Mechanisms underlying generation of cancer pain

As advances in cancer detection and treatment have increased the life expectancy of cancer patients, more attention to improving patient's quality of life (QOL) is needed. Among symptoms accompanying cancer, pain has strong impact on QOL. Most of cancer patients will experience moderate to severe pain and/or neuropathy during the course of their disease. Cancer pain can arise from different processes, either by direct tumor infiltration/involvement, or toxicity relating to chemotherapy used to treat cancer. The World Health Organization (WHO) has proposed a structured approach to drug selection for cancer pain, known as the "WHO analgesic ladder". However, several types of pain including bone cancer pain and chemotherapy-induced painful peripheral neuropathy are difficult to treat. The development of optimal analgesics for cancer pain has been hampered by the lack of understanding basic mechanisms that contribute to cancer pain. Recently, preclinical models of bone cancer pain and paclitaxel-induced painful peripheral neuropathy have been developed. These models have begun to provide insight into the mechanisms by which cancer pain is induced and how cancer pain-related sensory information is processed. In this paper, we review mechanism of cancer pain.     

Attenuation of pain in a randomized trial by suppression of peripheral nociceptive activity in the immediate postoperative period

Peripheral neuronal barrage from tissue injury produces central nervous system changes that contribute to the maintenance of postoperative pain. The therapeutic approaches to blocking these central changes remain controversial, because previous studies have not differentiated presurgical interventions from those administered after tissue injury, yet before pain onset. In this study, we evaluated the relative contributions of blockade of nociceptive input during surgery or during the immediate postoperative period on pain suppression. Subjects were randomly allocated to one of four groups: preoperative 2% lidocaine, postoperative 0.5% bupivacaine, both, or placebo injections. General anesthesia was induced and third molars extracted. Pain was assessed over 4 h and at 24 and 48 h. The beta-endorphin in blood samples increased twofold during surgery, which is indicative of activation of the peripheral nociceptive barrage in response to painful stimuli. Pain was decreased in the immediate postoperative period in the bupivacaine groups, whereas it increased in the lidocaine group over time. Pain intensity was less 48 h after surgery in the groups whose postoperative pain was blocked by the administration of bupivacaine, but no effect was demonstrated for the preoperative administration of lidocaine alone. These results in the oral surgery pain model suggest that minimizing the peripheral nociceptive barrage during the immediate postoperative period decreases pain at later time periods. In contrast, blocking the intraoperative nociceptive barrage does not appear to contribute significantly to the subsequent reduction in pain. IMPLICATIONS: Suppression of postoperative pain immediately after surgery attenuates the pain experienced 1 to 2 days after surgery. These findings suggest that pain after minor surgery can be prevented by blocking the development of pain processes that amplify pain for days after surgery.     

Repetitive strain injuries. Forearm pain caused by tissue responses to repetitive strain

According to the National Research Council, painful work-related upper limb disorders are caused by different pathophysiological mechanisms, one of which is repetitive strain injury (RSI). Forearm pain, tenderness, and paresthesias are thought to result from a continual risk of exceeding limits of "cumulative trauma load tolerance" (CTLT, cf. NRC 2001) in soft tissue by thousands of high-frequency, repetitive movements. On the other hand, repetitive painful stimulations also produce neuroplastic changes in the spinal and supraspinal nociceptive systems. Thus, repetitive motor and nociceptive impulses become part of the same motor programs, which are also responsible for high-frequency movements and tissue damage. In this way RSI pain may be felt as a task-related response, even after all injuries are completely healed. Consequences of this neuroplastic CTLT model for RSI prevention and therapy are discussed.     

