Brief Communication
`
`Naratriptan in the Preventive Treatment of Refractory
`Chronic Migraine: A Review of 27 Cases
`
`Alan M. Rapoport, MD; Marcelo E. Bigal, MD, PhD; Michel Volcy, MD;
`Fred D. Sheftell, MD; Michele Feleppa, MD: Stewart J. Tepper, MD
`
`Objective. -To review the efficacy of naratriptan as preventive treatment in 27 patients with chronic migraine
`refractory to other commonly used preventive therapies.
`Background. -The treatment of chronic migraine often poses a major challenge to the clinician. Even when
`given expert care, patients with chronic migraine may continue to have daily or near -daily headaches.
`Methods. -Clinical records and headache calendars were reviewed of 27 patients fulfilling the following in-
`clusion criteria: (1) aged 18 to 65 years; (2) diagnosis of chronic migraine (formerly transformed migraine), ac-
`cording to the criteria proposed by Silberstein et al; (3) previous failure of at least 4 preventive medications pre-
`scribed as part of a management program that included nonpharmacological measures, preventive medication,
`acute care medication, and detoxification from overused medication; and (4) have used daily naratriptan for no
`less than 2 consecutive months. The dose of naratriptan prescribed was 2.5 mg twice daily. We considered the fol-
`lowing outcomes: (1) frequency of headache, (2) intensity of pain, (3) number of days per month with severe head-
`ache, (4) headache index (frequency times intensity), and (5) proportion of patients who reverted to an episodic
`pattern of pain after 6 months of treatment.
`Results. -There was a statistically significant reduction in the frequency of headache days 2 months (15.3
`days versus 24.1 days at baseline, P <.001), 6 months (9.1 days, P <.001), and 1 year (7.3 days, P <.001) after daily
`treatment with naratriptan was initiated. There was also a statistically significant reduction in the number of days
`per month of severe pain at 1 month (5.6 days versus 12.5 days at baseline, P <.O1), 2 months (5.7 days, P <.01), 6
`months (2.8 days, P <.01), and 1 year (2.6 days, P <.01). Similarly, there was a statistically significant reduction in
`the headache index at 2 months (33 versus 56.4 at baseline, P <.001), 6 months (19.5, P <.001), and 1 year (17.2,
`P <.001).
`Of the 20 patients who continued to use naratriptan daily for at least 6 months, 13 (65 %) reverted to an epi-
`sodic pattern of pain (migraine). At 1 year, 11 (55 %) still continued to experience episodic headache, 1 (5 %) re-
`lapsed to chronic migraine, and 2 (1O %) were lost to follow -up. No patients had intolerability to naratriptan dur-
`ing the treatment period, and no one stopped treatment due to adverse events.
`Conclusion.-Naratriptan may have a role in the preventive treatment of intractable chronic migraine. Pro-
`spective, controlled studies should be considered.
`Key words: chronic migraine, chronic daily headache, transformed migraine, naratriptan, preventive treatment,
`prophylactic treatment
`
`Abbreviations: CDH chronic daily headache, CM chronic migraine
`(Headache. 2003;43:482-489)
`
`From the Department of Neurology, Columbia University College of Physicians and Surgeons, New York, NY (Dr. Rapoport);
`The New England Center for Headache, Stamford, Conn (Drs. Rapoport, Bigal, Sheftell, and Tepper); the Department of Neurol-
`ogy, Albert Einstein College of Medicine. Bronx, NY (Dr. Bigal); the Department of Neurology, University of Antioquia, Medel-
`lin, Colombia (Dr. Volcy); and Primario Unita Operativa di Neurologia e Neurofisiopatologia, A. O. G. Rummo, Benevento, Italy
`(Dr. Feleppa).
`
`Address all correspondence to Dr. Alan M. Rapoport, 778 Long Ridge Road, Stamford, CT 06902.
`
`Accepted for publication December 29, 2002.
