Commentary Open Access
Volume 3 | Issue 2 | DOI: https://doi.org/10.33696/pathology.3.038

Non-Interventional Treatment of Post-Dural-Puncture Headache; High-Flow Oxygen and Pro-Serotonin Agents a Safe and Effective Alternative

  • 1Department of Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  • 2Department of Emergency Medicine, McGovern Medical School, Houston, Texas, USA
+ Affiliations - Affiliations

*Corresponding Author

Carlos J. Roldan, MD, croldan@mdanderson.org, carlos.j.roldan@uth.tmc.edu

Received Date: August 29, 2022

Accepted Date: October 31, 2022


Lumbar punctures are commonly performed for diagnostic and/or therapeutic purposes by threading a needle through the outermost layer of the meninges, the dura mater, and into the intrathecal space within the lumbar region of the spine [1]. The intrathecal space contains cerebrospinal fluid (CSF), a clear and colorless fluid, which surrounds the brain and spinal cord and can provide information regarding intracranial pressures, presence of diseases involving the central nervous system (CNS) or surrounding meninges [2-4]. A common complication of dural puncture is a post-dural puncture headache (PDPH) which is defined by The International Headache Society as a “headache that develops within 5 days of dural puncture and resolves within 1 week spontaneously or within 48 hours after effective treatment of the spinal fluid leak” [5]. Symptoms of PDPH classically include a frontal and/or occipital headache that improves in the supine position, worsened by sitting or standing, and may be associated with nausea, nick stiffness, vertigo, vision changes, dizziness, or auditory disturbances [6]. PDPH has the propensity to cause significant morbidity; among affected patients, 39% report a duration of at least one week of significant impairment of daily activities while severe PDPH may require hospital admission [7]. The gold standard treatment for PDPH is to administer an epidural blood patch (EBP), autologous blood collected in the periphery vessels and delivered in the area of suspected CSF leak within the spinal canal to “mechanically plug the leak” [8]. However, in order to perform this intervention safely, training and specific equipment are necessary but unfortunately not a common part of the armamentarium of most clinical settings.

Among cancer patients, access to the intrathecal space for diagnostic or therapeutic purposes may be part of the standard of care and occurrences of headaches associated with dural puncture in these scenarios are not totally unavoidable. Furthermore, many patients with cancer often have clear contraindications to accessing the epidural space to perform a therapeutic blood patch [9]. Under these circumstances, non-invasive alternatives should be considered (Table 1).

Table 1. Contraindications for EBP.




Suspected bacteremia

Infection at needle placement site

Untreated HIV

Unexperienced provider

Uncooperative patient

In this article, we describe commonly used non-invasive options to treat PDPH including high-flow oxygen-metoclopramide, Caffeine, Cosyntropin, Gabapentin, Indomethacin and Theophylline. Mechanisms of action associated with each treatment modality are highlighted (Table 2).

Table 2. Mechanism of action and common side effects of agents used to treat PDPH.



Side effects

High-flow oxygen

COX inhibitor

PGE2 inhibitor




5-HT3 antagonist

CGRP inhibitor

Substance P antagonist


Lower seizure threshold



Adenosine receptor antagonist




Release of aldosterone to induce production of CSF

Fluid retention

Electrolytes imbalance


Irregular heartbeat

Increased growth hormone & Lipogenesis

Nausea & anxiety

Facial flushing & Diaphoresis


Inhibits central neuronal hyperexcitability

Inhibits release of substance P

Fluid retention



Confusion & memory changes


COX inhibitor

PG inhibitor

Nitric oxide modulation

Intracranial precapillary vasoconstriction


Peptic ulcer disease

Increase bleeding



Adenosine receptor antagonist


Anxiety & irritability

Nausea & vomiting



Pathophysiology of PDPH

There are several proposed mechanisms for PDPH including downward drag of pain-sensitive intracranial structures from reduced buoyancy related to CSF hypotension, particularly in the upright position, contributing to the development of headache [10]. Additionally, compensatory vasodilation of intracranial blood vessels to maintain a constant intracranial volume and resultant headache from cerebral arterial and venous distention (Monro-Kellie Hypothesis) [11]. Furthermore, alterations in substance P, a modulator of pain perception, and regulation of neurokinin-1 receptors may play a role [12].

