Korelasi Matriks Metalloproteinase-9, High Sensitivity Creactive Protein dan Glutamat Serum dengan Intensitas Nyeri Setelah Pemberian Flunarizin pada Penderita Tension-Type Headache Kronik

Abstract

Background: Despite the progress in basic and clinical research in recent years, the origin of pain in TTH is unknown. The role of inflammation has also been investigated in TTH. Several pieces of evidence show that pro-inflammatory mediators may be implicated in generating and maintaining pain while contributing to sensitization of neural structures; therefore it is reasonable to assume that they may be implicated in primary headaches pathophysiology. Some of exitatory neurotransmitters and pro-inflammatory cytokines have been suggested to involve in headache pathophysiology. Previous study found that flunarizine can be used for migraine prophylactic treatment and plasma glutamate level monitoring in migraine patients might serve as a biomarker of response to treatment. However, to our knowledge there is no publication about its efficacy in CTTH treatment. Aims: This study was aimed to see the effect of Flunarizine and Amitriptyline to serum levels of MMP-9, hs-CRP and Glutamate in CTTH patients and its correlation with pain intensity based on NRS scores. Method: This experimental study is a randomized, double blind, clinical trial with pre and post test design. Diagnosis of CTTH was based on the International Classification of Headache Disorders, 2nd edition (ICHD-II, 2004) diagnostic criteria. Chronic tension-type headache patients were recruited among those attended during April and August 2016in the out-patient clinic of the H. Adam Malik General Hospital Medan, Puteri Hijau Hospital and Medan Johor Primary Health Center.Eligible subjects were randomized into three interventional groups to receive one of the following drugs for 15 days that contained Flunarizine 5 mg/day or Flunarizine 10 mg/day or Amitriptyline 12.5 mg/day. The serum level of MMP-9, hs-CRP, Glutamate and Numeric Rating scale (NRS) score for pain intensity were measured before and after 15-day treatment. Results: Seventy-three CTTH patients had completed the study protocol until the end of the study. Most of them were female (82.8%), married (78.1), in the age group of 31-60 years old (71.2%), Java tribe (30.1%), housewife (54.8%), senior high school graduated (30.1%) , and wihout any history of hypertension (79.5%), no diabetes mellitus (90.4%) and not smoking (93.2%). There was no significant difference among these demographic factors (p>0.05). Compared to baseline, after 15 days of treatment the mean serum MMP-9 and mean serum Glutamate were significantly lower in the Flunarizine 5 mg group (12.04 ± 3.02 vs. 10.86 ± 2.89; p<0.001), significantly lower in the Flunarizine 10 mg group (11.60 ± 2.38 vs. 10.86 ± 2.49; p<0.001) and also significantly lower in the Amitriptyline 12.5 mg group (11.89 ± 1.76 vs. 11.69 ± 1.81; p<0.001).There were no significant difference of mean serum hs-CRP between baseline and after treatment in the Flunarizine 5 mg group (p=0.207) and Flunarizine 10 mg group (p=0.299), whereas in Amitriptyline group there was found a significant difference (p=0.009).At baseline, there was a non significant correlation between NRS scores and MMP-9(r = 0,063; p = 0,299), hs-CRP(r = 0,180; p =0,064) and Glutamate (r = 0,004; p= 0,488)serum levels. After Flunarizine 10 mg administration, there was found a significant (p=0.005) moderate negative correlation (r = - 0.506) between pain intensity and serum hs-CRP level and there was found a significant (p =0.007) moderate positive correlation (r = 0.508) between pain intensity and serum Glutamate levels after Amitriptyline 12.5 mg administration. However, there was no significant correlation between pain intensityand MMP-9(r = 0,245; p = 0,119), between pain intensity and hs-CRP and between pain intensity and Glutamate(r = 0,091; p = 0,333) serum level after Flunarizine 5 mg administration. There were significant differences (p<0.001) of serum Glutamate levels decrement after drug administration among Flunarizine 5 mg group (1.19±1.13), Flunarizine 10 mg group ( 0.75±0.60) and Amitriptyline 12.5 group (0.20±0.23). In the three interventional groups, there were significant difference of mean pain intensity decrement (p<0.001) , no significant difference of serum MMP-9 levels decrement (p=0.673) and no significant difference of serum hs- CRP decrement (p=0.845) after 15-day treatment. Amitriptyline 12.5 mg was more effective significantly (p<0.001) than Flunarizine 5 mg in reducing pain intensity , and also more effective significantly (p<0.001) than Flunarizine 10 mg, whereas Flunarizine 10 mg was more effective significantly (p<0.001) than Flunarizine 5 mg. Flunarizine 5 mg was more effective significantly (p<0.001) than Amitriptilyne 12.5 mg in reducing serum Glutamate concentration, Flunarizine 10 mg was more effective significantly (p=0.004) than Amitriptyline 12.5 mg, whereas Flunarizine 5 mg was more effective than Flunarizin 10 mg but not significantly difference (p=0.266). Conclusion: The all three drugs were found effective in reducing pain intensity in CTTH patients and Amitriptyline 12.5 mg was the most effective drug among them, whereas Flunarizine 5 mg was the most effective drug in reducing serum Glutamate concentration. At baseline, there was a non significant correlation between pain intensity and MMP-9, hs-CRP or Glutamate serum levels. After Flunarizine 5 mg administration, pain intensity had non significant correlations with MMP-9, hs-CRP and Glutamate serum levels. There was found a significant (p=0.005) moderate negative correlation (r = - 0.506) between pain intensity and serum hs-CRP level. There was found a significant (p=0.007) moderate positive correlation (r = 0.508) between NRS and serum Glutamate after Amitriptyline 12.5 mg administration. Key words: chronic tension-type headache, MMP-9, hs-CRP, Glutamate, pain intensity, Flunarizine.

