Does Ibuprofen Prevent Acute Mountain Sickness? (2012)

Two recent prospective double-blind, placebo controlled studies, one by Lipman et al in the Annals of Emergency Medicine1Lipman G.S. Kanaan N.C. Holck P.S. Constance B.B. Gertsch J.H. PAINS GroupIbuprofen prevents altitude illness: a randomized controlled trial for prevention of altitude illness with nonsteroidal anti-inflammatories.Ann Emerg Med. 2012; 59: 484-490Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar and another by Gertsch et al in this issue of Wilderness & Environmental Medicine,2Gertsch J.H. Corbett B. Holck P.S. 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 Environ Med. 2012; 23: 307-315Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar have evaluated the use of ibuprofen, for prevention of acute mountain sickness (AMS). These studies raise the questions of whether ibuprofen is useful to prevent AMS and, if so, how does it work? Because the current diagnostic criteria for AMS require the presence of a headache, does ibuprofen prevent AMS by preventing the headache without providing protection against the other features of the disease? Does ibuprofen speed acclimatization or does it mask the symptoms of AMS? Acute mountain sickness is a symptom complex that afflicts visitors to high altitude, generally above 2500 m.3Hackett P.H. Roach R.C. High-altitude illness.N Engl J Med. 2001; 345: 107-114Crossref PubMed Scopus (1025) Google Scholar Acute mountain sickness is unpleasant and is usually self-limited, but can progress to high altitude cerebral edema (HACE), a life-threatening illness. The Lake Louise Acute Mountain Sickness Scoring System—Lake Louise Score (LLS) for short—is the most commonly used method of diagnosing AMS. The LLS bases the diagnosis of AMS on “a recent gain in altitude, at least several hours at the new altitude and the presence of a headache, and at least one of the following symptoms: gastrointestinal upset (anorexia, nausea, or vomiting), fatigue or weakness, dizziness or lightheadedness, and difficulty sleeping.”4Roach R. Bärtsch P. Oelz O. Hackett P.H. The Lake Louise acute mountain sickness scoring system.in: Sutton J.R. Houston C.S. Coates G. Hypoxia and Molecular Medicine. Queen City Printers, Burlington, VT1993: 272-274Google Scholar (Table) A score of 3 points or more, with at least 1 of the points as a result of headache, establishes the diagnosis of AMS. There are several ways to prevent AMS when going to high altitude. The most reliable and safest method is gradual ascent to allow time for acclimatization. Two medications—acetazolamide and dexamethasone—have been shown to decrease the risk of AMS when given prophylactically.5Luks A.M. McIntosh S.E. Grissom C.K. et al.Wilderness Medical Society consensus guidelines for the prevention and treatment of acute altitude illness.Wilderness Environ Med. 2010; 21: 146-155Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar An herbal medication, Ginkgo biloba, has also been studied for AMS prevention, with mixed results.5Luks A.M. McIntosh S.E. Grissom C.K. et al.Wilderness Medical Society consensus guidelines for the prevention and treatment of acute altitude illness.Wilderness Environ Med. 2010; 21: 146-155Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar Individual double-blind placebo-controlled studies have reported reduction in the incidence of AMS with the use of gabapentin6Jafarian S. Gorouhi F. Salimi S. Lotfi J. Low-dose gabapentin in treatment of high-altitude headache.Cephalalgia. 2007; 27: 1274-1277Crossref PubMed Scopus (13) Google Scholar or sumatriptan.7Jafarian S. Gorouhi F. Salimi S. Lotfi J. Sumatriptan for prevention of acute mountain sickness: randomized clinical trial.Ann Neurol. 2007; 62: 273-277Crossref PubMed Scopus (33) Google Scholar In the first of the recent studies, Lipman et al1Lipman G.S. Kanaan N.C. Holck P.S. Constance B.B. Gertsch J.H. PAINS GroupIbuprofen prevents altitude illness: a randomized controlled trial for prevention of altitude illness with nonsteroidal anti-inflammatories.Ann Emerg Med. 2012; 59: 484-490Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar studied AMS in subjects who ascended rapidly from below 1240 m to 3810 m in the White Mountains of California. The authors concluded that ibuprofen was effective when compared with placebo in reducing the incidence of AMS. In the second, Gertsch et al2Gertsch J.H. Corbett B. Holck P.S. 