Lysine clonixinate vs naproxen sodium for the acute treatment of migraine a double blind, randomized, crossover study

2/21/2017 Lysine Clonixinate vs Naproxen Sodium for the Acute Treatment of Migraine: A DoubleBlind, Randomized, Crossover StudyLysine Clonixinate vs Naproxen Sodium for the Acute Treatm

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2/21/2017 Lysine Clonixinate vs Naproxen Sodium for the Acute Treatment of Migraine: A DoubleBlind, Randomized, Crossover Study

Lysine Clonixinate vs Naproxen Sodium for the Acute Treatment of Migraine: A Double-Blind, Randomized,

Crossover Study

Abouch Valenty Krymchantowski, MD, MSc, PhD, Coordinator; Director, Patrícia Peixoto, MD, Staff Physician, [ ], and Vivian Schutz, RN, Staff

Nurse

Abstract and Introduction

Abstract

Background and Objectives The process of inflammation is crucial in migraine, and several nonsteroidal antiinflammatory drugs (NSAIDs) are

effective in the treatment of migraine attacks. Despite their efficacy, the routine use of NSAIDs is limited by side effects as well as incomplete

efficacy in some patients. Among the available options, lysine clonixinate (LC) and naproxen sodium (NS) have proved effective in migraine. The

aim of this study was to compare the efficacy and tolerability of oral formulations of LC and NS in the treatment of moderate or severe migraine

attacks, with a doubleblind, crossover design

Methods Seventy subjects (62 women, 8 men) between ages 18 and 71 years (mean age, 41) with migraine according to the criteria of the

International Headache Society were prospectively enrolled. The patients were randomized into 2 groups and each participant treated 2 migraine

attacks. Group 1 treated the first attack with LC and the second attack with NS. Group 2 treated 2 attacks in a counterbalanced order. Doses were

250 mg of LC or 550 mg of NS, which were encapsulated for equal appearance. Headache intensity, nausea, photophobia, and side effects were

evaluated at baseline, 1 hour, and 2 hours after drug administration. Rescue drugs were allowed after 2 hours for those who didn't respond, and this

was also compared between groups

Results Sixty patients (54 women, 6 men) completed the study. At 1 hour, 13.6% patients who used LC were painfree compared with 11.9% who

used NS (P = .78). At 2 hours, 35.6% patients who took LC and 32.2% who took NS were painfree (P = .69). At baseline, 52.5% of the patients

randomized to group 1 reported nausea, compared with 33.9% in group 2, and both drugs eliminated nausea: At both 1 hour and 2 hours, nausea

diminished significantly for those taking LC, but only after 2 hours for those who took NS (P < .0001). Both drugs eliminated photophobia at 1 hour

and 2 hours; however, LC was superior to NS in reducing photophobia at 2 hours (P = .027). Ten patients who took LC and 8 who took NS required

rescue drugs after 2 hours. Twelve patients who used LC and 16 who took NS reported side effects

Comments Although this study did not include a placebo arm, which impairs any definitive efficacy claims, we found LC and NS to be similarly

effective and well tolerated in patients presenting moderate or severe attacks of migraine

Introduction

Migraine is a highly prevalent neurologic disorder that typically manifests as moderate or severe intermittent headache attacks with associated

symptoms.[1–3] Migraine attacks worsen with routine physical activities and may last 472 hours if not properly treated.[4] The burden of migraine

is severe, resulting in considerable economic and social losses.[5]

Newer agents for the acute treatment of migraine include the triptans,[6] but common analgesics, nonsteroidal antiinflammatory drugs (NSAIDs),

and even opioids continue to be the basic components of the therapeutic arsenal in most countries and specialized centers.[7] In addition, clinical

experience suggests that not all patients using a triptan reach a painfree or sustained painfree status. Headache recurrence within 24 hours, side

effects, and even high costs may also represent limiting factors for the use of triptans.[8]

Some patients find relief with simple or combination analgesics[9,10] and/or NSAIDs. Most NSAIDs have proved effective for treating migraine

and are still widely used in many countries despite the potential for gastrointestinal side effects and the current availability of more specific agents

[8–14] Different drug options and formulations are available. The choice for a specific type of medication depends on individual patient

characteristics, including pain intensity, speed of headache development, the presence of associated symptoms, degree of incapacitation, and

individual patient response.[11] In addition, in developing countries, such as Brazil, the choice of drugs may reflect cost issues

