Table of Contents  
Year : 2016  |  Volume : 9  |  Issue : 3  |  Page : 387-392

Comparison of the respective effects of paracetamol, pregabalin, and their combination in the treatment of postdural puncture headache following major gynecological surgery

1 Department of Anesthesiology, Critical Care and Pain, R.G. Kar Medical College, Kolkata, India
2 Department of Community Medicine, R.G. Kar Medical College, Kolkata, India
3 Department of Anesthesiology, MGM Medical College, Kishanganj, Bihar, India
4 Department of Anesthesiology, North Bengal Medical College, Darjeeling, West Bengal, India

Date of Submission24-Sep-2015
Date of Acceptance07-Apr-2016
Date of Web Publication31-Aug-2016

Correspondence Address:
Dipasri Bhattacharya
B26/10, Abhyudoy Housing, EKTP, Kolkata - 700 107, West Bengal
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1687-7934.189104

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Background and objective
Postdural puncture headache (PDPH) is a very distressing symptom after spinal anesthesia. It usually resolves spontaneously but may extend the length of hospital stay. Although there are different measures to reduce the incidence, most of the times, none of them are effective. Paracetamol is commonly used for the treatment of PDPH. Pregabalin is recently being used for PDPH with effective results. In this study, our aim was to compare the respective effects of paracetamol, pregabalin, and their combination in the treatment of PDPH.
Patients and methods
In total, 150 patients who had undergone major gynecological surgery under spinal anesthesia and subsequently developed PDPH (diagnosed by postdural components of the pain) were randomly allocated by using computer-generated random numbers placed in sealed opaque envelopes. The patients were allocated into three equal groups (n = 50, each group) to receive orally either a single dose of 150 mg pregabalin (group 1) or 1000 mg of paracetamol (group 2) or a combined dose of paracetamol 1000 mg plus pregabalin 150 mg (group 3). All the patients received the same drug that they had originally received, if required, and were then followed up for 4 days. A patient's headache was scored using the visual analogue scale.
Earlier relief from PDPH and favorable adverse event profile (overall and central nervous system-related) were found in for the pregabalin–paracetamol combination compared with either of the drugs being used alone (P < 0.05).
It was concluded that the pregabalin–paracetamol combination is a better option for the treatment of PDPH compared with both of the drugs when used alone.

Keywords: analgesia, major gynecological surgery, paracetamol, postdural puncture headache, pregabalin

How to cite this article:
Bhattacharya D, Paul S, Naskar S, Mitra M, Mandal M. Comparison of the respective effects of paracetamol, pregabalin, and their combination in the treatment of postdural puncture headache following major gynecological surgery. Ain-Shams J Anaesthesiol 2016;9:387-92

How to cite this URL:
Bhattacharya D, Paul S, Naskar S, Mitra M, Mandal M. Comparison of the respective effects of paracetamol, pregabalin, and their combination in the treatment of postdural puncture headache following major gynecological surgery. Ain-Shams J Anaesthesiol [serial online] 2016 [cited 2021 Oct 17];9:387-92. Available from:

  Introduction Top

Postdural puncture headache (PDPH) is a distressing problem after spinal anesthesia. The incidence of disabling headache following dural perforation ranges from 0.3 to 20% in patients who undergo spinal anesthesia [1]. PDPH may occur within 2 days following spinal anesthesia but may be delayed for as long as 2 weeks and resolves spontaneously within a few days in 30% cases [2],[3]. Factors that affect the incidence of PDPH are as follows: age, sex, pregnancy, needle size, and number of attempts [4]. The classic symptoms of PDPH are photophobia, nausea, vomiting, neck stiffness, tinnitus, diplopia, and dizziness, as well as severe cephalalgia most often [5]. Overhydration, paracetamol, NSAIDs, oral caffeine, theophylline, corticotropin, sumatriptan, epidural saline injection, and epidural blood patch are the most common treatment options [2],[3].

