Open-label Placebo Research Articles

Can open label placebos improve pain and gluten tolerance via open label placebos in fibromyalgia patients? A study protocol for a randomised clinical trial in an outpatient centre

IntroductionFibromyalgia syndrome (FMS) is defined as a medical condition with chronic widespread musculoskeletal pain accompanied by mood disorders, fatigue and sleep disturbances. Treatment of this condition can often be challenging....

Time to reflect on open-label placebos and their value for clinical practice.

Time to reflect on open-label placebos and their value for clinical practice.

Evidencing general acceptability of open-label placebo use for tackling overtreatment in primary care: a mixed methods study

BackgroundOvertreatment poses a challenge to healthcare systems due to harmful consequences of avoidable side-effects and costs. This study presents the first account for examining the feasibility of placebo use for reducing overtreatment in primary care, including whether public attitudes support the use of different placebo types in place of inappropriate prescriptions of antibiotics, antidepressants, or analgesics.MethodsWe used a multi-study, mixed-methods design, including patient and public (PPI) consultations, focus groups (Study 1) and two pre-registered online experiments (Studies 2 and 3).ResultsStudy 1 (N = 16) explored everyday conceptions and practicalities of potential placebo use in the context of respiratory infections. Findings highlighted the importance of trusting doctor-patient relationships and safety-netting. Study 2 employed a randomised experiment with a representative UK sample (N = 980), investigating attitudes towards 5 different treatment options for respiratory infections: (1) blinded + pure placebo, (2) open-label + pure placebo, (3) open-label + impure placebo, (4) antibiotic treatment, and (5) no treatment. Study 2 also examined how attitudes varied based on wording and individual differences. Findings indicated general support (ηp2 = .149, large effect size) for replacing inappropriate antibiotics with open-label + impure placebos, although personal placebo acceptability was lower. Also, older people, individuals suffering from chronic illness or those showing higher levels of health anxiety appeared less amenable to placebo use. Study 3 (N = 1177) compared attitudes towards treatment options across three clinical scenarios: respiratory infection, depression and pain. Findings suggested significant differences in the acceptability of placebo options based on the clinical context. In the infection scenario, options for open-label + pure placebos, open-label + impure placebos and no treatment were rated significantly more acceptable (ηp2 = .116, medium effect size) compared to the depression and pain scenarios. Again, general support for placebos was higher than placebo acceptability for personal use.ConclusionsFindings from PPI and three studies indicate general support for combatting overprescribing in primary care through clinical placebo use. This is an indicator for wider UK public support for a novel, behavioural strategy to target a long-standing healthcare challenge. General acceptability appears to be highest for the use of open-label + impure placebos in the context of antibiotic overprescribing.

Effects of an open-label placebo intervention on reactions to social exclusion in healthy adults: a randomized controlled trial

Social exclusion, that is being left out by others, can have adverse consequences for individuals’ psychological well-being. Even short-term experiences of social exclusion strongly threaten basic psychological needs and cause so-called social pain. Prior research suggests an overlap between the experience of social and physical pain that, amongst others, is reflected by the effectiveness of physical pain treatments in alleviating social pain. Drawing upon these prior findings, we here explore whether open-label placebos, which have previously been found to be effective in reducing physical pain, can alleviate social pain following social exclusion. Seventy-four healthy participants were randomly assigned to one of four conditions in a 2 × 2 between-subjects design: First, they either received an open-label placebo intervention or no treatment. Second, they either experienced inclusion or exclusion by their co-players in the interactive ball-tossing game Cyberball. We find that excluded participants in the open-label placebo condition experienced significantly less hurt feelings compared to those in the control condition (Cohen’s d = 0.77). There was no effect of treatment for need threat. The findings suggest new possibilities to alleviate social pain, which is of particular interest in the context of preventing destructive and maladaptive behaviors in situations where functional coping strategies are unavailable.

