Prochlorperazine maleate versus placebo for the prophylaxis of acute mountain sickness: a double-blind randomized controlled trial

Abstract

Background

Acute mountain sickness (AMS) is a debilitating condition that may occur on ascent to high altitude, with limited options for chemoprophylaxis. The pathophysiology of AMS is poorly understood, though it may be similar to migraine. This study aimed to determine the efficacy of prochlorperazine, a first-line agent for acute migraine, for AMS prophylaxis.

Methods

We performed a randomized, double-blind, placebo-controlled trial involving healthy, unacclimatized adult participants, primarily from the Denver area (1609 m), who received either oral prochlorperazine or placebo three times daily for 24 hours during rapid ascent to Mount Blue Sky, Colorado (4348 m). We evaluated individuals who received at least the first dose of placebo or intervention following a modified intent-to-treat approach. Participants travelled by vehicle to 3910 m, then hiked to the summit of Mount Blue Sky, where they slept overnight. The primary outcome was AMS incidence as defined by the 2018 Lake Louise Questionnaire, which was assessed on the evening of ascent and the following morning.

Results

We analysed 56 participants (25 women), with a mean age of 39 [IQR 28–49], with 28 participants in each study arm. Key baseline characteristics were equally distributed and well-matched between study arms. The incidence of AMS was 28 (50%), with 18 (64%) in the placebo arm and 10 (36%) in the prochlorperazine arm (P = 0.06). The absolute risk reduction was 28.6%, the number needed to treat was 4 and the odds ratio was 0.28 (95% C.I. 0.11–0.94). There were no serious adverse events, and there were no significant differences in the side effects between arms, including for drowsiness (P = 0.47).

Conclusion

Our results suggest that prochlorperazine is effective in preventing AMS. Larger studies are warranted to validate our findings.

Introduction

High-altitude travel incurs the risk of developing acute mountain sickness (AMS), a debilitating condition characterized by headache and other symptoms such as nausea and vomiting, fatigue and dizziness. AMS is altitude-dependent and common, occurring in 50–85% of those ascending rapidly to 4500–5500 m.^1,2 Despite decades of investigation, the exact pathophysiology of AMS remains unclear. However, current understanding suggests a primarily neurologic process involving cerebrovascular changes, likely increased intracranial pressure and potential trigeminal nerve sensitivity, similar to migraine.^1,3 The headache also shares clinical features with migraine, including a throbbing quality that worsens with activity and gastrointestinal symptoms.⁴ Further overlap between AMS and migraine includes evidence supporting sumatriptan for AMS prophylaxis⁵ and metoclopramide for high-altitude headache and AMS treatment.⁶

Prochlorperazine is a piperazine phenothiazine with anti-D2 dopaminergic activity and weak antagonism of alpha-adrenergic, serotonin, histamine and muscarinic receptors.⁷ As the American Headache Society recommends, it is commonly utilized as a first-line agent for acute migraine in a hospital setting.⁸ While the exact mechanism by which prochlorperazine improves migraine is elusive,⁹ limited evidence suggests that antidopaminergic medications may serve to abort migraines in the early premonitory phase.¹⁰ Given the similarities between AMS and migraines, and demonstrated early migraine abatement with other dopamine antagonists, prochlorperazine administration before or early in ascent may help prevent the pathophysiological cascade leading to AMS development. Additionally, studies have shown that prochlorperazine can stimulate ventilation and increase hypoxic ventilatory response (HVR).¹¹ Less robust HVR has been associated with the risk of developing AMS,¹² thus offering another potential benefit of prochlorperazine as a possible medication for AMS prophylaxis.

Currently, options for chemoprophylaxis of AMS are limited. Acetazolamide, first studied in the late 1970s,¹³ remains the first-line preventative medication for moderate-risk individuals,¹⁴ though dexamethasone and ibuprofen are additional potential agents.¹⁴ Acetazolamide has demonstrated heterogeneous efficacy in the literature¹⁵ with a significant side effect profile, notably potentially prohibitive paresthesias,¹⁶ and fatigue,¹⁷ highlighting the need for alternative options. Thus, this study aimed to investigate the utility of prochlorperazine for the prophylaxis of AMS. We hypothesized that prochlorperazine prophylaxis would prevent the development of AMS at 24 hours when compared to placebo during rapid ascent to 4348 m.

