Overview of the Placebo Response
For more than half-a-century, the placebo effect or placebo response has presented itself as an elusive phenomenon or concept that has had an appreciable number of detractors and proponents. The focus of recent research has not been to ascertain whether the placebo response exists or not, but rather, under what circumstances or with what disorders or conditions it may manifest itself. In addition, recent attention had been given to the nocebo phenomenon
Description of the Placebo and Nocebo Effects
The term placebo is derived from Latin and translates into “I shall please.” Historically, the placebo phenomenon fell victim to those who argued that the placebo phenomenon was nothing more than hokum or a sham treatment through mutations of inert substances. Such substances are dispersed by practitioners in order to mollify anxious or demanding patients. These placebo or inert substances are given as a medicine for its suggestive or seemingly palliative effect .
During the process of a placebo response, the patients condition may seem to improve, if the patient assigns to the medication or substance (which is essentially inactive, inert or non-medicinal) efficacious or curative qualities . Placebo responses or effects have been credited with treatment improvement and even the amelioration of a panoply of disorders and disease syndromes, including: pain states or conditions including post-surgical pain; symptoms of diabetes; multiple sclerosis; some types of headaches; ulcers; and Parkinsonism .
Forms of Placebos
While placebos may be presented in the form (inert) pills, placebo applications may also be proffered under the guise of a procedure, psychotherapy, or even, surgery. It is interesting to note that when a placebo is presented as a drug or medication, the pill’s size, shape, or even color, can impact upon the patient’s perception of the substance’s healing power . In actuality, the placebo, while resembling the qualities of an active drug, has no intrinsic pharmacological property or efficacy that could be linked to the perceived or expressed relief by the patient. Rajagopal  points out that there are placebos that may possess some active intrinsic properties, but are not linked in a healing fashion to the condition it is being offered for. For example, atropine has been utilized as a control medication in determining the efficacy of tricyclic antidepressants. It is standard practice in experimental designs which employ the double blind placebo control for the investigation, to attempt to ascertain whether the experimental drug possesses unique qualities and effects that cannot be assigned to patient or subject expectation.
There are instances in which placebos can be cast in the form of a procedural intervention. An example of a procedural placebo can be observed in an experimental procedure in which a patient is anesthetized but no administered an actual electroconvulsive therapy [ECT] procedure. In another application of a procedural placebo, a patient undergoing simulated acupuncture may actually have acupuncture needles placed at non- meridian points. Interestingly, Linde et al. have shown that actual acupuncture intervention proved to be superior to sham acupuncture procedures in the treatment of migraine headaches. Nonetheless, both authentic and simulated acupuncture procedures were observed, to yield some degree of migraine relief in comparison with the control subjects listed on a waiting list.
Utilization of surgical placebos have also been employed in order to observe its treatment efficacy. For example, under anesthesia, patients have undergone superficial procedures involving skin incisions, without undergoing actual surgery or intervention. Recently, a study had been undertaken in which blinded patients who were treated with a sham procedure under anesthesia, were compared with surgical patients who underwent percutaneous myocardial laser revascularization. The findings presented evidence of a substantial placebo effect significantly beyond the effects of the low or high dose laser treatments administered .
When the effects of a specific psychotherapeutic approach is being investigated, an attention-placebo control design may be employed. In this experimental arrangement, subjects in the control condition are given equal attention during an equivalent time frame as the subjects being treated with the psychotherapy of interest . In the attention-placebo condition, the subjects experience a non-therapeutic treatment during the course of the experiment; however, the element of therapist attention is provided, which is a given regardless of the psychotherapeutic technique employed. Nonetheless, the inherent flaw embedded in the attention-placebo approach is that, while the subjects may not be cognizant as to which treatment is being administered, the therapist can not be blinded. Hence, the extraneous influence of therapist expectation may serve as a confounding variable that obscures the true effects of the intervention.