A randomized trial that compared brain activity, efficacy and plausibility of open-label placebo treatment and cognitive reappraisal for reducing emotional distress

Placebo pills can reduce emotional distress even when recipients have been informed about the inert nature of the treatment. However, before such open-label placebos (OLPs) can be recommended for general clinical use, their efficacy and acceptability need to be further investigated and compared with established methods for emotion regulation, such as cognitive reappraisal (CR). The current study with functional magnetic resonance imaging compared the effects of an OLP pill with CR for reducing a specific form of emotional distress: disgust. Participants (150 healthy females) were randomly allocated to one of three groups, all of which were exposed to disgusting and neutral images (OLP, CR, PV: passive viewing). It was tested whether the three groups would differ in brain activity and reported disgust. Ratings for the perceived efficacy and plausibility of treatment were also compared between OLP and CR. Both OLP and CR increased the activity in a cognitive control region, the ventrolateral prefrontal cortex. Relative to PV and OLP, CR reduced activity in the putamen and pallidum. These regions play an important role in decoding disgust signals from different modalities. Self-reports indicated that CR was perceived as a more effective and plausible intervention strategy than OLP. In conclusion, CR was a superior method for disgust regulation compared to OLP, both on the subjective as well as the neurobiological level. Future OLP studies are needed to test whether the observed effects generalize to other forms of emotional distress.

The roles of expectation, comparator, administration route, and population in open-label placebo effects: a network meta-analysis

Three meta-analyses have demonstrated the clinical potential of open-label placebos (OLPs). However, there is a need to synthesize the existing evidence through more complex analyses that would make it possible to answer questions beyond mere efficacy. Such analyses would serve to improve the understanding of why and under what circumstances OLPs work (e.g., depending on induced expectations or across different control groups). To answer these questions, we conducted the first network meta-analyses in the field of OLPs. Our analyses revealed that OLPs could be beneficial in comparison to no treatment in nonclinical (12 trials; 1015 participants) and clinical populations (25 trials; 2006 participants). Positive treatment expectations were found to be important for OLPs to work. Also, OLP effects can vary depending on the comparator used. While the kind of administration route had no substantial impact on the OLP effects, effects were found to be larger in clinical populations than in nonclinical populations. These results suggest that the expectation, comparator, administration route, and population should be considered when designing and interpreting OLP studies.

Study protocol: randomised controlled trial of conditioned open-label placebo (COLP) for perioperative pain management in patients with head and neck cancer

IntroductionPatients with head and neck cancer have a substantial risk of chronic opioid dependence following surgery due to pain and psychosocial consequences from both the disease process and its treatments....

Open-label placebo treatment for reducing overeating in children: A study protocol for a randomized clinical trial with an app-assisted approach

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.

Placebos in pediatrics: A cross-sectional survey investigating physicians' perspectives

ObjectivePlacebo 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. MethodsA 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. ResultsFrom 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. ConclusionsPlacebo 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.

A randomized controlled trial of effects of open-label placebo compared to double-blind placebo and treatment-as-usual on symptoms of allergic rhinitis

Placebo effects are known for numerous clinical symptoms. Until recently, deception of placebos was thought to be essential for placebo effects, but intriguing new studies suggest that even placebos without concealment (open-label placebos) may help patients with various clinical disorders. Most of those studies compared open-label placebo treatments with no treatment conditions (or treatment “as usual”). Given that open-label placebo studies obviously cannot be blinded, additional control studies are important to assess the efficacy of open-label placebos. The current study aimed to fil this gap by comparing open-label with conventional double-blind placebos and treatment as usual. Patients with seasonal allergic rhinitis were randomly divided in different groups. The first group received open-label placebos, the second double-blind placebos, and the third was treated as usual. After 4 weeks, results demonstrated that open-label placebos improved allergic symptoms more than treatment-as-usual and even more as double-blind placebos. In addition, we observed that allergic symptoms in general (and also the open-label placebo effects) were reduced by the Covid-19 pandemic. The results suggest that seasonal allergic symptoms may be relieved by open-label placebos. We discuss these results by addressing possible different mechanisms of open-label and conventionally concealed placebo treatments.

