Headache attributed to airplane travel: diagnosis, pathophysiology, and treatment – a systematic review

Background Headache attributed to airplane travel, also named "airplane headache" (AH) is a headache that occurs during take-off and landing. Today, there are still uncertainties about the pathophysiology and treatment of AH. This systematic review was performed to facilitate identification of the existing literature on AH in order to discuss the current evidence and areas that remain to be investigated in AH. Methods The systematic literature search was performed in 3 relevant medical databases; PubMed, Scopus, and Embase. The search yielded 220 papers and the papers were sorted based on inclusion and exclusion criteria established for this study. Results This systematic review included 39 papers. Main findings revealed that AH attacks are clinically stereotyped and appear mostly during landing phases. The headache presents as a severe painful headache that often disappears within 30 min. The pain is unilateral and localized in the fronto-orbital region. Sinus barotrauma has been considered as the main cause of AH. Nonsteroidal anti-inflammatory drugs and triptans have been taken by passengers with AH, to relieve the headache. Conclusions Based on this systematic review, further studies seem required to investigate underlying mechanisms in AH and also to investigate the biological effects of nonsteroidal anti-inflammatory drugs and triptans for alleviating of AH. These studies would advance our understanding of AH pathogenesis and potential use of treatments that are not yet established.


Introduction
Headache attributed to airplane travel, also named "airplane headache" (AH) occurs in a population of passengers during airplane travels. The headache appears as an intense short lasting pain at landing and it is often located in the fronto-orbital region [1][2][3][4][5][6][7]. Despite its occurrence rate and high impact, only limited is known about AH, and this type of headache has only been defined and included in the headache classification since 2013 by International Headache Society (IHS), which provides headache classifications and maintains related updates [1]. The first case of AH was described in 2004, and since then, number of publications on AH has been added into the literature . Previous reports, before inclusion of AH in classification, could be based on diversity in diagnosis, which makes it difficult to determine whether reported patients suffered from AH or other conditions [1,6]. Despite the fact that some points are known based on these publications, there is still uncertainty around influence of ethnicity, gender or age on incidence or prevalence of AH. A male dominancy has been reported for AH [4,6,26]. Current knowledge about pathophysiology and treatment of AH is limited that calls for further investigation on both epidemiological aspects of AH, pathophysiology and treatment options.
There is also a diverse range of hypotheses about the pathophysiological causes of AH. Previous studies have suggested vasodilation in the cerebral arteries or sinus barotrauma as a result of cabin pressure change in the airplane [2,3,6,11,12,26]. These proposed mechanisms require further investigation to prove or falsify suggested theories. Besides, no specific treatment plan has been developed for AH, although several medications have shown beneficial effects, e.g. triptans [11]. Considering challenges and limitation of AH studies under real-time conditions, it might be an option to study this headache under controlled experimental conditions. This approach has also been used in studying other types of headaches [25]. An experimental model of AH has been developed recently [25] that can help in further understanding of potential mechanisms underlying AH, or to examine AH under different circumstances, and identification of potential biological biomarkers. This model [25] can also serve for testing treatment options for AH.
To provide a better overview of existing literature on diagnosis, pathophysiology, and treatment of AH, this systematic review was performed. It was proposed that outcome of this review would highlight existing evidences, missing information, and stimulate further research in AH. Understanding AH pathogenesis and efficient targeting would ultimately help millions of passengers who suffer from this condition.

Literature search
Both authors (SBDB and PG) contributed in performing the systematic literature search in PubMed, Scopus, and Embase by using the terms "airplane headache" and "aeroplane headache" (airplane OR aeroplane AND headache).

Selection criteria and data extraction
Due to limited information available about AH, all types of studies and levels of evidence about AH were considered eligible for inclusion, including i.e. case series, case reports, conference abstracts, and all types of publications providing knowledge on diagnosis, pathophysiology, or treatment of AH. All papers were exported and duplicates were excluded through the Excel 2010 (Microsoft Corp., Seattle, WA, USA). Titles that appeared relevant were assessed for inclusion. Papers were excluded if they were not available in English. All data from the included papers were reviewed and tabulated according to authors of study, year, study type, demographic data on the patients, and main outcomes.

Literature search
The flowchart for selection of papers is shown in Fig. 1. The search strategy identified 220 papers. The authors excluded 175 papers due to lack of relevance to AH. Furthermore, 6 additional papers were excluded as those did not contain relevant description of AH, were not written in English, and reported the same data from an existing case report on AH. The authors, therefore, included 39 papers for the final review, which provided sufficient information on diagnosis, pathophysiology and/or treatment of AH (see Table 1).

