To the Editor:

In many respects, the antimalarial drug mefloquine (previously marketed in the United States as Lariam) would seem to be an ideal candidate for repositioning for certain anesthetic indications. The drug is highly lipophilic, and at physiologic doses, it accumulates rapidly in the central nervous system, where it persists to act at multiple targets, including in the blockade of connexin-36 and connexin-43 gap junction communication that is plausibly involved in the pathogenesis and maintenance of certain forms of pain.

The recently published work by Chen et al.1  suggests that an intraperitoneal dose of 20 to 30 mg/kg in rats—which yields whole-blood levels comparable to those observed during use in humans for common antimalarial indications2 —results in a reduction in allodynia. In their editorial commenting on these results, Tawfik and Flood3  claim that mefloquine is “now an attractive candidate as an analgesic with a distinct mechanism.”

The experience of the malariology and travel medicine communities suggests that it may be impractical to reposition the drug for this or other anesthetic indications. Although Tawfik and Flood3  claim that mefloquine “is a well-tolerated drug,” current international mefloquine product inserts emphasize that when used in malaria prophylaxis, the drug must be discontinued at the onset of certain “very common” psychiatric symptoms, including abnormal dreams and insomnia, which occur in more than 10% of prophylactic users.4  The drug must also be discontinued at the onset of “common” symptoms of anxiety and depression, which occur in between 1 and 10% of prophylactic users.4  Since the drug’s initial licensing in the United States, these symptoms have been considered to be prodromal to “a more serious event”—a euphemism for the “permanent” and “irreversible” idiosyncratic neurologic sequelae—including vertigo, loss of balance, and symptoms of polyneuropathy that are now the subject of a boxed warning.5 

As certain preexisting conditions may confound recognition of these prodromal symptoms, mefloquine is also contraindicated for malaria prophylaxis among those with preexisting psychiatric disorders4 —which are present in approximately 10% of antimalarial users6,7 —and may be even more common among those patients for whom any new anesthetic indication might be sought. For example, in a recent study, 39% of patients treated for neuropathic pain had a comorbid, and hence contraindicating, mood disorder.8 

Given the recent increased regulatory scrutiny of mefloquine, it appears unlikely that the drug would be licensed for additional indications without careful attention during clinical testing to rule out such contraindications among clinical study subjects and to ensure the drug’s use was terminated, should prodromal symptoms develop. Similarly, any attempted off-label prescribing of the drug for analgesia would clearly be unethical without similar precautions.

Research Support

Support was provided solely from institutional and/or departmental sources.

Competing Interests

Dr. Nevin has been retained as consultant and expert witness in legal cases involving claims of antimalarial drug toxicity.

References

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Chen
ZY
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Shen
FY
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L
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Zhao
X
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Zhong
W
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Liu
S
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Wang
ZR
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Wang
YW
:
Attenuation of neuropathic pain by inhibiting electrical synapses in the anterior cingulate cortex.
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Electrical synapses: High-speed communication in the maintenance of neuropathic pain.
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Rational risk-benefit decision-making in the setting of military mefloquine policy.
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Nevin
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Idiosyncratic quinoline central nervous system toxicity: Historical insights into the chronic neurological sequelae of mefloquine.
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Nevin
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Prevalence of contraindications to mefloquine use among USA military personnel deployed to Afghanistan.
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Hill
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Pre-travel health, immunization status, and demographics of travel to the developing world for individuals visiting a travel medicine service.
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Gustavsson
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