Abstract: This study was conducted to evaluate and compare the efficacy and treatment effect of sodium valprovate with propranolol and tricyclic antidepressive drugs. This piece is a rarandomized clinical trial conducted on 126 migraine patients admitted to brain and nerves clinic in Arak, Iran. Patients were divided in two groups then randomized to study treatments. Data were gathered using a checklist and a complete examination. They were analyzed by Chi square and exact test. In patients with normal and abnormal encephalogram the effectiveness rate of two treatments were 35, 61.9, 95.6 and 28.6%, respectively. This difference between two treatments was statistically significant (p<0.001). But didn't observe significant differences between two sex groups (p>0.05). For treatment and control of the migraine, in patients with normal encephalogram, propranolol with tricyclic antidepressive drugs advised and for abnormal encephalogram sodium valprovate can be the better treatment for management and reduction of headache attacks.
INTRODUCTION
Migraine is a common chronic daily headache disease characterized by repeated episodes of head pain that can be caused frequent and severe attacks of headaches (Spasic et al., 2003; Calabresi et al., 2007; Silberstein et al., 1996). Among the primary headaches, migraine is identified as the most contributor in general people (Silberstein, 2006). Over 80% of these people suffer some degree of headache-related disability (Stewart and Lipton, 1993). The annual prevalence of this debilitating neurological disorder (Lipton et al., 2001) that is 12% for adults and ranged from 6% in men and 18% for women (Spasic et al., 2003; Lipton et al., 2001). The lifetime prevalence of disease within United States women exceeds from 25%, so one of four women affected by migraine at life duration (Lipton et al., 2001; Diamond et al., 2007) and the estimated annual cost, including costs of direct medical care and lost productivity, exceeds $17 billion in this country (De Lissvoy and Lazarus, 1994).
Although, over half of the patients didn’t diagnose or are taking a treatment (Lipton et al., 2001), more than 90% of patients with migraine have disability with their attacks and half these patients need to rest in bed (Mueller, 2007). Despite of high prevalence, because of undiagnosing or misdiagnosing of migraine it has been demonstrated that the disease has a significant impact on treatment, disability and quality of life, so early recognition and treatment is necessary (Hershey and Winner, 2005).
Several medications have been developed to establish efficacy of some treatments in migraine (Owens et al., 2008; Silberstein, 2000), such as valprovate sodium, valprovate acid, dopamine antagonist and tricyclic anti depressive and other drugs that were using for reduction or limitation of frequency and intensity of migraine (Hershey and Winner, 2005). However, migraine headaches have a great impact on disability and quality of life, so early recognition and treatment is necessary (Unalp et al., 2008).
There are many randomized clinical studies that ascertained the effect of valprovate sodium in reducing severity and duration of migraine attacks. For example, Unalp et al. (2008) reported that valproate able to manage successfully migraine as well as shaygannejad has previously been shown the effect of sodium valprovate in reduce migraine headache (Yurekli et al., 2008). Also, Spasic et al. (2003) approved the efficiency of valproate in prevention and treatment of patients with migraine by significant reduction in frequency, intensity and mean of episodic duration of attacks. In addition several studies ascertain the effective impact of tricyclic antidepressive drugs in management of migraine (Levinstein, 1991; Hershey et al., 2000).
Therefore, we designed and conducted this study to evaluate and compare the efficacy and treatment effect of sodium valprovate with propranolol and tricyclic antidepressive drugs in a clinical controlled randomized trial based on encephalogram test.
MATERIALS AND METHODS
This present randomized controlled clinical trial conducted on 140 admitted patients to brain and nerves clinic at Valiasr hospital of Arak, Iran. From all of them 126 subjects (40 male and 86 female) have inclusion criteria and enrolled for study. The study was carried out on 10-50 years old patients with the equal portion in each age and treatment group. Participants have been completed in 6 month, from March 2002 to August 2002.
Collection of data was conducted with a checklist that involves complete examination results such as encephalogram and computerized tomography scan of brain, blood exam and kidney and liver function. Then analyzed by chi square and fisher exact test in SPSS software, the values of less than 0.05 have been considered as significant level.
Inclusion criteria were patients with upper 10 years old and whom that permitted for use of treatment base of blood exam and kidney and liver function, so patients under 10 years old and whom can't take study drugs due to blood, kidney and liver function exams exclude from study. Also unintention in participations for concluding in study and have any pathologic damage were the exclusion criteria.
Patients divided in two groups based on normal and abnormal encephalography, then each group randomized in to one of treatments methods. (1) valprovate sodium pill (15 mg kg-1) 1-3 pills daily and (2) propranolol pill (40 mg) 1-2 pills daily with 50 mg amitriptyline or 25 mg nortriptyline (1-2 pills daily).
