- Email: [email protected]
Intravenous theophylline decreases post-dural puncture headaches
Available online at www.sciencedirect.com
Journal of Clinical Neuroscience 15 (2008) 1102–1104 www.elsevier.com/locate/jocn
Clinical Study
Intravenous theophylline decreases post-dural puncture headaches Ufuk Ergu¨n a,*, Bahar Say a, Gokhan Ozer a, Tugba Tunc a, Murat Sen a, Senem Tu¨fekcioglu b, Umit Akin a, Mustafa N. Ilhan c, Levent Inan a a
Department of Neurology, Ministry of Health, Ankara Training and Research Hospital, Nilgu¨n Sok. 4/3, Farabi, Cankaya, 06550 Ankara, Turkey b Department of Anaesthesiology and Reanimation, Atatu¨rk Training and Research Hospital, Ankara, Turkey c Department of Public Health, Gazi University Faculty of Medicine, Besevler, Ankara, Turkey Received 19 May 2007; accepted 6 November 2007
Abstract Post-dural puncture headache (PDPH) is a common complication of lumbar puncture. As invasive treatments for PDPH have known complications, pharmacologic management may be preferable. The aim of this study was to evaluate and to compare the efficacy of intravenous theophylline treatment for PDPH, in comparison with a placebo. We found that intravenous theophylline infusion was effective for decreasing the painfulness of PDPH compared with the control group. The mean visual analogue scale (VAS) value was 7.05 ± 1.47 before the theophylline infusion and 2.88 ± 2.31 after infusion. An average of 59.1% relief of pain was obtained in the group treated with theophylline infusion. The improvement in VAS in the study group was significant (p < 0.001), whereas that in the control group was not (p = 0.15). The mean VAS decrease after theophylline infusion was 4.17 ± 2.03 in the study group and 0.41 ± 0.71 in the control group; the difference in improvement between the groups was significant (p < 0.001). Intravenous theophylline infusion is an easy, rapid, minimally invasive, an effective treatment for PDPH. It may be attempted in PDPH patients before invasive techniques are used. To the best of our knowledge, this is the first report on the effect of intravenous infusion of theophylline compared with a placebo in the treatment of PDPH. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: Lumbar puncture; Headache; Theophylline; Cerebrospinal fluid; Orthostatic headache
1. Introduction Lumbar puncture (LP) is a routine technique performed for a variety of procedures, for example diagnosis, administration of drugs, myelography, and spinal anaesthesia. Post-dural puncture headache (PDPH) is a common complication (30–40%) of diagnostic LP.1 The International Classification of Headache Disorders – 2nd edition describes PDPH under paragraph 7.2.1.2 It typically begins within 2 days but may be delayed for as long as 2 weeks and resolves spontaneously within a few days. In one study, after LP, 1/ 3 of patients developed headache. Of these, 1/3 had severe headache, 1/3 moderate and 1/3 mild.3 Overhydration, per-
*
Corresponding author. Tel.: +90 532 393 59 57. E-mail address: [email protected] (U. Ergu¨n).