`
`482
`
`Lilly Exhibit 1294
`Eli Lilly & Co. v. Teva
`Pharms. lnt'1 GMBI -I
`
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`483
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`Chronic daily headache (CDH), usually defined
`as headache which occurs more than 15 days a month
`(or 180 days a year) for more than 4 hours a day, is
`one of the more frequently seen headache syndromes
`at major tertiary care centers worldwide.'-3 Its preva-
`lence is almost 5% in the general population.4 -5
`Chronic migraine (CM) is the most common form of
`CDH.2.30 This disorder has been variously called
`transformed migraine, evolutive migraine, or mixed
`headache syndrome. Patients with CM usually have a
`past history of episodic migraine, reporting a process
`of transformation characterized by headaches that
`become more frequent over months to years, with the
`pain intensity and associated symptoms becoming
`less severe.' Such patients often develop a pattern of
`CDH that phenomenologically may resemble chronic
`tension -type headache with attacks of typical mi-
`graine superimposed.' They often have headaches 28
`days or more per month.9
`The treatment of CM often poses a major chal-
`lenge to the clinician. It requires a multidisciplinary
`approach, employing behavioral medicine
`tech-
`niques, daily preventive and appropriate acute care
`medications, and partial or full withdrawal of any
`acute care medication that is being overused. To a
`great extent, treatment success depends upon the med-
`ications used, singly or in combination. Even with ex-
`pert care, a significant percentage of these patients still
`persist with daily or near -daily headaches.1 °-'3
`The triptans represent a benchmark in the acute
`treatment of migraine. Their mechanism of action is
`based on the stimulation of specific serotonin (5 -hy-
`droxytryptamine [5 -HT]) receptors, including periph-
`eral ,B and central and peripheral ID subtypes.14 The
`oral triptans can be divided into two groups. Group 1
`consists of those with faster onset and higher potency:
`sumatriptan, zolmitriptan, rizatriptan, almotriptan, and
`eletriptan. Group 2 consists of the slower -onset oral
`triptans with lower overall potency, lower rates of
`early headache recurrence, and a more favorable side
`effect profile: naratriptan and frovatriptan.15 -'9
`Naratriptan was the third selective 5- HT1B D ago -
`nist to be introduced in the United States for the
`acute treatment of migraine. In a previous study by
`Sheftell et al, three patients with CM previously re-
`fractory to a wide variety of traditional preventive
`
`pharmacologic and nonpharmacologic interventions
`experienced a remarkable reduction in the frequency
`and intensity of daily headache while receiving pre-
`ventive treatment with daily naratriptan.20 Subjective
`improvement in quality of life and restoration of nor-
`mal functioning (including a decrease in missed work-
`days) also was reported by those patients.
`The aim of this study was to review retrospec-
`tively the efficacy of naratriptan in the preventive
`treatment of 27 patients with CM refractory to other
`standard preventive medications.
`
`METHODS
`This study was performed at The New England
`Center for Headache (NECH), Stamford, Conn.
`Clinical records and headache calendars (diaries)
`were reviewed of 27 patients fulfilling the following
`inclusion criteria: (1) aged 18 to 65 years; (2) diagno-
`sis of CM (formerly transformed migraine) according
`to the criteria proposed by Silberstein et a121 (Table
`1); (3) previous failure of at least 4 preventive medi-
`cations prescribed as part of a management program
`included nonpharmacological measures and
`that
`detoxification trials; (4) daily use of naratriptan for
`no less than 2 consecutive months; and (5) stable
`dose of medication used to prevent CM in the last 2
`months.
