Comparison between the Effects of Sumatriptan Versus Naratriptan in the Treatment of Postdural Puncture Headache in Obstetric Patients: A Randomized Controlled Trial.

BACKGROUND: Postdural puncture headache (PDPH) in the obstetric anesthesia practice is one of the most annoying, common, and important problems. AIM: This comparative study was designed to assess the efficacy of naratriptan in relieving PDPH in parturients who gave birth by cesarean section under intrathecal anesthesia and to compare its efficacy with sumatriptan. SETTINGS AND
DESIGN: One hundred and eighty-nine adult parturients who complained of PDPH in the first 3 days postpartum period were enrolled in this study. They were divided into three equal parallel groups of 63 each.
MATERIALS AND METHODS: Group-1 controlled (C-group) received multivitamin tablets, Group-2 sumatriptan (S-group) received sumatriptan tablets and Group-3 naratriptan (N-group) received naratriptan tablets. The efficacy of naratriptan in relieving PDPH was studied and compared with that of sumatriptan. Incidences of complications of both drugs were also noted. STATISTICAL ANALYSIS: The collected data were organized, tabulated, and statistically analyzed using SPSS software statistical computer package version 18 (SPSS Inc., USA).
RESULTS: After the first 6 h, there were statistically significant differences between Groups S and N from one side and control group from the other side (P < 0.0001 and 0.001), respectively, and the difference between Group S and Group N was statistically significant (P = 0.004). After 12 h, there were statistically significant differences between Groups S and N from one side and the control group from the other side (P < 0.0001) and the difference between Group S and Group N was statistically significant (P = 0.002). After 72 h, there were statistically significant differences between Groups S and N from one side and control group from the other side (P < 0.001 and 0.009), respectively. The difference was nonsignificant between S and N group (P = 0.717).
CONCLUSION: The study revealed that anti-migraine drug naratriptan in combination with supportive treatment was effective in relieving PDPH in parturients.

INTRODUCTION

In the obstetric population, inadvertent dural break is one of the main concerns. Postdural puncture headache (PDPH) is a significant iatrogenic cause of patient morbidity in modern anesthetic practice.[1] The incidence of a headache after spinal anesthesia varies greatly between studies.[2] Incapacitating headache incidence is estimated to range between 0.3% and 45% following spinal anesthesia and up to 81% following unintended dural puncture during epidural insertion in parturients.[3] The size and design of the needle are the main factor that determines the frequency of PDPH following spinal anesthesia. The use of larger needles is accompanied by a greater incidence of PDPH. The incidence varies with the needle size and is about 40% with a 22G needle; 3%–25% with a 25G needle; 2%–12% with a 26G Quincke needle, and <2% with a 29G needle.[34] By using progressively smaller needles and changing the design of needle tips from cutting Quincke needles to pencil-point needles, further reduced the incidence.[56] Other risk factors for PDPH are multiple attempts, female sex, younger age group, and the obstetric population. The obstetric patient is at particular risk of a headache because of sex, young age, and the widespread application of regional anesthesia.[7] The accompanying symptoms are usually nausea, vomiting, neck stiffness, ocular complaints such as photophobia and diplopia, and auditory complaints like tinnitus.[8]

PDPH is usually a self-limiting process. If left untreated, 75% resolve within the 1st week and 88% resolve by 6 weeks. However, early treatment is indicated if symptoms are upsetting for the patients.[9] Once a diagnosis of PDPH is established, various treatment modalities are available, ranging from noninvasive pharmacological measures to invasive procedures. Conservative treatment for PDPH includes bed rest, flat postures, mild laxatives, additional fluids above those required for maintenance, analgesics, including paracetamol and nonsteroidal anti-inflammatory drugs, and antiemetics may control the symptoms and so diminish the necessity for interventional therapy. Caffeine, cosyntropin or synthetic adrenocorticotropic hormone, hydrocortisone, theophylline, pregabalin, and gabapentin, desmopressin (DDAVP) and triptans were also tried.[10111213]

Triptans were verified to be the most effective anti-migraine medications and are superior for menstruation-associated migraine. Sumatriptan has been tried in managing PDPH with satisfactory outcomes. It is well tolerated and effective when combined with analgesics. Furthermore, zolmitriptan, a second-generation triptan, was tried successfully in managing PDPH.[141516]

Naratriptan is a second-generation triptan and is available in the market and is being used as a drug for treatment of migraine.[1718] The literature did not mention that it had been studied for managing PDPH. Furthermore, the literature did not compare the efficacy of different triptans in relieving PDPH. Hence, this study examined the efficacy of naratriptan in managing PDPH and compared its efficacy with that of sumatriptan.