Materials and methods

Study design

This study was a double-blind, randomized, placebo-controlled trial investigating the utility of prochlorperazine maleate versus placebo for the chemoprophylaxis of AMS. A complete study protocol has previously been published.¹⁸ We report the study design and results following the Strengthening Altitude Research (STAR) parameters.¹⁹ This study received approval from the local Institutional Review Board, with prospective written informed consent from participants and was registered with clinicaltrials.gov (NCT06450899) before enrollment. There were no important changes to methodology after trial commencement.

Study logistics/ascent profile

This study occurred in a controlled ascent on Mount Blue Sky, Colorado. Participants convened in Golden (1934 m), travelled by vehicle to 3910 m, hiked to the summit and slept overnight at roughly 4348 m (Figure 1). We provided participants with food throughout, controlling for food intake.

Figure 1.

Schematic of trial events. Participants met on the morning of the trial in Golden, Colorado. Basic vital signs were recorded, and they received the first dose of a placebo or intervention. They were then driven to Summit Lake located at 3910 m, followed by a hike to the summit of Mount Blue Sky (4348 m). The second dose of placebo or intervention was administered 6 hours after the first dose. Participants remained at the summit, where they received the last dose of placebo or intervention and were assessed for AMS an additional 6 hours later. They then slept on the summit overnight and were evaluated for AMS in the morning.

Inclusion/exclusion criteria

We recruited participants via convenience sampling (largely from the Denver region) through word-of-mouth advertising, flyers, emails to hiking-focused organizations and social media posts. Eligible participants met the following inclusion criteria: >18 years old and having capacity to perform written informed consent. Exclusion criteria included: <18 years or > 75 years of age, currently pregnant, residing at or having slept at elevations >1800 m in the 2 weeks preceding the study dates, requiring supplemental baseline oxygen or having chronic disorders known to be significantly impacted by hypoxia, known allergy to prochlorperazine or phenothiazines, taking medications with significant medication interactions with prochlorperazine, history of dementia or lacking decision-making capacity. Notably, we excluded participants if they had taken any drugs that potentially impact AMS development in the 24 hours preceding the trial, including traditional chemoprophylaxis agents (dexamethasone or acetazolamide), steroids, analgesics (including acetaminophen or ibuprofen) or anti-emetics.

Randomization and blinding

After obtaining written consent, we randomized participants in a 1:1 ratio to the intervention or placebo arms using concealed allocation via computerized randomization. The team statistician generated a simple random sample sequence for randomization. Study team members enrolled participants and both participants and study team members were blinded to the assigned intervention arm. The placebo tablets were similar to the study intervention in appearance, though they were not identical due to budgetary and logistical constraints preventing an identical placebo. A designated non-blinded researcher administered the drug to participants to maximize blinding. They did not engage in outcome assessment or data analysis. All drugs were stored in opaque vials and were administered privately, away from other participants, to prevent inadvertent unblinding. We instructed participants to refrain from discussing the appearance of their study drug or attempting to identify it.

Interventions

Individuals in the intervention arm received 10 mg of prochlorperazine maleate (Zydus Pharmaceuticals); those in the placebo arm received non-identical, yet visually similar, generic tablets containing microcrystalline cellulose.¹⁸ The first dose was administered on the morning of the ascent day. The second dose was given at the summit ~6 hours later. The third and final dose was dispensed in the evening, 12 hours after the first (Figure 1).

Reasons for discontinuation from interventions included allergic reaction to study interventions, injuries or illnesses requiring descent, requests to drop out of the study, altitude sickness necessitating treatment or descent, or any injuries or illnesses that required treatment with confounding drugs, including ibuprofen, acetaminophen and antiemetics.

Outcomes

The primary outcome was the presence of AMS, as defined by the 2018 Lake Louise Questionnaire (LLQ)²⁰ score ≥ 3, including a headache, at any measured point during the study. Individuals filled out an LLQ the evening of and morning after arrival at the summit, or if a participant self-presented or required treatment for altitude illness. Exploratory endpoints included moderate AMS defined by a 2018 LLQ score ≥ 6, including a headache, raw LLQ score, demographic variables, medication side effects and vital sign changes. Akathisia as a side effect was captured under the self-reported category restlessness/unease.