The Nocebo Effect
When a patient anticipates or imagines experiencing pain, illness or harm as a consequence of an intervention or procedure, a nocebo effect is in operation. An nocebo effect can be thought of as the patients or subjects perception of experiencing an unpleasant experience attributable to the administration of a placebo . If a patient anticipates becoming ill after undergoing a placebo treatment, and actually expresses or manifests symptoms, a nocebo effect is in operation. The negative expectations can be of a specific or of a general nature; it might be chronic or acute; or may even prove to be fatal; notwithstanding evidence that the subject is not actually being administered a harmful agent or procedure . For example Lancman et al.  found that when a group of patients who experienced psychogenic seizures were led to believe that the placement of a skin patch would predispose them to seizures, actual seizures would ensue, replete with phenomena of sensations, bodily thrashing, the exhibition of uncontrollable movements and the experience of post-seizure confusion and sleepiness. Benedetti and his colleague  demonstrated that post-surgical pain could be heightened for patients with negative expectations after being given a dose of saline solution. Interestingly, the cholecystokin antagonist proglumide successfully reduced the nocebo hyperalgesia phenomenon. Rajagopal  asserts that the nocebo effect dramatically displays the potency of patient expectations when side effects are anticipated. Rajagopal points out that the since a number of psychiatric disorders tend to be chronic in nature, the patient being observed might have received previous treatment that included the use of psychotropic medications. If such patients serve as subjects in the placebo condition, they may expect side effects akin to what they might have experienced in the past after using an active drug. Alternatively, the patient/subject may anticipate experiencing side effects similar to those voiced by the experiences of significant others. At times, the nocebo effect can actually be stimulated by the discussions regarding side effects expressed by the investigators themselves as they engage in their duty to provide informed consent to experimental subjects or actual patients .
Theoretical Accounting of the Placebo Phenomenon
Many have pondered how to properly decipher the placebo conundrum. Both psychological and psychobiological explanations have been advanced in explaining the placebo effect. Jospe  noted that placebo responders to be more anxious, more physically labile, more dependent and are generally more submissive to others. Straus and Cavanaugh  found placebo responders to be generally more sensitive to physical and bodily sensations as tended to be more extroverted. Notwithstanding the foregoing, research has not completely crystallized a specific personality type that might consistently predict those might likely to be predisposed to a placebo response. Current investigators in this area generally maintain that it is probably the case that personality characteristics interplay in some fashion with situational variables. The exact nature of such interactions stimulate the demand for further inquiry [15, 16].
A number of studies centering on placebo analgesia links the promotion of the placebo effect with such practitioner characteristics as capacity for warmth and empathy; the projection of confidence, easy availability for patient-clinician contacts [17-19]. The maxim that “presentation is everything!” appears to resonate well with respect to the emergence of the placebo effect. Ernst  found that procedures characterized as invasive, impressive or painful tended to stimulate the placebo phenomenon. Chlordiazepoxide, or Librium, delived in capsule versus tablet form in the treatment of anxiety- related disorders appeared to be more effective  in reducing anxiety levels in patients.
Some investigators posit that the placebo effect can be explained within the frame of classical or Pavlovian Conditioning. This notion is advanced when it is demonstrated that subsequent to proximal pairings of an antihypertensive with a placebo or inert substance, the placebo appears to drive down a blood pressure reading . Classical conditioning has been presented as a viable explanation for placebo efficacy in accounting for pair reduction . There are those who emphasize that the strength of underlying psychical processes can best be accounted for by the intensity of cognitive expectations. It has been observed that pair threshold can be raised so that pair can be better tolerated, when the subject is provided with suggestions that increase the level of positive expectations. This, when it was suggested to subjects that they would benefit from ice water treatments, they appeared to better tolerate and withstand pair experiences .Cognitive psychologists explain that expectations of restored health may serve to reduce anxiety and enhance one’s coping mechanisms.
