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.     

Thalamus and pain

The thalamus is a key relay station for the transmission of nociceptive information to the cerebral cortex. We review the input–output connection, functional imaging, direct neuronal recording, stimulation, and lesioning studies on the involvement of thalamus in acute and chronic pain functions. Based on its specific reciprocal connection with the cerebral cortex, strong nociceptive responsiveness, and the severe chronic pain when it is damaged, the thalamus may hold the key to pain consciousness and the key to understanding spontaneous and evoked pain in chronic pain conditions. A work plan is proposed for future study.     

The role of dextromethorphan in pain control

PURPOSE: To review the clinical benefits of dextromethorphan (DM) in pain management, describe its neuropharmacological properties. SOURCE: A Medline search was made for experimental and clinical data on DM use from 1967 to date using keywords nociception, acute and chronic pain control, N-methyl-D-aspartate, antagonists, dextromethorphan. PRINCIPLE FINDINGS: The 930 DM citations mostly described its antitussive, metabolic and toxicological aspects, animal studies and its possible role in minimizing post-brain ischemia complications in humans. The use of DM in acute pain revealed eight original studies involving 443 patients, as well as two preliminary reports and our own unpublished data on 513 patients. Most of the 956 patients had general anesthesia. Eight studies (154 patients) and one case report dealt with chronic pain management. This N-methyl-D-aspartate (NMDA) receptor antagonist binds to receptor sites in the spinal cord and central nervous system, thereby blocking the generation of central acute and chronic pain sensations arising from peripheral nociceptive stimuli and enabling reduction in the amount of analgesics required for pain control. DM attenuated the sensation of acute pain at doses of 30-90 mg, without major side effects, and reduced the amount of analgesics in 73% of the postoperative DM-treated patients. Studies in secondary pain models in healthy volunteers and in various types of chronic pain showed DM to be associated with unsatisfactory pain relief. CONCLUSION: DM attenuates acute pain sensation with tolerable side effects. Its availability in oral form bestow advantages over other NMDA antagonists.     

脊髓环氧合酶与术后疼痛

前列腺素（prostaglandins,PGs）是广泛存在于动物和人体内的一组重要的组织激素,在疼痛的产生过程中发挥着重要作用,其中最主要的是前列腺素E2（PGE2）和前列环素（PGI2）。近年来研究发现,PG受体也存在于脊髓背根神经节,这是感觉传人神经轴索进入脊髓以及脊髓感受伤害的起始部位。行为学研究也证实,鞘内注射PGs可以引出伤害性感受反应。环氧合酶（cyclooxygenase,COX）是以花生四烯酸为底物生成前列腺素（prostaglandins,PGs）途径中的限速酶。非甾体抗炎药（NSAIDs）干预伤害性感受的过程在脊髓,可能是通过减少神经系统中前列环素的合成来实现的。术后疼痛是急性疼痛的一种常见形式,各种类型手术的病人术后没有得到有效的镇痛是急性疼痛转为慢性疼痛的主要原因之一,近年来脊髓中COX参与术后疼痛的研究取得了一些进展。     

The neurobiology of chronic pain states

Plasticity enables alterations in transmission in nociceptive systems. It is this plasticity in the nervous system that can alter the linear relation between noxious stimuli and the perception of pain and is important in the switch from acute to chronic pain. In this way, a number of CNS mechanisms can alter neuronal activity, leading to abnormal ongoing and stimulus-evoked pains due to peripheral and central changes. Peripheral nerves can become sensitized, spinal cord neurons can be rendered hyperexcitable and ascending projections to higher centres can further trigger changes in descending controls from the midbrain and brainstem. Together, these changes, all of which appear to involve reversible physiological and pharmacological plasticity, can alter the relationship between an applied stimulus and the perceived response and so lead to persistent pain states.     

Clinical application of adenosine and ATP for pain control

This review summarizes clinical application of adenosine and adenosine 5′-triphosphate (ATP) in pain conditions. Investigations have been performed in patients with acute perioperative pain or chronic neuropathic pain treated with intravenous adenosine or ATP, or intrathecal adenosine. Characteristic central adenosine A1 receptor-mediated pain-relieving effects have been observed after intravenous adenosine infusion in human inflammation/sensitization pain models and in patients with chronic neuropathic pain. Adenosine compounds, in low doses, can reduce allodynia/hyperalgesia more consistently than spontaneous pain, suggesting that these compounds affect neuronal pathophysiological mechanisms involved in central sensitization. Such pain-relieving effects, which are mostly mediated via central adenosine A1 receptor activation, have a slow onset and long duration of action, lasting usually for hours or days and occasionally for months. With acute perioperative pain, treatment with a low-dose infusion of adenosine compounds and the A1 receptor-mediated central antisensitization mechanisms may play only a minor part in the total perioperative pain experience. By administering sufficient doses of adenosine compounds during surgery, however, significant and long-lasting perioperative pain relief can be achieved via central A1 receptor-mediated antinociceptive/analgesic actions as well as via peripheral A2a or A3 receptor-mediated antiinflammatory actions. Thus, adenosine compounds have significant potential for alleviating various types of pain.     