Statistical analysis

We followed a modified intent-to-treat approach by analyzing all individuals who received at least the first dose of the study drug or placebo. The difference in the primary outcome (presence of AMS based on LLQ  ≥ 3, including headache, measured at any point during the study) between the intervention and placebo group was evaluated using a χ² analysis with a Yates continuity correction. We calculated the absolute risk reduction (ARR) and the number needed to treat (NNT) for prochlorperazine to prevent AMS. For exploratory analyses, we used two-sample t-tests and χ² analysis to compare continuous and categorical variables, respectively, in the intervention and placebo arm cohorts (e.g. age, sex, history of altitude illness). We did not adjust for multiplicity in the exploratory endpoint analysis. We used Fisher’s Exact tests for smaller sample sizes in subgroup exploratory analyses and a Firth regression for interaction term analysis. We conducted a separate multivariate Firth regression to evaluate AMS while adjusting for treatment arm, sex, history of altitude illness and history of migraine as explanatory variables. We set the alpha level at P = 0.05 for all analyses and reported 95% confidence intervals (CI). We used the R environment for statistical computing version 4.2.3 (R Core Team 2023) and STATA/BE 18.0 (College Station, Texas).

Sample size determination

Previous literature from comparable studies with similar recruitment catchments indicated an AMS incidence range of 45–68%,^21,22 including a study conducted on Pikes Peak (4302 m) that recruited from the Denver region and reported an AMS incidence of 55.5%.²² Additionally, a recent meta-analysis found a pooled ARR of 16.7% in preventing AMS with acetazolamide at the presently recommended standard dose.¹⁵ Thus, based on prior literature, we estimated an AMS incidence rate of 50%. To detect an ARR roughly double that of acetazolamide (33.4%), utilizing a two-sided alpha < 0.05, our study would require a total sample size of 62 participants to achieve 80% power.

Role of funding source

The funding body played no part in study design, data collection, interpretation/analysis of data or report drafting.

Results

We recruited and enrolled participants from May to August 2024, with trial dates occurring over three outings in August. We enrolled 73 individuals, 71 of whom were randomized after two dropped out. Fourteen individuals did not appear for the trial dates, and one was excluded based on clarification of home elevation; thus, 56 were ultimately included in the modified intent-to-treat analysis (Figure 2). Study arms were equally distributed and well-matched on key baseline characteristics (Table 1).

Figure 2.

Participant enrollment/randomization flow chart

Table 1.

Demographic variables in intervention arms

Variables n (%)	Placebo (n = 28)	Prochlorperazine (n = 28)
Age (mean [IQR])	40 (29–46)	38 (27–51)
Female sex	14 (50)	11 (39)
Race/ethnicity  White/non-Hispanic  Hispanic  Asian  Other	27 (96) 0 (0) 1 (4) 0 (0)	21 (75) 3 (11) 3 (11) 1 (3)
Home elevation group  0–350 m  351–1219 m  1219–1800 m	1 (4) 3 (11) 24 (86)	1 (4) 1 (4) 26 (93)
History of migraine	8 (29)	6 (21)
History of altitude illness	17 (61)	13 (46)

IQR corresponds to inter-quartile range. There were no statistically.

Significant differences between cohorts for any variables above.

