A multicenter clinical study on treating post-dural puncture headache with an intravenous injection of aminophylline

The study postulates that an IV injection of aminophylline can be considered as an effective and safe early-stage treatment for post-dural puncture headache.

Post-dural puncture headache (PDPH) has been found to be the most common complication of lumbar puncture. Its clinical manifestations are pain in the forehead and the occipital region, or diffuse headache. The pain is dull or fluctuating, becoming worse when standing and better when lying down, and is often accompanied by symptoms including a stiff neck, tinnitus, hearing loss, photophobia, and nausea, which cause great suffering to the patients. Research on data suggest that 10% to 30% of the patients who undergo lumbar puncture suffer from PDPH within 48 hours of the procedure. Interestingly, the prevalence of PDPH is higher in obese young women and pregnant women. Currently, commonly used treatments for PDPH include rehydration, the administration of corticotropin, caffeine, or sumatriptan, and the application of an epidural blood patch (EBP). The efficacy of theophylline has been proven in a placebo-controlled study in which 17 PDPH patients received an intravenous (IV) injection of 200 mg theophylline. The visual analogic scale (VAS) scores 4 hours after treatment were significantly different compared with those of the placebo group. At present, the clinical application of theophylline has been replaced by aminophylline and doxofylline because it is difficult to purchase theophylline in most hospitals in China and other countries. In this particular study, the effectiveness and safety of an IV injection of aminophylline on PDPH was assessed.

Rationale behind research:

Aminophylline has been reported to be effective in the prevention of PDPH in some clinical studies, but its efficacy for the treatment of PDPH has been unproven.

Objective:

To evaluate the efficacy and safety of an intravenous (IV) injection of aminophylline on PDPH.

Study outcomes

• Primary Outcome: The degree of headache when patients were in a standing position. The degree of headache was evaluated using the VAS (an 11-point scale from 0-10 with 0 being no headache.
• Secondary Outcome: Response to Overall treatment as assessed on the basis of the Patient Global Impression of Change (PGIC) scale. PGIC is a score evaluated by the patients. In this study, patients gave scores according to their overall condition before and after treatment: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; 7, very much worse.
• Safety: The safety of IV aminophylline treatment for PDPH was evaluated on the occurrence of adverse reactions

Time Points: Baseline, 30 minutes, 1 hour, 8 hours and 2 days after treatment.

Outcomes

Primary Outcome: The VAS score of 32 patients before the first treatment was 7.72 ± 1.65. Thirty minutes after treatment, headaches of all, but 2 patients were relieved to different extents, and the VAS score was decreased to 4.84 ± 2.53. The headaches in 2 patients completely disappeared after the first treatment, resulting in VAS scores of 0. The degree of headache further declined over time; one hour after aminophylline administration the VAS score was decreased to 3.53 ± 2.06. Two days after treatment, the VAS score was 0.81 ± 1.79 and headaches in 24 patients (75.0%) completely disappeared. The VAS scores at different time points after treatment were all statistically significantly different compared with those before treatment (P < 0.05).

Figure 1: Degree of headache evaluated using the VAS

Secondary Outcome: More than 50% of patients reported that they were “very much improved” or “much improved” 30 minutes after the initial treatment, increasing to 93.8%, two days after treatment

Safety: During follow-up, one patient experienced an allergic reaction about 30 minutes after the first treatment. The clinical manifestation of the allergic reaction was red rash with moderate itch in the trunk and limbs. The patient discontinued the study and received antihistamine drugs. The red rash disappeared 3 days after the treatment. No other treatment-related adverse reactions were observed in this study.

This study primarily demonstrated that the IV injection of aminophylline may be a straightforward, safe, and effective treatment for PDPH, and has improved early-stage effectiveness.

Apart from assessing the long-term effectiveness of an IV injection of aminophylline, the effectiveness of early-stage treatment for PDPH was also evaluated. It was found that the VAS scores were substantially and statistically significantly decreased already half an hour after treatment. PDPH is often accompanied by tinnitus, hearing loss, photophobia, and nausea.

Therefore, PGIC was used to evaluate the changes in the overall patient condition half an hour after treatment: 53.1% of the patients described their condition as “very much improved” and “much improved.” In other countries, studies on theophylline for treating PDPH have not evaluated the efficacy of theophylline at the early stage after treatment. Only one study showed that VAS score decreased from 7.07 ± 1.47 to 2.88 ± 1.47 4 hours after theophylline treatment. Although there have been studies with small population sample sizes that showed that theophylline could treat PDPH and mountain sickness, there has been no report on treating PDPH with aminophylline.

This results of this study proved the safety and effectiveness of aminophylline. However, further double-blind, controlled multi-center studies using an adequate number of patients are required to validate the findings and to explore efficacy comparisons between an intravenous injection of aminophylline and other treatments.