Published Ahead of Print on March 23, 2018 as 10.1212/WNL.

0000000000005351
ARTICLE

Aminophylline for treatment of postdural

puncture headache
A randomized clinical trial
Chuanjie Wu, MD, Dongsheng Guan, MD, Ming Ren, MD, Zhengfei Ma, MD, Changming Wan, MD, Correspondence
Yinglin Cui, MD, Ping Zhong, MD, Wenbo Zhao, MD, Chuanhui Li, MD, Feng Yan, MD, Jinqiu Xie, MD, Dr. N. Xie
Fang Xue, MD, Yajun Lian, MD, Hongbo Liu, MD, Cui Wang, MD, Xunming Ji, MD, and Nanchang Xie, MD xienanchanghn@163.com

®
Neurology 2018;0:1-7. doi:10.1212/WNL.0000000000005351

Abstract
Objective
To investigate the efficacy and safety of IV aminophylline for patients with postdural puncture
headache (PDPH).

Methods
We randomly assigned patients to groups receiving either 250 mg IV aminophylline or a pla-
cebo within 3 hours of symptom onset once daily for 2 consecutive days. The primary endpoint
was headache severity 8 hours after treatment. We assessed this using visual analog scale (VAS)
scores taken from patients in a standing position. We also recorded posttreatment VAS score
changes, Patient Global Impression of Change (PGIC) scores, and adverse events. We per-
formed an intention-to-treat analysis.

Results
We enrolled 126 patients with PDPH at 5 centers in China (62 assigned to the aminophylline
group and 64 to the placebo group). The median age was 37 years, and 96 (76.2%) patients
were women. Compared to the placebo-treated patients, the aminophylline-treated patients
had significantly lower mean VAS scores 8 hours after treatment (5.34 vs 2.98, p < 0.001) and
were significantly more likely to report improvements on the PGIC (39.1% vs 72.6%, p < 0.01).
This therapeutic effect was already evident at the 30-minute time point and persisted for 2 days.
There was no significant difference in the incidence of adverse events (4.8% vs 1.6%, p = 0.589).

Conclusions
IV aminophylline is an effective and safe early-stage treatment for patients with PDPH.

ClinicalTrials.gov identifier
NCT02522013.

Classification of evidence
This study provides Class I evidence that for people with PDPH, IV aminophylline reduces
headache severity.

From the Department of Neurology (C. Wu, Y.L., H.L., C. Wang, N.X.), First Affiliated Hospital of Zhengzhou University; Department of Neurology (D.G., Y.C.), Second Affiliated Hospital
of Henan University of Traditional Chinese Medicine; Department of Neurosurgery (M.R., W.Z., C.L., F.Y., X.J.), Xuanwu Hospital Capital Medical University, Beijing; Department of
Neurology (Z.M., P.Z.), Suzhou Municipal Hospital, Anhui; Department of Neurology (C. Wan, J.X.), Jinzhou Central Hospital, Liaoning; and Department of Neurology (F.X.), Second
Hospital of Hebei Medical University, Shijiazhuang, China.

Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

Copyright © 2018 American Academy of Neurology 1

Copyright ª 2018 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
 Glossary
EBP = epidural blood patch; PDPH = postdural puncture headache; PGIC = Patient Global Impression of Change; VAS =
visual analog scale.
Postdural puncture headache (PDPH) is among the most
common complications of lumbar punctures performed for
spinal anesthesia or neurologic investigation, with inci-
dence rates of 8% to 37% reported in different studies.1,2 The
common treatments currently for PDPH include rehydration,
nonsteroidal anti-inflammatory drugs, caffeine, sumatriptan,
and epidural blood patches (EBPs).3 EBPs provide effective,
long-lasting relief for many patients.4 The success rate of
therapeutic EBPs ranges from 77% to 96%,5,6 but they are an
invasive technique that probably increases the risk of com-
plications, including epidural infection, transient or persistent
neck or back pain, radicular symptoms, and meningeal irri-
tation symptoms.7 Thus, safer, better tolerated, and more
effective treatments for PDPH are needed.
We have previously reported that IV aminophylline injections
may be an effective and safe early-stage treatment for PDPH,
but this was in a single-arm preliminary study that did not
compare aminophylline to a placebo group or current standard
treatments for PDPH.8 Given that PDPH is usually a self-
limiting disease, we aimed to verify the therapeutic efficacy and
safety of IV aminophylline for PDPH by conducting a multi-
center, randomized, double-blind, placebo-controlled study.
Methods
Standard protocol approvals, registrations,
and patient consents
The executive committee and study site investigators designed
the study and performed data collection and analysis. The ethics
committee and research board of each participating center ap-
proved the study protocol, conducted according to the principles
of the Declaration of Helsinki. All patients or their legal repre-
sentatives provided written informed consent before enrollment.
All authors vouch for the accuracy and completeness of the data
and for the fidelity of this report of the study protocol. The study
is registered on clinicaltrials.gov (NCT02522013).
Participants
This was a randomized, double-blind, placebo-controlled, and
parallel-group clinical trial of IV aminophylline injections for
treating patients with PDPH. We conducted the study at 5
centers in China (the First Affiliated Hospital of Zhengzhou
University, the Second Hospital of Hebei Medical University,
the Second Affiliated Hospital of Henan University of Tra-
ditional Chinese Medicine, Jinzhou Central Hospital, and
Suzhou Municipal Hospital).
The inclusion criteria for patients were being 18 to 70 years
old, having a headache that developed after dural puncture,
2 Neurology | Volume , Number  | Month 0, 2018
Copyright ª 2018 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
having PDPH as defined by the International Classification of
Headache Disorders, 3rd edition (beta version) criteria, and
reporting a visual analog scale (VAS) score for the headache
of ≥5. The reasons for lumbar puncture included parturition
(subarachnoid anesthesia, epidural anesthesia, or concomi-
tant subarachnoid and epidural anesthesia), possible central
nervous demyelinating disease, possible central nervous in-
fection, and possible nervous system tumor. We did not
specify a uniform spinal needle type for all centers.
The exclusion criteria were having a history of headache that
could interfere with the PDPH diagnosis; having a history of
central nervous system diseases, including intracranial hemor-
rhage, seizures, intracranial hypertension, or hydrocephalus;
having a history of cardiovascular diseases, including coronary
heart disease, arrhythmias, or hypertension; having a history of
peptic ulcers; or being pregnant, nursing, or planning a preg-
nancy. We required women of childbearing potential to have
a negative pregnancy test result before the injection.
Randomization and masking
We randomly assigned the patients in a 1:1 ratio to groups
receiving either aminophylline or placebo. The randomization
procedure was computer based with the use of permuted
blocks. We stratified randomization by medical center and in-
dication for lumbar puncture. After randomization, we assigned
each patient a unique code according to the randomization list.
This unique number corresponded to an investigational drug.
Investigators did not have access to the randomization (treat-
ment) code except under exceptional circumstances such as the
