Open-Label Placebo for Chronic Pain

Overseen By Yang Wang, PhD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Maryland, Baltimore

Disqualifiers: Neuromuscular, Cardiovascular, Neurological, Psychiatric, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

111 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. It seems likely that you can continue your usual care, especially if you are in the standard of care group.

What data supports the effectiveness of the treatment Open-label placebo for chronic pain?

Research shows that open-label placebos, where patients know they are taking a placebo, can still lead to symptom relief in conditions like chronic pain. Studies suggest that patients' expectations and perceptions of treatment can significantly influence the effectiveness of placebos, even when they are aware that the treatment contains no active medication. ^{1 2 3 4 5}

Is open-label placebo treatment safe for humans?

Open-label placebo treatments have been studied for various conditions, including chronic low back pain and acute postoperative pain, and no long-term adverse effects have been reported. These treatments are generally considered safe, as they do not involve active medication, but more research is needed to fully understand their safety profile. ^{6 7 8 9 10}

How does open-label placebo treatment differ from other treatments for chronic pain?

Open-label placebo treatment is unique because it involves giving patients a placebo (a pill with no active medication) while fully informing them that it is a placebo. Unlike traditional treatments that rely on active ingredients, this approach leverages the psychological effects of taking a pill, which can still lead to symptom relief in conditions like chronic pain. ^{4 6 7 11 12}

What is the purpose of this trial?

The goal of this free-choice parallel design clinical trial is to examine the potential beneficial effects of using open-label placebo (OLP) in improving chronic pain related outcomes and sleep quality in people with temporomandibular disorders. This study will enroll a cohort of participants with temporomandibular disorders (TMD) which lasts for more than 3 months. The main questions it aims to answer are: 1. Will participants with TMD be more likely to take open-label placebo pills if they are introduced to the effects of placebo (e.g., going through an expectation management session)? 2. Will taking open-label placebo plus expectation management improve chronic pain related outcomes, such as chronic pain intensity, interference, levels of anxiety and depression, in the cohort of TMD? 3. Will open-label placebo plus expectation management improve sleep quality in participants suffering from TMD? To answer the above questions, participants with TMD will be randomly assigned to three groups: 1. Open-label placebo plus expectation management group, where participants will complete a 1-hour discussion session about their expectations toward open-lable placebo intervention, and then take 1 open-labe placebo pill per day for a total of 45 days. 2. Open-label placebo only group where participants will be asked to take open-label placebo pills, one pill per day, for a total of 45 days. 3. standard of care group where participants will maintain their usual care without introducing open-label placebo to them during the 45 days monitoring. Researchers will compare the chronic pain intensity, interference, mood, anxiety, and sleep quality between the open-label placebo group and the wait-list group. Daily chronic pain will be measured using visual analog scale (VAS) ranging from 0=no pain at all to 100=maximum tolerable pain. Chronic pain interference using Patient-Reported Outcomes Measurement Information System (PROMIS) pain interference and pain behavior. Anxiety and depression will be measured using PROMIS-anxiety, and PROMIS-depression scales respectively. Finally, sleep quality will be quantified using the objective measurement Motion Watch during the 45 days intervention and monitoring. In order to have a rigorous measurement of the baseline pain and sleep fluctuation, this study will include a 7-day phenotyping period before the starting of the 45-day intervention and monitoring. During the 7-day phenotyping period, participants will record their daily chronic pain and sleep quality using polysomnography.

Eligibility Criteria

This trial is for individuals aged 18-88 with chronic headaches lasting over 3 months, who can communicate via smartphone/text and speak English. They should have a minimum pain level on the Grade Chronic Pain Scale.

Inclusion Criteria

I can speak and write in English.

I have had chronic headaches for at least 3 months.

I have a smartphone and can send text messages.

Timeline

Phenotyping

Participants undergo a 2-day phenotyping phase to assess baseline chronic pain and sleep patterns

2 days

1 visit (in-person), 2 days (at-home monitoring)

Intervention

Participants are randomized into groups and undergo a 45-day intervention with open-label placebo and/or expectation management

45 days

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after the intervention

4 weeks

Treatment Details

Interventions

• Open-label placebo

Trial Overview The study tests if open-label placebo pills, especially when combined with expectation management sessions, can improve pain and sleep in people with temporomandibular disorders. Participants are divided into three groups: one receiving placebo plus expectation talks, another just the placebo, and a third continuing usual care without placebos.

Participant Groups

Group I: Open label placebo only arm Experimental Treatment 1 Intervention

Participants who are assigned to the OLP group will be given a bottle of OLP pills. They will be asked to take one pill per day for 45 days. They will be introduced to placebo effects and the therapeutic potential of using open-label placebo for chronic pain management and sleep improvement.

Group II: Open label placebo + expectation management Experimental Treatment 1 Intervention

Participants assigned to this arm will complete an 1 hour discussion about their expectations towards open-label placebo intervention. After that, they will continue with the 2-day run-in period and 45-day intervention. They will be asked to take 1 open-label placebo pill per day, for a total of 45 days.

Group III: Wait-list arm Active Control 1 Intervention

Participants in the wait-list group will not receive OLP pills until the end of the 45-day monitoring period. Therefore, the 45 days without OLP will serve as an no intervention comparators relative to the OLP group.