The mean age of participants was 39 (interquartile range 28–49), with 25 (45%) women. The overall incidence of AMS was 28 (50%), with 11 (20%) classified as moderate AMS. Prochlorperazine reduced the total incidence of AMS from 18 (64%) in the placebo arm to 10 (36%) in the prochlorperazine arm (P = 0.06) and reduced moderate AMS from 9 (32%) in the placebo arm to 2 (7%) in the prochlorperazine arm AMS (P = 0.04) (Table 2). The total ARR for preventing AMS was 28.6%, with a NNT of 4 and an odds ratio of 0.28 (95% C.I. 0.11–0.94). The ARR for preventing moderate AMS was 25.0%, with an NNT of 4 and odds ratio 0.14 (95% C.I. 0.05–0.88). The average LLQ score was significantly lower in the prochlorperazine arm [1.6 (95% C.I. -1.5–4.7)] compared to the placebo arm [3.1 (95% C.I. -1.7–7.9)] with a mean difference of 1.5 (95% C.I. -2.6 to -0.4, P = 0.01). When we calculated the mean score of each symptom category using the maximum LLQ for each participant, prochlorperazine significantly reduced headache, but not other symptoms (Table 3). Per STAR reporting guidelines, information regarding presentation and treatment for those with AMS is provided (Supplemental Table 1). Adjusted OR for prochlorperazine preventing AMS was 0.38 (95% C.I. 0.13–1.10, P = 0.07) when we adjusted for sex, history of altitude illness and history of migraines. Additionally, Firth regression analysis found no association between sex (P = 0.23), history of altitude illness (P = 0.16), or history of migraines (P = 0.67) and development of AMS.

Table 2.

Acute mountain sickness in placebo versus prochlorperazine

Outcome n (%)	Placebo	Prochlorperazine	P-value
AMS	18 (64)	10 (36)	0.06
Moderate AMS	9 (32)	2 (7)	0.04

AMS = acute mountain sickness. AMS was defined by a 2018

LLQ score  ≥ 3, including the presence of a headache. Moderate AMS was defined by a 2018 LLQ score ≥ 6 including the presence of a headache.

Table 3.

Analysis of LLQ symptoms by intervention arm

Symptom	Placebo arm mean (95% C.I.)	Prochlorperazine arm mean (95% C.I.)	P-value
Headache	1.4 (1–2)	0.8 (0.5–1)	0.02
Gastrointestinal	0.6 (0.3–0.9)	0.3 (0.05–0.5)	0.08
Fatigue	0.9 (0.6–1.2)	0.6 (0.4–0.9)	0.22
Dizziness	0.8 (.4–0.1.1)	0.5 (0.3–0.8)	0.24

95% C.I. = 95% confidence interval. LLQ = Lake Louise Questionnaire. We used each participant’s maximum LLQ score to calculate the mean score for each symptom category.

Subgroup analyses are shown in Table 4. Prochlorperazine reduced the incidence of AMS in those without a history of migraine and in female participants, but not in male participants (Table 4). Mean peripheral pulse oximetry (SpO₂) the evening of ascent was 85% (95% C.I. 83–86%) in the placebo group and 83% (95% C.I. 82–85%) in the prochlorperazine group (P = 0.20).

Table 4.

Subgroup analysis of AMS in placebo vs prochlorperazine arms

Subgroup	AMS in placebo arm n (%)	AMS in prochlorperazine arm n (%)	P-value	interaction P-value
History of migraine (n = 14)	5 of 8 (62.5%)	3 of 6 (50%)	1	0.47
No history of migraine (n = 42)	13 of 20 (65.0%)	7 of 22 (31.8%)	0.06	-
Female (n = 25)	11 of 14 (78.6%)	4 of 11 (36.4%)	0.05	0.32
Male (n = 31)	7 of 14 (50%)	7 of 17 (35.3%)	0.48	-
History of altitude illness (n = 30)	12 of 17 (71%)	6 of 13 (46%)	0.27	0.90
No history of altitude illness (n = 26)	6 of 11 (55%)	4 of 15 (27%)	0.23	-

AMS = acute mountain sickness. AMS was defined by the 2018 LLQ score as a score  ≥ 3 including a headache.

There were no significant unexpected or serious adverse events. There were no statistically significant differences in the reported side effects; however, the limited number of individuals reporting drowsiness and anxiety was higher in the prochlorperazine arm (Table 5). No participants were visibly drowsy, including during the summit hike where no injuries or falls occurred. No participants experienced dystonic reactions.

Table 5.

Reported side effects in placebo and prochlorperazine cohorts

Reported Symptoms n (%)	Placebo	Prochlorperazine
Dry mouth	6 (21)	4 (14)
Anxiety	0 (0)	4 (14)
Restlessness or unease	1 (4)	2 (7)
Constipation	0 (0)	1 (4)
Drowsiness	3 (11)	6 (21)

There were no statistically significant differences between cohorts.

