Open-label Placebo Research Articles

P.327 Efficacy and safety of AXS-05, an oral, NMDA receptor antagonist with multimodal activity in major depressive disorder

The 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. The aim of the present study was to assess the efficacy of OLP as an adjunct to treatment as usual (TAU) in the setting of a randomized controlled trial for the treatment of unipolar depression.Thirty-eight patients (age: 50 ± 17.1; 73.7% females) were randomized to either eight-week OLP treatment (n = 18) or four weeks of 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 QIDS SR-16.There 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 (<65years) with an early onset of depression (<50years), 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.Small sample size and the use of a self-report questionnaire to assess depressive symptoms.Our findings support the possibility that OLP is an effective treatment for the relatively young population of depressed patients. Additional studies are warranted to explore the use of OLP in clinical practice.

Open-Label Placebo Treatment: Outcome Expectations and General Acceptance in the Lay Population

BackgroundMost physicians sometimes apply therapies without specific active ingredients. Although patients seem to judge such placebo treatments as acceptable under certain circumstances, deception is still an ethical problem. Open-label placebos (OLPs) might be a promising approach to solve this dilemma. This study compared general acceptance and outcome expectations of OLPs and deceptive placebos (DPs).MethodsIn an experimental online study, 814 participants read a case vignette of a person with insomnia receiving a pill. The participants were then randomly allocated into two groups, where the second part of the vignette described the pill as either a deceptive placebo (DP group) or as an open-label placebo (OLP group). The Credibility/Expectancy Questionnaire (CEQ) assessed outcome expectations after the first (pre-assessment) and the second (post-assessment) parts of the vignette. Treatment acceptance was measured at post-assessment. Data from 798 participants were analyzed by a mixed multivariate analysis of variance (MANOVA), t-tests, and post-hoc mediation analyses.ResultsThe MANOVA revealed a significant group main effect and a significant time × group interaction effect. At post-assessment, outcome expectations were higher in the DP group than in the OLP group. Acceptance of the placebo treatment was also higher in the DP group than in the OLP group. Mediation analyses confirmed that higher acceptance in the DP group was mediated by higher expectations.ConclusionsWhen laypersons read about placebo treatment, their outcome expectations toward DPs were higher than toward OLPs. Surprisingly, the application of DPs was rated as more acceptable than OLPs. This result might be explained by indirect effects of treatment expectations.

Nocebo effects by providing informed consent in shared decision making? Not necessarily: a randomized pilot-trial using an open-label placebo approach

BackgroundThorough information of the patient is an integral part of the process of shared decision making. We aimed to investigate if detailed information about medication may induce nocebo (or placebo) effects.MethodsWe conducted a randomized, single-blind, pilot-study including n = 51 psychiatric in-patients aged between 18 and 80 years with a depressive disorder and accompanying sleeping disorders. In the intervention group we provided thorough information about adverse effects, while the control group received only a simple consent procedure. In both groups, patients received an open-label placebo pill instead of their sleeping medication.ResultsNo statistically significant differences between the intervention group and the control group were found regarding the main outcome parameter (a visual analogue scale indicating impairment by the new pill).ConclusionIn this study, we were not able detect an effect of informed consent vs. simple consent on the emergence of placebo or nocebo effects. This finding is contrary to most assumptions and publications about this topic.Trial registrationTrial registration number: DRKS00017653, registered August 30th 2018. Retrosprectively registered.

Open- and Closed-Label Placebo and Nocebo Suggestions About a Sham Transdermal Patch.

Placebo effects may occur when it is known that an inert substance is given (i.e., open-label placebo). It is not yet clear whether these effects are similar to concealed (i.e., closed-label) placebo effects for itch or whether nocebo effects can be induced under open-label conditions. Healthy volunteers (n = 112) were randomized to an open-label (I) or closed-label (II) positive suggestions group, or an open-label (III) or closed-label (IV) negative suggestions group. Participants were told, as cover story, that a transdermal caffeine patch would be applied that positively influences cognitive abilities and, as a side effect, positively or negatively (depending on group allocation) influences itch. Participants in the open-label groups were given a rationale explaining placebo and nocebo effect mechanisms. Itch (the primary outcome) was induced at baseline and postsuggestions by histamine iontophoresis. Analyses of variance revealed significantly lower itch in the positive compared with the negative suggestions groups for both open- and closed-label contexts (all, p ≤ .008, Cohen d ≥ 0.47). Self-rated skin response was less severe after positive versus negative suggestions (all, p ≤ .017, Cohen d ≥ 0.33), but no effects on physical skin response were found (all, p ≥ .23, Cohen d ≤ 0.30). Itch can be reduced by positive compared with negative suggestions under both open- and closed-label conditions. These findings indicate that open-label suggestions may potentially be a tool to use placebo effects for self-reported outcomes in clinical practice, for example, by explaining the role of expectancy in treatment. It needs to be investigated further under which circumstances an open-label rationale may impact placebo and nocebo effects.Trial Registration:www.trialregister.nl; NTR7174.

