Propranolol Meets Pain Relief Expectations Over Placebo

Anne Sanders, PhD

Propranolol was superior to placebo among chronic pain patients who had modest treatment expectations, new study findings showed.

Anne Sanders, PhD, and colleagues hypothesized that increased expectations differentially amplified placebo analgesia, which led to underestimation of the treatment effect in randomized clinical trials.

Sanders, from the Adams School of Dentistry at the University of North Carolina at Chapel Hill, and the investigative team conducted the Study of Orofacial Pain and Propranolol (SOPRANO), a double-blind, placebo-controlled, parallel-group, phase 2b randomized clinical trial. SOPRANO enrolled 200 adults 18-65 years old with examiner-verified temporomandibular disorder-associated myalgia from August 2015-January 2018 at 3 sites.

The investigators randomized patients 1:1 to either 60 mg of propranolol hydrochloride twice a day or placebo administered for 9 weeks. Propranolol hydrochloride is a beta-blocker that is typically used to treat high blood pressure, chest pain, and atrial fibrillation. The medication can also be used to treat tremors, proliferating infantile hemangioma, and to prevent migraine headaches.

Patients used daily pain diaries to measure treatment response, which was defined as the proportion with >30% reduction in mean pain index at 9 weeks.

Treatment expectation was defined from a participant’s baseline expectation that the study treatment would reduce their facial pain. Moderate and strong ratings were classified as high treatment expectations and ratings of none or slight were classified as low.

Overall, there were 198 participants in the intention-to-treat sample who rated their expectation. The mean age was 34 years old, 78.3% were women, and 59.6% had a high expectation of pain relief.

Pressure pain sensitivity in the masseter muscle (OR, 1.5; 95% CI, 1.1-2) and trapezius muscle (OR, 1.5; 95% CI, 1.1-2) were associated with a higher expectation of pain relief. For those with low expectation for relief, treatment responders made up 73.5% of the propranolol group and 42.7% of the placebo group.

The expectation difference corresponded to the number needed to treat of 3.2 (95% CI, 1.9-11.8; P=.007). Among those who had high expectations of pain relief, 67% of the patients in the propranolol group and 63.6% of the placebo group responded as such.

The presence of heightened expectation in the placebo analgesia group nullified efficacy (number needed to treat=29.6; 95% CI, 4.4 to -6.3; P=.73).

Although the small sample size of the study limited the ability to test if the magnitude of the effect of propranolol on temporomandibular disorder-associated pain was different based on treatment expectation, the findings showed a correlation.

Sensitivity to experimental pressure pain was 1 of the only clinical or psychological factors associated with heightened expectation.

The investigators suggested that more pain sensitivity could lead to a greater need for and expectation of pain to be relieved.

The study, “Effect of Treatment Expectation on Placebo Response and Analgesic Efficacy,” was published in JAMA Network Open.