Latar Belakang : Meski kemajuan penelitian dasar dan klinis berkembang akhir akhir ini namun asal timbulnya nyeri pada TTH masih belum dikeketahui. Peran inflamasi juga telah diselidiki pada TTH. Beberapa bukti menunjukkan bahwa mediator proinflamasi mungkin terlibat dalam patifisiologi nyeri kepala primer. Beberapa neurotransmiter eksitasi dan sitokin proinflamasi diduga terlibat terlibat dalam patofisiologi nyeri kepala. Penelitian terdahulu menemukan bahwa flunarizin dapat digunakan sebagai terapi profilaksis pada penderita migren dan pemantauan kadar Glutamat pada pasien migren dapat digunakan sebagai biomarker terhadap respons pengobatan. Akan tetapi sepanjang pengetahuan peneliti belum ada publikasi yang melaporkan efikasi flunarizin untuk pengobatan TTH. Tujuan : Penelitian ini bertujuan untuk meneliti kadar MMP-9, hs-CRP dan Glutamat serum pada penderita TTH kronik dan korelasinya dengan intensitas nyeri yang dinilai dengan skor NRS. Metode : Penelitian ini merupakan studi eksperimental dengan disain uji klinis pre dan post test, tersamar ganda dengan randomisasi. Diagnosa TTH kronik dibuat menurut kriteria diagnostik International Classification of Headache Disorders, 2nd edition (ICHD-II, 2004). Subjek penelitian diambil dari pasien yang datang berobat jalan di RSUP H. Adam Malik, Rumkit Putri Hijau dan Puskesmas Medan Johor dari April sampai Agustus 2016 setelah mendapat persetujuan dari Komite Etik Untuk Penelitian Bidang Kesehatan FK-USU. Subjek yang memenuhi kriteria dirandomisasi kedalam tiga kelompok perlakuan untuk mendapatkan salah satu obat berikut ini selama 15 hari yang berisikan Flunarizin 5 mg/hari atau Flunarizin 10 mg/hari atau Amitriptyline 12,5 mg/hari. Kadar MMP-9, hs-CRP, Glutamat serum dan skor NRS untuk intensitas nyeri diperiksa sebelum dan setelah pemberian obat selama 15 hari. Hasil : Tujuh puluh tiga penderita TTH kronik mengikuti protokol penelitian ini sampai selesai. Sebahagian besar subjek adalah wanita (82,8%), sudah menikah (78,1%), pada kelompok usia 31-60 tahun (71,2%), Suku Jawa (30,1%), ibu rumah tangga (54,8%), pendidikan SMA (30,1%) tidak memiliki riwayat menderita hipertensi (79,5%), tidak menderita diabetes mellitus (90,4%) dan tidak merokok (93,2%). Tidak dijumpai perbedaan yang signifikan dari faktor-faktor demografis tersebut antara ketiga kelompok perlakuan (p > 0,05). Dibandingkan dengan sebelum perlakuan, setelah 15 hari pengobatan nilai rerata kadar MMP-9 serum lebih rendah secara signifikan pada kelompok Flunarizin 5 mg (12,04 ± 3,02 vs. 10,86 ± 2,89; p<0,001), lebih rendah pada kelompok Flunarizin 10 mg (11,60 ± 2,38 vs. 10,86 ± 2,49; p<0,001) dan juga lebih rendah pada kelompok Amitriptyline 12.5 mg (11,89 ± 1,76 vs. 11,69 ± 1,81; p<0,001). Tidak dijumpai perbedaan yang signifikan rerata kadar hs-CRP serum antara sebelum dan setelah pemberian obat pada kelompok Flunarizin 5 mg (p=0.207) dan kelompok Flunarizin 10 mg (p=0.299), sedangkan pada kelompok Amitriptilin12,5 mg dijumpai