More than consent for ethical open-label placebo research

Recent studies have explored the effectiveness of open-label placebos (OLPs) for a variety of conditions, including chronic pain, cancer-related fatigue and irritable bowel syndrome. OLPs are thought to sidestep traditional...

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

BackgroundThe 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. The aim of the present study was to assess the efficacy of OLP as an adjunct to treatment as usual (TAU) in the setting of a randomized controlled trial for the treatment of unipolar depression. MethodsThirty-eight patients (age: 50 ± 17.1; 73.7% females) were randomized to either eight-week OLP treatment (n = 18) or four weeks of 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 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 (<65years) with an early onset of depression (<50years), 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. LimitationsSmall sample size and the use of a self-report questionnaire to assess depressive symptoms. ConclusionsOur findings support the possibility that OLP is an effective treatment for the relatively young population of depressed patients. Additional studies are warranted to explore the use of OLP in clinical practice.

Appearances are not deceptive: clinical evidence and new research approaches to open-label placebo

The efficacy of placebo effects is proven in experimental, clinical and meta-analytical studies. However, harnessing placebo effects in clinical treatment contexts is hampered legally and ethically, since it has been considered necessary to conceal the inert nature of aplacebo application. Interestingly, the results of recently published small, randomized trials suggest that patients can experience symptom relief after taking pills that they know lack any medication. In particular, these so-called open-label placebos (OLP) improved strongly fluctuating and individually distressing complaints such as gastrointestinal, neurological, psychosomatic and pain symptoms. Although the mechanisms are largely unknown, the open-label placebo application might be apromising way of fostering placebo effects in clinical settings. Initial study protocols already provide schedules for OLP use as an additional treatment in opioid use disorders. Likewise, the reduction of side effects, conversion effects or withdrawal symptoms through OLP applications in pharmacologically active treatments appear to serve as appropriate therapy goals. Further mechanistic studies are urgently needed to investigate the thus far only hypothetically proposed underlying mechanisms of OLP.

Placebos and placeboids in clinical practice: conceptual and ethical considerations

Reflecting on results of recent placebo research, this article analyzes relevant key concepts and ethical positions. "Placeboids" and possibly open-label placebo treatments should replace any deceptive use of sham medication. Their use should give rise to acritical consideration of the modern patient-physician relationship.

Conditioning open-label placebo: a pilot pharmacobehavioral approach for opioid dose reduction and pain control.

In this brief report, we evaluate the feasibility of COLP as a pharmacobehavioral intervention to decrease total opioid consumption in patients with pain hospitalized at Spaulding Rehabilitation Hospital. Inpatients with spinal cord injury and polytrauma (n = 20) with moderate to severe pain were randomized to receive COLP (n = 10) or treatment-as-usual for 6 consecutive days. Opioid utilization was measured by morphine equivalents using the morphine equivalent dose conversion; pain severity was assessed using the numerical visual analog scale. Conditioning open-label placebo significantly reduced total opioid consumption by the end of the intervention period (P ≤ 0.001). Pain reduction was also significant for the COLP group (P = 0.005), whereas the treatment-as-usual group demonstrated a trend towards pain reduction (P = 0.05). This study presents the first data in the use of a pharmacobehavioral intervention that capitalize on the benefits of open-label placebo and classical drug conditioning for opioid dose reduction in a population with moderate to severe pain exposed to intensive inpatient rehabilitation.

Primary care providers' use of and attitudes towards placebos: An exploratory focus group study with US physicians.

To examine how primary care physicians define placebo concepts, use placebos in clinical practice, and view open-label placebos (OLPs). Semi-structured focus groups that were audio-recorded and content-coded. Two focus groups with a total of 15 primary care physicians occurred at medical centres in the New England region of the United States. Prior experience using placebo treatments and attitudes towards open-label placebos were explored. Themes were analysed using an inductive data-driven approach. Physicians displayed a nuanced understanding of placebos and placebo effects in clinical contexts which sometimes focused on relational factors. Some respondents reported that they prescribed treatments with no known pharmacological effect for certain conditions and symptoms ('impure placebos') and that such prescriptions were more common for pain disorders, functional disorders, and medically unexplained symptoms. Opinions about OLP were mixed: Some viewed OLPs favourably or considered them 'harmless'; however, others strongly rejected OLPs as disrespectful to patients. Other issues in relation to OLPs included the following: lack of guidelines, legal and reputational concerns, and the notion that such treatments would run counter to customary medical practice. A number of physicians reported prescribing impure placebos in clinical care. Although some primary care physicians were resistant to the possibility of recommending OLPs, others regarded OLPs more favourably, viewing them as potential treatments, albeit with restricted potential. Statement of contribution What is already known? Many physicians report prescribing drugs for the purposes of eliciting a placebo effect. Initial evidence for the efficacy of open-label placebos is promising. What does this study add? A more nuanced description of the circumstances under which primary care physicians report placebo prescribing. A qualitative account of physician attitudes about using open-label placebos in clinical practice.

