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Children's and parents' perspectives on open-label use of placebos in the treatment of ADHD
Abstract
The purpose of this study was to examine the efficacy and acceptability of an open-label conditioned placebo dose reduction (CPDR) treatment in 70 children with attention deficit hyperactivity disorder (ADHD). This paper focuses on the qualitative data from the study.
Following a double-blind, crossover dose finding procedure to determine each subject's optimal dose of stimulant medication, subjects were randomized to the CPDR treatment or one of two control groups. Outcome measures included parent and teacher ratings of ADHD behaviours and stimulant side effects. Qualitative assessments were based on open-ended interviews of children and parents. Positive responders to CPDR and controls were followed for 3 months to assess persistence of treatment benefits.
Children randomized to CPDR showed an excellent treatment response, well maintained over time. Parents and children were generally accepting of the treatment. Most parents reported treatment benefits and 80% of the children found the placebo to be useful. Full disclosure of the placebo to parents and children did not appear to negate the placebo's effectiveness. Participation effects and changes in caregiver behaviour may have contributed to positive treatment outcomes.
Open-label use of placebos as part of CPDR treatment may represent an innovative, ethical way of harnessing the power of placebos in clinical therapeutics.
... To date, only three studies have been conducted that have looked at the effects of OLPs in children/adolescents [17][18][19]. These studies comprised participants diagnosed with attention-deficit hyperactivity disorder, functional abdominal pain, or irritable bowel syndrome. ...
... The participants in these studies were also concurrently receiving pharmacotherapy in the form of stimulants or spasmolytics. The OLP treatment was found to reduce medication intake [17][18][19] and reported pain [19]. Furthermore, the majority of these participants found the placebos to be beneficial [18], and there were no reported adverse treatment effects [19]. ...
... The effect size was large. These findings align with previous research on placebo effects in children, demonstrating the responsiveness of this age group to such treatments (e.g., [17][18][19]23]). ...
Background: A high level of food cue reactivity (FCR) is a risk factor for overeating and weight gain. This randomized trial investigated whether open-label placebos (OLPs: placebos honestly administered) can reduce FCR (reported appetite) in children and adolescents. Method: Children (n = 73; 8–12 years old) and adolescents (n = 187; 16–18 years old) were randomly assigned to either an OLP group or a control group (without OLP). Participants viewed images depicting food (sweets and fruits) and non-food items. Before viewing, the OLP group received a placebo for appetite reduction. Participants rated their desire to eat the depicted food items (0–100) and the perceived effectiveness of the OLP intervention. Results: The OLP exhibited a large effect in children, leading to a general reduction in appetite (group difference OLP vs. no OLP: M = −20.8; ηp2 = 0.20). This general effect was absent in adolescents, whose appetite reduction was restricted to fruits (OLP vs. no OLP: M = −8.1; ηp2 = 0.03). Additionally, children perceived the OLP as more effective than adolescents. Conclusion: The reduced response and skeptical attitudes of adolescents towards OLP treatment require further investigation.
... During open-label placebo administration, patients are typically told that the treatment substance is inert, with no active drug component, but they are also informed that these treatments have sometimes been found to produce therapeutic benefits in patients with their condition [19]. In the pediatric field two studies have investigated the clinical efficacy of open-label placebos [20,21]. In children with ADHD, administration of open-label placebo paired with stimulant medication successfully reduced the intake of medication in affected children by 50%, minimizing side effects without compromising the therapeutic benefit [20,22]. ...
... A change in treatment outcome can arise, not only from patients' expectancies but also from the expectancies of proxies, such as parents and physicians.Placebo by proxy is a complex phenomenon that attempts to explain a change in treatment outcome arising from an interaction between a patient and an effect from proxies such as parents, caregivers or physicians [40]. Only two studies have been published on parents and patients' perspectives about the use of placebos in children [21,41]. Data suggest that both children and parents are interested in and accepting of open-label placebos as a treatment option. ...
... This becomes particularly compelling to parents and physicians who generally want to see children treated with the lowest effective drug doses. Accordingly, previous survey data show that more than two-thirds of parents were interested in having their children take placebo because they believed it would allow their children to take lower doses of medication and result in fewer medication side effects [21]. Open-label placebos, which are consistent with the values of informed consent and patient autonomy, may represent a powerful, safe and ethical new methodology to replace, augment, or extend the effects of drugs, thus reducing drug loads and decreasing side effects in pediatric patients [52]. ...
Objective:
Placebo responses are significantly higher in children than in adults, suggesting a potential underused treatment option in pediatric care. To facilitate the clinical translation of these beneficial effects, we explored physicians' current practice, opinions, knowledge, and likelihood of recommending placebos in the future.
Methods:
A cross-sectional web-based survey administered by REDCap was conducted at Boston Children's Hospital between October 2021 and March 2022. Physicians (n = 1157) were invited to participate through an email containing a link to a 23-item survey designed to assess physicians' attitudes and perceptions towards the clinical use of placebo in pediatrics.
Results:
From 207 (18%) returned surveys, 109 (9%) were fully completed. Most respondents (79%) believed that enhancing the therapeutic components that contribute to the placebo response may be a way of improving pediatric care. However, whereas most (62%) found placebo treatments permissible, only one-third reported recommending them. In pediatrics, placebos are typically introduced as a medicine that "might help" (43%). The most common treatments recommended to enhance placebo effects are physical therapy, vitamins, and over-the-counter analgesics. Physicians most frequently recommend placebos for occasional pain, headaches, and anxiety disorders. Finally, the great majority of physicians (87%) stated they would be more likely to recommend placebo treatments if there were safety and ethical guidelines for open-label placebos.
Conclusions:
Placebo treatments seem permissible to physicians in pediatric care, but the development of safety and ethical guidelines may be necessary before physicians systematically incorporate the benefits of the placebo effect in pediatrics.
... After forming these associations, the CS in itself (e.g., a placebo tablet looking similar to the active medication) can elicit the CR. A number of studies have shown that pharmacological conditioning can improve treatment effects in different clinical conditions [3,[8][9][10][11][12][13][14]. For example, after pharmacological conditioning, comparable treatment effects and reduced side effects have been shown after the administration of reduced or subclinical dosages of active medication combined with placebo medication in comparison to regular active medication dosages [8][9][10][11][12][13]. ...
... A number of studies have shown that pharmacological conditioning can improve treatment effects in different clinical conditions [3,[8][9][10][11][12][13][14]. For example, after pharmacological conditioning, comparable treatment effects and reduced side effects have been shown after the administration of reduced or subclinical dosages of active medication combined with placebo medication in comparison to regular active medication dosages [8][9][10][11][12][13]. The formation of associations between contextual factors and the medicinal effect is a key factor in this process and occurs mainly automatically after the active medication had its effect on disease symptoms [3,15,16]. ...
... This combined reinforcement schedule was associated with significant treatment effects on a reduced dosage of active medication comparable to the treatment effects of the full dosage [8]. Although promising results arose from this and other studies, as of yet, pharmacological conditioning has only been studied in a few clinical populations, including patients with psoriasis, irritable bowel syndrome, Parkinson's disease, attention deficit hyperactivity disorder, and multiple sclerosis [8][9][10][11][12][13]. In order to broaden the knowledge on the potential of pharmacological conditioning and generalize the effects to other clinical populations, we designed a double-blind, randomized clinical trial to compare standard treatment to treatment with pharmacological conditioning in a population of patients diagnosed with recent-onset rheumatoid arthritis (RA). ...
Background:
In pharmacological conditioning associations are formed between the effects of medication and contextual factors related to the medication. Pharmacological conditioning with placebo medication can result in comparable treatment effects and reduced side effects compared to regular treatment in various clinical populations, and may be applied to achieve enhanced drug effects. In the current study protocol, pharmacological conditioning is applied to achieve enhanced treatment effects in patients with recent-onset rheumatoid arthritis (RA). The results from this study broaden the knowledge on the potential of pharmacological conditioning and provide a potential innovative treatment option to optimize long-term pharmacological treatment effectiveness for patients with inflammatory conditions, such as recent-onset RA.
Methods:
A multicenter, randomized controlled clinical trial is conducted in patients with recent-onset RA. Participants start on standardized pharmacological treatment for 16 weeks, which consists of methotrexate (MTX) 15 mg/week and a tapered schedule of prednisone 60 mg or 30 mg. After 4 months, participants in clinical remission (based on the rheumatologist's opinion and a targeted score below 1.6 on a 44-joint disease activity score (DAS44)) are randomized to 1 of 2 groups: (1) the control group (C), which continues with a standardized treatment schedule of MTX 15 mg/week or (2) the pharmacological conditioning group (PC), which receives an MTX treatment schedule in alternating high and low dosages. In the case of persistent clinical remission after 8 months, treatment is tapered and discontinued linearly in the C group and variably in the PC group. Both groups receive the same cumulative amount of MTX during each period. Logistic regression analysis is used to compare the proportion of participants with drug-free clinical remission after 12 months between the C group and the PC group. Secondary outcome measures include clinical functioning, laboratory assessments, and self-reported measures after each 4-month period up to 18 months after study start.
Discussion:
The results from this study broaden the knowledge on the potential of pharmacological conditioning and provide a potential innovative treatment option to optimize long-term pharmacological treatment effectiveness in patients with inflammatory conditions, such as recent-onset RA.
Trial registration:
Netherlands Trial Register, NL5652. Registered on 3 March 2016.
... Expectancies, which are an important learning mechanism and may steer placebo-effects [34], may have played a role in our study, since both parents and children were informed about the potential positive effect of hydrocortisone. Furthermore, a participation effect or classical conditioning may have occurred: by adding an oral suspension to standard treatment, patients can be triggered to show physiological responses to additional medication [29,[35][36][37]. However, since we did not include a third observational arm with treatment as usual, a direct comparison between the intervention with hydrocortisone or placebo and no intervention (natural course) cannot be made. ...
... A recent expert consensus paper regarding placebo-and nocebo-effects in adults stresses the importance of making optimal use of placebo-effects to achieve better treatment outcomes [38]. Studying the effect of hydrocortisone and openlabel placebo, which has been proven effective in children with functional abdominal pain or attention deficit hyperactivity disorder (ADHD), would be very interesting [37,39]. Besides further research on the placeboeffect, we propose to create awareness about possible nocebo-effects of dexamethasone in clinical practice. ...
Background:
Dexamethasone is a cornerstone of paediatric acute lymphoblastic leukaemia (ALL) treatment, although it can induce serious side-effects. Our previous study suggests that children who suffer most from neurobehavioural side-effects might benefit from physiological hydrocortisone in addition to dexamethasone treatment. This study aimed to validate this finding.
Methods:
Our phase three, double-blind, randomised controlled trial with cross-over design included ALL patients (3-18 years) during medium-risk maintenance therapy in a national tertiary hospital between 17th May 2018 and 5th August 2020. A baseline measurement before and after a 5-day dexamethasone course was performed, whereafter 52 patients with clinically relevant neurobehavioural problems were randomised to receive an intervention during four subsequent dexamethasone courses. The intervention consisted of two courses hydrocortisone (physiological dose 10 mg/m2/d in circadian rhythm), followed by two courses placebo, or vice versa. Neurobehavioural problems were assessed before and after each course using the parent-reported Strengths and Difficulties Questionnaire (SDQ) as primary end-point. Secondary end-points were sleep problems, health-related quality of life (HRQoL), hunger feeling, and parental stress, measured with questionnaires and actigraphy. A generalised mixed model was estimated to study the intervention effect.
Results:
The median age was 5.5 years (range 3.0-18.8) and 61.5% were boys. The SDQ filled in by 51 primary caregivers showed no difference between hydrocortisone and placebo in reducing dexamethasone-induced neurobehavioral problems (estimated effect -2.05 (95% confidence interval (CI) -6.00-1.90). Also, no benefit from hydrocortisone compared to placebo was found for reducing sleep problems, hunger, parental stress or improving HRQoL.