MATERIALS AND METHODS

After the Institutional Board and Ethical Committee approval of El Fayoum University Hospitals, 189 parturients, who had cesarean section under spinal anesthesia American Society of Anesthesiologists (ASA) physical status Classes I and II and aged between 18 and 35 years and complained from moderate-to-severe PDPH after 25G spinal needle puncture on the 2nd or 3rd postoperative day were included in this study. It was a prospective study and was held between March 2017 and the end of August 2018 that took 18 months. The study was registered at the Pan African Clinical Trial Registry (www.pactr.org) database with a unique identification number PACTR201901888984937. Patients with a history of ischemic heart disease, pregnancy-induced hypertension, chronic hypertension, cardiac, vascular, liver and renal impairment, or any other severe or disabling medical condition were excluded from the study. Individuals with a history of migraine, known hypersensitivity to study drugs, previous inadequate response to at least two triptans, currently using ergotamine, monoamine oxidase inhibitors, or selective serotonin reuptake inhibitors were excluded as well. They were divided into three parallel equal groups each contained 63 patients. Group (C) controlled or placebo group, Group (S) sumatriptan group, and Group (N) naratriptan group [Figure 1].

Figure 1

Follow-up (CONSORT) diagram of the participants

Patients were kept in the hospital for at least 3 days. Patients of the three groups had bed rest, Ringer's solution 3 L/day, along with oral fluids (including coffee and tea), and diclofenac potassium 50 mg three times per day. Patients of the sumatriptan (S) group were given oral sumatriptan (Imigran®) 50 mg tablet twice in the 1st day and then 50 mg once daily for the next 2 days. While those of the naratriptan (N) group were given naratriptan (Naredrix®) 2.5 mg tablet twice daily in the 1st day then 2.5 mg tablet once daily in the next 2 days. Patients of the control (C) group were given multivitamin tablets in the same dosage regimen. The patients, drug providers, and the data collectors were blinded for the given drugs.

Measured parameters

A 5-point visual analog pain scale was used to describe the intensity of pain that was first described by Hakim.[19]

0 = No pain

1 = Mild pain (pain which did not affect the everyday activity of patient)

2 = Moderate pain (pain which was present on standing but relieved somewhat on lying down, confining them to bed)

3 = Severe pain (pain which did not even relieve on lying down)

4 = Very severe pain (severe pain along with associated symptom, i.e., nausea, tinnitus, neck stiffness, etc.).[1116]

Patients were interviewed by an anesthesiologist regarding relief from a headache after 6 h and then at 12, 24, 48, and 72 h. Patients having complaints of nausea were given oral anti-emetic metoclopramide and those who suffered neck stiffness were managed with oral methocarbamol-paracetamol. The incidences of any adverse effects such as tingling sensation, dizziness, tightness, or heaviness in the chest, throat, neck, or jaws, drowsiness, and warm sensations in the body were also recorded. The primary outcome was the incidence of a headache after 72 h (pain scores 0 and 1 were considered as pain relief) and the incidences of side effects of the study drugs were secondary outcomes. At the end of the study, patients who did not experience pain relief, from any of the three study groups, were chosen whether to complete supportive treatment of PDPH or to have an epidural.

Sample size calculation

The sample size was calculated using G power version 3 (Düsseldorf, Germany). A minimal sample size of patients was 57 in each group needed to get power level 0.80, overall alpha level 0.05 (two-sided) and 16.7% as an expected difference in the proportions of patients with pain score 0 and 1 after 72 h in both treatment arms, sumatriptan group (96.7%) and naratriptan group (96.7%), compared to control group (80%).[16] To overcome the problem of loss of follow-up, the calculated sample size was increased by 10% to reach 63 in each group.

Statistical analysis

The collected data were organized, tabulated, and statistically analyzed using SPSS software statistical computer package version 18 (SPSS Inc, Chicago, IL, USA). Quantitative data were presented as mean and standard deviation (SD) or median and interquartile range. The Kolmogorov–Smirnov test (KS) test was performed as a test of normality. One-way ANOVA was used to compare between mean values of the age of the study groups. As regards pain score at a different time, Kruskal–Wallis test was used in comparing between the three groups then Dunn's test was performed as a pairwise comparison. The Friedman test was used to test the differences in visual analog scale scores at different times within the study groups. Qualitative data were presented as number and percentages; the Chi-square was used as a test of significance. For interpretation of the results of tests of significance, significance was adopted at P ≤ 0.05.

RESULTS

There were no statistically significant differences among the three study groups regarding age, BMI, ASA physical status classification, and multiple pregnancies (twins or triplets) [Table 1].