Lysine clonixinate (LC) is an anthranilic derivative of nicotinic acid that resembles the chemical structure of flufenamic acid.[15,16] Several

controlled and openlabel trials support the use of LC for acute migraine treatment.[17–19] The agent's structural formula (2[3chloroo

toluidine]piridino3carboxilate) allows fast absorption. LC is 96% to 98% proteinbound, and hepatic metabolism results in 4 inactive metabolites

Excretion is 75% renal and 25% fecal.[20] LC costs approximately 20 cents per 125mg tablet

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Naproxen sodium (NS) is an arylpropionic acid derivative with a potency similar to aspirin and indomethacin but with a more favorable tolerability

profile. This agent is a fully orally absorbed NSAID with peak plasma concentrations developing within 24 hours and a halflife of 14 hours; it is

almost completely (99%) bound to plasma proteins. Roughly 30% of the drug undergoes 6demethylation, with most of this metabolite excreted as a

glucuronide or other conjugates.[21] NS has proved effective for the treatment of migraine attacks.[22] The cost of a 550mg tablet is approximately

65 cents

The goal of this study was to compare the efficacy and tolerability of the oral formulations of LC and NS for the treatment of moderate or severe

migraine attacks

Patients and Methods

From April to December 2004, we prospectively studied 70 patients (62 women, 8 men) between ages 18 and 71 years (mean age, 41) with the

diagnosis of migraine without aura according to the International Headache Society criteria.[23] Participants were recruited from outpatient

headache units from 2 neurology hospitals in Rio de Janeiro and Brasilia, Brazil. All patients were receiving headache prophylaxis treatment with

drugs other than NSAIDs. An institutional review board approved the study, and all patients gave written informed consent

We conducted a doubleblind, crossover study in which patients treated 2 attacks of moderate or severe migraine intensity with either 250 mg of LC

or 550 mg of NS. Patients were randomized to 2 groups through arrival order. They treated attacks in counterbalanced order. The first patient who

was recruited took LC for the first attack and NS for the second attack. The next patient was randomized to take NS for the first attack and LC for

the second attack. To ensure against a sequence effect on treatment, the patients were clearly oriented to take the study medications only after a

minimal interval of 2 days. Those patients with persisting moderate or severe head pain 2 hours after taking the medication were allowed to use 100

mg of rectal indomethacin. The drugs were encapsulated to appear the same and maintain blindedness throughout the study. All patients received the

drugs in boxes marked A and B, each containing 1 capsule. The severity of the migraine attack was measured with a verbal categoric scale in which

0 = no pain; 1 = mild headache; 2 = moderate headache; and 3 = severe headache

Headache severity and the presence of nausea, photophobia, and side effects were evaluated at baseline (time of intake), 1 hour, and 2 hours after

the drug administration. All patients completed an attack report for each of the treated attacks (Figure 1). The use of rescue medications after 2

hours was also compared . Patients receiving treatment for any other medical conditions, women of childbearing age not using contraceptive

methods, and those who had used any type of symptomatic migraine medications within the previous 6 hours were excluded

Figure 1

Attack report.

We performed statistical comparisons by the nonparametric chisquare test and the Friedman analysis of variance to verify the association

differences between treatment responses at 1 hour and 2 hours, consumption of rescue medication at 2 hours, and the incidence of side effects found

in the 2 patient groups. To separately analyze time to treatment response in each of the groups, we performed an analysis of variance for repeated

measures of categoric data (McNemar test corrected at the 1.7% level). We used the CATMOD procedure by SAS System software to calculate a

2tailed P value < .05 for significance levels.

Results

Of the 70 patients enrolled, 60 (54 women, 6 men) completed the study. Six patients did not fill out the protocol and/or treated the attacks when mild,

and 4 were lost to followup. LC was used to treat 16 severe and 43 moderate attacks; NS was used to treat 19 severe and 39 moderate attacks

At 1 hour, 13.8% of attacks treated with LC and 11.9% of attacks treated with NS were painfree (P < .0001 compared with baseline for both

drugs). At 2 hours, 35.6% of the attacks treated with LC and 35.2% of the attacks treated with NS were painfree (P < .0001 compared with

baseline for both drugs). Table 1 compares painfree measures between groups, and Figure 2 shows the pain evolution with time in the 2 groups

Figure 2

Headache evolution with the time after drug intake.

2

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Table 1

Statistical Analysis of Painfree Measures Between Drugs LC and NS

The evolution of nausea is shown in Table 2 and Table 3. At baseline, 52.5% of the attacks treated with LC and 34% of the attacks treated with NS

were associated with nausea. After 1 hour, nausea was reduced significantly for both those who used LC (P < .0001) and those who took NS (P =

.014). At 2 hours, relief of nausea was significant for both groups (P < .0001). However, compared with NS, significantly more attacks treated with

LC were nauseafree at 1 hour (P < .0005) but not at 2 hours (P = .25).