A comparative evaluation of placebo effect on pain perception parameters in open-label versus double-blind groups: a prospective randomized pilot study in healthy volunteers

Background: Considerable placebo response rate is commonly observed in placebo-controlled trials involving analgesics. However, there is paucity of evidence with regard to comparison of effect of open-label placebo versus double-blind placebo on pain perception. Methods: In this study, cold water maintained at 4±1°C was used to induce experimental pain. Enrolled subjects were randomized to receive either 2% lignocaine gel as active drug or K-Y jelly as placebo as per the groups in open-label (two groups) and double-blind (two groups) study. Pain perception was evaluated using pain threshold time and pain tolerance time after immersion of subject’s hand in the cold water. Pain intensity was assessed using visual analogue scale (VAS). Results: Sixty-nine subjects were randomized into 4 study groups namely open-label lignocaine (OLL; N=17), open-label placebo (OLP; N=18), double-blind lignocaine (DBL; N=17) and double-blind placebo (DBP; N=17). OLP application increased pain intensity on VAS from 67 (47, 84) to 72 (39, 88) mm (p=0.018). OLL application reduced pain perception pain threshold time from 20.4 (4.0, 45.1) to 24.1 (6.3, 124.2) seconds (p=0.049) and pain tolerance time from 32.7 (6.8, 110.2) to 40.0 (7.7, 156.7) seconds (p=0.019). The change in pain parameters (before and after application of study intervention) was comparable without any significant difference among the four study groups (p=0.257 for pain threshold time, p=0.165 for pain tolerance time and p=0.563 for pain intensity score). Conclusions: Lignocaine and placebo gel application showed comparable change in pain perception irrespective of blinding.

The impact of pharmaceutical form and simulated side effects in an open-label-placebo RCT for improving psychological distress in highly stressed students

Open-label placebo (OLP) may be utilized to reduce psychological distress. Yet, potential contextual effects have not been explored. We investigated the impact of pharmaceutical form and the simulation of side effects in a parallel group RCT (DRKS00030987). A sample of 177 highly stressed university students at risk of depression were randomly assigned by computer generated tables to a 1-week intervention with active or passive OLP nasal spray or passive OLP capsule or a no-treatment control group. After the intervention, groups differed significantly in depressive symptoms but not regarding other outcomes of psychological distress (stress, anxiety, sleep quality, somatization), well-being or treatment expectation. OLP groups benefitted significantly more compared to the no-treatment control group (d = .40), OLP nasal spray groups significantly more than the OLP capsule group (d = .40) and the active OLP group significantly more than the passive OLP groups (d = .42). Interestingly, before intervention, most participants, regardless of group assignment, believed that the OLP capsule would be most beneficial. The effectiveness of OLP treatments seems to be highly influenced by the symptom focus conveyed by the OLP rationale. Moreover, pharmaceutical form and simulation of side effects may modulate efficacy, while explicit treatment expectation seems to play a minor role.

Effectiveness of Conditioned Open-label Placebo With Methadone in Treatment of Opioid Use Disorder

Methadone treatment is the most effective evidence-based treatment for opioid use disorder (OUD), but challenges related to dosing and premature treatment dropout argue for adjunct interventions to improve outcomes. One potential behavioral intervention with low risk involves harnessing placebo effects. To determine the effect of a pharmacologically conditioned open-label placebo (C-OLP) on 90-day methadone dose, retention, drug use, withdrawal, craving, quality of life, and sleep. This 2-arm, open-label, single-blind randomized clinical trial was conducted between December 5, 2017, and August 2, 2019, in an academically affiliated community opioid treatment program. Analyses were conducted between October 1, 2019, and April 30, 2020. A total of 320 newly enrolled adults seeking treatment for moderate to severe OUD were assessed for study eligibility; 131 met eligibility criteria, provided informed consent, and were randomized to either C-OLP or treatment as usual (TAU) in an unequal-block (3:2) manner. Exclusion criteria were pregnancy, hospital/program transfers, and court-ordered treatment. Participants randomized to C-OLP received pharmacologic conditioning and a placebo pill and methadone, and participants randomized to TAU were given methadone only. Participants met with the study team 5 times: at baseline (treatment intake) and 2, 4, 8, and 12 weeks postbaseline. Interactions were balanced between the 2 groups. Outcomes included 90-day methadone dose (primary) and treatment retention, drug use, withdrawal, craving, quality of life, and sleep quality (secondary). Analyses were conducted as intention-to-treat. Of the 131 people enrolled in the study, 54 were randomized to TAU and 77 to C-OLP. Mean (SD) age was 45.9 (11.2) years; most of the participants were Black or African American (83 [63.4%]) and male (84 [64.1%]). No significant group differences were observed in the mean (SD) 90-day methadone dose (83.1 [25.1] mg for group TAU, 79.4 [19.6] mg for group C-OLP; t = 0.621991; P = .43), but the groups differed significantly in their retention rates: 33 (61.1%) for TAU and 60 (77.9%) for C-OLP (χ21 = 4.356; P = .04; number needed to treat for the beneficial outcome of 3-month treatment retention, 6; 95% CI, 4-119). C-OLP participants also reported significantly better sleep quality. In this randomized clinical trial, C-OLP had no effect on the primary outcome of 90-day methadone dose. However, C-OLP participants were significantly more likely to remain in treatment. These findings support the use of C-OLP as a methadone treatment adjunct, but larger trials are needed to further examine the use of C-OLP. ClinicalTrials.gov Identifier: NCT02941809.