Non-Invasive Therapeutic Options

High-flow oxygen - metoclopramide

Oxygen concentration can influence prostaglandin synthesis via cyclooxygenase (COX) activity altering prostaglandin levels, notably prostaglandin E2 (PGE2), a vasodilator [13]. In hypoxic conditions, COX is activated with subsequent increase in PGE2 and downstream vasodilation [14] contributing to the development of a headache, commonly seen in high-altitude settings. Whereas in hyperoxic conditions, COX activity is diminished [15] which may result in downstream vasoconstriction. This vasoconstriction may explain the symptomatic improvement observed in patients with postdural puncture headaches receiving high flow oxygen (12L/min via a non-rebreathing mask) [16], as the effect counteracts the pathophysiologic hypothesis related to compensatory vasodilation of intracranial blood vessels in PDPH.

Metoclopramide is a dopamine antagonist used in the treatment of nausea and vomiting and has also evolved to be utilized as an effective analgesic medication during migraine exacerbations [17]. The pain-relieving mechanism underlying metoclopramide may be influenced by its antagonistic role at the serotonin type 3 (5-HT3) receptor as several studies indicate 5-HT3 receptors are expressed in primary afferent nociceptors [18-20]. Furthermore, 5-HT3 receptor antagonists have been shown to inhibit calcitonin gene-related peptide (CGRP) release in the rat spinal cord [21]. In the CNS, CGRP is involved in pain modulation, perception, and central sensitization [22]. CGRP potentiates the release of substance P from primary afferent terminals and promotes nociceptive signaling induced by noxious stimuli [23]. Additionally, CGRP is implicated in promoting vasodilation on arterial smooth muscle [24]. Therefore, metoclopramide may produce analgesia by its antagonistic activity at 5-HT3 receptors, inhibiting CGRP release and downstream influence on substance P and arterial vasodilation.

Caffeine is a central nervous stimulant of the methylxanthine class and is used worldwide to enhance concentration and memory [25], with first report of usage as a treatment for PDPH in 1949 [26]. Caffeine is hypothesized to treat PDPH by inducing cerebral vasoconstriction as an adenosine receptor antagonist [27,28] since adenosine receptor activation can produce downstream vasodilatory effects via its G protein-coupled receptor activity [29]. In forty postpartum patients with postdural puncture headache who were randomly assigned to receive oral caffeine or a placebo, assessment using visual analogue pain scale four hours after administration was significantly improved regarding headache intensity in the group receiving oral caffeine [30].


Adrenocorticotropic hormone (ACTH) is produced by the pituitary gland of the brain and controls the production of cortisol, the primary physiologic stress hormone [31]. Cosyntropin is the synthetic version of adrenocorticotropic hormone. Cosyntropin is hypothesized to be effective in the treatment of PDPH by stimulating the release of aldosterone and influencing the downstream production of CSF [32]. In twenty-eight patients who were diagnosed with PDPH and randomized to receive EBP (gold standard) or intravenous Cosyntropin, effectiveness was similar for each intervention arm immediately after treatment, along with days 3 and 7 regarding headache intensity and function [33].


Gabapentin is an anticonvulsant medication that serves as a ligand for voltage-gated calcium channels and functions as a gamma aminobutyric acid (GABA) analogue [34,35]. The role of gabapentin for analgesic relief is not yet fully elucidated but may be related to inhibition of central neuronal hyperexcitability [36] along with the observation that gabapentin reduces the release of substance P in rats [37,38]. These factors may have contributed to the analgesic effect seen in twenty patients diagnosed with PDPH who were randomized to receive either gabapentin or placebo, with the gabapentin group reporting improved pain relief during the four-day study period [39].


Although better known for its absolute effectiveness on a heterogeneous group of primary headache disorders, Indomethacin has been used on the treatment of PDPH. By inhibiting COX, it reduces PG synthesis possibly via calcium channel blockade with a more potent anti-inflammatory effect than aspirin [40]. Other mechanisms include reduction of cerebral blood flow via modulation nitric oxide (NO) pathway and causing intracranial precapillary vasoconstriction which can reduce intracranial pressure by 37% [41].


Theophylline is a member of the xanthine family and is used primarily in the treatment of respiratory diseases (e.g. COPD and asthma) [42]. In PDPH, theophylline is thought to work similarly as caffeine via its action as an adenosine antagonist with downstream vasoconstriction since there is overlap in structure and pharmacologic properties of xanthine’s (e.g. theophylline) and methylxanthines (e.g. caffeine) [43,44]. In forty patients diagnosed with PDPH and randomized to receive either conservative treatment or oral Theophylline, assessment using visual analogue scale score for pain demonstrated significantly better relief for those receiving theophylline [45].