Paracetamol, a COX-3 inhibitor, is commonly used in the treatment of PDPH [5]. Pregabalin, an antiepileptic drug and a structural analogue of GABA, has been tried recently and has resulted in a significant decrease in the severity of PDPH [6],[7]. Pregabalin is rapidly absorbed and its bioavailability exceeds 90%, which may produce more predictable patient response [8].

We have undertaken the study to compare between the respective effectiveness of pregabalin, paracetamol, and a combination of both for the management of PDPH following a major gynecological surgery under spinal anesthesia.

  Patients and methods Top

After obtaining approval from the institutional ethics committee and receiving patients’ informed consent, the patients who developed PDPH subsequently after undergoing elective major gynecological surgeries were recruited for the study. Only patients aged 18–55 years, weighing between 45 and 70 kg, and belonging to the American Society of Anesthesiologists physical status I and II were included in the study spanning from January 2012 to December 2014. Exclusion criteria were patients of American Society of Anesthesiologists III or more with a history of cardiovascular or respiratory disease, dizziness or frequent headache or drug usage, impaired renal and/or hepatic function, and pregnant patients.

All patients who met the inclusion criteria were hydrated with 0.5 l of intravenous Ringer's lactate solution before the procedure. Standard monitoring used included noninvasive arterial blood pressure, heart rate, pulse oximetry (SpO2), and ECG. Dural puncture was performed at the L3–L4 interspace, in the sitting position, using a midline approach with a 25-G Whitacre spinal needle. The bevel of the needle was kept parallel to the dural fibers. After observing the flow of cerebrospinal fluid (CSF) through the needle, 3 ml (15 mg) of 0.5% hyperbaric bupivacaine was injected. For all patients, spinal anesthesia was induced with a single puncture by the same person.

When block level reached T6 ± 1 dermatome level, surgical procedures were successfully carried out under spinal anesthesia. In total, 150 patients who had undergone major gynecological surgery under spinal anesthesia and subsequently developed PDPH (diagnosed by postural components of the pain) were randomly allocated to one of the three groups by using the block randomization method. Thus, one patient had every chance to get allocated in any group and to receive any mode of therapy. Allocation concealment was achieved by placing the computer-generated random numbers in opaque sealed envelopes, which were handled by an independent nurse blind to the group allocation method. Thus, the patients were allocated into three equal groups (n = 50, each group) to receive orally either a single dose 150 mg of pregabalin (group 1) or 1000 mg paracetamol (group 2) or a combined dose of paracetamol 1000 mg and pregabalin 150 mg (group 3). All the patients received the same drug that they originally received, if required, and were followed up for 4 days. A patient's headache was scored using the visual analogue scale (VAS) where the pain intensity of headache ranged from 0 to 100 mm (0 = no pain, 100 = worst possible pain).

According to the anamnesis (severe VAS: 80–90 mm, dull permanent and nonthrobbing pain in the fronto-occipital location) and examination findings (moderate to severe headache when sitting or ambulating and no neck stiffness), it was decided that they had PDPH [6].

The time of drug administration (single dose or subsequent dose) was noted and the time of relief from PDPH was also noted. All medications were provided to the nurse by an independent anesthesiologist and were administered orally with sips of water. The patients were observed for relief from headache. The randomization results were not disclosed until data analysis to ensure blinding.

Statistical analysis

A sample size of 42 patients for each group was calculated, setting the power of the study at 80%, confidence interval at 95%, and a margin of error accepted to 5%. The level of significance was 0.05. Considering a dropout possibility of about 15–20% owing to patient refusal, altogether 150 patients were recruited.

