The placebo effect has piqued the interest of researchers and physicians since the beginning of medicine. A placebo is defined as an inert procedure or substance, understood to have no actual physical effects, administered either therapeutically (as treatment) or nontherapeutically (in a clinical trial) (Spiro, 10). The placebo effect is therefore a reported change in either symptoms or actual pathology due to administration of a placebo. Pain is of particular interest in studying the placebo effect. Patients experiencing pain respond well to placebo treatment and this phenomenon also helps us better understand the experience of pain and how it occurs in the body.

The function of pain is simple: to alert an individual that there has been injury to the body. The experience of pain begins at the tissue that has been exposed to a noxious stimulus (i.e. cut, scrape, bruise, or burn). Nocioceptors, minimally specialized nerve cells, are activated when a stimulus reaches a high level of intensity and bypasses the other somatic sensory neurons. The axons of the nocioceptors extend from the spinal cord and terminate in free endings in the periphery (Purves et al., 209). There are two types of nocioceptive fibers that conduct pain sensation: Ad fibers conduct at 20 m/s and are responsible for sharp, sudden pain; C fibers take over if the sensory stimulus continues to be intense and conduct at about 2 m/s, giving a long-lasting, dull pain.

Pain is perceived when the impulse from the nocioceptor dendrites is transmitted to the spinal cord and ascends the spinothalamic tract to the thalamus. From the thalamus the information is sent to the somatosensory cortex, which localizes the pain, and to the hypothalamus to produce a behavioral or emotional response (Purves et al 2001). At this point the hypothalamus can stimulate the release of endogenous opioids via the reticular formation, a network of neurons inhabiting the core of the brainstem (Purves et al 2001). It is these endogenous opioids that are released to help relieve pain that are of great importance in placebo analgesia.

There are two types of analgesics: those that act centrally, effecting pain over the whole body, and those that are anti-inflammatory (NSAIDs) and are effective for muscular or skeletal pain. Centrally acting analgesics are opiates, like morphine, which mimic the actions of endogenous opioids in the body. When released, endogenous opioids bind to receptor sites on the synaptic terminals of pain fibers. When opioid receptors are activated they inhibit the release of Substance P, a neurotransmitter released at all axons in the transmission process from the initial nocioceptor to the somatosensory cortex (Beck 4/7/03). The inhibition of Substance P effectively reduces pain.

Fabrizio Benedetti and Martina Amanzio, leading researchers of placebo analgesia, suggest that opioid responses can be triggered through cognitive expectation or classical conditioning mechanisms (Amanzio et al., Jan. 1999). Their 1999 study examined expectation versus conditioning-activated opioid responses (Amanzio et al., Jan. 1999). Using the model of human ischemic arm pain in healthy volunteers, placebo analgesia was induced using expectation cues. Expectation cues were established by verbal instructions like, "You are going to receive a powerful analgesic now and your pain will subside." The placebo response induced with this method was completely reversed with an injection of naloxone, an opioid antagonist. Naloxone binds to opioid receptor sites, blocking endorphins and other endogenous opioids from doing so.

In the conditioning test group the non-opioid pain reliever ketorolac was administered intravenously for 2 consecutive days before being replaced by saline on the third. Subjects were told they were receiving the same analgesic as previously, establishing expectation. In this situation naloxone partially blocked the placebo response. The same procedure was repeated on other subjects, except on the third day when subjects received saline, they were told it was an antibiotic, eliminating all expectation of pain relief. This time the placebo response was naloxone-insensitive.

When this experiment was repeated with morphine instead of ketorolac both conditioning-induced and expectation-induced placebo responses were naloxone-reversible. This is because morphine works through the same pathway as endogenous opioids do, activating the same receptors. This study demonstrates that expectation induced placebo analgesia is mediated by endogenous opioids. The systems involved in conditioning-induced placebo responses depend on the drug used to condition. As seen with ketorolac conditioning, alone it was naloxone-insensitive, but when accompanied by expectation, the opioid component comes in, explaining why it was partially naloxone reversible (Amanzio et al., Jan. 1999).