Conclusions:
Hydrocortisone, when compared to placebo, had no additional effect in reducing clinically relevant dexamethasone-induced neurobehavioural problems. Therefore, hydrocortisone is not advised as standard of care for children with ALL who experience dexamethasone-induced neurobehavioural problems.
Trial registration:
Netherlands Trial Register NTR6695/NL6507 (https://trialsearch.who.int/) and EudraCT 2017-002738-22 (https://eudract.ema.europa.eu/).
... Although their design and methods were different from ours, they also showed a clear benefit of OLP. 28 The only other trials of OLP for DGBI were 2 studies conducted for adults with irritable bowel syndrome. 7,8 In both studies, OLP produced improvement and significantly lower symptom severity. ...
... 4 Another potential factor is the effect of nonconscious expectations, as it has been shown that external influences may have an association with placebo effects. 4 That parents in our study expected placebos to "work" confirms previous observations, 28,33,34 and it has been argued that some pediatric placebo effects are due to parents' expectations (placebo effect by proxy). 35,36 Given that expectations were not associated with the response to the placebo, this possibility seems ...
Importance:
Although it is widely believed that concealment or deception is required to elicit a placebo response, recent studies with adults suggest that open-label placebo (OLP) (ie, honestly prescribed placebos) can yield significant benefits. No studies of OLP have been performed with children.
Objective:
To evaluate the efficacy of OLP for the treatment of children and adolescents with functional abdominal pain or irritable bowel syndrome.
Design, setting, and participants:
This multicenter crossover randomized clinical trial was conducted from July 1, 2015, to June 15, 2018, at 3 US centers among children and adolescents aged 8 to 18 years with functional abdominal pain or irritable bowel syndrome defined per Rome III criteria. Statistical analysis was performed from March 1, 2019, to September 30, 2020, on an intention-to-treat basis.
Interventions:
Patients completed 1 week of observation prior to randomization to 1 of 2 counterbalanced groups: OLP for 3 weeks followed by a 3-week control period or control period for 3 weeks followed by OLP for 3 weeks. During the OLP period, participants took 1.5 mL of an inert liquid placebo twice a day. A standardized method for explaining the OLP was used, and the interaction with clinicians had the same duration and style for both time periods. Hyoscyamine was allowed as a rescue medication.
Main outcomes and measures:
The primary outcome was the mean daily pain score during each of the interventions, measured on a 0- to 100-mm visual analog scale, where higher scores indicated greater pain. The number of rescue medications taken during each intervention served as an objective secondary measure.
Results:
Thirty patients (mean [SD] age, 14.1 [3.4] years; 24 female participants [80.0%]; 16 [53.3%] with functional abdominal pain and 14 [46.7%] with irritable bowel syndrome) completed the study. The mean (SD) pain scores were significantly lower during OLP treatment compared with the control period (39.9 [18.9] vs 45.0 [14.7]; difference, 5.2; 95% CI, 0.2-10.1; P = .03). Patients took nearly twice as many hyoscyamine pills during the control period compared with during the OLP period (mean [SD] number, 3.8 [5.1] pills vs 2.0 [3.0] pills; difference, 1.8 pills; 95% CI, 0.5-3.1 pills).
Conclusions and relevance:
During OLP, patients with functional abdominal pain or irritable bowel syndrome reported significantly less pain and took significantly fewer pain medications. Open-label placebo may be an effective treatment for children and adolescents with functional abdominal pain or irritable bowel syndrome.
Trial registration:
ClinicalTrials.gov Identifier: NCT02389998.
... 6 In the ADHD study described in the preceding paragraph, the authors found that parents expressed positive and supportive attitudes toward placebo treatments and that children believed the placebos were useful. 7 At the completion of the study, more than two-thirds of parents were interested in having their child take the placebo in the future, as they believed it would allow their children to take lower doses of medication and result in fewer medication side effects. Patients did not appear to view placebos as deceptive and, on the contrary, expressed significant interest and curiosity about the possibility of integrating placebos into their arsenal of treatments. ...
... Patients did not appear to view placebos as deceptive and, on the contrary, expressed significant interest and curiosity about the possibility of integrating placebos into their arsenal of treatments. 7 However, there are some concerns over the potential negative effects of widespread use of clinical placebos. The precise functional mechanism of the placebo effect is poorly understood, raising concerns about the potential for unknown risks or "nocebo effects, " whereby the expectation of an adverse effect by patients precipitates or exacerbates the experience of that symptom. ...
... First, extending the effects of a medication by interspersing placebos rather than using only medication for a treatment of equal duration may reduce the overall intake of painkillers. Side effects associated with the medicine are likely to be reduced as well, 70,71 although there is some risk of conditioned side effects. 25 Second, in cases in which the medicine is habitforming, dose-extending placebo use may decrease physiological or psychological dependence on medication. ...
... Although open label vs concealed placebos may produce different degrees of effect, preauthorized placebos would avoid the ethical problems associated with deception and satisfy requirements of informed consent. 70,71 We elaborate this point in the following section. ...
Placebos are often used by clinicians, usually deceptively and with little rationale or evidence of benefit, making their use ethically problematic. In contrast with their typical current use, a provocative line of research suggests that placebos can be intentionally exploited to extend analgesic therapeutic effects. Is it possible to extend the effects of drug treatments by interspersing placebos? We reviewed a database of placebo studies, searching for studies that indicate that placebos given after repeated administration of active treatments acquire medication-like effects. We found a total of 22studies in both animals and humans hinting of evidence that placebos may work as a sort of dose extender of active painkillers. Wherever effective in relieving clinical pain, such placebo use would offer several advantages. First, extending the effects of a painkiller through the use of placebos may reduce total drug intake and side effects. Second, dose-extending placebos may decrease patient dependence. Third, using placebos along with active medication, for part of the course of treatment, should limit dose escalation and lower costs. Importantly, provided that nondisclosure is pre-authorized in the informed consent process and that robust evidence indicates therapeutic benefit comparable to that of standard full-dose therapeutic regimens, introducing dose-extending placebos into the clinical arsenal should be considered. This novel prospect of placebo use has the potential to change our general thinking about painkiller treatments, the typical regimens of painkiller applications, and the ways in which treatments are evaluated.
... Full disclosure of the placebo and open label usage during treatments did not reduce the reported effectiveness. It was concluded that changes in parenting styles and behaviour might have contributed to the positive outcome (Sandler, Glesne & Geller, 2008). ...
... These findings could relate to Sandler, Glesne and Geller's (2008) study in which they attributed treatment benefits of open label placebo drug treatments to changes in parenting style. Therefore, the qualitative accounts of experiences of medication use in children may offer further insight into the active agent or causal factor in medication use. ...
... The majority of parents reported treatment benefits and expressed supportive attitudes towards the CPDR treatment. 21 A majority of the children found the placebo to be useful. An additional provocative finding is that disclosing the true nature of the placebo did not appear to negate the placebo's effectiveness. ...
... Our published data on the qualitative aspects of the study show that the placebo dose reduction treatment had a high level of acceptability to children and their parents. 21 A comparison of retention of subjects in recent ADHD clinical trials shows that our rate of attrition (approximately 25%) is similar or lower than most. For example, in a recent trial of extended-release guanfacine, 113 of 324 (35%) did not complete the study. ...
This study examined if pairing a placebo with stimulant medication produces a placebo response that allows children with attention-deficit hyperactivity disorder (ADHD) to be maintained on a lower dose of stimulant medication. The primary aim was to determine the efficacy, side effects, and acceptability of a novel conditioned placebo dose reduction procedure.
Participants included 99 children ages 6 to 12 years with ADHD. After an initial double-blind dose finding to identify optimal dose of mixed amphetamine salts, subjects were randomly assigned to 1 of 3 treatments of 8-week duration: (a) conditioned placebo dose reduction condition (50% reduced dose/placebo [RD/P]) or (b) a dose reduction only condition (RD) or (c) a no reduction condition (full dose). The innovative conditioned placebo dose reduction procedure involved daily pairing of mixed amphetamine salts dose with a visually distinctive placebo capsule administered in open label, with full disclosure of placebo use to subjects and parents.
Seventy children completed the study. There were no differences in subject retention among the 3 groups. Most subjects in the RD/P group remained stable during the treatment phase, whereas most in the RD group deteriorated. There was no difference in control of ADHD symptoms between the RD/P group and the full dose group, and both RD/P and full dose groups showed better ADHD control than the RD group. Treatment emergent side effects were lowest in the RD/P group.
Pairing placebos with stimulant medication elicits a placebo response that allows children with ADHD to be effectively treated on 50% of their optimal stimulant dose.
... Other studies, however, have reported positive effects of OLPs (concerning both effectiveness and acceptability) in children with ADHD and functional abdominal pain. [9][10][11] In those studies, the OLP was administered as an adjunctive treatment to pharmacotherapy. Moreover, in a survey with pediatric patients and their parents, 12 76% of the parents but only 55% of the children reported a positive attitude toward OLP treatment (willingness to take a placebo pill for two weeks to explore if symptom reduction would occur). ...
Background
Open-label placebos (OLPs), honestly prescribed regarding their inert nature, have been associated with positive health-related effects in both children and adults. However, OLPs are not always perceived by laypeople as a viable treatment option.
Methods
A brief online survey with 806 adult participants (age range: 18–75 years; 29% parents) was conducted to identify predictor variables that are associated with the willingness to take an OLP pill (criterion 1) or to give an OLP to one’s child (criterion 2). The survey covered aspects including the perceived plausibility of the treatment concept for both OLPs and deceptive placebos (DPs), self-reported knowledge about placebos, the expected effectiveness of OLPs in treating emotional/ somatic problems, and attitudes concerning taking pills in general. Multiple hierarchical regressions were carried out.
Results
The expected effectiveness of OLPs in alleviating both emotional and physical ailments and the plausibility of the treatment concepts for both OLPs and DPs significantly predicted the willingness to use OLPs (R² = 0.485). A similar finding was observed when predicting the willingness to administer an OLP to one’s child (R² = 0.443).
Conclusion
Favorable expectations regarding the reduction of emotional and somatic symptoms with OLPs, along with a strong belief in the credibility of placebo mechanisms, play a vital role in influencing the willingness to accept this kind of treatment. These factors can be incorporated into psychoeducational programs.
... The concept of pharmacological conditioning has only been studied in a few clinical populations for specific drugs (e.g., renal transplant, psoriasis, irritable bowel syndrome, attentiondeficit hyperactivity disorder, multiple sclerosis, and Parkinson's disease) [8,18,[22][23][24][25][26]. These studies have provided insight into the optimal learning schedules to maximize pharmacological learning effects. ...
Medication regimens using conditioning via variable reinforcement have shown similar or improved therapeutic effects as full pharmacological treatment, but evidence in patient populations is scarce. This proof-of-principle double-blind randomized clinical trial examined whether treatment effects in recent-onset rheumatoid arthritis (RA) can be optimized through pharmacological conditioning. After four months of standardized treatment (n = 46), patients in clinical remission (n = 19) were randomized to the Control group (C), continuing standardized treatment (n = 8), or the Pharmacological Conditioning (PC) group, receiving variable treatment according to conditioning principles (n = 11). After eight months, treatment was tapered and discontinued linearly (C) or variably (PC). Standard treatment led to large improvements in disease activity and HRQoL in both groups. The groups did not differ in the percentage of drug-free clinical remission obtained after conditioning or continued standard treatment. The PC group did show a larger decrease in self-reported disease activity (Cohen’s d = 0.9) and a smaller increase in TNF-α levels (Cohen’s d = 0.7) than the C group. During all phases, more differences between groups were found for the patients who followed protocol than for the intention-to-treat sample. Although the results are not conclusive, pharmacological conditioning may have some advantages in terms of disease progression and stability, especially during the conditioning phase, compared with standard clinical treatment. The effects may be particularly beneficial for patients who show a good initial response to increased medication dosages.
