Gastroenterology
Volume 137, Issue 4 , Pages 1207-1210, October 2009

The Power of Placebo in Pediatric Functional Gastrointestinal Disease

  • Marc A. Benninga

      Affiliations

    • Department of Pediatric Gastroenterology, Emma Children's Hospital/Academic Medical Center, Amsterdam, The Netherlands
    • Corresponding Author InformationReprint requests Address requests for reprints to: Marc A. Benninga, MD, PhD, Emma Children's Hospital/Academic Medical Centre, Department of Pediatric Gastroenterology and Nutrition, Room G8-261, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
    • ,
  • Emeran A. Mayer

      Affiliations

    • Center for Neurobiology of Stress, Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, California

published online 31 August 2009.

Article Outline

 

See “Multicenter, randomized placebo-controlled trial of amitriptyline in children with functional gastrointestinal disorders,” by Saps M, Youssef N, Miranda A, et al, on page 1261.

Apley and Naish, in their landmark paper, defined recurrent abdominal pain in children as ≥3 episodes of abdominal pain severe enough to affect daily activities occurring over a period for >3 months.1 To date, the term recurrent abdominal pain has been abandoned and replaced by the term “pain-related functional gastrointestinal disorders” (FGIDs), namely, functional dyspepsia, irritable bowel syndrome (IBS), abdominal migraine, and functional abdominal pain (syndrome). This set of pain-related FGIDs was introduced in 1999 and updated in 2006.2 The revision of criteria for pain-related FGIDs has increased the proportion of pediatric patients with chronic abdominal pain who meet the symptom criteria for an FGID.3

Chronic abdominal pain is the most common gastrointestinal (GI) complaint in childhood, with reported prevalence's in Western countries of 0.3%–19%.4 In children, chronic abdominal pain is often associated with headache, and back and limb pain; in accordance with adults, females have a higher prevalence compared with males, but this difference manifests not earlier than around puberty.5 A recent systemic review showed that in 29.1% (95% confidence interval, 28.1–30.2) of children, symptoms can persist for ≥5 years.6 Consequently, the quality of life reported by these children is lower compared with their healthy peers, and similar to children with inflammatory bowel disease or gastroesophageal reflux disease.7

In the present issue of Gastroenterology, Saps et al8 present results from a fairly large, prospective, multicenter, randomized, double-blind, placebo-controlled trial of 4 weeks duration, comparing low-dose amitriptyline with placebo for the treatment of children with pain-related FGIDs.8 The study showed that there was no significant difference in the effectiveness of amitriptyline (63%) and placebo (58%) in the treatment of these pediatric pain-related FGIDs. Although improvement was found on both primary and secondary end points, surprisingly, no differences were found between treatment groups with respect to pain relief and interference with daily activities, nor in terms of psychologic variables, such as depression and somatization. However, improvement in anxiety scores was found only in the amitriptyline group.

Prospective, double-blind, placebo-controlled studies examining clinical problems are considered the “gold standard” for evidence-based medicine. The objectives of these kinds of studies are to control adequately for variations in natural history of disease progression, regression to the mean, and if blinded, for recognition bias.9 Because the variation in response to treatment in pain-related disorders such as IBS is high, an understanding of the placebo effect is essential. A recent meta-analysis comparing no treatment, placebo, and active intervention in randomized, controlled trials (RCTs) demonstrated that both spontaneous improvement and the effect of placebo were the key contributions to the therapeutic effect observed in the patients receiving active compound.10 In addition, Kaptchuk et al11 demonstrated in IBS patients that the patient–practitioner relationship is probably the most robust factor contributing to the placebo effect.11 The authors showed, in a 3-component RCT of acupuncture treatment in IBS patients, that patient–practitioner relationship produced clinically significant outcomes (global improvement, adequate relief of symptoms, symptom severity score and quality of life) compared with a waiting list (neither placebo treatment nor interaction with a health care professional list) and limited interaction with a practitioner (sham acupuncture). Homogeneous patient populations and number of visits were identified as potential predictors of the placebo effect in a meta-analysis of IBS trials.12 Significant progress has been made in the identification of the neural substrate, including brain networks and signaling systems, underlying the placebo response. For example, several studies have shown that the engagement of lateral prefrontal regions associated with the expectation of symptom relief, results in the inhibition of limbic regions (reducing anxiety and arousal) and greater engagement of endogenous pain inhibition systems, involving opioid and dopamine signaling systems.13, 14 The fact that engagement of similar regions are observed during experimental pain stimuli in the absence of a placebo context suggests that the brain engages the same systems during any painful experience, and that the “healing context” (presence of a practitioner, sugar pills, etc) simply increases the activity of these systems.

