Placebo analgesic is reliable and effective.

The placebo effect is a reduction in pain intensity that is caused by a “sham” treatment that is disguised to be identical to the “active” treatment. And according to a provocative meta-analysis of RCTs, the strength of the placebo response is steadily increasing each year (1). Read on to learn about the biopsychosocial basis of placebo analgesia, how it works, and who can benefit from it.

The Many Faces of Placebo

Depending on who you ask, “placebo” can mean many different things. The most common assumption is that placebo response is conditioned learning to expect relief with certain healthcare cues (e.g., verbal cues, the act of taking medication, social support).  Research also supports biological predispositions to placebo (2).

1. The Psychosocial Camp

One camp considers placebo to be a learned expectation that reflects a lifetime of health behaviors. The logic goes something like this: every time your parents gave you acetaminophen for a sports injury, or you reached for ibuprofen to get rid of a headache, or you felt better after going to the doctor, you learned that certain cues will likely relieve your physical discomfort. These cues include pills, topical creams, medical procedures, and even talking with a doctor or nurse. The association between these healthcare cues and feeling better caused a certain type of learning to occur, called classical conditioning. In some cases, additional instructions are needed to create a strong placebo response. The importance of learning and causal attributions mean that the placebo effect is a cognitive process (2).

A common example of a conditioned placebo response is the rapid and dramatic pain relief with ibuprofen. Peak serum levels of ibuprofen are reached in 1-2 hours, and yet many people claim full pain relief within 20 minutes of taking the medication. The psychological effect of taking the medication works 3-6 times faster than the medication itself!

2. The Contextual Camp

Psychotherapy research supports the idea that treatment success, including the placebo effect, can be explained by nonspecific treatment “ingredients” that are found in all interventions. In particular, the psychiatrist Jerome Frank argued that all medical treatments, psychotherapies, spiritual counseling, and other healing rituals are effective because they share similar treatment rituals (3).  A ritual is the formal process by which change is expected to occur. The treatment ritual has four major ingredients:

1. 1. An intimate relationship between the practitioner and patient;
   2. The patient believes they will benefit from their interactions with the practitioner, and the practitioner believes they can heal the patient;
   3. Both the patient and practitioner believe that a specific treatment will be effective in relieving the patient’s condition; and
   4. The patient and practitioner actively engage in “rituals” that are part of their chosen treatment approach.

All of these ingredients have to be present for a treatment to be effective, but the patient’s perception of the therapeutic relationship is the most important predictor of change. Treatment rituals can include a large range of behaviors that the patient and provider both take part in, and ritual communication could account for some placebo effects (4). Some examples of treatment rituals include:

• • Physical exams

• • Patient interviews

• • Co-creating treatment plans

• • Writing prescriptions

• • Discussing test results

• • Performing surgery

• • Supervising exercises

• • Patient/researcher interactions

Although this approach may seem similar to the psychosocial camp, the psychosocial camp really emphasizes the patient’s interpretations of their pain care (based on previous learning) as the most important “ingredient” in successful treatment. In contrast, the contextual view of the placebo response focuses on the quality of the interpersonal relationship between a patient and their provider as the most important ingredient for treatment success.

3. The Biological Camp

 “Biological” basis for placebo is an outdated product of arguments that dismissed the placebo effect as psychological and therefore not “real.” Today, we know that all psychological processes have a neurobiological basis because they are produced by the brain. Current thinking is that placebo is rooted in neural circuits that deal with prediction and cognitive judgments, including brain regions that:

• • Recognize and keep track of the value of an experience or cue (e.g., ventromedial prefrontal cortex and lateral orbitofrontal cortex);

• • Mediate more abstract concepts (dorsolateral prefrontal cortex);

• • Identify rewards (nucleus accumbens); and

• • Play more specific roles in pain (i.e., rostroventral medulla and periaqueductal grey).

Some placebo responses may affect pain by interacting with the body’s natural opioid system. This approach was based on a landmark study showing that post-surgery “treatment” with saline (placebo) dramatically reduced pain levels in 30% of the patients. This placebo analgesia was then effectively blocked by a drug that prevents normal opioid processing (naloxone), proving that, in these patients, the placebo response worked just like morphine (5). More recent research describes biological effects of placebo that are independent of endogenous opioids.

Who Responds to Placebo?

Most research on placebo has been conducted in healthy people without chronic pain. These studies show brief placebo effects that last minutes to hours and that, in these cases,  neural correlates can explain the effect (2). This research clearly shows that the placebo effect is a cognitive process. Personality is a major factor that predicts the likelihood that a person will be a placebo responder. The major weakness of this research is that “placebo” has been defined in so many ways, it’s unclear whether all forms of placebo are equally effective.