occurrence of a serious adverse event for which knowledge of
the study medication was considered essential for treating the
patient.
We stored all investigational drugs used in the study in a se-
cure place in the pharmacies under the responsibility of one of
the authors (C. Wang) or another authorized individual and
under the conditions described on the labeling. The 2 types of
study drugs (active aminophylline and placebo) were in-
distinguishable in both powder and solution and identical in
packaging, color, and appearance. Minor side effects are un-
usual with the study dose of aminophylline, so we did not
anticipate that either patients or clinicians would be able to
distinguish the active drug from the placebo. Standard labo-
ratory tests cannot detect the effects of aminophylline.
Interventions
To ensure that the interval between the headache onset and the
initial treatment was within 3 hours, we recommended that all
patients who satisfied the inclusion and exclusion criteria were
randomized within 2 hours of the PDPH diagnosis.
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The aminophylline group received 250 mg aminophylline
dissolved in 100 mL saline for IV injection. The clinicians
administered each injection over ≥30 minutes once daily for 2
consecutive days. We selected this dose because it was effec-
tive in our previous study.8 The placebo group received iso-
choric, isotonic saline injections (the placebo was also
dissolved in 100 mL saline) on the same schedule. The par-
ticipants received no other treatment for PDPH during the
intervention period.
Efficacy and safety measures
All patients were hospitalized at the study sites during the
follow-up period. The primary endpoint was headache se-
verity 8 hours after the first treatment, which has been used as
an endpoint in our previous study8 and other studies.9,10 The
clinicians assessed this using an 11-point VAS (0 = no head-
ache, 10 = worst possible pain) taken from standing patients
who had lain flat for ≥10 minutes and then stood for 5
minutes. The clinicians also recorded VAS scores at 30
minutes, 1 hour, 1 day, and 2 days after treatment. The
clinicians recorded the 1-day VAS scores immediately before
the second injection.
The secondary outcomes included overall treatment respon-
ses on the Patient Global Impression of Change (PGIC) at 2
days after treatment. The PGIC is a self-evaluation of the
patient’s overall change since the start of the study according
to a 7-point Likert scale (1 = very much improved, 2 = much
improved, 3 = minimally improved, 4 = no change, 5 =
minimally worse, 6 = much worse, 7 = very much worse).
We assessed safety on the basis of the occurrence of adverse
events, which the clinicians recorded and documented with
information regarding the onset dates, severities, durations,
frequencies, relationships to study treatment, treatments re-
quired (if any), and outcomes. The clinicians also monitored
body temperature, pulse, respiration, blood pressure, and
ECG results before, during, and after the treatment.
Statistical analysis
We performed all analyses in the intention-to-treat pop-
ulation. We implemented statistical analyses using SPSS for
Windows (version 19.0, IBM, Armonk, NY). The results are
expressed as percentages for categorical variables, as means ±
SDs for normally distributed continuous variables, and as
medians (with interquartile ranges) for nonnormally distrib-
uted continuous variables. We used the Kolmogorov-Smirnov
test to assess the normality of data distributions. We used the
χ 2 test or Fisher exact test for categorical variables and the
Student t test or Mann-Whitney U test for continuous vari-
ables. We used repeated-measures analyses of variance on
different time points to assess posttreatment VAS scores. We
defined statistical significance as p < 0.05 (2 sided).
We calculated the sample size on the basis of the means and
SDs observed for pain scores in our previous trials.8 We as-
sumed that the mean VAS score decrease of the placebo group
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Copyright ª 2018 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
would be 50% at 8 hours after treatment, which means that
our sample size would have 90% power at p = 0.05 (2 sided).
Primary research question
Is IV aminophylline effective and safe for patients with
PDPH?
Classification of evidence
This study provides Class I evidence that for people with
PDPH, IV aminophylline reduces headache severity.
Results
Participants
Between August 2015 and October 2016, we assessed 183
patients at 5 Chinese centers for eligibility, and we enrolled
126 and randomized them to either the aminophylline (n =