The effects of ketamine on the temporal summation (wind-up) of the R(III) nociceptive flexion reflex and pain in humans

Animal studies have suggested that the temporal summation of nociceptive inputs might play a significant role in the development of central sensitization (i.e., hyperexcitability of central nociceptive neurons) and hyperalgesia via the activation of N-methyl-D-aspartate receptors. To further analyze these processes in humans, we evaluated the effects of small systemic doses of ketamine on the temporal summation (i.e., wind-up) of both the nociceptive flexion (R(III)) reflex and sensations of pain in six healthy volunteers. The R(III) reflex was recorded from the biceps femoris and was elicited by electrical stimulation of the sural nerve. First, the recruitment (stimulus/response) curve for the reflex was built using stimuli up to the pain tolerance threshold (applied once every 6 s). A series of 15 stimuli was then applied once a second at an intensity of 1.2 times the reflex threshold. These procedures were performed both before and after the randomized IV injection of either 0.15 mg/kg ketamine or a placebo. The R(III) reflex threshold and its recruitment curve were not significantly altered after the injection of ketamine or placebo. By contrast, the significant increases (i.e., wind-up) in both the reflex responses and the sensations of pain observed during the higher frequency stimulation were significantly reduced after the administration of ketamine, but not placebo. This method might be useful for quantifying and analyzing the wind-up phenomenon and, thus, for studying the neurophysiological and pharmacological mechanisms underlying hyperalgesia in humans. IMPLICATIONS: The wind-up phenomenon (i.e., the progressive increase of the responses induced by repetitive nociceptive stimuli) was characterized in humans by using electrophysiological recordings of the nociceptive flexion reflex. We showed that, as in animals, this phenomenon, which might represent an elementary form of the central sensitization involved in various painful syndromes, depends on the activation of N-methyl-D-aspartate receptors, because it was selectively reduced after the administration of ketamine.     

Chronic pain and thoracic surgery

The development of chronic pain after thoracic surgery is a particularly undesirable yet common complication. As the study of the pathophysiology of chronic pain with regard to the plasticity of the central nervous system advances, new insights are being gained into not only the potential origins of chronic postthoracotomy pain, but also its potential treatment options. Pain that is originally nociceptive in nature in the acute postoperative period after thoracotomy may become neuropathic in time, requiring a different paradigm for its treatment. The ongoing research into the development of chronic pain, including that observed after thoracic surgery, portends the development of further advances in options for its control. The employment of multidisciplinary strategies of pharmacologic, behavioral, and interventional procedural techniques provides the current foundation for the management of this challenging condition.     

The pathophysiology of chronic pain

The International Association for the Study of Pain (ISAP) describes pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage". Pain is the sensation that usually arises when noxious stimulus causes real or potential damage to bodily tissue. The neural encoding and further processing elicited by such stimuli is called nociception. Pain can be essentially divided into two categories: adaptive and maladaptive. Adaptive pain contributes to survival by protecting organism from injury. Contrary, maladaptive pain is an expression of the pathologic operation of nervous system. Chronic pain in humans has been arbitrarily defined as pain lasting for more than 6 months. It is not only results from prolonged sensitization of nociceptive neurons but also from influence of social and psychological factors.     

Chronic pain: not only a matter of time

The term "chronic" is often used in daily clinical practice to indicate a type of pain that lasts over time and is accompanied by diagnostic and therapeutic difficulties. The common feeling is that in this category are actually collected many different clinical cases with the unique characteristic that the pain lasts a long time. It follows that treatment failures are common and patients roam from doctor to doctor in search of an effective care program. At the same time the health spending for the treatment of these patients is becoming increasingly high. In clinical practice we meet many patients with obscure pain syndromes which are classified as "chronic" and untreatable only because persist for long time and that obtain a complete pain relief after a right diagnosis and a specific treatment. In this review the Authors want to argue that the term chronic should not be used only when the pain persists for some time or just when signs and symptoms of mechanisms in the central nervous systems are present. The authors suggest that there is a clear difference between acute and chronic pain but also that in chronic pain patients there are three different painful conditions: 1) patients with a chronic disease (or sequelae) and with chronic pain in which the pain mechanisms are closely related to the underlying chronic disease (e.g., rheumatoid arthritis) or to previous injury that has generated other unsolvable mechanisms (e.g., deafferentation pain after plexus avulsion); 2) patients with a chronic disease and chronic pain in which new mechanisms overlap those related to the underlying disease; 3) patients with chronic pain in whom the correlation between pain and the initial tissue injury is lost and the persistence of pain is due to new developed mechanisms. According to this classification we can distinguish patients with "painful chronic disease" by patients with "independent chronic pain". In these latter cases the complexity of the clinical picture is to be found in a maladaptative response to pain, in emergence of central nervous system mechanisms and in behavioral changes that, in turn, can cause long-term social, psychological and physical sequelae. Differences among patients in developing chronic pain can be related to differences in the ability of the brain to continuously adapt its functional and structural organization. It is obvious that the care plan for these complex patients is profoundly different from that needed for patients with pain linked to a chronic disease or stabilized pain mechanisms. The purpose of the present article is to provide a review of the most noteworthy developments in this field and to propose some observations that may help to understand this pain condition and the patients.     