Questions arise from these results about where endogenous opioids are released in the body. The mechanism of how expectation triggers this release is still unknown, but where in the body it is happening has been examined more closely. A study published in the Journal of Neuroscience examined target-directed expectations of placebo analgesia. After inducing experimental pain in different areas of the body simultaneously and applying a topical placebo cream to specific spots, it was found that placebo analgesia occurs only at the body part where expectation is directed. This clearly testifies that the underlying mechanisms do not affect the entire body, but rather act through specific circuits and sub-systems yet to be defined (Benedetti et al., May 1999).

As these studies show, there are many psychosocial factors involved in the efficacy of medical treatment. One significant component is the "meaning response." Meaning responses follow from the patient’s interaction with the context in which treatment or healing occurs (Moerman, 16). Meaning responses can be witnessed in experiments that incorporate the doctor’s behavior and language and visual or other sensory aspects of treatment. These factors were clearly integral in establishing expectation cues in Amanzio and Benedetti’s study. This indicates that there is a behavioral approach to healing. What the patient knows or experiences from medicine can enhance or inhibit the healing process (Moerman, 19). Evidence shows that it is not the placebo itself that is effective, but the patient’s awareness that they are being treated that creates the placebo effect. This is what makes the difference between no treatment and administering an inert substance. Placebo used for pain relief (placebo analgesia) is a good example of how perception affects physiology, as it is both a biological and meaningful process.

A study explicated in Daniel Moerman’s book Medicine, Meaning, and the Placebo Effect, demonstrates this point. In the experiment doctors prepared an inert topical anesthetic, which they called Trivaricane, and applied it to one finger on each test subject. A painful stimulus was applied to both the finger that had the experimental Trivaricane and the same finger on the test subject’s other hand. The large majority of the test subjects reported less pain in the Trivaricane finger. What mattered in this experiment was the context in which the placebo analgesia was used. The doctors wore gloves so as to not "overexpose themselves to the solution"; they also made sure the Trivaricane had a medical smell and color by using iodine in the solution (Moerman, 17-18). This outcome illustrates a profound link between the patient’s perception of a pain reliever and its efficacy.

The difference between open and hidden injections has been examined recently in a study of postoperative patients (Amanzio et al., 2001). By analyzing the effects of various common pain relievers that were administered either by a doctor at bedside or by an automatic infusion machine, researchers concluded that open injections were more effective. The analgesic dose needed to reduce pain by 50% was much higher with hidden infusions and pain ratings were also higher within the first hour after surgery (Amanzio et al., 2001). The importance of doctor/patient interactions is apparent in these examples.

The type of placebo a patient receives can also influence its efficacy. Colored capsules are more effective than colored tablets, which are superior to white tablets with corners, and least effective are round white tablets (Benedetti et al., Jun. 1997). Traditionally, pills are not as effective as injections, which are not as effective as intravenous treatment. It is thought that placebo injections are so effective because it is a definable act that requires the intervention of another person (Benedetti et al., Jun. 1997).

The role of expectation in placebo analgesia clearly demonstrates the connection between perception and physiology and is a phenomenon in the true spirit of psychoneuroimmunology. Though we do not yet understand how, it is clear that both opioid and non-opioid systems are directly involved in placebo analgesia. What mechanisms are triggered depends on the context. Research supports the notion that context matters in the course of one’s treatment and can help or hinder the healing process.

Bibliography
 
 

Amanzio et al., "Neuropharmacological Dissection of Placebo Analgesia: Expectation-

Activated Opioid Systems versus Conditioning-Activated Specific Subsystems."

Journal of Neuroscience. Jan. 1999, 19(1): 484-94.

Benedetti, Fabrizio. "How the Doctor’s Words Affect the Patient’s Brain." Evaluation &

the Health Professions." Dec. 2002, 25(4): 369-86.

Benedetti et al. "Somatotopic activation of opioid systems by target-directed expectations of analgesia." Journal of Neuroscience. 19: 3639-3648.

Benedetti et al., "The neurobiology of placebo analgesia; From endogenous opioids to

cholecystokinin." Progress in Neurobiology. Jun. 1997, 52(2): 109-125.

Moerman, Daniel. Meaning, Medicine and the ‘Placebo Effect.’ New York: Cambridge

University Press, 2002.

Spiro, Howard. Doctors, Patients, and Placebos. New Haven, CT: Yale University Press,

1986.

Purves et al. Neuroscience 2^nd Ed. Sunderland, MA: Sinauer Associates, Inc., 2001.

Beck, Cindy. Lecture: Pain. 4/7/03.