A particular treatment effect may exert both non-specific and specific effects. A non-specific treatment effect is an outcome that does not arise according to an intended mechanism of action. This can be a response to a placebo but can also reflect a spontaneous symptom improvement. A placebo is usually thought of as a sugar pill, but placebos can come in any form; they may be things (syringes, medical devices), rituals (anamnesis, ingestion of drugs), places (hospital, doctor’s office), relationships (with doctor, self-help group), medical beliefs to suggestive wordings [1
]. The response to a placebo can be either positive for the outcome of interest, defined as a placebo effect, or negative for the outcome of interest, defined as a nocebo effect.
These effects are commonly explained by expectancy and conditional learning [2
]. These two concepts overlap, so for convenience, we will use the term ‘expectancy’ to describe the mechanism behind placebo and nocebo effects.
Studies have shown that expectations can induce very powerful effects. In an experiment with an opioid painkiller, remifentanil, the presence of positive treatment expectancies was found to double the analgesic effect. Conversely, negative treatment expectancies interfered with the analgesic potential of the painkiller to the extent that the analgesic effect was completely abolished [3
]. In a double-blind sham surgery trial, investigating a new surgical transplant technique for treatment of Parkinson’s disease, sham and real surgery interventions were equally effective. However, participants who thought they received the transplant reported better quality of life [4
]. It seems that positive expectations were triggered by the perceived benefit from the treatment.
To control for the effects of expectations, the double-blind randomized controlled trial (RCT) design is commonly employed to study a novel intervention for its specific effects. Because neither participants nor investigators know who gets the intervention or the placebo, expectancies are balanced across groups. Double blinding makes groups comparable so that specific and non-specific treatment effects (that is, the effect size of the placebo group) can be ascertained with less potential for bias. Both intervention and placebo groups may have two important expectations in common: ‘I get the intervention or the placebo,’ and ‘The intervention under study can cure my problem.’
However, there is little evidence that RCTs are, in fact, double-blinded [5
]. Many factors can undermine double-blinded methodology, including poor randomization methods, imperfect concealment of allocation, and the use of a placebo that is distinguishable from the intervention. Furthermore, in RCTs of pharmacological agents, the presence of side effects may allow participants or investigators to guess correctly who has been allocated to intervention or placebo [6
]. Therefore, the use of an active placebo that mimics some of the intervention’s side effects has been advocated to improve clinical trial blinding.
If an RCT is not double-blinded, participants and investigators will know who gets what type of treatment. Expectations, therefore, could become unbalanced among treatment arms. A participant allocated to the intervention would have altered expectations: ‘I get the intervention’ and ‘The intervention under study can cure my problem.’ This enhances the participant’s prior expectations and can generate an enhanced placebo effect. For participants receiving the placebo, expectations could be ‘I get the placebo,’ and ‘The intervention under study can cure my problem.’ This can lower participants’ expectations and generate a nocebo effect.
This review will test the hypothesis that unblinding in RCTs is associated with enhanced placebo effects for intervention groups and nocebo effects for placebo groups. We will investigate this research question by conducting a meta-epidemiological study of phosphodiesterase-5 (PDE-5) inhibitors. For many years, this treatment has been an established baseline treatment for erectile dysfunction (ED). Numerous trials, overviews, and systematic reviews provide evidence for the efficacy and safety of sildenafil, tadalafil, and vardenafil. There is also a growing evidence base for the newer molecules mirodenafil, udenafil, lodenafil, and avanafil. The PDE-5 inhibitors have been tested in many different populations, including those with broad-spectrum and specific comorbid conditions. The role of treatment expectations is of particular relevance to these medications for several reasons. Firstly, the evidence for efficacy relies solely on subjectively assessed outcomes, such as self-administered questionnaires (International Index of Erectile Functioning (IIEF)), event logs, and a global efficiency question (GEQ) [7
]. Randomized control trials that use these subjective outcome measures are especially vulnerable to unblinding: non-blinded RCTs report 25% higher estimates of treatment effects than their blinded counterparts [8
]. Whether this can be explained by nocebo effects in placebo groups or enhanced placebo effects for intervention groups was not reported. Secondly, since PDE-5 inhibitors are a well-tolerated and effective treatment for ED, initial expectations to treat this common male sexual problem are high for doctors, patients, and drug companies. Lastly, as suggestion can create expectancies [9
], the domain of male sexual performance is a very suggestive domain, where expectations can play a fundamental role.
This meta-epidemiological study will explore magnitude of expectancy and mediating factors in RCTs. If the mechanisms mediating placebo effects such as expectations can be used in a non-deceptive way to produce clinically advantageous outcomes, then it may be possible to incorporate these mechanisms into evidence-based healthcare decision-making.