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 concept has a long and rich tradition in the history of medicine and psychology (Grunbaum, 1981). A placebo is usually defined as an inert substance and the placebo effect as some kind of helpful or therapeutic change in response to administering a placebo. By contrast, some patients develop noxious adverse effects with a placebo, which has been termed the nocebo effect (Barsky, Saintfort, Rogers, & Borus, 2002).
Placebos are often thought of in the context of pill taking, but the placebo concept importantly applies as well to nonpharmacological interventions such as medical procedures and psychotherapy (Birch, 2006; Herbert & Gaudiano, 2005). Hence, the definition and characterization of the placebo—what it is, what it does, and how it works—is very complex (Koshi & Short, 2007). In this article, I will discuss some important aspects of the placebo effect on the basis of clinical research studies in pharmacology. Next month, I will describe recent findings about the psychological and neurobiological processes that underlie the placebo effect.
The Placebo and Randomized Clinical Trials
In clinical pharmacology, randomized, double-blind, placebo-controlled trials (RCTs) are the standard approach for establishing the efficacy of a drug. For this purpose, a placebo-drug should be similar in all ways to the active-drug, with the exception of the “active” component of the drug being studied. The active component presumably represents the mechanism of action that explains drug-specific physiological changes, clinical benefits, and side effects.
The use of a placebo-drug ideally serves to control for all of the various nondrug-specific factors that occur with the treatment setting and pill taking (i.e., those factors that are common to administering and taking the placebo-drug and active-drug). If a drug is significantly better than a placebo in an RCT, then the added clinical benefit, as well as reported side effect differences, should be attributable to a particular pharmacological property of the drug. If the drug and placebo effects are similar, however, then the drug must not have a particularly unique therapeutic pharmacological property—at least not for the condition being studied.
© 2008/ Photos.com, Jupiterimages Corporation
Placebo effects have been described for a wide range of therapeutic uses and physiological measures (Ross & Buckalew, 1983). In RCTs, placebo response rates vary widely across studies of different medical conditions (Moyad, 2002) and psychiatric disorders (Straus & von Ammon Cavanaugh, 1996). Placebo response rates also vary widely across RCTs for the same disorder. On the basis of meta-analyses, some authors have suggested that the placebo effect is not very significant compared with no-treatment conditions (Hróbjartsson & Gøtzsche, 2004) or that the placebo effect might be a statistical regression phenomenon (McDonald, Mazzuca, & McCabe, 1983).
However, placebo effects are not uniform, and they may be influenced by many different factors (Birch, 2006). The prevalence and magnitude of a placebo effect likely depends on how the clinical placebo effect is measured, the characteristics of the condition being studied, and the experimental or clinical context in which the placebo is administered.
Characteristics of the Placebo Effect in Research Studies
How Outcomes Are Assessed
Interpreting the results of RCTs in which no apparent difference between active-drug and placebo-drug is found is not as straightforward as it seems. Most RCTs are designed such that an outcome of interest is specifically defined in advance, and the active-drug and placebo-drug are compared with this outcome measure. For example, a treatment study may last for 8 weeks and use a standard symptom rating scale. The primary outcome might be defined as the magnitude of change in symptom scores from baseline to week 8 or perhaps as the final symptom score at week 8 (which might be characterized as a “response” or “remission” rate). These outcomes would be averaged and compared for each group of participants. If the between-group difference is statistically significant, then the active-drug is considered effective compared with the placebo-drug. If not, then the active-drug is deemed no better than placebo.
However, assessing outcomes only on the basis of changes measured between two discrete time points or on a final symptom score at endpoint is a very narrow approach to examine how patients’ symptoms might change. This standard approach is problematic because it does not capture the heterogeneity of clinical changes over time related either to active-drug or to placebo-drug. All medical and psychiatric conditions have signs and symptoms that fluctuate. Collecting symptom information more frequently could allow researchers to more closely examine the pattern of changes that occur over time.
For example, the use of pattern analysis in depression studies can better distinguish participants who respond to the active-drug from those who respond to placebo (Quitkin, 1999). The pattern and persistence of symptom changes in those who respond to placebo often look different than does the pattern of symptom changes in individuals responding to the drug, but the use of this kind of analysis to report the results of RCTs is not common.
