The final selection included 16 studies. Overall, those studies indicate that conditioning of immunosuppression, conditioning of allergic responses, and conditioning of insulin and glycemic responses is possible. Regarding immunostimulants, antiallergic effects, and cortisol conditioning, the preliminary results are promising, but additional studies are needed. Conclusions: This systematic review shows classical conditioning of immune and endocrine responses for various pharmaceutical substances. The studies reviewed here indicate that the number of acquisition and evocation sessions, and characteristics of the unconditioned and conditioned stimuli, are important determinants of the effectiveness of pharmacological conditioning on immune and endocrine parameters. In the future, conditioned pharmacological effects may be used clinically as adjunct therapy in various patient populations. KeywordsPharmacological conditioning · Associative learning · Placebo effect · Placebo · Endocrine system · Immune system · Allergy Abstract Background: Conditioned pharmacological effects may provide relevant clinical opportunities to improve treatment for patients with a variety of conditions. The aim of this systematic review was to create an overview of studies in this field of research and to investigate whether specific characteristics of the study design make for successful conditioning. Methods: The protocol of this review was registered in Prospero (PROSPERO 2015: CRD42015024148). A systematic literature search was conducted in the databases PubMed, Embase, and PsychInfo. Studies were included if they were placebo-controlled trials in humans in which the effects of a pharmacological agent on immune or endocrine outcomes (e.g., interleukin-2 and cortisol) were conditioned, using a specific conditioned stimulus. The risk of bias of each study was assessed using the Cochrane risk-of-bias tool. Results:

In this chapter, we review recent studies on conditioned pharmacological effects on immune and endocrine responses in humans, and discuss challenges and opportunities for bringing these effects into clinical practice. By altering physiological mechanisms in part independent of pharmacological agents, pharmacological conditioning has high clinical relevance, as illustrated in some patient studies. Methodological challenges for further investigation include broadening the spectrum of opportunities for conditioned pharmacological effects, by investigating conditioning of substances that have not or not often been used before (e.g., corticosteroids) and unraveling mechanisms by which pharmacological responses become conditioned, thereby identifying characteristics that make conditioning designs effective. As an opportunity to optimize external validity, we introduce a design in which the potential of pharmacological conditioning can be pretested in the laboratory. The feasibility of this design is demonstrated by a pilot study.

BackgroundPlacebo effects on pain have been found to vary in size for different routes of medication administration (e.g. oral vs. injection). This has important implications for both clinical research and practice. To enhance our understanding of these differential placebo effects, research on the underlying expectations about multiple routes and symptoms other than pain is vital.MethodsA cross‐sectional, Internet‐based survey was conducted in a representative sample of the Dutch population (n = 508). Respondents rated the expected effectiveness of pain‐ and itch‐relieving medication in six forms, representing oral, injection and topical routes of administration.ResultsInjected medication was expected to be most effective for relieving pain, and topical medication for relieving itch. Furthermore, exploratory analyses showed that injections were expected to have the most rapid onset and long‐lasting effects, and to be most frightening and expensive, while topical medication was expected to be the safest and the easiest to use, and oral medication was expected to have the most side effects. Higher expected effectiveness was moderately associated with expectations of more rapid onset and long‐lasting effects, and better safety and ease of use. Associations of expected effectiveness with respondent characteristics (e.g. medication use and personality characteristics) were statistically small or nonsignificant.ConclusionsExpected effectiveness of medication differed depending on route of administration and targeted symptom. These findings have important implications for the design and interpretation of clinical trials and suggest that medication effects might be enhanced by prescribing medicine via the route that patients expect to be most effective for their complaint.SignificanceDifferences in the expected effectiveness of medication depend on the route of administration (oral, injection, topical) and targeted symptom (pain, itch). These findings have important implications for clinical practice and the design and interpretation of clinical trials.