May 29, 2002 - Medical Paper: A Returned Volunteer looks at Larium
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May 29, 2002 - Medical Paper: A Returned Volunteer looks at Larium
A Returned Volunteer looks at Larium
Read and comment on this paper written by RPCV Rebecca Brodsky about the Neurological Side Effects of Mefloquine at:
Neurological Side Effects of Mefloquine: A Trans-Atlantic Debate*
* This link was active on the date it was posted. PCOL is not responsible for broken links which may have changed.
Neurological Side Effects of Mefloquine: A Trans-Atlantic Debate
Rebecca Brodsky, Environmental Health Science Paper #1, October 2, 2001
Mefloquine (Larium) is the most effective malaria prophylaxis currently available, yet its general use remains highly controversial in Europe, especially in England. Neuropsycological disorders among users including depression, vivid dreams, fatigue, headache and insomnia are well documented in British medical journals as well as in the general media. In contrast, American medical journals have paid relatively little attention to side effects of the drug even though it is used more widely in the United States than in England. The Center for Disease Control (CDC) recommends mefloquine for travelers in malarial regions with a minimum a warning about possible neurological side effects. The few American observational studies have been conducted either on military personnel or Peace Corps Volunteers, not typical tourists. In contrast, data gathered in England have been based on the personal experiences of business and leisure travelers.
Both in letters and articles, American researchers have not convincingly defended the CDC position that neurological side effects of mefloquine are rare. Although mefloquine is likely the most effective malarial prophylaxis available today, patients should be counseled concerning their options and possible, not rare, side effects. Patient compliance with prophylaxis regimens outside of a military setting is disturbingly poor, possibly in part due to side effects of the drugs. Both European and American doctors should be vigilant that the information they provide to patients regarding mefloquine is accurate. This information should include a review of the dangers of malaria balanced with a prophylaxis regimen that the patient will adhere to armed with full knowledge of possible side effects.
The Need for Malaria Prophylaxis:
Malaria is a common and potentially fatal disease; there are between 300 to 500 million cases worldwide each year and 1.5-2.7 million deaths annually. Every year 25 to 30 million people from non-tropical countries visit malarial regions of the world, often for extended periods of time. Of these, approximately 30 thousand North American and European travelers contract malaria annually. Even when travelers are treated for malaria, mortality can be as high as 10% and even higher (20%) for cerebral malaria. Studies have shown that travelers who do not take malaria prophylaxis have a high risk of contracting malaria, especially in sub-Saharan Africa. Thus there is a demonstrated need for an effective preventive drug regimen for non-immune travelers when they travel to countries where the disease is common.
Mefloquine has been used to treat some cases of malaria since 1980 and has been used as a malaria prophylaxis since 1986. Since then mefloquine has been prescribed to over 12 million travelers worldwide. Data gathered in the early 1990's confirmed that mefloquine was both safe and effective, however more recent studies in England have challenged the safety of the drug and suggested that serious neurological side effects may make mefloquine difficult for some people to take.
Mefloquine Studies: United States
Hans Lobel et al argue in a December 1997 issue of JAMA, that mefloquine is safe and effective with rare side effects. Lobel bases his argument largely on two observational studies, one done on US soldiers in Somalia and a second on Peace Corps volunteers serving in West Africa. Both studies compared mefloquine with other malaria prophylaxes and found mefloquine to be the more effective drug and with few side effects. The basis for this conclusion however, lies largely with the characteristics of the populations chosen for the study. The populations in these two studies are not representative of typical travelers; both groups are relatively young, and in the case of the Somalia study, almost entirely male.
The Somalia study was conducted from December 1992 though May 1993 and included all documented malarial cases among the approximately 30 thousand US troops who served in Somalia during that time. Interestingly, the authors neglect to provide an age profile of the population in their demographic description; however given the demographics of the American military and the nature of the operation, it is safe to assume most were male and most were relatively young. This scenario is problematic given that previous studies have shown that men tolerate mefloquine better than women do.
All military units were given doxycycline, an alternative malaria prophylaxis, or mefloquine in approximately equal numbers during the first weeks of the Somalia operation. After 6 weeks everyone was switched to mefloquine for reasons of uniformity and soldiers found it easier to remember to take the weekly dosage of mefloquine as opposed to daily doxycycline. Possible side effects due to prophylaxis were studied through a survey of one Marine unit (n=499.) 94% of them returned the survey, evidence of the strict discipline that characterizes this population. Interestingly, investigations into malaria cases among doxycycline users revealed that the soldiers contracted malaria because they forgot to take the daily dosage, not because the drug itself was ineffective. Therefore the conclusion that mefloquine is more effective is specific to the social characteristics of the military population studied; this group of soldiers found the weekly mefloquine dosage easier to remember. The possibility of different effects of the prophylaxis on women and men was not addressed in the study (probably could not be given the likely demographics). There is a significant chance that women who take birth control pills may find the doxycycline dosage regimen easier to comply with than male soldiers because they are accustomed to adhering to a daily dosage regimen.
