Placebo for Pain Management

(WASABI Trial)

Overseen By Tor D Wager, PhD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Trustees of Dartmouth College

Must not be taking: Antidepressants, Mood stabilizers, Opiates, others

Disqualifiers: Cancer, Cardiovascular disease, Neurological disorders, others

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

Compensation: Varies

Number of Visits: 2

150 Participants Needed

Trial Summary

What is the purpose of this trial?

This functional magnetic-resonance imaging study of the brain will feature a within-subject crossover design to investigate the effects of a placebo cream on painful thermal stimulation rendered upon eight body sites. The investigators aim to 1.) improve the understanding of how the brain represents thermal pain responses somatotopically (i.e., across different body-sites) 2.) to test these brain representations with and without the presence of a pain-targeted placebo intervention, and 3.) to examine how these brain representations change prior to vs. during the delivery of thermal pain. They predict that placebo cream will downregulate the intensity of aversive brain activity representations, and to a lesser degree, sensation and somatotopic representations, both prior to and during painful thermal stimulation.

Will I have to stop taking my current medications?

The trial requires that participants have not been treated with certain medications like antidepressants, mood stabilizers, glucocorticoids, opiates, antipsychotics, and some others within the last month. If you are currently taking these, you may need to stop before participating.

Is the placebo cream safe for use in humans?

A small survey of prescribing providers found that topical compounded pain creams, which include placebo creams, were considered safe for patients. These creams are commonly used for musculoskeletal and neuropathic pain, and prescribers felt they were a safe alternative to narcotics. ^{1 2 3 4 5}

How does the placebo treatment for pain management differ from other treatments?

The placebo treatment for pain management is unique because it relies on the psychological effect of believing in the treatment rather than active ingredients, and it can be enhanced by giving patients control over when they receive it, which can increase its effectiveness and duration. ^{1 3 6 7 8}

Research Team

Tor D Wager, PhD

Principal Investigator

Dartmouth College

Eligibility Criteria

This study is for volunteers over 18, with no history of pathological pain or chronic conditions, who can tolerate heat on their forearm. They must not be pregnant, have metal in their body, suffer from severe cardiovascular issues or neurological disorders, smoke heavily, use alcohol frequently, or have had recent psychoactive substance abuse.

Inclusion Criteria

You should not have any current or recent history of severe pain.

If female, the subject must be non-lactating, not pregnant, and using a reliable contraception method

Subject must be able to understand and follow the instructions of the investigator and understand all screening questionnaires

Exclusion Criteria

You have metal in your body or have worked with metal fragments in the past (like as a machinist).

You cannot handle heat pain applied to your forearm.

If female, pregnancy

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

fMRI Scanning - Sensation and Aversiveness

Participants undergo fMRI scanning to isolate sensation, aversiveness, and somatotopic subcomponents of pain using thermal and auditory stimuli.

1 hour

1 visit (in-person)

fMRI Scanning - Placebo Treatment

Participants undergo fMRI scanning to examine the response of isolated subcomponents to placebo treatment for heat pain.

1 hour

1 visit (in-person)

Follow-up

Participants are monitored for any delayed effects or adverse reactions post-treatment.

2-4 weeks

Treatment Details

Interventions

• Control Cream
• Placebo Cream

Trial Overview The trial tests the effects of a placebo cream on brain activity during painful heat exposure to different body sites using fMRI scans. It aims to see if the placebo alters how the brain processes and anticipates pain before and during thermal stimulation.

Participant Groups

Group I: Placebo Cream first Experimental Treatment 2 Interventions

Each participant will undergo thermal pain tasks after being administered a "treatment" cream to one of eight body sites.

Group II: Control Cream first Experimental Treatment 2 Interventions

Each participant will undergo thermal pain tasks after being administered a "control" cream to one of eight body sites.

Who Is Running the Clinical Trial?

Trustees of Dartmouth College

Lead Sponsor

Trials

32

Recruited

14,500+

Findings from Research

In a study involving 87 healthy volunteers, providing individuals with control over when they administer a placebo treatment significantly enhanced the effectiveness and duration of placebo analgesia compared to standard passive conditioning.

