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Three Part Question

[In healthy adults traveling at high altitude] is [ibuprofen better than placebo] in the [prevention of headache associated with acute mountain sickness]

Clinical Scenario

A 32 year old patient reports having a persistent headache during his most recent mountaineering trip to Colorado. He notes the headache occurred just prior to reaching the summit of Pikes Peak (14,115 ft)and persisted until his decent. He wants to know if there are any safe and effective medications he can take to help alleviate his symptoms during future high altitude climbs.

Search Strategy

Medline 1946-08/14 using OVID interface, Cochrane Library (2014), PubMed clinical queries

[(acute mountain sickness or altitude sickness or altitude headache) AND (ibuprofen)]

Search Outcome

19 papers were identified; of which four were RCT comparing ibuprofen to placebo.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Gertsch JH, Lipman GS, Holck PS, et al. 2010 Sep 21 United States	A total of 343 adult trekkers were enrolled and compared at baseline with 265 subjects presenting at the endpoint.	RCT	Prevention of High Altitude Headache.	Ibuprofen and acetazolamide were similarly effective in preventing HAH. Incidence (acetazolamide 27.1%, ibuprofen 27.5%; P = .95).	Participants had already been exposed to significant altitudes for several days prior to baseline enrollment which could introduce selection bias and limit comparison with other studies. This study involved a diverse population in typical trekking conditions; these results cannot necessarily be applied to other high altitude trekking environments where ascent rate, demographics, and final elevation may differ. Over a fifth of enrollees were lost to follow-up which could introduce selection bias. Small sample sizes limited the power to identify small differences (if any) between the two treatments.
Lipman GS, Kanaan NC, Holck PS, et al. 2012 Jun United States	Two hundred ninety-four total adult participants were enrolled in the study, with 183 completing the entirety of the protocol.	RCT	Prevention of acute mountain sickness incidence and severity.	Significantly fewer participants randomized to ibuprofen developed acute mountain sickness compared with participants receiving placebo (number needed to treat3.9; 95% confidence interval 2 to 33). No statistical difference was found between the groups in reducing the severity of acute mountain sickness symptoms.	Results are applicable to conditions congruent to this study and outcomes can not be extrapolated to higher altitudes or those of other hiking populations. There were numerous factors that were not or could not be controlled such as ambient temperature, wind speed, rate of ascent, liquid and caloric intake of the participants, or underlying physiologic condition of the participants that could potentially confound the study results and conclusions. Acute mountain sickness symptoms vary per individual in time to presentation thus any point measurement is inherently limited and acts as a surrogate marker for the spectrum of disease. All participants spent the first night at 1,240 m, and it is possible that there was a mild degree of acclimatization prior to the study.
Gertsch JH, Corbett B, Holck PS, et al. 2012 Dec United States	294 total adult participants were enrolled, with 183 completing the entirety of the protocol.	RCT	Prevention and treatment of Acute Mountain Sickness	Ibuprofen was found to be effective in preventing AMS in the intent-to-treat analysis group but not in those who completed the trial.	Ibuprofen is effective in prevention and treatment of headache, which is not only the most prevalent symptom of AMS but a compulsory criterion for the diagnosis of AMS. Acclimation of participants prior to the study was not accounted for. One fifth of enrollees were lost to follow-up opening the potential for bias. The mean baseline oxygen saturation of the group lost to follow-up was significantly lower than that of persons who completed the study. There was a statistically significant difference between the age of participants and the age of persons excluded from the trial.
Broome JR, Stoneham MD, Beeley JM, Milledge JS, Hughes AS. 1994 January England	22 members of a military expedition whom were residents at sea level prior to their climb.	RCT with in-patient crossover design.	Prevention and treatment of high altitude headache.	Ibuprofen was significantly superior to placebo both in reducing headache severity and in speed of relief (a mean difference of 94 min in time to no/minimal headache).	The small sample size severely limits this study’s reliability despite the statistically significant differences. Primary outcomes were subjective and thus may vary and not accurately represent the spectrum of disease. There were numerous factors that were not or could not be controlled such as liquid and caloric intake of the participants, or underlying physiologic condition of the participants that could potentially confound the study results and conclusions. Results are applicable to conditions congruent to this study and outcomes cannot be extrapolated to alternate altitudes or those of other hiking populations. Acclimation of participants just prior to the study was not accounted for.

Comment(s)

Acute mountain sickness (AMS) is a constellation of symptoms, including headache, sleep disturbance, fatigue, dizziness, nausea, vomiting, or anorexia, that commonly occurs in travelers ascending to altitudes above 2,500 m (8,250 ft). Ibuprofen works by inhibiting the cyclooxygenase enzyme which is involved in mediating inflammation (swelling), and pain. Although the pathophysiology of AMS is not well understood, it is theorized that ibuprofen could be an effective treatment for high altitude headache. Acetazolamide has been used as the standard prophylactic medicine for decades but more recent studies support the use of ibuprofen as potential treatment for the most prevalent of symptoms, headache.

Clinical Bottom Line

In healthy adults traveling at high altitude ibuprofen has been found to be more effective than placebo in the prevention of headache associated with acute mountain sickness.

References

1. Gertsch JH, Lipman GS, Holck PS, et al. Prospective, double-blind, randomized, placebo-controlled comparison of acetazolamide versus ibuprofen for prophylaxis against high altitude headache: the Headache Evaluation at Altitude Trial (HEAT) Wilderness and Environmental Medicine 2010 Sep;21(3):236-43
2. Lipman GS, Kanaan NC, Holck PS, et al. Ibuprofen prevents altitude illness: a randomized controlled trial for prevention of altitude illness with nonsteroidal anti-inflammatories Annals of Emergency Medicine 2012 Jun;59(6):484-90
3. Gertsch JH, Corbett B, Holck PS, et al. Altitude Sickness in Climbers and Efficacy of NSAIDs Trial (ASCENT): randomized, controlled trial of ibuprofen versus placebo for prevention of altitude illness Wilderness and Environmental Medicine 2012 Dec;23(4):307-15
4. Broome JR, Stoneham MD, Beeley JM, Milledge JS, Hughes AS. High altitude headache: treatment with ibuprofen Aviation, Space, and Environmental Medicine 1994 Jan;65(1):19-20