Discussion

Our study demonstrated that prochlorperazine effectively prevented AMS and was well-tolerated in participants ascending rapidly to 4348 m. We found a large effect size with an ARR of 28.6% and NNT of 4. The drug was without serious adverse events. Our controlled ascent and overall trial conditions, including food intake, strengthen our results.

Vanderkooi et al. recently published a single-blinded, randomized trial with 30 participants that similarly evaluated prochlorperazine to prevent AMS and reported an ARR of 20%, although this result was not statistically significant.²³ Our findings support the general conclusions regarding risk reduction with prochlorperazine, and our trial design addresses several important limitations of their study that may account for the smaller effect size they observed. Aside from a smaller sample size (n = 30), participants in the Vanderkooi et al. study spent less time at the peak altitude and were assessed for AMS only 4 hours after reaching that altitude.²³ This short duration likely overlooked individuals who might have developed AMS in a longer study, as AMS typically occurs between 6 and 10 hours after arrival at high altitude.²⁴ Moreover, information on the tolerability of prochlorperazine was not provided.

Compared to other chemoprophylaxis agents for AMS, our results demonstrate an ARR nearly double that of acetazolamide based on recent meta-analyses (16.7 and 12.8%),^15,16 and greater than that observed with ibuprofen (16.0%).²⁵ Dexamethasone is also effective in preventing AMS (ARR 31.2%);²⁶ however, given its side effect profile, it is reserved as a second-line option or for high-risk ascents.¹⁴

Prochlorperazine was overall well tolerated without significant differences in reported side effects between cohorts. Extra-pyramidal symptoms (EPS) are potential side effects of prochlorperazine, with akathisia being the most common. The occurrence of akathisia with intravenous administration varies widely (including from 1.3 to 16%),^27,28 whereas the risk of akathisia and EPS with oral dosing is substantially lower.²⁹ Participants in one study comparing buccal and oral prochlorperazine for migraine did not experience any EPS, reporting no cases of akathisia or dystonic reactions.²⁹ Similarly, our study found no significant occurrence of akathisia, as determined by inquiries about feelings or restlessness of unease, and no participants experienced dystonic reactions.

In our subgroup analysis, prochlorperazine was more effective in those without a history of migraine, suggesting that prochlorperazine did not interrupt acute migraine at altitude. Furthermore, we found prochlorperazine reduced AMS more in women than in men, although sex has not been established as a definitive risk factor for AMS.³⁰ In contrast, one study on acetazolamide for AMS prevention found a higher incidence of AMS in women taking acetazolamide compared to men taking the drug, although neither group was significantly different from the placebo.³¹ Men are less likely to respond to migraine therapeutics during acute migraine episodes,³² and sex-specific responses to other drugs are well documented.³³ Prochlorperazine did not reduce AMS more in those with a history of altitude illness, and history of altitude illness was not associated with the development of AMS when adjusting for treatment arm, sex and history of migraine. While a history of altitude illness is considered a potential risk factor for AMS,¹⁴ the data remain inconclusive.^34,35 Given the small sample sizes in our subgroups, a larger study is needed to confirm a sex difference in response to prochlorperazine for AMS prophylaxis and further clarify the significance of migraine and altitude illness history.

Examining prochlorperazine for preventing AMS provides an exciting opportunity to understand the elusive pathophysiology of AMS and identify a link between AMS and migraine. While prochlorperazine effectively treats acute migraine,⁹ its specific mechanism remains unknown. Dopamine has been implicated in the premonitory phase of migraines,³⁶ suggesting that dopamine antagonists may act during this phase.¹⁰ Our results suggest that prochlorperazine helps prevent the neuropathological cascade leading to AMS. At doses of oral prochlorperazine substantially higher than those we used, the medication has a half-life of around 8 hours.³⁷ In our study, participants received their last dose of prochlorperazine nearly 12 hours before the final AMS assessment, by which time prochlorperazine would have been eliminated. Therefore, prochlorperazine was not merely masking or treating symptoms. Additionally, prochlorperazine enhances ventilation.¹¹ In our study, we did not observe a difference in the mean observed SpO₂ between intervention arms, but we did not measure ventilation parameters. Measuring SpO₂ and its utility at altitude is contentious under field conditions,³⁸ and more comprehensive ventilatory measurements are necessary to confirm the role of the respiratory effects of prochlorperazine in preventing AMS.

