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

Severe headaches are common after subarachnoid hemorrhage. Guidelines recommend treatment with acetaminophen and opioids, but patient data show that headaches often persist despite multimodal treatment approaches. Considering an overall slim body of data for a common complaint affecting patients with SAH during their intensive care stay, we set out to assess practice patterns in headache management among clinicians who treat patients with SAH. We conducted an international cross-sectional study through a 37-question Web-based survey distributed to members of five professional societies relevant to intensive and neurocritical care from November 2021 to January 2022. Responses were characterized through descriptive analyses. Fisher’s exact test was used to test associations. Of 516 respondents, 329 of 497 (66%) were from North America and 121 of 497 (24%) from Europe. Of 435 respondents, 379 (87%) reported headache as a major management concern for patients with SAH. Intensive care teams were primarily responsible for analgesia during hospitalization (249 of 435, 57%), whereas responsibility shifted to neurosurgery at discharge (233 of 501, 47%). Most used medications were acetaminophen (90%), opioids (66%), corticosteroids (28%), and antiseizure medications (28%). Opioids or medication combinations including opioids were most frequently perceived as most effective by 169 of 433 respondents (39%, predominantly intensivists), followed by corticosteroids or combinations with corticosteroids (96 of 433, 22%, predominantly neurologists). Of medications prescribed at discharge, acetaminophen was most common (303 of 381, 80%), followed by opioids (175 of 381, 46%) and antiseizure medications (173 of 381, 45%). Opioids during hospitalization were significantly more prescribed by intensivists, by providers managing higher numbers of patients with SAH, and in Europe. At discharge, opioids were more frequently prescribed in North America. Of 435 respondents, 299 (69%) indicated no change in prescription practice of opioids with the opioid crisis. Additional differences in prescription patterns between continents and providers and while inpatient versus at discharge were found. Post-SAH headache in the intensive care setting is a major clinical concern. Analgesia heavily relies on opioids both in use and in perception of efficacy, with no reported change in prescription patterns for opioids for most providers despite the significant drawbacks of opioids. Responsibility for analgesia shifts between hospitalization and discharge. International and provider-related differences are evident. Novel treatment strategies and alignment of prescription between providers are urgently needed.


Introduction
Subarachnoid hemorrhage (SAH) classically presents with an excruciating headache of sudden onset that reaches maximal severity within seconds, known as "thunderclap" or described as "worst headache of life" [1,2]. Nearly all patients with SAH experience headaches, and in about 90%, headaches are severe [3]. On average, patients with SAH suffer from severe headaches for ≥ 7 days during their index hospitalization [4]. Moreover, headaches persist beyond hospitalization in > 50% of patients [5] and have been associated with reduced health-related quality of life [6]. The etiology of post-SAH headaches is multifactorial and includes meningeal irritation by blood in the subarachnoid space, inflammation, and sequela from treatment (i.e., craniotomy or endovascular intervention) and elevated intracranial pressure in some cases [7].
SAH can be a devastating life event because of increased risk for ongoing structural brain injury and significant systemic complications. Hence, patients with SAH are commonly managed in intensive care units with multidisciplinary collaboration, and guidelines largely focus on mitigation of secondary brain injury and systemic complications [8]. However, data and guidance on the optimal pharmacological and supportive management for post-SAH headaches are scarce. Current European guidelines recommend the use of acetaminophen (i.e., paracetamol) for mild-tomoderate headaches, with escalation to opioids (i.e., codeine, tramadol, or piritramide) if symptoms are severe or resistant [9]. However, studies suggest that post-SAH headaches are only partially relieved and often persist despite provision of guideline-recommended treatment [3]. Importantly, opioid use is not without risks. Excess sedation from opioids can cloud neurologic examination, increase risk of delirium, and blunt chemosensitivity to hypercapnia, potentially contributing to respiratory suppression [10]. Furthermore, opioid prescriptions have been increasingly scrutinized because of their incurred risk for addiction [11]. However, because of the lack of alternative effective treatment options, opioids are commonly employed for post-SAH headache management [4]. More recently, multimodal pharmacotherapy with agents such as gabapentinoids, magnesium infusions, corticosteroids, and nerve blocks has been reported [12][13][14][15].
In the absence of data-proven effective headache management strategies, of updated guidelines for such management, and of complete understanding of trajectories of post-SAH headache [16,17], we hypothesized that significant practice variability exists in the management of acute post-SAH headaches in the critical care setting. The objective of this study is to examine the variety of different approaches to manage headaches in patients with nontraumatic SAH during hospitalization and at discharge from the hospital, with an emphasis on characterizing opioid administration and spanning international practice.