... One study paired amphetamine salts with placebo pills in pediatric attention deficit hyperactivity disorder and found that patients and their parents had low expectations and were supportive of the approach but mostly neutral or doubtful of its effects. Yet, they nonetheless improved with less medication and C+OLP [48]. The second C+OLP study was a pilot observational study that found patients suffering from acute pain and taking opioids were comfortable with the C+OLP rationale, thereby supporting the feasibility of a future larger trial [49]. ...
Open-label (honestly prescribed) placebos are an ethical way to evoke placebo effects in patients. As part of a mixed-methods study, we conducted in-depth interviews with eight menopausal women who underwent and benefitted from open-label placebo treatment in a randomized-controlled trial of hot flushes. Data were analyzed using Interpretative Phenomenological Analysis. We found that the women had low expectations about the placebo treatment yet endorsed what they referred to as “hope” and openness to “see what happens”. Recording hot flushes via the symptom diary was viewed as a valuable opportunity for self-examination and appraising outcomes. Receiving relief from the placebo treatment empowered women and enhanced their sense of control and agency. In summary, participants’ initial openness towards placebos, their hopes to get better, monitoring symptoms closely, and taking the initiative to address symptoms were components of a positive open-label placebo experience.
... 26,29,97,123 A growing body of literature is focusing on how the positive effects that can be reached by using placebo effects can be optimized for use in clinical practice. 2,39,58,102,103 Much less attention has been paid to the question on how to prevent, minimize, or extinguish negative expectations by means of the nocebo effect in clinical practice. However, since negative or nocebo expectations (eg, "The pain will worsen," "I always react hypersensitive to medication") have shown even stronger effects than positive or placebo expectations, possibly due to the evolutionary determined bias for negative threatening information, looking into ways to diminish the nocebo effect is highly relevant. ...
Nocebo effects, such as side effects due to negative expectations regarding the pain treatment, are a concern for health care providers and come with significant costs. This narrative review focuses on underlying mechanisms and possible factors that contribute to the susceptibility to the nocebo effect on pain and related outcomes and suggests strategies that can prevent, minimize, or extinguish nocebo effects in clinical settings. Nocebo effects are the result of psychological (eg, conditioning, verbal suggestions, and observational learning) and neurobiological (eg, cholecystokinin and dopamine regulation) mechanisms. Evidence from clinical and experimental studies lead to various recommendations and strategies to alter the nocebo effect in order to optimize pain treatments, such as providing patients with enhanced information, optimizing patient-physician communication and relationships, and offering psychoeducation on coping skills in order to manage patient expectations. The current literature from both clinical and experimental studies provides a better understanding of the nocebo effect and possible factors that modulate its strength on treatment outcomes. This allows for the development of evidence-based strategies aimed at the prevention, minimization, and treatment of the nocebo effect in pain conditions and possible other somatic disorders.
... Likewise, partial reinforcement strategies have been suggested as a placebo-controlled dose reduction strategy, describing a procedure by which a certain amount of a pharmacological treatment is replaced by an inert placebo while maintaining a treatment's efficacy (7,133). Such strategies have been successfully tested in placebo analgesia (35,101), in reducing glucocorticoid doses and symptoms in patients with psoriasis (22), in lowering the dose of medication by 50% in chronic insomnia (373,374), and in enabling children with attention-deficit hyperactivity disorder to be treated effectively with a lower dose of stimulant medication (401). An example for applying placebo-controlled dose reduction strategies is given in FIGURE 8, de-picting a "medication-placebo pack" for learned immune or endocrine responses. ...
The phenomenon of behaviorally conditioned immunological and neuroendocrine responses has been investigated for the past 100 years. The observation that peripheral immune functions can be modified by associative learning processes was first reported and investigated by Ivan Petrovic Pavlov and his co-workers. Their work later fell into oblivion, also because so little was known about the immune system's function and even less about the underlying mechanisms of how learning, a central nervous system activity, could affect peripheral immune responses. This phenomenon was re-discovered 45 years ago as one of the most fascinating examples of the reciprocal functional interaction between behavior, the brain, and peripheral immune functions, and it established psychoneuroimmunology as a new research field. Relying on growing knowledge about efferent and afferent communication pathways between the brain, neuroendocrine system, primary and secondary immune organs, and immunocompetent cells, experimental animal studies demonstrate that cellular and humoral immune and neuroendocrine functions can be suppressed or activated via distinct associative learning protocols. These (from the classical perspective) learned immune responses are clinically relevant, since they affect the development and progression of immune-related diseases and, more importantly, are also inducible in humans. The increased knowledge about the neuropsychological machinery steering learning and memory processes together with recent insight into the mechanisms mediating placebo responses provides fascinating perspectives to exploit these learned immune and neuroendocrine responses as supportive therapies, the aim being to reduce the amount of medication required, diminishing unwanted drug side effects while maximizing the therapeutic effect for the patient's benefit.
... The up to now only study of dose-extending OLP has been conducted with children diagnosed with attention deficit hyperactivity disorder (ADHD), which enabled the same benefits while reducing adverse events. Supplementary interviews indicated a high acceptance of OLP among parents [92]. Comparably, a telephone survey study in the general population has found that over 50% of the participants regarded OLP administration as ethical and would consider using OLP if recommended by their physician [66]. ...
Background:
Beneficial effects of placebos are high in double-blind hot flush trials. Studies in various conditions suggest that honestly prescribed placebos may elicit symptom improvement.
Objective:
To determine whether open label placebo (OLP) treatment is efficacious in alleviating hot flushes among peri- and postmenopausal women.
Methods/design:
In this assessor-blinded, randomized-controlled trial, n = 100 women experiencing five or more daily hot flushes of at least moderate severity and bothersomeness are assigned 1:1 to a 4-week OLP treatment or no treatment. To explore the duration and maintenance of placebo effects, the OLP group is randomized a second time to either discontinue or continue the OLP treatment for another 4 weeks. All participants receive a briefing about placebo effects and study visits at baseline, post-treatment (4 weeks), and follow-up (8 weeks, OLP group only). Qualitative interviews about subjective experiences with the OLP treatment are conducted. Primary outcomes are differences between the OLP and the no-treatment group in the hot flush composite score (frequency × severity), and bothersomeness of hot flushes as assessed with the Hot Flush Rating Scale at post-treatment. Secondary outcomes include hot flush frequency, health-related quality of life, global improvement, and the number of responders at post-treatment. Data are analyzed by fitting (generalized) linear mixed models. An exploratory analysis of maintenance and duration is performed including follow-up data.
Discussion:
This trial will contribute to the evaluation of OLP treatments in clinical practice and further our understanding about the magnitude of placebo effects in hot flush treatments.
Trial registration:
Clinicaltrials.gov, NCT03838523 . Retrospectively registered on February 12th, 2019. The first patient was enrolled on October 10th, 2018.
... This is counterintuitive since placebos supposedly work because people believe they do, but (presumably) knowing a treatment is a mere sugar pill makes it difficult to believe they will work. In spite of the lack of intuitive appeal, numerous studies have demonstrated that deception may not be needed to elicit placebo effects and have also demonstrated potential effectiveness at improving significant clinical outcomes in patients with irritable bowel syndrome (IBS) (Kaptchuk et al., 2010), chronic low back pain (Carvalho et al., 2016), depression (Park & Covi, 1965), attention-deficit hyperactivity disorder (ADHD) (Sandler, Glesne, & Geller, 2008), rhinitis (Schaefer, Harke, & Denke, 2016), and cancer-related fatigue (Hoenemeyer, Kaptchuk, Mehta, & Fontaine, 2018). Park and Covi (1965) were the first to attempt we are aware of to test the apparent paradoxical effect of open-label placebos in patients suffering from a range of anxiety symptoms (Park & Covi, 1965). ...
Scientific research indicates that open-label and dose-extending placebos (that patients know are placebos) can elicit behavioral, biological, and clinical outcome changes. In this chapter, we present the state-of-the-art evidence and ethical considerations about open-label and dose-extending placebos, discussing the perspective of giving placebos with a rational, as dose extension of active drugs, or expectancy boosters. Previous comprehensive reviews of placebo use have considered how to harness placebo effects in medicine and the need to focus on elements of the clinical encounter as well as patient-clinician relations. Here, we illustrate the similarities and differences between standard (deceptive) placebos, open-label placebos and dose-extending placebos. We conclude that placebos without deception would override ethical barriers to their clinical use. This paves the way to future large-scale, pragmatic randomized trials that investigate the potential of ethical open-label and dose-extending placebos to improve patients' outcomes, and reduce side effects.
... It is a systematic, monitored "experiment" for parents who are wary or distrustful of ADHD pharmacotherapy, and it has notable benefi ts. 18 It is also useful for teenagers who are reluctant to use medicine to treat symptoms. It arrives at optimal treatment in a timely manner, usually about 4 to 5 weeks. ...
In today's changing medical climate, physicians need to treat attention-defi cit/hyperactivity disorder (ADHD) better and more cost-effectively. The authors review recommendations supported by recent research and offer simple practices that integrate medicine and behavioral health for patients with ADHD.
... 36 Thus, parental education might result in a preference for placebo over pharmacotherapy owing to potential placebo effectiveness and decreased use of pharmacologic agents with potential side effects. 37 Understanding how parents weigh the risks and benefits related to placebo may be central to pediatrics. Within the field of pediatric research, there is a significant need for placebo-controlled data, 11-15 and within the pediatric clinic, the need for parental support for noninvasive interventions and minimal risk interventions is also important. ...
Objective:
To assess parental attitudes regarding placebo use in pediatric randomized controlled trials and clinical care.
Study design:
Parents with children under age 18 years living in the US completed and submitted an online survey between September and November 2014.
Results:
Among all 1300 participants, 1000 (76.9%; 538 mothers and 462 fathers) met the study inclusion criteria. The majority of surveyed parents considered the use of placebos acceptable in some pediatric care situations (86%) and some pediatric trials (91.5%), whereas only 5.7% of parents found the use of placebos in children always unacceptable. The clinical use of placebo was considered acceptable by a majority of parents for only 7 (mostly psychological) of the 17 conditions presented. Respondents' judgment about acceptability was influenced by the doctors' opinions about the therapeutic benefits of placebo treatment, the conditions for pediatric placebo use, transparency, safety, and purity of placebos.
Conclusion:
Most surveyed parents accepted the idea of using placebos in pediatric trials and within the clinic for some conditions without the practice of deception and with the creation of guidelines for ethical and safe use. This study suggests a need to reconsider pediatric trial design and clinical therapy in the light of generally positive parental support of appropriate placebo use.
... A contagem de leucócitos foi avaliada após a ingestão do xarope apenas, não mais pareado ao tratamento endovenoso, e oito dos dez pacientes mostraram redução nos níveis de leucócitos, um efeito que mimetizou o efeito da ciclofosfamida. 12 Respostas placebo condicionadas têm sido mostradas em várias outras situações além daquelas envolvendo o sistema imune, como em casos de depressão, ansiedade, dor 13,1 déficit de atenção e hiperatividade, [14][15][16] psoríase 17 e doença de Parkinson. 18 A capacidade de um estímulo condicionado previamente associado a um estímulo incondicionado levar à resposta original explica parcialmente a resposta condicionada em humanos. ...
Placebo é definido em termos farmacológicos como uma substância inerte, sem propriedades farmacológicas intrínsecas. No entanto, essa definição é superficial, visto que o placebo pode gerar efeitos terapêuticos que dependem de diversos fatores como palavras, rituais, símbolos e significados que acompanham seu uso. Assim, o efeito placebo não diz respeito apenas a uma substância, mas, envolve fatores cognitivos, genéticos e mecanismos de aprendizagem implícita e explícita. Nessa revisão nós abordamos os aspectos gerais do efeito placebo apoiados em diversos estudos com diferentes enfoques, visando uma melhor compreensão desse fenômeno que pode se somar ao tratamento ativo e otimizar os resultados na prática médica.
