Mefloquine for malarial prophylaxis in military personnel
BMJ 2015; 351 doi: https://doi.org/10.1136/bmj.h5797 (Published 03 November 2015) Cite this as: BMJ 2015;351:h5797
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I am sorry to say that I made an error in the referencing of the previous version of our response to Dr Green and others. The text is unchanged. Here is the corrected version.
We are grateful to Dr Green and others for their comments. We fully understand the dangers of malaria. [1] It is gratifying that no operational British service personnel have died from malaria for over two decades, although Green et al do not make it clear to what extent this is a consequence of treatment rather than prophylaxis.
Our respondents maintain that ‘mefloquine has never been the “preferred drug” for chemoprophylaxis in the British Army,’ and that Service policy has been to follow national best practice. Mefloquine was adopted by the Army in July 1993 for use in Kenya on the advice of the United Kingdom Malaria Advisory Committee. [2] As the Malaria Reference Laboratory stated in 1995, “Experience suggests [mefloquine] is the preferred antimalarial for those at high risk of highly chloroquine resistant falciparum malaria.” [3]
In the five years 2010–2014, 13 045 regular armed forces personnel were prescribed mefloquine, so its safety is still relevant. [4] The House of Commons Defence Committee is currently investigating mefloquine. Dr Frances Nichol, Head of Drug Safety at Roche, stressed to the Committee this month that a physician would be expected to assess the individual risks that the patient is carrying before prescribing mefloquine. [5] Dr Green and colleagues state that mefloquine is used after detailed assessment both of the malaria risk and of ‘individual factors that might influence its use,’ but service personnel may not undergo such risk assessment before receiving an individual prescription. This would be understandable in logistic terms, but incomplete assessment and a reluctance of serving troops to disclose a history of mental illness [6] might skew the balance of benefit to harm.
We have not advocated the abandonment of mefloquine, as the response implies. Armed forces in other countries, including Australia and the United States, agree that it is not the first-line agent. We are glad that Green et al accept this too; but many UK military personnel still receive mefloquine.
Robin Ferner Nithya Gogtay
References
1. Gogtay NJ, Kshirsagar NA, Vaidya AB. Current challenges in drug-resistant malaria. J Postgrad Med 2006; 52(4): 241-2
2. R v. Ministry of Defence, ex parte Colin James Murray [1997] EWHC Admin 1136
3. Bradley DJ et al. Malaria prophylaxis: guidelines for travellers from Britain. BMJ 1995;310:709-14
4. Anonymous. Number of personnel who were prescribed the antimalarial drug mefloquine (lariam) and thereafter assessed for a mental health condition. Ref: Defence Statistics FOI2015/00772. https://www.gov.uk/government/publications/foi-responses-released-by-mod... Accessed 2015-11-21
5. Anonymous. An acceptable risk: The use of Lariam for military personnel HC 567 Evidence given by Dr Frances Nichol, Head of Drug Safety and Quality and Mike Kindell, Lead, Established Products, Roche. Published 11 Nov 2015. http://data.parliament.uk/writtenevidence/committeeevidence.svc/evidence... Accessed 2015-11-21.
6. Schreiber M, McEnany GP. Stigma, American military personnel and mental health care: challenges from Iraq and Afghanistan. J Mental Health 2015; 24: 54- 9
Competing interests: No competing interests
We are grateful to Dr Green and others for their comments. We fully understand the dangers of malaria. [1] It is gratifying that no operational British service personnel have died from malaria for over two decades, although Green et al do not make it clear to what extent this is a consequence of treatment rather than prophylaxis.