The quantitative data such as age, weight, height, time of medicine dose, time of subsidence of headache, etc., were statistically expressed as mean ± SD and were analyzed using one-way analysis of variance with post-hoc least significant difference, whereas the qualitative data such as number of patients requiring ‘subsequent doses’, ‘requiring more than two doses’, overall adverse events, central nervous system (CNS)-related adverse events, etc., were expressed as number and percentages, and were analyzed using the χ2-test or Fisher's exact test as appropriate. Pearson's correlation coefficient or multiple linear regressions (enter method) were used where appropriate. A P value of less than 0.05 was considered statistically significant. For the estimation of sample size and data analysis, we used the Epi Info statistical program version 3.4.3 (Centers for Disease Control and Prevention, Atlanta, Georgia, USA) and statistical package for the social sciences (SPSS, version 19.0 for Windows; SPSS Inc., Chicago, Illinois, USA).

  Results Top

Age of the study participants was 39.52 ± 8.30 years (mean ± SD) with a range of 18–55 years. The continuous predictor variables were found to follow normal distribution pattern as ascertained by the histogram and normal curve.

The outcome variable ‘time for subsidence of headache’ was found to have no significant linear correlation with predictor variables — for example, age (r = −0.018, P = 0.829), BMI (r = 0.077, P = 0.352), initial VAS score (r = 0.077, P = 0.350), and the onset of headache after surgery followed by administration of medicines (r = −0.118, P = 0.151). In multiple linear regression, statistically significant results were found when paracetamol was considered as the dummy variable [Table 1] and only 6.3% variability in the ‘time taken for subsidence of headache’ could be explained by the predictor variables like age, BMI, time for onset of headache, initial VAS score, and medicines given to manage the headache, which meant the time interval between the application of medicine and subsidence of headache seemed to be independent of the input variables considered. The total regression was found to be significant (F = 2.453; [Table 2] and the significant regression coefficient for the dummy variable meant that paracetamol required 10.398 min more for relieving headache compared with the pregabalin group [Table 3].
Table 1 Model summary

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Table 2 Analysis of variancea

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Table 3 Coefficientsa

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However, judging from the intergroup distribution of variables all demographic parameters and ‘time of medicine dose’ were comparable except the time interval for subsidence of headache, which was found to be significant [Table 4]. When multiple comparisons between the groups were carried out, the variation in ‘time to subsidence of headache’ was found to be significant between groups 2 and 3 and groups 1 and 3 [Table 5], indicating that the effectiveness of pregabalin plus paracetamol combination was better than either of the drug alone. Moreover, pregabalin alone also appeared not to be superior to paracetamol alone. It was further substantiated by judging other outcome parameters of the groups treated by three different regimens of analgesics. However, the proportion of patient requiring ‘subsequent doses’ for analgesia, including the percentage of subjects needing ‘more than two doses’, were significantly more in group 3 — that is, receiving both drugs in combination (Table 6). But the incidence of adverse events, both ‘overall’ and ‘CNS-related’, was found to be higher in groups 1 and 2 — that is, receiving pregabalin and paracetamol, respectively. However, only the difference for overall adverse event was found to be statistically significant [Table 6].
Table 4 Intergroup distribution of variables (analysis of variance)

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Table 5 Multiple comparisons between the groups

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Table 6 Comparison of some other attributes among the three groups

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  Discussion Top

PDPH is a well-established complication after spinal anesthesia in which the dura mater of the spinal cord is punctured. There is a considerable variability in the incidence of PDPH, which is affected by many factors such as age, sex, pregnancy, and needle type and size. The incidence is 40% with a 20 G needle; 25% with a 25 G needle; 2–10% with a 26 G needle, and less than 2% with a 29 G needle [3]. However, technical difficulties are common when spinal block is attempted with needles sized 29 G or smaller. Most experts agree that 25–26 and 27 G needles probably represent the optimum needle size for spinal anesthesia [4]. The actual mechanism producing PDPH remains unclear. The widely accepted theory explaining the pathophysiology of PDPH is based on the assumption of persistent leakage of CSF through the hole made by the spinal or epidural needle and a decrease in the CSF volume or pressure, or both, which leads to shifts in intracranial contents and traction on pain sensitive structures. Loss of CSF leads to intracranial hypotension and a demonstrable reduction in CSF volume and pressure. The adult subarachnoid pressure of 5–15 cmH2O may be reduced to 4 cmH2O or less. The rate of CSF loss through the dural hole is generally greater than the rate of CSF production, particularly with needle sizes greater than 25 G [4]. Therefore, we used 25 G needle. As the Whitacre needle does not cut fiber but separates it, the incidence of PDPH is less [4]. The sudden decrease in the CSF volume may also activate adenosine receptors, thus producing arterial and venous vasodilatation and subsequently clinical symptoms of PDPH [4].