Placebo is pharmacologically defined as an inert substance, with nointrinsic pharmacological properties. However, this is a superficial definition, since placebo may trigger therapeutic effects and its effectiveness depends on various factors such as words, rituals, symbols and meanings following its use. Thus, placebo effect does not refer just to the substance, but it also involves cognitive and genetic factors and learning mechanisms. Here, we review general aspects of the placebo effect supported by several studies with different approaches, to better understand this phenomenon which may contribute to active treatment as well as optimize the results in the clinical practice.
... dry mouth, drowsiness, low sex drive) make it a particularly potent placebo: individuals expect that they are receiving 'strong' medication, which somehow triggers palliative expectancy effects (Kirsch 2009); in the case of electroconvulsive therapy it has been hypothesised that the " theatre " of the intervention, the attention given to the patient, the side effects (including headaches and memory loss), the patient's belief in the effectiveness of the treatment (Blease 2013a, b) may trigger beneficial effects. In addition, new research also appears to challenge the assumption that placebos necessitate deception: recent 'open placebo' research purports to show that disclosing to patients that they are receiving a placebo does not diminish the placebo effect (Park and Covi 1965; Sandler et al. 2008 Sandler et al. , 2010 Kaptchuk et al. 2010; Kelley et al. 2012). These studies used placebo 'sugar pills' and, (for example, in the Kapthcuk study, 2010) patients were informed that they were being given " placebo pills made of an inert substance, like sugar pills, that have been shown in clinical studies to produce significant improvement in IBS symptoms through mind-body self-healing processes. ...
The study of paternalism arguably becomes most penetrating when the discussion moves to authentic case studies. In the medical setting, paternalism was – until recently – the sine qua non of professional excellence. Physicians were guided by the principle of therapeutic privilege: a physician’s knowledge and training, it was gauged, trumped the right to patient choice. Nowadays in (Western countries) the medical profession eschews these ethical norms: patient autonomy and choice are now (in codified form, at least) principles to which physicians must legally adhere.
... Potential value also lay in providing evidence of acceptability of an effective, but controversial, intervention. 61 A subset of articles presented findings on feasibility and acceptability as part of a broader 'process evaluation' that sought to capture and evaluate a range of contextual and behavioural issues relating to SYSTEMATIC MAPPING REVIEW OF PUBLISHED QUALITATIVE RESEARCH UNDERTAKEN WITH SPECIFIC RCTS USA/ Madagascar Pilot RCT of the effectiveness of continuous diaphragm use amongst low-income women highly exposed to STIs in Madagascar (DD) ...
Background:
Researchers sometimes undertake qualitative research with randomised controlled trials (RCTs) of health interventions.
Objectives:
To systematically explore how qualitative research is being used with trials and identify ways of maximising its value to the trial aim of providing evidence of effectiveness of health interventions.
Design:
A sequential mixed methods study with four components.
Methods:
(1) Database search of peer-reviewed journals between January 2008 and September 2010 for articles reporting the qualitative research undertaken with specific trials, (2) systematic search of database of registered trials to identify studies combining qualitative research and trials, (3) survey of 200 lead investigators of trials with no apparent qualitative research and (4) semistructured telephone interviews with 18 researchers purposively sampled from the first three methods.
Results:
Qualitative research was undertaken with at least 12% of trials. A large number of articles reporting qualitative research undertaken with trials (n=296) were published between 2008 and 2010. A total of 28% (82/296) of articles reported qualitative research undertaken at the pre-trial stage and around one-quarter concerned drugs or devices. The articles focused on 22 aspects of the trial within five broad categories. Some focused on more than one aspect of the trial, totalling 356 examples. The qualitative research focused on the intervention being trialled (71%, 254/356), the design and conduct of the trial (15%, 54/356), the outcomes of the trial (1%, 5/356), the measures used in the trial (3%, 10/356), and the health condition in the trial (9%, 33/356). The potential value of the qualitative research to the trial endeavour included improving the external validity of trials and facilitating interpretation of trial findings. This value could be maximised by using qualitative research more at the pre-trial stage and reporting findings with explicit attention to the implications for the trial endeavour. During interviews, three models of study were identified: qualitative research as peripheral to the trial, qualitative research as an 'add-on' to the trial and a study with qualitative research and trial as essential components, with the third model offering more opportunity to maximise the value of the qualitative research. Interviewees valued the use of qualitative research with trials and identified team structures and wider structural issues which gave more value to the trial than the qualitative research as barriers to maximising the value of the qualitative research.
Conclusion:
A large number of articles were published between 2008 and 2010, addressing a wide range of aspects of trials. There were examples of this research affecting the trial by facilitating interpretation of trial findings, developing and refining interventions for testing in the trial and changing the measures used in the trial. However, researchers were not necessarily maximising the value of qualitative research undertaken with trials to the endeavour of generating evidence of effectiveness of health interventions. Researchers can maximise value by promoting its use at the pre-trial stage to ensure that the intervention and trial conduct is optimised at the main trial stage, being explicit about the conclusions for the trial endeavour in peer-reviewed journal articles reporting the qualitative research and valuing the contribution of the qualitative research as much as the trial. Future recommendations for researchers include: plan the qualitative research, design and implement studies not trials, use qualitative research at the feasibility and pilot stage of trials, be explicit in publications about the impact of the qualitative research on the trial and implications for the trial endeavour, undertake in-depth qualitative research, allow qualitative research to take a challenging role and develop a learning environment around the use of qualitative research and trials.
Funding:
This project was funded by the Medical Research Council (MRC) as part of the MRC-National Institute for Health Research Methodology Research programme.
... That's why it's called a Dose Extender. I won't be surprised when I hear from you and your parents and your teachers that you're able to control your ADHD better [20]. ...
Studies designed to elicit the full strength of the placebo effect differ from those in which the placebo effect represents a nuisance factor to be accounted for in order to establish the efficacy of a treatment. In the latter, informed consent is the rule; in the first, while consent may be informed in some narrow sense of the word, deception is common. However, the trickery of placebo experimentation goes beyond straightforward lies to include the use of crafty ambiguities, half-truths, and deliberate omissions in scripts read to the subjects of these studies. As words come to resemble therapeutic agents in their own right, it is only to be expected that researchers would methodically exploit verbal effects to evoke the responses they are looking for. Even experiments in which placebo is disclosed as placebo have used language in leading and misleading ways. Such studies are conducted in the hope of yielding results that might translate into clinical practice, but it should be noted that good clinical practice has a placebo value of its own - that is, confers a benefit over and beyond the specific effects of treatments - even if nothing like a sugar pill is administered.
... The placebo treatment was described to both parents and children transparently. They were informed that placebos consisted of a pill with no medication in it, thus overcoming the ethical problem of deception and consistent with requirements of informed consent [51,52]. ...
Laboratory research recently has greatly enhanced the understanding of placebo and nocebo effects by identifying specific neuromodulators and brain areas associated with them. However, little progress has been made in translating this knowledge into improved patient care. Here, we discuss the limitations in our knowledge about placebo (and nocebo) effects and the need for translational research with the aim of guiding physicians in maximizing placebo effects and minimizing nocebo effects in their routine clinical practice. We suggest some strategies for how, when and why interventions to promote beneficial placebo responses might be administered in the clinical setting.
Food advertising has become almost ubiquitous in Western societies. In adults as well as in children this omnipresence of food cues has been shown to trigger cravings and overeating, which can lead to overweight or even obesity. This is concerning because obesity is a leading cause of preventable diseases. The planned project aims at reducing craving and overeating in overweight/obese children using a placebo treatment. A total of 80 children (40 girls, 40 boys; aged between 8 and 12 years; body mass index >90th percentile) will take part in the study. A randomized controlled cross-over design will be implemented, which will include four weeks with daily placebo treatment and four weeks without placebo treatment. The placebo will be introduced without deception as an open-label placebo (OLP), that can help to control food cravings. The study will use an app-assisted approach: The children will rate the intensity of their cravings, the occurrence of binge-eating episodes, their emotional state, and placebo usage via a smartphone application. It is expected that the OLP will help the children to reduce cravings and body weight. If effective, this OLP approach could be implemented in weight-control programs for children.
Background:
Pain after spine surgery is difficult to manage, often requiring the use of opioid analgesics. While traditional "deceptive" or concealed placebo has been studied in trials and laboratory experiments, the acceptability and patient experience of taking honestly prescribed placebos, such as "open-label" placebo (non-deceptive placebo), or conditioned placebo (pairing placebo with another active pharmaceutical) is relatively unexamined.
Methods:
Qualitative thematic analysis was performed using semi-structured, post-treatment interviews with spine surgery patients (n = 18) who had received conditioned open-label placebo (COLP) during the first 2-3 weeks after surgery as part of a RCT. Interview transcripts were reviewed by 3 investigators using an immersion/crystallization approach, followed by iterative large-group discussions with additional investigators, to identify, refine, and codify emergent themes.
Results:
Patients' experiences and perceptions of COLP efficacy varied widely. Some emergent themes included the power of the mind over pain, how COLP might provide distraction from or agency over pain, bandwidth required and engagement with COLP, and its modulation of opioid tapering, as well as negative attitudes toward opioids and pill taking in general. Other themes included uncertainty about COLP efficacy, observations of how personality may relate to COLP efficacy, and a recognition of the greater impact of COLP on reduction of opioid use rather than on pain itself. Interestingly, participant uncertainty, disbelief, and skepticism were not necessarily associated with greater opioid consumption or worse pain.
Conclusion:
Participants provided insights into the experience of COLP which may help to guide its future utilization to manage acute pain and tapering from opioids.
Objective
The present systematic review aims to analyze the evidence about the influence of placebo effect on craving and cognitive performance in alcohol, caffeine, and nicotine consumers.
Methods
Relevant studies were identified via Pubmed, Web of Science, and Scopus databases (up to March 2020). Only those papers published between 2009 and 2019 were searched.
Results
Of the 115 preliminary papers, 8 studies of database search and 9 of the manual search were finally included in this review. Findings showed that while alcohol expectancies increased craving, caffeine and nicotine expectancies tend to decrease it. Alcohol expectancies caused similar or slower reaction time when alcohol was not consumed, impairments on inhibitory control (especially after alcohol consumption) and similar post-error slowing. The effect of caffeine and nicotine on reaction time has not been elucidated yet, however, caffeine expectancies have been shown to improve accuracy and the attentional filtering of distracting stimuli.
Conclusions
Alcohol, caffeine, and nicotine expectancies play an important role on craving. Although expectancies produce an effect on cognitive performance, caffeine and nicotine beliefs show an ambiguous impact on reaction time. Only the influence of alcohol expectancies on reaction time has been clarified. Furthermore, caffeine beliefs enhance accuracy.
Children are not being provided with the same opportunities as adults to participate in the medicines research and development (R&D) process. Reticence to accepting children as active participants in research beyond that of clinical trial participants might be due to how researchers view children. // AIM: To examine how professionals associated with medicines R&D construct children and involvement and understand how this affects the uptake of children’s involvement. // METHODS: This multimethod study comprises a systematic analysis of political speeches focusing on children’s medicines regulation, a scoping review of pharmaceutical medicines research presenting children’s views and a discourse analysis of key informant interviews. Bakhtinian discourse analysis is used to examine the explicit and implicit attitudes and ideas surrounding children’s involvement in the context of role theory. Suggested barriers, facilitators and potential opportunities to improve its uptake are presented. // FINDINGS: Children have clear views on medicines that have been reported in peer-reviewed journals, which some researchers find informative and valuable. Children are mainly constructed as passive actors, rarely considered beyond the role of clinical trial participants, and involvement as problematic and resource intensive. However, participants suggest that children’s insight could prove valuable for generating new ideas, improving research designs, and understanding the medicine taking experience. Findings from the interviews suggest that children can be constructed differently by the same speaker, depending on the speaker’s assumed role from a cast of identified salient roles - the dramatis intrapersonæ. This has implications for how children’s involvement is perceived and adopted. A conceptual framework of factors affecting children’s involvement is presented. // CONCLUSIONS: Children’s involvement in early-stage medicines R&D can only be successful if there are fundamental changes in the mind-set of researchers regarding children’s ability to actively contribute. This requires improved resources and education for researchers, and encouragement for those who develop medicines to talk directly with sick children.