Study Design
The study was designed as a cross-sectional survey targeting health care providers who manage headaches in patients with nontraumatic (spontaneous, both aneurysmal and nonaneurysmal) SAH during the acute phase (index hospitalization and at discharge from index hospitalization).
To ensure proper reporting of results from an electronic survey, guidelines set by the Checklist of Reporting Results of Internet E-Surveys were followed. The survey study was approved by the University of Florida Institutional Review Board (IRB202100254), and electronic consent was obtained from all participants.

Instrument
The study used an open Web-based survey (Qualtrics, Provo, UT) consisting of 37 questions (see Supplemental File) with the skip logic feature whenever applicable. All questions were designed by the authors (AG, BL-W, CBM, KMB, NAM, and ZA-M) to capture the demographics of the participants (including health care profession and subspecialty, region of practice, years of practice, specialized training, and the number of patients with SAH managed per year by the individual provider practice of opioids with the opioid crisis. Additional differences in prescription patterns between continents and providers and while inpatient versus at discharge were found.

Conclusions:
Post-SAH headache in the intensive care setting is a major clinical concern. Analgesia heavily relies on opioids both in use and in perception of efficacy, with no reported change in prescription patterns for opioids for most providers despite the significant drawbacks of opioids. Responsibility for analgesia shifts between hospitalization and discharge. International and provider-related differences are evident. Novel treatment strategies and alignment of prescription between providers are urgently needed.
Keywords: Subarachnoid hemorrhages, Headache, Opioids, Prescription, Corticosteroids and their affiliated institution) as well as the individual approaches to the management of headaches experienced by patients with nontraumatic SAH. Eight beta testers in two groups (four beta testers in each group) were selected by the authors to take and evaluate the survey prior to dissemination for content, usability, and technical functionality. The European Society of Intensive Care Medicine Clinical Sensibility Testing Tool was used to assess the quality of the instrument. The first group of beta testers was invited to provide feedback on the survey (with the Clinical Sensibility Testing Tool in addition to unstructured narrative feedback), the survey was revised accordingly, and the process was repeated with the second group of beta testers prior to generation of the final version of the survey. The survey's first question sought consent of the individual respondent to participate. Responses to questions were voluntary, the back button function allowed respondents to change answers after initial response, and respondents were able to skip questions.

Dissemination of the Survey
Participants included in this study received the survey through professional networks or through distribution by the following societies: • American Academy of Neurology The survey was disseminated by the societies to their members via email or via posting on relevant forums and advertised on social media platforms, with no incentives offered, these methods of dissemination precluded generation of response rates. The study was conducted from November 2, 2021, to January 26, 2022.

Statistical Analysis
This was a cross-sectional study design, with results reported as percentages based on study question. Participants were divided into five groups based on the frequency of medication prescription: (1) always, (2) often (> 75%), (3) sometimes (25-75%), (4) rarely (< 25%), and (5) never. We calculated the frequency table for each variable of interest by medication prescription. In the observation of small values in some cells of frequency tables, we used Fisher's exact test to test the association between each variable and the medication prescription at the significance level of 0.05 [18]. Data analysis was conducted using R Studio software v4.0.2 [19].
Participants had the opportunity to skip questions, which resulted in variability in the total number of answers given per question; thus, the denominator varied according to each question. Percentages are rough estimates of prevalence, with limitation of incomplete surveys. Missing data were excluded when calculating the percentage.