`The decision to use naratriptan in the patients
`presented was based on their refractoriness to other
`preventive therapies (alone and in combinations), as
`
`Table 1.- Proposed Revision to International Headache
`Society (IHS) Criteria for Transformed Migraine21
`
`A. History of episodic migraine meeting any IHS criteria 1.1
`to 1.6
`B. Daily or almost daily ( >15 days /month) head pain for >1
`month
`C. Average headache duration of 4 hours /day (if untreated)
`D. History of increasing headache frequency with decrease in
`severity of migrainous features over at least 3 months
`E. At least one of the following:
`1. There is no suggestion of one of the disorders listed in
`groups 5 -11
`2. Such disorder is suggested, but is ruled out by
`appropriate investigation
`3. Such disorder is present, but first migraine attacks do
`not occur in close temporal relation to the disorder
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`May 2003
`
`well as on the good results obtained in three previous
`patients followed in the same headache center (not
`included in this study).2° Patients were enrolled in this
`study no less than 6 months after they had tried and
`failed a headache management program. Patients
`were formally informed that daily dosing of a triptan
`was an "out -of- label" use, that this was an experi-
`mental treatment and certain risks would be under-
`taken, and were included after informed consent.
`Once the patient decided to participate in the
`study, all preventive drugs were stabilized and naratrip-
`tan 2.5 mg twice daily was added. The medication was
`often begun at one half tablet in the morning and in-
`creased every 3 days by half a tablet until the final
`dose of one tablet twice per day was attained. Head-
`ache calendars were reviewed and the parameters of
`the month immediately previous to the naratriptan
`prescription were considered as the baseline. For ex-
`tremely severe breakthrough headaches, occasional
`use of fast -onset triptans was permitted (after careful
`explanation that this was an off -label use, and in-
`creased the risk of cardiovascular adverse effects).
`We considered the following outcomes: (1) fre-
`quency of pain; (2) intensity of pain, measured on a
`scale ranging from 0 (no pain) to 3 (severe pain); (3)
`number of days with severe headache per month; (4)
`headache index (frequency times intensity); and (5)
`proportion of patients that reverted to an episodic
`pattern of pain after 6 months of treatment. The out-
`comes from numbers 1 through 4 were compared to
`the baseline period after 1 month, 2 months, 6 months,
`and 1 year.
`Descriptive statistics were applied. The assump-
`tion was that the values were sampled from Gaussian
`distributions and tested using the normality test of
`Kolmogorov- Smirnov. Matched comparisons in non -
`parametric distributions were performed using the
`Friedman test with posttest. Nonmatched compari-
`sons in nonparametric distributions were performed
`using the Kruskal- Wallis test with posttest.
`
`RESULTS
`Our sample consisted of 27 patients, 20 (74.1%)
`of whom were women. Ages ranged from 18 to 64
`years, with a mean age of 44.5 years (standard devia-
`tion [SD], 12.0; 95% confidence interval [CI], 42.8 to
`
`52.3). All patients were followed for at least 1 year
`after being given naratriptan. The average length of
`treatment at The NECH, for these patients, was 5.3
`years.
`Prior to their first visit to the center, 24 patients
`(88.9 %) had taken at least 1 preventive drug (Table
`2). At The NECH, all patients were submitted to an
`optimized approach to CM that included nonpharma-
`cological techniques, detoxification when the patient
`was overusing acute medications, and a regimen of
`preventive medication. The number of preventive
`drugs tried before inclusion in the naratriptan study
`ranged from 4 to 21 (average of 7.2). When included,
`14 patients (51.8 %) were using 1 preventive drug, 12
`(44.4%) were using 2 preventive drugs, and 1 (3.7%)
`was using 3 different preventive drugs. At the mo=
`ment of inclusion in the study, 13 patients (43.1%)
`were overusing acute care medications; despite the
`previous attempts at detoxification. Four (14.8 %)
`were overusing butalbital compounds; 4 (14.8 %), acet-
`aminophen combined with acetylsalicylic acid (ASA)
`and caffeine; 2 (7.4 %), opioids; 2 (7.4 %), nonste-
`roidal anti -inflammatory drugs (NSAIDs); and 1
`(3.7 %), ASA.
`Of the 27 patients who completed the evaluation
`at 2 months (criteria of inclusion), 20 (74.1%) continued
`to use naratriptan after 6 months and 18 (66.7 %) after 1
`year of inclusion. All the patients who stopped using
`naratriptan except 1 were acute medication overusers.