Duration, severity and frequency of AH
Collectively, based on available evidences, landing appears to be the phase of the flight during which most of patients experience AH-attack with a duration within 30 min. During the AH-attack, the pain is described as severe with a rating of 8-10 on a scale from 0 (no pain) to 10 (worst possible pain), (n = 229/275). In few cases, patients have had experienced a second mild phase headache after the AH-attack that resolved within 4-24 h (n = 2/275). The frequencies of the AH-attacks were reported by some patients: 42 patients experienced AH in every flight travel, while AH occurred in more than 50% of the flight travels in 39 patients.

Symptoms characteristics of AH
The AH-attack is often experienced as jabbing, stabbing and/or pulsating in the unilateral fronto-orbital region and is not associated with accompanying symptoms in most of the AH-attacks. However, few patients did experience these accompanying symptoms; dizziness (n = 2/275), sensation of paraesthesias starting from the left thumb accompanied by spread to the hand and perioral region (n = 1/275).

AH pathophysiology
The pathophysiology of AH is still unknown, but speculative hypotheses have been proposed. The most frequently discussed mechanism for AH is that the changes in the cabin pressure during take-off and landing may lead to sinus barotrauma, local inflammation, and thereby development of AH [2-7, 9-14, 18-21, 24-27, 32, 35, 39, 40].
Due to possible variations in the anatomical and structural construction in the individual ethmoid sinuses, including ethmoid cells, these patients cannot equalize the pressure during the take-off or landing [7]. Ethmoid cells are innervated by branches of the trigeminal nerve, where these nerve endings may trigger a stimulus as a consequence of sinus barotrauma and thereby inflammation due to the lack of pressure equalization [7]. This may lead to the characteristic of pain localized in the fronto-orbital region [7].
So far, there has been only one experimental study that has attempted to investigate the mechanism in AH [25]. Prostaglandin E 2 (PGE 2 ) has been shown to be significantly high in AH-patients during a simulated flight when compared with healthy subjects. It is speculated that PGE 2 is elevated due to local inflammation, which may cause vasodilation in the cerebral arteries and induce AH [25]. Based on one case occurred during landing, reversible cerebral vasoconstriction syndrome (RCVS) has been advanced as a possible mechanism in the pathophysiology of AH [23].    • The 2 other patients with inflamed nasal mucosal walls were given antihistamine and anti-inflammatory medications and were completely headache-free after treatment. • The authors stated that their effective treatment with antihistamine and anti-inflammatory medications support the theory that sinus barotrauma plays a central role in the mechanism of AH.
2010, Pfund et al. [19] 1 1 F 27 Case report • The patient developed bilateral headache located in her ear, cheek, forehead, and on the top of the head. The pain was described as stabbing, jabbing and rated as 10/10. • The severe headache pain disappeared after landing, but was followed by a mild headache that lasted two weeks after the flight travel. • MRI and paranasal sinus computed tomography and revealed bilateral inflammation in the sphenoid, maxillary and ethmoid sinuses. Furthermore, the patient had increased number of eosinophilic cells and swelled nasal mucosa. These findings supported the diagnosis of chronic non-allergic rhinosinusitis. • Patient was given antihistamine and experienced almost painless airplane travels. • The authors supported the sinus barotrauma as a central role in the mechanism of AH. Case reports • All the patients developed a severe headache during the ascending or the descending phase. The pain was located in the unilateral fronto-orbital region and lasted between 15 and 25 min. • Triptans were prescribed to all patients and they were instructed to take a triptan (either naratriptan, zolmitriptan, eletriptan or sumatriptan) 30 min before the start of the airplane travel. There was a follow-up period of 2-4 years and all patients were completely headache-free in all their airplane travels. • The authors indicated that sinus barotrauma might play a role in the mechanism of AH. They also hypothesized that the use of triptans may cause vasospasm in cerebral arteries and thereby prevent the AH-attack.    Some flight passengers develop anxiety of flying, which may have a psychological impact on the passengers during flight travels [12,25]. The stress hormone cortisol has also been shown to be significantly elevated in AHpatients during a simulated flight when compared to healthy subjects indicating a physiological response during an AH-attack [25]. In addition, hypoxia has also been considered to be one of the other factors that may affect the development of AH [2,25,26].

Literature search
In this systematic review, 39 articles were included. The authors decided to include all types of articles as the literature within AH is very limited. Therefore, the main purpose was to present and discuss the current evidence on diagnosis, pathophysiology, and treatment of AH. However, a restriction was made in the literature search strategy where only English articles were included. Articles that have not been indexed in PubMed, Scopus and Embase, may have not been included in this review. Despite of this, our systematic review presents 275 AH-patients, which, together give a stereotypical clinical picture of AH.