Demographics
Of 521 total respondents who started the survey, four indicated that they did not consent to participate, and one indicated that they did not treat patients with nontraumatic SAH; these responses were excluded. Of the 516 returned surveys included in the final analysis, 371 participants completed the survey in its entirety. Table 1 displays the demographics of respondents and characteristics of health care settings. Of respondents from six continents, 329 of 497 (66%) were from North America and 121 of 497 (24%) were from Europe. The majority were staff physicians (359 of 491, 73%). Neurology and intensive care medicine were the most listed provider specialties (each 115 of 516, 22%). More than half of respondents (186 of 339, 55%) had completed medical training ≥ 10 years ago. The majority (321 of 464, 69%) worked in academic centers, and 361 of 464 (78%) had a dedicated neurointensive care unit. Seventy-six percent (352 of 464) reported that their centers managed ≥ 30 patients with SAH per year, and 242 of 464 (52%) responded that they personally manage > 20 patients with SAH per year.

Headache Management for SAH
Headache post SAH was named a major clinical concern by 379 of 435 (87%) respondents. In most practice settings (249 of 435, 57%), the intensive care team was primarily responsible for management of post-SAH headache during the hospital admission (see Fig. 1).
The most frequently used medications to treat post-SAH headaches are shown in Fig. 2. Acetaminophen was most commonly used, with 378 of 421 (90%) respondents indicating prescription "always" or "often. " Opioids followed as the second most used medication, with 276 of 421 (66%) respondents indicating use "always" or "often. " Corticosteroids and antiseizure medications were mostly "sometimes" prescribed by 32% and 30% of respondents, respectively. Nonsteroidal anti-inflammatory drugs (NSAIDs) and magnesium were mostly indicated as "never" employed, with half of the providers indicating that they would order those medications "rarely" or "sometimes. " Anesthetic blocks, antihistamines, barbiturates, botulinum toxin, caffeine, continuous infusions, muscle relaxants, topical medications, and vitamin supplements were predominantly "never" used (see Supplemental Table 1).
Of the 433 individual respondents who answered the question of which medication(s) they perceived as the most effective treatment for headache post SAH (see Fig. 3), 169 (39%) indicated opioids or medication combinations containing opioids, 96 (22%) indicated corticosteroids or medication combination regimens with corticosteroids as part of the combination, and 32 (7%) indicated multimodal therapy not further specified. Six percent (27 of 433) of respondents indicated either that no medication therapy is helpful or that the most helpful management approach is to focus on supportive and nursing care.
Nine percent (31 of 371) of respondents indicated that their institution had an established protocol or guidelines for headache management post SAH.

Opioid-Based Therapy for Post-SAH Headaches
The duration for opioid therapy was noted to be determined on a case-by-case basis in 233 of 304 (77%) responses; 45 of 304 (15%) respondents would prescribe for a limited number of days only, and 26 of 304 (9%) respondents would prescribe for the duration of the hospitalization. Prescription mode, when used, was mostly on an "as needed" basis, as opposed to scheduled dosing. Factors (selection of multiple answer options was allowed) influencing the choice of duration and daily dose of opioids included individual patient characteristics (211 of 304, 69%), pain intensity scores (210 of 304, 69%), concern for or presence of side effects (142 of 304, 47%), and institutionally specified dosing and duration (25 of 304, 8%). Table 2 shows demographic differences in opioid prescribing practices during the index hospitalization. Opioids were significantly more prescribed by providers practicing in Europe compared with North America and other world regions (81% vs. 61% vs. 59% for "often" or "always", respectively; p = 0.029). Anesthesiologists and intensive care medicine specialists relied on opioids more compared with neurology providers (71% vs. 70% vs. 51%, respectively; p = 0.006). Professional role, years in practice, type of health care facility, presence of a dedicated neurocritical care unit, and number of the institution's SAH admissions per year were not significantly associated with practitioners' reported opioid prescription practices. Providers who manage more patients with SAH per year indicated a higher rate of opioid prescriptions than those who manage fewer patients with SAH (p = 0.007).
Of the 435 participants who answered whether the opioid crisis had changed their approach to managing post-SAH headaches, 299 (69%) answered "no"; providers who indicated that their prescription practice had changed were predominantly from North America as opposed to Europe (109 of 293 or 37% vs. 15 of 86 or 17%; p < 0.001).
Providers who indicated that they changed prescription patterns in light of the opioid crisis indicated less frequent (i.e., less "often" or "always") prescription of opioids during the hospital stay (72 of 132 or 55% vs. 204 of 289 or 71%; p = 0.007) and more frequent use of antiseizure medications (100 of 132 or 76% vs. 146 of 289 or 51%; p < 0.001 for use at least "sometimes"). We found no significant difference in use of steroids (88 of 132 or 67% vs. 165 of 289 or 57%; p = 0.206 for use at least "sometimes") or NSAIDs (62 of 132 or 47% vs. 128 of 289 or 44%; p = 0.092 for use at least "sometimes").

