Pain is highly prevalent in hospital settings, with up to 84% of adult patients reporting it as a symptom and up to 36% describing it as severe (1). Standard systemic treatment for acute pain mainly consists of multimodal analgesic concepts including acetaminophen, metamizol, non-steroidal anti-inflammatory drugs, and opioids (2–7). However, the use of these drugs is often restricted due to contraindications, side-effects, and adverse events (2–8). Therefore, broadly applicable new treatment options with fewer side-effects would be valuable.

The word placebo is used nowadays to describe sham treatments and “inert” substances like sugar pills and saline injections (9–12). Placebos have been proven to elicit clinically significant effects in various conditions, including pain (9–16). Moreover, due to the “inert” nature of placebos, there are few to no contraindications. Side-effects occurring after the administration of placebos, termed the nocebo effect, are rare and usually stem from the expectation of adverse events (11, 17). So, one could argue that placebos themselves are very safe and could be used in most patients. Nevertheless, ethical concerns about the deceptive nature of placebos (18–20) have prevented their implementation in clinical practice.

To address this issue, it might be possible to prescribe placebos openly, without deception. This concept was proposed and found to be effective back in 1965 (21). Over the last two decades, this topic has become an emerging field of research with several studies focusing on these so-called open-label placebos (OLPs) (22–55). Two meta-analyses summarize clinical OLP studies and highlight significant effects in various conditions, such as allergic rhinitis, menopausal hot flushes, attention deficit hyperactivity disorder, cancer-related fatigue, irritable bowel syndrome, and chronic low back pain (56, 57). Findings on acute pain, though limited, are promising (25–29, 32, 35, 49, 55). To our knowledge, the effects of OLPs on acute pain-associated phenomena, hyperalgesia and allodynia, have only been investigated in one study thus far (55).

As mentioned by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT), characterizing the efficacy of a new analgesic is crucial to its development (58). Attributes of efficacy include onset of effect, maximum analgesic effect, duration of analgesia, and overall analgesic effects across the therapeutic dose range of the drug (58). In a proof-of-concept study from our own research group, we were able to show that OLP injections were able to significantly reduce pain (21% reduction), hyperalgesia and allodynia (47% reduction for both) in a population of healthy adult males experiencing induced pain (55). Although onset of OLP analgesia was nearly immediate, duration could not be observed in full as the analgesic effects lasted beyond the entire 70-min measurement period (55). In a study investigating OLP analgesia in migraine attacks, significant reduction of pain could still be measured two hours after intake of OLP pills (49). To our knowledge, observations over the full duration of OLP analgesia and placebo analgesia are absent. Therapeutic dose range of OLPs – although not for acute pain, but for participant well-being – was investigated by El Brihi et al. (31), but they did not find an influence of dose on their outcomes.

Furthermore, IMMPACT emphasizes the need to establish profiles of new analgesic therapies (58) and recommends the use of both single-dose and multiple-dose study designs (58). In using deceptive placebos, multiple placebos and more frequent intake have been shown to increase effects (59, 60). However, there is – to the best of our knowledge – only one study investigating possible superiority of repeated OLP administration over one-time OLP administration (31), showing no statistically significant influence of OLP repetition on participant well-being. Nevertheless, there are several studies administering multiple-dose OLPs in multiple day interventions on various conditions (e.g., 31, 33–39, 42, 43, 45, 46, 48, 51). But, none of these studies investigated whether repeated OLP intake actually is superior to single-dose intake and none did determine the optimal timing of repeat dosing. Likely, the decision to use multiple-dose OLPs (i.e., two OLP pills twice a day in most studies) comes from weighting the evidence on deceptive placebos mentioned above with evidence suggesting that “simple dosing regimens encourage higher adherence and thus larger placebo effects” (31).

This randomized study aims to fill the gaps in characterizing the efficacy of OLPs in acute pain. We will measure subjective pain ratings and areas of hyperalgesia and allodynia in a well-established experimental pain model (61) and investigate analgesia elicited by OLP injections accompanied by a short evidence-based treatment rationale, as in a previous study (55). To achieve this goal, Part 1 of our study will examine the duration of OLP analgesia and reevaluate the onset and size of the effect. Given the “inert” nature of OLPs, we assume that results of El Brihi et al. (31) concerning OLP dose effects on participant well-being will be generalizable to all outcomes and will, therefore, not evaluate different OLP dosages. Nevertheless and as stated above, multiple doses of placebos and more frequent intake increase effects (59, 60). Furthermore, participants given a choice over their (deceptive) placebo treatment experience enhanced placebo effects (62). For example, participants in control of the time point of administration of their placebo treatment experienced more placebo analgesia than participants without this control [(63); please note: this study investigated deceptive placebos and used conditioning effects]. This leads us to Part 2 of our study in which we will compare outcomes between participants receiving one OLP injection, participants receiving one repetition of the injection at a fixed time point, and participants receiving one repetition of the injection on demand (i.e., the last group will choose if and when they would like to receive the placebo “Booster”). This form of multiple-dose study aims to fill knowledge gaps concerning OLPs.