Our respondents maintain that ‘mefloquine has never been the “preferred drug” for chemoprophylaxis in the British Army,’ and that Service policy has been to follow national best practice. Mefloquine was adopted by the Army in July 1993 for use in Kenya on the advice of the United Kingdom Malaria Advisory Committee. [2] As the Malaria Reference Laboratory stated in 1995, “Experience suggests [mefloquine] is the preferred antimalarial for those at high risk of highly chloroquine resistant falciparum malaria.” [3]
In the five years 2010–2014, 13 045 regular armed forces personnel were prescribed mefloquine, so its safety is still relevant. [3] The House of Commons Defence Committee is currently investigating mefloquine. Dr Frances Nichol, Head of Drug Safety at Roche, stressed to the Committee this month that a physician would be expected to assess the individual risks that the patient is carrying before prescribing mefloquine. [4] Dr Green and colleagues state that mefloquine is used after detailed assessment both of the malaria risk and of ‘individual factors that might influence its use,’ but service personnel may not undergo such risk assessment before receiving an individual prescription. This would be understandable in logistic terms, but incomplete assessment and a reluctance of serving troops to disclose a history of mental illness [5] might skew the balance of benefit to harm.
We have not advocated the abandonment of mefloquine, as the response implies. Armed forces in other countries, including Australia and the United States, agree that it is not the first-line agent. We are glad that Green et al accept this too; but many UK military personnel still receive mefloquine.
Robin Ferner Nithya Gogtay
References
1. R v. Ministry of Defence, ex parte Colin James Murray [1997] EWHC Admin 1136
2. Bradley DJ et al. Malaria prophylaxis: guidelines for travellers from Britain. BMJ 1995;310:709-14
3. Anonymous. Number of personnel who were prescribed the antimalarial drug mefloquine (lariam) and thereafter assessed for a mental health condition. Ref: Defence Statistics FOI2015/00772. https://www.gov.uk/government/publications/foi-responses-released-by-mod... Accessed 2015-11-21
4. Anonymous. An acceptable risk? The use of Lariam for military personnel, HC 567 Evidence given by Dr Frances Nichol, Head of Drug Safety and Quality and Mike Kindell, Lead, Established Products, Roche. Published 11 Nov 2015. http://data.parliament.uk/writtenevidence/committeeevidence.svc/evidence... Accessed 2015-11-21
5. Schreiber M, McEnany GP. Stigma, American military personnel and mental health care: challenges from Iraq and Afghanistan. J Mental Health 2015; 24: 54- 9
Competing interests: No competing interests
Sir
Gogtay and Ferner raise some important issues surrounding the use of mefloquine for malaria chemoprophylaxis in British Service personnel [1]. There are a number of points that we feel need clarification.
Context is extremely important. Malaria as a disease has historically played a major role in causing significant morbidity and mortality in the British Armed Forces. During World War 1 in the Salonika campaign over 162,000 cases occurred, while in World War 2 General Slim was able to lead his successful Burma campaign only after malaria had been reduced in his troops to enable them to fight effectively. The last operational death of a British Serviceman occurred in 1992 in Cambodia, and it is a testament to the efficacy of malaria prevention policies since then that no further deaths have occurred despite large numbers of personnel deploying to areas with high rates of malaria transmission including West Africa. Other countries in contrast have suffered more recent fatalities [2,3], with France having on average one death every two years [4].
The title of the Editorial is “Mefloquine for malarial prophylaxis in military personnel - not the first choice”, is in fact a statement of the current UK Armed Forces current policy with respect to use of this drug [5]. In contrast to the comment made in the opening sentence of the article, mefloquine has never been the “preferred drug” for chemoprophylaxis in the British Army. In fact Service policy has always followed national best practice, and is based on the regularly updated guidance issued by the UK Advisory Committee on Malaria Prevention [6]. The drug is available as one of the options for use, which will follow a detailed assessment of the malaria risk related to travel balanced against individual factors that might influence its use. For example in recently published data, mefloquine only accounted for 0.4% of personnel deployed to Afghanistan between 2007 and 2014, and for 5.7% of personnel who deployed to Sierra Leone in 2014 as part of the International Ebola Response [7].
The adverse effects associated with mefloquine are as the authors state difficult to quantify, despite being taken by over 35 million people worldwide for chemoprophylaxis since its introduction in the 1980s. It remains licensed in the UK and all other countries, and still remains a drug that forms part of the guidance for most national expert bodies including the Centers for Disease Control [8] and the World Health Organization [9]. The observational study cited suggesting that the incidence of psychosis in mefloquine users was twice that of other antimalarials, actually notes that this difference was not statistically significant and also comments that “the absolute risk of developing psychosis or panic attack appears low with all the antimalarials tested” and that there was “no evidence for increased risk of first-time diagnosis of depression with mefloquine use” [10].