Nonpharmacologic Management of Post-SAH Headaches
Of 418 respondents who answered whether CSF diversion was adjusted to headache severity, 278 (67%) respondents answered "yes" or "sometimes. " The use of alternative treatment options (e.g., acupuncture, herbal medicine, massage therapy, Reiki therapy, music therapy, etc.) was reported by 77 of 418 (18.4%) respondents.

Differences in Practice Patterns by Demographic Characteristics
Several differences in practice patterns were noted for demographic variables (see Supplemental Table 2 for details). Use of antiseizure medication differed between continents, specialties, and years in practice for both in-hospital and at-discharge prescriptions. Antiseizure medications were used more commonly (i.e., prescribed "often" or "always") in North America as compared with Europe and other continents both in-hospital (35% vs. 9% vs. 19%, respectively; p < 0.001) and at discharge (22% vs. 10% vs. 16%, respectively; p = 0.020). They were also significantly prescribed more commonly by neurologists than other providers both during hospitalization and at discharge and were prescribed more frequently by providers with fewer years of practice.
Corticosteroids during hospitalization were significantly prescribed more commonly by neurologists or neurosurgeons compared with other providers and were coprescribed with antiseizure medications, NSAIDs, and opioids more often than individually.
Perceived effectiveness of therapies significantly varied across providers' specialties (details shown in Supplemental Table 3). Opioids and opioid combinations were perceived as the best analgesic nearly twice as commonly by anesthesiologists and intensivists compared with neurologists and neurosurgeons (46% and 46% vs. 24% and 27%, respectively; p = 0005). By contrast, steroid and steroid combinations were perceived as the best analgesic strategy much more commonly by neurologists and neurosurgeons compared with anesthesiologists and intensive care specialists (33% and 23% vs. 8% and 6%, respectively; p = 0.0005).
Providers considering alternative treatment options (e.g., acupuncture, herbal medicine, massage therapy, Reiki therapy, music therapy, etc.) were more likely from North America compared with Europe and other continents (62 of 269 or 23% vs. 15 of 114 or 13%; p = 0.029) and were more likely to be practicing in a setting where the intensive care team was responsible for analgesia compared with a setting where the neurosurgery, neurology, or other team was responsible (57 of 231 or 25% vs. 20 of 167 or 12%; p = 0.016). No differences were found for professional role, background, years in practice, hospital setting, and number of yearly patients with SAH.

Discussion
In this cross-sectional analysis, we captured current practice patterns in the management of post-SAH headache among an international cohort. Post-SAH headache is widely recognized as a major clinical concern by 87% of providers. Our findings unveil a nearly ubiquitous reliance on acetaminophen (i.e., paracetamol) and heavy reliance on opioids and corticosteroids in addition to multimodal analgesic approaches. Importantly, opioid-based strategies predominate as the analgesic modality perceived as the most effective (by two of five providers) and are at least sometimes prescribed at discharge by nearly half of providers. We further documented a shift in primary responsibility in headache management between hospitalization and discharge as well as regional and provider-related differences in management practices. Additionally, providers indicated a widespread lack of institutional guidance for analgesia in post-SAH headache, with only 9% of respondents indicating the presence of a standardized approach to pain management at their institutions.

