Drug side effects are underreported

It’s old news that our medical system isn’t the most reliable truth-finding enterprise ever invented. Recently I stumbled over a concrete example that even surprised me. 

I searched on google scholar for side effects of zopiclone, a supposedly safe, relatively new hypnotic. With 123 citations on google scholar, one of the most promising hits was this review (Terzano et al., 2003) of the side effects and tolerability of the so-called Z-drugs (zolpidem, zaleplon and zopiclone). For comparison, this rather unfavorable meta-analysis of the Z-drugs by Joya et al. (2009) has only 3 citations.

After reading the first few pages doubts about the credibility of this paper already emerged. They write:

Zopiclone appears to be well tolerated….. The most commonly reported adverse event is bitter taste, found in 5 out of 49 (Tamminen & Hansen, 1987) and 8 out of 37 patients (Anderson, 1987) in various studies.

Everyone I know (about 7 people) who has taken zopiclone is disgusted by its bitter taste. This made me obviously suspicious of the whole study. But maybe I know only unusually sensitive people.

But it get’s worse:

In a large postmarketing surveillance study on 20513 patients (Allain et al., 1991) no serious adverse events were reported. The overall percentage of reported events was 9,2%. The most frequent were bitter taste (3,64%), dry mouth (1,6%), difficulty arising in the morning (1,3%) and daytime sleepiness (0,5%).

Only 1,3% reported ‘difficulty arising in the morning’ and only 0,5% reported ‘daytime sleepiness’! Way more than that percentage of healthy individuals who don’t take any drugs experience difficulty arising in the morning or daytime sleepiness on any given day. The only possibility is that the authors operationalized those constructs in such a ridiculous way that e.g. ‘daytime sleepiness’ meant something like literally falling asleep while driving to work and crashing. Which would make this study pretty useless, obviously.

As a side note, SSRIs present us with a similar phenomenon. Initial studies which relied on spontaneous reporting methods found that sexual side effects where only reported by less than 10% of all patients. However, newer studies which did not rely on unprompted reporting methods found that up to 80% of patients experienced sexual side effects (Serretti & Chiesa, 2009).

Thus, we can conclude that many drug side effects go unnoticed. In the case of sexual dysfunction, this can be easily explained. Many depressed people were probably too embarrassed to talk about their sex-life. But bitter taste or daytime sleepiness?

Besides bizarre operationalizations and the usual suspects like e.g. publication bias or skewed incentives, I can think of a few other explanations. Maybe patients are intimidated by their doctors and don’t dare to question the safety of the holy pills handed to them by these high-status people in white coats. Maybe they are simply too lazy to report side effects because they would have to stay longer and complete more questionnaires.

Perhaps many patients report these side effects, but the doctors are too lazy to write them down or don’t take these reports seriously.

Regardless of how this phenomenon of underreported adverse events can be explained, one should be wary of new drugs which are supposedly safe and without side effects. I only became suspicious of this review because I had first-hand experience with the drug. If it had been a drug I had never taken I probably wouldn’t have noticed that there is something fishy about this whole review.

References

Allain, H., Delahaye, C. H., Le Coz, F., Blin, P., Decombe, R., & Martinet, J. P. (1991). Postmarketing surveillance of zopiclone in insomnia: analysis of 20,513 cases. Sleep14(5), 408.

Anderson, A. A. (1987). Zopiclone and nitrazepam: a multicenter placebo controlled comparative study of efficacy and tolerance in insomniac patients in general practice. Sleep10, 54.

Billiard, M., Besset, A., De Lustrac, C., Brissaud, L., & Cadilhac, J. (1989). Effects of zopiclone on sleep, daytime somnolence and nocturnal and daytime performance in healthy volunteers. Neurophysiologie clinique= Clinical neurophysiology19(2), 131.

Joya, F. L., Kripke, D. F., Loving, R. T., Dawson, A., & Kline, L. E. (2009). Meta-analyses of hypnotics and infections: eszopiclone, ramelteon, zaleplon, and zolpidem. Journal of clinical sleep medicine: JCSM: official publication of the American Academy of Sleep Medicine5(4), 377.

Serretti, A., & Chiesa, A. (2009). Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis. Journal of clinical psychopharmacology29(3), 259-266.

Tamminen, T., & Hansen, P. P. (1987). Chronic administration of zopiclone and nitrazepam in the treatment of insomnia. Sleep10, 63.

Terzano, M. G., Rossi, M., Palomba, V., Smerieri, A., & Parrino, L. (2003). New drugs for insomnia: comparative tolerability of zopiclone, zolpidem and zaleplon. Drug Safety26(4), 261-282.

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