Creating Placebo Nonresponders in the Lab.

Conditioning and expectation are known to be the main mechanisms of placebo analgesia. They may operate together, so that expectations may be enhanced by a conditioning procedure. Although most of the studies have tried to potentiate expectations through conditioning in order to generate good placebo responders, a few studies have tried to mismatch conditioning and expectations in order to investigate the subsequent administration of a placebo. In this study, we want to further investigate this mismatch. We generated incongruent associations during a conditioning procedure in which the study participants did not get what they expected. In fact, although the participants received verbal instructions of pain decrease following the administration of a placebo, we surreptitiously increased the painful electric stimulation. Two pairings of these incongruent associations (mismatch between what was expected and what was experienced) disrupted expectations of analgesia as well as the placebo effect, as assessed by measuring electric pain thresholds on the hand. The effects of mismatch conditioning on the hand extended to the contralateral arm and to a different type of pain (tourniquet), which suggests that local mismatch conditioning may affect the whole body. In all cases, expectations predicted placebo analgesia. These findings indicate that placebo nonresponders can be created in the laboratory by acting on expectations and that local effects can be generalized to other parts of the body. They also stress the importance of expectations in the therapeutic outcome, with important implications for clinical trials. PERSPECTIVE: By using mismatch conditioning, in which study participants did not get what they expected, we reduced expectations of analgesia, and this reduction abolished placebo analgesia. This effect extended to other parts of the body and other types of pain, which indicates that placebo nonresponders can be created in the laboratory.

Open-label nondeceptive placebo analgesia is blocked by the opioid antagonist naloxone.

ABSTRACT: Open-label placebos, or placebos without deception, have been found to induce analgesia, a challenging concept that need to be investigated in detail. In particular, what we need to know is the mechanism through which analgesia is induced when no deception is involved. In this study, we show for the first time that open-label placebo analgesia can be reversed by the opioid antagonist naloxone, as already shown for deceptive placebos. To do this, we used the tourniquet technique to induce experimental ischemic arm pain. The open-label placebo challenge started when pain scores reached 7 on a 0 to 10 rating scale. Although 59.4% of the subjects did not respond to the open-label placebo, 40.6% showed a substantial response. On the basis of the natural history control group, a placebo responder reported pain scores equal to or less than 7 after 9 minutes from the open-label placebo administration. In these responders, we found that a hidden injection of 10 mg naloxone could reverse placebo analgesia compared with a hidden injection of saline solution. At least 2 control groups showed that naloxone per se was not hyperalgesic, thus ruling out naloxone-induced hyperalgesia as a confounding variable. In light of the need to better understand open-label placebo effects, these findings represent the first experimental evidence that nondeceptive placebo analgesia may be mediated by the same mechanisms as deceptive placebo analgesia, namely the endogenous opioid systems.

Are Nocebo Effects in Adulthood Linked to Prenatal Maternal Cortisol Levels?

Objective: Placebo-induced adverse events, or nocebo effects, occur when doctor-patient communication anticipates the onset of negative symptoms. They have been found to correlate with the anxiety-related activity of the hypothalamic-pituitary-adrenal system. Here we try to determine if prenatal hyperactivity of this system, as assessed through plasma cortisol, may influence nocebo effects in adulthood. Method: We investigated the rate and magnitude of nocebo effects in 378 adults whose prenatal maternal plasma cortisol was measured during the first, second and third trimester of pregnancy. The healthy subjects underwent a nocebo oxygen challenge. This consisted of the inhalation of fake (placebo) oxygen and assessment of the following adverse events: headache, chest pain, abdominal pain, and cough. Plasma cortisol responses during the nocebo adverse events were also measured. Results: 41 out of 46 (89.1%) subjects who reported 3 adverse events, and 37 out of 37 (100%) subjects who reported 4 adverse events had prenatal maternal cortisol above normal levels. By contrast, only 10 out of 143 (7%) subjects who reported 0 adverse events showed prenatal maternal cortisol above the normal range. Moreover, whereas subjects who reported 3 and 4 adverse events showed a significant increase in plasma cortisol following the nocebo challenge, subjects who reported 0 adverse events showed no changes. Conclusions: These findings emphasize the importance of the doctor-patient communication in perceiving symptoms like pain, and suggest that those subjects with high prenatal maternal cortisol may be more sensitive to the effects of a negative communication in adulthood.