The study on Peace Corps volunteers was conducted between October 1989 and May 1992 in six West African nations, all with uniformly high malarial rates. Age and gender demographics were not specified. Since most volunteers join the Peace Corps right after graduating from college, it is again a relatively young population. A breakdown of the numbers of men and women in the study was also missing from the demographics. Gender stratification to adjust for possible confounding is not mentioned in the methods section, a possible serious flaw in the analysis.
Both a dose response study of mefloquine and a comparison of mefloquine and chloroquine with proguanil and chloroquine with pyrimethamine-sulfadoxine regimens were compared in the study. Doxycycline, the current alternative to mefloquine, was not included in the study. A weekly dosage of mefloquine was found to be the most effective of the three regimens in the study. In addition, a cohort of 152 volunteers who had used mefloquine exclusively were monitored for a year to test side effects over time. Only seven (0.9%) requested a different prophylaxis because of severe side effects. The authors concluded that mefloquine is safe for long-term use with rare side effects.
The study of Peace Corps volunteers was published before observational studies conducted in England found significant neurological side effects; however individual reports of neurological problems with the drug were surfacing in the European media. The authors of the Peace Corps study dismiss these complaints in their discussion by denying there is evidence of a causal relationship as indicated by their data. They cite the stresses of traveling and being in a new environment as possibilities for individual neurological disorders. Further, they stress the importance of a uniform prophylaxis regimen so as not to confuse members of the medical profession, hardly a justifiable concern in light of new data! Medical professionals should be aware of prophylactic options so as to prescribe the one most suitable for the patient. Careful consideration of all the evidence available is more important for doctors prescribing medication than the possible confusion that could result.
The only further monitoring concerning mefloquine the authors suggest focuses on the possible development of mefloquine-resistant strains of malaria. Any further questions concerning the safety of the drug they consider minor, especially in light of its effectiveness and the severe morbidity and mortality issues associated with contracting malaria. Lobel et al also dismiss possible neurological side effects by citing that depression in the general US population is 16 times higher than among mefloquine users. Such a comparison the worst kind of ecological fallacy; it is not possible to make a valid comparison between a highly selective study population and the general population.
The lax attitude on the part of the researchers toward a relatively new drug, which has primarily been tested on specific social groups, is dangerous. Both studies fail to address and control for gender and age, possible significant confounders. The study of Peace Corps volunteers is dated in that it did not compare mefloquine with doxycycline; chloroquine regimens are rarely recommended today because many regions of the world have chloroquine-resistant malaria. A new study that takes into account both gender and age demographics and includes a mix of business and leisure travelers is necessary.
Mefloquine Studies: England
In response to the growing debate in England regarding the safety of mefloquine, Croft et al conducted a systematic review of mefloquine randomized trials published in the British Medical Journal in 1997. Ten studies met their qualifications for inclusion. One placebo controlled trial found mefloquine effective however four placebo controlled trials found that mefloquine had serious neurological side effects. Of the five trials that compared mefloquine with other malaria prophylaxes, researchers found higher withdrawal rates in mefloquine users. This finding was used as evidence that the side effects of the drug were causing people to stop taking it. The authors' ultimate conclusion was that mefloquine should only be used in specific regions with high rates of chloroquine-resistant malaria and little access to medical care. Mefloquine should thus not be the standard malaria prophylactic treatment as suggested by Lobel et al.
Croft's conclusions, however, were not universally accepted in England. Several letters to BMJ cited two major flaws with Croft's conclusions. First, mefloquine withdrawal is not evidence that the drug has neurological side effects. There is no evidence of a causal relationship; there are many reasons for a person to decide to stop taking a drug. Secondly, all malaria prophylactic drugs have side effects, therefore a comparison between a placebo and mefloquine is problematic. Croft's response is not particularly convincing; she emphasizes the need for a field trial of tourists and business travelers in order to resolve the debate. True such a trial is necessary, however this explanation does not resolve methodological problems upon which she based her conclusion.
The mefloquine debate confusion:
While the basis of the conclusions in Croft's review is problematic, a closer look at one of the trials included in his review and more recent data indicate that the debate concerning neurological side effects attributed to mefloquine remains unresolved. A telephone and postal survey conducted in 1996 found that a significant proportion of mefloquine users experienced neurological side effects. The survey included British travelers recently returned from trips during which they took mefloquine or proguanil plus chloroquine. Twenty-seven percent of mefloquine users indicated they experienced neurological side effects (0.7% "disabling") compared with only 16% (0.09% "disabling") of the chloroquine plus users. The authors recommend mefloquine only in high-malaria and chloroquine-resistant areas. While again, no age or gender demographics are provided, this study of typical travelers presents a strong argument that some neurological effects are relatively common.