Headache is described as severe, ‘searing and spreading like hot metal’, distributed over the frontal and occipital areas and radiating to neck and shoulders. Neck stiffness may be present. Pain is exacerbated by head movement, and in upright posture, and relieved by lying down. An increase in severity of headache on standing is the hallmark of PDPH. Other symptoms include nausea, vomiting, hearing loss, tinnitus, vertigo, dizziness, paresthesia of the scalp, upper and lower limb pain, visual disturbances, and cranial nerve palsies [9]. Neurological symptoms may precede the onset of grand mal seizures. Overall, 72% of the headaches have been shown to resolve within 7 days, whereas 87% take up to 6 months to resolve [10].

Paracetamol is widely used in treating PDPH. Recent research has shown the presence of a new, previously unknown cyclooxygenase enzyme COX-3, found in the brain and spinal cord, that is selectively inhibited by paracetamol, and is distinct from the two already known cyclooxygenase enzymes, COX-1 and COX-2. It is now believed that this selective inhibition of the enzyme COX-3 in the brain and the spinal cord explains the effectiveness of paracetamol in relieving pain and reducing fever without unwanted gastrointestinal side effects [11].

Pregabalin has a similar pharmacologic profile as gabapentin [1-(aminomethyl)cyclohexane acetic acid], but its exact mode of action is still unclear [12],[13]. Biochemical studies have identified the α2δ (type 1) receptor as the primary binding site for both gabapentin and pregabalin [14]. Binding of pregabalin to the α2δ subunit of voltage-gated calcium channels alters the kinetics and voltage dependence of calcium currents [15]; by reducing the calcium influx at nerve terminals, pregabalin reduces the release of several neurotransmitters, including glutamate, noradrenaline, calcitonin, gene-related peptide, and substance P [16]. This reduction in neurotransmitter release is presumed to account for pregabalin's analgesic actions. Binding affinity for the α2δ subunit, and potency, is six times more than that of gabapentin [17]. Upregulation of the α2δ subunit may play an important role in the hypersensitization processes [18]. Pregabalin inhibits modulation of neuronal excitability [19], particularly in areas of the CNS dense in synaptic connections such as the neocortex, amygdala, and hippocampus [20].

As with gabapentin, pregabalin is inactive at GABAA and GABAB receptors, is not converted metabolically into GABA or a GABA antagonist, and it does not alter GABA uptake or degradation [21]. N-type calcium channels are thought to have a role in pain sensitization processes where pregabalin binds and reduces pain [22]. Pregabalin has no effect on arterial blood pressure or cardiac function. It has a linear pharmacokinetic profile [8]. Although the actual mechanism of action of pregabalin is not clear, a few studies have shown its efficacy and safety for the management of PDPH [6],[7],[23]. The authors’ clinical experiences and the result of the present study are in agreement with that. The present study demonstrated that a combination of 150 mg pregabalin and1000 mg paracetamol is much effective than pregabalin and paracetamol alone. The former is commonly used as the first line drug for the management of PDPH. Although the group receiving paracetamol alone required around 10.4 min more than the pregabalin group to relieve headache and is significant on judging the regression coefficient for the dummy variable, it is clinically not significant. Further study is warranted with adequate power to find any significant difference between pregabalin and paracetamol alone. Future studies would evaluate whether pregabalin can be a better viable alternative than paracetamol alone.

  Conclusion Top

Combination of pregabalin and paracetamol is an effective method of treating PDPH compared with both of them used alone in major gynecological surgery under spinal anesthesia.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]


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