Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.
The author discloses that he has no significant financial interests in any product or class of products discussed directly or indirectly in this activity, including research support.
Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.
The placebo effect is an interesting and complex phenomenon (Koshi & Short, 2007). In last month’s article, I discussed various aspects of the placebo on the basis of clinical research studies in pharmacology (Howland, 2008). The expression of a placebo effect depends on how the effect is measured, the characteristics of the condition being treated, and the experimental or clinical context in which the placebo is administered. Although placebos are not likely to work as well in real-world settings compared with their apparent effectiveness in randomized controlled trials, the placebo effect is real. The ways in which placebo effects are influenced suggest that underlying processes are at work. In this article, I discuss some of the psychological and neurobiological processes that may bring about the placebo effect.
Cognitive Psychological Processes
If the placebo effect is real, what processes underlie the phenomenon? From a psychological perspective, expectancy and conditioning theories have been used to explain the placebo effect (Brody & Brody, 2000; Stewart-Williams & Podd, 2004). Expectancy theory proposes that the expectations or beliefs patients have about treatment will influence how they respond to treatment. Such expectations may be conscious or unconscious. Patients who have positive expectations that treatment will help demonstrate a significantly higher level of response to an active medication compared with those who have less positive expectations taking the same medication (Krell, Leuchter, Morgan, Cook, & Abrams, 2004).
Patients with positive expectations may therefore get better even if they are taking only a placebo. By contrast, negative expectations may have a deleterious effect. As a result, some patients may develop noxious adverse effects with a placebo. This effect has been termed the nocebo effect (Barsky, Saintfort, Rogers, & Borus, 2002). Similarly, positive or negative expectations harbored by treatment providers (including physicians and nurses) may subtly (or not so subtly) affect what patients believe will happen with treatment, and this may contribute to placebo and nocebo effects.
Conditioning theory proposes that past experiences may lead to learning (conditioning) that contributes to symptom changes or adverse effects. This process is more unconscious. There is some debate about the extent to which expectancy and conditioning effects can be distinguished from each other to explain placebo effects and even whether conditioned placebo effects without expectancies are prominent in people (Kirsch, 2004).
Placebo effects have been demonstrated in animals, and this effect is likely explained by Pavlovian conditioning (Jaeger, Larsen, & Moe, 2005). It is possible that conditioning might be somewhat more relevant in explaining the development of nocebo effects in people, through negative past experiences and aversive learning (Barsky et al., 2002; Li, Howard, Parrish, & Gottfried, 2008). The experimental or clinical context of placebo administration will also influence the placebo effect (Howland, 2008), and these findings are consistent with expectancy and conditioning theories.
How do these psychological processes translate into physiological effects? Neurobiological studies have begun to explore the placebo effect in conditions such as pain, Parkinson’s disease, and depression. Pain research studies have shown that administering opioid antagonists can block the analgesic effects of placebo (Sauro & Greenberg, 2005). Brain imaging studies have shown that placebo-analgesia results in opioid activation in certain brain regions (i.e., anterior cingulate, orbitofrontal and insular cortices, nucleus accumbens, amygdala, periaqueductal gray matter), as well as dopamine activation in other particular areas (i.e., ventral basal ganglia, nucleus accumbens) (Scott et al., 2008). These regions are part of overlapping brain circuits that are important for cognitive information processing, analgesia, and reward expectations (Scott et al., 2007).
Studies in Parkinson’s disease have demonstrated placebo-induced release of endogenous dopamine in the ventral striatum with consequent reduction of motor symptoms (Benedetti, Mayberg, Wager, Stohler, & Zubieta, 2005). Placebo-responsive patients show specific reductions of activity in the subthalamic nucleus, an area that is the target of deep brain stimulation in Parkinson’s disease (Benedetti et al., 2005). In addition, patients’ expectations of poor versus good motor performance modulate the therapeutic effect of deep brain stimulation of the subthalamic nucleus (Benedetti et al., 2005).
Abnormal metabolism/perfusion in the prefrontal and anterior cingulate cortices is a consistent finding from brain imaging studies in depression (Mayberg et al., 2002). These areas are important segments of a cortical-limbic-thalamicstriatal neural circuit that is involved in emotional regulation. Imaging studies during treatment have reported differences in prefrontal/cingulate activity between those who respond to antidepressant agents and those who do not.
