The Placebo Effect

Eija Kalso

Placebo Domino in regione vivorum.

—Psalm 116:9

I. THE POWERFUL PLACEBO

Patrick D. Wall writes about the placebo response in Textbook of Pain. He argues that the word placebo alludes to Psalm 116:9: “Placebo Domino in regione vivorum,” which is the first line of the vespers for the dead. Priests and friars harassed the people for money to sing vespers for the dead. Placebo was an expression of contempt for the unpopular and expensive prayers, as Francis Bacon writes in 1625: “Instead of giving Free Counsell sing him song of placebo.” Three years later, Burton writes in Anatomy of Melancholy, “An empiric oftentimes, or a silly chirurgeon, doth more strange cures than a rational physician because the patient puts more confidence in him.” Now, nearly four hundred years later, the placebo response is still used in medicine and the mechanisms of this phenomenon are beginning to be understood.

The first chairperson of the department of anesthesia at the Massachusetts General Hospital, Henry Beecher, published his classic study, “The Powerful Placebo,” in 1955. In that communication, he surmised that patients’ expectations of benefit were sufficient to achieve therapeutic benefit. He also suggested that the overall analgesic effect of morphine is composed of its drug effect plus a placebo effect. Some fifty years later, with help from modern imaging technology, research has been able to provide evidence to support Beecher’s hypothesis and to suggest a neurobiologic mechanism for the phenomenon. Recent research has also shown that the placebo effect is far from nonspecific. Depending on the condition, the placebo effect can be highly targeted and somatotopically organized.

II. MECHANISMS OF PLACEBO ANALGESIA

1. Cognitive Theory

The cognitive theory states that the expectations of patients play an important role in the placebo response. A patient’s expectation is one of the best predictors of outcome in pain management. In 1978, Levine et al. suggested that placebo analgesia could be at least partially mediated by endogenous opioids because the effect was inhibited by the opioid antagonist naloxone. Later, it was suggested that expectation of pain relief could trigger the release of endogenous opioids in the central nervous system (CNS).

2. Conditioning Theory

The conditioning theory states that learning through association is important in the placebo response. Further, the conditioning theory proposes that the placebo response is a conditioned response that can be elicited by stimuli that produce a reduction in symptoms through prior conditioning. It has been suggested that a classical conditioning response operates in the placebo response. Ivan Pavlov first described the classical conditioning response in dogs. He reported that dogs that were given morphine in a certain experimental chamber displayed morphinelike effects when placed again in the same chamber although morphine was not available. Repeated associations between active analgesics, pain relief, and the therapeutic environment can produce a conditioned placebo analgesic response.

3. Endogenous Opioids

As already stated, endogenous opioids may be at least partially responsible for placebo analgesia because naloxone, an opioid antagonist, has been shown in studies to reverse placebo analgesia. Amanzio and Benedetti studied the expectation-activated and the conditioning-activated systems in opioid analgesia in an elegant set of experiments. They used the human experimental model of ischemic pain and evoked placebo analgesic responses with cognitive expectation cues, with drug conditioning (morphine or ketorolac), and with cues and drug conditioning combined. Expectation cues produced placebo responses that were completely blocked by the opioid antagonist naloxone. Expectation cues together with morphine conditioning produced placebo responses that were completely antagonized by naloxone. Morphine conditioning in the absence of expectation cues elicited a naloxone-reversible placebo effect. However, the placebo effect elicited by ketorolac conditioning with expectation cues was only partially blocked by naloxone. Ketorolac conditioning alone with no expectation cues produced placebo responses that were naloxone insensitive. The authors concluded that expectation triggers the release of endogenous opioids, whereas conditioning activates specific subsystems. If conditioning is performed specifically with opioids, the conditioning part of the placebo analgesia is mediated by endogenous opioids.

Only gold members can continue reading. Log In or Register to continue