

Category 2

  • (a)
    Drafting the Manuscript
    Roger Cady, Fred Freitag
  • (b)
    Revising It for Intellectual Content
    Roger Cady, Fred Freitag, Kent Dexter, Heather Manley, M.E. Beach

Category 3

  • (a)
    Final Approval of the Completed Manuscript
    Roger Cady, Fred Freitag, Kent Dexter, Robert Nett, M.E. Beach, Heather Manley

References

  1. Top of page
  2. Abstract
  3. Study Design and Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgment
  8. Statement of Authorship
  9. References
  • 1
    Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia. 1988;8(Suppl. 7):1-96.
  • 2
    Headache Classification Committee of the International Headache Society. The international classification of headache disorders. Cephalalgia. 2004;24(Suppl. 1):1-160.
  • 3
    Headache Classification Committee; Olesen J, Bousser MG, Diener HC, et al. New appendix criteria open for a broader concept of chronic migraine. Cephalalgia. 2006;26:742-746.
  • 4
    Headache Classification Committee of the International Headache Society (IHS). The international classification of headache disorders, 3rd edition (beta version). Cephalalgia. 2013;33:609-808.
  • 5
    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.
  • 6
    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.
  • 7
    Limmroth V, Katsarava Z, Fritsche G, Przywara S, Diener HC. Features of medication overuse headache following overuse of different acute headache drugs. Neurology. 2002;59:1011-1014.
  • 8
    Katsarava Z, Muessig M, Dzagnidze A, Fritsche G, Diener HC, Limmroth V. Medication overuse headache: Rates and predictors for relapse in a 4-year prospective study. Cephalalgia. 2005;25:12-15.
  • 9
    DeFelice M, Ossipov MH, Wand R, et al. Triptan-induced latent sensitization: A possible basis for medication overuse headache. Ann Neurol. 2010;67:325-337.
  • 10
    Bigal ME, Serrano D, Buse D, Scher A, Stewart WF, Lipton RB. Migraine medications and evolution from episodic to chronic migraine: A longitudinal population based study. Headache. 2008;48:1157-1168.
  • 11
    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.
  • 12
    Tzeng SF, Hsiao HY, Mak OT. Prostaglandins and cyclooxygenases in glial cells during brain inflammation. Curr Drug Targets Inflamm Allergy. 2005;4:335-340.
  • 13
    Peterlin BL, Calhoun AH, Siegel S, Mathew NT. Rational combination therapy in refractory migraine. Headache. 2008;48:805-819.
  • 14
    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.