Finding Clues to the Mysterious Nocebo Effect in Hyperalgesia

Every pain practitioner is familiar with the placebo effect—a perceived or actual improvement in a medical condition that results from a simulated or otherwise medically ineffectual treatment. Countless studies have been done to try and understand the brain’s role in physical health and medication outcomes.

Studies that have nothing to do with the placebo effect nonetheless touch on the often controversial concept, since placebos are often used as the control group in a randomized clinical study. Placebos are controversial for many reasons, including three prominent ones:

• Placebo effects are unreliable and difficult to measure and predict
• The effect is a component of any active medical intervention
• No matter how the use of a placebo is handled, there is a level of deception involved that could potentially erode trust between caregiver and patient.

Perhaps even more controversial than the placebo effect is its converse, the nocebo effect—an adverse reaction to an ineffectual medication or procedure. For example, simply talking with a patient about potential side effects of a medication as part of an informed consent process can itself contribute to producing adverse effects.

Several studies have looked at conditioning-induced nocebohyperalgesia, including a 2014 meta-analysis in Pain, which found that the nocebo effect is higher when induced by conditioning combined with verbal suggestions as compared to verbal suggestions alone. “Therefore,” the authors noted, “it is likely that the efficacy of future pain treatments may be enhanced if both positive and negative experiences with treatments are addressed in pain patients.”

A recent study in The Journal of Pain looked at whether nocebohyperalgesia can result following partial reinforcement as opposed to continuous reinforcement schedules. The study involved using electrodermal pain stimulation in healthy volunteers under the guise of a hyperalgesic. Participants were randomly allocated to continuous reinforcement (CRF), partial reinforcement (PRF), or control (no conditioning). Conditioning involved surreptitiously increasing pain stimulation on nocebo trials relative to control trials.

According to the study authors, “In the test phase, pain stimulation was equivalent across nocebo and control trials. Partial reinforcement was sufficient to induce nocebohyperalgesia, however, this was weaker than continuous reinforcement. Interestingly, nocebohyperalgesia failed to extinguish irrespective of the training schedule…Overall, these findings suggest that once established, nocebohyperalgesia may be difficult to disrupt. As such, partial reinforcement may be one method of reducing the intensity of nocebohyperalgesia in the clinic, which may be particularly important given its persistence.”