Due to the fact that general anesthesia is associated with an increased risk of death in cesarean delivery, spinal anesthesia is currently used as the preferred method for cesarean delivery (1). The odds of maternal death and postpartum infection is significantly higher in women with cesarean section (2). Other complications following cesarean delivery are infection bleeding, placenta accreta and abdominal adhesions (3, 4).
One of the most common complications, which is related to the cesarean section after post spinal is headache which is caused by cerebrospinal fluid leakage. The prevalence of post-spinal headache is relatively higher in obese and young pregnant women (5-8). Previous studies have demonstrated a wide prevalence range of post-spinal headache, about 1-32% and higher (9-11).
The pain is dull or fluctuating; it is more painful when standing up and it is better at the bed time. This pain is often accompanied by symptoms such as stiff neck, tinnitus, hearing loss, photophobia and nausea (12). According to the evidence, post-spinal headache has been reported in approximately 30% of the patients, who  have undergone lumbar puncture (13, 14).
There are various treatment methods such as oral caffeine, over hydration and some medications including: gabapentin, pregabalin and hydrocortisone for post-spinal headache (15-19). The gold standard treatment is an epidural blood patch.
Autologous blood transfusion into the epidural space of the lumbar spine creates a clot which is particularly attached to the dura mater; it patches the perforation directly, thus, prevents cerebrospinal fluid (CSF) leakage. The volume of blood injected into the epidural space also increases CSF pressure, and therefore reduces traction in the brain and meningeal structures. Finally, it leads to the release of symptoms (20). Given that epidural blood patch is an invasive treatment method, medical therapy may be preferable (1).
Gabapentin is a structural analogue of gamma amino butyric acid; it was used as an anticonvulsant drug for the first time. This drug is now applied in diabetic neuropathy, neuropathic cancer pain and inflammatory injury (21, 22). Theophylline as a form of methyl xanthine, is an adenosine receptor antagonist and can decrease intracranial blood flow and venous enlargement (23).
Evidence shows that intravenous theophylline infusion is a rapid, effective, non-invasive, practical and low-cost method to treat post-spinal headache (24-26).
As mentioned above, invasive methods for post spinal headache have complications. Oral medication is difficult when the patient has nausea and vomiting; efficacious, fast-acting, useful and harmless method is desired. There are limited reports about the effect of theophylline and gabapentin on post-spinal headache. Therefore, in this study we compared the effect of gabapentin and theophylline on post-spinal headache after cesarean section in Zanjan City, Iran.
 

In the present study, 129 patients who underwent spinal anesthesia due to cesarean section and with post-dural puncture headache (PDPH) were screened. Of these, five patients did not meet the inclusion criteria, and 4 patients denied to participate. Therefore, 120 patients were evaluated in the two groups. These patients were randomly assigned to the groups (60 patients in Gabapentin group and 60 patients in Theophylline group) (Figure 1).

Figure 1. Flowchart on the allocation of patients to the study groups

In Table 1, we compared age and anthropometric characteristics of patients in the two investigated groups. As it was shown, both groups were homogenous in regards of baseline age, weight and BMI (P>0.05), while the mean height of patients in the two groups was significantly different (P=0.013).

 
Table 1. Age and anthropometric characteristics of patients in Theophylline and Gabapentin groups

In Table 2, the pain score at 0, 8, 16 and 24 hours after the onset of pain has been compared between the two groups. There were not any significant differences in terms of VAS score between the two groups, in the pre- intervention phase and 8 and 16 hours after the intervention; VAS score was significantly lower in the theophylline group 24 hours after the intervention (0.7±1.79 vs. 2.23±2.58, P=0.014).

 
Table 2. Mean pain in the two groups receiving Theophylline and Gabapentin

In Figure 2, we showed the VAS score in specific times; the VAS reduced at 8, 16 and 024 hours after the intervention compared to the pre-intervention, in the two investigated group. The reduction of VAS score at 8 (3.14 vs. 2.67), 16 (4.7 vs. 3.47) and 24 (5.5 vs. 3.8) hours after the intervention was higher compared to pre-intervention in patients who received theophylline.
 

Figure 2.  Mean pain reduction in the two groups receiving Theophylline and Gabapentin at 8, 16 and 24 hours after the intervention compared to the pre-intervention

Discussion

This study demonstrated that the reduction in the VAS score only within 24 hours was significantly higher in the theophylline group (200 mg each 8 hours) compared to the gabapentin group (400 mg each 8 hours). Both gabapentin and theophylline were effective on post-spinal headache, but theophylline was more effective in pain relief within 24 hours.
Although our results suggest that both medications can successfully reduce the post-spinal headache, we did not find any studies, which compared the effects of gabapentin and theophylline on post-spinal headache after cesarean section. However, the effect of gabapentin or theophylline on post-spinal headache have been evaluated in separate studies. 
In 2013, Mahmoori et al. conducted a study to evaluate the efficacy of theophylline and acetaminophen on post-spinal headache treatment. The results showed that the main VAS score was significantly lower in the patients in the theophylline group. Therefore, it seems that theophylline is a safe and effective drug for post-spinal headache. Also, no adverse effects were seen in their study (25).
Wu et al. (2016) evaluated the efficacy and safety of intravenous (IV) injection of aminophylline on post-spinal headache in their study. The results showed that intravenous injection of aminophylline was an effective and safe early-stage treatment for post-spinal headache (24). These results were in line with our findings.
In consistence with our findings, in 2006, Erol et al. showed that oral administration of gabapentin in patients with post-spinal headache significantly reduces the pain score, nausea and vomiting in patients with post-dural puncture headaches (22). Beneficial effects of gabapentin on the management of patients with post-dural puncture headaches also has been shown in a study by Wagner et al. (27). Inconsistent with our results, Nofal et al. (2014) revealed that gabapentin has no effects on incidence of post-dural puncture headache, but  it delays the onset of headache and reduces its severity and duration in parturient undergoing cesarean section with spinal anesthesia (28).
Theophylline is a form of methyl xanthine. This drug acts as an adenosine receptor antagonist and reduces intracranial blood flow as well as vein enlargement (23). The methyl xanthine acts via following mechanisms: (1) Interference with calcium absorption by the sarcoplasmic reticulum; (2) phosphodiesterase block activity, and (3) antagonizing the effects of adenosine. Moreover, Methyl xanthine increases CSF production through stimulating sodium–potassium pumps (29). Theophylline is also thought to manage this condition by controlling compensatory vasodilatation repairs of low CSF pressure or CSF leakage (29).
Gabapentin is an anti-epileptic drug and a structural analogue of Gamma-Aminobutyric acid (GABA). It was approved as an effective agent to manage the neuropathic pains by Food and Drug Administration (FDA) in 2002.
Limitation of this study was the small sample size. Therefore, it is suggested to conduct similar studies with larger sample sizes using other settings and by considering the side effects of these drugs.
 

Conclusion

The present clinical trial study showed that reduction in the VAS score only within 24 hours was significantly higher in the theophylline group compared to the gabapentin group. Both gabapentin and theophylline were effective against post-spinal headache, but theophylline was more effective than gabapentin in pain relief within 24 hours.

 

Acknowledgements

This study was supported by Zanjan University of Medical Sciences. We gratefully acknowledge the kind support of the participants for their precious collaboration in this study as well as staff of Mousavi Hospital.

 

Conflicts of Interest

The authors have no conflicts of interest to declare.