Table 2

Longitudinal Analysis of the Nausea and Photophobia for Drug A (LC)

Table 3

Longitudinal Analysis of the Nausea and Photophobia for Drug B (NS)

Table 2 and Table 3 show results related to photophobia. Photophobia was significantly reduced at 1 hour for attacks treated with LC (P < .0001) but

not with NS, and differences between the groups reached statistical significance (P < .016). At 2 hours, photophobia had improved significantly for

attacks treated with either medication (P < .0001), but photophobiafree attacks differed between groups (P = .027). Figures 3 and 4 show the

nausea and photophobia evolution for both LC and NStreated attacks

Figure 3

Evolution of nausea relief for LC and NS.

Figure 4

Evolution of photophobia improvement for LC and NS.

Among the 59 attacks treated with LC, 8 required rescue medication after 2 hours, compared with 10 of the 58 attacks treated with NS. For attacks

that were painfree at 2 hours, sustained painfree rates at 24 hours were 55% for LC and 60.1% for NS. In all, 45% of attacks treated with LC and

38.9% of attacks treated with NS recurred (defined as the return of the headache within 24 hours after achieving painfree status at 2 hours)

Twelve patients using LC and 18 using NS reported side effects, including vomiting (2 attacks with LC and 3 attacks with NS), dizziness (3 attacks

with each drug), heartburn or stomachache (4 attacks with LC and 7 attacks with NS), and malaise or asthenia (5 attacks with LC and 7 attacks with

NS). Few patients reported more than 1 side effect with either drug. Finally, 25 patients expressed a preference for LC and 25 patients expressed a

preference for NS. Eight patients reported no preference whatsoever and 2 did not express preferences

Discussion

This doubleblind, randomized, crossover study demonstrated that both LC and NS are moderately effective in reducing or eliminating the headache

of a migraine attack within 2 hours, and in eliminating nausea and photophobia in the same time frame. The methodology that we used involved

assessing pain intensity and the presence of nausea and photophobia at baseline, 1 hour, and 2 hours (in which the pain intensity was expressed by a

categoric visual scale from 0 to 3), and rescue medication use at 2 hours, as suggested by the International Headache Society guidelines.[24]

However, because we did not use a placebo arm, which impairs true efficacy claims, our results should be viewed with caution. Furthermore, we

didn't assess differences in outcomes based on original headache intensity, and we examined sustained painfree rates only for those who were pain

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free at 2 hours and not all patients treated. However, we conducted this study because developing countries, such as Brazil, need inexpensive

medications to use in the public health system, which is free for everyone. We chose to include LC because it is 22.5 times less expensive than NS,

an accepted and effective agent for migraine attacks

Comparison With Triptans

Triptans are expensive and contraindicated in patients with vascular disease. In addition, many patients using a triptan report side effects (up to 89%

in one study) or limited efficacy; up to 31% of those taking sumatriptan discontinue it because of poor efficacy.[25–28] Moreover, the efficacy

parameters of triptans, particularly painfree measures, are modest, with a therapeutic gain (pain relief) of roughly 29% to 30%.[29] Clinical

comparisons of performance have suggested that some NSAIDs, such as lysine acetylsalicylic acid and tolfenamic acid, present efficacy outcomes

similar to sumatriptan, although sumatriptan studies include more patients with severe pain, which may bias comparisons and impede definitive

conclusions. However, NSAIDs in adequate dosages and in combination with antiemetic drugs may produce efficacy measures similar to some of

the oral triptans.[9,30–32]

In fact, systematic reviews and metaanalyses comparing triptans with other interventions, including NSAIDs, have demonstrated that although

clinical practice and expert opinion suggest the superiority of triptans, welldesigned clinical trials do not support such observations.[31,33–35] This

discrepancy may result from inadequate statistical analysis; differences in response rates favoring patients from clinical practice compared with

those who take part in trials; and reliance on end points at 2 hours in clinical trials, which may not fully capture the benefits of triptans relative to

other therapies. Finally, waiting to treat a headache until it has become moderate or severe may disadvantage the triptans, because early treatment

with these 5HT agonists (triptans) improves benefits compared with other pharmacologic agents.[36]

