Addition of Neostigmine and Atropine to Conventional Management of Postdural Puncture Headache

A Randomized Controlled Trial

Ahmed Abdelaal Ahmed Mahmoud, MD, FCAI; Amr Zaki Mansour, MD; Hany Mahmoud Yassin, MD; Hazem Abdelwahab Hussein, MD; Ahmed Moustafa Kamal, MD; Mohamed Elayashy, MD, FCAI; Mohamed Farid Elemady, MD; Hany W. Elkady, MD; Hatem Elmoutaz Mahmoud, MD; Barbara Cusack, LRCP&SI, MB MCh, NUI, MCAI; Hisham Hosny, MD; Mohamed Abdelhaq, MD


Anesth Analg. 2018;127(6):1434-1439. 

In This Article


This is the first randomized controlled trial to examine the addition of neostigmine and atropine to conservative treatment for PDPH. For ethical reasons, all patients received conservative treatment. Those not treated with neostigmine/atropine received a saline placebo. Neostigmine significantly lowered VAS scores, shortened the duration of PDPH and avoided the need for EBP. No >2 doses were needed to reach the study end point. Other secondary outcomes were comparable between the 2 groups. Treatment-associated muscle twitches, abdominal cramps, and hyperactivity were more frequent in the neostigmine/atropine group.

Neostigmine is a quaternary amine anticholinesterase that increases acetylcholine levels.[20] In animal studies,[10–13] neostigmine was found to have an initial direct stimulatory action on depolarization of cerebrospinal ganglia and resulted in cerebral vasoconstriction.[14] This effect of neostigmine antagonizes the cerebral vasodilation associated with PDPH and explains the rapid improvement of a headache. The central vascular action of neostigmine was confirmed by functional magnetic resonance imaging in the study of the vascular activity of anticholinergics on cognitive function and the ability of neostigmine to reverse it.[21] Those results suggested that neostigmine restored the normal vascular tone of cerebral vessels. In line with that, neostigmine was reported to be effective in the treatment of migraine headaches, which may share some pathophysiological mechanisms with PDPH.[22,23]

Neostigmine does not cross the blood–brain barrier but can enter the CSF because the blood–brain and blood–CSF barriers are anatomically distinct.[3–6] Systemic neostigmine can enter the CSF but is not be able to enter the brain parenchyma through the blood–brain barrier.[3–6] The presence of neostigmine in CSF would be expected to increase the level of acetylcholine in CSF and subsequently in the brain through inhibition of cholinesterase. The increased level of acetylcholine would produce cerebral vasoconstriction.[10,24] Neostigmine produces intracerebral vasoconstriction[10,24] with clinically relevant effects[21–23,25–27] that include migraine relief[22,23] and treatment of central cholinergic syndrome.[26,27] At least 2 mechanisms can explain neostigmine-induced intracerebral vasoconstriction. Neostigmine has a biphasic effect on sympathetic ganglia, ie, depolarization followed by hyperpolarization.[10–13] Hyperpolarization that results in vasoconstriction reflects sympathetic regulation of the blood supply to cerebral vessels.[14] An increase in central acetylcholine[3–6,21–23,25,26] can maintain cerebral vasoconstriction[10,24] initiated by the direct stimulation of the cerebrospinal ganglia.[10–13] Entry of neostigmine into the CSF[3–6] can provide the analgesic effects that have been observed following the direct administration of neostigmine neuroaxially.[9]

The choroid plexus is the primary source of CSF.[28,29] Sympathetic inhibition can reduce CSF secretion by about 30%.[8,30–32] Sympatholysis, as with neostigmine-induced late hyperpolarization of cerebrospinal ganglia,[10–13] can increase secretion by 30%. As the effect of neostigmine on cerebrospinal ganglia fades, ganglion function is restored, but another mechanism can increase CSF secretion. Acetylcholine inhibits choroid plexus secretion,[8,30–32] and in addition to its anticholinesterase activity, neostigmine inhibits the uptake of acetylcholine by the choroid plexus[7] because it competes with acetylcholine for the same transport system.[7,33] That mechanism can account for an increase in CSF secretion in response to neostigmine and can help to explain the rise in CSF pressure following neostigmine/atropine administration reported in a series of 12 patients with cerebral aneurysms.[34]