Placebo effects have already been observed for a long time. Since Beecher’s often-quoted 1955 study (82), several publications have reported on placebos and placebo effects. Hrobjartsson and Gotzsche (13) provide a nice overview. Significant effects on various conditions have been found, especially patient-reported outcomes, such as pain (13, 16). However, ethical concerns about the deceptive use of placebos have grown (18–20). Therefore, OLPs have been proposed (21) as a means of using placebos in an ethical manner. There is a rising body of knowledge concerning OLPs, and they have been proven to be effective in various clinical conditions including chronic pain. Charlesworth et al. (56) and von Wernsdorff et al. (57) provide an overview of these effects.

Although a well-known challenge, pain management remains difficult in many situations. Therapy options are limited, and positive effects are often diminished by contraindications, side effects, and adverse events (e.g., 2–8). This illustrates the need for new broadly applicable treatments, preferably with few or no side effects, which could augment existing multimodal analgesic concepts (7). OLPs potentially fit this description given the near absence of contraindications and few if any side effects, which are likely avoidable and usually present as nocebo effects (11, 17). Already, a small amount of evidence supports the use of OLPs in acute pain (25–29, 47, 49, 52, 53). However, for clinical implementation, the efficacy of these interventions need to be characterized to a greater extent. This study contributes to this by measuring the duration of OLP analgesia in acute pain. To our knowledge, this is the first study investigating whether repeated OLP doses are more beneficial than a single-dose and when repeated dosing should occur.

A strength of this study is the cross-over design of Part 1, in which participants serve as their own control, thereby enabling comparison between the interventional and control group. Part 2 does not have a cross-over design. Rather, participants are randomized into three different groups, establishing the classic form of randomized controlled trial. In addition, all procedures will be highly standardized, as the same investigators and respective study staff will be interacting with all participants included in each study part. Further strengths include the use of a well-established pain model (61) and the long 200-min measurement period. Finally, in this experimental setting, the assessor will perform measurements every 5 min, which should result in no missing data, contrary to what would be expected for experiments utilizing self-reported questionnaires.

This study also has a few limitations. As this is an experimental study with highly standardized procedures, results will have to be transferred to clinical application with caution. The placebo effect could be altered in clinical populations with possible interfering variables such as comorbidities [particularly if the cognition is impaired (83)], concomitant medication, (negative) emotions (84) or deviant procedures [e.g., no sufficient OLP rationale (26)]. In summary, with this study, we strive to find hypotheses concerning OLPs, which can later be translated to and tested in clinical populations (32).

Three further factors compromise generalizability. First, the population will be recruited through an advertisement on the homepage of the local university, which may lower the diversity of the study population. Second, some bias cannot be ruled out. Due to the nature of OLPs, blinding of participants is not possible. In addition, due to organizational reasons, even the assessor will not be blinded to the intervention in Part 2. Furthermore, it could also be argued, that not providing an interventional rationale to the control group in Part 1 could result in a difference in patient-provider relationship between interventional and control group. Third, for Part 1, we assume that there are no carry-over effects (i.e., we assume that the treatment sequence will not modify the treatment effect). Specifically, while we account for period effects (e.g., in the form of learning to better deal with pain from the first to the second treatment period), we assume that this will not depend on whether the participant received the placebo or the control intervention during the first visit.

In addition, the measurement period could also be seen as a limitation: Although with 200 min it is quite long, and – to our knowledge – longer than the observation time of previous comparable studies, it could still be insufficiently long to fully observe OLP analgesia for acute pain.

In conclusion, although the study faces a few limitations, we are convinced that it has been designed in a way that will extend the knowledge about the use of OLPs in the treatment of acute pain. In particular, the duration of OLP analgesia and possible “Booster” effects will need to be evaluated before implementation to clinical practice is possible. Therefore, this study will add another step towards clinical implementation of a new, broadly applicable treatment for acute pain with few to no contraindications or side effects.

This study is conducted in compliance with the protocol, the current version of the Declaration of Helsinki (85), the ICH-GCP (86), the HRA (87) as well as other locally relevant legal and regulatory requirements.

The protocol of this study was approved by “Ethikkomission Nordwest- und Zentralschweiz” (BASEC 2023-00296) on March 15, 2023. Trial and protocol design were developed according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines (74). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

MdL, ML, JG, WR, and TS contributed to the conception and design of the study. MdL, ML, and TS drafting of the manuscript. All authors contributed to the critical revision, proofreading, and approving of the submitted version.