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Nocebo and placebo effects have been found to modulate several neurochemical systems, such as cholecystokinin, endogenous opioids, and endocannabinoids. Here we show that also the cyclooxygenase-prostaglandins pathway can be modulated by both nocebos and placebos. In fact, we found that negative expectation, the crucial element of the nocebo effect, about headache pain led to the enhancement of the cyclooxygenase-prostaglandins pathway, which, in turn, induced pain worsening. As an experimental model, we studied hypobaric hypoxia headache at high altitude in 2 populations of subjects. Whereas the experimental nocebo group received negative information by a single individual who was informed about the risk of headache, the control group did not know about the possible occurrence of headache. We found a significant increase in headache and salivary prostaglandins and thromboxane in the nocebo group compared to the control group, suggesting that negative expectations enhance cyclooxygenase activity. In addition, placebo administration to headache sufferers at high altitude inhibited the nocebo-related component of pain and prostaglandins synthesis, which indicates that the cyclooxygenase pathway can be modulated by both nocebos and placebos. Our results show for the first time how nocebos and placebos affect the synthesis of prostaglandins, which represent an important target of analgesic drugs, thus emphasizing once again the notion that placebos and drugs may use common biochemical pathways.

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.

Pain management in elderly people with cognitive impairment poses special challenges, due to difficulties in pain assessment and specific neurodegenerative changes along pain pathways. Most studies have concentrated on Alzheimer's disease (AD) patients, in whom some contrasting findings have been found. For example, while psychophysical data suggest a selective blunting of the affective dimension of pain, pain-related fMRI signal increases have also been described. Few data have been reported in patients with frontotemporal dementia (FTD). By electrical stimulation, we have measured pain threshold and pain tolerance in clinically diagnosed FTD patients with SPECT cerebral hypoperfusion. We performed our analysis on two separate and overlapping subgroups selected on the basis of (1) neuropsychological scores below cut-off values (2) a strictly localized frontal and/or temporal hypoperfusion. We observed increased pain threshold in the first group and increased pain threshold and pain tolerance in the second group. Our results suggest differences in pain processing changes in distinct types of dementia, while at the same time caution that pain perception assessment may depend on the criteria adopted for diagnosis.

High-altitude, or hypobaric hypoxia, headache has recently emerged as an interesting model to study placebo and nocebo responses, and particularly their peripheral mechanisms. In this study, we analyze the response of this type of headache to either real or sham (placebo) oxygen (O(2)) administration at an altitude of 3500 m, where blood oxygen saturation (SO(2)) drops from the normal value of about 98% to about 85%. In a trial in which a double-blind administration of either 100% O(2) or sham O(2) was administered, we tested pre- and post-exercise headache, along with fatigue, heart rate (HR) responses, and prostaglandin E(2) (PGE(2)) salivary concentration. Although real O(2) breathing increased SO(2) along with a decrease in pre- and post-exercise headache, fatigue, HR, and PGE(2), placebo O(2) changed neither pre-/post-exercise headache nor SO(2)/HR/PGE(2), but it decreased fatigue. However, in another group of subjects, when sham O(2) was delivered after 2 previous exposures to O(2) (O(2) preconditioning), it decreased fatigue, post-exercise headache, HR, and PGE(2), yet without any increase in SO(2). Three main findings emerge from these data. First, placebo O(2) is effective in reducing post-exercise headache, along with HR and PGE(2) decrease, only after O(2) preconditioning. Second, pre-exercise (at rest) headache is not affected by placebo O(2), which emphasizes the limits of a placebo treatment at high altitude. Third, fatigue is affected by placebo O(2) even without prior O(2) conditioning, which suggests the higher placebo sensitivity of fatigue compared with headache pain at high altitude.

Placebo-activated endogenous opioids act on pain mechanisms inducing analgesia, as well as on the respiratory centers inducing respiratory depression. Here, we show that placebo analgesia is accompanied by a reduced beta-adrenergic activity of the heart. We measured heart rate during placebo-induced expectation of analgesia, both in the clinical and the laboratory setting. In the clinical setting, we found that the placebo analgesic response to an electrical noxious stimulus was accompanied by a reduced heart rate response. In order to investigate this effect from a pharmacological viewpoint, we reproduced the same effect in the laboratory setting by using experimental ischemic arm pain. We found that the opioid antagonist naloxone completely antagonized both placebo analgesia and the concomitant reduced heart rate response, whereas the beta-blocker propranolol antagonized the placebo heart rate reduction, but not placebo analgesia. By contrast, both placebo responses were present during muscarinic blockade with atropine, indicating no involvement of the parasympathetic system. In order to better understand the effects of naloxone and propranolol, we performed a spectral analysis of the heart rate variability for the identification of the sympathetic and parasympathetic components, and found that the beta-adrenergic low frequency (0.15 Hz) spectral component was reduced during placebo analgesia, an effect that was reversed by naloxone. These findings indicate that placebo analgesia is accompanied by a complex cascade of events which affect the cardiovascular system.

The treatment of neuropathic pain with opioid analgesics is a matter of controversy among clinicians and clinician scientists. Although neuropathic pain is usually believed to be only slightly responsive to opioids, several studies show that satisfactory analgesia can be obtained if adequate doses are administered. In the present study, we tested the effectiveness of buprenorphine in 21 patients soon after thoracic surgery (nociceptive postoperative pain) and 1 month after surgery in the same 21 patients who developed postthoracotomy neuropathic pain with a burning, electrical and shooting quality. According to a double-blind randomized study, the analgesic dose (AD) of buprenorphine needed to reduce the long-term neuropathic pain by 50% (AD50) was calculated and compared to the AD50 in the immediate postoperative period. We found that long-term neuropathic pain could be adequately reduced by buprenorphine. However, the AD50 in neuropathic pain was significantly higher relative to the AD50 in the short-term postoperative pain, indicating a lower responsiveness of neuropathic pain to opioids. We also found a strict relationship between the short-term and long-term AD50, characterized by a saturating effect. In fact, if the AD50 soon after surgery was low, the AD50 increase in the long-term neuropathic pain was threefold. By contrast, if the AD50 soon after surgery was high, the AD50 in neuropathic pain was only slightly increased. This suggests that, though neuropathic pain is indeed less sensitive to opioids, in some neuropathic patients a large amount of opioid resistance is already present in other painful conditions.

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.