By Philip R. Fischer, MD, DTM&H

Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN

Dr. Fischer reports no financial relationships relevant to this field of study.

SYNOPSIS: Mefloquine is known as an effective agent for malaria chemoprophylaxis. However, concerns about serious adverse effects have limited its use. Now, a careful review of data suggests that fatal outcomes related to mefloquine prophylaxis are very rare.

SOURCE: Tickell-Painter M, Saunders R, Maayan N, et al. Deaths and parasuicides associated with mefloquine chemoprophylaxis: A systematic review. Travel Med Infect Dis 2017;20:5-14.

Mefloquine has been available for malaria chemoprophylaxis for three decades. It has been effective and is widely used. However, there is a belief that prophylactic mefloquine can prompt psychosis, suicidal ideation, and death. To better determine if data supported such a belief, an expert investigative group, in conjunction with a Cochrane review of efficacy and safety of mefloquine,1 systematically reviewed scientific reports about death and suicidal attempts in patients using preventive mefloquine.

Using rigorous search criteria, 2,521 potentially relevant papers were identified. Of these, 71 papers mentioned mefloquine being potentially linked to death and/or suicide attempts; 17 papers reported death and suicide attempt in apparent association with prophylactic mefloquine. These papers were analyzed carefully; some papers did not actually provide data supporting death and/or suicide related to mefloquine, some dealt with treatment doses, some cited other articles which, in fact, did not corroborate the claims, and some did not provide enough information to determine any hint of a causal association between the medication and the outcome.

From this extensive literature review, two deaths were linked to what seemed to be idiosyncratic reactions “probably caused by” mefloquine (one with pulmonary fibrosis, one with an exfoliative illness with neutropenia), and there was one suicide attempt “possibly caused by” mefloquine. Using a causality framework, there were eight other reports of death deemed “unclassifiable” or “unlikely” related to mefloquine.

The investigators thought that it was “striking” that so few deaths could be causally linked to mefloquine. Despite a vigorous and rigorous search for potential cases, they found only these three cases that potentially could be linked to mefloquine. These three cases were many fewer than previously cited cases that had not been subjected to such careful scrutiny.

COMMENTARY

There are three main malaria chemoprophylaxis medications mefloquine, atovaquone-proguanil, and doxycycline. No medication is perfect, and travelers can experience bothersome and life-threatening events no matter which malaria medication they are taking. Thus, it is helpful to have a good grasp of existing scientific data to sort through risks and benefits of various anti-malarial options when caring for international travelers. To that end, Tickell-Painter and colleagues have provided a good summary of published data on the possibility of mefloquine being associated with death and suicide.

Decades ago when mefloquine was introduced as a chemoprophylactic agent, caution was urged in using the medication in people with cardiac rhythm disturbances, active seizure disorders, and psychiatric difficulties. Bad psychiatric reactions seemed to be more common with larger treatment doses than with smaller weekly preventive doses. Nonetheless, there was anecdotal concern that even prophylactic dosing could trigger serious psychiatric effects in people without pre-existing psychiatric disorders. These safety concerns led to black box warnings on package inserts, a New York Times opinion article about “crazy pills,”2 and a decrease in the use of mefloquine.

How large is the actual risk of serious adverse events with prophylactic mefloquine? Beyond anecdotes and case reports, Tickell-Painter and colleagues now provide a helpful systematic review of published safety data. Not surprisingly, but perhaps counter to widely held belief, mefloquine is not associated with statistically significant increased risks of either death or suicide-prone psychiatric reactions. This knowledge could help mefloquine return to a position of accepted use in the prevention of malaria in travelers.

Of course, travel itself can be associated with bad outcomes. Sleepless nights on airplanes, jetlag, and culture shock all can yield diminished psychological reserves and might provoke the emergence of symptoms related to underlying anxiety, depression, or psychosis.

Mefloquine does have some side effects, even if not life-threatening ones. Sleep disturbances (insomnia, vivid dreams) are seen in up to 20% of travelers taking prophylactic mefloquine. Cardiac rhythm disturbances, active seizure disorders, and known psychiatric disorders remain contraindications to mefloquine use. Mefloquine is readily available in pill form, but the crushed pills taste unpleasant; children don’t always enjoy taking mefloquine. Despite all this, though, mefloquine still is very effective in preventing malaria. The oral dose is 5 mg/kg/dose up to an adult dose of 250 mg taken weekly starting one to two weeks prior to travel and continuing through four weeks after leaving the malarial area.