Objectives@ placebo effects can be clinically meaningful but are seldom fully exploited in clinical practice. This review aimed to facilitate translational research by producing a taxonomy of techniques that could augment placebo analgesia in clinical practice.
Design: literature review and survey.
Methods: we systematically analysed methods which could plausibly be used to elicit placebo effects in 169 clinical and laboratory-based studies involving non-malignant pain, drawn from 7 systematic reviews. In a validation exercise we surveyed 33 leading placebo researchers (M=12 years’ research experience, SD=9.8), who were asked to comment on and add to the draft taxonomy derived from the literature.
Results: the final taxonomy defines 30 procedures that may contribute to placebo effects in clinical and experimental research, proposes 60 possible clinical applications, and classifies procedures into 5 domains: the Patient’s Characteristics and Belief (5 procedures and 11 clinical applications); the Practitioner’s Characteristics and Beliefs (2 procedures and 4 clinical applications); the Healthcare Setting (8 procedures and 13 clinical applications); Treatment Characteristics (8 procedures and 14 clinical applications); and the Patient-Practitioner Interaction (7 procedures and 18 clinical applications).
Conclusions: the taxonomy provides a preliminary and novel tool with potential to guide translational research aiming to harness placebo effects for patient benefit in practice.<br/
The placebo effect refers to a therapeutic benefit arising as a rule from the expectation of benefit itself, not from the actual composition of a treatment. Thus patients who are told they are receiving a painkiller but actually get saline solution can still enjoy an analgesic effect owing to the evocative power of the medical ritual. Note that this model doesn’t entail that the benefit of the treatment is illusory. On the contrary, placebos can stimulate the release of the body’s opioids, an effect that can be blocked by the opioid antagonist, naloxone. Correspondingly, the nocebo effect refers to a harm arising from the expectation of harm, as when people led to believe they have suffered a toxic exposure fall ill. While the nocebo effect is ethically difficult to study and much of the knowledge about it derives from observation and accidental findings rather than experiment, both the placebo and nocebo effect appear to operate largely through the power of suggestive messages, enhanced in many cases by theatrical effects. Among the messages capable of springing to life in our minds and bodies are those that propel the process of medicalization. “Telling people they are sick undoubtedly has a strong negative placebo effect.”1
Als Störgröße in klinischen Interventionsstudien sind Placebos mittlerweile gut untersucht. Allerdings können Placeboeffekte auch gezielt (offen) therapeutisch genutzt werden, wenn man weiß, unter welchen kontextuellen Bedingungen sie eintreten.
Prior to the development of the pharmaceutical industry and the advocacy of evidence based medicine in the late 20th century, placebo treatments were commonly used by physicians. In current clinical practice, neither a physician's confidence in the efficacy of a specific treatment nor his personal ethical norms are any longer sufficient to initiate a given therapy. We will discuss whether placebo treatments can be ethically used in clinical practice as an alternative to standard therapy, and propose an innovative conceptualization of the factors involved in the exclusion of placebo treatments from the clinical setting. Patient-related ethical and interpersonal arguments and physician-related legal and ideological arguments concerning placebo usage are presented. We describe current use of placebo treatments in the healthcare system and suggest that placebo therapy thrives and that its therapeutic efficacy is widely acknowledged. There is currently "underground" use of placebo medication, open label placebo trials, and innovative approaches to informed consent to facilitate ethical prescription of placebo therapy. Finally, using the specific example of treatment for depression, we demonstrate how the arguments against placebo use might be undermined, to retrieve the legitimacy of placebo therapy.
Recent substantial laboratory and theoretical research hints for different learning mechanisms regulating the formation of placebo and nocebo responses. Moreover, psychological and biological variants may play a role as modulators of learning mechanisms underlying placebo and nocebo responses. In this chapter, we present pioneering and recent human and nonhuman research that has impressively increased our knowledge of learning mechanisms in the context of placebo and nocebo effects across different physiological processes and pathological conditions.
Of more than 155,000 PUBMED citations found with the search term "placebo" only about 9,000 (5.8%) included the terms "children" or "adolescents". When all these papers were screened, only about 2,000 of them investigated the placebo effects per se, and of those only about 50 (2.5%) discussed the placebo effect in children and adolescents. In this narrative review we explore four aspects of the placebo response in children and adolescents: 1) the legal and ethical limitations and restrictions for the inclusion of children in clinical trials as well as in experimental (placebo) research that may explain the poor knowledge base; 2) the question whether or not the placebo effect is larger in children and adolescents as compared with adults; 3) whether the mechanisms underlying the placebo effect are similar between children and adults; and 4) whether mediators and moderators of the placebo effect are comparable between children and adults. We finally discuss some of the consequences from the current placebo research in adults that may affect both experimental and clinical research in children and adolescents.Pediatric Research (2013); doi:10.1038/pr.2013.66.
Objectives:(1) Compare effectiveness and adverse events of interventions (pharmacological, psychosocial, or behavioral, and the combination of pharmacological and psychosocial or behavioral interventions) for preschoolers at high risk for attention deficit hyperactivity disorder (ADHD); (2) compare long-term effectiveness and adverse events of interventions for ADHD among persons of all ages; and (3) describe how identification and treatment for ADHD vary by geography, time period, provider type, and sociodemographic characteristics, compared with endemic prevalence.
Data Sources:MEDLINE®, Cochrane CENTRAL, EMBASE, PsycInfo, and ERIC (Education Resources Information Center) were searched from 1980 to May 31, 2010. Reference lists of included studies and gray literature were searched manually.
Review Methods:Reviewers applied preset criteria to screen all citations. Decisions required agreement between two independent reviewers, with disagreements regarding inclusion or exclusion resolved by a third. The Effective Public Health Practice Project (EPHPP) process was used to evaluate internal validity of publications regarding interventions for preschoolers at high risk of ADHD and long-term outcomes following interventions for ADHD in persons of all ages. Overall strength of the evidence (SOE) was assessed using the GRADE approach, accounting for risk of bias and study design, consistency of results, directness of evidence, and degree of certainty regarding outcomes of interest.
Results:Of included studies, only a subset could be pooled statistically using meta-analytic techniques. For the first objective, we rated as “good” quality eight studies of parent behavior training (PBT) with 424 participants. These demonstrated high SOE for improving child behavior (standardized mean difference [SMD] = −0.68; 95-percent confidence interval [CI], −0.88 to −0.47). A single “good” quality study of methylphenidate (MPH) with 114 preschool children provided low SOE for improving child behavior (SMD = −0.83; 95-percent CI, −1.21 to −0.44). Adverse effects were present for preschool children treated with MPH; adverse effects were not mentioned for PBT.
For the second objective, the majority of studies were open extension trials without continuation of untreated comparison groups. Evidence from the single “good” quality study of MPH demonstrated low SOE for reduction of symptoms, with SMD = −0.54 (95-percent CI, −0.79 to −0.29). Evidence from the single “good” quality study of atomoxetine demonstrated low SOE for reduction of symptoms, with SMD = −0.40 (95-percent CI, −0.61 to −0.18). Evidence from the single “good” quality study of combined psychostimulant medication with behavioral/psychosocial interventions provided low SOE, with SMD = −0.70 (95-percent CI, −0.95 to −0.46). Safety reports for pharmacological interventions derived from observational studies on uncontrolled extensions of clinical trials, as well as from administrative databases, provided inconclusive evidence for growth, cerebrovascular, and cardiac adverse effects. Evidence that psychostimulant use in childhood improves long-term outcomes was inconclusive.
For the third objective, a discussion of contextual issues and factors relating to underlying prevalence and rates of diagnosis and treatment was included. Population-based data were relatively scarce and lacked uniform methods and settings, which interfered with interpretation. The available evidence suggested that underlying prevalence of ADHD varies less than rates of diagnosis and treatment. Patterns of diagnosis and treatment appeared to be associated with such factors as locale, time period, and patient or provider characteristics.
Conclusions:The SOE for PBT as the first-line intervention for improved behavior among preschoolers at risk for ADHD was high, while the SOE for methylphenidate for improved behavior among preschoolers was low. Evidence regarding long-term outcomes following interventions for ADHD was sparse among persons of all ages, and therefore inconclusive, with one exception. Primary school–age children, mostly boys with ADHD combined type, showed improvements in symptomatic behavior maintained for 12 to 14 months using pharmacological agents, specifically methylphenidate medication management or atomoxetine. Other subgroups, interventions, and long-term outcomes were under-researched. Evidence regarding large-scale patterns of diagnosis and treatment compared with endemic rates of disorder was inconclusive.
Participants in placebo-controlled clinical trials give informed consent to be randomized to verum or placebo. However, researchers rarely tell participants which treatment they actually received. We interviewed 4 participants in a trial of acupuncture for irritable bowel syndrome before, during, and after they received a course of placebo treatments over 6 weeks. During the final interview, we informed participants that they had received a course of placebo treatments. We used an idiographic phenomenological approach based on the Sheffield School to describe each participant’s experiences of being blinded to and then debriefed to placebo allocation. The participants’ experiences of blinding and debriefing were embodied, related to their goals in undertaking the study, and social (e.g., embedded in trusting and valued relationships with acupuncturists). We suggest ways in which debriefing to placebo allocation can be managed sensitively to facilitate positive outcomes for participants.
Much literature has been written in the field of child psychiatry regarding the placebo as a tool to test drug efficacy in clinical trials, but quite little regarding the placebo effect itself or its clinical use in child psychiatry. In this article, we aim to critically review the literature regarding the placebo effect in children and adolescents with mental disorders, focusing especially on factors influencing the placebo effect and how they may influence the interpretation of clinical trials. The placebo effect seems to be more marked in children than adults, and particularly in children and adolescents with depression, although it is pervasive across ages and is present in non-psychiatric conditions as well. The use of a placebo in clinical trials as a comparator with drugs that have moderate efficacy at most makes it difficult to obtain positive results, and much effort is needed to design very high quality clinical trials that may overcome the limitations of using a placebo. In addition, the placebo effect across ages and clinical conditions must be tested directly (compared with no treatment whenever possible), in order to characterise which placebos work for what and to determine their use in clinical settings.
Physicians commonly recommend 'placebo treatments', which are not believed to have specific efficacy for the patient's condition. Motivations for placebo treatments include complying with patient expectations and promoting a placebo effect. In this article, we focus on two key empirical questions that must be addressed in order to assess the ethical legitimacy of placebo treatments in clinical practice: 1) do placebo treatments have the potential to produce clinically significant benefit? and 2) can placebo treatments be effective in promoting a therapeutic placebo response without the use of deception? We examine evidence from clinical trials and laboratory experiments bearing on these two questions. The conclusion is reached that based on currently available evidence, it is premature to judge whether placebo treatments are ethically justifiable, with the possible exception of acupuncture for pain relief.
This study examined short-term efficacy, side effects and acceptability of a placebo treatment procedure designed to maintain children with attention deficit hyperactivity disorder (ADHD) on 50% of their usual stimulant dose.
An open-label prospective crossover trial was conducted in 26 children with ADHD, ages 7-15 years, stable on stimulant therapy, followed at a community-based developmental paediatrics ADHD clinic. Subjects were randomly assigned to one of two orders of experimental conditions: (1) baseline (100%) dose (1 week), then 50% dose (1 week), then 50% dose + placebo (1 week), or (2) baseline (100%), then 50% dose + placebo, then 50% dose. The inert nature of the placebo was fully disclosed to parent and child. Treatment was open-label for child, parents and physician, but single blind for teachers. Main outcome measures included weekly IOWA Conners parent and teacher rating scales, the Pittsburgh side effects rating scale (PSERS) and the Clinical Global Impressions (CGI) scale.
