Placebos Are Part of the Solution, Not the Problem. An Exemplification of the Case of Antidepressants in Pediatric Chronic Pain Conditions

Chronic pain is highly prevalent among adolescents and up to one in four youths will develop chronic pain (1). Also, more than 10% of hospitalized children and adolescents show features of chronic pain (2), which is inherently linked to emotional distress and functional disability (3). Interventions for chronic pediatric pain comprise a range of treatment approaches, among them antidepressants (ADs). Pharmacological treatment indications for pediatric populations are usually based on data extrapolated from adults where ADs are described to be effective and frequently used for the treatment of chronic pain (4–6). Furthermore, chronic pain is multi-faced, therefore the use of ADs may be utilized not only to address pain but also underlying or comorbid psychiatric symptoms such as depression, anxiety, or different sleep disorders (4, 7). However, although ADs are frequently used in clinical practice, a recent Cochrane review could only include four studies that examined the use of ADs in pediatric chronic non-cancer pain and was therefore not able to report effect sizes (4). In addition, the small to moderate effect sizes reported in many pediatric AD trials in the common psychiatric disorders are potentially due to large placebo effects, with effect sizes as high as high as 1.57 (Hedges g) (8). Moreover, the use of ADs in children and adolescents remains controversial (9), as severe adverse events—including an increased risk of suicidal thoughts and behaviors–have been reported, leading to a black box warning by the Food and Drug Administration (FDA) in 2004 (10). Placebo Effects and Mechanisms in Children and Adolescents To date, placebo effects in children and adolescents with clinical conditions are poorly understood. A review from 2013 concludes that from all citations found with the search term “placebo,” only around 2.5% discussed the placebo effect in children and adolescents, and most of them were conducted in the field of attention-deficit hyperactivity disorder (ADHD), depression and migraine (11). Existing literature reports generally higher placebo effects in pediatric populations compared to adults across different disorders (e.g., obsessive compulsive disorder, anxiety disorders, depression, and epilepsy) (11–14). For children with ADHD, Waschbusch et al. (15) reported average rates of positive response to placebo to be up to 20–30% in a review of drug treatments. Notably, while this is an interesting finding, it is not equivalent to a placebo effect which requires a no-treatment control group for comparison (16). It has been proposed that some of the psychological mechanisms underlying the placebo effect in children and adolescents are similar to those in adults, such as the patient-provider relationship, positive expectations (of parents and child), a plausible narrative, as well as a powerful ritual (11, 17–19), but the specific underlying mechanisms of placebo effects in children and adolescents remain poorly understood. It has, for example, been argued that placebo analgesia can be induced via social observational learning (20); children and adolescents may be more susceptible for social learning mechanisms by imitation and role models (11). Furthermore, it has been speculated that children aged 6 years or older have higher learning capacities than adults, at least for the process of associative learning. Associative learning, in turn, is a well-known underlying mechanism associated with placebo responses (11).