Participants with instrumental control not only experienced greater pain relief but also showed reduced anxiety responses, suggesting that giving patients control could be a simple and ethical way to improve pain management outcomes in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Instrumental Control Enhances Placebo Analgesia. Tang, B., Geers, A., Barnes, K., et al.[2020]

A systematic review of 234 randomized placebo trials involving 10,525 patients found that placebo interventions generally do not have clinically important effects across various health conditions, with a pooled effect size indicating minimal benefit.

However, placebo interventions showed some influence on patient-reported outcomes, particularly for pain and nausea, although the effects varied widely and were often difficult to separate from reporting biases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Placebo interventions for all clinical conditions. Hróbjartsson, A., Gøtzsche, PC.[2022]

A survey of 11 U.S. physicians revealed that topical compounded pain creams are commonly used for treating musculoskeletal and neuropathic pain, and most prescribers believe these creams are more effective than FDA-approved alternatives.

The majority of physicians reported that using these compounded creams allowed them to reduce narcotic prescriptions, and they considered these compounds to be safe for their patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A brief survey on prescriber beliefs regarding compounded topical pain medications. Warner, M., Tuder, D.[2015]

Topical treatments for pain have a long history, utilizing various substances like menthol and capsaicin, which work by interacting with pain-sensing nerves and reducing inflammation.

The future of topical pain relief looks bright, with new drugs being developed to target specific pain mechanisms and improved methods for enhancing skin penetration and ensuring safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topical treatment in pain medicine: from ancient remedies to modern usage. Finch, PM., Drummond, PD.[2015]

Topical analgesic creams for neuropathic pain are underutilized despite their advantages over patches, such as ease of application and patient involvement in treatment.

Targeting keratinocytes in the skin with these creams can provide effective and safe pain relief, suggesting that topical formulations may be a promising new approach for managing neuropathic pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Skin matters! The role of keratinocytes in nociception: a rational argument for the development of topical analgesics. Keppel Hesselink, JM., Kopsky, DJ., Bhaskar, AK.[2021]

In a randomized, double-blind, placebo-controlled trial involving 15 children, a topical anesthetic cream significantly reduced pain during venepuncture compared to a placebo.

The effectiveness of the topical anesthetic was confirmed through both visual analogue and verbal rating scales, indicating its reliable pain-relief properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topical anaesthesia for venepuncture. Clarke, S., Radford, M.[2019]

In a study involving 2177 patients with various chronic pain conditions, two compounded topical creams (Cream I and Cream II) significantly reduced pain intensity scores by 37% and 35%, respectively, compared to a 19% reduction with Voltaren gel.

Both Cream I and Cream II were found to be more effective than Voltaren gel, suggesting that compounded topical formulations may offer better pain relief options for patients with chronic pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Evaluation on the Analgesic Activities of 2 Compounded Topical Creams and Voltaren Gel in Chronic Noncancer Pain. Somberg, JC., Molnar, J.[2022]

In a study involving 18 healthy volunteers, the use of a sham analgesic cream led to a significant reduction in pain ratings and laser-evoked potentials, suggesting that placebo responses can effectively reduce perceived pain.

The findings indicate that the observed placebo effects are not due to sensory habituation or compliance, as the control group (13 volunteers) showed no change in pain response, highlighting the genuine impact of placebo treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Placebo analgesia is not due to compliance or habituation: EEG and behavioural evidence. Watson, A., El-Deredy, W., Vogt, BA., et al.[2007]

References

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

Instrumental Control Enhances Placebo Analgesia. [2020]

2. England pubmed.ncbi.nlm.nih.gov

Placebo interventions for all clinical conditions. [2022]

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

A brief survey on prescriber beliefs regarding compounded topical pain medications. [2015]

4. England pubmed.ncbi.nlm.nih.gov

Topical treatment in pain medicine: from ancient remedies to modern usage. [2015]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Skin matters! The role of keratinocytes in nociception: a rational argument for the development of topical analgesics. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Topical anaesthesia for venepuncture. [2019]

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

Retrospective Evaluation on the Analgesic Activities of 2 Compounded Topical Creams and Voltaren Gel in Chronic Noncancer Pain. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Placebo analgesia is not due to compliance or habituation: EEG and behavioural evidence. [2007]