Parent IOWA showed ADHD behaviour tended to remain the same when the dose of stimulant medication was reduced with placebo but to deteriorate when the dose was reduced without placebo. There were no significant differences between conditions on the Teacher IOWA. PSERS scores were higher at baseline than on 50% dose. On the CGI, there was a significant difference (P = 0.004) between the 50% dose and the 50% + placebo conditions. Individual subject analysis showed that eight subjects met criteria for responder.
Results indicate that the open-label placebo treatment was acceptable and efficacious in the short term for some children.
Background: Intent-to-treat analyses of the study revealed that medication management, alone or combined with intensive behavioral treatment, was superior to behavioral treatment and community care in reducing attention-deficit/hyperactivity disorder (ADHD) symptoms; but only combined treatment showed consistently greater benefit than community care across other outcome domains (disruptive and internalizing symptoms, achievement, parent-child relations and social skills). We examine response patterns in subgroups defined by baseline variables (moderators) or variables related to treatment implementation (mediators).
Methods: We reconducted random-effects regression (RR) analyses, adding factors defined by moderators (ses, prior medication use, comorbid disruptive or anxiety disorder, and public assistance) and a mediator (treatment acceptance/attendance).
Results: Study outcomes (N = 579) were upheld in most moderator subgroups (boys and girls, children with and without prior medication, children with and without co-morbid disruptive disorders). Comorbid anxiety disorder did moderate outcome. in participants without anxiety, results paralleled intent-to-treat findings. For those with anxiety disorders, however, behavioral treatment yielded significantly better outcomes than community care (and was no longer statistically different from medication management and combined treatment) regarding ADHD-related and internalizing symptoms. In families receiving public assistance, medication management yielded decreased closeness in parent-child interactions, and combined treatment yielded relatively greater benefits for teacher-reported social skills. In families with high treatment acceptance/attendance, intent-to-treat results were upheld. Acceptance/attendance was particularly important for medication treatments. Finally, two thirds of children given community care received stimulants. Behavioral treatment did not significantly differ from, but medication management was superior to, this subgroup.
Conclusions: Exploratory analyses revealed that our study (the Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder [MTA]) re suits were confirmed across most baseline variables and treatment acceptance/attendance. Tn children with ADHD plus anxiety, behavioral treatment surpassed community. care and approached medication-based treatments regarding parent-reported ADHD symptoms.
Although childhood hyperactivity is a common, serious, and treatable disorder, most affected children in Britain do not receive effective treatment.
To investigate the views that parents and GPs hold about hyperactivity, and to explore how far these views, and clashes between these views, influence access to services.
Qualitative study making use of semi-structured interviews with 10 general practitioners (GPs) and 29 parents of hyperactive children drawn from parents' groups, community services, and specialist clinics.
The views of parents and GPs differed markedly. Parents generally saw severe hyperactivity as a long-lasting, biologically-based problem that needed treatment in its own right and that benefited from diagnosis. Most of the GPs were unsure whether hyperactivity was a medical disorder warranting a label and specific treatment, and often saw it as a passing phase related to family stresses. Parents worried that professionals would blame them for their child's problem, whereas many GPs saw the parent's tendency to medicalise as a way to avoid thinking about their own shortcomings in parenting.
Access to treatment was influenced by the views of parents and GPs, by the clashes between these views, and by each group's perceptions of the other group's beliefs. Clashes between the views of parents and GPs were particularly likely to lead to misunderstandings, dissatisfaction, and lack of access to effective help.
The placebo response is commonly invoked as a factor in the therapeutic relationship between the family physician and the patient, but important recent literature can be difficult for family physicians to access. Coordinated interdisciplinary research into the placebo response as it occurs in primary care settings is lacking. Although there is controversy about the nature and scope of the placebo response, important suggestions are emerging about its psychological mechanisms (expectancy and conditioning) and the biochemical pathways that act as psychosomatic linkages (endorphins, catecholamines and cortisol, psychoneuroimmumunology). The available research justifies interventions by family physicians that maximize the placebo response in everyday patient encounters. These include the sustained partnership approach, working with patients on the narratives they construct to explain illness, listening to patients, providing them with satisfactory explanations, expressing care and concern, and enhancing their sense of control. Notable opportunities exist for family medicine investigators to expand the understanding of this phenomenon.
We provide a new perspective with which to understand what for a half century has been known as the "placebo effect." We argue that, as currently used, the concept includes much that has nothing to do with placebos, confusing the most interesting and important aspects of the phenomenon. We propose a new way to understand those aspects of medical care, plus a broad range of additional human experiences, by focusing on the idea of "meaning," to which people, when they are sick, often respond. We review several of the many areas in medicine in which meaning affects illness or healing and introduce the idea of the "meaning response." We suggest that use of this formulation, rather than the fixation on inert placebos, will probably lead to far greater insight into how treatment works and perhaps to real improvements in human well-being.
The reinforcing effects of drugs of abuse result from the complex interaction between pharmacological effects and conditioned responses. Here we evaluate how expectation affects the response to the stimulant drug methylphenidate in 25 cocaine abusers. The effects of methylphenidate (0.5 mg/kg, i.v.) on brain glucose metabolism (measured by [18F]deoxyglucose-positron emission tomography) and on its reinforcing effects (self-reports of drug effects) were evaluated in four conditions: (1) expecting placebo and receiving placebo; (2) expecting placebo and receiving methylphenidate; (3) expecting methylphenidate and receiving methylphenidate; (4) expecting methylphenidate and receiving placebo. Methylphenidate increased brain glucose metabolism, and the largest changes were in cerebellum, occipital cortex, and thalamus. The increases in metabolism were approximately 50% larger when methylphenidate was expected than when it was not, and these differences were significant in cerebellum (vermis) and thalamus. In contrast, unexpected methylphenidate induced greater increases in left lateral orbitofrontal cortex than when it was expected. Methylphenidate-induced increases in self-reports of "high" were also approximately 50% greater when subjects expected to receive it than when they did not and were significantly correlated with the metabolic increases in thalamus but not in cerebellum. These findings provide evidence that expectation amplifies the effects of methylphenidate in brain and its reinforcing effects. They also suggest that the thalamus, a region involved with conditioned responses, may mediate the enhancement of the reinforcing effects of methylphenidate by expectation and that the orbitofrontal cortex mediates the response to unexpected reinforcement. The enhanced cerebellar activation with expectation may reflect conditioned responses that are not linked to conscious responses.
Fathers tend to be largely absent from research and clinical settings related to attention-deficit/hyperactivity disorder (ADHD), as well as from public forums related to ADHD, such as educational conferences and parent support groups. Because of these absences, little is known about fathers' perspectives on ADHD symptoms, diagnosis, and drug treatment. This article presents findings from a qualitative study involving 39 mothers and 22 fathers of boys with ADHD. In-depth interviews were conducted with participants using a picture-based method that elicited detailed narratives. Results of this study suggest that fathers' perspectives on ADHD behaviors, diagnosis, and drug treatment can be categorized along two dimensions: "reluctant believers" and "tolerant nonbelievers." Across these two dimensions, several related factors are relevant to fathers' perspectives: resistance to a medical framework for understanding their sons' behaviors; identification with the sons' symptomatic behaviors; and resistance to drug treatment with stimulants. These factors may help to explain, in turn, fathers' absences from clinical evaluations of their sons' behaviors. The study affirms the importance of fathers' perspectives to the clinical evaluation and treatment of boys' symptomatic behaviors.
This study describes parents' explanatory models of Attention Deficit Hyperactivity Disorder (ADHD) and examines model variation by child characteristics.
Children with ADHD (N = 182) were identified from a school district population of elementary school students. A reliable coding system was developed for parental responses obtained in ethnographic interviews in order to convert qualitative into numerical data for quantitative analysis.
African-American parents were less likely to connect the school system to ADHD problem identification, expressed fewer worries about ADHD-related school problems, and voiced fewer preferences for school interventions than Caucasian parents, pointing to a potential disconnect with the school system.
More African-American than Caucasian parents were unsure about potential causes of and treatments for ADHD, indicating a need for culturally appropriate parent education approaches.
The frequency and severity of 17 side effects presumably associated with stimulant medication were assessed during a rigorous, triple-blind, placebo-controlled, crossover evaluation of methylphenidate, 0.3 and 0.5 mg/kg twice a day, in 83 children with attention deficit hyperactivity disorder. Side effects were rated by parents and teachers at the end of each weekly drug condition. Three children (3.6%) had side effects that were sufficiently serious to warrant immediate discontinuation of medication. Parent ratings indicated that only the side effects of decreased appetite, insomnia, stomachaches, and headaches increased significantly in frequency and severity during the two active medication doses as compared with the placebo condition. Fewer than half of the children experienced these side effects and among those who did, ratings of mean severity remained in the mild range. Teacher ratings showed little change over drug conditions, except on ratings of staring, sadness, and anxiety, which declined with increasing dose of medication. Surprisingly, a high frequency of these behavior side effects were reported during the placebo condition. Stimulant medication within this therapeutic range, therefore, results in few, generally mild side effects. However, the wide variation in individual responses and the high rate of these behaviors during placebo treatment argue for the systematic monitoring of side effects before and during pediatric trials of stimulant medication.
Objective. To estimate the increased use and the prevalence of methylphenidate (Ritalin) treatment of youth with attention deficit disorder (ADD) during the 1990s.
Design. Using time-trend findings from two large population-based data sources, three pharmaceutical databases, and one physician audit, a best-fit estimate of the usage and the usage trends for methylphenidate treatment over the half decade from 1990 through 1995 was sought.
Setting. Five regions in the United States (US) and the nation as a whole.
Patients. Youths on record as receiving methylphenidate for ADD.
Results. The findings from regional and national databases indicate that on average, there has been a 2.5-fold increase in the prevalence of methylphenidate treatment of youths with ADD between 1990 and 1995. In all, approximately 2.8% (or 1.5 million) of US youths aged 5 to 18 were receiving this medication in mid-1995. The increase in methylphenidate treatment for ADD appears largely related to an increased duration of treatment; more girls, adolescents, and inattentive youths on the medication; and a recently improved public image of this medication treatment.
Conclusion. The database findings presented serve to correct exaggerated media claims of a 6-fold expansion of methylphenidate treatment, although they do not clarify the issue of the appropriateness of this treatment.
This clinical practice guideline provides evidence-based recommendations for the treatment of children diagnosed with attention-deficit/hyperactivity disorder (ADHD). This guideline, the second in a set of policies on this condition, is intended for use by clinicians working in primary care settings. The initiation of treatment requires the accurate establishment of a diagnosis of ADHD; the American Academy of Pediatrics (AAP) clinical practice guideline on diagnosis of children with ADHD1 provides direction in appropriately diagnosing this disorder.
The AAP Committee on Quality Improvement selected a subcommittee composed of primary care and developmental-behavioral pediatricians and other experts in the fields of neurology, psychology, child psychiatry, education, family practice, and epidemiology. The subcommittee partnered with the Agency for Healthcare Research and Quality and the Evidence-based Practice Center at McMaster University, Ontario, Canada, to develop the evidence base of literature on this topic.2 The resulting systematic review, along with other major studies in this area, was used to formulate recommendations for treatment of children with ADHD. The subcommittee also reviewed the multimodal treatment study of children with ADHD3 and the Canadian Coordinating Office for Health Technology Assessment report (CCOHTA).4 Subcommittee decisions were made by consensus where definitive evidence was not available. The subcommittee report underwent extensive review by sections and committees of the AAP as well as by numerous external organizations before approval from the AAP Board of Directors.
The guideline contains the following recommendations for the treatment of a child diagnosed with ADHD:Primary care clinicians should establish a treatment program that recognizes ADHD as a chronic condition.The treating clinician, parents, and child, in collaboration with school personnel, should specify appropriate target outcomes to guide management.The clinician should recommend stimulant medication and/or behavior therapy as appropriate to improve target outcomes in children with ADHD.When the selected management for a child with ADHD has not met target outcomes, clinicians should evaluate the original diagnosis, use of all appropriate treatments, adherence to the treatment plan, and presence of coexisting conditions.The clinician should periodically provide a systematic follow-up for the child with ADHD. Monitoring should be directed to target outcomes and adverse effects, with information gathered from parents, teachers, and the child.
