From Bench to Bedside: Converting Placebo Research into Belief Activation

Abstract

Research on the placebo effect contains important elements that can be harnessed to improve clinical care. This paper proposes a new term, “Belief Activation,” to describe the deliberate use of placebo effect tools by both patients and clinicians to catalyze healing. Belief Activation includes, but is not limited to, maximizing patient and practitioner expectations, classical and social conditioning, spirituality and prayer/intention, therapeutic relationship, healing environments, and minimizing the nocebo effect. This paper demonstrates ways in which Belief Activation is a form of evidence-based medicine and seeks to translate knowledge from placebo research into medical practice.

From Bench to Bedside: Converting Placebo Research into Belief Activation

There is a large body of evidence on the placebo effect that reveals useful clinical tools. While in research we seek to minimize the placebo effect to gauge the effectiveness of a specific therapy, in clinical practice we can harness the powerful and innate healing mechanisms that are called placebo. This paper proposes a new term, “Belief Activation,” to describe the conscious use of different aspects of the placebo effect by patients and clinicians to maximize healing. Belief Activation has the potential to offer patients safety, efficacy and co-creation in a new form of evidence-based medicine.

There are three main myths regarding the placebo effect. The first myth is that placebo is purely subjective—that patients “think” they are getting better, but there is no physiological healing. Studies demonstrate that placebo medication can improve objective measures such as C-reactive protein,¹ liver enzymes,² pulmonary function,^3,4 white blood cell count,⁵ postprandial glucose,⁶ brain glucose metabolism,⁷ dopamine⁸ pCO₂ levels,⁹ beta adrenergic activity of the heart,¹⁰ opioids¹¹ and cortisol levels.¹² In reality, the mind helps the body to make the medicine.

The second myth is that the placebo effect is limited to a 30% effectiveness rate. This belief originated from a 1955 study whose conclusions about the overall placebo effect size were biased due to methodological errors in analysis.¹³ Many studies have since reported that placebo effect is not limited to this low percentage.^14

–17 In a systematic review, 193 placebo-controlled trials on the treatment of osteoarthritis examined a range of nonpharmacological, pharmacological, and invasive treatments in 16,364 patients and reported the placebo response rate to be 51%.¹⁸ In contrast, the 14 trials on osteoarthritis with no treatment controls (placebo effect lacking) showed a response rate of almost 0.¹⁸

The final myth is that placebo requires deceiving our patients,¹⁹ when in fact some “open label” or transparent placebo trials have been highly successful.^17,20 In a controlled trial with migraine sufferers, the benefits of placebo persisted even when placebo was honestly described.²⁰ In a randomized controlled trial (RCT) of patients with irritable bowel syndrome (IBS), patients were given placebo of two gel caps twice daily versus no-treatment. Patients were told “the placebo effect is powerful, the body can automatically respond to taking placebo pills, a positive attitude helps, but is not necessary,” and that “taking the pills faithfully is critical.” The study reported that 59% of patients with open placebo had adequate relief versus 35% with the no-treatment control at 21 days (p = 0 .03).¹⁷ To put this result in perspective, a meta-analysis of double-blind placebo-controlled trials of Alosetron in IBS, estimated that 51% of patients taking Alosetron had adequate relief versus 38% reporting relief with placebo.²¹ If a 51% response rate indicates a successful drug to be marketed and prescribed for IBS, then clearly open placebo with 59% response rate should also be considered a treatment option.

Placebo could become a form of evidence-based medicine. Oral placebo was effective for 56% of patients experiencing cancer-related fatigue,¹⁶ 70% of women experiencing menopausal hot flashes,¹⁵ and may account for 75%–82% of the effectiveness of antidepressants.²² Oral placebo has also been associated with decreased mortality.²³ More adherent placebo participants in the Heart and Estrogen/Progestin Replacement Study had significantly lower total mortality compared with less adherent participants (hazard ratio, 0.52; 95% confidence interval, 0.29–0.93).²³ Placebo vaginal cream was 73% effective at eradicating human papilloma virus.¹⁴ Sham surgery was as effective as arthroscopy lavage or debridement for osteoarthritis of the knee,²⁴ and sham surgery was also as effective for angina as ligation of the internal mammary artery.²⁵ It has been observed that placebo effectiveness increases when the treatment is a procedure²⁶ versus a cream or versus a pill.²⁷ These studies provide an indication that we can dig deeper into safe and potentially effective placebo approaches.

