Safety, Tolerability, and Efficacy of Pain Reduction by Gabapentin for Acute Headache and Meningismus After Aneurysmal Subarachnoid Hemorrhage: A Pilot Study

Abstract

Introduction: Severe, often sudden-onset headache is the principal presenting symptoms of aneurysmal subarachnoid hemorrhage (aSAH). We hypothesized that gabapentin would be safe and tolerable for aSAH-induced headaches and would reduce concurrent opioid use. Methods: We performed a single-center, double-blind, randomized, placebo-controlled trial (registered at ClinicalTrials.gov; NCT02330094) from November 24, 2014, to June 24, 2017, where aSAH patients received either dose-escalating gabapentin or oral placebo, both alongside a standard of care pain regimen. After 7 days, patients had the option to continue in an open-label period until 14 days after enrollment or until discharge from the intensive care unit. Our primary endpoint was the efficacy of gabapentin in reducing headache numeric pain scores and opioid usage in patients with aSAH compared to the placebo group. We identified 63 potential patients with aSAH for the study. After applying stringent exclusion criteria, 16 eligible patients were enrolled into one of two arms. Results: The study ended prematurely after reaching a pre-specified funding period and an unexpected drop in aSAH cases. There was a trend toward lower headache numeric pain scores and opioid use in the gabapentin treated arm; however this was not significantly different. Gabapentin was well tolerated by participants and no adverse effects were reported. Conclusions: While there was a trend toward lower pain scores and opioid requirement in the gabapentin group, the study was underpowered to detect a difference. Larger multicenter trials are required to evaluate the efficacy of gabapentin to reduce opioid requirements after aSAH.

Acute Headache Management for Patients with Subarachnoid Hemorrhage: An International Survey of Health Care Providers

“…Investigated analgesic strategies alternative to opioids for post-SAH headache include gabapentin, pregabalin, and magnesium. While these provide only modest pain relief [13,36,37] and also carry a risk of sedation and hypotension, our survey data show that these medications are used, with both regionalmore use of antiseizure medications in North America compared to Europe-and specialty-driven (more commonly prescribed by neurologists compared to other specialty providers) differences. Interestingly, corticosteroids were both commonly used-preferentially by neurologists and neurosurgeons-and were second to opioids in perceived effectiveness, albeit data to support its effectiveness for headache management after SAH are lacking.…”

“…More recently, multimodal pharmacotherapy with agents such as gabapentinoids, magnesium infusions, corticosteroids, and utilization of nerve blocks have been reported [13][14][15][16].…”

Headache persisting after aneurysmal subarachnoid hemorrhage: A narrative review of pathophysiology and therapeutic strategies

“…The most commonly utilized medications for treating these post‐SAH headaches identified from the literature are opioids, and the combination medication of acetaminophen/butalbital/caffeine (A/B/C), with Viswanathan et al 73 noting in a single institution study of 114 aneurysmal SAH patients from 2012 to 2019 that 91.2% of patients received morphine and 98.3% received A/B/C for headache pain. Literature review demonstrates that thus far, pregabalin and gabapentin, 9,10,15 fentanyl, 11 lidocaine, 18 and magnesium 13,16 are the only medications to have any published findings demonstrating some level of headache improvement in post‐SAH patients, while other studies demonstrate little to no benefit for other opioids, 4,6,11,13 acetaminophen, 6,13 dexamethasone, 3,7 ketorolac, 13 ibuprofen, 13 or A/B/C; the findings of these studies with more details are summarized in Table 1 along with interventions including local nerve blockade, CSF drainage, and others 13 . Milrinone infusion has been used in some institutions for particularly severe headaches, where reversible cerebral vasospasm of various causes (not necessarily aneurysmal SAH) is thought to be etiologic 25,74,75 .…”

“…1 Severe, recurrent headaches are common in post-SAH patients, being classed as persistent headache attributed to past non-traumatic SAH if lasting for >3 months (per the International Classification of Headache Disorders, third edition, hereby referred to as post-SAH headache), 5 and their persistence for years is an important cause of post-SAH morbidity. [6][7][8] These headaches are a major clinical challenge in care, as they are the main cause of post-SAH pain; however, little data exists on the efficacy of analgesic medications and differential approaches in controlling these headaches 4,6,[9][10][11][12][13] which were briefly reviewed previously. 3 Persistent headaches are also common following ischemic stroke; 14 however, the differences in etiologic mechanism and patient population warrant focused study of these headaches in post-SAH patients.…”

Evaluating common medications utilized in aneurysmal subarachnoid hemorrhage and association with delayed cerebral ischemia

“…DCI has been associated with younger age and high score on the modi ed Fisher scale, however clear risk factors for DCI remain sparse [3,4]. Although promising medical and interventional therapies are undergoing trials to prevent DCI [3], few studies have evaluated associations between DCI and commonly used analgesic and anti-seizure medication dosages already utilized in the management of many SAH patients [6][7][8][9][10][11][12].…”