Probiotic treatment (Enterococcus faecalis) improves symptoms of seasonal allergic rhinitis: A randomized controlled trial.

Probiotic treatment (Enterococcus faecalis) improves symptoms of seasonal allergic rhinitis: A randomized controlled trial.

The role of positive information provision in open-label placebo effects.

Open label placebos (OLPs) appear generally efficacious among clinical samples, but the empirical evidence regarding their use in non-clinical and sub-clinical samples, as well as when administered independent of a convincing rationale, is mixed. Healthy participants (N = 102) were randomised to either a 6-day course of OLP pills with information provision (OLP-plus: N = 35), without information provision (OLP-only: N = 35), or no-treatment control group (N = 32). OLP pills were described as enhancing physical (symptoms and sleep) and psychological (positive and negative emotional) well-being. Well-being was assessed at baseline and on Day 6. Expectancies and adherence were measured. OLP administration interacted with baseline well-being. The OLP-plus group demonstrated increased well-being on all outcomes other than positive emotions, but only when they reported decreased baseline well-being. OLP-only and control groups did not differ. The OLP-plus group demonstrated elevated expectancies, that mediated the OLP effect on physical symptoms relative to control, but only when well-being was lower than average at baseline (i.e. moderated-mediation). Results demonstrate the importance of information provided with OLPs. The moderating effect of baseline outcomes may reconcile inconsistent results regarding clinical and non-clinical samples. Accounting for baseline symptoms in non-clinical and sub-clinical samples is likely to enhance our understanding of when OLPs are effective.

"A wolf in sheep's clothing": when so-called placebo interventions are not what they seem.

"A wolf in sheep's clothing": when so-called placebo interventions are not what they seem.

Open-label placebos—a systematic review and meta-analysis of experimental studies with non-clinical samples

The use of open-label placebos (OLPs) has shown to be effective in clinical trials. We conducted a systematic review and meta-analysis to examine whether OLPs are effective in experimental studies with non-clinical populations. We searched five databases on April 15, 2021. We conducted separate analyses for self-reported and objective outcomes and examined whether the level of suggestiveness of the instructions influenced the efficacy of OLPs. Of the 3573 identified records, 20 studies comprising 1201 participants were included, of which 17 studies were eligible for meta-analysis. The studies investigated the effect of OLPs on well-being, pain, stress, arousal, wound healing, sadness, itchiness, test anxiety, and physiological recovery. We found a significant effect of OLPs for self-reported outcomes (k = 13; standardized mean difference (SMD) = 0.43; 95% CI = 0.28, 0.58; I2 = 7.2%), but not for objective outcomes (k = 8; SMD = − 0.02; 95% CI = − 0.25, 0.21; I2 = 43.6%). The level of suggestiveness of the instructions influenced the efficacy of OLPs for objective outcomes (p = 0.02), but not for self-reported outcomes. The risk of bias was moderate for most studies, and the overall quality of the evidence was rated low to very low. In conclusion, OLPs appear to be effective when examined in experimental studies. However, further research is needed to better understand the mechanisms underlying OLPs.