Limitations

Our study comprised primarily white/non-Hispanic individuals, limiting overall generalizability. While many variables were controlled (e.g. diet, ascent profile), and while the trial took place under similar conditions in the same month, variables such as specific weather and temperature differences on trial dates and caffeine intake were not controlled. While maximal efforts were taken in blinding, a similar but non-identical placebo was utilized due to budget and logistical constraints. Given the similarities between migraine and AMS, migraine may have been present in some participants; however, we did not find that a history of migraine increased the risk of AMS. Further studies capturing more detailed characteristics of participant headaches would be beneficial. Since dizziness is a feature of AMS, it is unclear to what degree any dizziness may have occurred as a side effect of prochlorperazine. Lastly, our sample size was relatively small. We were six participants short of our calculated sample size and despite demonstrating a clinically important effect size, a larger study is needed to confirm our findings, including those from our subgroup analysis.

Conclusion

Our results demonstrate that prochlorperazine effectively prevents AMS and may offer an alternative strategy to acetazolamide. These findings support a potential link between migraine and AMS that requires further study, including investigating biomarkers associated with acute migraine and understanding how a prior history of migraine impacts the risk and prevention of AMS. More work is needed to confirm whether prochlorperazine is more effective for AMS prevention in women. Finally, additional studies with larger sample sizes, longer durations of drug use and a trial directly comparing prochlorperazine to acetazolamide would be beneficial to validate our findings and further explore the tolerability, efficacy and utility of prochlorperazine for AMS prevention.

Funding

This study was funded by the International Society of Travel Medicine in partnership with the GeoSentinal Foundation and was presented as an oral presentation at the International Hypoxia Symposia in 2025.

Author contributions

Elan Small (Conceptualization, Data Curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Software, Resources, Supervision, Validation, Visualization, Writing—original draft, Writing—review & editing), Harrison Steins (Data Curation, Investigation, Project administration, Writing—original draft, Writing—review & editing), Martin Musi (Investigation, Methodology, Resources, Supervision, Writing—original draft, Writing—review & editing), Julia Perry (Investigation, Writing—original draft, Writing—review & editing), Elizabeth Goldberg (Investigation, Methodology, Writing—original draft, Writing—review & editing), Mary Ryan (Investigation, Writing—original draft, Writing—review & editing), Lake Crawford (Investigation, Writing—original draft, Writing—review & editing), Brian Strickland (Investigation, Resources, Writing—original draft, Writing—review & editing), Tiana Linkus (Investigation, Writing—original draft, Writing—review & editing), Caleb Phillips (Data Curation, Formal analysis, Investigation, Methodology, Software, Writing—original draft, Writing—review & editing), Ryan Paterson (Investigation, Methodology, Resources, Writing—original draft, Writing—review & editing), Nathaniel Zona (Data Curation, Investigation, Project administration, Writing—original draft, Writing—review & editing), Max Smolkin (Investigation, Methodology, Writing—original draft, Writing—review & editing), Mia Derstine (Investigation, Writing—original draft, Writing—review & editing), Jay Lemery (Investigation, Writing—original draft, Writing—review & editing), Jennifer L. Hoffman (Resources, Writing—original draft, Writing—review & editing), Steven R. Hick (Resources, Writing—original draft, Writing—review & editing), Adit A. Ginde (Investigation, Methodology, Supervision, Writing—original draft, Writing—review & editing), Peter Hackett (Conceptualization, Funding acquisition, Investigation, Methodology, Supervision, Validation, Visualization, Writing—original draft, Writing—review & editing), and Linda E. Keyes (Conceptualization, Funding acquisition, Investigation, Methodology, Resources, Supervision, Validation, Visualization, Writing—original draft, Writing—review & editing)

Conflict of interest

The authors have declared no conflicts of interest.

Data availability

The data underlying this article are available in the article and in its online supplementary material.