AH diagnosis
The cumulative analysis in this review revealed that 127 females (46%) and 148 males (54%) have suffered from AH (275 patients in total). At present, it is difficult to conclude whether gender affects the development of AH. By instance, there was a predominance of males in few studies [4,6,26], whereas there was a predominance of females in the study by Bui et al. [2]. Gender difference in some primary headaches has been documented [41,42], and if similar difference is identified in AH, it will provide knowledge of which particular gender is more susceptible to AH. The mean diagnosis age for AH was 28.7 ± 4.8 years (n = 275/275), while the age at first AH-attack was 26.4 ± 3.8 years (reported by 163/275 patients). These data may indicate that the diagnosis age of AH and the first AH-attack may occur in a relatively Table 1 Demographic characteristics and main outcomes of the current literature regarding headache attributed to airplane travel (Continued) • ENT, CT and MRI showed normal findings. Both patients had no history of tension headache, migraine or cluster headache. • The authors ascertained that the duration of the headache and the pain localization in the occipital and parieto-occipital area are not in accordance with the AHcriteria set by "International Classification of Headache Disorders 3 beta version" [1].
2017, Bui et al. [25] 7 1 M/ 6 F 29.7 ± 9.6 Journal article • All patients fulfilled the AH-criteria set by "International Classification of Headache Disorders 3 beta version" [1]. • A pressure chamber was used as an experimental model to induce simulated AH in the patients. The clinical features of the headache were in accordance with an AH-attack in a real-time flight travel. • Saliva samples, saturation pulse oxygen, blood pressure and thermo imagining were collected and measured before, during and after their simulated flight in the pressure chamber. • The data showed that the values for saturation pulse oxygen, prostaglandin E 2 and cortisol significant different in AH-patients in comparison with the healthy participants.
AH Airplane headache also called headache attributed to airplane travel. CT computerized tomography. MRI brain magnetic resonance imagining.
MRA magnetic resonance angiography. ENT ear-nose-throat, EEG Electroencephalography, NSAIDs Non Steroidal Anti-Inflammatory Drugs young age regardless of gender. There is no explanation on association of age with AH. This needs further investigation to identify whether it is related to pathophysiology of AH or demographic characteristics of travelers. The stereotypical clinical symptom of AH is an intense unilateral pain locating in the fronto-orbital region. The pain is very severe and is often described as 8-10 on a pain scale from 0 to 10, where 0 is no pain and 10 is the worst imaginable pain [2,4,6,9,25,35,40]. The pain disappears within 30 min in most cases, where it seems that the AH duration might correspond to the duration of take-off and landing. However, there is a smaller group of AH passengers who experience a second-phase headache, which is a mild headache that may last hours to days; but, it may not be considered as a direct continuation of the intense headache that occurs within the airplane.
AH is experienced without accompanying symptoms in almost all cases; but, there are few cases that cannot be considered as part of the stereotypical clinical symptoms of AH [13,18]. In the current literature, there are 54 patients suffering from migraine [2,4,6,7,18]. Although there are many who suffer from migraine, it does not indicate that there is a direct link between migraine and AH [2]. In addition, these migraine patients have reported that they experienced AH and not migraine attacks (2,4,6,7,18). Furthermore, 22 patients suffering from tension type headache, did also report a pure AH-attack and not a tension type headache-attack [6,12,21]. In relation to sinus infections, only few cases have been reported, where there was an active sinus infection in the passengers who experienced AH [16]. This indicates that AH is a separate headache that is not associated with other headaches and conditions; but, it is currently unclear whether certain headaches or conditions (such as stress and anxiety) are potential risk factors for developing AH.
In 2013, AH was formally classified by IHS, where diagnostic criteria for AH were established [1]. This makes it possible for future studies to use the diagnostic criteria for harmonizing the research within this field (e.g. Bui et al. [2,25]). It will also make it easier for doctors to diagnose AH at clinic as the criteria can be used identically.