The Influence of Disorder Characteristics
Different inherent characteristics of a disorder may influence the expression of a placebo effect. For example, in studies of depressive disorders (Howland et al., 2001; Khan, Leventhal, Khan, & Brown, 2002) and anxiety disorders (Rosenberg, 1994), greater symptom severity is often associated with a poorer response to placebo. In addition, underlying neurobiological aspects of a disorder may moderate the placebo effect. For example, greater degrees of abnormal hypothalamic-pituitary-adrenal axis activity are associated with a poorer response to placebo in depression (Brown, Shrivastava, & Arato, 1987).
Interpreting the results of RCTs and understanding drug-placebo differences should ideally take into account these kinds of individual clinical and biological differences among participants (Kent & Hayward, 2007). Unfortunately, most reports of RCTs describe only average group outcomes.
The Context of Administration
The experimental or clinical context of placebo administration will also influence the placebo effect. One example is comparing the placebo effect when the placebo is given under double-blind conditions versus deceptively administering the placebo. Kirsch and Weixel (1988) described a study in which participants were given varying dosages of a caffeine placebo with either double-blind or deceptive instructions. With deceptive instructions, participants were led to believe they were receiving an active drug (caffeine) but were actually given placebo. By contrast, participants given double-blind instructions were aware they might receive the active drug (caffeine) or placebo, but all were actually given placebo. Surprisingly, double-blind and deceptive administration of the placebo produced different effects on the participants’ pulse rate, blood pressure, and subjective mood.
In another example highlighting the importance of context, a double-blind study of dental extractions (Gracely, Dubner, Deeter, & Wolskee, 1985) was conducted in which placebo responses were compared for patients in two groups: those whose clinicians knew they would administer a narcotic analgesic, a placebo analgesic, or a narcotic antagonist agent and those whose clinicians knew they would administer only a placebo analgesic or a narcotic antagonist agent. Patients receiving placebo in the first group had significantly less pain than did such patients in the second group.
In a more recent example, a double-blind study of healthy volunteers described the effect of price on the analgesic response to placebo given for experimentally induced pain (Waber, Shiv, Carmon, & Ariely, 2008). All participants were told they would be receiving a newly approved opioid analgesic drug but were actually given a placebo. After randomization, half of the participants were informed that the new drug had a regular price of $2.50 per pill, and half were told that the drug had been discounted to 10 cents per pill. Pain reduction was significantly greater for participants taking the regular-price placebo.
Understanding the placebo effect is important for nursing practice (Ernst & Abbot, 1997). Do the placebo response rates from RCTs suggest that a placebo is effective and can be used clinically as an alternative to medication? Placebos can have side effects, but they might be considered safer and cheaper for patients than active medications.
Although some studies using placebo-analgesia have suggested longer term benefits (Koshi & Short, 2007), the quality and persistence of clinical benefit with placebo treatment for most conditions is probably questionable at best. As a result, placebos are unlikely to work as effectively in real-world settings. In addition, the effective use of placebo in treatment settings is likely dependent on using it deceptively, which poses obvious ethical concerns (Sherman & Hickner, 2007). Does this mean the placebo effect is not real?
Clearly, the different ways in which placebo effects are observed and how they are in-fluenced suggest that important and interesting processes are at work. In next month’s article, I will discuss some of the psychological and neurobiological processes that may underlie the placebo effect.
- Barsky, AJ, Saintfort, R, Rogers, MP & Borus, JF2002. Nonspecific medication side effects and the nocebo phenomenon. Journal of the American Medical Association, 287, 622–627. doi:10.1001/jama.287.5.622 [CrossRef]
- Birch, S2006. A review and analysis of placebo treatments, placebo effects, and placebo controls in trials of medical procedures when sham is not inert. Journal of Alternative and Complementary Medicine, 12, 303–310. doi:10.1089/acm.2006.12.303 [CrossRef]
- Brown, WA, Shrivastava, RK & Arato, M1987. Pre-treatment pituitary-adrenocortical status and placebo response in depression. Psychopharmacology Bulletin, 231, 155–159.