0967-5868/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2007.11.001
oral caffeine and theophylline, corticotropin, sumatriptan, epidural saline injection, and epidural patches are common treatments.1,3,4 PDPH can be avoided by using small-gauge needles and possibly by using the lateral approach, as opposed to the midline approach.4 Invasive treatments for PDPH have known complications, such as infection and exacerbation of pain.5 The efficacy of theophylline has been proven in a double-blind and placebo-controlled study. In a study of 11 patients with typical headache following diagnostic LP the effect of peroral treatment with 281.7 mg theophylline (Euphyllin retardÒ) was compared with that of a placebo and found to be effective.6 Pharmacological management of PDPH is a minimally invasive treatment modality. Severe headaches such as PDPH commonly present with nausea and this limits the
U. Ergu¨n et al. / Journal of Clinical Neuroscience 15 (2008) 1102–1104
effect of peroral medications. It would be useful to use parenteral medications for rapid and effective treatment and a non-invasive procedure is preferable. The aim of this study was to evaluate and compare the efficacy of intravenous theophylline for the treatment of PDPH in comparison with a placebo. 2. Materials and methods Patients who had undergone LP for diagnosis or epidural anaesthesia and subsequently developed PDPH were included in this study according to the exclusion and inclusion criteria listed below. Patients who had intracranial disorders (central nervous system infections, intracranial haemorrhage, hydrocephalus, intracranial hypertension, migraine, central nervous system malignancies, convulsions) or systemic disorders (hypertension, cardiac arrhythmia as determined by electrocardiography, hyperthyroid disorders) and those older than 65 years were excluded. Cranial MRIs and detailed neurological examinations were performed. This study was performed in accordance with the Helsinki Declaration, had local ethics committee approval, and all patients gave informed consent. The patients were divided into a study group and a control group. PDPH was defined according to the International Classification of Headache Disorders II (ICHD II) criteria. Patients were asked to describe the severity of their headache on a visual analogue scale (VAS) before and 4 h after medication, while in the standing position. Patients in the study group were given 200 mg intravenous theophylline (200 mg theophylline in 100 mL 5% dextrose) infusion over 40 min, and patients in the control group were given 100 mL 5% dextrose intravenously over 40 min. Then the two groups were asked for their VAS values 4 h after the infusion while in the standing position, and then the values were compared. Patients who reported a VAS decrease of <50% of pretreatment values 4 h after the theophylline infusion were given a second theophylline infusion under the same conditions. They were then asked for their VAS values again 4 h after the second infusion. The control group did not receive a second dextrose infusion. Statistical analysis was performed using SPSS V.13.0 (SPSS Inc., Chicago, IL, USA). VAS values before and after infusions in the study group and in the control group were compared using the Wilcoxon signed rank test. The Mann-Whitney U-test was used for comparing VAS values of the study and the control groups. Comparisons for age and gender were performed using the chi-squared test; pvalues <0.05 were considered significant. 3. Results The study group was composed of 10 (58.8%) women and seven (41.2%) men, aged 19–46 years. The control group was composed of eight (50%) women and eight
1103
(50%) men, aged 23–44 years. Mean age was 31.88 ± 7.55 years for the study group and 31.75 ± 6.32 years for the control group. Mean age and gender did not differ significantly between the two groups (p = 0.50, p = 0.73, respectively). None of the patients given a theophylline infusion reported any cardiac or other complaints. The study and the control groups did not differ significantly in terms of VAS values before the intravenous infusions (p = 0.27) but did differ significantly afterwards (p < 0.001). In the study group, a comparison of VAS values before and after theophylline infusion revealed a significant decrease afterwards (p < 0.001). Mean VAS values were 7.05 ± 1.47 for pre-infusion and 2.88 ± 2.31 for postinfusion in the study group. In the control group, although VAS values seemed to decrease after dextrose infusion, the difference was not significant (6.62 ± 1.66 for pre-infusion and 6.37 ± 1.58 for post-infusion, p = 0.15). The mean VAS score after theophylline infusion was 4.17 ± 2.03 in the study group and 0.41 ± 0.71 in the control group; the difference between the groups was significant (p < 0.001). Six patients (35.3%) needed a second theophylline infusion. VAS values were significantly decreased after this second infusion (p = 0.02). Mean VAS values were 5.66 ± 0.51 for pre-infusion and 2.33 ± 1.75 for post-infusion. Eleven (64.7%) patients did not need a second theophylline infusion. 