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 Environ Med. 2012; 23: 307-315Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar studied AMS in the Nepal Himalayas in trekkers who walked from about 4300 m to 4928 m. The authors found that ibuprofen was “effective in preventing AMS in the intent-to-treat analysis group, but not in those who completed the trial.” They suggested that subjects in the placebo group were more likely to experience AMS and therefore to drop out of the trial. As with many previous studies in the Everest region, the sample size was large, but the rate of noncompletion was also relatively high. Is the apparent benefit of ibuprofen in preventing AMS based only on its ability to prevent headache? Because headache is an essential symptom in the current diagnosis of AMS, the efficacy of ibuprofen may be an artifact of the scoring system. A recent debate over the merits of changing the LLS to eliminate that requirement that a headache be present underscores the uncertainty of diagnosis. West8West J.B. Con: headache should not be a required symptom for the diagnosis of acute mountain sickness.High Alt Med Biol. 2011; 12 (discussion 27): 23-25Crossref PubMed Scopus (21) Google Scholar argued that there are many people who suffer from acute altitude-related symptoms but do not have a headache, whereas Roach et al9Roach R. Kayser B. Hackett P. Pro: headache should be a required symptom for the diagnosis of acute mountain sickness.High Alt Med Biol. 2011; 12 (discussion 29): 21-22Crossref PubMed Scopus (19) Google Scholar maintained that the presence of headache was important, at least for research purposes. Complicating this question is the existence of another entity, high altitude headache (HAH), a necessary but not sufficient condition for AMS using the LLS. In the Headache Evaluation at Altitude Trial (HEAT),10Gertsch J.H. Lipman G.S. Holck P.S. 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 Environ Med. 2010; 21: 236-243Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar acetazolamide and ibuprofen had similar efficacy in preventing HAH and both were more effective than placebo. As with AMS, the differential diagnosis of headache at high altitude is broad. Both AMS and HAH can be simulated by other conditions, such as migraine and carbon monoxide poisoning, that are not necessarily related to altitude exposure. The authors of both recent studies cite the importance of inflammation in the pathophysiology of AMS11Richalet J.P. Hornych A. Rathat C. Aumont J. Larmignat P. Rémy P. Plasma prostaglandins, leukotrienes and thromboxane in acute high altitude hypoxia.Respir Physiol. 1991; 85: 205-215Crossref PubMed Scopus (79) Google Scholar, 12Tissot van Patot M.C. Leadbetter G. Keyes L.E. et al.Greater free plasma VEGF and lower soluble VEGF receptor-1 in acute mountain sickness.J Appl Physiol. 2005; 98: 1626-1629Crossref PubMed Scopus (76) Google Scholar, 13Julian C.G. Subudhi A.W. Wilson M.J. Dimmen A.C. Pecha T. Roach R.C. Acute mountain sickness, inflammation, and permeability: new insights from a blood biomarker study.J Appl Physiol. 2011; 111: 392-399Crossref PubMed Scopus (72) Google Scholar as supporting evidence that a nonsteroidal anti-inflammatory drug (NSAID) such as ibuprofen should be of benefit in preventing AMS. The study by Lipman et al1Lipman G.S. Kanaan N.C. Holck P.S. Constance B.B. Gertsch J.H. PAINS GroupIbuprofen prevents altitude illness: a randomized controlled trial for prevention of altitude illness with nonsteroidal anti-inflammatories.Ann Emerg Med. 2012; 59: 484-490Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar showed a similar prevalence of headache in the AMS and placebo groups. As the authors point out, this favors the conclusion that ibuprofen acts to prevent the constellation of symptoms rather than just treating the headache. Burtscher et al in a small, randomized, double-blind, placebo-controlled trial14Burtscher M. Likar R. Nachbauer W. Philadelphy M. Aspirin for prophylaxis against headache at high altitudes: randomised, double