perbedaan yang signifikan (p=0.009). Sebelum perlakuan, dijumpai korelasi yang tidak signifikan antara nilai skor NRS dengan kadar MMP-9 serum (r = 0,063; p = 0,299), kadar hs-CRP serum (r = 0,180; p =0,064) dan kadar Glutamat serum (r = 0,004; p= 0,488). Setelah pemberian obat Flunarizin 10 mg, dijumpai korelasi negatif sedang yang signifikan (r = - 0,506; p = 0.005) antara skor intensitas nyeri dengan kadar hs-CRP serum. Dijumpai korelasi positip sedang yang signifikan (r = 0,508; p < 0,007) antara intensitas nyeri dengan kadar Glutamat serum setelah pemberian Amitriptilin12,5 mg. Akan tetapi tidak dijumpai korelasi yang signifikan antara intensitas nyeri dengan kadar MMP-9 serum (r = 0,245; p = 0,119), antara intensitas nyeri dengan kadar hs-CRP serum (r = 0,091; p = 0,333) dan antara intensitas nyeri dengan kadar Glutamat serum (r = - 0,062 ; p = 0,385) setelah pemberian Flunarizin 5 mg. Dijumpai perbedaan yang signifikan (p<0,001) rerata penurunan kadar Glutamat serum setelah perlakuan antara kelompok Flunarizin 5 mg (1,19 ± 1,13), Flunarizin 10 mg (0,75 ± 0,60) dan Amitriptilin 12,5 mg (0,20 ± 0,23). Pada ketiga kelompok ini dijumpai perbedaan rerata penurunan intensitas nyeri yang signifikan (p<0,001), tidak dijumpai perbedaan yang signifikan pada rerata penurunan kadar MMP-9 (p = 0,673) dan juga tidak dijumpai perbedaan yang signifikan pada rerata penurunan hs- CRP serum (p = 0,845) setelah 15 hari pemberian obat. Amitriptilin 12,5 mg lebih efektif secara signifikan (p<0,001) menurunkan intensitas nyeri dari pada Flunarizin 5 mg, juga Amitriptilin 12,5 mg lebih efektif secara signifikan (p<0,001) dari pada Flunarizin 10 mg, sedangkan Flunarizin 10 mg lebih efektif secara signifikan (p < 0,001) dari pada Flunarizin 5 mg. Flunarizin 5 mg lebih efektif secara signifikan (p=0,001) menurunkan kadar Glutamat serum dari pada Amitriptilin 12,5 mg. Flunarizin 10 mg lebih efektif secara signifikan (p=0,004) menurunkan kadar Glutamat serum dari pada Amitriptilin 12,5 mg. Flunarizin 5 mg lebih efektif menurunkan kadar Glutamat serum dari pada Flunarizin 10 mg namun secara statistik tidak signifikan (p=0,266). Kesimpulan : Ketiga obat baik Flunarizin 5 mg, Flunarizin 10 mg maupun Amitriptilin 12,5 mg efektif dalam menurunkan intensitas nyeri pada penderita TTH kronik. Amitriptilin 12,5 mg merupakan obat yang paling efektif menurunkan inten sitas nyeri, sedangkan Flunarizin 5 mg paling efektif dalam menurunkan kadar Glutamat serum. Setelah pemberian obat Flunarizin 5 mg, tidak dijumpai korelasi yang signifikan antara skor NRS dengan kadar MMP-9 serum , dengan kadar hs-CRP serum dan dengan kadar Glutamate serum. Setelah pemberian obat Flunarizin 10 mg dijumpai korelasi negatif sedang yang signifikan (r = - 0,506; p= 0,005) antara intensitas nyeri dengan kadar hs-CRP serum. Setelah pemberian obat Amitriptilin 12,5 mg, dijumpai korelasi negatif sedang yang signifikan (r = 0,508; p= 0,007) antara intensitas nyeri dengan kadar Glutamat serum.