Pain as a reward: changing the meaning of pain from negative to positive co-activates opioid and cannabinoid systems.

Pain is a negative emotional experience that is modulated by a variety of psychological factors through different inhibitory systems. For example, endogenous opioids and cannabinoids have been found to be involved in stress and placebo analgesia. Here we show that when the meaning of the pain experience is changed from negative to positive through verbal suggestions, the opioid and cannabinoid systems are co-activated and these, in turn, increase pain tolerance. We induced ischemic arm pain in healthy volunteers, who had to tolerate the pain as long as possible. One group was informed about the aversive nature of the task, as done in any pain study. Conversely, a second group was told that the ischemia would be beneficial to the muscles, thus emphasizing the usefulness of the pain endurance task. We found that in the second group pain tolerance was significantly higher compared to the first one, and that this effect was partially blocked by the opioid antagonist naltrexone alone and by the cannabinoid antagonist rimonabant alone. However, the combined administration of naltrexone and rimonabant antagonized the increased tolerance completely. Our results indicate that a positive approach to pain reduces the global pain experience through the co-activation of the opioid and cannabinoid systems. These findings may have a profound impact on clinical practice. For example, postoperative pain, which means healing, can be perceived as less unpleasant than cancer pain, which means death. Therefore, the behavioral and/or pharmacological manipulation of the meaning of pain can represent an effective approach to pain management.

Loss of expectation-related mechanisms in Alzheimer's disease makes analgesic therapies less effective.

Expectation/placebo-related mechanisms and specific effects of therapies show additive effects, such that a therapy is less effective if the placebo component is absent. So far, the placebo component has been disrupted experimentally by using covert administrations of treatments. Here, we show for the first time that disruption of expectation/placebo-related analgesic mechanisms may occur in a clinical condition, Alzheimer's disease (AD). In order to assess the placebo component of a therapy, we used the recently developed open-hidden paradigm. A local anesthetic was applied, either overtly or covertly, to the skin of AD patients to reduce burning pain after venipuncture. The placebo (psychological) component is represented by the difference between the analgesic effect after open (expected) and after hidden (unexpected) application. We correlated the placebo component with both cognitive status and functional connectivity among different brain regions. We found that AD patients with reduced Frontal Assessment Battery scores showed reduced placebo component of the analgesic treatment. We also found that the disruption of the placebo component occurred when reduced connectivity of the prefrontal lobes with the rest of the brain was present. Remarkably, the loss of these placebo-related mechanisms reduced treatment efficacy, such that a dose increase was necessary to produce adequate analgesia. These findings highlight the active role of cognition and prefrontal lobes in the therapeutic outcome and underscore the need of considering a possible revision of the therapeutic approach in Alzheimer patients in order to compensate for the loss of the endogenous expectation and placebo mechanisms.

Pain reactivity in Alzheimer patients with different degrees of cognitive impairment and brain electrical activity deterioration.

Pain perception and autonomic responses to pain are known to be altered in dementia, although the mechanisms are poorly understood. We studied patients with Alzheimer's disease (AD) whose cognitive status was assessed through the Mini Mental State Examination test and whose brain electrical activity was measured by means of quantitative electroencephalography. After assessment of both cognitive impairment and brain electrical activity deterioration, these patients underwent sensory measurements in which the minimum stimulus intensity for both stimulus detection and pain sensation was determined. In addition, heart rate responses to pain threshold x 1.5 were recorded. We found that neither stimulus detection nor pain threshold was correlated to cognitive status and brain electrical activity decline. By contrast, we found a correlation between heart rate responses and deterioration of both cognitive functions and brain electrical activity. In particular, the heart rate increase after pain stimulation was correlated to the presence of slow brain electrical activity (delta and theta frequencies). This correlation was also found for the anticipatory heart rate increase just before pain stimulation. These results indicate that pain anticipation and reactivity depend on both the cognitive status and the frequency bands of the electroencephalogram, whereas both stimulus detection and pain threshold are not affected by the progression of AD. These findings indicate that, whereas the sensory-discriminative components of pain are preserved even in advanced stages of AD, the cognitive and affective functions, which are related to both anticipation and autonomic reactivity, are severely affected. This sensory-affective dissociation is well correlated with the neuropathological findings in AD.