Irrespective of physician comfort level with the use of placebo, patient acceptability has been found to be surprisingly high. A large survey of diverse patient populations reported that 70% of patient respondents viewed placebo use acceptable even when the patient has no knowledge of its use, and approximately 79% of respondents viewed placebo use as acceptable with transparent communication about its use.²⁸ In a second large qualitative survey, patients described the reasoning behind their support of placebo as being lack of harm and potential benefit, with 85–96% of patients reporting belief that the mind can influence clinical care and outcomes. In the minority of patients who did not find placebo acceptable, reasons included obligation of the doctor to do more and the desire for transparency.²⁹ In fact, there is an opportunity for physicians to “do more” simply by accessing Belief Activation strategies in addition to routine medical care.

There are a number of aspects of Belief Activation that we could deliberately use to improve outcomes in clinical practice. These include maximizing patient expectancy, classical conditioning, social conditioning, healing environment, practitioner expectancy, exploring spirituality/religious beliefs, strengthening the therapeutic relationship, harnessing telecebo effect, and minimizing nocebo. In this review are thirteen methods that put placebo evidence into practice:

1. Patient expectations are a large part of Belief Activation. In a systematic review, 15 of 16 studies showed that positive expectations of outcome were associated with better health outcomes.³⁰ As practitioners, we can help patients access Belief Activation by speaking positively about treatments^31

–34 and by being enthusiastic.³² While we do not want to promise patients that they will be healed using a particular technique, we do want to be hopeful and build on our patients' strengths. We can reinforce patients' beliefs in themselves with phrases such as “it sounds like your body has recovered well from serious illnesses in the past” or “you are a resilient person.” Also, we can reinforce patients' beliefs in treatments by mentioning patients who responded positively in a similar situation.

2. Goal activation is when unconscious goals (such as the desire to cooperate with medical staff, social inclusion, personal empowerment, or the need to achieve) get activated by situational cues.³⁵ When study participants were primed with an incompatible or unattainable goal with placebo, no evidence of placebo effect was found.³⁵ Understanding and confirming patient motivations³⁵ and understanding and considering potential opposing goals (such as secondary gain from an illness) are useful steps in solidifying patient expectancy.

3. Patient preference and Sense of control help to maximize expectancy. Patient preference helps replicate past successes³⁶; whenever possible, it is best to offer treatments for patients to choose from. Actively engaging patients to have a sense of control over their disease processes may also produce better outcomes.³⁷ In pain, anxiety, and Parkinson's disease studies, patients informed of timing and potential benefit of receiving treatment had significantly better outcomes than those from whom treatments were concealed.³⁸

4. Classical conditioning is a process in which a certain stimulus evokes a specific response when repeatedly paired with another stimulus. Procedures of any kind tend to activate Classical Conditioning,²⁷ for example, acupuncture, cranio-electrical stimulation, laser, intravenous therapies, and hands-on therapies. It may also be beneficial and supportive to lean toward delivery systems with a distinct smell or taste to access classical conditioning.^5,36 An example would be chewable natural health products or herbs with a distinct smell/taste.

5. Conditioned placebo substitution is a new dosing strategy where physicians begin to dose patients with full strength medication and then give lower doses or placebo for maintenance. In psoriasis, patients receiving 25% to 50% of the initial dose long term had the same response rates as full dose long term.³⁹ In children with attention-deficit disorder, after the optimal stimulant dose was determined, pairing placebos with stimulant medication allowed for maintenance at 50% dose that was as effective as full strength maintenance.⁴⁰ In another example, a child with lupus had a beneficial outcome and response when half of the standard 12 monthly cyclophosphamide sessions were replaced with the taste and smell stimuli of the treatment alone.⁴¹

6. Social conditioning is based on the idea that we learn health responses by observing others and “beliefs are contagious”⁴² (a concept described by Bertrand Russell). Placebo analgesia rates were enhanced in two different studies by watching a demonstrator receive pain relief from a placebo.^43,44 In practice, we can harness the tool of social conditioning by asking about health successes among family or friends and, when appropriate, use similar treatment approaches. Conversely, social conditioning may also include negative expectations or beliefs regarding therapies. In these situations, we can help by voicing the patient's concern or fear, and leverage ourselves as part of a patient's social conditioning. An example from cancer care would be, “It's true that some women get joint pain with hormone blockers. If I can share with you my experience…I have a large group of breast cancer survivors in my practice who do not feel any different on or off of their hormone blocker. Every person is completely unique in how they respond to medication, so one never knows until one tries.”