Doxycycline and atovaquone-proguanil also are reasonable chemoprophylactic options, but each requires daily use. Doxycycline can stain developing teeth, so it is not suggested for use prior to 8 years of age. Vaginal yeast infections and photosensitivity skin reactions also limit the use of doxycycline for a minority of travelers. Atovaquone-proguanil has only rare bothersome side effects. Each of these medications should be started a day prior to arrival in the malarial area and then continued until after leaving the area of risk for malaria (28 days after leaving for doxycycline, seven days after leaving for atovaquone-proguanil).

The cost of doxycycline has gone up in recent years. The cost per pill of atovaquone-proguanil is higher than that of the other agents; a trip of longer than 10 days usually makes mefloquine less costly than atovaquone-proguanil.

A recent Cochrane review, also led by Dr. Tickell-Painter of the Liverpool School of Tropical Medicine, highlighted relative risks of bothersome adverse effects of various anti-malarial prophylactic medications as determined in studies involving hundreds of thousands of subjects.1 While mefloquine was very effective in preventing malaria, side effects were reported.1 Compared to atovaquone-proguanil, mefloquine was associated with abnormal dreams (relative risk [RR], 2.04), insomnia (RR, 4.42), anxiety (RR, 6.12), and depressed mood (RR, 5.78). Nausea and dizziness also were more common with mefloquine. Overall, 6% of travelers opted to discontinue mefloquine use, while only 2% of atovaquone-proguanil users opted to discontinue treatment. Mefloquine and doxycycline had similar rates of discontinuation and serious adverse effects; while mefloquine was associated with more abnormal dreams, insomnia, anxiety, and depression than doxycycline, doxycycline was associated with more dyspepsia, photosensitivity, vomiting, and vaginal candidiasis.1 Physicians providing pre-travel consultation often need to help travelers balance potential adverse reactions with the varying costs of the medications.

Emerging data suggest that primaquine is another reasonable option for chemoprophylaxis of malaria, especially in areas where Plasmodium vivax and Plasmodium ovale are common.3 However, glucose-6-phosphate dehydrogenase deficiency should be ruled out before initiating treatment with primaquine.3

The majority of travelers who are diagnosed with malaria in the United States (about 2,000 per year) were traveling to visit friends and relatives and did not take appropriate chemoprophylaxis.4 Choosing a medication during a pre-travel consultation is important, but it is even more important to try to ensure that all travelers to areas with risk of malaria receive appropriate pre-travel counsel and interventions. Travelers visiting friends and relatives are at particular risk compared to those who travel strictly for business or tourism.4,5,6

There is wide variation in travel medicine practice,7 and it behooves all physicians seeing travelers to stay current with evidence-based recommendations. There also are regional and temporal variations in the management of malaria risk in travelers. Realizing that the actual risk of malaria is very low (< 1% per month) in typical business and tourist travelers, European travel medicine specialists increasingly have used stand-by treatment (providing a curative dosing regimen to have available for use when symptoms develop and a rapid malaria test is positive) instead of providing widespread chemoprophylaxis.8 Malaria continues to be a problem for international travelers. Travelers should seek pre-travel consultation, and physicians should choose anti-malarial chemoprophylactic regimens wisely.

REFERENCES

  1. Tickell-Painter M, Maayan N, Saunders R, et al. Mefloquine for preventing malaria during travel to endemic areas. Cochrane Database Syst Rev 2017;10:CD006491.
  2. MacLean DS. Crazy pills. New York Times Aug. 7, 2013. Available at: http://www.nytimes.com/2013/08/08/opinion/crazy-pills.html. Accessed Feb. 11, 2018.
  3. Kolifarhood G, Raeisi A, Ranjbar M, et al. Prophylactic efficacy of primaquine for preventing Plasmodium falciparum and Plasmodium vivax parasitemia in travelers: A meta-analysis and systematic review. Travel Med Infect Dis 2017;17:5-18.
  4. Mace KE, Arquin PM. Malaria surveillance – United States, 2014. MMWR Surveill Summ 2017;66:1-24.
  5. Rees E, Saavedra-Campos M, Usdin M, et al. Trend analysis of imported malaria in London: Observational study 2000 to 2014. Travel Med Infect Dis 2017;17:35-42.
  6. Zanotti P, Odolini S, Tomasoni LR, et al. Imported malaria in northern Italy: Epidemiology and clinical features observed over 18 years in the Teaching Hospital of Brescia. J Travel Med 2018;25:doi: 10.1093/jtm/tax081.
  7. Hagmann SH, Leshem E, Fischer PR, et al. Preparing children for international travel: Need for training and pediatric-focused research.
    J Travel Med 2014;21:377-383.
  8. Boubaker R, Herard Fossati A, Meige P, et al. Malaria prevention strategies and recommendations, from chemoprophylaxis to stand-by emergency treatment: A 10-year prospective study in a Swiss Travel Clinic. J Travel Med 2017;24:doi: 10.1093/jtm/tax043.