4. Discussion Lumbar puncture is a well-known cause of orthostatic headaches, related to cerebrospinal fluid (CSF) leakage from the puncture site. The headaches typically begin within 2 days but may be delayed for as long as 2 weeks and resolve spontaneously within a few days.3 The overall incidence of PDPH has been reported to range from 1% to 75%.7 As a result of CSF leakage and CSF volume depletion, the brain descends. This leads to traction or distortion of various anchoring pain-sensitive structures in the brain, causing orthostatic or primarily orthostatic headaches. Dilation of the cerebral veins and venous sinuses may also play a role in the production of these headaches. It seems that the low CSF pressure itself is not the cause of the headache but rather the non-physiological increased vasodilatation of intracranial and epidural veins. The venous dilatation theory could explain the effectiveness of vasoconstrictive drugs such as caffeine and theophylline in the treatment of these headaches.8–10 Theophylline causes vasoconstriction of rat pial vessels by blocking adenosine receptors.11 Methylxanthines are beneficial in controlling the compensatory vasodilatation associated with PDPHs. Methylxanthines are thought to: (i) interfere with the uptake of calcium by the sarcoplasmic reticulum; (ii) block activity of phosphodiesterase; and (iii) antagonise the effects of adenosine. The cerebral vasoconstriction is most likely
1104
U. Ergu¨n et al. / Journal of Clinical Neuroscience 15 (2008) 1102–1104
due to the antagonising effect of adenosine. In addition, methylxanthines increase CSF production by stimulating sodium-potassium pumps.5 Several treatment modalities have been implemented in patients with intracranial hypotension, including bed rest, hydration or overhydration, peroral caffeine or theophylline, corticosteroids, sumatriptan, abdominal binder, epidural blood patches (EBP), intrathecal fluid infusion, epidural saline infusion, epidural infusion of dextran, epidural injection of fibrin glue, CSF shunting, and surgical repair of the leak.9,12 One of the most effective treatments for PDPH is the EBP. The success rate ranges between 80% and 97%.1 This is an invasive procedure associated with complications including seizures, back pain, and infection.5 Pharmacologic management of PDPH is a less invasive treatment modality than the EBP. There is a report in the literature of a patient whose prolonged refractory headache was characterised by the clinical symptoms of occipital neuralgia, but was also associated with the radiographic appearance of a type I Arnold-Chiari malformation, and low CSF pressure. Symptomatic relief was sustained only with long-term theophylline administration. The apparent Arnold-Chiari malformation resolved with treatment of the low CSF pressure.13 Another report concerned the case of a 58-year-old woman with a 1.5-year history of chronic headache in the upright position, nausea and vomiting. In that case the headache was alleviated by theophylline therapy.14 In a study of 11 patients with typical headache following diagnostic LP, the effect of peroral treatment with 281.7 mg theophylline (Euphyllin retardÒ) thrice daily was compared with that of a placebo and was found to be effective for relieving pain.5,6 In another report, in three consecutive patients suffering from life-threatening asthma in a comatose state and treated with theophylline 1.5 g/24 h, intracranial hypertension followed a bronchospasm and then disappeared with it. The authors commented that hypoxemia, hypercapnia, and high-peak airway pressures could explain the intracranial hypertension.15 We found a significant decrease (p < 0.001) in the painfulness of PDPH in the group treated with theophylline infusion. Although patients experienced pain relief immediately after the theophylline infusion, VAS values were obtained 4 h after the infusion while the patient was standing. The mean value was 7.05 ± 1.47 before theophylline infusion and 2.88 ± 2.31 thereafter. An average of 59.1% relief of pain was obtained in the group treated with theophylline infusion, while 35.3% of patients reported pain relief of < 50%. A second theophylline infusion was administered for these patients, and a significant decrease in VAS was obtained (p = 0.02). The mean VAS value before the second theophylline infusion was 5.66 ± 0.51, and after the infusion it was 2.33 ± 1.75; that is, a decrease of
58.8% was noted. We observed the patients for 4 h, and, if a second infusion was required, we observed them for another 4 h after the second infusion. In the control group, mean VAS values were decreased after the dextrose infusion (6.62 ± 1.66 to 6.37 ± 1.58) but the change was not significant (p = 0.15). None of the patients developed any side-effects. We found that intravenous theophylline infusion is effective for decreasing the painfulness of PDPH. Larger groups, the effects of repeated theophylline infusions, and longer observation periods should be considered in further studies. Intravenous theophylline infusion is an easy, rapid, minimally invasive and effective treatment for PDPH that seems to be clinically useful. It may be attempted in PDPH patients before invasive techniques are used. To the best of our knowledge, this is the first report of the effect of intravenous infusion of theophylline compared with a placebo for the treatment of PDPH. References 1. Schwarz U, Schwan C, Stumpf M, et al. Postdural puncture headache: diagnosis, prevention and therapy. Schmerz 1999;13:332–40. 2. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders. 2nd edn. Cephalalgia 2004;24(suppl. 1):1–160. 3. Mokri B. Headache associated with abnormalities in intracranial structure or function: Low cerebrospinal fluid pressure headache. In: Silberstein SD, Lipton RB, Dalessio DJ, editors. Wolff’s Headache and Other Head Pain. New York: Oxford University Press; 2001. p. 417–8, 430–431. 4. Hess JH. Postdural puncture headache: a literature review. AANA J 1991;59:549–55. 5. Choi A, Laurito CE, Cunnigham FE. Pharmacologic management of postdural puncture headache. Ann Pharmacother 1996;30:831–9. 6. Feuerstein TJ, Zeides A. Theophylline relieves headache following lumbar puncture. Placebo controlled, double-blind pilot study. Klin Wochenschr 1986;64:216–8. 7. Davignon KR, Dennehy KC. Update on postdural puncture headache. Int Anesthesiol Clin 2002;40:89–102. 8. Straube A, Neudert C, Glas M, et al. The so-called spontaneous low CSF pressure syndrome. Case results indicating a disturbance in CSF/ blood volume. Nervenarzt 2004;75:1194–9. 9. Mokri B. Headaches caused by decreased intracranial pressure: diagnosis and management. Curr Opin Neurol 2003;16:319–26. 10. Forderreuther S, Yousry I, Empl M, et al. Dilated cervical epidural veins and extra arachnoid fluid collection in orthostatic headaches. Neurology 2001;57:527–9. 11. Ibayashi S, Ngai AC, Meno JR, et al. The effects of dipyridamole and theophylline on rat pial vessels during hypocarbia. J Cereb Blood Flow Metab 1988;8:829–33. 12. Connely NR, Parker RK, Rahimi A, et al. Sumatriptan in patients with postdural puncture headache. Headache 2000;40:316–9. 13. Kasner SE, Rosenfeld J, Farber RE. Spontaneous intracranial hypotension: headache with a reversible Arnold-Chiari malformation. Headache 1995;35:557–9. 14. Hungs M, Schoen SW, Topper R, et al. Spontaneous intracranial hypotension: a rare cause of chronic headache. Fortschr Neurol Psychiatr 1999;67:387–90. 15. Gaussogues P, Piperno D, Fouque P, et al. Intracranial hypertension during status asthmaticus. Ann Fr Anesth Reanim 1987;6:38–41.
Journal of Clinical Neuroscience 15 (2008) 1102–1104 www.elsevier.com/locate/jocn
Clinical Study
Intravenous theophylline decreases post-dural puncture headaches Ufuk Ergu¨n a,*, Bahar Say a, Gokhan Ozer a, Tugba Tunc a, Murat Sen a, Senem Tu¨fekcioglu b, Umit Akin a, Mustafa N. Ilhan c, Levent Inan a a
Department of Neurology, Ministry of Health, Ankara Training and Research Hospital, Nilgu¨n Sok. 4/3, Farabi, Cankaya, 06550 Ankara, Turkey b Department of Anaesthesiology and Reanimation, Atatu¨rk Training and Research Hospital, Ankara, Turkey c Department of Public Health, Gazi University Faculty of Medicine, Besevler, Ankara, Turkey Received 19 May 2007; accepted 6 November 2007
Abstract Post-dural puncture headache (PDPH) is a common complication of lumbar puncture. As invasive treatments for PDPH have known complications, pharmacologic management may be preferable. The aim of this study was to evaluate and to compare the efficacy of intravenous theophylline treatment for PDPH, in comparison with a placebo. We found that intravenous theophylline infusion was effective for decreasing the painfulness of PDPH compared with the control group. The mean visual analogue scale (VAS) value was 7.05 ± 1.47 before the theophylline infusion and 2.88 ± 2.31 after infusion. An average of 59.1% relief of pain was obtained in the group treated with theophylline infusion. The improvement in VAS in the study group was significant (p < 0.001), whereas that in the control group was not (p = 0.15). The mean VAS decrease after theophylline infusion was 4.17 ± 2.03 in the study group and 0.41 ± 0.71 in the control group; the difference in improvement between the groups was significant (p < 0.001). Intravenous theophylline infusion is an easy, rapid, minimally invasive, an effective treatment for PDPH. It may be attempted in PDPH patients before invasive techniques are used. To the best of our knowledge, this is the first report on the effect of intravenous infusion of theophylline compared with a placebo in the treatment of PDPH. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: Lumbar puncture; Headache; Theophylline; Cerebrospinal fluid; Orthostatic headache
1. Introduction Lumbar puncture (LP) is a routine technique performed for a variety of procedures, for example diagnosis, administration of drugs, myelography, and spinal anaesthesia. Post-dural puncture headache (PDPH) is a common complication (30–40%) of diagnostic LP.1 The International Classification of Headache Disorders – 2nd edition describes PDPH under paragraph 7.2.1.2 It typically begins within 2 days but may be delayed for as long as 2 weeks and resolves spontaneously within a few days. In one study, after LP, 1/ 3 of patients developed headache. Of these, 1/3 had severe headache, 1/3 moderate and 1/3 mild.3 Overhydration, per-
*
Corresponding author. Tel.: +90 532 393 59 57. E-mail address: [email protected] (U. Ergu¨n).