The debate in England rages on. More recently in 1998, BMJ reported an increase in malaria cases in England, which coincided with a reduction in the use of mefloquine. Many people simply stopped taking any prophylaxis when they traveled. The resulting cost of treatment for those that contract malaria as a result is a concern for the National Health Service. An examination of malaria cases indicated many patients received, "misleading or inadequate advice from health care professionals."
Confusion in the healthcare profession regarding malaria prophylaxis is also common in the United States. According to the CDC, there were 4685 reported cases of malaria among US civilian travelers from 1992-2001. Nineteen percent took an inappropriate prophylaxis (such as chloroquine in a chloroquine resistant region) and in 56% of the cases the travelers took no prophylaxis at all. This suggests a lack of knowledge regarding the severity of malaria among the traveling population and significant misinformation in the medical community that prescribed the wrong medication.
The use of qualitative evidence:
Interestingly the incidence of serious neurological side effects was similar in both the US (0.9%) and British studies (0.7%). The British study went a step further to capture any neurological side effects, while US studies did far less analysis in this area. Furthermore, British researchers used qualitative data collection and analysis to carefully document the symptoms of the 0.7% of people who experienced severe side effects. The use of qualitative data to investigate the small group had significant effects on the British general population. Logically numbers should convince both researchers and the general public alike that a drug is safe. Personal accounts, however rare, can be a powerful influence on person's decision concerning whether they would choose to take a particular medication. The American public and research community was not influence by publicized personal experiences with mefloquine. In contrast, British medical journals and the general media publicized several case studies including moving accounts of personal experiences with the side effects of mefloquine. The following is one patient's experience:
I continued the treatment even though my hair began to fall out and my eyesight seemed to be getting worse…Throughout the night…my dreams were vivid, and I was convinced I was going to die. The next day the flowers were larger and brighter and the stones on the way to work were hairy. I was on a trip I hadn't planned. Fortunately, that morning 4 issues of the BMJ arrived; in one of them was an article on prophylaxis against malaria. Doxycycline is readily available..so I started a daily dose. I now feel well and energetic and am sleeping, and my appetite has returned-I feel normal.
Multiple accounts similar to this one are not only cited in BMJ, but also in the general British media. Watchdog, a BBC television program, has featured, "graphic accounts of severe, sometimes long lasting, largely neuro-psychiatric, symptoms they attribute to mefloquine." This is probably at least partially responsible for the alarm concerning the drug in England. The fact that it is the most effective defense against contracting malaria was lost in the scare. Indeed mefloquine, "which in most people's minds has a terrifying reputation," became rather demonized. Many travelers arrived at the dangerous conclusion that the risks of contracting malaria were less than taking mefloquine. Thus incidence of malaria cases in England began to rise. Qualitative data is important for identifying who is at risk for side effects. However both researchers and the media should be prudent concerning how they release such information and try and lessen the tendency to sensationalize the evidence.
The US has failed to personalize the debate in this form of qualitative research both the general media in its medical journals. The general public is thus not effected by personal accounts however it is disturbing that the 27% of travelers in the British study who reported some neurological side effects remains unacknowledged in the American medical community. Dismissing these accounts as anecdotal is not defendable especially in light of the flaws in the quantitative methods in both the Somalia and West African studies. The British, however, have yet come up with the kind of large-scale study that offers answers to the concerns raised in their qualitative research.
Conclusions and the need for further research:
To date, I could find no evidence of a comprehensive observational study using a typical travel population. The possibility of gender bias was mentioned in only one article and even then as barely a footnote. For reasons unknown to me, none of the major articles stratified the study population by age.
The CDC continues to promote mefloquine as the best line of defense against malaria, specifically stating that side effects are rare and minor. This information is misleading in light of the 27% of travelers who reported side effects in the British study. More information is needed on who these 27% of people are; who is more likely to experience side effects, men or women, older or younger people.
Additionally the two studies upon which the CDC information is based have serious design flaws that questions their validity when applied to a larger, more diverse population. While the British survey of travelers provided a more accurate picture of a typical travel population, it too suffered from the same flaws concerning gender and age analysis. In addition, sensationalizing the qualitative data concerning severe side effects of only 0.7% of mefloquine users demonized the drug in England. As a result both mefloquine's effectiveness and the dangers of malaria were severely downplayed.
The information on the CDC website declares that doxycycline and a newer drug Malarone should be considered only as alternatives to mefloquine. Once more information is available on who is at risk for side effects due to mefloquine both doctors and their patients can make a more informed choice concerning which prophylaxis is most appropriate and effective for them.
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