Opioids in Post-SAH Headache Management
The recognition of post-SAH headache as a major clinical concern aligns with the near universal occurrence of post-SAH headache during the acute phase [3,4,20]. Our data confirm heavy use of acetaminophen and opioidsthe suggested guideline-recommended mainstay of acute therapy for severe headache [9] in prior cohort-based reports [3][4][5]21]. Daily oral morphine equivalent ranging from 22 to 63 mg, commonly exceeding 400 mg over the hospital stay even after introduction of opioid-sparing initiatives, has been reported in single-center reports [4,5,21]. Although our survey indicates that opioids were also perceived as the most effective analgesic strategy,  prior data have shown that opioid analgesia is suboptimal for post-SAH headache and oftentimes fails to alleviate headache on the standard assessments in a meaningful way (i.e., reduction of pain scores by at least 2 points on the 11-point numeric rating scale) [4,13,22]. Suboptimal efficacy of opioid analgesia has also been found in migraine, in which hydromorphone was inferior to prochlorperazine in a randomized clinical trial [23]. This might explain why opioids or opioid-based combinations were only half as commonly perceived as the best analgesic by neurologists and neurosurgeons compared with anesthesiologists and intensivists. In addition to the documented inadequacy of opioids for post-SAH headache, early opioid administration can also impair adequate neurologic examinations for patients with SAH and impede effective initiation of care [24]. Specifically in the critically ill population, inadequate pain control and opioid use are both associated with delirium [25]. Furthermore, opioid-related depressed consciousness and respiratory drive, nausea, ileus, urinary retention, and hypotension are common [26]. These drawbacks of opioids, albeit used for their perceived analgesic potency, are reflected in our survey's finding that nearly half of providers based selection of opioid dosing on concern for side effects.

Impact of Opioid Crisis
Our data in this international survey capturing worldwide practice patterns confirm the frequent continuation of opioid prescriptions beyond hospitalization despite the well characterized drawbacks of prescription opioid therapy. Approximately 40% of all opioid overdose deaths in the United States involve a prescription by health care professionals [27,28]. Nearly 5% of patients with opioid prescriptions misuse them or develop dependence [29]. Additionally, as known from other headache disorders, the use of around-the-clock analgesics may also render patients with poor headache control susceptible to headache due to medication overuse over time-a vicious cycle that may affect the patients in whom opioids are continued beyond discharge [5] and may perpetuate the long-term use of opioids [30,31], requiring further research in the subacute-to-chronic phase post SAH. When considering the opioid crisis, however, it is important to understand international differences. The opioid crisis is a phenomenon with variable impact depending on geographic location. Although prescription opioid use increased in Europe by almost 40% between 2005 and 2015, it still only reached about half of the US volume, with almost ten times less opioid-related deaths in western Europe compared with the United States [32]. There are likely various reasons creating this steep difference, including a different approach to medical use of opioids [33,34]. Considering this differential understanding of the opioid crisis, it is not surprising that a perceived change in prescription pattern was mostly indicated by North American providers, with decreased use of opioids and increased use of antiseizure medications. On the contrary, despite the recognition of the opioid crisis in North America, opioid prescription at discharge was significantly more common in North America than in Europe, a finding supporting the urgent call to finding alternative analgesic strategies.

Alternative Analgesic Strategies
Investigated analgesic strategies alternative to opioids for post-SAH headache include gabapentin, pregabalin, and magnesium. Although these provide only modest pain relief [12,35,36] and also carry a risk of sedation and hypotension, our survey data show that these medications are used, with both regional-more use of antiseizure medications in North America compared with Europe-and specialty-driven (more commonly prescribed by neurologists compared with other specialty providers) differences. Interestingly, corticosteroids both were 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. There are, however, data on dexamethasone use after SAH-based on the premise of disturbed corticoid homeostasis after SAH and possible benefits of antiedematous and antiinflammatory effects of steroids-showing that 5-dayor-longer courses of dexamethasone after SAH were independently associated with adverse events, such as infection and hyperglycemia, and unfavorable outcomes at discharge [37,38]. Based on our finding of frequent use of corticosteroids in the management of post-SAH headaches, further study is required to identify optimal analgesics to inform guidelines and improve consensus on management. Similarly, albeit used less frequently, data on the effectiveness and safety of NSAIDs post SAH are lacking. For antiseizure medications, there are some data-albeit obtained in a context different from when used specifically for mitigation of post-SAH headachethat indicate worse outcomes for patients with SAH who received prophylactic antiseizure medications [39]. Although preliminary data for use of gabapentin and pregabalin are available, long-term effects of gabapentinoids and other antiseizure medications for patients with SAH are unknown.
Another frequent consideration in headache management was the adjustment of CSF diversion to headache severity: two thirds of respondents indicated considering this as a therapeutic strategy. However, phenotypic descriptions of headache types that could guide the clinician as to whose headache might be CSF-responsive are also lacking.
Further alternative strategies, including nerve blocks, acupuncture, and herbal medicine, were used at least occasionally by nearly one of five respondents. Although most published data on any of these treatments are based on case reports or smaller case series, pterygopalatine fossa blocks, occipital nerve blocks, and acupuncture have been reported with potentially promising results [14,15,40,41] and may offer potential additions to the multidrug regimens that are most commonly employed. Providers considering such alternative strategies were more likely based in North America-possibly a reflection of the regional shift from opioid-based analgesiaand these strategies were more likely to be considered in a setting where the intensive care team was responsible for analgesia.