0967-5868/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2007.11.001
oral caffeine and theophylline, corticotropin, sumatriptan, epidural saline injection, and epidural patches are common treatments.1,3,4 PDPH can be avoided by using small-gauge needles and possibly by using the lateral approach, as opposed to the midline approach.4 Invasive treatments for PDPH have known complications, such as infection and exacerbation of pain.5 The efficacy of theophylline has been proven in a double-blind and placebo-controlled study. In a study of 11 patients with typical headache following diagnostic LP the effect of peroral treatment with 281.7 mg theophylline (Euphyllin retardÒ) was compared with that of a placebo and found to be effective.6 Pharmacological management of PDPH is a minimally invasive treatment modality. Severe headaches such as PDPH commonly present with nausea and this limits the
U. Ergu¨n et al. / Journal of Clinical Neuroscience 15 (2008) 1102–1104
effect of peroral medications. It would be useful to use parenteral medications for rapid and effective treatment and a non-invasive procedure is preferable. The aim of this study was to evaluate and compare the efficacy of intravenous theophylline for the treatment of PDPH in comparison with a placebo. 2. Materials and methods Patients who had undergone LP for diagnosis or epidural anaesthesia and subsequently developed PDPH were included in this study according to the exclusion and inclusion criteria listed below. Patients who had intracranial disorders (central nervous system infections, intracranial haemorrhage, hydrocephalus, intracranial hypertension, migraine, central nervous system malignancies, convulsions) or systemic disorders (hypertension, cardiac arrhythmia as determined by electrocardiography, hyperthyroid disorders) and those older than 65 years were excluded. Cranial MRIs and detailed neurological examinations were performed. This study was performed in accordance with the Helsinki Declaration, had local ethics committee approval, and all patients gave informed consent. The patients were divided into a study group and a control group. PDPH was defined according to the International Classification of Headache Disorders II (ICHD II) criteria. Patients were asked to describe the severity of their headache on a visual analogue scale (VAS) before and 4 h after medication, while in the standing position. Patients in the study group were given 200 mg intravenous theophylline (200 mg theophylline in 100 mL 5% dextrose) infusion over 40 min, and patients in the control group were given 100 mL 5% dextrose intravenously over 40 min. Then the two groups were asked for their VAS values 4 h after the infusion while in the standing position, and then the values were compared. Patients who reported a VAS decrease of <50% of pretreatment values 4 h after the theophylline infusion were given a second theophylline infusion under the same conditions. They were then asked for their VAS values again 4 h after the second infusion. The control group did not receive a second dextrose infusion. Statistical analysis was performed using SPSS V.13.0 (SPSS Inc., Chicago, IL, USA). VAS values before and after infusions in the study group and in the control group were compared using the Wilcoxon signed rank test. The Mann-Whitney U-test was used for comparing VAS values of the study and the control groups. Comparisons for age and gender were performed using the chi-squared test; pvalues <0.05 were considered significant. 3. Results The study group was composed of 10 (58.8%) women and seven (41.2%) men, aged 19–46 years. The control group was composed of eight (50%) women and eight
1103