Despite the high-quality research on placebo in healthy people, we know from brain imaging studies that there are dramatic differences in the brain anatomy and activity of people with chronic pain.  The reorganization of normal brain anatomy makes it unclear whether the placebo effect acts on different brain processes in chronic pain patients (6).  We know that a large placebo effect is reported across chronic pain populations, with reductions in pain that could meaningfully improve daily function. For example, similar rates of placebo response—about a 30% reduction in pain sustained over months—are described people with chronic back pain and osteoarthritis.

5 Explanations for Increasing Placebo Response Rates

So far, we have looked at placebo from the patient perspective. Recent research shows that the placebo effect for neuropathic pain is having a massive influence on the healthcare system in the United States, as it steadily increases in popularity each year (1). These clinical trials are considered the best available scientific evidence of the placebo effect within medical fields, and they even affect FDA approval for new medications. As a result, there are many people who are invested in learning why placebo responses are more common today than 10 years ago.

Explanation #1: Medications for Neuropathic Pain Aren’t Improving

The simplest explanation is that the pharmaceutical companies are cranking out medications that just don’t work. Despite all of the progress in the pain science field, very few new analgesic medications have made it past Phase I and II clinical trials due to unacceptable side effects. We haven’t cracked the code of chronic pain mechanisms yet, and that information is needed to guide new biomedical treatments of chronic pain.

Explanation #2: Measures of Placebo Response Need Improvement

Placebo responses are defined by statistically significant reductions in pain intensity. Statistical differences do not mean that the pain patients had clinically meaningful pain relief. The arbitrary definition of “clinically meaningful” will always be up for debate, but some argue that a 20-40% reduction in pain intensity is needed to positively impact a patient’s ability to function in their day-to-day life.  

Explanation #3: Study Confounds Prevent this Interpretation

Experts like to remind us that the study of placebo is riddled with biases in study design that prevent us from accurately measuring placebo response. Potential confounds range from publication bias (e.g., uninteresting placebo studies never make it to press), huge variation in the methods used to elicit placebo response, drop-outs of patients in placebo groups that don’t get better, and even response bias in patients due to poorly worded questionnaires(2).

Explanation #4: Americans are World Leaders in Placebo Learning

The surge in placebo response in the United States happened as a result of the fast expanding pharmaceutical industry. Super aggressive marketing of medications to cure every ailment—even the ailments you didn’t know you had!—has increased consumption of healthcare services. More healthcare means more doctors visits, more pills, and more opportunity to expect pain relief from a pill. A reasonable explanation is that these experiences have increased expectations of treatment success, and have thus increased a large part of the increasing placebo response rates.

Explanation #5: Patient Expectations Increase with Study Size

The researchers noted that during this same period, large-scale, multiple site pharmaceutical trials are relying on privatized research firms to conduct their research. People who sign up for clinical trials for neuropathic pain medications may be a unique self-selected group that expects this type of treatment setting to give them access to newer, more effective medications.

Do Placebo Responders Have Placebo Brains?

A couple of well-designed brain imaging studies looked at the brain systems related to placebo response in people with chronic back pain (7–8). 

These researchers emphasized that they did not give special instructions about placebo to pain patients. The first study was a double-blind brain imaging RCT that found a moderate placebo response, but this pain relief was equal to benefits provided by 5% lidocaine patches (the “active” treatment in this trial). The researchers argued that the lack of a lidocaine treatment response meant that lidocaine patches were basically placebo treatment, and therefore the treatment groups showed similar placebo effects. They also found brain changes that were detected only in the placebo responders. In the same paper, the researchers validated these findings with an entirely new group of back pain patients. Using the brain markers of placebo response that were found in the first group of patients, they wanted to see if they could identify placebo responders in a new group of patients based on baseline brain scans alone. It worked –these brain changes could single out placebo responders based on brain imaging data obtained before the clinical trial began. On average, pain levels dropped 50% in the placebo responders and didn’t significantly change in nonresponders.

In a second double-blind placebo-controlled RCT of chronic pain patients with knee osteoarthritis, the same research group found a similar sized placebo effect. The researchers included a clever two week “washout” period to make sure they were really seeing a placebo response. They reasoned that true placebo responders would need the experimental “cue”—in this case, sugar capsules—to continue to feel pain relief. Taking the placebo “cues” away during a washout period should cause the pain in the placebo responders to return to baseline pain levels. After washout, the re-introduction of placebo capsules should cause placebo analgesia to develop. These confirmed placebo responders could be detected from baseline brain scans using the brain markers from the chronic back pain patients. By showing that the placebo effect could be reversed and re-introduced, this study provided stronger evidence that placebo response could be strategically used to relieve chronic pain (8).

We don’t know how long these placebo effects would have lasted, so it’s still not clear how useful placebo would be in long-term pain care. The researchers also did not measure disability, so we don’t know whether placebo analgesia improved daily function for these patients.

Can we Identify Placebo Responders?