Headache Management in the Transition from Intensive Care to Hospital Discharge
Several important findings were retrieved from this survey concerning the prescription of medications for post-SAH headache at discharge. First, despite up to 47% of patients with SAH having headaches in the months and year after discharge [5,6], 74% of respondents indicated that they do not prescribe any medications at discharge. With post-SAH headache constituting the fourth most common cause for 30-and 90-day readmissions, surpassed only by stroke, hydrocephalus, and sepsis [42], this practice constitutes a gap that may be worthwhile for a systematic and multidisciplinary approach. Second, the most commonly prescribed medications were acetaminophen, a medication likely not sufficient in many instances [13], and opioids, with the drawbacks as discussed above. Last, there is a common shift in the prescribing provider from the intensive care team during the inpatient stay to the neurosurgical team at discharge. With 91% of respondents reporting no availability of an institutional protocol for managing headaches in this population, scarce data available to guide such management, and the shift in responsibility on transition to outpatient management, it is not surprising that overall dissatisfaction with headache management has been reported by patients during both inpatient and outpatient care [20]. Specifically, SAH survivors with persistent headache face more anxiety and stress, cognitive dysfunction, weariness, and impaired sleep, all factors that negatively impact quality of life [6,43].

Limitations
Our study is the first to characterize a broad spectrum of analgesic practices for treatment of post-SAH headache across disciplines and world regions; however, it has important limitations. The method of survey dissemination precluded an exact summary of all recipients to be ascertained and, consequently, did not allow for the evaluation of response rates. We mitigated this impact by obtaining additional granular data characterizing respondents to better clarify the source of answers, including practice settings. However, our large sample size, with participation of health care providers from various continents, training backgrounds, and roles within the health care teams, supports that our sample is representative [44]. Because most participants who responded were based in academic hospitals, generalizability of our findings to the larger community setting could potentially be limited. Additionally, not all participants answered all questions, limiting interpretation of the questions with fewer respondents and hampering more granular subgroup analysis because of a smaller sample size. The data were not stratified by geographic region to account for potential regional variance across the world. Clustering due to several responses from the same hospital system is also a possibility. Further, although distribution was sought through multiple professional organizations, North American providers were overrepresented. Considering that most responses were from North America, the data are most consistent with practice patterns from this region. Provided that the survey was only distributed in the English language, language barriers might also have played a role in response patterns. To further characterize medication prescription versus actual medication dispensation for medications prescribed on an as needed basis, future research is needed. Finally, because data were collected at a single point in time regarding generalized practice patterns, no individual determination about specific patient-focused metrics can be made.

Conclusions
This large cross-sectional study evaluated practice patterns for post-SAH headache management throughout the world. Current treatment heavily relies on systemic therapy including opioids despite recognized drawbacks and lack of sufficient pain control. Provider-specific differences in approach to analgesia are evident. The need for a multidisciplinary approach, novel treatment strategies, and data guiding optimal approach to post-SAH headache management is apparent and should be undertaken in a rigorous scientific manner.