OverviewAttention-deficit/hyperactivity disorder (ADHD) is one of the most common disorders diagnosed in children and adolescents.
The American Psychiatric Association (APA) describes the essential feature as "a persistent pattern of inattention and/or hyperactivity-impulsivity that is more frequent and severe than is typically observed in individuals at a comparable level of development." Terms that have been used to describe children with "distractability, impulsivity, and usually overactivity" include minimal brain dysfunction/damage (MBD), hyperkinetic reaction, and hyperkinesis.ADHD has been surrounded by great controversy involving clinicians, teachers, policymakers, parents, and the media.
The range of opinion regarding the validity of ADHD extends from those who do not believe it exists and regard it as a myth, to those who believe that there is genetic and physiological evidence supporting its existence.Prevalence estimates of ADHD vary according to the methods of ascertainment, diagnostic criteria, informants, and population sampled.
According to the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV), the prevalence of ADHD in school-age children is 3 to 5 percent.
However, prevalence studies using the two previous versions of the DSM (DSM-III and DSM-III-R) in the United States, Canada, United Kingdom, Germany, and New Zealand have shown rates that vary from 1.7 to 16.1 percent. Although it was previously thought that ADHD remitted before or during adolescence, it has been estimated that more than 70 percent of hyperactive children continue to meet criteria for ADHD as adolescents and up to 65 percent as adults.Problems with the diagnosis and treatment of this condition can also arise because approximately 65 percent of ADHD patients may have at least one comorbid disorder in the form of:
Anxiety, communication, mood, conduct, oppositional defiant, and learning disorders.Tourette's syndrome.Subnormal intelligence.ADHD has been associated with impaired academic achievement, rejection by peers, and family resentment and antagonism.
The rich terminology may reflect the broad spectrum and the high frequency with which it is described with other comorbid conditions.There is also variation and controversy around the treatment of ADHD, which often includes stimulant medication.
To reduce inappropriate variation in treatment, major organizations in North America have developed, or are in the process of developing, practice parameters or clinical practice guidelines to guide treatment decisions.In 1997, the Agency for Health Care Policy and Research (AHCPR) charged the McMaster University Evidence-based Practice Center (MU-EPC) with producing an evidence report on the treatment of ADHD. The objectives of this work were to:
Conduct a comprehensive systematic review of the literature on the treatment of ADHD, with input from different groups of stakeholders.Support guideline development initiatives, while building on existing work and focusing on answerable, clinically relevant questions.
Adherence (or compliance) is the extent to which a person's behavior coincides with medical or health advice. Recent evidence indicates that patients who adhere to treatment, even when that treatment is a placebo, have better health outcomes than poorly adherent patients. Based on this evidence, we now believe that the outcomes of treatment are not solely attributable to the specific action of a drug, but may also depend on other nonspecific therapeutic effects. We consider the implications of these findings for the design and interpretation of clinical research as well as for the care of patients.
(Arch Intern Med. 1993;153:1863-1868)
In this chapter, we examine 2 fundamental aspects of stimulant pharmacotherapy for children with attention deficit hyperactivity disorder (ADHD) that seem inextricably enmeshed: its scientific respectability and its widespread notoriety. We begin by examining the empirical justification for stimulant pharmacotherapy. Next, we identify complications and causes for concern, followed by an exploration of current developments in combination treatments. The chapter concludes with an attempt to integrate the science and the rhetoric in a discussion of pharmacotherapy in multiple contexts: child and family systems, professional and institutional forces, and societal trends. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Introduction
THE PLACEBO effect, that is, the effect obtained when a presumably inert substance is given to normal or diseased individuals, has been the object of many studies in the last decade. A considerable amount of attention has been paid to the psychological factors underlying this effect, and many workers in the field would subscribe to what Gliedman et al5 write: "The so-called placebo effect should be looked upon as an epiphenomenon of complicated psychological processes, which are far more important than the disarmingly simple means utilized for its realization."What is the nature of these processes? Kurland13 states that ". . . the placebo reaction is generally accepted to be a manifestation of suggestion . . ."; in this framework, one common assumption is that the patient should believe he is taking an active drug.22 Throughout the vast literature on the placebo effect there is a
Discusses the class of drugs labeled as stimulants, the neural and chemical basis of their psychoactive properties, and their pharmacologic characteristics with respect to treating children with attention deficit hyperactivity disorder (ADHD). The clinical use of 3 primary stimulants (methylphenidate, amphetamine, and pemoline) are described, including the typical clinical titration methods, dose-related effects on behavior and cognition, and the time course of available (approved and marketed) preparations of these drugs. Significant historical events that have affected the literature on stimulant pharmacotherapy are presented. A synthesis of the literature is also provided, based on a "review of reviews" conducted for the US Department of Education. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
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Contenido: Parte I.Cuestiones conceptuales en la investigación cualitativa: Naturaleza de la investigación cualitativa; Temas estratégicos en la investigación cualitativa; Diversidad en la investigación cualitativa: orientaciones teóricas; Aplicaciones cualitativas particulares. Parte II. Diseños cualitativos y recolección de datos: Estudios de diseños cualitativos; Estrategias de trabajo de campo y métodos de observación; Entrevistas cualitativas. Parte III. Análisis, interpretación e informe: Análisis cualitativo e interpretación; Incrementar la calidad y la credibilidad del análisis cualitativo.
To find evidence of classically conditioned placebo effects in a placebo-controlled crossover drug study. Specifically, we tested a prediction of the conditioning model that the placebo response will be greater after drug exposure than before.
Twenty-four patients with mild to moderate essential hypertension and no contraindications to atenolol participated in the study. The study design required randomized assignment to one of three groups: placebo followed by 50 mg atenolol daily, followed by no treatment, each for 1 week; atenolol followed by placebo; and atenolol followed by nothing (to show residual drug effects). Twice-daily blood pressure measurements were made by patients at home; once-weekly measurements of blood pressure and heart rate were made by a research nurse.
Before drug treatment, there were no differences in the antihypertensive responses of patients taking placebo and patients taking nothing (difference, 0.98 mm Hg; 95% confidence interval, -0.98 to 2.93). After atenolol treatment, placebo treatment produced a significantly greater antihypertensive response than no treatment (difference, -6.09 mm Hg; 95% confidence interval, -11.81 to -0.38). Thus the placebo response after atenolol administration was more than a residual drug effect. Similar patterns were observed for heart rate but not for blood pressure readings taken in the office.
These observations are consistent with a conditioning model of placebo effects. These findings warrant further investigation in larger studies and in other disease models.
The frequency and severity of 17 side effects presumably associated with stimulant medication were assessed during a rigorous, triple-blind, placebo-controlled, crossover evaluation of methylphenidate, 0.3 and 0.5 mg/kg twice a day, in 83 children with attention deficit hyperactivity disorder. Side effects were rated by parents and teachers at the end of each weekly drug condition. Three children (3.6%) had side effects that were sufficiently serious to warrant immediate discontinuation of medication. Parent ratings indicated that only the side effects of decreased appetite, insomnia, stomachaches, and headaches increased significantly in frequency and severity during the two active medication doses as compared with the placebo condition. Fewer than half of the children experienced these side effects and among those who did, ratings of mean severity remained in the mild range. Teacher ratings showed little change over drug conditions, except on ratings of staring, sadness, and anxiety, which declined with increasing dose of medication. Parent ratings indicated that only the side effects of decreased appetite, insomnia, stomachaches, and headaches increased significantly in frequency and severity during the two active medication doses as compared with the placebo condition. Fewer than half of the children experienced these side effects and among those who did, ratings of mean severity remained in the mild range. Teacher ratings showed little change over drug conditions, except on ratings of staring, sadness, and anxiety, which declined with increasing dose of medication. Surprisingly, a high frequency of these behavior side effects were reported during the placebo condition. Stimulant medication within this therapeutic range, therefore, results in few, generally mild side effects.(ABSTRACT TRUNCATED AT 250 WORDS)
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The placebo response rate in depression consistently falls between 30 and 40%. Among more severely depressed patients antidepressants offer a clear advantage over placebo; among less severely depressed patients and those with a relatively short episode duration the placebo response rate is close to 50% and often indistinguishable from the response rate to antidepressants. In the treatment of depression none of the psychotherapies have consistently been shown to offer an advantage over pill placebo. This is not entirely surprising given the fact that the common, and arguably the therapeutic, features of the psychotherapies (expectation of improvement, support, mobilization of hope) are provided with pill placebo treatment.
The placebo response in depression has been viewed as a nuisance rather than as a therapeutic and research opportunity. I propose that the initial treatment for selected depressed patients should be four to six weeks of placebo. Patients so treated should be informed that the placebo pill contains no drug but that this treatment can be helpful.
Adherence (or compliance) is the extent to which a person's behavior coincides with medical or health advice. Recent evidence indicates that patients who adhere to treatment, even when that treatment is a placebo, have better health outcomes than poorly adherent patients. Based on this evidence, we now believe that the outcomes of treatment are not solely attributable to the specific action of a drug, but may also depend on other nonspecific therapeutic effects. We consider the implications of these findings for the design and interpretation of clinical research as well as for the care of patients.
To estimate the increased use and the prevalence of methylphenidate (Ritalin) treatment of youth with attention deficit disorder (ADD) during the 1990s.
Using time-trend findings from two large population-based data sources, three pharmaceutical databases, and one physician audit, a best-fit estimate of the usage and the usage trends for methylphenidate treatment over the half decade from 1990 through 1995 was sought.
Five regions in the United States (US) and the nation as a whole.
Youths on record as receiving methylphenidate for ADD.
The findings from regional and national databases indicate that on average, there has been a 2.5-fold increase in the prevalence of methylphenidate treatment of youths with ADD between 1990 and 1995. In all, approximately 2.8% (or 1.5 million) of US youths aged 5 to 18 were receiving this medication in mid-1995. The increase in methylphenidate treatment for ADD appears largely related to an increased duration of treatment; more girls, adolescents, and inattentive youths on the medication; and a recently improved public image of this medication treatment.
The database findings presented serve to correct exaggerated media claims of a 6-fold expansion of methylphenidate treatment, although they do not clarify the issue of the appropriateness of this treatment.
Despite several name changes over the past 50 years, the current diagnosis of attention-deficit–hyperactivity disorder (ADHD) shares the core group of symptoms — impulsivity, inattention, and motor restlessness — with earlier terms such as minimal brain dysfunction, hyperactive child syndrome, and attention-deficit disorder with or without hyperactivity. The disorder is extremely common, affecting approximately 4 percent of all children, although estimates vary widely, from 3 to 11 percent or more.1,2 The cause of ADHD remains unknown. The presentation, although highly variable, is captured in the following vignettes: The parents of a nine-year-old boy are seeking help because their son . . .
Secretin is a peptide hormone that stimulates pancreatic secretion. After recent publicity about a child with autism whose condition markedly improved after a single dose of secretin, thousands of children with autistic disorders may have received secretin injections.
We conducted a double-blind, placebo-controlled trial of a single intravenous dose of synthetic human secretin in 60 children (age, 3 to 14 years) with autism or pervasive developmental disorder. The children were randomly assigned to treatment with an intravenous infusion of synthetic human secretin (0.4 microg per kilogram of body weight) or saline placebo. We used standardized behavioral measures of the primary and secondary features of autism, including the Autism Behavior Checklist, to assess the degree of impairment at base line and over the course of a four-week period after treatment.