Table 1

Basic characteristics

Variables	Study groups			P
	Control (n=63)	Sumatriptan (n=63)	Naratriptan (n=63)
Age (years), mean±SD	25.4±4.7	25.3±4.3	24.5±4.2	0.445*
BMI, mean±SD	29.97±2.63	29.54±3.07	29.05±3.08	0.215*
Multiple pregnancies, n (%)	7 (11.1)	8 (12.7)	7 (11.1)	0.950†
ASA, n (%)
I	54 (85.70)	56 (88.9)	51 (81.0)	0.451†
II	9 (14.3)	7 (11.1)	12 (19.0)

*One-way ANOVA, †Chi-square test. BMI=Body mass index, ASA=American Society of Anesthesiologists, SD=Standard deviation

Six hours after the treatment, 35 (55.6%) of patients in the sumatriptan group got relieved from a headache; 25 patients (39.7%) had mild pain (pain score 1) and 10 patients (15.9%) were with no pain (pain score 0). 19 (30.2%) of patients in the naratriptan group got relieved from a headache 18 patients (28.6%) had mild pain (pain score 1) one patient (1.6%) was with no pain (pain score 0). While in the control group, only 5 patients (7.9%) had mild pain (pain score 1) and no patient hand no pain (pain score 0). There were statistically significant differences between Groups S and N from one side and the control group from the other side (P < 0.0001 and 0.001), respectively, and the difference between Group S and Group N was statistically significant (P = 0.004) [Table 2]. After 12 h, in the sumatriptan S-group, 48 patients (86.2%) were relieved from headache (mild pain-23, no pain-25). Whereas in naratriptan N-group, 31 patients (49.2%) were relieved from headache (mild pain-25, no pain-6). While, in the control group, 8 patients (12.7%) were relieved from headache (mild pain-6, no pain-2). Again, there were statistically significant differences between groups S and N from one side and the control group from the other side (P < 0.001) and the difference between Group S and Group N was statistically significant (P = 0.002) [Table 2]. Similar results at 24 and 48 h, but the differences between S and N groups were not statistically significant (P = 0.06 and 0.38), respectively. At the end of the study after 72 h, 60 patients (95.3%) in S group got relieved from headache 58 patients (92.1%) with no pain and 2 (3.2%) patients with minimal pain. While, 58 patients (92.1%) in N group got relieved from headache 49 (77.8%) patients with no pain and 9 patients (14.3%) patients with minimal pain whereas, 47 patients (74.6%) in the control group were relieved from headache 27 patients (42.9%) with minimal and 20 patients (31.7%) with no pain. There were statistically significant differences between Groups S and N from one side and control group from the other side (P < 0.001 and 0.009), respectively, and the difference between Group S and Group N was not significant (P = 0.717) [Table 2 and Figure 2]. Headache severity in the three study groups at different study time points is presented in Table 3.

Table 2

Pain scores in relation to the study groups. Values are in number (n) and percentages (%)

Pain score	Study groups			P†
	Control (n=63), n (%)	Sumatriptan (n=63), n (%)	Naratriptan (n=63), n (%)
0 h
2	14 (22.2)	16 (25.4)	11 (17.5)	0.147
3	40 (63.5)	30 (47.6)	32 (50.8)
4	9 (14.3)	17 (27.0)	20 (31.7)
6 h
0	0 (0.0)	10 (15.9)	1 (1.6)	1 versus 2: <0.001*1 versus 3: 0.001*2 versus 3: 0.004*
1	5 (7.9)	25 (39.7)	18 (28.6)
2	23 (36.5)	21 (33.3)	29 (46.0)
3	30 (47.6)	5 (7.9)	15 (23.8)
4	5 (7.9)	0 (0.0)	0 (0.0)
12 h
0	2 (3.2)	25 (39.7)	6 (9.5)	1 versus 2: <0.001*1 versus 3: <0.001*2 versus 3: 0.002*
1	6 (9.5)	23 (36.5)	25 (39.7)
2	33 (52.4)	13 (20.6)	25 (39.7)
3	21 (33.3)	2 (3.2)	7 (11.1)
4	1 (1.6)	0 (0.0)	0 (0.0)
24 h
0	5 (7.9)	37 (58.7)	22 (34.9)	1 versus 2: <0.001*1 versus 3: <0.001*2 versus 3: 0.060
1	17 (27.0)	19 (30.2)	26 (41.3)
2	29 (46.0)	6 (9.5)	12 (19.0)
3	12 (19.0)	1 (1.6)	3 (4.8)
48 h
0	13 (20.6)	50 (79.4)	39 (61.9)	1 versus 2: <0.001*1 versus 3: <0.001*2 versus 3: 0.380
1	17 (27.0)	8 (12.7)	16 (25.4)
2	28 (44.4)	5 (7.9)	8 (12.7)
3	5 (7.9)	0 (0.0)	0 (0.0)
4	0 (0)	0 (0)	0 (0)
72 h
0	20 (31.7)	58 (92.1)	49 (77.8)	1 versus 2: 0.001*1 versus 3: 0.009*2 versus 3: 0.717
1	27 (42.9)	2 (3.2)	9 (14.3)
2	10 (15.9)	3 (4.8)	5 (7.9)
3	6 (9.5)	0 (0.0)	0 (0.0)
4	0 (0)	0 (0)	0 (0)