The pathophysiology of PDPH is not yet precisely known, but CSF volume loss, intracranial blood vessel vasodilation, and substance P may play a role. The gold standard of treatment is an epidural blood patch, which may not be an accessible option at all practice settings or contraindicated depending on the clinical context. Therefore, treatment options that are non-invasive and readily accessible should be considered and may include high-flow oxygen, metoclopramide, caffeine, Cosyntropin, gabapentin, indomethacin or theophylline in the management of PDPH.


1. Sempere A, Berenguer-Ruiz L, Lezcano-Rodas M, Mira-Berenguer F, Waez M. Lumbar puncture: its indications, contraindications, complications and technique. Rev Neurol. 2007;45:433-436.

2. Sakka L, Coll G, Chazal J. Anatomy and physiology of cerebrospinal fluid. European Annals of Otorhinolaryngology, Head and Neck Diseases. 2011;128:309-316.

3. Bothwell S, Janigro D, Patabendige A. Cerebrospinal fluid dynamics and intracranial pressure elevation in neurological diseases. Fluids Barriers CNS. 2019;16.

4. Xiao F, Lv S, Zong Z, Wu L, Tang X, Kuang W, et al. Cerebrospinal fluid biomarkers for brain tumor detection:clinical roles and current progress. Am J Transl Res. 2020;12:1379-1396.

5. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorder. 2nd edition. Cephalalgia 2004;24.

6. Kwak K. Postdural puncture headache. Korean J Anesthesiol. 2017;70:136-143.

7. Van Kooten F, Oedit R, Bakker SL, Dippel DW. Epidural blood patch in post dural puncture headache:A randomized, observer-blind, controlled clinical trial. J Neurol Neurosurg Psychiatry. 2008;79:553-558.

8. Boonmak P, Boonmak S. Epidural blood patching for preventing and treating post‐dural puncture headache. Cochrane Database of Systematic Reviews. 2010;1.

9. Engelborghs S, Niemantsverdriet E, Struyfs H, Blennow K, Brouns R, Comabella M, et al. Consensus guidelines for lumbar puncture in patients with neurological diseases. Alzheimers Dement. 2017;8:111-126.

10. Ahmed S, Jayawarna C, Jude E. Post lumbar puncture headache:diagnosis and management. Postgraduate Medicine. 2006;82:713-6.

11. Shahriari A, Sheikh M. Post-Spinal Headache: A New Possible Pathophysiology. Anesth Pain Med 2016;7.

12. Clark J. Substance P concentration and history of headache in relation to post lumbar puncture headache:Towards prevention. J Neurol Neurosurg Psychiatry. 1996;60:681-683.

13. Lands W, Sauter J, Stone GW. Oxygen requirement for prostaglandin biosynthesis. Prostaglandins and Medicine. 1978;117-120.

14. Zhao L, Wu Y, Xu Z, Wang H, Zhao Z, Li Y, et al. Involvement of COX-2/PGE2 signalling in hypoxia-induced angiogenic response in endothelial cells. J Cell Mol Med. 2016;16:1840-55.

15. Ishii Y, Morita I, Murota S, Kitamura S. Hyperoxia decreases cyclooxygenase activity in endothelial cells. Prostaglandins, Leukotrienes and Essential Fatty Acids. 1993;48:455-461

16. Roldan C, Chung M, Mc C, Cata J, Huh B. High-flow oxygen and pro-serotonin agents for non-interventional treatment of post-dural-puncture headache. Am J Emerg Med. 2020:2625-2628.

17. Becker W. Acute Migraine Treatment in Adults. Headache 2015;55:778–793.

18. Nicholson R, Small J, Dixon A, Spanswick D, Lee K. Serotonin receptor mRNA expression in rat dorsal root ganglion neurons. Neuroscience Letters. 2003;337:119-122.

19. Kia HK, Miquel MC, McKernan RM, Laporte AM, Lombard MC, Bourgoin S, et al. Localization of 5-HT3 receptors in the rat spinal cord. Immunohistochemistry and in situ hybridization. Neuroreport. 1995;6(2):257-261.

20. Kidd EJ, Laporte AM, Langlois X, Fattaccini CM, Doyen C, et al. 5-HT3 receptors in the rat central nervous system are mainly located on nerve fibers and terminals. Brain Research. 1993;612:289-298.

21. Saria A, Javorsky F, Humpel C, Gamse R. 5-HT3 receptor antagonists inhibit sensory neuropeptide release from rat spinal cord. Neuroreport. 1990;1:104-106.