62) or the placebo (n = 64) group (figure 1). The mean
infusion time was 46.4 ± 6.2 minutes in the aminophylline
group and 47.3 ± 5.6 minutes in the control group (p = 0.23).
These 2 groups were well balanced in their demographic and
clinical characteristics (table 1).
Efficacy
The aminophylline-treated group had significantly lower
mean VAS scores recorded 8 hours after treatment than the
placebo-treated group (aminophylline group 2.98 ± 1.46,
placebo group 5.34 ± 1.48, p < 0.001). The absolute mean
VAS change was 2.36 (95% confidence interval 1.82–2.90).
Repeated-measures analysis of variance indicated that ami-
nophylline treatment yielded significantly greater pain allevi-
ation than placebo (F = 68.09, p < 0.001) (figure 2). This
effect of aminophylline was already evident at the 30-minute
time point and persisted at later time points (figure 2 and table
e-1, links.lww.com/WNL/A383).
On the PGIC, 45 (72.6%) aminophylline-treated patients
reported that their pain symptoms were much improved or
very much improved, whereas only 25 (39.1%) placebo-
treated patients did the same (p < 0.01) (figure 3). The ab-
solute risk reduction was 33.5%, and the number needed to
treat was 3.0.
Safety
The 2 groups did not differ significantly in the incidence of
adverse events (aminophylline group 4.8%, placebo group
1.6%, p = 0.589). Two aminophylline-treated patients experi-
enced mild palpitations and chest tightness ≈1 hour after
treatment, and 1 patient withdrew from the study. ECG and
emergency myocardial enzyme tests revealed no abnormalities,
and the symptoms gradually disappeared within ≈30 minutes.
One aminophylline-treated patient had an allergic reaction ≈3
hours after the first treatment. This manifested as a red rash
over the trunk and limbs with moderate itching. This patient
withdrew from the study and received antihistamines. The rash
disappeared 2 days after the injection. In the placebo group, 1
patient experienced dizziness after treatment, but no special
Neurology | Volume , Number  | Month 0, 2018 3
 Figure 1 Flowchart of study patients
VAS = visual analog scale.
treatment was given. The symptom disappeared within 3 hours,
but this patient also withdrew from the study. For all patients,
common adverse reactions such as nausea, vomiting, insomnia,
diarrhea, tremor, and diuresis, as well as serious reactions such
as seizures, arrhythmias, hypotension, shock, and exfoliative
dermatitis, did not occur.
Two aminophylline-treated patients and 6 placebo-treated
patients withdrew from the study because of a lack of per-
ceived efficacy. Two placebo-treated patients withdrew be-
cause of noncompliance.
Discussion
In this double-blind, placebo-controlled, multicenter clinical trial
involving patients with PDPH, we found that early application of
aminophylline achieved a greater-than-placebo reduction of pain
intensity and that this effect persisted at all follow-up time points.
The incidence of adverse effects with IV aminophylline was not
significantly greater than that with placebo treatment. Among
our more intriguing findings is the fact that aminophylline pro-
duced significantly greater-than-placebo scores on the PGIC,
4 Neurology | Volume , Number  | Month 0, 2018
Copyright ª 2018 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
which is suitable for assessing overall changes in PDPH,11 which
may be accompanied by other subjective symptoms such as
nausea and neck stiffness.12
These results confirm those obtained in our previous open
study, which indicated that aminophylline may be a useful
therapeutic strategy for PDPH.8 Other studies have found
that aminophylline is also useful for preventing PDPH.13,14 In
addition, a previous study found that theophylline injections
alleviated headaches within 4 hours.15 Aminophylline is the
pharmacologically active metabolite of theophylline, but other
drugs in the same family or even different formulations of the
same drug could have different pharmacologic effects.16
Furthermore, in China and other countries, aminophylline
has already replaced theophylline because of the unavailability
of theophylline. We therefore used aminophylline instead of
theophylline in this study.
Aminophylline is a methylxanthine drug. Its therapeutic
mechanism in PDPH remains uncertain, although it is believed
to involve several factors. First, aminophylline may block
adenosine receptors,17 contract blood vessels,18 and block pain
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Table 1 Baseline characteristics of the patients
Total Aminophylline Placebo group
Characteristic (n = 126) group (n = 62) (n = 64)