It is stated that European aircrew are not allowed to take mefloquine because of the “risk of spatial disorientation”. The drug is not permitted by most aviation authorities worldwide, including the Federal Aviation Authority, in common with many other drugs that have unpredictable or theoretical effects on the central nervous system. In aviators this is a precautionary approach related to high consequence effect, and there is no evidence of detrimental impact on flying ability either in simulator studies [11] or operational deployments when the drug has been used in sub-Saharan Africa [12].
It should also be noted that the comments about the Australian Army refer to a trial of the safety and efficacy of mefloquine when compared to doxycycline, which was conducted as a result of the East Timor campaign in 1999-2000. There were 320 reported cases representing failures both of doxycycline prophylaxis and “terminal prophylaxis” with primaquine for all troops on return to Australia [13]. The conclusion of the study was that “mefloquine was generally well tolerated by Australian soldiers and should continue to be used for those intolerant of doxycycline”, which remains extant policy in that country.
Gogtay and Ferner conclude by stating “the introduction of any new strategy should be accompanied by prospective assessment of benefit and harm, enumerating both the cases of suspected adverse events and of malaria”. The change in US Military policy in 2009 led to mefloquine becoming a reserved agent of choice for those unable to take alternative medication, for all operational deployments including those to Afghanistan. In 2011 the number of cases of malaria reported in the US Armed Forces was the highest for 4 years worldwide; there were more Afghanistan acquired malaria infections than in any of the prior eight years, and more than double the number of Plasmodium falciparum cases than in any of the previous nine years [14].
The UK MOD has a duty to provide the best care to it’s deploying personnel. To do this, it relies on expert advice, national and international guidelines applied to a military environment. Unless there is scientifically sound evidence supported by those experts and bodies, we would be failing in our duty in this regard. The consequence of removing a licensed and effective drug from the options available to deploying military personnel will undoubtedly be a reduction in risk of rare albeit severe adverse effects, affecting previously healthy individuals. The unintended consequence may be an increase in incidence of cases of malaria and deaths from an infectious disease that is largely preventable.
1. Gogtay NJ, Ferner RE. Mefloquine for malaria chemoprophylaxis in military personnel - not the first choice. BMJ 2015;351:h5797 (published 3 November 2015)
2. Novak L. Sailor deployed to Liberia dies of malaria at Landstuhl. Stars and Stripes. December 29, 2009
3. Sanchez JL, Bendet I, Grogl M, et al. Malaria in Brazilian Military Personnel Deployed to Angola. J Travel Med 2000; 7:275–282.
4. Migliani R, Pradines B, Michel et al. Malaria control strategies in French armed forces. Travel Medicine and Infectious Disease 2014; 12; 307-317
5. JSP 950 Leaflet 3.3.1. Preventing malaria in military populations.
6. Chiodini PL, Patel D, Whitty CJM and Lalloo DG. Guidelines for malaria prevention in travellers from the United Kingdom, 2015. London: Public Health England; September 2015.
7. Mefloquine hydrochloride prescriptions in the UK Armed Forces. Defence Statistics. August 2015.
8. http://wwwnc.cdc.gov/travel/page/yellowbook-home-2014
10. Meier CR, Wilcock K, Jick SS. The risk of severe depression, psychosis or panic attacks
with prophylactic antimalarials. Drug Safety 2004;27:203-13.
11. Schlagenhauf P, Lobel H, Steffen R, et al. Tolerance of mefloquine by Swissair trainee pilots. US J Trop Med and Hygiene 1997;56(2):235-40.
12. Joshi VV, Agarwal A, Kumar R. Aeromedical experiences in Indian Peace Keeping Missions
under United Nations in Sierra Leone (UNAMSIL) and Democratic Republic of Congo (MONUC)Ind J Aerospace Med 51(1), 2007: 32-37
13. Kitchener SJ, Auliff AM, Rieckmann KH. Malaria in the Australian Defence Force during and after participation in the International Force in East Timor (INTERFET). Med J Aust 2000; 173: 583-585.
