Luana Colloca

Overt versus covert treatment for pain, anxiety, and Parkinson's disease

The recent introduction of covert administration of treatment to biomedical research has produced some interesting results, with many clinical and ethical implications. Concealed treatment has been used in people with nervous system conditions including pain, anxiety, and Parkinsons disease. The main finding is that when the patient is completely unaware that a treatment is being given, the treatment is less effective than when it is given overtly in accordance with routine medical practice. The difference between open and hidden administrations is thought to represent the placebo component of the treatment, even though no placebo has been given. The decreased effectiveness of hidden treatments indicates that knowledge about a treatment affects outcome and highlights the importance of the patient-provider interaction. In addition, by use of covert administration, the efficacy of some treatments can be assessed without the use of a placebo and associated ethical issues.

WHEN WORDS ARE PAINFUL: UNRAVELING THE MECHANISMS OF THE NOCEBO EFFECT

The nocebo effect is a phenomenon that is opposite to the placebo effect, whereby expectation of a negative outcome may lead to the worsening of a symptom. Thus far, its study has been limited by ethical constraints, particularly in patients, as a nocebo procedure is per se stressful and anxiogenic. It basically consists in delivering verbal suggestions of negative outcomes so that the subject expects clinical worsening. Although some natural nocebo situations do exist, such as the impact of negative diagnoses upon the patient and the patients distrust in a therapy, the neurobiological mechanisms have been understood in the experimental setting under strictly controlled conditions. As for the placebo counterpart, the study of pain has been fruitful in recent years to understand both the neuroanatomical and the neurochemical bases of the nocebo effect. Recent experimental evidence indicates that negative verbal suggestions induce anticipatory anxiety about the impending pain increase, and this verbally-induced anxiety triggers the activation of cholecystokinin (CCK) which, in turn, facilitates pain transmission. CCK-antagonists have been found to block this anxiety-induced hyperalgesia, thus opening up the possibility of new therapeutic strategies whenever pain has an important anxiety component. Other conditions, such as Parkinsons disease, although less studied, have been found to be affected by nocebo suggestions as well. All these findings underscore the important role of cognition in the therapeutic outcome, and suggest that nocebo and nocebo-related effects might represent a point of vulnerability both in the course of a disease and in the response to a therapy.

Placebos and painkillers: is mind as real as matter?

Considerable progress has been made in our understanding of the neurobiological mechanisms of the placebo effect, and most of our knowledge originates from the field of pain and analgesia. Today, the placebo effect represents a promising model that could allow us to shed new light on mind–body interactions. The mental events induced by placebo administration can activate mechanisms that are similar to those activated by drugs, which indicates a similarity between psychosocial and pharmacodynamic effects. These new neurobiological advances are already changing our conception of how clinical trials and medical practice must be viewed and conducted.

How prior experience shapes placebo analgesia

Abstract Some studies indicate that placebo analgesia is stronger when pre‐conditioning with effective analgesic treatments is performed, thereby suggesting that the placebo response is a learning phenomenon. Here we further tested this hypothesis in order to better understand when and how previous experience affects the placebo analgesic response. To do this, we used a conditioning procedure whereby the intensity of painful stimulation was reduced surreptitiously, so as to make the subjects believe that an analgesic treatment was effective. This procedure induced strong placebo responses after minutes, and these responses, albeit reduced, lasted up to 4–7 days. In addition, in a second group of subjects we repeated the same conditioning procedure 4–7 days after a totally ineffective analgesic treatment, and found that the placebo responses were remarkably reduced compared to the first group. Thus we obtained small, medium and large placebo responses, depending on several factors, such as the previous positive or negative experience of an analgesic treatment and the time lag between the treatment and the placebo responses. We also ran extinction trials, and found that these effects did not undergo extinction in a time span of several minutes. These findings indicate that placebo analgesia is finely tuned by prior experience and these effects may last, albeit reduced, several days. These results emphasize that the placebo effect is a learning phenomenon in which many factors come into play, and may explain the large variability of the placebo responses that is found in many studies.

The role of learning in nocebo and placebo effects

&NA; The nocebo effect consists in delivering verbal suggestions of negative outcomes so that the subject expects clinical worsening. Here we show that nocebo suggestions, in which expectation of pain increase is induced, are capable of producing both hyperalgesic and allodynic responses. By extending previous findings on the placebo effect, we investigated the role of learning in the nocebo effect by means of a conditioning procedure. To do this, verbal suggestions of pain increase were given to healthy volunteers before administration of either tactile or low‐intensity painful electrical stimuli. This nocebo procedure was also carried out after a pre‐conditioning session in which two different conditioned visual stimuli were associated to either pain or no‐pain. Pain perception was assessed by means of a Numerical Rating Scale raging from 0 = tactile to 10 = maximum imaginable pain. We found that verbal suggestions alone, without prior conditioning, turned tactile stimuli into pain as well as low‐intensity painful stimuli into high‐intensity pain. A conditioning procedure produced similar effects, without significant differences. Therefore, in contrast to placebo analgesia, whereby a conditioning procedure elicits larger effects compared to verbal suggestions alone, learning seems to be less important in nocebo hyperalgesia. Overall, these findings indicate that, by defining hyperalgesia as an increase in pain sensitivity and allodynia as the perception of pain in response to innocuous stimulation, nocebos can indeed produce both hyperalgesic and allodynic effects. These results also suggest that learning is not important in nocebo hyperalgesia compared to placebo analgesia.