Age, y 37 (29–54) 36.5 (29–53.3) 37.5 (28–55.7)

Women, n (%) 96 (76.2) 49 (79.0) 47 (73.4)

Height, cm 163.1 ± 7.2 162.9 ± 6.6 163.2 ± 7.8

Weight, kg 62.9 ± 9.9 63.8 ± 8.6 62.1 ± 11.1

Indication for lumbar puncture, n (%)

Parturition 57 (45.2) 27 (43.5) 30 (46.9)

Possible central nervous demyelinating disease 35 (27.8) 18 (29.0) 17 (26.6)

Possible central nervous infection 23 (18.3) 10 (16.1) 13 (20.3)

Possible nervous system tumors 11 (8.7) 4 (6.5) 7 (10.9)

Time from onset to randomization, min 53.2 ± 23.9 50.7 ± 23.7 55.7 ± 24.1

Time from randomization to treatment, min 34.5 ± 12.8 35.8 ± 12.7 33.2 ± 12.9

Pain intensity at baseline, VAS 7.32 ± 1.49 7.37 ± 1.52 7.27 ± 1.47

Abbreviation: VAS = visual analog scale.

Data are mean ± SD, number (percent), or median (interquartile range).

transmission through nociceptive structures.19 Second, it may
inhibit phosphodiesterase and raise intracellular cyclic adeno-
sine monophosphate levels.20,21 Third, it may suppress calcium
uptake by the endoplasmic reticula of endothelial cells,22
stimulate calcium-potassium pumps, and increase CSF secre-
tion.23 Doxofylline, another clinically used methylxanthine
drug, does not inhibit adenosine receptors.24 Compared to
theophylline and aminophylline, it has weaker effects on the
CNS.24 Future studies should examine whether it is also ef-
fective for PDPH.
Clinical pharmacology studies have shown that adverse
reactions to aminophylline appear mainly when plasma ami-
nophylline concentrations exceed 15 μg/mL.25 These adverse
reactions include nausea, vomiting, arrhythmia, and con-
vulsions. Our patients received an aminophylline dose lower
than that used for typical clinical treatments, and the infusion
speed was slower. It would therefore not have caused high
plasma concentrations, which explains the paucity of adverse
reactions in this study. EBPs are believed to be among the
most effective treatments for PDPH,26 but we did not com-
pare aminophylline to EBPs in this study. However, consid-
ering the invasive character of EBPs, the self-limiting character
of PDPH, and the observed safety and tolerability of ami-
nophylline infusions in this study, it may be reasonable to
apply aminophylline infusions as an optional acute-phase
treatment before applying EBPs. However, further studies
are needed to compare aminophylline infusions to other
treatments.
The IV administration route may have enhanced the early
analgesic effects of aminophylline by enabling rapid attainment
of therapeutic plasma concentrations. However, PDPH is
usually treated in outpatient settings in which oral adminis-
tration would be more feasible. Future studies should examine
whether orally administered aminophylline has the same effects
as intravenously administered aminophylline.
A well-known problem in daily clinical practice is the difference
between the conditions of randomized clinical trials and the
conditions of individual patients in regular medical practice.
Our participants received treatment within 3 hours of headache
onset, but longer intervals often occur before treatment initi-
ation in regular practice.27 This may limit the generalizability of
our findings. In a previous study, we described a 57-year-old
woman with PDPH who received aminophylline therapy 4
days after symptom onset. The aminophylline injection com-
pletely relieved her pain.28 Although limited data are available
for delayed aminophylline treatment, such treatment is still
worth attempting because, theoretically, the safety of ami-
nophylline does not change over time.
This study has several limitations. First, we did not specify
a uniform puncture needle type or a recommended body
position after the dural puncture. These factors may affect the
incidence of PDPH but may not affect PDPH treatment.
Furthermore, this variability reflects that encountered in
clinical practice settings. Second, although we assessed the
early-stage effectiveness of aminophylline, we did not assess
its effects beyond 2 days in this study because we feared that
some patients would be discharged by then, which could bias
the evaluation of efficacy. The long-term effects of ami-
nophylline on PDPH warrant further study. Third, we did not
use the pain relief rate as the endpoint, which is used in some

Neurology.org/N Neurology | Volume , Number  | Month 0, 2018 5

Copyright ª 2018 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Figure 2 Mean pain scores
clinical practices. However, the conclusion of our study would
not change even though we used the pain relief rate (a re-
duction of VAS by at least 50%) at 8 hours after treatment as
the endpoint. The pain relief rate was 71.0% (44 of 62) in the
aminophylline group and 15.6% (10 of 64) in the control
group (p ＜ 0.0001) after a post hoc analysis, which showed
that the 2 approaches of pain evaluation would lead to the
same conclusion for our study.
This 2-day follow-up, randomized, double-blind, placebo-
controlled trial generated encouraging results. Our study
shows that IV aminophylline injections may be a straightfor-
ward, safe, and effective treatment for PDPH, especially in the
early stages. This makes aminophylline an attractive drug for
noninvasively managing PDPH.
Figure 3 Patient Global Impression of Change results
6 Neurology | Volume , Number  | Month 0, 2018
Copyright ª 2018 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Author contributions
Dr. Wu coordinated the study, performed statistical analysis,
and wrote the manuscript. Drs. Guan, Ma, Wan, and Cui con-
tributed to data acquisition. Drs. Zhong and Zhao supervised
the statistical analysis and designed the study. Drs. Li, Yan, Xie,
Xue, Lian, Liu, Wang, and Ji critically revised the manuscript for
important intellectual content. Dr. Ren analyzed the data, per-
formed statistical analysis, and revised the manuscript for in-
tellectual content. Dr. Xie was the chief investigator for this
study, supervised this study, and took responsibility for the final
submission of the manuscript.
Study funding
Study funded by grants from National Natural Science
Foundation of China (81701287, 81571260, 81701272),
China Postdoctoral Science Foundation, and Beijing Post-
doctoral Research Foundation.
Disclosure
The authors report no disclosures relevant to the manuscript.
Go to Neurology.org/N for full disclosures.
Received August 28, 2017. Accepted in final form January 25, 2018.
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Aminophylline for treatment of postdural puncture headache: A randomized clinical
trial
Chuanjie Wu, Dongsheng Guan, Ming Ren, et al.
Neurology published online March 23, 2018
DOI 10.1212/WNL.0000000000005351

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