By Robert L. Moore, MD, MPH, MBA, Chief Medical Officer

“It is better to light the candle than to curse the darkness.”

– William L. Watkinson

All clinicians should have a mastery of the placebo effect, not for nefarious purposes such as pushing sham treatments on patients, but to understand the natural history of disease and the role of the placebo effect in mainstream treatments that sometimes provide benefit.

The strength of the placebo effect is related to the strength of belief in the treatment and conditioning.  In October, this newsletter highlighted some key studies on the power of belief, showing that the belief that a treatment works is stronger when the placebo treatment hurts, when it has brand name recognition, when it costs more, and when the prescribing physician expresses the conviction that the treatment will work.

This month I will review the power of conditioning.

The placebo effect for a placebo pain pill study is stronger in patients with a history of chronic pain for which they had taken pain medication in the past. This illustrates the effect of conditioning. It is well documented that in patients with chronic pain, their pain begins to subside when they know their pain medication is coming, before they even receive the medication. The end result is to reinforce the benefit of the pain medication (or placebo).

Conditioning can also affect prescribers! When multiple patients say, with great conviction, that the expensive brand name medication works better than the inexpensive generic equivalent, the clinician may start to believe this also and discount FDA studies showing bio-equivalence. The clinician’s belief can affect their prescribing pattern, leading them to initiate treatment with more expensive medications. It can also influence the degree to which they reassure their patients that the medication they prescribe will help them.

The over-use of expensive medications by prescribers because of conditioning leads to the important and disturbing conclusion that the placebo effect impacts not just the patient being treated, but also affects the clinician recommending the treatment. Here are some examples of the placebo effect on prescribers:

1. Generic citalopram contains both the active levo-isomer and the inactive dextro-isomer of the medication. Brand name Lexapro contains only the l-isomer. While there is a small possibility of an unfavorable side effect profile from the d-isomer, the presence of the d-isomer should have no effect on the efficacy of the l-isomer. If the l-isomer dose is the same, the efficacy should be equivalent. Only the price and the brand designation could explain increased perceived efficacy.
2. Patients with chronic, non-malignant pain taking greater than 120 mg of morphine per day will often, with time, develop more pain and request ever-higher doses of narcotics. It is a vicious cycle, with higher doses temporarily alleviating pain. But with time, the pain becomes more severe and disabling. Counseling patients on this vicious cycle is difficult because of their belief in the power of narcotic medications and the conditioning that changes the physiology of patients taking these medications chronically. This belief is reinforced by withdrawal symptoms when a dose is missed or a clinician begins reducing the dose. Any drug with withdrawal symptoms will be harder for a patient to stop, because they often deeply believe that only that medication is actually controlling the disease. This is true of narcotic medications, benzodiazepine anxiolytics, many antidepressants, muscle relaxants, and even NSAIDS. In all these cases, prolonged use of the medication produces long-term changes in the synapses. These changes cause patients to feel symptoms when the medication is withdrawn. Thus, withdrawal symptoms strengthen the placebo effect! In fact, if the patient can get through the withdrawal, they may feel the same or better than they did on chronic therapy, but it is hard to get the patient there. Trust between the clinician and patient and detailed education are keys to success, but may not be enough in some cases. For this reason we should avoid initiating prolonged use of medications which can cause withdrawal symptoms until all other options are exhausted.
3. When reviewing evidence for effectiveness of a given treatment, journal articles often compare only the effectiveness relative to placebo because this is the standard for FDA approval. I recommend always digging into the article to look at the treatment’s effect on the control/placebo group; it gives valuable information. For example, early studies comparing amoxicillin to placebo for treatment of acute otitis media (AOM) in children showed the control group improved in 82% of cases (presumably most cases were viral and did not need antibiotics), while about 90% of the amoxicillin group improved. In this case, the mechanism of the placebo effect is not related to belief or conditioning, but on the natural course of the disease. Nonetheless, use of antibiotics in pediatric otalgia conditions parents to expect antibiotics for treatment of all ear pain, since their child improved with treatment the last time antibiotics were prescribed. Looking closely at the placebo effect in studies helps clinicians interpret marketing for new products.

For example, should we preferentially prescribe a more expensive, more powerful antibiotic that is reported to improve 50% more cases of AOM than amoxicillin (i.e. a 12% benefit over placebo compared to 8%)? Perhaps we should just recommend ibuprofen for a few days (which would work 82% of the time) and reserve antibacterial treatment for cases where this conservative approach fails. This approach has been recommended by the American Academy of Pediatrics as an option since 2004, but clinicians in the U.S. have been slow to adopt it due to clinician conditioning.

Adapting our clinical practice and communication with patients to account for the placebo effect may be the most important skill we develop. We must use our scientific training to inform the art of medicine. As clinicians, we owe it to our patients and society to account for the placebo effect and use only low cost, relatively safe treatments when the major effect is likely to be placebo.