In a double-blind treatment study of major depression, Mayberg et al. (2002) used brain imaging to compare the effects of fluoxetine (Prozac®) with placebo. Placebo response was associated with metabolic increases in certain regions (i.e., prefrontal, anterior cingulate, premotor, parietal, posterior insula, and posterior cingulate areas) and metabolic decreases in other regions (i.e., subgenual cingulate, parahippocampus, thalamus). Regions of change overlapped those seen in patients who responded to fluoxetine. Fluoxetine response was associated with additional changes in the brain stem, striatum, anterior insula, and hippocampus. Other studies have found that recovery from depression with placebo treatment correlates with changes in frontal and cingulate cortical activity, although similar changes can be found in recovery without treatment (Vallance, 2007).
Quantitative electroencephalography (QEEG) studies have found that theta-wave brain activity (more so than other frequency bands) characterizes prefrontal/anterior cingulate function in depression (Leuchter, Cook, Witte, Morgan, & Abrams, 2002). Of particular interest, theta activity changes in response to antidepressant treatments (Cook et al., 2002).
Cook et al. (2002) investigated the use of QEEG for predicting treatment response in major depression. Patients first entered a 1-week, single-blind, placebo lead-in phase. Those patients still depressed were then randomized to fluoxetine versus placebo or to venlafaxine (Effexor®) versus placebo for 8 weeks. QEEG was performed at baseline and after 48 hours and 1 week taking drug or placebo. Baseline and change from baseline QEEG values were examined in different brain regions among four groups of patients: drug and placebo responders and nonresponders. Drug responders uniquely showed significant decreases in prefrontal theta activity at 48 hours and at 1 week, although clinical differences did not emerge until after 4 weeks of treatment (Cook et al., 2002). The QEEG change was specific to the prefrontal region. By contrast, placebo responders showed a significant increase in prefrontal theta activity starting early in treatment (Leuchter et al., 2002). Drug nonresponders and placebo nonresponders did not exhibit any QEEG changes.
The identification of early, but different, QEEG changes during a placebo lead-in differentially predicted the eventual treatment outcome to medication or to placebo (Hunter, Leuchter, Morgan, & Cook, 2006). That effective placebo treatment is associated with changes in prefrontal brain function that are distinct from those associated with effective drug treatment—detectable before a clinical response—is an intriguing finding. Early, detectable, regional brain function and physiology changes (as demonstrated by these QEEG and brain imaging studies) support the notion that the placebo effect is mediated by psychological expectations and rewards that involve frontal and ventral striatum brain circuits (Benedetti et al., 2005). These brain circuits may represent a common fundamentally important underlying pathway that mediates the placebo effect in such disparate conditions as pain, Parkinson’s disease, and depression.Although less well studied, the nocebo effect may involve psychological and neurobiological processes similar to those involved in the placebo effect. In an analysis of data from the venlafaxine versus placebo arm of the study by Cook et al. (2002) described above, decreases in prefrontal QEEG theta activity at the end of the initial 1-week placebo lead-in phase were significantly associated with the later development of side effects in venlafaxine patients but not in placebo patients (Hunter et al., 2005). QEEG changes during placebo lead-in were not related to side effects at lead-in. Changes in prefrontal brain function occurring at the end of placebo lead-in (prior to administration of the drug) predicted the development of side effects in patients who later took venlafaxine. Pre-frontal brain function changes during placebo treatment may therefore reveal an underlying negative expectancy that makes some patients susceptible to developing side effects.
This study did not find an association between prefrontal QEEG changes and later development of placebo side effects, but this might have been because so few of the 15 placebo-treated patients actually experienced side effects compared with the 17 venlafaxine-treated patients. Investigating placebo and nocebo effects using QEEG in a larger sample of patients would be important. Curiously, the brain imaging pain study by Scott et al. (2008) found that placebo and nocebo effects were associated with opposite dopamine and opioid activation patterns. Whether placebo-nocebo differences reflect differences in aversive learning (conditioning) on the basis of past experience (Li et al., 2008) or are due to inherent underlying differences in cognitive-psychological or neurobiological function is not known.
Fundamentally important cognitive psychological and neurobiological processes appear to underlie placebo and nocebo effects. Nurses working in clinical practice or in research are part of the “context” in which patients or participants are treated, openly or experimentally. Understanding these effects is therefore important for designing clinical treatment studies and interpreting their results and is highly relevant for nursing practice (Berthelot, Maugars, Abgrall, & Prost, 2001; Sherman & Hickner, 2007).
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