Pain Response to Open Label Placebo in Induced Acute Pain in Healthy Adult Males.

Open label placebos with patient education are effective in reducing chronic pain, and recent studies on their effect on pain have established interest in this field. Nevertheless, data on their effect on acute pain are scarce, and on hyperalgesia and allodynia, absent. This study assessed the effect of open label placebos on acute pain in healthy adult males and the influence of placebo education. Thirty-two healthy males were included in this prospective, randomized, assessor-blinded crossover, single-center study assessing pain intensities (via numeric rating scale), area of hyperalgesia (von Frey filament), and allodynia (dry cotton swab) in a pain model utilizing intracutaneous electrical stimulation. The authors compared the effect of intravenous open label placebo on pain compared to no treatment. The authors further examined the effect of placebo on hyperalgesia and allodynia, and the influence of education (short vs. detailed) before placebo application. Saliva cortisol concentrations were also measured. Pain ratings (median, first to third quartile) were 21% lower during placebo treatment compared to no treatment, 4.0 (3.2 to 4.9) versus 5.1 (4.7 to 5.4), respectively (P = 0.001). The areas of hyperalgesia and allodynia were lower during placebo treatment compared to no treatment (hyperalgesia, 30 cm [17 to 47] vs. 55 cm [42 to 68], P = 0.003; allodynia, 24 cm [11 to 39] vs. 45 cm [31 to 62], P = 0.007). This corresponds to reductions of 47%. The extent of placebo education had no effect on pain. Saliva cortisol decreased significantly over time and was under the limit of detectability in the majority of participants in postbaseline measurements in both treatment branches. Baseline cortisol was not associated with the placebo effect or strength applied of current to reach defined pain ratings. Open label placebos might play a role in multimodal analgesic concepts.

Placebos in primary care? a nominal group study explicating UK GP and patient views of six theoretically plausible models of placebo practice

ObjectivesTo better understand which theoretically plausible placebogenic techniques might be acceptable in UK primary care.DesignA qualitative study using nominal group technique and thematic analysis. Participants took part in audio-recorded face-to-face...

Open-label placebo treatment of women with premenstrual syndrome: study protocol of a randomised controlled trial

IntroductionRecent evidence suggests that for certain clinical conditions, placebos can improve clinical outcomes even without deception. These so-called open-label placebos (OLPs) bear the advantage of a significant lower risk of...

Taking Open Label Placebo Further: Randomized Controlled Trial of Imaginary Pills in Test Anxiety

Taking Open Label Placebo Further: Randomized Controlled Trial of Imaginary Pills in Test Anxiety

Can an Open-Label Placebo Be as Effective as a Deceptive Placebo? Methodological Considerations of a Study Protocol.

Background: Placebo has been studied for many years and is ever-present in healthcare. In clinical practice, its use is limited by ethical issues raised by the deception entailed by its administration. Objective: To investigate whether, when given detailed information about pain and underlying placebo mechanisms, subjects will have a response similar to that of those subjected to a procedure in which they receive a conventional placebo treatment. Methods: The study is designed as a non-inferiority randomized, parallel with a nested crossover trial. In addition, 126 subjects without any known pathology will be included. They will be randomized into two groups. Each subject will undergo three Cold Pressor Tests (CPT): calibration, condition of interest (deceptive placebo or educated placebo), and control. Our main judgment criterion will be the comparison in pain intensity experienced on the visual analog scale between the two CPTs with placebo conditions. Results: This study will allow us to rule on the non-inferiority of an “educated” placebo compared to a deceptive placebo in the context of an acute painful stimulation. It is another step towards the understanding of open-label placebo and its use in clinical practice. Conclusions: This study has been approved by the ethics committee in France (2017-A01643-50) and registered on ClinicalTrials.gov (NCT03934138).

Deceptive and Nondeceptive Placebos to Reduce Pain: An Experimental Study in Healthy Individuals.