14. Medical Surveillance Monthly Report. Vol. 19 No.1 January 2012
Competing interests: No competing interests
Re: Mefloquine for malarial prophylaxis in military personnel
The use of mefloquine in the military has long been a controversial subject. Recent evidence presented to the current Defence Select Committee inquiry called mefloquine the ‘least safe of the available antimalarial regiments currently used’(1) and yet anecdotal evidence suggests that mefloquine has been routinely issued without an individual risk assessment, due to operational requirements, for several decades. The Ministry of Defence (MoD) has revealed that they possessed defined protocols for prescribing mefloquine since 1997, yet lacked internal measures to ensure that they were being applied in practice (Oral evidence, 12 January 2016). Given the high incidence of neuropsychiatric side effects (2), and the difficulty in ensuring appropriate prescribing and follow-up practices in the military setting (3) this seems is odds with principles of good military medicine as well as being against the manufacturer’s own (4) and GMC Good Practice guidelines (5).
To date there has also been little attention focused within the UK military on the long-term outcomes of military members who have been exposed to mefloquine for active service. The syndrome of mefloquine toxicity has been formally described (6, 7), yet military practitioners have been slow to accept this as a plausible diagnosis when individuals present with complex neurological and psychiatric issues, and where mefloquine exposure can be confirmed in their medical history. A lack of recognition their symptoms is likely contributing to poorer mental health outcomes in military personnel affected by this disorder, constituting a ‘moral’ as well as a physical injury (8).
At the recent DSC inquiry, the MoD asked those who feel they have suffered from adverse effects of mefloquine to come forward. Given the issues surrounding self-reporting of mental health disorders in the militaryand limited post-deployment psychological monitoring for symptom identification (9), this approach may well incite few takers. A better approach might be to instigate an immediate retrospective review of all prescribing records to identify those who have been exposed during military service; delivery of a bi-yearly psychological health assessment protocol for those currently serving which is capable of identifying symptoms for which exposure to mefloquine might be causal, and implementation of targeted programs using the veterans support agencies to provide specific treatment and support for those affected.
References
1. Anonymous. Inquiry: An acceptable risk? Use of Lariam for military personnel HC567: Hearing before the Defence Select Committee. Oral evidence from Lt Col AG Marriott, Mrs T Foster, Dr R Nevin and Dr A Croft. London, UK.2015.
2. Meier CR, Wilcock K, Jick SS. The risk of severe depression, psychosis or panic attacks with prophylactic antimalarials. Drug Safety. 2004;27(3):203-13. PubMed PMID: WOS:000220077900005. English.
3. Nevin RL. Mefloquine prescriptions in the presence of contraindications: prevalence among US military personnel deployed to Afghanistan, 2007. Pharmacoepidemiol Drug Saf. 2010 Feb;19(2):206-10. PubMed PMID: 19998269.
4. Anonymous. The use of Lariam for military personnel HC 567. Evidence given by Dr Frances Nichol, Head of Drug Safety and Quality and Mike Kindell, Lead, Established Products, Roche. London, UK.2015.
5. General Medical Council. Good practice in prescribing and managing medicines and devices. 2013.
6. Nevin RL. Mefloquine and posttraumatic stress disorder. In: Ritchie EC, editor. Textbook of Military Medicine, Forensic and ethical issues in military behavioural health. Washington D.C. : Borden Institute; 2015. p. 277-96.
7. Nevin RL, Ritchie, E.C. The mefloquine intoxication syndrome: A significant potential confounder in the diagnosis and management of PTSD and other chronic deployment-related neuropsychiatric disorders. Post-Traumatic Stress Disorder and Related Diseases in Combat Veterans (In press). Switzerland: Springer International; 2016.
8. Farnsworth JK, Drescher KD, Nieuwsma JA, Walser RB, Currier JM. The Role of Moral Emotions in Military Trauma: Implications for the Study and Treatment of Moral Injury. Rev Gen Psychol. 2014 Dec;18(4):249-62.
9. O'Donnell M, Dell, L., Fletcher, S., Couineau, AL., Forbes, D. The Australian Defence Force Mental Health Screening Continuum Framework: Full Report. . Canberra, Australia.: Deparment of Defence, 2014.
Competing interests: No competing interests