`At inclusion, 13 (43.1 %) of 27 were overusing
`acute care medications. At 6 months, 6 (30 %) of 20;
`at 1 year, 5 (27.8 %) of 18. These differences are not
`statistically significant.
`
`Table 2.- Pharmacologic Classes of Preventive Drugs
`Used by Patients Prior to Admission to Headache Center
`
`Pharmacologie Class
`
`Beta -blockers
`Tricyclic antidepressants
`Selective serotonin reuptake inhibitors
`Anticonvulsants
`Calcium -blockers
`Serotonin agonists
`
`No. ( %) of
`Patients
`
`21 (77.8)
`15 (55.6)
`10 (27.3)
`10 (27.3)
`6 (22.2)
`2 (7.4)
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`Baseline
`
`1 month ®2 months 06 months 01 year
`
`Fig. 1.- Comparison of the frequency of pain at baseline and after the start of daily naratriptan, overall and by groups of overusers
`and non -overusers of acute medication. * * *P <.001 compared to baseline. +P <.05 versus 1 month. + +P<.01 versus 1 month.
`
`Figure 1 compares the frequency of headache at
`baseline and after initiation of naratriptan therapy in
`those patients who 'were overusers and non -overusers
`of acute medications and overall. Overall, a statisti-
`cally significant reduction of headache frequency was
`obtained in 2 months (15.3 days versus 24.1 days at
`baseline, P <.001), 6 months (9.1 days, P <.001), and 1
`year (7.3 days, P<.001). Statistical significance also was
`reached between 6 months (9.1) and 1 month (19.7)
`(P <.05) and between 1 year (7.3) and 1 month (19.7)
`(P <.01). The same pattern was obtained in the over -
`user and non -overuser subgroups.
`The mean number of severe attacks per month is
`presented in Figure 2. Overall, a significant reduction
`compared to baseline (12.5) was obtained in 1 month
`(5.6, P <.01), 2 months (5.7, P <.01), 6 months (2.8,
`P <.01),. and 1 year (2.6, P <.01). The same pattern
`was verified in the overuser and non -overuser sub-
`groups, the response being more evident in the non -
`overuser subgroup.
`Figure 3 displays the headache index. Similar to
`the outcome frequency, a statistically significant re-
`duction of the headache index was obtained in 2
`
`months (33.0 versus 56.4 at baseline, P <.001), 6
`months (19.5, P <.001), and 1 year (17.2, P <.001). Sta-
`tistical significance also was reached between 6 months
`(19.5) and 1 month (42.2, P <.05) and between 1 year
`(17.2) and 1 month (42.2, P <.01). Again, the same pat-
`tern was obtained in both subgroups.
`Of the 20 patients who continued to use naratrip-
`tan daily after 6 months of inclusion, 13 (65 %) re-
`verted to an episodic pattern of pain (migraine). At 1
`year, 11 (55 %) still continued to experience episodic
`headaches, 1 (5 %) relapsed to CM, and 2 (10 %) were
`lost to follow -up.
`No patients were intolerant to naratriptan during
`the treatment period, and no one stopped treatment
`due to adverse events. There were no increased ad-
`verse effects to the occasional use of faster - acting
`triptans for severe breakthrough headache.
`
`COMMENTS
`Chronic migraine is the most frequently encoun-
`tered headache syndrome at major tertiary care
`headache centers and, as reflected by their Migraine
`Disability Assessment (MIDAS) scores, patients with
`
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`
`14
`
`12 -
`
`4
`
`2
`
`0
`
`* *+
`
`r;
`
`Overusers
`
`Nonoverusers
`
`Overall
`
`Baseline
`
`1 month 02 months 06 months 01 year
`
`Fig. 2.- Comparison of the mean number of days per month with severe pain at baseline and after the start of daily naratriptan,
`overall and by groups of overusers and non -overusers of acute medication. *P <.05 compared to baseline. * *P <.01 compared to
`baseline. +P <.05 compared to 1 month.
