CommentaryNonspecific side effects of oral contraceptives: nocebo or noise?
Introduction
Nonspecific side effects are the most common reason why women quit taking oral contraceptives. Indeed, studies around the world consistently identify reported side effects as the principal reason for pill discontinuation [2]. In the 2002 National Survey of Family Growth, the 12-month discontinuation rate for oral contraceptives (corrected for underreporting of abortion) was 33% (95% CI 30–35%) [3]. That a third of US pill users stop this contraceptive method within a year has profound adverse public health implications [4], [5], [6]. Most of these women switch to a less effective contraceptive or, worse yet, to no method at all [7]. In addition, women who are unhappy with oral contraceptives because of alleged side effects are prone to inconsistent use, which can lead to irregular bleeding and then to discontinuation because of the bleeding [8].
Women around the world share a common mythology about alleged ill effects of oral contraceptives [9]. A recent systematic review of the international literature (including 28 studies) on attitudes about oral contraceptives revealed widespread concern about perceived side effects [10]. Even if respondents could not name any side effect, many women still associated pills with health problems. This mythology, which dates back decades [11], is perpetuated by gossip, rumors and illogic. The misinformation transcends continents [12], [13], [14] and is shared by highly educated women as well as by women with little education [15].
Most studies that have described nonspecific pill side effects did not have appropriate comparison groups [16]. Thus, no conclusions could be drawn about whether these nonspecific side effects were caused by oral contraceptives. For example, FDA-approved package labeling for oral contraceptives contains lengthy lists of side effects that have been reported in pill users. However, without a control group, one cannot infer that these side effects were due to the pills. A common error in logic is post hoc ergo propter hoc reasoning: “after this, therefore because of this.”
In this commentary, we will summarize the Level I evidence concerning vague pill side effects, describe the nocebo phenomenon, document the background prevalence of nonspecific complaints and explain why counseling women about nonspecific pill side effects is both unwarranted and probably unethical. Most vague complaints attributed to oral contraceptives can be explained by women's negative expectations (the nocebo phenomenon) or by the high background prevalence of such complaints.
Section snippets
The best evidence: placebo-controlled randomized trials
Although more than 44,000 reports on oral contraceptives have been archived in PubMed over the last half century, few placebo-controlled trials with blinding have been done. An early crossover trial by Goldzieher et al. [1], [17] compared a sequential formulation, two monophasic combination pills with high estrogen doses, a progestin-only pill and placebo. All pills were identically packaged, and neither the participants nor investigators knew the treatment assignment. Although the trial
The nocebo phenomenon: making matters worse
The nocebo phenomenon is the causation of illness or death by the expectation of these outcomes and by associated emotional states [24]. Nocebo is the “evil twin” of placebo. While placebo means “I will please,” nocebo is translated as “I will harm.” Beliefs can make one sick or well, depending on the expectation. In the purest sense, an inert substance (nocebo) is given to a trial participant who has been advised to anticipate adverse effects; these effects then occur because of the power of
Pharmacology
Suggestion can modulate pharmacological effects. When the bronchoconstrictor carbachol was inhaled by asthmatic patients, it produced more airway resistance in those told it was a bronchoconstrictor than in those told it was a bronchodilator [29]. Nocebos can make innocuous tactile stimulation painful and convert low-intensity pain into high-intensity pain [30]. One hundred twenty men with benign prostatic hypertrophy were randomized to receive finasteride 5 mg; half were warned of potential
Nocebo epidemiology
The elderly may be more susceptible to the nocebo phenomenon than are the young; likewise, women may be at greater risk than are men [36]. Negative conditioning plays an important role. Chemotherapy patients commonly become nauseated when entering a room painted the same color as their infusion room. Type A personalities and depressed persons may be more vulnerable to nocebo effects [36], [37].
Social systems can play a role as well. The prototype is mass (or epidemic) hysteria, a sociogenic
Background noise: complaints are common
Another explanation for commonly reported oral contraceptive side effects is background prevalence. Nonspecific health complaints are common in the population. The pioneering placebo-controlled randomized trial of oral contraceptives by Goldzieher et al. [1], [17] provided an early indication. It featured a pretreatment cycle with a standard questionnaire administered to all participants. Before starting an active or inert pill, 22% of participants reported depression and 29% nervousness (both
Association or causation?
The common nonspecific side effects reported by pill users may reflect either the nocebo phenomenon or background prevalence of these complaints [17], [38], [39]. Alternatively, some women may describe side effects as “a scapegoat for far more obscure motivation” [17], such as ambivalence about pregnancy. Women have been told (by conventional wisdom or clinicians' counseling) to expect troublesome side effects from the oral contraceptives [10]. This then becomes a self-fulfilling prophecy. In
Potential harms of counseling
The benefit/risk calculus of oral contraceptives tips decidedly toward benefit for most women. On balance, using oral contraceptives is associated with longer life expectancy [41]. In terms of cardiovascular risks, taking the pill is safer than not using contraception for most women except those over 35 years who smoke cigarettes [42]. In the Royal College of General Practitioners' Study, the net effect on cancers of all types is protection [43].
Women who quit the pill often choose a less
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