Recent research has shown that placebos can be effective even if they are openly prescribed to participants. Yet, it is unclear how such "open-label placebos" (OLPs) compare to deceptive placebo (DP) and what the mechanisms of actions are. In this study, we therefore compared 2 versions of OLP to DP and no treatment (NT). Using a standard heat pain paradigm, 117 healthy volunteers underwent a baseline and a posttreatment pain assessment. With the exception of NT, all groups received an inert placebo cream after the first assessment. OLP was administered by either evoking positive expectancies or by raising hope for placebo analgesia, thus distinguishing for the first time conceptually between expectancy and hope in experimental pain research. The primary outcome was pre-post change in pain tolerance. Increase in pain tolerance was larger in the 3 treatment groups compared with NT, whereas the treatment groups did not differ from each other. Further results showed that participants receiving DP reported a large reduction of subjective pain intensity and unpleasantness, whereas no such reduction was found for the 2 OLP groups. The 2 OLP versions did not differ in terms of their analgesic effects. The study provided evidence for traditional placebo analgesia on the basis of deception. For OLP, we found that OLP indeed increased pain tolerance; however, participants receiving OLP were reluctant to report any subjective analgesic effects. Combined with previous studies, the present findings suggest that the effects of OLP are weaker in healthy volunteers than in clinical samples.

Placebos as a Source of Agency: Evidence and Implications.

Bioethical discussions surrounding the use of placebos in clinical practice have long revolved around the moral permissibility of deceiving a patient if it is likely to benefit them. While these discussions have been insightful and productive, they reinforce the notion that placebo effects can only be induced through deception. This paper challenges this notion, looking beyond the paradigmatic clinical encounter involving deceptive placebos and towards many other routes that bring about placebo effects. After briefly describing the bioethical terrain surrounding the deceptive use of placebos in clinical practice, section 1 offers an examination of the various mechanisms known to contribute to placebo effects: classical conditioning, expectations, affective pathways, open-label placebo treatments, and additional factors that do not fall easily into a single category. The following section explores how each of these routes can be harnessed to bring about clinical benefits without the use of deception. This provides grounding for reconceiving of the placebo effect as a clinical tool that is not always in conflict with patient autonomy and can even be seen as a source of agency. In the final section, implications of the shift away from seeing placebos as necessarily deceptive are discussed. These include the necessity of looking beyond the clinical encounter and mainstream medicine as the primary sites of placebo responses, how important acknowledging the limits of placebo effects will be when we do so, as well as the difficulties of disentangling agency, responsibility, and blame within medicine.

The role of placebos in family medicine: Implications of evidence and ethics for general practitioners.

Placebo use is prevalent in primary care. A wealth of discourse on the ethical use of placebos in clinical contexts invariably assumes that placebos oblige practitioners to peddle in deception. However, the recent surge in empirical findings within the field of 'placebo studies' provides a very different perspective: namely, that placebos may yet prove to be both effective and ethical. The aim of this article is to synthesise state-of-the-art scientific and bioethical research to provide up-to-date recommendations on placebo use for general practitioners. After disambiguating placebo concepts, this article outlines experimental studies into placebo effects and explores the ethical and evidence-based arguments for prescribing placebos. Evaluating the latest research into 'open-label placebos', it can be surmised that there are not yet persuasive grounds to incorporate these treatments into routine clinical care. Notwithstanding, the quality of physician interactions may go some way to harnessing remedial placebo effects among patients.

Effects of a probiotic treatment (Enterococcus faecalis) and open-label placebo on symptoms of allergic rhinitis: study protocol for a randomised controlled trial

IntroductionSeveral studies suggest that gut microbiota may play an important role in allergic diseases. The present trial aims to examine effects of the probiotic Enterococcus faecalis on symptoms of allergic...

Open-label placebos reduce test anxiety and improve self-management skills: A randomized-controlled trial

Test anxiety is a condition in which people experience extreme distress and anxiety before and in test situations. It affects up to 40 percent of all students. Conventional treatment includes both medication and psychotherapy, but studies also demonstrated that placebos affect anxiety symptoms. Although in the traditional understanding placebos need to be administered in a concealed way, intriguing new studies report that open-label placebos can be effective. Since prescription of fake pills involves ethical problems, open-label placebos may provide important new treatment possibilities. Here we report results of a pilot study examining whether open-label placebos may reduce test anxiety and improve self-management skills. 58 students participated in a two-group randomized controlled trial. Two weeks before an exam at the university participants received open-label placebos or no pills (control group). Participant – provider relationship and amount of contact time was held similar for all groups. After two weeks we found that test anxiety and self-management abilities (skills and resources) of the open-label placebo group were more improved than in the control group. Thus, our results seems to indicate that open-label placebos may reduce test anxiety and enhance self-management skills in students.