Although the design of the Saps study fulfills the current guideline recommendations by the European Medicines Agency and included important components influencing the placebo effect such as a run-in period and multiple visits were taken into account, it is unclear why the placebo effect of 58% was higher compared with results reported from high-quality RCTs in placebo-controlled trials in adult patients with IBS.15 Several factors may be responsible for this finding. For example, one might speculate that treatment in a tertiary center by 6 well-known academic pediatric gastroenterologists with respect to FGIDs may have increased the placebo effect. In addition, the physicians involved in this study were experienced in pediatric functional GI problems and well aware of the importance of education, reassurance, and allocation of time to the initial consultation to validate the patients' symptoms and respond to the patient's specific needs and fears, which might also have increased the placebo effect. However, the most intriguing explanation may be related to the fact, in contrast with the straightforward physician patient interactions in the adult, the treating physician exerts a dual effect on the pediatric patient: One directly on the patient, the other on the parent–child “dyad,” thereby indirectly influencing the child's expectation through changing parents' attitudes and expectations. There is a close correlation between parental anxiety sensitivity and pain sensitivity in children.16 Consistent with this concept, chronic abdominal pain is more common in families with higher rates of reported physical illness and psychologic symptoms like anxiety.17 The relation between abdominal pain in childhood and these parental factors suggests that parental anxiety and preoccupation with physical health may reinforce the child's own concerns about physiologic, minor medical bodily sensations and influence treatment outcome. Lindley et al18 demonstrated in a retrospective analysis performed on a cohort of 23 children <16 years pain-related FGIDs that prognostic indicators for poor outcome, as defined by continued pain and failure to return to normal functioning >12 months after onset, included refusal to engage with psychologic services, involvement of >3 consultants, lodging of a manipulative complaint with the hospital management by the child's family, and lack of development of insight into psychosocial influences on symptoms.18 One might hypothesize that parents willing to participate in a trial in which centrally acting medication is used are motivated believers in the biopsychosocial model, reducing their own anxiety about the child's symptoms, and thereby increasing the placebo effect in the child.

Few studies exist on the pharmacologic and behavioral therapy of pain-related FGIDs in children. Moreover, no placebo-controlled trials have been performed with adequate sample size and adequate duration of medications or psychologic interventions in the treatment of any of the specific Rome-defined subtypes of pain-related FGIDs. Why is it that in such a prevalent condition well-designed studies in large patient samples in children with FGIDs are lacking? The Saps trial is a good example to answer this question. Despite the high prevalence of pain-related FGIDs, it is remarkable that even in this multicenter study only 90 of these patients in nearly 5 years time could be recruited. Unfortunately, the authors give no insight into how many patients were invited to participate and the reason(s) why parents refused their children's participation in this study. One might presume that many parents were unwilling to consent their children being involved in this placebo-controlled medication trial because of the negative connotations of antidepressants. Behar et al, evaluating the efficacy of amitriptyline in adolescents with IBS in a double-blind, placebo-controlled trial, experienced an amplifying effect of refusal to participate in their study after the US Food and Drug Administration issued formal “black box” warnings regarding the increased potential for “suicidality” in children consuming antidepressant medications.19, 20 More than half of the eligible adolescents or their guardians refused to participate in their study. Other reasons why recruitment rate was low in this study is the possibility of receiving the placebo instead of the active drug, the duration of the study, and its associated pretreatment period in the face of a strong desire for immediate symptom relief. These aspects need to be taken into account by investigators undertaking similar types of clinical trials in the future, especially in children.

Do findings of this study alter the daily practice of caretakers of children with pain-related FGIDs? Most children with functional abdominal pain have mild symptoms that are usually of short duration and are easily managed in primary care. The current practice of many health care professionals in treating these children is that of support and empathy for the family with the assurance that no serious disease is present and that children will likely outgrow it.21 The primary goal of the therapy is not complete eradication of pain, but resumption of a normal lifestyle with regular school attendance, school performance to the child's ability, participation in desired extracurricular activities, and a normal sleep pattern. With this approach approximately 40%–70% of the children have complete resolution of their complaints.18 Furthermore, education of the family and the patient is an important part of the treatment of the child with a pain-related FGID. Parents often believe that attention to somatic complaints is a good thing and distraction is potentially harmful. However, the landmark study by Walker et al22 clearly showed that, compared with parents giving “no instruction,” symptoms of abdominal pain nearly doubled in those parents giving attention to the child's symptoms, and were reduced by half in the group of parents who distracted their child by involving him or her in a conversation about something he or she enjoys.22 Surprisingly, parents rated the strategy of distraction as having greater potential negative long-term impact on the child than attention. However, acknowledging parents' worries, beliefs, and fears opens the discussion changing parental behavior from solicitousness toward child's symptoms to more beneficial coping strategies such as distraction and relaxation.23