22. Powell KJ, Ma W, Sutak M, Doods H, Quirion R, Jhamandas K. Blockade and reversal of spinal morphine tolerance by peptide and non-peptide calcitonin gene-related peptide receptor antagonists. Br J Pharmacol. 2000;131:875-884

23. Oku R, Satoh M, Fujii N, Otaka A, Yajima H, Takagi H. Calcitonin gene-related peptide promotes mechanical nociception by potentiating release of substance P from the spinal dorsal horn in rats. Brain Res. 1987;403:350-354.

24. Kee Z, Kodji X, Brain SD. The Role of Calcitonin Gene Related Peptide (CGRP) in Neurogenic Vasodilation and Its Cardioprotective Effects. Front Physiol. 2018;9:1249

25. Cappelletti S, Piacentino D, Sani G, Aromatario M. Caffeine:cognitive and physical performance enhancer or psychoactive drug? Curr Neuropharmacol. 2015;13:71-88.

26. Shahriari A, Nataj-Majd M, Khooshideh M, Salehi-Vaziri S. The comparison of post-dural puncture headache treatment with acetaminophen-caffeine capsule and intravenous mannitol infusion:A randomized single-blind clinical trial. Curr J Neurol. 2021;20:95-101.

27. Mathew R, Wilson W. Caffeine induced changes in cerebral circulation. Stroke 1985;16:814-817

28. Biaggioni I, Paul S, Puckett A, Arzubiaga C. Caffeine and theophylline as adenosine receptor antagonists in humans. Journal of Pharmacology and Experimental Therapeutics. 1991;258:588-93.

29. Shryock J, Belardinelli L. Adenosine and Adenosine Receptors in the Cardiovascular System:Biochemistry, Physiology, and Pharmacology. The American Journal of Cardiology. 1997;79:2-10.

30. Camann W, Murray R, Mushlin P, Lambert D. Effects of oral caffeine on postdural puncture headache. A double- blind, placebo-controlled trial. Anesthesia and Analgesia. 1990;70:181-4.

31. Rhodes M. Adrenocorticotropic hormone (ACTH). Encyclopedia of Stress. 2007;1:69-72.

32. Zeger W, Younggren B, Smith L. Comparison of cosyntropin versus caffeine for post-dural puncture headaches:a randomized double-blind trial. World Journal of Emergency Medicine. 2012;3:182.

33. Hanling S, Lagrew J, Colmenar D, Quiko A, Drastol C. Intravenous Cosyntropin Versus Epidural Blood Patch for Treatment of Postdural Puncture Headache. Pain Medicine. 2016;17:1337-1342.

34. Hendrich J, Van Minh A, Heblich F, Nieto-Rostro M, Watschinger K, Striessnig J, et al. Pharmacological disruption of calcium channel trafficking by the α2δ ligand gabapentin. Proceedings of the National Academy of Sciences. 2008;105:3628-33.

35. Cheng J, Chiou L. Mechanisms of the antinociceptive action of gabapentin. Journal of Pharmacological Sciences. 2006.

36. Eroglu C, Allen N, Susman M, O'Rourke N, Park C, Özkan E, et al. Gabapentin receptor α2δ-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. Cell. 2009;139:380-92.

37. Maneuf Y, Hughes J, McKnight A. Gabapentin inhibits the substance P-facilitated K+-evoked release of [3H] glutamate from rat caudal trigeminal nucleus slices. Pain. 2001;93:191-6.

38. Fehrenbacher J, Taylor C, Vasko M. Pregabalin and gabapentin reduce release of substance P and CGRP from rat spinal tissues only after inflammation or activation of protein kinase C. Pain. 2003;105:133-41.

39. Dogan D. The effect of oral gabapentin on postdural puncture headache. Acute Pain. 2006;8:169-73.

40. Crook D, Collins AJ. Comparison of effects of aspirin and indomethacin on human platelet prostaglandin synthetase. Annals of the Rheumatic Diseases. 1977;36:459-463.

41. Vander Pluym J. Indomethacin-responsive headaches. Curr Neurol Neurosci Rep. 2015;15(2):516.

42. Persson C. Overview of effects of theophylline. Journal of Allergy and Clinical Immunology. 1986;78:780-7.

43. Trask A, Motherwell W, Jones W. Physical stability enhancement of theophylline via crystallization. International Journal of Pharmaceutics. 2006;320:114-23.

44. Smits P, Lenders JW, Thien T. Caffeine and theophylline attenuate adenosine‐induced vasodilation in humans. Clinical Pharmacology & Therapeutics. 1990;48:410-8.

45. Sen J, Sen B. Noninvasive management of post dural puncture headache-a comparison. Bangladesh Journal of Medical Science. 2014;13:114-8.

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