`
`3.- Comparison of the headache index at baseline and after the start of daily naratriptan, overall and by groups of over -
`users and non -overusers of acute medication. *"P <.001 compared to baseline. +P <.05 versus 1 month. + +P<.01 versus 1
`month.
`
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`

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`487
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`chronic migraine suffer significant functional impair -
`ment.9,22 -24
`Most patients with CM benefit to some degree
`from treatment, but those suffering from long -dura-
`tion CM can be very difficult to treat, especially when
`the disorder is complicated by medication overuse,
`comorbid medical disease, low frustration tolerance,
`depression and anxiety, and physical and emotional
`dependence.' 25 27 There is a subgroup of patients who,
`despite optimal care, will persist in a pattern of daily
`or near -daily headache and often overuse acute care
`medications.
`There are few studies that have addressed the
`preventive treatment of CM, and most published re-
`ports are anecdotal. In an open -label trial, Mathew
`and Ali assessed the possible benefits of sodium val-
`proate in consecutive patients with CDH who were re-
`fractory to multiple standard treatments.28 Fifty -five
`percent responded positively, and 10% discontinued
`medication due to side effects. Shuaib et al treated 37
`patients with refractory migraine or CDH with topira-
`mate in an open -label study.29 Thirty percent enjoyed
`an excellent response, and 30% had a less pronounced
`but still positive response. The prevention of CDH with
`botulinum toxin type A, zonisamide, tizanidine (in a
`double -blind study), and quetiapine recently has been
`studied.3 °-33 The reduction in headache frequency was
`30% at 1 month in patients treated with tizanidine
`and 37% at 3 months in patients treated with zonisa-
`mide.31,32 In our patients treated with daily naratrip-
`tan, we found a reduction of 36.5% at 2 months. The
`reduction of the headache index at 1 month in pa-
`tients treated with tizanidine was 54% and 65% at 3
`months in patients treated with zonisamide.3',32 We
`found a 41.5% reduction in the headache index at 2
`months, 65.4% at 6 months, and 69.5% at 1 year.
`Although this may be the first article to suggest
`that naratriptan may be used in the long -term pre-
`ventive treatment of CM, "mini- prophylaxis" with
`naratriptan has been investigated and reported upon.
`A short course of daily naratriptan may be used as an
`adjunctive therapy in the process of detoxification of
`patients with CDH and overuse of acute medication.
`In one study, such patients treated with daily naratrip-
`tan experienced a reduction in headache frequency
`and intensity and an improvement in quality of life.34
`
`Mini -prophylaxis with naratriptan also may be effec-
`tive in women with menstrual migraine.35 -37
`Several methodologic flaws limit the conclusions
`that may be drawn from our results. First, this was a
`retrospective study, open label, and neither placebo
`controlled nor blinded. Second, only patients with
`very refractory CM were included, perhaps skewing
`our results towards a less positive outcome. Third,
`the study measured neither the disability nor the
`quality of life of our patients and did not make any
`attempt to assess the cost -effectiveness of the treat-
`ment. Fourth, some of the patients stopped overusing
`acute care medication during the study, and at least a
`portion of the benefit they received reasonably could
`be attributed to analgesic discontinuation rather than
`naratriptan alone. Finally, since some patients were
`expected to have difficulty obtaining reimbursement
`for their medication, compliance was perceived as a
`potential problem. To counter this, we decided to an-
`alyze just patients who used daily naratriptan for at
`least 2 months, an approach that may have biased the
`tolerability analysis. Moreover, despite assessment of
`tolerability, the safety of the chronic utilization of
`naratriptan was not evaluated uniformly by subsid-
`iary examinations and laboratory tests.
`The results of this study suggest that naratriptan
`should be considered as a potential preventive treat-
`ment for refractory CM.
`Acknowledgments: This study was conducted with-
`out financial support.
`
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