A novel neurocognitive approach for placebo analgesia in neurocognitive disorders.

Neural correlates of placebo analgesia (PA) in patients with neurocognitive disorders have not yet been elucidated. The present study aimed to evaluate how and to what extent executive (dys)functions of the medial prefrontal cortex (MPFC) may be related to PA. To this end, twenty-three subjects complaining of different cognitive deficits (from mild cognitive impairment likely due to Alzheimer's disease to mild AD) were recruited. PA was investigated by a well-known experimental venipuncture pain paradigm (open versus hidden [O-H] application of lidocaine). Patients also underwent a comprehensive neuropsychological evaluation and a functional magnetic resonance imaging (fMRI) GO/No-GO task for eliciting selective activation of the MPFC. Selected neuropsychological variables were correlated to the OH-PA paradigm. The association between the fMRI response on the "No-GO" versus "GO" contrast and PA was investigated over the whole-brain by regression analysis. We showed the existence of a relationship between a lower PA and MPFC dysfunctions through the neuropsychological and fMRI assessment. A separate voxel-based morphometry (VBM) analysis controlled for possible influence of grey matter (GM) volume reduction on both fMRI results and PA. fMRI results were not directly affected by, and therefore independent of, disease-specific GM atrophy, which was indeed located more anteriorly within the rostral anterior cingulate and inversely correlated with PA. Our findings shed new light on the underestimated contribution of executive (dys)functions mediated by the MPFC (response-inhibition, self-monitoring and set-shifting abilities) in PA pathogenesis, with a special purely (i.e. independently from brain structural alterations) functional role played by the MCC. Results are discussed in terms of possible clinical relevance in the management of patients with neurocognitive disorders.

Nocebo vs. placebo: the challenges of trial design in analgesia research.

The placebo effect in randomized clinical trials appears to have increased thereby contributing to problems of demonstrating statistically reliable effects of treatments that directly target biological mechanisms. The shortcomings of randomized clinical trials are currently discussed along with potential improvements of trial designs. In this review we explain how utilizing knowledge from the placebo and nocebo mechanisms literature could improve the information that can be obtained from randomized clinical trials. We present three major challenges in randomized clinical trials: (i) increasing placebo effects, (ii) variability of the placebo effect, and (iii) risk of un-blinding. We then explain how recent placebo and nocebo studies of effects of verbal suggestion, expectancy, and emotions may improve understanding and discussion of increasing placebo effects, account/control for large parts of the variability of placebo effects, and suggest ways to improve blinding in future trials.

Unawareness of bipolar disorder: the role of the cingulate cortex.

Reduced awareness of illness is a well-known phenomenon that has been understudied in remitted patients with bipolar disorder. In particular, the relationship between reduced awareness and executive dysfunction is an intriguing question that has yet to be resolved. The aim of the current study is to analyze the link between reduced awareness, brain dysfunction, and concomitant cognitive-behavioral disturbances from a neurocognitive perspective. In previous studies, we demonstrated the role of the anterior cingulate cortex (ACC) in the unawareness of distinct pathologies that exhibit overlapping symptoms in the context of overlapping circuit-specific dysfunction. Given the clinical importance of the results obtained, the present study considers six aware and four unaware remitted bipolar disorder patients. Cingulate functionality was assessed with functional magnetic resonance imaging while patients performed a go/no-go task. Patients were also studied on an overall cognitive task battery and with behavioral assessment of mood changes in terms of apathy and disinhibited behavior. Unaware patients showed frontoparietal hypo-perfusion, with a significant reduction of task-sensitive activity in the bilateral superior and middle frontal gyrus, putamen, insular, and ACCs.

Unawareness of deficits in ischemic injury: role of the cingulate cortex.

Reduced awareness of illness is a well-known phenomenon that has been studied in patients with vascular disease, but the precise nature of their executive dysfunction is an intriguing question that still has to be resolved. It would be particularly interesting to study patients with reduced awareness of disease possibly related to vascular lesions of the prefrontal cortex. Due to the clinical importance of the case, here we present a patient with a selective right anterior cingulate ischemic injury and impaired awareness of deficits. We suggest that the cingulo-frontal area dysfunction may represent one of the corresponding neurobiological substrates of his persistent unawareness, which has not yet been evaluated in the literature on patients with acquired brain injury (ABI).

