Boosting Open-Label Placebo Effects in Acute Induced Pain in Healthy Adults

Study Overview
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Brief Summary
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This study is to investigate the effect of open-label placebo (OLP) application on acute pain in an experimental model of acute pain (simulating wound pain: this installation will apply monophasic, rectangular electrical pulses of 0.5ms duration with alternating polarity at 2 Hz frequency. The current will be increased to target a pain rating of 6 of 10 on the NRS (0 = no pain, 10 = worst imaginable pain). Three further adjustments in current will be made every 5 minutes for the next 15 minutes to compensate for habituation. This final current will be kept constant until the end of the particular experiment). In Part 1 duration of OLP analgesia will be examined, and onset and size of the effect will be reevaluated. In Part 2 of this study outcomes between subjects receiving one OLP injection, subjects receiving one repetition of the injection on a fixed time point and subjects receiving one repetition of the injection on-demand will be evaluated

Detailed Description
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Pain is highly prevalent in hospital settings. Standard systemic treatment for acute pain consists mainly of basic analgesia. The use of these drugs is often restricted due to their contraindications. Placebo is used nowadays to describe sham treatments and inert substances like sugar pills and saline injections. Placebos are proven to elicit clinically significant effects in various conditions, including pain. Ethical concerns about the use of deceptive placebos have prevented their implementation in clinical practice. A possibility to address this issue would be to prescribe placebos openly, that means, without deception. This randomized crossover study evaluates the efficacy of open-label placebo (OLP) in acute pain. Subjective pain ratings and areas of hyperalgesia and allodynia will be measured in a well-established experimental pain model (intradermal electrical stimulation model evoking pain: this installation will apply monophasic, rectangular electrical pulses of 0.5ms duration with alternating polarity at 2 Hz frequency. The current will be increased to target a pain rating of 6 of 10 on the NRS (0 = no pain, 10 = worst imaginable pain). Three further adjustments in current will be made every 5 minutes for the next 15 minutes to compensate for habituation. This final current will be kept constant until the end of the particular experiment) and analgesia elicited by OLP injections will be investigated. In Part 1 duration of OLP analgesia will be examined, and onset and size of the effect will be reevaluated. In Part 2 of this study outcomes between subjects receiving one OLP injection, subjects receiving one repetition of the injection on a fixed time point and subjects receiving one repetition of the injection on-demand will be evaluated (which leaves the last group a choice over when they would like to have the placebo booster).

Official Title
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Boosting Open-Label Placebo Effects in Acute Induced Pain in Healthy Adults

Conditions
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Acute Pain

Intervention / Treatment
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* Procedure: OLP-injection
* Other: Scripted Evidence-based treatment rationale
* Other: Experimental model of acute pain