blind, placebo controlled trial.BMJ. 1998; 316: 1057-1058Crossref PubMed Scopus (77) Google Scholar found that aspirin helped to prevent HAH. The authors theorized that aspirin “may support adaptation to high altitude by reducing sympathetic activity mediated by prostaglandin.” In contrast, a small study of the NSAID calcium carbasalate, an aspirin analog, failed to show any preventive effect against AMS compared with placebo.15Kayser B. Hulsebosch R. Bosch F. Low-dose acetylsalicylic acid analog and acetazolamide for prevention of acute mountain sickness: the authors reply.High Alt Med Biol. 2008; 9: 351-352Crossref Scopus (2) Google Scholar This study, on Mt Kilimanjaro, was limited by a very rapid ascent rate, but acetazolamide did provide significant protection in the study. A study comparing paracetamol (acetaminophen) with ibuprofen for the prevention of AMS might shed light on the relative importance of antiheadache and anti-inflammatory effects because paracetamol has no significant anti-inflammatory effect but is effective against headache. Does ibuprofen speed acclimatization or does it just mask symptoms? One answer for an anti-inflammatory medication that is not an NSAID comes from a hypobaric chamber study of the use of dexamethasone to prevent AMS in 6 subjects.16Levine B.D. Yoshimura K. Kobayashi T. Fukushima M. Shibamoto T. Ueda G. Dexamethasone in the treatment of acute mountain sickness.N Engl J Med. 1989; 321: 1707-1713Crossref PubMed Scopus (106) Google Scholar Although dexamethasone was effective in preventing AMS, the authors found no improvement in objective physiologic abnormalities related to hypoxia. Alarmingly, they identified cerebral edema in 1 subject. They concluded that dexamethasone works to prevent AMS by mood enhancement and by decreasing nausea. Withdrawal of dexamethasone after rapid ascent to high altitude, without sufficient time for acclimatization, can cause “rebound” symptoms. Further ascent after taking dexamethasone for prevention or treatment of AMS carries a greater risk of AMS or HACE than does further ascent after use of acetazolamide, which speeds acclimatization. The usual explanation has been that dexamethasone “masks” symptoms of AMS. Ibuprofen is a relatively benign drug, although its use does carry potentially serious risks such as gastrointestinal hemorrhage. Ibuprofen tends to have fewer side effects than acetazolamide. Unlike dexamethasone, it does not cause euphoria or decrease nausea. Its analgesic and anti-headache properties are limited and unlikely to mask significant symptoms. The widespread popularity of ibuprofen and the fact that it is widely available without a prescription make it an attractive option for prevention of AMS if the early reports of its effectiveness prove to be true. One could speculate that travelers to high altitude who are taking ibuprofen for prevention of AMS, like those taking dexamethasone, should be cautious not to discontinue it too soon and should also be cautious about continued ascent. However, there is no evidence to suggest that this is the case and no reports of problems to suggest that these precautions are necessary. Current evidence suggests that ibuprofen is effective in the prevention of AMS and that its benefit is not limited to preventing headache. It is likely that ibuprofen acts to protect against AMS by decreasing inflammatory responses to hypoxia. Whether ibuprofen masks symptoms or speeds acclimatization is still an open question. The bright side of these questions is that there is ample scope for further research! Altitude Sickness in Climbers and Efficacy of NSAIDs Trial (ASCENT): Randomized, Controlled Trial of Ibuprofen Versus Placebo for Prevention of Altitude IllnessWilderness & Environmental MedicineVol. 23Issue 4PreviewTo study the effectiveness of ibuprofen versus placebo in preventing acute mountain sickness (AMS) and high altitude headache (HAH). Full-Text PDF ErratumWilderness & Environmental MedicineVol. 24Issue 2PreviewIn Dr Zafren's Editorial entitled “Does Ibuprofen Prevent Acute Mountain Sickness?” in Wilderness & Environmental Medicine (2012;23:297-299), the table showing the Lake Louise Score was omitted. Below is the referenced Table. Full-Text PDF