Variabilidad de la respuesta a los analgésicos: papel de la activación inespecífica de los opiáceos endógenos / Response variability to analgesics: a role of non-specific activation of endogenous opiates

Las diferencias individuales en farmacocinética y farmacodinámica, el tipo de dolor y el método de administración de la medicación, pueden explicar la variabilidad de la respuesta a los analgésicos. Integrando un enfoque clínico y otro experimental, en este artículo se demuestra la existencia de otra importante fuente de variabilidad representada por diferencias individuales en la activación inespecífica (placebo) de los sistemas opiáceos endógenos. En la primera parte de este estudio se analiza la eficacia de buprenorfina, tramadol, ketorolaco y metamizol en la práctica clínica, eliminando por completo el efecto placebo por medio de infusiones a escondidas. Se observó que las inyecciones a escondidas eran significativamente menos eficaces y menos variables que las inyecciones al descubierto (a la vista del sujeto), lo que sugiere que parte de la variabilidad de la respuesta se debía a factores no específicos (placebo). Puesto que no pudimos administrar el antagonista opiáceo naloxona a estos pacientes, en la segunda parte del estudio provocamos dolor isquémico experimental de brazo en voluntarios sanos y comprobamos que, al igual que ocurría con el dolor clínico, la respuesta analgésica a la inyección a escondidas del analgésico no opiáceo ketorolaco era menos eficaz y menos variable que las inyecciones a la vista. Pero lo más importante es que obtuvimos los mismos efectos añadiendo naloxona a una inyección a la vista de ketorolaco, bloqueando con ello el componente placebo de la analgesia mediado por los opiáceos. Estos hallazgos indican que tanto el bloqueo psicológico (inyección a escondidas) como farmacológico (naloxona) de la respuesta al placebo, reducen la eficacia y la variabilidad de la respuesta a los analgésicos. Por consiguiente, una importante fuente de variabilidad de la respuesta a los analgésicos parece deberse a diferencias en la activación inespecífica de los sistemas opiáceos endógenos (AU)

Quantitative EEG responses to ischaemic arm stress in migraine.

Several studies suggest that patients with migraine respond physiologically to stress differently from controls, yet experimental data are scarce. In order to evaluate the reactivity to stress in migraine, we recorded the quantitative electroencephalogram (qEEG) during non-noxious and noxious ischaemic arm stress in two groups of healthy controls and compared the results with the effects of non-noxious ischaemic arm stress in a group of patients with migraine. In the controls, non-noxious mild stress did not produce any qEEG change but noxious stress induced a significant decrease of the alpha power. By contrast, in migraine patients the non-noxious mild stress was sufficient to induce a significant decrease of the alpha power in all brain regions. The results of our study show that migraine sufferers display a lower threshold to physical stress and confirm previous studies indicating that migraine is a disease characterized by a state of altered neuronal excitability.

Somatotopic activation of opioid systems by target-directed expectations of analgesia.

We induced specific expectations of analgesia on four different parts of the body to understand how endogenous opioid systems are activated by expectancies. The left hand, right hand, left foot, and right foot were simultaneously stimulated by means of a subcutaneous injection of capsaicin, which produces a painful burning sensation. Specific expectations of analgesia were induced by applying a placebo cream on one of these body parts and by telling the subjects that it was a powerful local anesthetic. In such a way, expectancy of the anesthetic effect was directed only toward the part on which the placebo cream was applied. We found that a placebo analgesic response occurred only on the treated part, whereas no variation in pain sensitivity was found on the untreated parts. If the same experiment was performed after an intravenous infusion of the opioid antagonist naloxone, this highly spatial-specific placebo response was totally abolished, indicating that it was completely mediated by endogenous opioid systems. These findings show that a spatially directed expectation of pain reduction is capable of inducing a specific effect only on the part of the body which is the target of the expectation. Most important, this specific effect is mediated by endogenous opioids, indicating that placebo-activated opioids do not act on the entire body but only on the part where expectancy is directed. This suggests that a highly organized and somatotopic network of endogenous opioids links expectation, attention, and body schema.

Inducing placebo respiratory depressant responses in humans via opioid receptors.

Several lines of evidence indicate that placebos produce analgesia through the activation of endogenous opioid systems. Recently, we showed that placebos may also produce respiratory depressant responses, a typical side-effect of narcotics, when a subject had a prior experience of respiratory depression in the course of narcotic treatment. In the present study, we report that the placebo respiratory depression can be induced after repeated administrations of the partial opioid agonist buprenorphine. The placebo respiratory depressant effect that resulted from the buprenorphine conditioning was completely blocked by a dose of 10 mg of naloxone, indicating that it was mediated by endogenous opioids. These findings show that placebos act, via the activation of opioid receptors, not only on pain mechanisms but on the respiratory centres as well, thus mimicking a typical side-effect of narcotics. In addition, the experimental procedure we used did not produce any expectation of respiratory depression and, similarly, the subjects did not notice any sign of respiratory discomfort. Thus, the placebo respiratory depression elicited in the present study cannot be explained on the basis of cognitive or motivational mechanisms. Rather, it appears to be a sequence effect due to learning, thus suggesting a conditioning mechanism mediated by endogenous opioids.

Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems.

We investigated the mechanisms underlying the activation of endogenous opioids in placebo analgesia by using the model of human experimental ischemic arm pain. Different types of placebo analgesic responses were evoked by means of cognitive expectation cues, drug conditioning, or a combination of both. Drug conditioning was performed by means of either the opioid agonist morphine hydrochloride or the nonopioid ketorolac tromethamine. Expectation cues produced placebo responses that were completely blocked by the opioid antagonist naloxone. Expectation cues together with morphine conditioning produced placebo responses that were completely antagonized by naloxone. Morphine conditioning alone (without expectation cues) induced a naloxone-reversible placebo effect. By contrast, ketorolac conditioning together with expectation cues elicited a placebo effect that was blocked by naloxone only partially. Ketorolac conditioning alone produced placebo responses that were naloxone-insensitive. Therefore, we evoked different types of placebo responses that were either naloxone-reversible or partially naloxone-reversible or, otherwise, naloxone-insensitive, depending on the procedure used to evoke the placebo response. These findings show that cognitive factors and conditioning are balanced in different ways in placebo analgesia, and this balance is crucial for the activation of opioid or nonopioid systems. Expectation triggers endogenous opioids, whereas conditioning activates specific subsystems. In fact, if conditioning is performed with opioids, placebo analgesia is mediated via opioid receptors, if conditioning is performed with nonopioid drugs, other nonopioid mechanisms result to be involved.

Neurophysiologic assessment of nerve impairment in posterolateral and muscle-sparing thoracotomy.

OBJECTIVE: This study was aimed at analyzing the degree of intercostal nerve impairment in posterolateral and muscle-sparing thoracotomy and at correlating the nerve damage to the severity of long-lasting postthoracotomy pain. METHODS: Neurophysiologic recordings were performed 1 month after either posterolateral or muscle-sparing thoracotomy to assess the presence of the superficial abdominal reflexes (mediated in part by the intercostal nerves), the somatosensory-evoked responses after electrical stimulation of the surgical scar, and the electrical thresholds for tactile and pain sensations of the surgical incision. RESULTS: The patients who underwent a posterolateral thoracotomy showed a higher degree of intercostal nerve impairment than the muscle-sparing thoracotomy patients as revealed by the disappearance of the abdominal reflexes, a larger reduction in amplitude of the somatosensory-evoked potentials, and a larger increase of the sensory thresholds to electrical stimulation for both tactile perception and pain. In addition, these neurophysiologic parameters were highly correlated to the postthoracotomy pain experienced by the patients 1 month after surgery, indicating a causal role for nerve impairment in the long-lasting postoperative pain. CONCLUSIONS: This study shows for the first time the pathophysiologic differences between posterolateral and muscle-sparing thoracotomy and suggests that the minor long-lasting postthoracotomy pain in muscle-sparing thoracotomy patients is partly due to a minor nerve damage. In addition, because nerve impairment is responsible for the long-lasting neuropathic component of postoperative pain, it is necessary to match specific treatments to the neuropathic pain-generating mechanisms.

The specific effects of prior opioid exposure on placebo analgesia and placebo respiratory depression.

Although in most of the cases the placebo response appears to be unpredictable, several factors have been considered in order to explain the placebo analgesic effect. For example, it is widely recognized, albeit with little empirical evidence, that placebo analgesia is more likely to occur after a successful analgesic therapy. On the basis of this assumption, we tested the placebo response in a population of patients who were treated with buprenorphine the day before for relieving postoperative pain. However, due to the high variability of opioid responsiveness, buprenorphine was effective in some patients and poorly effective in some others. Similarly, buprenorphine produced respiratory depression with a large variability, ranging from mild depression to no effect. We found that the placebo analgesic response depended on the buprenorphine analgesic effectiveness of the previous day. Analogously, we found that a placebo respiratory depressant response was more pronounced in those patients with a respiratory depressant response to buprenorphine on the day before, irrespective of the analgesic effectiveness. These specific effects suggest that (1) the placebo effect is experience-dependent; (2) the mechanisms underlying placebo analgesia and placebo respiratory depression are independent from each other and, by considering the role of endogenous opioids in placebo analgesia, might involve different subpopulations of opioid receptors.

Dose-response relationship of opioids in nociceptive and neuropathic postoperative pain.

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.

Postoperative pain and superficial abdominal reflexes after posterolateral thoracotomy.

