Ibuprofen seems effective in preventing high altitude headaches (HAH) and may, therefore, represent a good alternative to Acetazolamide or Dexamethasone in HAH prophylaxsis. 

Acute mouth sickness (AMS) is prevalent in non-altitude-acclimatized individuals upon acute exposure to hypobaric hypoxia, generally above 2500 m.  This condition results from hypoxemia and is characterized headache, nausea, weakness, dizziness, and sleep disturbances. High altitude headache (HAH) is a necessary criterion used for diagnosis of AMS that occurs in isolation or as a sentinel symptom during the development of AMS. Both these conditions are self-limiting but can transform into life-threatening high altitude cerebral edema (HACE), if left untreated for a long time. There is a lack of high-quality evidence regarding effects of pharmacological and preventive therapies for HAH. The most efficient regimen for prophylaxis against HAH is by ascending gradually to allow enough time for altitude acclimatization. Acetazolamide is considered as first-line treatment for managing AMS and HAH for decades, but multiple studies have confirmed the use of non-steroidal anti-inflammatory drugs (NSAIDs) in HAH and possibly AMS. Ibuprofen is an NSAID that counters production of prostaglandins and inflammatory cascade via cyclooxygenases inhibition. It limits the chemical irritants known to sensitize meningovascular receptors that mediate nociception. There is still a controversy behind the use of ibuprofen in masking HAH symptom of AMS without preventing AMS or prevent AMS and accelerating high-altitude acclimatization.

Rationale behind the research:

The is a lack of data confirming the efficacy of Ibuprofen in preventing HAH.

Objective:

To conduct systematic meta-analysis of the efficacy of Ibuprofen for preventing HAH.

Outcome measures

• Primary outcomes: The difference in incidence of HAH between Ibuprofen and placebo groups
• Secondary outcomes: The incidence of severe HAH, difference in arterial oxygen saturation (SpO2), and the severity of headache on VAS
  

Study outcomes

Primary outcomes:

• HAH occurred in 101 of 239 (42%) patients who took Ibuprofen and 96 of 168 (57%) who received placebo (RR=0.79, 95% CI 0.66 to 0.96, Z=2.43, P=0.02, I2=0%). The absolute risk reduction (ARR) was 15%. The Number needed to treat (NNT) to prevent HAH was 7 (Fig 1).

Fig. 1: Forest plot of weighted mean difference in incidence of HAH in placebo and Ibuprofen groups for all clinical trials.

Secondary outcomes:

• The incidence of severe HAH was notable in the two groups (RR = 0.40, 95% CI 0.17 to 0.93, Z=2.14, P=0.03, I2=0%). Severe HAH happened in 3% patients treated with Ibuprofen and 10% with placebo.
• There were no considerable differences between Ibuprofen and placebo group in change in SpO2 from baseline to altitude and headache severity using a VAS
  

In this systematic review, three valid RCTs were evaluated and Ibuprofen was found to be effective in the treatment of HAH. However, Ibuprofen did not reduce VAS quantified severity of HAH, indicating that Ibuprofen's preventive effect does not relate to its analgesic properties. The exact mechanism of developing HAH and how Ibuprofen prevents HAH is still elusive. It is believed that hypoxia induces a series of neurohumoral and hemodynamic responses, including an inflammatory response, disruption of the blood-brain barrier (BBB), occurrence of (sub-clinical) cerebral edema, nitric oxide-mediated activation of the trigeminovascular system, and/or inadequate venous drainage capacity, whereas Ibuprofen benefits in preventing HAH via cyclooxygenases inhibition. It is noticed that Paracetamol and Ibuprofen both possess similar efficacy in preventing AMS, but Paracetamol acts by its analgesic properties rather than its anti-inflammatory action. There was no effect seen on SpO2 reduction from baseline induced by the gain in altitude. This indicates that Ibuprofen manages HAH through modulation of the inflammatory process rather than through increasing SpO2.

The present line of medications for HAH include use of Acetazolamide and Dexamethasone, but they suffer from various adverse effects. Acetazolamide's adverse effects include nausea, vertigo, and fatigue, whereas Dexamethasone was associated with hyperglycemia, adrenal suppression, delirium, depression, insomnia, and mania. Ibuprofen was also reported to cause several adverse effects like gastrointestinal upset and kidney injury symptoms. There are some evidences that hypoxia in combination with NSAIDs may lead to an increased risk of gastrointestinal bleeding.