Friday, May 27, 2011

Positive Reinforcement Boosts Analgesic Effects

Placebo Convincing new evidence demonstrates how patients’ beliefs and expectations of benefit or adverse effects can directly influence response to opioid analgesic therapy. This has important implications for the role of healthcare providers in helping to shape and optimize patient response to any pain relieving treatment.

Researchers from Britain and Germany examined how divergent expectancies may alter the efficacy of potent opioid analgesia. Efficacy of a fixed concentration of the intravenous (IV) μ-opioid agonist remifentanil in ameliorating a heat pain stimulus was assessed in each of 22 healthy volunteers under 3 experimental conditions. Besides subject self-reports of pain decrease/increase, functional magnetic resonance imaging (fMRI) was used to record brain activity to corroborate subjective responses and to reveal underlying neural mechanisms. The procedure was as follows…

  • First, heat was applied to a leg at a level sufficient for each subject to rate the pain at about 70 points on a 1-to-100 scale. Unknown to the participant, researchers then started giving remifentanil via an already established IV drip to see what impact it would have in the absence of any knowledge or expectation of treatment effect.

  • Next, the participant was told the drug would start being administered, though no change was actually made in the continuing medication dose. This established expectancy of a positive analgesic efficacy, and a potential add-on placebo effect.

  • Finally, the subject was made to think the pain relief medication had been stopped (when it was actually continued) and was warned that the pain might increase. This created an expectation of pain exacerbation, and invoked a possible nocebo response.

Writing in the journal Science Translational Medicine, the researchers report that, in the first condition, without any expectations of drug effects or even knowing that the drug was already being administered, the average initial pain rating of 66 decreased by 17% to 55. This might characterize the baseline analgesic effect of remifentanil itself.

When told the analgesic was starting to be administered, the average pain ratings dropped another 29% to 39. And, then, when informed that the medication had been stopped and that pain might increase, the participants rated their pain back at the 64-point level on average — even though they still were receiving the same amount of the analgesic. These substantial subjective effects also were evidenced by significant changes in neural activity in brain regions involved with the coding and interpretation of pain intensity.

COMMENTARY: This cleverly-designed, observational experiment clearly demonstrated that positive treatment expectancy substantially enhanced (nearly doubling) pain-relieving benefits of the analgesic. This might be considered an add-on placebo effect of the therapeutic milieu. In contrast, during the third part of the experiment, a negative treatment expectancy abolished both the placebo and baseline effects of remifentanil analgesia; producing a 64% increase in pain-rating score and demonstrating a strong nocebo response. All of the effect sizes (mean differences in pain scores) were medium to large and statistically significant.

The fMRI scans showed that the brain’s pain networks responded according to the expectations of the volunteers. Anticipation of increased pain was accompanied by greater activity in a number of limbic-brain regions, including the hippocampus, mid-cingulate cortex, and medial prefrontal cortex — areas known to mediate mood and anxiety. Whereas, expectation of pain reduction resulted in increased activity in the anterior cingulate cortex — associated with rational cognitive functions and reward anticipation.

On the basis of subjective and objective evidence, the researchers contend that an individual’s expectation of an analgesic’s effects may critically influence its therapeutic efficacy. They propose that it may be necessary and appropriate to integrate patients’ beliefs and expectations into pain-treatment regimens to help optimize treatment outcomes.

Prior Pain-Topics UPDATES have discussed in more detail placebo effects [here] as well as nocebo responses [here]. The role of limbic brain regions in modulating pain was discussed [here], and how words/language used during clinical interactions can trigger pain-center activation was described [here]. This latest study is an impressive demonstration reinforcing benefits of incorporating knowledge of placebo effects (and avoiding nocebo responses) in daily clinical pain practice.

REFERENCE: Bingel U, Wanigasekera V, Wiech K, et al. The Effect of Treatment Expectation on Drug Efficacy: Imaging the Analgesic Benefit of the Opioid Remifentanil. Sci. Transl. Med. 2011;3:70ra14 [abstract here].