7. Creating a Healing environment can potentially trigger the mobilization of a patient's emotion regulatory resources.⁴⁵ Research has demonstrated that patients with a window view to nature had shorter stays at the hospital and took less potent analgesic medication.⁴⁶ Other data suggest that exposure to natural environments may improve mental well-being and reduce stress.^47,48 The representation of nature through art has also been associated with health benefits.⁴⁵ Strategies to improve noise control in a hospital improved cardiac patient recovery,⁴⁹ and noise can be managed by lowering telephone volumes, placing occupants in single rooms, and dimming lights.⁵⁰ Attention to the healing environment not only impacts patients but also supports clinicians by helping to prevent compassion fatigue or burnout.⁵¹

8. Practitioner expectancy refers to our own beliefs and is surprisingly impactful. In a double-blind RCT, when doctors were lead to believe that the medication could not work, patients experienced almost no placebo effect.⁵² We can boost our own positive expectancy through things like reading positive research on our therapies, reviewing successful cases with colleagues, and reading thank-you letters from patients. We can also notice when we do not expect a therapy to work, and make a deliberate choice about how much of this doubt we communicate to patients who may be invested in that therapy.

9. Spirituality and religious belief are powerful health resources.^53
–55 While many researchers believe that patient expectancy is the primary determinant of placebo response, spiritual belief impacts placebo independently from patient expectancy, and possibly with greater effect.^55,56 Connection to a religious community can positively affect health because it is associated with social support, increased sense of coherence,⁵⁴ avoidance of health risk behaviors, hope in the face of illness and adversity, and maintaining meaning and purpose in life.⁵³ Religiosity/spirituality is linked to health-related physiological processes, including blood pressure, immune function, and neuroendocrine balance.⁵⁷ We do not have to agree with our patients' spiritual beliefs. Rather, we can ask open-ended questions regarding spirituality, and affirm that spirituality has a powerful and positive impact on health.^53
–55 This posture reinforces individuals' internal and external resources.

10. The Therapeutic relationship between doctor and patient captures interpersonal healing. In a meta-analysis of 13 RCTs, therapeutic relationship was found to statistically significantly affect healthcare outcomes.⁵⁸ A key feature of the therapeutic relationship is communication. In a systematic review of 21 trials, effective physician–patient communication significantly improved patient health outcomes.⁵⁹ Aspects of good communication include listening and providing reassurance,^33,60 as well as detailed instructions. Providing reassurance does not mean it is ok to reassure patients about ultimate outcomes in life-threatening cases. Rather, it is by having a warm, friendly, and reassuring manner,³¹ demonstrating certainty about the diagnosis,³⁶ using diagnostic tests,⁶¹ and providing detailed instructions.^62,63

11. Emotional care ultimately supports the therapeutic relationship. Emotional care includes mutual trust, empathy, respect, genuineness, acceptance, and warmth.^34,58 Emotional care is strengthened by asking open-ended questions, resisting interrupting patients, checking patients' understanding of the diagnosis and recommended treatment, and identifying and responding to patient expectations and fears.⁵⁸ In an antidepressant trial, variance in depression scores were more determined by psychiatrists than by medication.⁶⁴ In addition, patients of physicians with high empathy scores were significantly more likely to have good control of hemoglobin A1c (56%) than were patients of physicians with low empathy scores (40%, p < 0.001).⁶⁵

12. Telecebo effect is a term coined by physician and author Larry Dossey.⁶⁶ Telecebo is “the exteriorization of the intentions, thoughts, and emotions of a clinician toward a patient.” Most clinicians are not trained in distance healing and consider prayer or intention outside of our scope. However, it cannot hurt, and may help to create some brief personal ritual or demonstrative action, to add our healing intentions to our patients' own placebo responses. This can be as simple as thinking positively of our patients outside of visits or could include praying for patients while at your own place of worship. Positive findings on intention and distance healing have been demonstrated in six different systematic reviews and meta-analyses.^67