(50%) men, aged 23–44 years. Mean age was 31.88 ± 7.55 years for the study group and 31.75 ± 6.32 years for the control group. Mean age and gender did not differ significantly between the two groups (p = 0.50, p = 0.73, respectively). None of the patients given a theophylline infusion reported any cardiac or other complaints. The study and the control groups did not differ significantly in terms of VAS values before the intravenous infusions (p = 0.27) but did differ significantly afterwards (p < 0.001). In the study group, a comparison of VAS values before and after theophylline infusion revealed a significant decrease afterwards (p < 0.001). Mean VAS values were 7.05 ± 1.47 for pre-infusion and 2.88 ± 2.31 for postinfusion in the study group. In the control group, although VAS values seemed to decrease after dextrose infusion, the difference was not significant (6.62 ± 1.66 for pre-infusion and 6.37 ± 1.58 for post-infusion, p = 0.15). The mean VAS score after theophylline infusion was 4.17 ± 2.03 in the study group and 0.41 ± 0.71 in the control group; the difference between the groups was significant (p < 0.001). Six patients (35.3%) needed a second theophylline infusion. VAS values were significantly decreased after this second infusion (p = 0.02). Mean VAS values were 5.66 ± 0.51 for pre-infusion and 2.33 ± 1.75 for post-infusion. Eleven (64.7%) patients did not need a second theophylline infusion. 4. Discussion Lumbar puncture is a well-known cause of orthostatic headaches, related to cerebrospinal fluid (CSF) leakage from the puncture site. The headaches typically begin within 2 days but may be delayed for as long as 2 weeks and resolve spontaneously within a few days.3 The overall incidence of PDPH has been reported to range from 1% to 75%.7 As a result of CSF leakage and CSF volume depletion, the brain descends. This leads to traction or distortion of various anchoring pain-sensitive structures in the brain, causing orthostatic or primarily orthostatic headaches. Dilation of the cerebral veins and venous sinuses may also play a role in the production of these headaches. It seems that the low CSF pressure itself is not the cause of the headache but rather the non-physiological increased vasodilatation of intracranial and epidural veins. The venous dilatation theory could explain the effectiveness of vasoconstrictive drugs such as caffeine and theophylline in the treatment of these headaches.8–10 Theophylline causes vasoconstriction of rat pial vessels by blocking adenosine receptors.11 Methylxanthines are beneficial in controlling the compensatory vasodilatation associated with PDPHs. Methylxanthines are thought to: (i) interfere with the uptake of calcium by the sarcoplasmic reticulum; (ii) block activity of phosphodiesterase; and (iii) antagonise the effects of adenosine. The cerebral vasoconstriction is most likely
1104
U. Ergu¨n et al. / Journal of Clinical Neuroscience 15 (2008) 1102–1104
due to the antagonising effect of adenosine. In addition, methylxanthines increase CSF production by stimulating sodium-potassium pumps.5 Several treatment modalities have been implemented in patients with intracranial hypotension, including bed rest, hydration or overhydration, peroral caffeine or theophylline, corticosteroids, sumatriptan, abdominal binder, epidural blood patches (EBP), intrathecal fluid infusion, epidural saline infusion, epidural infusion of dextran, epidural injection of fibrin glue, CSF shunting, and surgical repair of the leak.9,12 One of the most effective treatments for PDPH is the EBP. The success rate ranges between 80% and 97%.1 This is an invasive procedure associated with complications including seizures, back pain, and infection.5 Pharmacologic management of PDPH is a less invasive treatment modality than the EBP. There is a report in the literature of a patient whose prolonged refractory headache was characterised by the clinical symptoms of occipital neuralgia, but was also associated with the radiographic appearance of a type I Arnold-Chiari malformation, and low CSF pressure. Symptomatic relief was sustained only with long-term theophylline administration. The apparent Arnold-Chiari malformation resolved with treatment of the low CSF pressure.13 Another report concerned the case of a 58-year-old woman with a 1.5-year history of chronic headache in the upright position, nausea and vomiting. In that case the headache was alleviated by theophylline therapy.14 In a study of 11 patients with typical headache following diagnostic LP, the effect of peroral treatment with 281.7 mg theophylline (Euphyllin retardÒ) thrice daily was compared with that of a placebo and was found to be effective for relieving pain.5,6 In another report, in three consecutive patients suffering from life-threatening