The successful use of placebo to treat chronic pain depends on how well we can identify the placebo responders who walk into our offices. Recent research has made great strides in understanding which chronic pain patients will be placebo responders. In a double-blind placebo-controlled RCT of patients with chronic low back pain, baseline brain anatomy (including the volume of the hippocampus and amygdala) is able to predict placebo response with over 80% accuracy. The researchers also administered over 30 questionnaires related to pain, mood, and health to demonstrate that the majority of research measures were unable to identify placebo responders. To their surprise, two sub-scales of the Multidimensional Assessment of Interoceptive Awareness (MAIA, 9) scale predicted placebo response just as accurately as brain anatomy. High scores in the “Noticing” subscale (which measures awareness of uncomfortable, comfortable, and neutral body sensations) and the “Self-Regulation” subscale (which measures the perceived ability to use attention to physical sensations to regulate distress) predicted placebo response with over 80% accuracy (10).

How to Use Placebo Analgesia To Help Your Patients

A strategic use of the placebo effect can relieve pain in patients who are either “hardwired” to respond to placebo, or who have previously learned to expect pain relief with intervention. Either way, placebo response results from a person’s subjective response to being treated, which depends on a range of neural processes that connect more abstract types of thinking with expectations of reward. Placebo effects are higher when the patient is given more information about them. A patient has to be aware that they are receiving some kind of treatment, even if they don’t know it is intended to work as a placebo. Providing specific instructions that affect a patient’s expectations is generally more powerful than simply giving a pill.  

So how can you harness the placebo response to help patients heal their own pain? We recommend taking the following steps to maximize the benefits of placebo:

• Administer the MAIA “Noticing” and “Self-Regulation”’ subscales to your patients to identify potential placebo responders.
• Ask your patients about whether their healthcare experiences have been generally positive. Placebo response is related to the perception that healthcare interactions will improve health and reduce suffering, so patients who describe positive expectations have what it takes to be placebo responders.
• Pay attention to the way that treatment effects unfold over time. Research shows that placebo effects take about 4 weeks to develop fully, so it may be less likely that rapid treatment responses are due to placebo.
• Ask your patient if they think they have responded to placebo treatment before. You may be surprised at how aware placebo responders are of their biased treatment responses.

There are many reasons to consider adding placebo to your treatment toolbox. Share your experiences with placebo in the comments section below. I want to hear from you! Reply below or contact us here.

REFERENCES:

1. Tuttle AH, Tohyama S, Ramsay T, Kimmelman J, Schweinhardt P, Bennett GJ, Mogil JS. Increasing placebo responses over time in U.S. clinical trials of neuropathic pain. Pain. 2015;156(12):2616–26

https://www.ncbi.nlm.nih.gov/pubmed/26307858

2. Geuter S, Koban L, Wager TD.

The Cognitive Neuroscience of Placebo Effects: Concepts, Predictions, and Physiology. Annu Rev Neurosci. 2017;40:167-188.

https://www.ncbi.nlm.nih.gov/pubmed/28399689

3. Frank E1, Kupfer DJ, Wagner EF, McEachran AB, Cornes C. Efficacy of interpersonal psychotherapy as a maintenance treatment of recurrent depression. Contributing factors. Arch Gen Psychiatry. 1991;48(12):1053-9.

https://www.ncbi.nlm.nih.gov/pubmed/1845438

4. Kaptchuk TJ. Placebo studies and ritual theory: a comparative analysis of Navajo, acupuncture and biomedical healing. Philos Trans R Soc Lond B Biol Sci. 2011;366(1572):1849-58.

https://www.ncbi.nlm.nih.gov/pubmed/21576142

5. Levine JD, Gordon NC, Smith R, Fields HL. Analgesic responses to morphine and placebo in individuals with postoperative pain. Pain. 1981;10(3):379-89.

https://www.ncbi.nlm.nih.gov/pubmed/7279424

6. Farmer MA, Baliki MN, Apkarian AV. A dynamic network perspective of chronic pain.

Neurosci Lett. 2012;520(2):197-203.

https://www.ncbi.nlm.nih.gov/pubmed/22579823

7. Hashmi JA1, Baliki MN, Huang L, Parks EL, Chanda ML, Schnitzer T, Apkarian AV. Lidocaine patch (5%) is no more potent than placebo in treating chronic back pain when tested in a randomised double blind placebo controlled brain imaging study. Mol Pain. 2012;8:29. https://www.ncbi.nlm.nih.gov/pubmed/2253148

8. Hashmi JA, Baria AT, Baliki MN, Huang L, Schnitzer TJ, Apkarian AV. Brain networks predicting placebo analgesia in a clinical trial for chronic back pain. Pain. 2012;153(12):2393-402. https://www.ncbi.nlm.nih.gov/pubmed/22985900

9. Mehling WE, Price C, Daubenmier JJ, Acree M, Bartmess E, Stewart A. The Multidimensional Assessment of Interoceptive Awareness (MAIA). PLoS One. 2012;7(11):e48230. https://www.ncbi.nlm.nih.gov/pubmed/?term=23133619

10. Berger et al. (Paper recently accepted for publication, will get entire reference soon)