In accordance with tertiary referred patients, as described in the study by Saps et al, 25%–66% of children either continue to experience abdominal pain symptoms or develop other symptoms such as chronic headache, back pain, fibromyalgia, anxiety, and sleep disturbances throughout adolescence and adulthood.24, 25, 26 Current treatment strategies for these patients include dietary or pharmacologic interventions, including analgesics, antispasmodics, sedatives, and recently probiotics. Although some of these studies were placebo controlled, none had an adequate sample size or adequate duration of the intervention.27 Antidepressants have been used widely in the treatment of IBS in adult and pediatric patients primarily with the rationale that FGID patients show high levels of comorbid depression and anxiety, and that an effective treatment of the comorbidity reduces IBS symptoms.28, 29 However, in patients without psychiatric comorbidity the rationale is different. Although full therapeutic doses of selective serotonin reuptake inhibitors have shown only limited effectiveness in small adult trials, tricyclic antidepressant (TCA) medications are commonly used for IBS symptoms, often in low doses (eg, amitriptyline 10–75 mg).30 Hypothesized mediators of their effects include antihyperalgesia (via peripheral and/or central mechanisms), improvement in sleep, and normalization of GI transit.31 Despite their frequent use in practice, evidence to support the efficacy of TCAs in IBS patients is inconsistent. Two meta-analyses (including 11 RCTs) concluded that TCAs significantly improved pain and overall symptoms in patients with IBS, but have been criticized on methodologic grounds.32, 33 A third meta-analysis that excluded these studies concluded that TCAs were not superior to placebo.34 In the largest RCT to date, treatment with desipramine (escalating dose from 50 to 150 mg; eg, beyond the low-dose regimen) was not superior to placebo in intention-to-treat analyses.35 Effects of TCAs on somatic pain sensitivity and sleep suggest that they may have particular benefit in patients with widespread somatic pain or poor sleep, although this has not been explicitly studied.30, 36

However, in view of the largely negative findings in adult RCTs, the lack of effect in the Saps study is not entirely unexpected. The unusually high placebo effect in combination with a low number of participants may have contributed to these negative findings.

Other nonpharmacologic therapies, such as cognitive–behavioral therapy (CBT) and gut-directed hypnotherapy have been demonstrated, in well-designed but small RCTs, to be highly effective in the treatment of children with long-lasting complaints of pain-related FGIDs.37, 38, 39 The study by Vlieger et al39 demonstrated a clinical remission rate of 85% at 1-year follow up. This high success rate is remarkable; most children were tertiary referrals after extensive other treatments and suggests that in the near future gut-directed hypnotherapy might become the treatment of choice in children with persisting complaints of abdominal pain in who first-line therapies, like support, empathy for the family, and education, have failed. It is of interest to note that current evidence from neuroimaging studies in adults support the general concept that different mind-based therapies, including placebo, CBT, and hypnotherapy involve the engagement of similar brain networks, which in turn reduce experimental pain perception and presumably clinical symptoms.40 Based on the study of Saps et al, at this moment it seems reasonable to reserve pharmacologic interventions such as TCAs for anxious patients with pain-related FGIDs who fail hypnotherapy or CBT, or are unwilling to consider it.

The current study by Saps et al is a major step forward and an important contribution to the pediatric literature that may open the door to a new line of studies on the placebo effect in children with GI disorders such as gastroesophageal reflux disease, constipation, and functional nonretentive fecal incontinence. National and/or international collaboration is necessary to perform well designed medication studies in children describing an unbiased interpretation of safety, efficacy, effect size, and number needed to treat.

Back to Article Outline

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 Conflicts of interest The authors disclose no conflicts.

PII: S0016-5085(09)01488-7

doi:10.1053/j.gastro.2009.08.023

Refers to article:

  • Editorial Accompanies ArticleLinking Article with CGHVideo Abstract Multicenter, Randomized, Placebo-Controlled Trial of Amitriptyline in Children With Functional Gastrointestinal Disorders , 13 July 2009

    Miguel Saps, Nader Youssef, Adrian Miranda, Samuel Nurko, Paul Hyman, Jose Cocjin, Carlo Di Lorenzo
    Gastroenterology October 2009 (Vol. 137, Issue 4, Pages 1261-1269)

Gastroenterology
Volume 137, Issue 4 , Pages 1207-1210, October 2009