asthma in a comatose state and treated with theophylline 1.5 g/24 h, intracranial hypertension followed a bronchospasm and then disappeared with it. The authors commented that hypoxemia, hypercapnia, and high-peak airway pressures could explain the intracranial hypertension.15 We found a significant decrease (p < 0.001) in the painfulness of PDPH in the group treated with theophylline infusion. Although patients experienced pain relief immediately after the theophylline infusion, VAS values were obtained 4 h after the infusion while the patient was standing. The mean value was 7.05 ± 1.47 before theophylline infusion and 2.88 ± 2.31 thereafter. An average of 59.1% relief of pain was obtained in the group treated with theophylline infusion, while 35.3% of patients reported pain relief of < 50%. A second theophylline infusion was administered for these patients, and a significant decrease in VAS was obtained (p = 0.02). The mean VAS value before the second theophylline infusion was 5.66 ± 0.51, and after the infusion it was 2.33 ± 1.75; that is, a decrease of
58.8% was noted. We observed the patients for 4 h, and, if a second infusion was required, we observed them for another 4 h after the second infusion. In the control group, mean VAS values were decreased after the dextrose infusion (6.62 ± 1.66 to 6.37 ± 1.58) but the change was not significant (p = 0.15). None of the patients developed any side-effects. We found that intravenous theophylline infusion is effective for decreasing the painfulness of PDPH. Larger groups, the effects of repeated theophylline infusions, and longer observation periods should be considered in further studies. Intravenous theophylline infusion is an easy, rapid, minimally invasive and effective treatment for PDPH that seems to be clinically useful. It may be attempted in PDPH patients before invasive techniques are used. To the best of our knowledge, this is the first report of the effect of intravenous infusion of theophylline compared with a placebo for the treatment of PDPH. References 1. Schwarz U, Schwan C, Stumpf M, et al. Postdural puncture headache: diagnosis, prevention and therapy. Schmerz 1999;13:332–40. 2. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders. 2nd edn. Cephalalgia 2004;24(suppl. 1):1–160. 3. Mokri B. Headache associated with abnormalities in intracranial structure or function: Low cerebrospinal fluid pressure headache. In: Silberstein SD, Lipton RB, Dalessio DJ, editors. Wolff’s Headache and Other Head Pain. New York: Oxford University Press; 2001. p. 417–8, 430–431. 4. Hess JH. Postdural puncture headache: a literature review. AANA J 1991;59:549–55. 5. Choi A, Laurito CE, Cunnigham FE. Pharmacologic management of postdural puncture headache. Ann Pharmacother 1996;30:831–9. 6. Feuerstein TJ, Zeides A. Theophylline relieves headache following lumbar puncture. Placebo controlled, double-blind pilot study. Klin Wochenschr 1986;64:216–8. 7. Davignon KR, Dennehy KC. Update on postdural puncture headache. Int Anesthesiol Clin 2002;40:89–102. 8. Straube A, Neudert C, Glas M, et al. The so-called spontaneous low CSF pressure syndrome. Case results indicating a disturbance in CSF/ blood volume. Nervenarzt 2004;75:1194–9. 9. Mokri B. Headaches caused by decreased intracranial pressure: diagnosis and management. Curr Opin Neurol 2003;16:319–26. 10. Forderreuther S, Yousry I, Empl M, et al. Dilated cervical epidural veins and extra arachnoid fluid collection in orthostatic headaches. Neurology 2001;57:527–9. 11. Ibayashi S, Ngai AC, Meno JR, et al. The effects of dipyridamole and theophylline on rat pial vessels during hypocarbia. J Cereb Blood Flow Metab 1988;8:829–33. 12. Connely NR, Parker RK, Rahimi A, et al. Sumatriptan in patients with postdural puncture headache. Headache 2000;40:316–9. 13. Kasner SE, Rosenfeld J, Farber RE. Spontaneous intracranial hypotension: headache with a reversible Arnold-Chiari malformation. Headache 1995;35:557–9. 14. Hungs M, Schoen SW, Topper R, et al. Spontaneous intracranial hypotension: a rare cause of chronic headache. Fortschr Neurol Psychiatr 1999;67:387–90. 15. Gaussogues P, Piperno D, Fouque P, et al. Intracranial hypertension during status asthmaticus. Ann Fr Anesth Reanim 1987;6:38–41.