Pathophysiology of pain

Progress in the knowledge of the pathophysiology of pain allow to associate clinical symptoms of painful syndroms to physiological, morphological and neurobiochemical changes observed both at peripheral and central sites. Thus, nociceptive pains involve both a sensitisation of nociceptors and a secondary central sensitisation. Numerous mediators are involved in these phenomena which reflect neuroplasticity. Peripherally, they come from plasma, immune cells and afferent fibres involved in neurogenic inflammation. Their number explains how the peripheral mechanisms of pain are complex and how it is difficult to pharmacologically suppress the activity of nociceptors. Other mediators are involved in the dorsal horn of the spinal cord. Excitatory amino acids are particularly involved by acting on NMDA receptors; substance P seems to work as a facilitatory neuromodulator rather than as a neurotransmitter. The mechanisms of neuropathic pains are different because both small and large diameter afferent fibers are involved. Ectopic discharges from lesional sites of C fibers, sprouting and abnormal neuronal connections have been described. Up regulation of ionic, especially sodic, channels has been demonstrated and could explain spontaneous discharges. Here again, central sensitisation is also observed but present knowledge does not allow to distinguish specific mechanisms. These progress in the knowledge of pathophysiology of pain allow to improve the understanding of the mechanism of action of analgesic drugs. They also give basis to the discovery of novel drugs with original mechanisms.     

Imaging pain

Pain that persists or recurs for more than 3 months is defined as chronic and as such is one of the largest medical health problems in the developed world. Although the management and treatment of acute pain is reasonably good, the needs of chronic pain patients are largely unmet, creating an enormous emotional and financial burden to sufferers, carers, and society. Improvements in our ability to diagnose the causes of chronic pain are desperately needed. Furthermore, the pharmaceutical industry is struggling to find new and better drugs to treat chronic pain sufferers. Innovative methods that can aid decisions regarding choice and targeting of treatments alongside conventional clinical measures are therefore needed. Neuroimaging methods have the capacity to fulfil this need as they provide a non-invasive, systems-level understanding of the central mechanisms involved in pain processing. To date, the focus has been to dissect the physiological, psychological, and cognitive factors that influence nociceptive inputs to alter pain perception in healthy subjects and patients suffering from chronic pain. Obtaining reliable objective information related to the individual's subjective pain experience provides a powerful means of understanding not only the central mechanisms contributing to the chronicity of pain states but also the potential diagnostic information. Identifying non-invasively where plasticity, sensitization and other amplification processes might occur along the pain neuraxis for an individual and relating this to their specific pain experience or measure of pain relief is therefore of considerable interest to the clinical pain community and pharmaceutical industry. In this review, I shall briefly summarize our current state of knowledge regarding the central representation of pain perception in varying situations.     

Cancer pain classification

About three quarters of patients with advanced cancer experience pain. Most of these have multiple pains. Causes of pain fall into four broad categories: the cancer itself, related to the cancer +/- debility, related to treatment, concurrent disorder. From a neuropathological perspective, pain is either nociceptive or neuropathic. This distinction is important because neuropathic pain is generally less responsive to analgesics than nociceptive pain. Recognition of functional muscle pain is important. Patients with severe chronic pain do not necessarily look in pain because of the absence of autonomic concomitants. Whatever the cause, pain is a 'somatopsychic' experience.     