Who Is Running the Clinical Trial?

University of Maryland, Baltimore

Lead Sponsor

Trials

729

Recruited

540,000+

Findings from Research

In a study involving knee osteoarthritis and non-radicular low back pain patients, significant placebo effects were observed, particularly in pain intensity and range of motion, indicating that the placebo response can influence both self-reported and performance-based outcomes.

The study found that gender and diagnosis affected the magnitude of placebo responses, with women in the knee osteoarthritis group showing notable improvements, suggesting that these factors should be considered in future clinical trials to better understand and potentially mitigate placebo effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

"Managing" the Placebo Effect: The Single-Blind Placebo Lead-in Response in Two Pain Models. Harden, RN., Saracoglu, M., Connolly, S., et al.[2018]

In a review of 42 trials on neuropathic pain and 29 trials on low back pain, it was found that participants on placebo consumed significantly more rescue medication (RM) than those on active drugs, which could mask the true effectiveness of the treatments.

Specifically, in trials showing a small to medium effect size for the investigational drugs, placebo participants used 17% to 30% more RM, highlighting the need for better analytical methods to account for RM consumption in chronic pain studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of rescue medication in placebo-controlled trials of pharmacotherapy for neuropathic pain and low back pain. Grøvle, L., Hasvik, E., Haugen, AJ.[2023]

A 5-year follow-up of patients who participated in a 3-week open-label placebo trial for chronic low back pain showed significant long-term reductions in pain and disability, with improvements persisting over time.

Participants also reported a substantial decrease in the use of pain medications, suggesting that the benefits of open-label placebo treatment may lead to lasting changes in pain management behaviors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-label placebo for chronic low back pain: a 5-year follow-up. Carvalho, C., Pais, M., Cunha, L., et al.[2023]

This ongoing randomized controlled trial involves 70 patients recovering from dorsal lumbar interbody fusion surgery, investigating the effectiveness of adding open-label placebos to standard opioid treatment to reduce opioid consumption and side effects.

The study aims to provide insights into how open-label placebos can enhance pain management without compromising efficacy, potentially offering a cost-effective strategy to minimize opioid use in acute postoperative pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-Label Placebo Treatment for Acute Postoperative Pain (OLP-POP Study): Study Protocol of a Randomized Controlled Trial. Sezer, D., de Leeuw, M., Netzer, C., et al.[2021]

In a review of 18 studies involving 3546 patients with fibromyalgia syndrome, a significant 18.6% of participants experienced a 50% reduction in pain from placebo treatments, highlighting the strong placebo effect in chronic pain trials.

The study also found that 10.9% of patients in placebo groups dropped out due to adverse events, indicating a notable nocebo effect, which suggests that both placebo and nocebo responses play a critical role in the perceived efficacy and safety of drug treatments for fibromyalgia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Placebo and nocebo responses in randomised controlled trials of drugs applying for approval for fibromyalgia syndrome treatment: systematic review and meta-analysis. Häuser, W., Sarzi-Puttini, P., Tölle, TR., et al.[2022]

In a study involving 52 Japanese patients with chronic low back pain, the addition of open-label placebo (OLP) to standard treatment did not show superior benefits compared to standard treatment alone after 3 and 12 weeks.

Both groups experienced significant improvements in functional disability, indicating that while OLP did not enhance outcomes, standard treatment was effective in reducing disability in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-Label Placebo Trial among Japanese Patients with Chronic Low Back Pain. Ikemoto, T., Ueno, T., Arai, YC., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

"Managing" the Placebo Effect: The Single-Blind Placebo Lead-in Response in Two Pain Models. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Impact of rescue medication in placebo-controlled trials of pharmacotherapy for neuropathic pain and low back pain. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Open-label placebo for chronic low back pain: a 5-year follow-up. [2023]

4. Germany pubmed.ncbi.nlm.nih.gov

[Appearances are not deceptive: clinical evidence and new research approaches to open-label placebo]. [2020]

5. Germany pubmed.ncbi.nlm.nih.gov

Can insights from placebo and nocebo mechanisms studies improve the randomized controlled trial? [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Pain Response to Open Label Placebo in Induced Acute Pain in Healthy Adult Males. [2020]

7. United States pubmed.ncbi.nlm.nih.gov

No long-term effects after a 3-week open-label placebo treatment for chronic low back pain: a 3-year follow-up of a randomized controlled trial. [2023]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Open-Label Placebo Treatment for Acute Postoperative Pain (OLP-POP Study): Study Protocol of a Randomized Controlled Trial. [2021]

9. Italy pubmed.ncbi.nlm.nih.gov

Placebo and nocebo responses in randomised controlled trials of drugs applying for approval for fibromyalgia syndrome treatment: systematic review and meta-analysis. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Evaluating the benefits of a second pain treatment following a clinical trial. [2023]

11. United States pubmed.ncbi.nlm.nih.gov

Effects of open-label placebo on pain, functional disability, and spine mobility in patients with chronic back pain: a randomized controlled trial. [2020]

12. United States pubmed.ncbi.nlm.nih.gov

Open-Label Placebo Trial among Japanese Patients with Chronic Low Back Pain. [2021]