AH pathophysiology
Berilgen et al. [7] were the first to suggest "sinus barotrauma" as a potential mechanism underlying AH, which has been a key element in the subsequent discussion for AH mechanisms [2-5, 9-14, 18-21, 24-27, 32, 35, 39, 40]. It is well known that imbalance between atmospheric pressure changes and pressure inside the sinuses can cause tissue damage [43][44][45]. This means, for example, that the pressure in the sinuses is lower than the cabin pressure during the landing [6,26]. At take-off, the cabin pressure is lower than the sinuses [6,26]. It has also been shown that the cabin pressure changes during a flight travel, where the cabin pressure will decrease with around by 8 hPa for every 300 m the airplane increases in altitude [46]. The normal altitude for airplanes is 2500 m with a stabilized cabin pressure at 846 hPa [46].
Berilgen et al. [7] suggest that the first-degree sinus barotrauma is the key mechanism underlying AH. During the first-degree sinus barotrauma, nerve endings in the ethmoid sinuses, which are invaded by the trigeminal nerve [47], are affected. This causes pain in the frontoorbital region [7,48], which explains that the pain is mainly experienced in the orbital region [2, 4-13, 15-18, 21, 25-28, 35]. The proposal of first-degree sinus barotrauma may be reasonable as it is explained by the fact that neurological examinations, such as CT, MRI, MRA and ENT, have shown normal sinus conditions in several studies [5, 7-13, 15, 17, 18, 21, 26, 35]. However, few studies have shown cases of thickened nasal mucosa among 2 AH-patients with allergy and chronic rhinosinusitis [16,19]. The patient with allergy was treated with antihistamines and subsequently experienced headache-free flight travels [16]. Data from these studies indicate that thickened nasal mucosa resulted from the allergy and chronic rhinosinusitis and not as a result of the flight travels. Coutinho et al. [17] suggest that MRI should be used to rule out other conditions including sinus barotrauma. This indicates that Coutinho et al. [17] have not taken into account the degrees of sinus barotrauma as those are only the second-degree and thirddegree that show thickened nasal mucosa [45]. Relative to the pain of AH, the pain usually disappears within 30 min [2, 5-13, 15-19, 21, 25-27, 35], which is consistent with the short-term pain at the first-degree sinus barotraume [45]. However, neurological examinations were not performed on all the presented 275 AH-patients in this review and this should be considered in the future for proper diagnosis of AH at clinic.
It is still unknown which specific substances play a role in the mechanism of AH. Bui et al. have speculated that vasodilation may occur in the cerebral arteries during an AH-attack [25]. One of the substances investigated in that study was PGE 2 , where PGE 2 levels were significantly higher in a group of AH-patients compared with healthy subjects during a simulated flight in a pressure chamber [25]. Wienecke et al. have shown that PGE 2 can induce vasodilation in the cerebral arteries and headache in healthy subjects by infusion of PGE 2 [49]. Authors suggested that PGE 2induced headache might be due to activation and sensitization of cranial perivascular sensory afferents [49]. As local inflammation may occur in the sinuses during an AH-attack [2-7, 9-14, 18-21, 24-27, 32, 35, 39, 40], it may be reasonable to consider that PGE 2 increases as a consequence of this inflammatory condition [25]. This makes PGE 2 an interesting potential biomarker for AH and infusion of PGE 2 in AH-patients in future studies may provide knowledge whether PGE 2 play a role in the AH mechanism.
The theoretical mechanism of AH is mainly based on barotrauma [2-7, 9-14, 18-21, 24-27, 32, 35, 39, 40] and possibly vasodilation in the cerebral arteries [25]. A study by Hiraga et al. [23] considers the opposite. The authors point out that vasoconstriction may be the cause of AH. The female patient in their study experienced a headache, which lasted for several hours and days when they performed a neurological examination and contraction of her cerebral arteries was seen. Mainardi et al. [22], however, proposed that patient's symptoms do not match with the diagnostic criteria for AH and hence it is unclear whether vasoconstriction in the cerebral arteries can be a cause or a consequence of AH. For future studies, it would be valuable to use imaging techniques during a real or simulated flight travel to investigate whether vasoconstriction or vasodilation occurs in the cerebral arteries during an AH-attack.
It has been shown that cortisol levels were significantly higher before and during a simulated flight in a small group of AH-patients compared with a healthy matched group tested in a pressure chamber [25]. Some AHpatients reported that they felt stressed and had anxiety during the simulated flight [25]. In addition, Kararizou et al. [12] has also presented an AH-patient with anxiety. This might indicate that psychological aspects can also contribute in AH [12,25]. However, flight passengers frequently present stress and anxiety in dealing with the flight and in most of cases they do not complain of AH. On the contrary, patients who do not have any negative emotional impact may start to present anxiety and stress when they experience AH. Therefore, stress and anxiety could be considered as a consequence of the fearing to develop AH instead of being one of principal pathogenetic mechanisms of AH. If anxiety and stress did have a predominant role in the pathogenesis of AH, then it should be expected that AH may occur in almost every flight, which is not the case.
It may be difficult to run experiments during a real-time flight travel both from practical points and also safety issues. However, an experimental model might be a reasonable alternative that can be used to induce AH, which allows investigating more physiological aspects of AH. Bui et al. [25] used a pressure chamber to study AH under controlled experimental conditions. In the chamber, pressure changes, which correspond to the changes during take-off and landing, are applied. This study presented occurrence of AH during simulated flight in those who suffer from this condition but not healthy controls [25]. The clinical symptoms of the simulated AH were found similar to the symptoms of the real-time AH-attacks [25]. This indicated that it is possible to use the pressure chamber as a platform experimental model to induce AH and to investigate AH under fully controlled conditions. Furthermore, it can also be used to investigate whether AH is associated with risk factors or comorbidities in future studies.