In the study period checking for blood exam, kidney and liver function, effect of drugs on frequency, severity and period of migraine attacks, drugs side effects such as vertigo, vomiting, nausea, depression and fatigue feeling at third month conducted in participations, for change in dosage or treatment type, if the result of these examinations have been shown any side effect. The study protocol has been approved by ethical committee of the Arak University of Medical Sciences.
RESULTS
forty patients (31.8%) were male and 82 patients (65.1%) have a normal encephalogram.
encephalogram taken for each patient, then computerized tomography scan of brain
performed too, but didn’t observe any pathologic damage in patients.
| Table 1: | Frequency distribution of migraine patients base of amelioration status, encephalogram and treatment type |
| Values in brackets are percentage | |
| Table 2: | Frequency distribution of side effects of two treatments method in patients |
| Values in brackets are percentage | |
As indicated in Table 1 in normal encephalogram group, 40 patients (48.8%) consumed valprovate sodium and 42 patients (52.2%) consumed propranolol with amitriptilin or nortiliptilin, the effectiveness ate of these treatments were 35 and 61.9%, respectively. This difference between two treatments was statistically significant (p<0.001).
Among the 44 patients (34.9%) with abnormal encephalogram, 23 patients (52.3%) consumed Valprovate sodium and 21 patients (47.7%) consumed propranolol with Amitriptilin or Nortiliptilin that effectiveness rate of these treatments were 95.6 and 28.6%, respectively. This difference between two treatments was significant statistically (p<0.001).
The amelioration rate in males and females was 54.6 and 52.5%, also this rate in patients with normal and abnormal encephalogram was 48.8 and 63.6%, respectively. There weren’t any statistically significant differences between male and female patients as between patients with normal and abnormal encephalogram (p>0.05).
The amelioration rate in patients that treated with valprovate was 57.1% and this rate in patients that treated with propranolol with amitriptilin or nortiliptilin calculated 50.8%, this difference was significant statistically (p<0.001).
As shown in Table 2, the most common side effect for valprovate was vertigo and in patients that treated with propranolol with amitriptilin or nortiliptilin was fatigue feeling.
DISCUSSION
The result of this study showed that encephalogram can be considered as a diagnostic test for migraine; because after conducting encephalogram test, computerized tomography scan of brain tested in whole patient didn’t show any pathologic damage in the patients brains. However, it has been reported that encephalogram caused an encephalopathy in a 11 old year child (Topczewski et al., 2008). Therefore, it is recommended to use this diagnosis method cautiously due to the adverse effects of radiation.
Another result of our study showed that in patients with normal encephalogram, Valprovate sodium can consider as a good treatment and based on these results. Several study (Yurekli et al., 2008; Pascual et al., 2007) approved the efficacy of sodium valprovate and its derivatives in management of migraine. A double-blind, randomized, placebo-controlled trial that conducted as parallel design approved the efficacy of the extended-release version of VPA recently (Freitag et al., 2002).
Other results of present study showed that in patients with abnormal encephalogram, propranolol and tricyclic antidepressive drugs have an impact in amelioration of patients. Two studies (Levinstein, 1991; Hershey et al., 2000) showed that tricyclic antidepressive drugs have a good effect in reduction of frequency and intensity of migraine. In a crossover study that used tricyclic antidepressive for headache prevention, comparing amitriptyline with propranolol and cyproheptadine, Levinstein (1991) showed that amitriptyline to be effective in 50 to 60% of the children. Also in another (Hershey et al., 2000) clinical study ascertained that amitriptyline hydrochloride caused a perceived improvement in more than 80% of the children, with a subsequently decreasing headache frequency and impact on the migraine. But it is considerable that the effect of tricyclic antidepressive may cause the better amelioration in children.
In present study, amelioration rate due to sodium valprovate in males and females, normal and abnormal encephalogram was 54.6 and 52.5%, 48.8 and 63.6%, respectively. Present results was same to other studies, as Freitag et al. (2002) reported 52-59% improvement in their study. Although, seems the same result with our finding but it is necessary that consider about differential dosage and duration of intervention in two study.
Assessing the adverse effects of these treatments in patients showed that all of these side effects such as vertigo, fatigue feeling, depression, vomiting and nausea were higher than in valprovate arm. In other study (Yurekli et al., 2008) somnolence and fatigue feeling was also a most important side effect of sodium valprovate.
CONCLUSION
Results of this study suggest that in neurological clinics, for treatment and control of the attacks in migrainic patients, first screening by encephalogram test should be done and then divided in two normal and abnormal groups. For normal encephalogram group, propranolol with tricyclic antidepressive drugs advised and for abnormal encephalogram group sodium valprovate can be the better treatment for management and reduction of headache attacks.
ACKNOWLEDGMENTS
We would like to thank nerve ward of Valiasr Hospital staffs for collaboration in this study, and Arak University of Medical Sciences for financial support from this study.