Neurobiology of the Placebo Response
There is a growing body of findings that support the view that placebo responses are accompanied by corresponding neurobiological processes. Brody , in a cogent article, asserts that the placebo effect can not simply be accounted for theories of conditioning or positive expectancy; that is it has been observed that the altered perception in a patient’s mind actually activates physiological changes. The specific biochemical and neuroanatomical processes that are altered or activated is still being explored. Nonetheless, three “pathways” have been identified in research undertakings; endorphin activity; catecholamine activity and psychoneuroimmunological processes. There is research support that shows that these pathways to the placebo response have been observed as impacting upon bodily sensations and is linked to an individual’s affective and emotional states. Levine et al  demonstrated that placebo analgesia could actually be blocked by naloxone,a known opioid agonist. The finding was heavily suggestive of an endogenous- based opioid effect. In a more recent study, Colloca and Benedetti  showed that a placebo intervention was quite capable of reducing pair via opioid and non-opioid processes. These researchers reasoned that placebo-induced analgesia is thwarted by the opioid antagonist naloxone, but when the placebo-induced analgesia is activated through a non-opioid mechanism, naloxone does not effectively block the placebo analgesic effect. This phenomenon was also observed in the work of Amanzio and Benedetti . These researchers also found that placebo analgesia can be effectively blocked by the working of naloxone, when patient expectation had been heightened; contrariwise, when patient expectation was lowered the placebo response became insensitive to naloxone. Such findings strongly stimulate the release of endogenous opioids. The researchers focused on two conditions underlying placebo response to pair-expectancy in comparison to conditioning and conditioning paired with morphine versus conditioning paired with an NSAID such as Ketrolac.
Since the findings ultimately revealed that placebo analgesic effects stemming from expectancy could be blocked or reversed through the administration of the agonist naloxone; it might be posited that endogenous endorphins had been activated in the anticipation of pain. In fact, it was observed that placebo conditioning with an actual opiate, morphine, was able to be reversed through the administration of naloxone, but naloxone was unable to reverse the placebo response stimulated by ketorolac, a non-opiate (26). Petrovic et al. (27), using positron emission tomography, observed that whether analgesia was effected by a placebo or by the opioid agonist, remifentanil, a number of pain regulating regions in the brain appeared activated: specifically, the rostral anterior cingulate cortex; the orbitofrontal cortex; as well as the anterior insula.
Benedetti, Mayberg, Wager et al. (28), in a comprehensive review relating to the neurobiological mechanisms of the placebo effect, convincingly conclude that there is a plethora of support to advance the notion that expectancy-based placebo effects are regulated by endogenous opioids. The fMRI studies of Wager et al. (29) serve to sustain the view that placebo effectiveness in pain reduction materializes by tamping down the anxiety of the patient, as placebo-induced reductions in anticipatory reactions were observed in regions of the amygdala and the temporal lobes; areas of the brain linked to noxious expectancies (30-32). Petrovic et al. (32) found that placebo-induced expectations of anxiety relief activated regions in the rostral anterior cingulate and the orbitofrontal cortices. Scott et al. (35) conclude that both placebo and nocebo effects are tied to reverse or opposite neurotransmitter pathways of dopaminergic and endogenous opioids within a network of linked regions (including the anterior cingulate, orbitofrontal cortex, nucleus accumbens, amygdala and periaqueductal gray matter). These are regions that are thought to be linked to reward and incentive based behaviors. Benedetti et al. (28) urge further research so as to explore the impact of placebo-induced effects on brain function and neurobiological mechanisms.
One cannot ignore findings that the placebo effect can stimulate positive conditions that arise from anxiety reduction. Fricchione and Stefano (34) speculate that moderations in the mesolimbic and mesocortical regions during the experience of stress may be the consequence of positive expectancy arising from the placebo effect. Vase et al. (35) maintain that the reduction in the experience of negative emotions might prove to
be a crucial element in placebo analgesia. Cortisol, a stress-related hormone, has also been impacted during experimental manipulation of expectation in the study of placebo analgesia (36). Ribeiro et al. (37) assert that the nonsuppression of the cortisol level subsequent to the administration of a dexamethasone suppression test can serve as a predictor of a poor placebo responder. Ader et al. (38) assert that many facets of psychoneuroimmunology can interplay in the placebo response process, especially when exploring the impact of conditioning in the nature of patient-professional communications.