阿片类药物诱发痛觉过敏的研究进展

阿片类药物是治疗各种中到重度疼痛的最常用药物。它们在缓解患者疼痛的同时,可能会使患者对某些刺激变得敏感化。这一矛盾性现象可能就是阿片类药物诱发痛觉过敏（Opioid—Induced Hyperalgesia,OIH）引起的。OIH是指使用阿片类药物后导致患者对伤害性刺激的动物实验和临床研究证实TOIH的存在。虽然OIH的发生机制至今尚未完全阐明感性增加。大量的但目前主要认为阿对疼痛传导过程的改变可能导致了OIH的发生。随着0IH发生机制研究的进展．OIH的治疗手段也日益丰富。本文就OIH的证据．可能机制及治疗策略等做一综述。     

From pain research to pain treatment: the role of human experimental pain models

There is no objective measure of a complete pain perception; we can, however, measure different aspects of nociceptive processing and pain perception. Earlier, experimental pain models often only involved induction of cutaneous pain using a single stimulus modality. Recently new experimental models have been developed eliciting various modalities of deep and visceral pain which more closely resemble clinical pain conditions. It is imperative to use multi-modal and multi-structure pain induction and assessment techniques, because a simple model cannot describe the very complex and multi-factorial aspects of clinical pain. Furthermore, it is important to assess pain under normal and pathophysiological conditions.The importance of peripheral and central hyperexcitability for acute and chronic pain has been demonstrated in animals and, to some extent, in humans. However, in spite of our immense knowledge, we still do not know how to prevent and treat this hyperexcitability efficiently. Our understanding of nociceptive mechanisms involved in acute and chronic pain and the effects of anaesthetic drugs or combinations of drugs on these mechanisms in humans may also be expanded using human experimental models. This mechanism-based approach may help us to develop and test therapeutic regimes in patients with acute and chronic pain.     

Pathophysiology of pain

Pain is a major symptom of many different diseases. Modern pain research has uncovered important neuronal mechanisms that are underlying clinically relevant pain states, and research goes on to define different types of pains on the basis of their neuronal and molecular mechanisms. This review will briefly outline neuronal mechanisms of pathophysiological nociceptive pain resulting from inflammation and injury, and neuropathic pain resulting from nerve damage. Pain is the sensation that is specifically evoked by potential or actual noxious (i.e. tissue damaging) stimuli or by tissue injury. Pain research has not only explored the neuronal and molecular basis of the pain system of the healthy subject but has also provided insights into the function and plasticity of the pain system during clinically relevant pains such as post-injury pain, inflammatory pain, postoperative pain, cancer pain and neuropathic pain. This review will briefly describe the pain system and then address neuronal mechanisms that are involved in clinical pain states.     

Somatotopy in human primary somatosensory cortex in pain system

BACKGROUND: Compared with somatotopical organization (somatotopy) in the postcentral gyrus in the tactile system, somatotopy in the pain system is not well understood. The aim of this study is to elucidate whether there is somatotopy in the human pain system. METHODS: To elucidate the somatotopy of nociceptive neurons in the postcentral gyrus, the authors recorded pain-evoked cortical responses to noxious intraepidermal electrical stimulation applied to the left hand and left foot in 11 male subjects, using magnetoencephalography. RESULTS: Brief painful stimuli evoked sustained cortical activity in the primary somatosensory cortex (SI) in the hemisphere contralateral to the stimulated side and in the secondary somatosensory cortex in both hemispheres. In SI, representations of the hand and foot were distinctly separated, with a more medial and posterior location for the foot, whereas no significant difference was found in the locations for the secondary somatosensory cortex dipole. The SI arrangement along the central sulcus was compatible with the homunculus revealed by Penfield using direct cortical stimulation during surgery. CONCLUSIONS: The human pain system contains a somatotopical representation in SI but with less somatotopical organization in the secondary somatosensory cortex. The current results provide supporting evidence of SI involvement in human pain perception and suggest that human SI subserves the localization of the stimulated site in nociceptive processing.     

Acute pain mechanisms.