Recent evidence suggests that combining an NSAID with a triptan may improve efficacy and sustained painfree rates without increasing side

effects.[37–39] Although this has not been demonstrated with LC, it has been seen with NS. In one study, the combination of NS (500 mg) and

sumatriptan (50 mg) was superior to the single use of either NS or sumatriptan.[40] Finally, the evidence that migraine seems to involve different

pathophysiologic mechanisms, including impaired function of serotonergic pathways, neurogenic inflammation, and dopaminergic hypersensitivity,

implies that addressing only one of the involved biological systems is less than ideal; therefore, examining new options, including traditional agents

(such as NS and LC), may enhance our opportunities to treat migraine patients, or may provide evidence for using these traditional medications.[41]

Mechanism of Action of NSAIDs

Although the precise mechanism by which NSAIDs function in the relief of migraine and other headaches remains controversial, these agents seem

to inhibit the synthesis of prostaglandins, free radicals, and superoxide, and promote partial inhibition of platelet aggregation secondary to the

inhibition of thromboxane A2.[42–44] In addition, NSAIDs inhibit serotonin release from platelets and exert a central pharmacologic action in the

thalamus and spinal cord.[42,44] In animal studies, LC has been shown to interact directly with the central serotonergic system and indirectly with

opioid receptor systems in the thalamic nuclei, dentate gyrus, and layers of parietal cortex.[6,16,17,45] Furthermore, some of the NSAIDs that are

effective in migraine treatment reveal highaffinity binding to nociceptive structures in the dorsal horn and brainstem nuclei.[46] Thus, LC and the

other NSAIDs may act in migraine through a combination of central and peripheral mechanisms

Conclusion

Despite the limitations of a study with no placebo arm, this trial demonstrated that LC and NS may be similarly effective to treat moderate or severe

migraine attacks. In addition, both drugs presented reasonable tolerability and may be good candidates to be used alone in certain subsets of patients

and combined with other classes of pharmacologic agents, such as triptans, in order to improve the efficacy of both. Moreover, LC may represent an

attractive option for the treatment of acute migraine attacks in outpatients because it provides an efficacy and tolerability profile that is similar to

that of NS, but is considerably less expensive than NS. Patients from developing countries, especially those, such as Brazil, where the health plans

or government authorities do not provide medication for those not hospitalized, may benefit from this particular medication as well as others not yet

studied

Readers are encouraged to respond to George Lundberg, MD, Editor of MedGenMed, for the editor's eye only or for possible publication via email:

glundberg@medscape.net

Contributor Information

Abouch Valenty Krymchantowski, Outpatient Headache Unit, Instituto de Neurologia Deolindo Couto, Department of Neurology, Hospital Pasteur,

Universidade Federal do Rio de Janeiro Rio de Janeiro, Brazil; Headache Center of Rio de Janeiro, Rio de Janeiro, Brazil

Patrícia Peixoto, Headache Center of Rio de Janeiro, Rio de Janeiro, Brazil

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Rafael Higashi, Outpatient Headache Unit, Instituto de Neurologia Deolindo Couto, Department of Neurology, Hospital Pasteur, Universidade

Federal do Rio de Janeiro, Rio de Janeiro, Brazil

Ariovaldo Silva, Jr., Headache Center of Rio de Janeiro, Rio de Janeiro, Brazil

Vivian Schutz, Headache Center of Rio de Janeiro, Rio de Janeiro, Brazil

Article information

MedGenMed 2005; 7(4): 69

Published online 2005 Dec 14

PMCID: PMC1681714

Abouch Valenty Krymchantowski, MD, MSc, PhD, Coordinator; Director, Patrícia Peixoto, MD, Staff Physician, Rafael Higashi, MD, Staff Physician, Ariovaldo Silva, Jr., MD, Staff

Physician, and Vivian Schutz, RN, Staff Nurse

Abouch Valenty Krymchantowski, Outpatient Headache Unit, Instituto de Neurologia Deolindo Couto, Department of Neurology, Hospital Pasteur, Universidade Federal do Rio de

Janeiro Rio de Janeiro, Brazil; Headache Center of Rio de Janeiro, Rio de Janeiro, Brazil;

Contributor Information

Disclosure: Abouch Valenty Krymchantowski, MD, MSc, PhD, has disclosed no relevant financial relationships

Disclosure: Patrcia Peixoto, MD, has disclosed no relevant financial relationships

Disclosure: Rafael Higashi, MD, has disclosed no relevant financial relationships

Disclosure: Ariovaldo Silva, Jr., MD, has disclosed no relevant financial relationships

Disclosure: Vivian Schutz, RN, has disclosed no relevant financial relationships

This article has been cited by other articles in PMC

Articles from Medscape General Medicine are provided here courtesy of WebMD/Medscape Health Network

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