Applications of the Placebo Effect in Clinical Practice
Brown (39) estimates that approximately 30% to 40% of patients experience relief from their symptoms after being treated with a placebo-type intervention. Nonetheless, based on the discussion abve, the placebo effect is not a mere artifact of the psyche; physical benefit or improved health that accrues to the patient can not be explained as mental figments. During the past several decades inert or placebo substances have been applied in the amelioration of symptoms of allergy, headaches, GI upset and chronic pain. As Turner et al. (40) point out, the placebo effect demonstrates its greatest utility when applied to the alleviation of pain. Oken (41), in a recent and comprehensive overview, shows the value of the placebo effect in its treatment application to Parkinson’s Disease, Multiple sclerosis, Epilepsy and to some aspects of dementia. Meyhoff et al. (42) found that female patients decreased their experience of incontinence and nocturia when the placebo response was induced. Freeman and Richels found success with placebo application in the treatment of premenstrual syndrome (43). Fulda and Wetter (44), in a recent meta-analysis, showed the value of the placebo effect in the treatment of restless leg syndrome.
It is precisely because the placebo response is an actual phenomenon with observable positive effects that a newly developed experimental drug must prove its efficacy in the treatment of a particular disorder by demonstrating that it surpasses the effects that a placebo, or inert substance, might offer. Notwithstanding the foregoing, the placebo response has been devalued by its detractors. Hrobjarttson and Gotzche (45), in a well known meta-analysis of over 100 studies, compared patients in placebo conditions for a wide range of illnesses and disorders with those who received no treatment and formed the conclusion that placebos are essentially ineffectual. However, those who undertook to closely probe Hrobjarttson and Gotzche’s investigation determined that their study suffered from several methodological flaws. For example, the investigators’ conclusions were based on averaging the data from more than 40 disorders, many for which a placebo effect would not be expected (46). Kirsch and Scorboria (47), in their critique of the Hrobjarttson and Gotzche investigation, point out that they combined studies of diverse illnesses and applied a single analysis. Even Hrobjarttson and Gotzche, in their own report, concede a level of effectiveness of the placebo in the alleviation of pain as observed in a number of applications.
In a Danish study (48), 86% of the general practitioners admitted to treating with some form of placebo intervention; 54% of hospital –based physicians and 41% of specialists admitted to placebo use as well. Sherman and Hickner (49) reported that 45% of the 231 internists interviewed in their investigation admitted to placebo use.
The essential ethical issue that a practitioner is confronted with when treating with a placebo is not that the patient is receiving a useless substance, but rather, the patient is not being duly informed that an inert substance is being employed, and is, thus, a victim of sham or deception. A cogent reply to this oft-cited argument has been offered by Lichtenberg and his colleagues (50). They express that what is specious about the complaint of patient deception is that it is hingent on the premise that pharmacological intervention is the preferred treatment of choice. Actually, they assert that an effective physician engages with the patient on a “biopsychosocial continuum” through dint of his/her personality and his/her assurances and expressions of concern. Lichtenberg et al. express that “the placebo is a deception only for those who would reduce treatment to a purely biomedical pursuit… (It) might take the form of: “I would like to offer you a pill which I believe can help lessen your suffering… (50, p. 552).” The primary focus is, and should always be, alleviating patient pain, discomfort and stress.
In a national survey conducted during 2008(51), 62% of the physicians interviewed expressed that the utilization of prescribed placebo treatments represent ethical encounters. The survey’s findings highlight that the prescription of placebo treatments are actually frequent occurrences and is viewed as an ethical practice by the internists and rheumatologists who were interviewed. Vitamins and non-prescription analgesics are often recommended, although physicians often do not reveal that a placebo is being suggested.
In the matter of surgical placebo use, Article II. 3 of the Declaration of Helsinki cites, in part: “In any medical study, every patient-including those of a control group… should be assured of the best proven diagnostic and therapeutic method. This does not exclude the use of inert placebos in studies where no proven diagnostic or therapeutic method exists (52).”
Olshansky (53) reminds us that placebo treatments are part-and-parcel of medical care. Physician caring engenders trust in the provider-patient interaction and will tend to induce a strong placebo effect. Future research should focus on what types of disorders or disease syndromes could benefit most from placebo interventions and the extent of its utility.
I wish to express my sincere gratitude to Daniel Peikes (DMD-pending) for his invaluable assistance in providing a number of the relevant and seminal works cited in this article.
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Stanley Bodner, Ph.D
Adelphi University-University College
Department of Social Science
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Garden City, NY 11530
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