The systems activated by tissue-injuring stimuli are complex. The nociceptive primary afferents have little spontaneous activity under normal conditions; however, after tissue injury, they display longlasting, ongoing activity. This results, in part, because the injury elicits the release of active factors that sensitize or excite the peripheral nerve terminal. A threshold that is lowered to the extent that body temperature and the pressure of edema are adequate stimuli results in spontaneous pain. This phenomenon is mediated by a variety of blood-borne active factors released during plasma extravasation, by agents released from local inflammatory cells, and by neurotransmitters released from the peripheral terminals of the primary afferent fibers themselves. Well-defined projections into the dorsal horn convey the "pain message" to at least two well-defined populations of neurons: those that are nociceptive specific and those that display an intensity-linked discharge over a range of stimuli from innocuous to noxious. Convergence from various fiber types, modalities, and end organs permits the encoding of afferent traffic with respect to intensity and location. The convergence of axons from somatic and visceral structures reflects the mechanism for the so-called "referred pain state." Most importantly, these dorsal horn systems have a dynamic component in addition to the hard-wiring; their output can be regulated both up and down. The up-regulation provides the basis for much of the facilitated processing that is believed to account for a significant percentage of the postinjury pain state. The facilitated state has a unique pharmacology, with the underlying mechanisms reflecting a cascade of actions that starts with the NMDA receptor and proceeds through the spinal release of intermediaries, such as prostaglandins and nitric oxide. Conversely, the ability to down-regulate the dorsal horn stimulus response function accounts for the powerful control exerted by a wide variety of diverse factors, including the spinal delivery of opioid and nonopioid analgesics and the "endogenous analgesia system." These linkages reflect the complexity of the encoding mechanisms that transduce the tissue injury into the behavioral sequela known as pain. This article also emphasizes that, although considerable progress has been made in the past decade, the current pace of research promises greater insights.     

Neurophysiological coding of traits and states in the perception of pain

Perception is not a simple reflection of sensory information but varies within and between individuals. This applies particularly to the perception of pain, which, in the brain, is associated with neuronal responses at different frequencies. Here, we show how these different neuronal responses subserve interindividual and intraindividual variations in the perception of identical painful stimuli. A time-frequency analysis of single trial electroencephalographic data indicates that pain-related responses in the theta frequency range but not at higher gamma frequencies code for interindividual variations in the perception of pain. In contrast, both pain-related theta and gamma responses provide different and complementary information on intraindividual variations in the pain experience. We conclude that theta responses reflect rather constant physiological and psychological traits of the individual, whereas gamma responses relate to short-term modulations of the individual's state. These findings reveal how neuronal responses at different frequencies differentially contribute to the translation of sensory information into a subjective percept.     

Implantable devices for pain control: spinal cord stimulation and intrathecal therapies

Untreated chronic pain is costly to society and to the individual suffering from it. The treatment of chronic pain, a multidimensional disease, should rely on the expertise of varying health care providers and should focus not only on the neurobiological mechanisms of the process but also on the psychosocial aspects of the disease. Implantable devices are costly and invasive, and such efficacious therapies should be used only when more conservative and less costly therapies have failed to provide relief of pain and suffering. Spinal cord stimulation provides neuromodulation of neuropathic, but not nociceptive, pain signals and when used for appropriate indications in the right individuals provides approximately 60–80% long-term pain relief in 60–80% of patients trialled for efficacy. Intrathecal therapies with opioids such as morphine, fentanyl, sufentanil or meperidine – or non-opioids such as clonidine or bupivacaine – provide analgesia in patients with nociceptive or neuropathic pain syndromes. Baclofen, intrathecally, provides profound relief of muscle spasticity due to multiple sclerosis, spinal cord injuries, brain injuries or cerebral palsy.     

Contribution of thalamotomy, cordotomy and dorsal root entry zone Caudalis trigeminalis lesions in the treatment of chronic pain

Ablative neurosurgical methods are mainly proposed in cases of nociceptive pain, but, at present, medical treatments and local pharmacotherapy (intrathecal and intracerebroventricular) are often very effective in this context. Moreover, neuropathic pain is well controlled by ?ugmentative techniques, except painful paroxysms. If a destructrive method is necessary, it is selective, performed according to precise neurophysiological and anatomical data with the frequent use of percutaneous and/or stereotactic techniques: the lesion of caudalis DREZ in treatment of neuropathic trigeminal pain, the antero-lateral cordotomy in the treatment of unilateral severe cancer pain and several kinds of thalamotomy.