*Significant, †Chi-square test. P values were calculated among the three groups according to clinically significant pain as pain scores (0, 1) were considered as no pain, whereas pain scores (2, 3, 4) considered as clinically significant pain

Figure 2

Percentage of patients with no pain (0) or mild pain (1) at different study time points

Table 3

Pain scores at different study time points. Values are presented as median and IQR

	Median (IQR)			P†
	Control (n=63)	Sumatriptan (n=63)	Naratriptan (n=63)
Time 0	3 (3-3)	3 (2-4)	3 (3-4)	0.178
6 h	3 (2-3)	1 (1-2)	2 (1-2)	1 versus 2: <0.001*1 versus 3: <0.001*2 versus 3: 0.007*
12 h	2 (2-3)	1 (0-2)	2 (1-2)	1 versus 2: <0.001*1 versus 3: <0.001*2 versus 3: 0.0005*
24 h	2 (1-2)	0 (0-1)	1 (0-2)	1 versus 2: <0.001*1 versus 3: <0.001*2 versus 3: 0.019*
48 h	2 (1-2)	0 (0-0)	0 (0-1)	1 versus 2: <0.001*1 versus 3: <0.001*2 versus 3: 0.137
72 h	1 (0-2)	0 (0-0)	0 (0-0)	1 versus 2: <0.001*1 versus 3: <0.001*2 versus 3: 0.193
P‡	<0.0001*	<0.0001*	<0.0001*

*Significant, †Kruskal-Wallis and post hoc analysis by Dunn’s test. ‡Friedman test. IQR=Inter quartile range

There were no statistically significant differences among the three groups regarding the incidences of nausea, vomiting, and dizziness (P > 0.05). However, the incidences of tingling and tightness were significantly higher in the naratriptan group than the other two groups (P = 0.004 and 0.006), respectively [Table 4]. No patient required an epidural blood patch.

Table 4

Complications data are presented as number (%)

	Study groups			P†
	Control (n=63), n (%)	Sumatriptan (n=63), n (%)	Naratriptan (n=63), n (%)
Nausea and vomiting	21 (33.3)	14 (22.2)	20 (31.7)	0.332
Dizziness	10 (15.9)	9 (14.3)	14 (22.2)	0.463
Tingling	0 (0.0)	2 (3.2)	8 (12.7)	0.004*
Tightness	3 (4.8)	1 (1.6)	10 (15.9)	0.006*

*Significant, †Chi-square test

DISCUSSION

This is the first study, to our knowledge, involving the use of anti-migraine drug naratriptan (Naredrix® Organo Pharma) as a treatment of PDPH. The International Headache Society describes PDPH as “Headache occurring within 5 days of a lumbar puncture, caused by cerebrospinal fluid (CSF) leakage through the dural puncture. It is usually accompanied by neck stiffness and/or subjective hearing symptoms. It remits spontaneously within 2 weeks, or after sealing of the leak with autologous epidural lumbar patch.”[20] PDPH is thought to be caused by CSF leakage through the dural tear at a greater rate than its production leading to a drop in CSF pressure. This causes headache by two mechanisms; one is the drooping of the intracranial structures in the standing position; with traction on the meninges, cranial nerves, and upper cervical nerves causing frontal, occipital, and cervical pain. Traction on the fifth cranial nerve causes the frontal headache. Pain in the occipital region is due to the traction of the 9th and 10th cranial nerves.[12] The second mechanism is compensatory vasodilatation in response to the low intracranial pressure which furthermore, causes a headache. Sitting and standing intensify pain while lying recumbent alleviates it. Other associated symptoms include nausea, vomiting, hearing loss, tinnitus, vertigo, dizziness, diplopia, and paresthesia of the scalp.[182122]