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy volunteers (ASA Class I or II), aged 18 to 65 years BMI between 18 and 25kg/m2 Able to understand the study and the NRS Able to give informed consent Exclusion Criteria: Participation in a previous open-label placebo study; for Part 2, this includes Part 1 of this study Regular intake of medications or drugs potentially interfering with pain sensation (analgesics, opioids, antihistamines, calcium and potassium channel blockers, serotonin/ noradrenaline reuptake inhibitors, corticosteroids) Neuropathy Chronic pain Neuromuscular disease Dermatological disease (i.e. Atopic Dermatitis) Psychiatric disease Pregnancy / Lactation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: The first part of this study is designed as a confirmatory, randomized, two-arm, assessor-blinded cross-over trial in a monocentric setup at the University Hospital of Basel. The second part is designed as a proof-of-concept, randomized, controlled, three-arm trial in a monocentric setup at the University Hospital of Basel.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Part 1: Visit 1 (No treatment) followed by Visit 2 (OLP intervention)<br>In Part 1, participants will receive one injection (administration of open-label placebo injections without any active ingredient (5 ml 0.9% saline)) at twenty minutes after start of the experiment during the intervention visit 2. Visit 1 (No treatment) will be the control of the study intervention. | Procedure: OLP-injection<br>* Open-label placebo injections without any active ingredient (5 ml 0.9% saline). All participants will be informed that the administered injections are placebo infusions.<br>Other: Scripted Evidence-based treatment rationale<br>* As a second component the intervention will consist of an evidence-based treatment rationale, which will be delivered to patients receiving the intervention prior to the OLP-injections, explaining placebo analgesia in pain in general and specifically in OLP. In the context of OLP treatments this rationale is important in order to create a mental state of positive expectations.<br>Other: Experimental model of acute pain<br>* Experimental model of acute pain (simulating wound pain: this installation will apply monophasic, rectangular electrical pulses of 0.5ms duration with alternating polarity at 2 Hz frequency. The current will be increased to target a pain rating of 6 of 10 on the NRS (0 = no pain, 10 = worst imaginable pain). Three further adjustments in current will be made every 5 minutes for the next 15 minutes to compensate for habituation. This final current will be kept constant until the end of the particular experiment).<br>|
| Other: Part 1: Visit 1 (OLP intervention) followed by Visit 2 (No treatment)<br>In Part 1, participants will receive one injection (administration of open-label placebo injections without any active ingredient (5 ml 0.9% saline)) at twenty minutes after start of the experiment during the intervention visit 1. Visit 2 (No treatment) will be the control of the study intervention. | Procedure: OLP-injection<br>* Open-label placebo injections without any active ingredient (5 ml 0.9% saline). All participants will be informed that the administered injections are placebo infusions.<br>Other: Scripted Evidence-based treatment rationale<br>* As a second component the intervention will consist of an evidence-based treatment rationale, which will be delivered to patients receiving the intervention prior to the OLP-injections, explaining placebo analgesia in pain in general and specifically in OLP. In the context of OLP treatments this rationale is important in order to create a mental state of positive expectations.<br>Other: Experimental model of acute pain<br>* Experimental model of acute pain (simulating wound pain: this installation will apply monophasic, rectangular electrical pulses of 0.5ms duration with alternating polarity at 2 Hz frequency. The current will be increased to target a pain rating of 6 of 10 on the NRS (0 = no pain, 10 = worst imaginable pain). Three further adjustments in current will be made every 5 minutes for the next 15 minutes to compensate for habituation. This final current will be kept constant until the end of the particular experiment).<br>|
| Other: Part 2/ Group A: 1x OLP (Control)<br>In Part 2, the Group A (Control) receives just one single OLP injection and no repetition. | Procedure: OLP-injection<br>* Open-label placebo injections without any active ingredient (5 ml 0.9% saline). All participants will be informed that the administered injections are placebo infusions.<br>Other: Scripted Evidence-based treatment rationale<br>* As a second component the intervention will consist of an evidence-based treatment rationale, which will be delivered to patients receiving the intervention prior to the OLP-injections, explaining placebo analgesia in pain in general and specifically in OLP. In the context of OLP treatments this rationale is important in order to create a mental state of positive expectations.<br>Other: Experimental model of acute pain<br>* Experimental model of acute pain (simulating wound pain: this installation will apply monophasic, rectangular electrical pulses of 0.5ms duration with alternating polarity at 2 Hz frequency. The current will be increased to target a pain rating of 6 of 10 on the NRS (0 = no pain, 10 = worst imaginable pain). Three further adjustments in current will be made every 5 minutes for the next 15 minutes to compensate for habituation. This final current will be kept constant until the end of the particular experiment).<br>|