Open-Label placebo for the treatment of unipolar depression: Results from a randomized controlled trial

IntroductionThe response to placebo is robust in studies of various antidepressant treatments. The strong placebo response, combined with the absence of side-effects, has prompted suggestions to use the ethically sound open-label placebo (OLP) as a treatment for depression.ObjectivesThe aim of the present study was to assess the efficacy of OLP in the setting of a randomized controlled trial for the treatment of unipolar depression.MethodsThirty-eight patients (28 females, 73.7%) were randomized to either an eight-week treatment with OLP (n=18) or four week of treatment as usual (TAU) followed by four weeks of OLP (n=20). Clinical and socio-demographic measures were assessed at baseline, after four weeks, and at the end of the trial. Response to treatment was determined using the Quick Inventory of Depressive Symptomatology (QIDS SR-16).ResultsThere was an overall decrease in depression levels over time, F(2,35) = 3.98, p = .028). A significant group x time interaction was found only among non-geriatric patients (<65y) with an early onset of depression (<50y), F(2,22) = 3.89, p = .036]. Post-hoc tests indicated a significant decrease during the first four weeks, but only in the OLP group, t(11) = 2.29, p = .043. Table 1:Demographic measures of OLP and TAU patients.MeasuresOLP (n = 18)TAU (n =20)Statistical analysesAge (years) [Mean ± SD]48.17 ± 16.8651.65 ± 17.68t(36) = -0.62, p = .539Education level (years) [Mean ± SD]15.61 ± 3.6614.22 ± 2.62t(34) = 1.31, p = .200Gender (male/female) [no.]4 / 146 / 14X2(1) = 0.30, p = .587Age of onset (years) [Mean ± SD]34.19 ± 15.8232.45 ± 17.72t(36) = 0.32, p= .752Number of depressive episodes (no.) [Mean ± SD]2.58 ± 2.616.64 ± 9.16t(21) = -1.47, p = .156Number of hospitalizations (no.) [Mean ± SD]0.12 ± 0.330.17 ± 0.38t(33)= -0.40, p = .689NotesOLP = Open label placebo; SD = Standard deviation; TAU = Treatment as usual.Image 3:ConclusionsOur findings support the possibility that OLP is an effective treatment for the relatively young population of patients suffering from depression. Additional studies are warranted in order to explore the use of open-label placebo in clinical work.Disclosure of InterestNone Declared

Cognitive Science Below the Neck: Toward an Integrative Account of Consciousness in the Body

Our culture and its scientific endeavor direly need a holistic characterization of mind and body. Many phenomena attest to the profound effects of beliefs on bodily function (e.g., open-label placebo's effects on chronic pain) and interoceptive systems' role in mental processes (e.g., the emerging role of gut microbiomes in the mood). We need a mechanistic, integrative framework to account for these phenomena and generate novel predictions. Major advances have been made in understanding how the nervous system senses and regulates the body and in modeling how the brain implements the computations that subserve such activities. However, the vestiges of Cartesianism haveentrained a style of thinking in which systems from the brainstem downwardexist as the implementation layer of computational processes supporting sensation and behavior, rather than a complementary locus of information processing. As speakers and microphones, rather than other members of the chorus. We are thus forced to perceive well-documented, belief-driven phenomena like placebo, ritual, and psychosomatic disorders as mysterious obstacles or dubious allies rather than as a wellspring of potential.

Imaginary pills and open-label placebos can reduce test anxiety by means of placebo mechanisms

Placebos have been shown to be beneficial for various conditions even if administered with full transparency. Hence, so-called open-label placebos (OLPs) offer a new way to harness placebo effects ethically. To take this concept one step further, this study aimed at evaluating placebo effects without the use of a physical placebo, i.e., by imagining taking a pill. Healthy students (N = 173) with self-reported test anxiety were either randomized to an imaginary pill (IP; n = 55), an OLP (n = 59) or a control group (CG; n = 59). Both intervention groups were instructed to take two pills daily for three weeks. Primary outcome was test anxiety, secondary outcomes were sleep quality, general well-being and test performance. Groups test anxiety differed at study-endpoint, F(2,169) = 11.50, p < .001. Test anxiety was lower in the intervention groups compared to the CG, t(169) = − 4.44, p < .001, d = − 0.71. The interventions did not differ significantly, i.e., both were similarly efficacious, t(169) = 0.61, p = .540, d = 0.11. The interaction between group and time in explaining test anxiety was significant, F(5,407.93) = 6.13, p < .001. OLPs and IPs reduced test anxiety in healthy participants compared to the CG. This finding opens the door for a novel and ethical method to harness placebo effects.