The 5-hydroxytryptamine (5HT 1B/1D) agonists, together known as triptans, are major progress in the treatment of migraine headache.[23] Sumatriptan has been displayed to be well tolerated and effective in providing pain relief when administered in the mild pain phase, also in combination with analgesics.[11] Lhuissier et al. also found sumatriptan advantageous in relieving PDPH.[24] Second-generation triptans such as zolmitriptan and frovatriptan have been also successfully tested.[1625] Naratriptan is a 5-HT 1B and 5-HT 1D receptor agonist with cerebral vasoconstrictive effects. It is used principally in the management of migraine. Naratriptan applies its effects on migraine-induced pain by cranial blood vessel vasoconstriction; avoiding or reversal of cranial blood vessels vasodilatation; reversing of the inflammation and extravasation of cranial blood vessels; trigeminal sensory transmission interference; hindering transmission at the first sensory synapse; stimulating the descending pain inhibitory pathway; or blockade of neurotransmission at the level of brainstem, thalamus, or cerebral cortex.[18]

The results of the current study showed that sumatriptan and naratriptan are effective in treating PDPH in the first 72 h significantly more than the placebo. The effect of sumatriptan was more significant than naratriptan at 6 and 12 h, but the effect became nonsignificant at the rest of the study time points.

Ghanei et al. studied the effect of sumatriptan on the prevention of PDPH and found that the incidence was 25.49% in cases versus 37.25% in controlled cases and found no significance in pain scores between the case and control group at 8 h interval in the study time (first 48 h) (P > 0.05).[11] The difference in the results of Ghanei et al. from ours could be attributed to the use of sumatriptan in prophylaxis (before the occurrence of headache), different target population (males and females), whereas females only were included in the current study, nonrandomization of the sample (52 males and 52 females in each study group), different types of operations (cesarean section only in our study), and different drug (they used lidocaine 5% while the current study used 0.5% heavy bupivacaine).

The current results came in agreement with Riaz et al. who studied the effect of zolmitriptan in managing PDPH against placebo in parturients and found that the effect of zolmitriptan was statistically significant at 6, 12, 24, 48, and 72 h.[16] The higher significance of the effect of the drugs in our study than that of Riaz et al. could be explained by a higher sample size in the ours and also, they included only patients with severe and very severe pain (pain scores 3 and 4) at the beginning of their study, but we included mild, severe, and very severe pain (pain scores 2, 3, and 4) at the beginning of our study.

Our results came in agreement with that of Havanka et al. who found that naratriptan 2.5 mg was less effective than sumatriptan 100 mg in the treatment of acute migraine at 4 h after dosing, the two medications showed similar efficacy at 24 h.[26] Furthermore, our results coincide with that of Ashcroft and Millson in their meta-analysis of randomized controlled trials in the treatment of acute migraine who found that rizatriptan 10 mg and sumatriptan 100 mg were superior to naratriptan in terms of headache relief.[27]

The present study found that sumatriptan effect in the treatment of PDPH was significantly more effective than naratriptan at 6 and 12 h. A study by Gallagher et al. found that zolmitriptan, 2.5 mg was significantly more effective than sumatriptan 50 mg in terms of migraine headache response at 2 and 4 h and concluded that patients taking zolmitriptan were significantly more likely to have pain relief over 24 h than those taking sumatriptan.[28]

The current study reported that there were no significant differences among the three groups regarding nausea, vomiting, and dizziness. Although the incidences of tingling and chest or throat tightness were significantly higher in the naratriptan group than the other two groups, they were well tolerated by most of the patients. These results were near to those found by Havanka et al. in the treatment of migraine who reported that the incidences of adverse events were similar in patients treated with naratriptan 1 mg (20%), naratriptan 2.5 mg (21%), and placebo (23%). And for naratriptan 5, 7.5, and 10 mg, the incidences of adverse events were 32%, 37%, and 35%, respectively, and for sumatriptan 100 mg they were 26%.[26] In contrary to our results, Ashcroft and Millson found that naratriptan (1 and 2.5 mg) was associated with lower incidences of adverse effects than rizatriptan, sumatriptan, and zolmitriptan and were similar to placebo.[27]

The limitation of this study is that pain assessment is a subjective method that differs from one person to another depending on their cultures and backgrounds. We recommend further studies using different doses of naratriptan, other triptans, and more studies comparing the relative potencies of different triptans on the management of PDPH.

CONCLUSION

The current study concluded that anti-migraine drug naratriptan (2.5 mg) in combination with supportive treatment is effective in relieving PDPH in parturients with near potency to that of sumatriptan and well-tolerated side effects after 72 h.

Financial support and sponsorship

This study was financially supported by Fayoum University Hospitals.

Conflicts of interest

There are no conflicts of interest.