| Other: Part 2/ Group B: 2x OLP; booster time fixed<br>In Part 2, Group B participants will receive two injections, the first at twenty minutes after start of the experiment, and the second at a time point derived from Part 1 (if data is inconclusive; at 100 minutes). For every subsequent OLP administration, patients will be reminded of the inertness of the injection and that this injection might help with regulating pain. | Procedure: OLP-injection<br>* Open-label placebo injections without any active ingredient (5 ml 0.9% saline). All participants will be informed that the administered injections are placebo infusions.<br>Other: Scripted Evidence-based treatment rationale<br>* As a second component the intervention will consist of an evidence-based treatment rationale, which will be delivered to patients receiving the intervention prior to the OLP-injections, explaining placebo analgesia in pain in general and specifically in OLP. In the context of OLP treatments this rationale is important in order to create a mental state of positive expectations.<br>Other: Experimental model of acute pain<br>* Experimental model of acute pain (simulating wound pain: this installation will apply monophasic, rectangular electrical pulses of 0.5ms duration with alternating polarity at 2 Hz frequency. The current will be increased to target a pain rating of 6 of 10 on the NRS (0 = no pain, 10 = worst imaginable pain). Three further adjustments in current will be made every 5 minutes for the next 15 minutes to compensate for habituation. This final current will be kept constant until the end of the particular experiment).<br>|
| Other: Part 2/ Group C: 2x OLP; booster on- demand<br>In Part 2, Group C participants will receive two injections, the first at twenty minutes after start of the experiment, and the second on demand. For every subsequent OLP administration, patients will be reminded of the inertness of the injection and that this injection might help with regulating pain. | Procedure: OLP-injection<br>* Open-label placebo injections without any active ingredient (5 ml 0.9% saline). All participants will be informed that the administered injections are placebo infusions.<br>Other: Scripted Evidence-based treatment rationale<br>* As a second component the intervention will consist of an evidence-based treatment rationale, which will be delivered to patients receiving the intervention prior to the OLP-injections, explaining placebo analgesia in pain in general and specifically in OLP. In the context of OLP treatments this rationale is important in order to create a mental state of positive expectations.<br>Other: Experimental model of acute pain<br>* Experimental model of acute pain (simulating wound pain: this installation will apply monophasic, rectangular electrical pulses of 0.5ms duration with alternating polarity at 2 Hz frequency. The current will be increased to target a pain rating of 6 of 10 on the NRS (0 = no pain, 10 = worst imaginable pain). Three further adjustments in current will be made every 5 minutes for the next 15 minutes to compensate for habituation. This final current will be kept constant until the end of the particular experiment).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Change in Area under the Pain Curve (AUPC) | Area under the Pain Curve (AUPC) using the numeric rating scale (NRS; 0 = no pain, 10 = worst imaginable pain) during three hours after administering an OLP | During three hours after administering an OLP | 
| Part 2: Change in Area under the Pain Curve (AUPC) | Area under the Pain Curve (AUPC) using the numeric rating scale (NRS; 0 = no pain, 10 = worst imaginable pain). Comparison of the AUPCs of subjects receiving just one OLP injection with subjects additionally receiving one repetition of OLP administration at a time point derived from Part 1 and subjects getting the second OLP injection on-demand. | During three hours after administering an OLP | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 and 2: Change in subjective pain ratings on each measurement point using the numeric rating scale (NRS) | Change in subjective pain ratings on each measurement point using the numeric rating scale (NRS); NRS; 0 = no pain, 10 = worst imaginable pain) every five minutes after OLP administration) | Up to 200 minutes after electrical pain stimulation | 
| Part 1 and 2: Change in Area under the Curve (AUC) of area of hyperalgesia | Change in Area under the Curve (AUC) of area of hyperalgesia comparing the intervention and control (no treatment) visit. Pinprick hyperalgesia will be assessed every 10 minutes after OLP administration) using a 600 millinewton (mN) von Frey filament. | Up to 200 minutes after electrical pain stimulation | 
| Part 1 and 2: Change in Area under the Curve (AUC) of area of allodynia | Change in Area under the Curve (AUC) of area of allodynia comparing the intervention and control (no treatment) visit. Allodynia will be determined using a dry cotton swab every 10 minutes after OLP administration). | Up to 200 minutes after electrical pain stimulation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Open-Label Placebo (OLP), OLP analgesia, acute pain, hyperalgesia, allodynia