Placebo-responsive Parkinson patients show decreased activity in single neurons of subthalamic nucleus

Placebo administration is known to affect the brain both in pain and in Parkinson disease. Here we show that placebo treatment caused reduced activity in single neurons in the subthalamic nucleus of placebo-responsive Parkinsonian patients. These changes in activity were tightly correlated with clinical improvement; no decrease in activity occurred when the clinical placebo response was absent.

Placebo analgesia induced by social observational learning.

ABSTRACT Although it has long been known that psychosocial factors play a crucial role in placebo responses, no attempt has been made to understand if social observation shapes the placebo analgesic effect. To address this question, we compared placebo analgesia induced through social observation (Group 1) with first‐hand experience via a typical conditioning procedure (Group 2) and verbal suggestion alone (Group 3). In Group 1, subjects underwent painful stimuli and placebo treatment after they had observed a demonstrator (actually a simulator) showing analgesic effect when the painful stimuli were paired to a green light. In Group 2, subjects were conditioned according to previous studies, whereby a green light was associated to the surreptitious reduction of stimulus intensity, so as to make them believe that the treatment worked. In Group 3, subjects received painful stimuli and were verbally instructed to expect a benefit from a green light. Pain perception was assessed by means of a Numerical Rating Scale (NRS) ranging from 0 = no pain to 10 = maximum imaginable pain. Empathy trait and heart rate were also measured. We found that observing the beneficial effects in the demonstrator induced substantial placebo analgesic responses, which were positively correlated with empathy scores. Moreover, observational social learning produced placebo responses that were similar to those induced by directly experiencing the benefit through the conditioning procedure, whereas verbal suggestions alone produced significantly smaller effects. These findings show that placebo analgesia is finely tuned by social observation and suggest that different forms of learning take part in the placebo phenomenon.

Nocebo Effects, Patient-Clinician Communication, and Therapeutic Outcomes

by negative expectations and represent the nega-tive side of placebo effects. It is now recognizedthat nocebo effects exist and operate during rou-tine treatments, negatively affecting clinical outcomes evenwhen placebos are not administered. The nocebo effectsand placebo effects are the direct result of the psychosocialcontext or therapeutic environment on a patient’s mind,brain, and body. Both phenomena can be produced bymultiple factors, such as verbal suggestions and past expe-rience.

The Nocebo Effect and Its Relevance for Clinical Practice

Negative expectations deriving from the clinical encounter can produce negative outcomes, known as nocebo effects. Specifically, research on the nocebo effect indicates that information disclosure about potential side effects can itself contribute to producing adverse effects. Neurobiological processes play a role in the nocebo effect, and this article provides a selective review of mechanistic research on the nocebo effect. Comparatively little attention has been directed to clinical studies and their implications for daily clinical practice. The nocebo response is influenced by the content and the way information is presented to patients in clinical trials in both the placebo and active treatment conditions. Nocebo effects adversely influence quality of life and therapy adherence, emphasizing the need for minimizing these responses to the extent possible. Evidence further indicates that the informed consent process in clinical trials may induce nocebo effects. This article concludes with ethical directions for future patient-oriented research and routine practice.SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; BPH = benign prostatic hyperplasia

Nocebo hyperalgesia: how anxiety is turned into pain.

Purpose of review Nocebo hyperalgesia is a phenomenon that is opposite to placebo analgesia and whereby expectation of pain increase plays a crucial role. In recent times, both the neuroanatomical and the neurochemical bases of the nocebo effect and of nocebo-related effects have begun to be explored. Here, we highlight recent advances in our understanding of the neurobiology of the nocebo hyperalgesic effect. Recent findings A typical nocebo hyperalgesic response occurs following the administration of an inert substance which the subject believes to be a hyperalgesic agent (negative placebo or nocebo). It has been shown that the subjects negative expectations of pain worsening induce anticipatory anxiety about the impending pain increase and this triggers the activation of cholecystokinin that, in turn, facilitates pain transmission. Accordingly, cholecystokinin antagonists have been found to prevent this anxiety-induced hyperalgesia. Brain-imaging studies have shown that the perceived intensity of a painful stimulus following negative expectations of pain increase is higher than in the absence of negative expectations and this is associated with changes in activation of specific brain regions. Summary Since pain appears to be amplified by anxiety through the activation of cholecystokininergic systems, new therapeutic strategies, such as new cholecystokinin antagonists, can be envisaged whenever pain has an important anxiety component.