AH treatment
There is no specific treatment plan for AH, that might be due to the fact that this headache is considered short lasting and terminated after the flight travel is over. However, evidences in the literature demonstrate that some passengers suffering from AH, have been required to take medications to subside the headache. This systematic review, only focused on pharmacological treatment, although there have been cases of non-pharmacological treatments [6]. Several flight passengers have been self-medicated in order to relieve AH, where only ibuprofen, naproxen, and triptans have been found the most effective [2,6,9,11,16,17,26,35]. Only Berilgen et al. [26] have prescribed naproxen to their 21 subjects and all subjects experienced no headache after intake of naproxen before the start of their flights. Today, the effects of ibuprofen, naproxen, and triptans are based on the patient's own narratives [2,6,9,11,16,17,26,35]. Therefore, future studies seem necessary to provide a clear guideline as whether or not medications are actually needed and which patient will get the best benefit. Since most studies are based on case series and case reports, it is reasonable to perform future randomized controlled trials (RCTs) on pharmacological treatments of AH. Setting up a double blind RCT, where a control group is given placebo, and the other group, medication (ibuprofen, naproxen or triptans), can reveal the actual effect of medications on AH.
Based on the finding of this review, 6 flight passengers have taken ibuprofen, where 4 of those have experienced a relieving effect [6,9,16]. For the naproxen, 24 flight passengers have taken this medication with all experiencing a relieving effect [17,26,35]. If PGE 2 has a central role in the mechanism of AH, then ibuprofen and naproxen seem reasonable choices, as these medications inhibit COX, reduce elevated levels of PGE 2 during an AH-attack, and can abort headaches [25,50].
Ipekdal et al. [11] performed a study in 2011 and included 5 patients who took triptans 30 min before flight travels and this prevented development of AH completely [11]. Cumulative findings of this systematic review showed that 12 patients have taken triptans in order to relieve AH [2,4,11]. Triptans are a class of drugs developed for abortion of migraine headaches [11,[51][52][53]. In relation to AH, Ipekdal et al. [11] have suggested that triptans may cause vasospasms during an AH-attack and thereby prevent it. There is, however, no evidence to present a mechanism-based explanation for use of triptans for AH.
Calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) are believed to play a role in vasodilation in the cerebral arteries leading to development of migraine attacks [54]. Bellamy et al. have shown that CGRP and VIP levels are significantly reduced when patients take triptans during a migraine attack [54], which is associated with a significant relief of headache [54]. Future studies are required to investigate whether CGRP and VIP also play a role in development of AH. If AH is a result of vasodilation in the cerebral arteries, elevated levels of CGRP and VIP might be seen in AH and triptans that have shown some benefits for AH may act on these headache biomarkers.
The frequencies of AH-attacks are relatively high; 42 flight passengers experience AH in every flight travels and 39 flight passengers experience AH in more than 50% of the flight travels [4-6, 12, 19, 21, 27, 39, 40]. For the rest of 194 AH-patients presented in this systematic review it is not known how often AH occurs. Clinical trials, such as RCTs, seem necessary for better understanding of AH and the value of considering strategic plans for treatment or prevention of AH.

Conclusions
Based on this systematic review, it is now evident that further studies are required to investigate AH systematically. Investigations may clarify unknown aspects of AH diagnosis that can be taken in updates of AH classification by IHS. Future experimental studies are also essential to further investigate proposed mechanisms underlying AH; barotrauma and vasodilation in the cerebral arteries, and also to investigate the biological effects of most used medications, ibuprofen, naproxen and triptans for alleviating of AH-attacks. These studies would advance our understanding of AH pathogenesis and value of treatment options that are not yet established. This would subsequently help millions of passengers suffering from this condition.