–72 For example, in a double-blind RCT, impact of distance healing was evaluated for narcotic analgesic use after foot and ankle surgery. Subjects in the distance healing group took, on average, seven less narcotics than controls (p = 0.01).⁷³ In a double-blind crossover trial, the impact of healing intention was demonstrated even in the absence of patient belief in its possibility. The impact of herbal teas that were prayed over by Buddhist monks was compared to the impact of tea that was not prayed over. Those who received the treated tea, regardless of their belief, showed a greater increase in mood than the untreated tea group (Cohen's d = 0.65, p = 0.02, two-tailed).⁷⁴

13. The Nocebo effect is the opposite of placebo—when negative expectations lead to side effects.⁷⁵ Cancer patients with higher expectations of chemotherapy side effects are reported to have more side effects.⁷⁶ While research is mixed on whether describing side effects in detail increases nocebo,^77,78 we can heighten our awareness that the way side effects are communicated may be quite important. Nocebo can be minimized by framing potential side effects with treatment benefits and personalizing informed consent.⁷⁹ Nocebo can also be reduced by reassuring word choice. For example, use of languages such as “You will feel a big bee sting, this is the worst part of the procedure” resulted in much more reported pain than “We are going to give you a local anesthetic that will numb the area and you will be comfortable during the procedure.”⁶⁰ Furthermore, it appears that assessing treatment side effects does not increase the likelihood of nocebo⁷⁶; so it may support the therapeutic relationship and provide optimal care to freely inquire about side effects and to offer reassurance.⁶⁰

The above considerations are strategies for transforming placebo into Belief Activation, which may improve outcomes without side effects or harm. One area of potential abuse of Belief Activation would be failure to treat life-threatening conditions. Patients or integrative practitioners who overestimate the power of natural therapies may then fail to use curative conventional therapies. This happens in integrative oncology, where patients can believe so strongly in a website or a film series that they refuse conventional care. It is in these situations that a thoughtful integrative practitioner can redirect patients toward “the best of both worlds,” show respect for patient beliefs, and yet advocate for and ensure that responsible conventional treatment is used.

Another area of potential abuse is when Belief Activation is used to prop up a clinician rather than help a patient. It can be alluring for healthcare practitioners to adopt a savior complex, where they believe they are the only practitioner who can help a person or create stories of cures to draw patients. The savior complex has been reinforced by much of the popular culture portrayal of physicians.⁸⁰ This dynamic hurts the patient and the practitioner alike by abusing trust, replacing good rapport with unattainable expectations and replacing patient empowerment with patient dependency. Ideally, Belief Activation keeps the practitioner and the patient as partners in health.

A final area of potential abuse is when Belief Activation is used to justify interventions that are not more effective than placebo, while being costly or causing significant side effects. Both conventional and complementary physicians may treat difficult conditions with therapies that are no more effective than placebo with the hopes that the placebo effect will help. An honest evaluation must be made about the level of evidence supporting a therapy and the level of harm. With options such as open-label placebo, it is possible to use Belief Activation honestly. Alternatively, with gentle therapies such as guided imagery, nutrition, mind–body medicine, and exercise, it is possible to intervene without the negative side effects of pharmaceuticals or natural agents.

Belief Activation occurs when we are attentive to our words, our setting, our beliefs, our manner, our intentions, and our treatment choices. It maximizes patient expectancy, classical conditioning, social conditioning, healing environment, practitioner expectancy, religious beliefs, therapeutic relationship, and practitioner prayer/intention, and minimizes nocebo. Belief Activation strategies not only remind us of the significant power and responsibility we have as physicians but also highlight the power of the will and intent of our patients and the sacred bond of trust that we forge together. As the science of Belief Activation emerges, we can see the Vis Medicatrix Naturae (“Healing Power of Nature”) speak to us through medical research. Clearly, the research validates Belief Activation techniques. It is in the unique way that each practitioner channels their gifts, however, that the benefits of this elegant and adaptable tool will impact patients.

Footnotes

Acknowledgments

Special thanks to Dr. Tori Hudson, ND, for her mentorship.

Author Disclosure Statement

No competing financial interests exist.

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