Seminars in Pain Medicine最新文献

Although most of the neurobiological mechanisms of the placebo response have been described in pain and analgesia, new models have emerged in recent times. These models include the respiratory and cardiovascular system, the immune and endocrine system, Parkinson’s disease, and depression. We believe that the integration of the pain studies with those in other pathological conditions will lead to a better understanding of the mechanisms underlying the placebo response.

A broad view of the “placebo effect” incorporating neurobiology, individual psychology, epistemology, history, and culture deeply enriches our understanding of these complex and powerful forces and, indeed, urges us to abandon that narrow and logically inconsistent concept for a much more interesting one. We review some of the data and background for such a contention in a thoroughly interdisciplinary way showing how differently presented, but equally “inert,” treatments (2 placebo tablets versus 4, for example) can have different effects; how the same inert treatment can act differently in different historical times and cultural places; and how crucial is the attitude of the clinician in shaping these intensely meaningful forces. These matters, which typically are left to chance, to ideology, or to market forces, should be embraced by the scientific community. We believe that fundamental insights into human biology remain to be discovered in this area.

The relationship between the endogenous opioid system and placebo analgesia has fascinated the research community for decades. Using functional imaging methods, it is now possible to study the underlying opioid and placebo processes in the brain. Such studies have shown overlapping activity in the anterior cingulate cortex (ACC) and the insula stretching into the orbitofrontal cortex. Because the ACC is involved in top-down attentional regulation, this region may mediate the interaction between higher cognitive processes and the endogenous opioid network. Moreover, data also indicate that the ACC may exert its modulation through the brainstem opioid network. The orbitofrontal cortex also shows placebo-dependent activation, but it does not have similar access to the opioid network. Thus, this region may be involved in other aspects of the placebo response such as processing treatment expectations.

The factors that contribute to the magnitude of placebo analgesia have, until recently, been elusive. This review explores the roles of external factors, such as conditioning, and experienced factors, such as expectation and desire for pain reduction, in placebo analgesia. Placebo analgesia effects have been found to reflect decreases in pain beyond that accounted for by the natural history of a pain condition. These effects clearly are influenced by the effectiveness of previous active treatments (ie, conditioning) as well as by environmental factors that provide cues/suggestions for analgesia. However, external factors are effective insofar as they provide expectations for pain reduction and a lowering of desire for relief. Experienced factors, such as expectation and desire for relief, also are integral dimensions of some human emotional states, such as anxiety. We present an explanation of placebo analgesia that suggests that it is the result of mechanisms that also regulate emotional states.

In recent years, the topic of placebo has gained momentum. Basic scientists started elucidating the neurophysiological and neuropharmacological processes that mediate the placebo response. At the same time, questions arose about the purported power of placebos. In addition, the debate on the ethics of the use of placebos heated up after the publication of some recent surgical trials using invasive placebo surgery procedures. In this article, we discuss the clinical relevance and the ethical problems associated with the use of placebos. Although a recent meta-analysis questioned the power of placebo, good evidence exists that placebos can lead to important improvement in many clinical conditions. A part of the conflict on the ethics of the use of placebos in randomized clinical trials can be solved by distinguishing between ethical guidelines for good clinical practice and for clinical research. We will also discuss some of the difficulties in finding proper placebo controls in clinical trials involving neurosurgical procedures.

Numerous studies of experimental and clinical pain show that placebo treatments reduce reported pain and that expectancies play a key role in their effectiveness. However, very little is known about the neurobiological mechanisms of either placebo analgesia or the generation of expectancy that enables it. To address this issue, I used functional magnetic resonance imaging to quantify placebo-induced changes in pain-processing brain regions during the experience of pain. Results show placebo-induced decreases in contralateral thalamus, anterior insula, and anterior cingulate, and increases in prefrontal brain regions that may maintain expectations for pain relief. These findings are discussed in light of several proposed neuropsychological mechanisms of placebo analgesia: altered appraisal of threat, diversion of attention, and activation of descending opioid systems for spinal control. These results suggest that placebo treatment alters the appraisal process, reducing the subjective distress caused by pain.

Placebo responses occur in a wide range of medical conditions, yet the underlying mechanisms remain poorly understood. On the basis of our observations of patients in Parkinson’s disease, we have argued that the placebo effect is partly mediated by the activation of reward circuitry and that mesocorticolimbic dopamine release, particularly in the ventral striatum, plays a central role. Expectation has been shown to be critically involved in placebo responses. We argue that in patients with Parkinson’s disease, placebo-induced expectation of clinical improvement is a form of expectation of reward, which results in striatal dopamine release. Reward circuitry also may be involved in other placebo responses, such as placebo analgesia, given the interactions between dopamine and endogenous opioid systems. Despite the heterogeneity of placebo responses, we propose that activation of reward circuitry may represent a common mechanism underlying the placebo effect, and that dopamine and prefrontal cortical circuits interact to produce a condition-specific physiological response.

Opioid therapy, both short- and long-term, has potential adverse effects related to: (1) occupancy of opioid receptors in the nociceptive system: analgesia (antinociception), biochemical tolerance, physical dependence and hyperalgesia; (2) occupancy of other opioid receptors—gastrointestinal slowing/constipation, nausea and vomiting, respiratory depression, pruritus, reward behaviors, immunosuppression; (3) effects on cognitive and psychomotor function, sleep; (4) metabolic by-products (morphine-6-glucuronide, normeperidine); (5) drug interaction, especially with other centrally active agents; (6) method of delivery; and (7) social and legal factors. Management of complications is based on: (1) dose reduction of opioid; (2) optimization of adjuvants; (3) symptomatic management of adverse effects; (4) opioid rotation; and (5) switching route of administration.