BACKGROUND: Posterolateral thoracotomy can produce stretching of/or damage to the intercostal nerves and their branches. To assess intercostal nerve impairment after operation, we measured the superficial abdominal reflexes, which are mediated, at least in part, by the most inferior intercostal nerves. METHODS: Using electrophysiologic techniques, we made recordings from the left and right abdominal walls to study the responses evoked by mechanical stimulation of the skin after operation. In addition, we assessed postoperative pain intensity according to a numeric rating scale and recorded postoperative opioid dose. RESULTS: We found that the patients with complete disappearance of the superficial abdominal reflexes experienced more severe postoperative pain than those in whom the reflexes were maintained. Moreover, opioid treatment was less effective in the patients with no reflexes postoperatively. CONCLUSIONS: Our findings show a strict correlation between pain intensity after posterolateral thoracotomy and absence of abdominal reflexes. We suggest that the higher pain intensity together with the absence of reflexes may be due to intercostal nerve impairment, be it anatomic or functional, and thus to a larger neuropathic component of postoperative pain. This finding may be used as a predictor of patients with high analgesic requirements.

The neurobiology of placebo analgesia: from endogenous opioids to cholecystokinin.

Placebo is a widespread phenomenon in medicine and biology and its mechanisms are understood only partially. Most of our understanding of placebo comes from studies on pain. In particular, placebo analgesia represents a situation where the administration of a substance known to be non-analgesic produces an analgesic response when the subject is told that it is a pain killer. Several theories try to explain this effect by means of anxiety mechanisms, cognitive processes and classical conditioning. However, the placebo response is bidirectional, i.e. analgesic and algesic. In fact, if a subject is told that the ineffective substance is a hyperalgesic drug, a pain increase may occur. The negative effects of placebo are called nocebo and, in extreme cases, they lead to severe pathological conditions. The neurobiology of placebo was born when some authors discovered that placebo analgesia is mediated by endogenous opioids. This claim comes from the observation that the opioid antagonist naloxone can reverse placebo analgesia. On the basis of the discovery of the anti-opioid action of the neuropeptide cholecystokinin, recent studies demonstrate that the blockade of cholecystokinin receptors potentiates the placebo analgesic response, thus suggesting an inhibitory role of cholecystokinin in placebo analgesia. Thus, by antagonizing the anti-opioid action of cholecystokinin during a placebo procedure, a potentiation of the endogenous opioid systems can be obtained.

Blockade of nocebo hyperalgesia by the cholecystokinin antagonist proglumide.

In patients who reported mild postoperative pain, we evoked a nocebo response, a phenomenon equal but opposite to placebo. Patients who gave informed consent to increase their pain for 30 min received a substance known to be non-hyperalgesic (saline solution) and were told that it produced a pain increase. A nocebo effect was observed when saline was administered. However, if a dose of 0.5 or 5 mg of the cholecystokinin antagonist proglumide was added to the saline solution, the nocebo effect was abolished. A dose of 0.05 mg of proglumide was ineffective. The blockade of the nocebo hyperalgesic response was not reversed by 10 mg of naloxone. These results suggest that cholecystokinin mediates pain increase in the nocebo response and that proglumide blocks nocebo through mechanisms not involving opioids. Since the nocebo procedure represents an anxiogenic stimulus and previous studies showed a role for cholecystokinin in anxiety, we suggest that nocebo hyperalgesia may be due to a cholecystokinin-dependent increase of anxiety.

Control of postoperative pain by transcutaneous electrical nerve stimulation after thoracic operations.

BACKGROUND: Transcutaneous electrical nerve stimulation (TENS) has been used extensively to control postoperative pain, but its effects are controversial. This is probably due to the different types of operations performed and, therefore, to the varying intensity of postoperative pain. Here we present an extensive study with TENS in 324 patients who underwent different types of thoracic surgical procedures: posterolateral thoracotomy, muscle-sparing thoracotomy, costotomy, sternotomy, and video-assisted thoracoscopy. METHODS: Each patient cohort was randomly subdivided into three treatment groups: TENS, placebo TENS and control. The effectiveness of TENS was assessed by two factors: the time from the beginning of treatment to the request for further analgesia and the total medication intake during the first 12 hours after operation. RESULTS: Whereas posterolateral thoracotomy produced severe pain, muscle-sparing thoracotomy, costotomy, and sternotomy caused moderate pain, and video-assisted thoracoscopy caused only mild pain. The TENS treatment was not effective in the posterolateral thoracotomy group, but it was useful as an adjunct to other medications in the muscle-sparing thoracotomy, costotomy, and sternotomy groups. In contrast, representing the only pain control treatment with no adjunct drugs, it was very effective in patients having video-assisted thoracoscopy. CONCLUSIONS: These findings show that TENS is useful after thoracic surgical procedures only when postoperative pain is mild to moderate; it is uneffective for severe pain.