Atropine crosses the blood–brain barrier and is a parasympatholytic[20] that was found to inhibit parasympathetic cholinergic cerebral vasodilatation in an animal study.[17] Block of the sphenopalatine parasympathetic ganglion by atropine has been reported successful in treating PDPH by reversing PDPH-associated cerebral vasodilation.[35,36] Atropine increases CSF secretion by antagonizing the effect of acetylcholine[8] on the choroid plexus, possibly by its effect on muscarinic receptors in the choroid plexus[8,30] and possibly on nicotinic acetylcholine receptors.[37]

Recent studies[38–40] discovered that CSF is predominantly drained by cerebral vessels on the brain surface and not by the subarachnoid villi. Considering the combined effects of neostigmine and atropine on cerebral vasoconstriction,[3–6,8,17,21–23,25,26] neostigmine may act to increase CSF pressure by reducing CSF absorption by vessels on the brain surface. The possible pathways and mechanisms by which the neostigmine/atropine combination acts to resolve PDPH are shown in the Figure.


Pathophysiology of postdural puncture headache and the mechanisms of action of neostigmine and atropine treatment. BL-CSF, blood-cerebro-spinal fluid barrier; CSF, cerebrospinal fluid; CSG, cervical sympathetic ganglia; VC, vasoconstriction; VD, vasodilation.

Following World Health Organization recommendations, breastfeeding was withheld for 24 hours after the last dose of neostigmine/atropine[18] for the safety of the newborn. As no participants required >2 doses, breastfeeding was resumed within a relatively short average time of 36 hours after the start of the study intervention. The clinical side effects associated with neostigmine/atropine were primarily cholinergic effects of neostigmine such as abdominal cramps, muscle twitches, and urinary bladder hyperactivity. These effects were clinically transient, self-limiting, and well tolerated. None require any medical intervention. The addition of atropine probably minimized the cholinergic side effects of neostigmine. Dilution of the medications in 20 mL of normal saline and slow administration over 5 minutes probably decreased the occurrence of clinically significant side effects associated with either neostigmine or atropine.

A 22-gauge cutting spinal needle is not consistent with the standard practice for providing spinal anesthesia for elective cesarean delivery in the developed world. However, this is the type of spinal needle used at our institution based on cost and availability considerations. The size and type of the needle may not directly influence the effect of neostigmine/atropine in PDPH, but the use of this needle may increase not only the incidence of PDPH in our institution but also the severity of PDPH experienced by our patients.

PDPH after cesarean delivery is a disabling condition that limits the ability of the new mother to resume walking or breastfeed in a semirecumbent position. In addition to delayed hospital discharge, patients may require an EBP or the prolonged use of analgesics that are not free of side effects. The use of neostigmine/atropine significantly accelerated the recovery from PDPH.

Limitations and Future Research

As this was the first study to evaluate neostigmine/atropine in PDPH, ethical reasons prevented investigation of neostigmine/atropine alone. All participants received routine conservative care including analgesics. This limitation was partially compensated by the randomized, controlled, double-blind design of the trial. All study participants were of American Society of Anesthesiology physical status II because of pregnancy. Clinical parameters could be measured without the use of invasive monitors. Future studies in either animals or critical patients in whom the use of invasive monitors is planned or required can include the measurement of cerebral blood flow (an indirect measure of cerebral vascular resistance), CSF pressure, or plasma and CSF neostigmine concentration by chromatography.[41] The effect of neostigmine on intracranial pressure should be studied in neurosurgery patients in whom increased pressure related to increased CSF may be detrimental.

A combination of neostigmine and atropine was effective in managing PDPH by lowering the associated VAS score and preventing headache persistence. The required 2 doses were well tolerated.