Of the 60 children, 4 could not be evaluated - 2 received secretin outside the study, and 2 did not return for follow-up. Thus, 56 children (28 in each group) completed the study. As compared with placebo, secretin treatment was not associated with significant improvements in any of the outcome measures. Among the children in the secretin group, the mean total score on the Autism Behavior Checklist at base line was 59.0 (range of possible values, 0 to 158, with a larger value corresponding to greater impairment), and among those in the placebo group it was 63.2. The mean decreases in scores over the four-week period were 8.9 in the secretin group and 17.8 in the placebo group (mean difference, -8.9; 95 percent confidence interval, -19.4 to 1.6; P=0.11). None of the children had treatment-limiting adverse effects. After they were told the results, 69 percent of the parents of the children in this study said they remained interested in secretin as a treatment for their children.
A single dose of synthetic human secretin is not an effective treatment for autism or pervasive developmental disorder.
To determine (a) the long-term and short-term effectiveness and safety of pharmacological and nonpharmacological interventions for attention-deficit/hyperactivity disorder (ADHD) in children and adults and (b) whether combined interventions are more effective than individual interventions.
MEDLINE (from 1966), CINAHL (from 1982), HEALTHStar (from 1975), PsycINFO (from 1984), EMBASE (from 1984), and the Cochrane Library searches were completed in November 1997. Reference lists of eligible studies and files of members of the research team and partner organizations were also searched.
Studies were selected if they focused on the treatment of ADHD in humans and were published in any language as a full report in peer-reviewed journals. Studies including conditions other than ADHD were reported if separate subgroup analyses for patients with ADHD were provided.
Two reviewers independently extracted data for 41 variables on general characteristics, along with detailed information on interventions, outcomes, and tests. Differences were resolved by consensus or by a third researcher. Studies were not combined quantitatively because the quality of reporting was low and heterogeneity existed across outcome measures and tests.
Seventy-eight studies (77 randomized controlled trials) met the inclusion criteria. Twenty-three studies compared drugs and showed few, if any, differences among methylphenidate (MPH), dextroamphetamine (DEX), and pemoline; studies comparing stimulants with tricyclic antidepressants (2) were inconclusive. Six studies compared drugs with nondrug interventions and showed consistently that stimulants, particularly MPH, may be more effective than nonpharmacological interventions. Twenty studies compared combination therapies with a stimulant or a nondrug intervention alone; no additional beneficial effects for combination therapies were shown. Nine studies compared tricyclic antidepressants with placebo and showed that desipramine may be more effective than placebo; no consistent effect was shown for imipramine. Fourteen studies (13 in school children and 1 in adults) evaluated long-term therapy (> or = 12 weeks) and showed a trend to general improvement regardless of treatment, but the length of followup was inadequate. MPH may reduce behavioral disturbance in children with ADHD while it is taken. Academic performance does not appear to be improved with stimulants. Twelve studies evaluated treatment in adults with ADHD. For MPH vs. placebo, the results were contradictory. Antidepressants may be effective in adults, but no beneficial effect was seen with pemoline, nicotine, or phenylalanine compared with placebo. Thirty-two reports (29 studies) evaluated adverse effects of drug therapy; many of the side effects associated with stimulant use appear to be relatively mild and of short duration and to respond to dosing or timing adjustments. Data are inadequate on the long-term effects and severity of adverse effects of most interventions.
This report describes rigorous systematic reviews on the treatment of ADHD, ready for incorporation into evidence-based clinical practice guidelines or performance measures. The report also provides a detailed description of the many limitations of the evidence available and provides recommendations to fill existing knowledge gaps. Studies on ADHD have low reporting quality, methodological flaws, and heterogeneity across outcome measures and tests. A detailed description is included of the many limitations of the available evidence plus recommendations to fill existing knowledge gaps. Fulfilling such knowledge gaps will not be easy and will require genuine collaboration among decisionmakers.
This practice parameter describes treatment with stimulant medication. It uses an evidence-based medicine approach derived from a detailed literature review and expert consultation. Stimulant medications in clinical use include methylphenidate, dextroamphetamine, mixed-salts amphetamine, and pemoline. It carries FDA indications for treatment of attention-deficit/hyperactivity disorder and narcolepsy.
The use of complementary and alternative medicine (CAM) in pediatrics has become widespread. Parents of young children with developmental and behavioral problems such as attention-deficit hyperactivity disorder (ADHD) are particularly drawn to CAM interventions to avoid or decrease use of psychotropic medications. This paper reviews the epidemiology of CAM use for ADHD, describes a conceptual model of CAM, discusses a variety of commonly used therapies for ADHD, and introduces a systematic, pragmatic approach to discussing CAM therapy use with parents.
There has been considerable debate about the ethical acceptability of using placebo-controls in clinical research. Although this debate has been rich in rhetoric, considering that much of this research is predicated upon the assumption that data from this research is vital to clinical decision-making, it is ironic that researchers have introduced little data into these discussions. Using some published research concerning the use of placebo-controls in clinical research in hypertension and psychiatric drug trials, I suggest some ways that such data might be incorporated into the ethical analysis concerning placebo use in clinical trials. This approach promises to be important for enhancing conceptual and scientific understanding as well as public policy decision-making.
The authors reviewed various statements describing the ethical use of placebo-controls in clinical trials involving minors. Attention was focused upon the Guidelines for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric Populations, published by the American Academy of Pediatrics (AAP) (Kaufman et al. 1995). A brief review of certain key documents and a possible expansion of the guidelines are presented. Specifically, it is recommended that a review and update of guidelines for the use of placebo-controlled trials in children be undertaken by a working group comprised of stakeholders, including academic clinical and research professionals, bioethicists, consumers, members of key government agencies, and the pharmaceutical industry.
Recent clinical trials of secretin in children with autism showed robust placebo effects and no benefit of secretin over placebo. This article explores the reasons for the observed placebo effects, focusing on the heightening of positive expectancy by media attention and by the sensory experiences associated with intravenous injections. Comparisons are drawn with research involving other novel treatments and other clinical populations of children with developmental disabilities and neurobehavioral disorders. Research regarding mechanisms of placebo effects is reviewed, including patient and clinician attributes, expectancy effects, participation effects, changes in caregiver behavior, and conditioning. New evidence regarding the biological basis of placebo effects is briefly presented. Since placebo effects are ubiquitous and may operate by a variety of mechanisms, research design is critical in designing clinical trials and in evaluating other outcomes research. Measurement issues important for research in developmental disabilities are emphasized. Ethical concerns have been raised regarding the use of placebo in clinical research, but current analysis suggests that placebo controls are necessary and defensible on ethical grounds, if certain conditions are met. The study of placebo effects ("placebology") holds great promise as a new area of research in therapeutics. The author's research in the potential augmentation of stimulant effects in children with attention deficit/hyperactivity disorder (ADHD) by adding placebo in open label is briefly presented. The placebo has always been integral to the practice of medicine, but advances in scientific medicine and medical ethics have diminished the role and use of placebo in practice. An innovative approach to the ethical use of placebo is proposed.
This study examines the impact of interrater reliability on the diagnosis of attention-deficit hyperactivity disorder (ADHD). A screening of 6171 elementary school children identified 1573 children with a high risk for ADHD according to teacher rating. Follow-up parent interviews and information from teachers were collected on 243 children. Before screening, health care professionals had diagnosed ADHD in 40% of the identified children. There was low agreement between the parent and teacher reports of ADHD symptoms according to DSM-IV-based questionnaires: Inattentive (r =.34, kappa = 0.27), Hyperactive/Impulsive (r =.27, kappa = 0.22), and Performance Impairment (r =.31, kappa = 0.07). When the two-setting requirement was strictly enforced, poor interrater agreement decreased diagnostic rates for all three types of ADHD in this clinical sample: Inattentive (15%-5%), Hyperactive/Impulsive (11%-3%), and Combined (23%-7%). Parent and teacher agreement was low concerning ADHD symptoms and performance. The recommendation of multiple informants significantly decreased the prevalence. Allowing for observer disagreement by using more lenient core symptom scores could reduce the effect.
As a postmodern illness, attention-deficit/hyperactivity disorder (ADHD) is embedded in controversy, reflective of the cultural times in which we live. Within this debate, 2 perspectives, ADHD as myth and ADHD as behavioral disorder, are most frequently voiced. This article describes these 2 differing perspectives and reports qualitative data from 39 children and adolescents with a diagnosis of ADHD regarding their perceptions, meanings,and experiences of living with this disorder. None of the participants in this study denied that they had difficulties and many of the difficulties they described corresponded to DSM-IV-R criteria and the scientific literature. Given these discoveries, the continual debate about the authenticity of ADHD only further victimizes families who are in desperate need of services.
This study examined short-term efficacy, side effects and acceptability of a placebo treatment procedure designed to maintain children with attention deficit hyperactivity disorder (ADHD) on 50% of their usual stimulant dose.
An open-label prospective crossover trial was conducted in 26 children with ADHD, ages 7-15 years, stable on stimulant therapy, followed at a community-based developmental paediatrics ADHD clinic. Subjects were randomly assigned to one of two orders of experimental conditions: (1) baseline (100%) dose (1 week), then 50% dose (1 week), then 50% dose + placebo (1 week), or (2) baseline (100%), then 50% dose + placebo, then 50% dose. The inert nature of the placebo was fully disclosed to parent and child. Treatment was open-label for child, parents and physician, but single blind for teachers. Main outcome measures included weekly IOWA Conners parent and teacher rating scales, the Pittsburgh side effects rating scale (PSERS) and the Clinical Global Impressions (CGI) scale.
Parent IOWA showed ADHD behaviour tended to remain the same when the dose of stimulant medication was reduced with placebo but to deteriorate when the dose was reduced without placebo. There were no significant differences between conditions on the Teacher IOWA. PSERS scores were higher at baseline than on 50% dose. On the CGI, there was a significant difference (P = 0.004) between the 50% dose and the 50% + placebo conditions. Individual subject analysis showed that eight subjects met criteria for responder.
Results indicate that the open-label placebo treatment was acceptable and efficacious in the short term for some children.
A Review of Therapies for Attention-Deficit/Hyperactivity Disorder. Canadian Coordinating Office for Health Technology Assessment
- A Miller
- S Lee
- P Raina
- A Klassen
Miller, A., Lee, S., Raina, P. & Klassen, A. (1998) A Review of Therapies for Attention-Deficit/Hyperactivity Disorder. Canadian Coordinating Office for Health Technology Assessment, Ottawa, Canada.
Moderators and mediators of treatment response for children with attention-deficit/hyperactivity disorder: the multimodal treatment study of children with ADHD
- Mta
- Group
MTA Cooperative Group (1999) Moderators and mediators of treatment response for children with attention-deficit/hyperactivity disorder: the multimodal treatment study of children with ADHD. Archives of General Psychiatry, 56, 1088–1096.
Stimulant medications and the treatment of children with ADHD Expectation enhances the regional brain metabolic and the reinforcing effects of stimulants in cocaine abusers
- J M Mcburnett
- K Christian
- D L T H Ollendick
- R J Prinz
, J. M., McBurnett, K. & Christian, D. L. (1995) Stimulant medications and the treatment of children with ADHD. In: Advances in Clinical Child Psychology (eds T. H. Ollendick & R. J. Prinz), pp. 265–322. Plenum Press, New York, NY, USA. Volkow, N., Wang, G., Ma, Y., Fowler, J. S., Zhu, W., Maynard, L., Telang, F., Vasha, P., Ding, Y. S., Wong, C. & Swanson, J. M. (2003) Expectation enhances the regional brain metabolic and the reinforcing effects of stimulants in cocaine abusers. Journal of Neuroscience, 23, 11461–11468.
Contextual factors and receipt of evidence-based treatments for ADHD. Abstract presented at Society for Developmental and Behavioral Pediatrics Annual Meeting
- L L Leslie
- D Plemmons
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Leslie, L. L., Plemmons, D. & Murphy, R. M. (2005) Contextual factors and receipt of evidence-based treatments for ADHD. Abstract presented at Society for Developmental and Behavioral Pediatrics Annual Meeting, San Diego; September, 2005.
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