- Ernst, E & Abbot, NC1997. Placebos in clinical practice: Results of a survey of nurses. Perfusion, 10, 128–130.
- Gracely, RH, Dubner, R, Deeter, WR & Wolskee, PJ1985. Clinicians’ expectations influence placebo analgesia. Lancet, 1, 43. doi:10.1016/S0140-6736(85)90984-5 [CrossRef]
- Grunbaum, A1981. The placebo concept. Behaviour Research and Therapy, 19, 157–167. doi:10.1016/0005-7967(81)90040-1 [CrossRef]
- Herbert, JD & Gaudiano, BA2005. Moving from empirically supported treatment lists to practice guidelines in psychotherapy: The role of the placebo concept. Journal of Clinical Psychology, 61, 893–908. doi:10.1002/jclp.20133 [CrossRef]
- Howland, RH, Fasiczka, AL, Berman, SR, Lis, JA, Friedman, ES & Thase, ME2001. Predictors of placebo response in a prospective treatment study of major depression [Abstract]. Biological Psychiatry, 49Suppl. 8, 163S.
- Hróbjartsson, A & Gøtzsche, PC2004. Is the placebo powerless? Update of a systematic review with 52 new randomized trials comparing placebo with no treatment. Journal of Internal Medicine, 256, 91–100. doi:10.1111/j.1365-2796.2004.01355.x [CrossRef]
- Kent, DM & Hayward, RA2007. Limitations of applying summary results of clinical trials to individual patients: The need for risk stratification. Journal of the American Medical Association, 298, 1209–1212. doi:10.1001/jama.298.10.1209 [CrossRef]
- Khan, A, Leventhal, RM, Khan, SR & Brown, WA2002. Severity of depression and response to antidepressants and placebo: An analysis of the Food and Drug Administration database. Journal of Clinical Psychopharmacology, 22, 40–45. doi:10.1097/00004714-200202000-00007 [CrossRef]
- Kirsch, I & Weixel, LJ1988. Double-blind versus deceptive administration of a placebo. Behavioral Neuroscience, 102, 319–323. doi:10.1037/0735-7044.102.2.319 [CrossRef]
- Koshi, EB & Short, CA2007. Placebo theory and its implications for research and clinical practice: A review of the recent literature. Pain Practice, 7,4–20. doi:10.1111/j.1533-2500.2007.00104.x [CrossRef]
- McDonald, CJ, Mazzuca, SA & McCabe, GP Jr. 1983. How much of the placebo “effect” is really statistical regression?Statistics in Medicine, 2, 417–427.
- Moyad, MA2002. The placebo effect and randomized trials: Analysis of conventional medicine. Urologic Clinics of North America, 29, 125–133. doi:10.1016/S0094-0143(02)00038-1 [CrossRef]
- Quitkin, FM1999. Placebos, drug effects, and study design: A clinician’s guide. American Journal of Psychiatry, 156, 829–836.
- Rosenberg, R1994. Prediction of placebo response in panic disorder: A short review. Nordic Journal of Psychiatry, 48, 153–158. doi:10.3109/08039489409081352 [CrossRef]
- Ross, S & Buckalew, LW1983. The placebo as an agent in behavioral manipulation: A review of problems, issues, and affected measures. Clinical Psychology Review, 3, 457–471. doi:10.1016/0272-7358(83)90024-7 [CrossRef]
- Sherman, R & Hickner, J2007. Academic physicians use placebos in clinical practice and believe in the mind-body connection. Journal of General Internal Medicine, 23, 7–10. doi:10.1007/s11606-007-0332-z [CrossRef]
- Straus, JL & Von Ammon Cavanaugh, S1996. Placebo effects. Psychosomatics, 37, 315–326.
- Waber, RL, Shiv, B, Carmon, Z & Ariely, D2008. Commercial features of placebo and therapeutic efficacy. Journal of the American Medical Association, 299, 1016–1017. doi:10.1001/jama.299.9.1016 [CrossRef]