Leveraging the Placebo Effect to Reduce Opioid Requirements

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A growing body of evidence indicates that placebos may provide an analgesic effect.
A growing body of evidence indicates that placebos may provide an analgesic effect.

A growing body of evidence indicates that placebos may provide an analgesic effect.1 Naloxone was shown to reverse the effects of placebos given in place of opioids, giving rise to the hypothesis that placebos may benefit patients who would otherwise be prescribed opioids.1 The current debate does not focus on determining whether placebos may have some efficacy but, rather, on whether clinicians should offer open placebos to improve pain or deceive patients into thinking they have been prescribed analgesics.1

"Since we know that placebos reliably reduce pain, and poor pain management is implicated in the opioid crisis, then it might be possible to use placebos to minimize the amount of opioid medication patients are taking," said Michael H Bernstein, PhD, from the School of Public Health, Center for Alcohol and Addiction Studies at Brown University, Providence, Rhode Island. "If placebos are shown to be opioid-sparing, they could hold considerable promise as a novel but well-supported strategy to address the opioid epidemic."

Placebos Are Meant to Heal, Not to Deceive

The purpose of placebo is not to withhold analgesia from patients who have a critical need for it (ie, in the postoperative period or in individuals with debilitating pain). Because pain is a subjective measure, it is highly prone to suggestion.2

In a trial in which 108 healthy women (mean age, 22.1 years) were enrolled and given a nasal spray of oxytocin, placebo, oxytocin with positive verbal suggestion, or placebo with positive verbal suggestion, study participants were tested for pain with a cold pressor test and for itch with a histamine iontophoresis test.2 Participants who had been exposed to positive verbal suggestions experienced placebo analgesia, but not reduced itching. They also reported lower expectations of both pain and itch.

"We recruited only women in this study to form a homogenous group," said lead author Aleksandrina Skvortsova, a PhD candidate from the Health, Medical and Neuropsychology Department at Leiden University in the Netherlands. "We conducted a follow-up study in men and found similar findings: men experienced a placebo effect."

Priming Patients for Optimal Results

Results from a meta-analysis of studies investigating placebo analgesia in patients with clinical pain (5 studies) or induced pain (11 studies) and in healthy participants (55 studies) indicate a larger effect size in patients vs healthy individuals, which could be interpreted as motivation to improve being a predictive factor for achieving pain relief.3

"The main point of the paper is that even when the research participants expected pain relief, pain relief was not observed. That means that there was no placebo effect, even in the presence of positive expectations," explained coauthor Magne A. Flaten, PhD, professor of psychology at the Norwegian University of Science and Technology in Trondheim. "Thus, positive expectations may be a necessary condition for placebo analgesia but are not a sufficient condition to generate a reduction in pain. We do not know what conditions must be present for positive expectations to be translated into a reduction in pain, but there are studies that show that the nonverbal behavior of the person providing pain-relieving treatment can have quite a large effect."

The Art of Administering Placebo Therapy

The effect of supportive care with placebo was examined in 262 individuals (mean age, 39 years; 76% women) with irritable bowel syndrome.4 During the 6-week, 3-group study, patients were randomly assigned to a waiting list (control), sham acupuncture with limited clinician involvement (placebo), or sham acupuncture with supportive clinicians (ie, "a patient-practitioner relationship augmented by warmth, attention, and confidence"). After 3 weeks, half the patients were randomly assigned to the same group for another 3 weeks.4

At the 3-week assessment, the global improvement scale scores were comparable in the control, placebo, and augmented therapy groups, at 3.8±1.0, 4.3±1.4, and 5.0±1.3, respectively (P <.001 for trend). Similar patterns were established for pain relief, symptom severity, and quality of life scores, and with comparisons between the augmented and limited clinician involvement groups. These results indicate that the involvement of the clinician (ie, how the placebo is administered) may be critical to achieve a placebo effect.4

"The extensive research in the field of placebo showed that placebo effect can substantially reduce pain, and that the placebo effect mimics the action of analgesic drugs," said Ms Skvortsova. "Placebo analgesia, in the same manner as analgesic medications, was found to activate opioid5 and endocannabinoid6 systems. The idea that a placebo is an 'empty' medication does not correspond to these insights, and instead of ignoring or even trying to avoid the placebo effect, physicians might try to exploit it to enhance the effects of pain treatments."

"The way a physician interacts with their patient, the expected benefit a patient will receive, and prior medical experiences are all components of treatment success or failure," said Dr Bernstein. "In the near-term, clinicians should be mindful of harnessing these therapeutic practices. Eventually, I believe that honest placebos should be used in standard medical settings, although we first need more research to verify that they are effective. But if patients get better while taking nondeceptive placebos, why would we not use their power to improve patient outcomes?"

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1. Bernstein MH, Magill M, Beaudoin FL, Becker SJ, Rich JD. Harnessing the placebo effect: a promising method for curbing the opioid crisis? [published online July 10, 2018] Addiction. doi: 10.1111/add.14385

2. Skvortsova A, Veldhuijzen DS, Van Middendorp H, Van den Bergh O, Evers AWM. Enhancing placebo effects in somatic symptoms through oxytocin. Psychosom Med. 2018;80(4):353-360.

3. Forsberg JT, Martinussen M, Flaten MA. The placebo analgesic effect in healthy individuals and patients: a meta-analysis. Psychosom Med. 2017;79(4):388-394.

4. Kaptchuk TJ, Kelley JM, Conboy LA, et al. Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. BMJ. 2008;336(7651):999-1003.

5. Levine JD, Gordon NC, Fields HL. The mechanism of placebo analgesia. Lancet. 1978;2(8091):654-657.

6. Benedetti F, Amanzio M, Rosato R, Blanchard C. Nonopioid placebo analgesia is mediated by CB1 cannabinoid receptors. Nat Med. 2011;17(10):1228-1230.

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