Measurement of clinical outcomes in pain medicine

How we measure pain and patients’ responses to pain is key in developing both our understanding and treatment of it. This article outlines the application of tools for the measurement of clinical outcomes used in acute and chronic pain medicine; what makes a good outcome measurement and how this can be utilized in clinical and research practice is discussed. Various tools for outcome measurement are described including those which may be utilized in various patient groups.     

The place of pharmacological treatment in chronic pain

Pharmacological treatment may be required for the successful management of chronic pain. The use of drugs should be considered alongside other multidisciplinary strategies including active physical rehabilitation, psychological support to assist self-management and, if appropriate, targeted injections. In clinical practice there may be a substantial overlap in drug management options for neuropathic and nociceptive pain. We present an overview of clinical use and associated problems of commonly used pharmacological agents in current practice.     

Pharmacology of pain and analgesia

Physiological events involved in nociception and pain perception are examined. Substance P could be a primary afferent transmitter of certain nociceptive information. Transmission of this information can be modulated within the spinal cord by intrinsic and descending mechanisms. The intrinsic mechanism involves inhibitory opiate effects within substantia gelatinosa. Centres for descending systems are located in medulla and periaqueductal gray matter. They are activated by exogenous narcotic agonists, and by regional connections. Descending inhibitory pathways are serotonergic and noradrenergic. GABA and glycine are also possibly involved in antinociception. Narcotics have been shown to produce analgesia when administered to the intrathecal or epidural spaces of humans. These routes are still experimental. The place of clinical modification of transmitter system is discussed, but no conclusions or recommendations can be made at this early stage.     

Has basic research contributed to chronic pain treatment?

Our understanding of nociceptive processing and of plastic changes after persistent noxious input has increased immensely within the last two decades. It is now clear that long-lasting noxious stimulation or damage to the nervous system give rise to a neuronal hyperexcitability and that this sensitisation of the nervous system plays an important role for development and maintenance of chronic pain. The manifestations of such hyperexcitability are numerous and include among others: increased neuronal response to a suprathreshold stimulus, expansion of the peripheral areas from where a central neurone can be activated and the recruitment of previous non-responding nociceptive neurones. Furthermore, it has been possible to modulate this neuronal hyperexcitability by the discovery of molecular targets for pain, by sequencing DNA of ion channels and receptors and by development of new molecules that exert their effects on these molecular targets. The changes in responsiveness appear to be partly time and intensity dependent and partly dependent on the cause of injury. Whereas relatively short-lasting and moderate noxious input leads to reversible plastic changes, more intense and long-lasting noxious stimulation implies a risk for persistent and more profound alterations in transmitters, receptors, ion channels and in neuronal connectivity. Despite the explosion of new knowledge in pain processing and in molecular background for neuroplasticity, this progress has unfortunately not resulted in a corresponding improvement of our ability to treat chronic pain. The number of patients with chronic unrelieved pain is still high and newer types of treatment have so far not resulted in a substantially better treatment. Nevertheless, there is now an ongoing systematic research in which chronic pain conditions are assessed in a fashion so that mechanisms underlying pain can be dissected. Moreover, controlled clinical trials together with systematic reviews are carried out which in the future should permit formulation of treatment algorithms for chronic pain. Finally, it is likely that the development of new specific types of treatment will show efficacy if they are evaluated and analysed not on the global pain experience, but more specifically on those targets and elements of the pain experience they are aimed to deal with.     

Novel targets in pain research: The case for CB2 receptors as a biorational pain target

The prevalence of neuropathic pain is rising, and is expected to further increase in aging populations. However, drug treatment for neuropathic pain remains inadequate, with the best available treatments having limited efficacy and dose-limiting side effects. Cannabinoids have been shown in clinical trials to be moderately effective at reducing neuropathic pain, but doses of cannabinoids currently in use are severely curtailed by psychoactive side effects through actions on the cannabinoid CB1 receptor. A relatively new class of drugs, selective cannabinoid CB2 receptor agonists, have shown considerable efficacy in a variety of animal models of neuropathic pain. Importantly, these drugs lack the psychoactivity of non-selective cannabinoid receptor agonists. The mechanisms by which CB2 receptor agonists reduce neuropathic pain are under intense investigation, and there are a number of plausible mechanisms by which CB2 agonists have antinociceptive effects. In this article, we review the preclinical evidence for the efficacy of CB2 agonists in the treatment of neuropathic pain. We also review the state of clinical development and trial of CB2 agonists, and argue that the need to test CB2 agonists for neuropathic pain in humans is urgent.     

Sympathetic nervous system and chronic bladder pain: a new tune for an old song

Chronic bladder pain (CBP) patients present with pelvic pain or discomfort during bladder filling, for at least a period of 6 months, which may be accompanied by lower urinary tract symptoms such as frequency, nocturia, and urgency. However, both the etiology of CBP and pathophysiological mechanisms are not well described. A number of clinical and basic animal model findings support involvement of sympathetic nervous system in chronic pain syndromes such as CBP. Examples include sympathetic overactivity and high plasma or urinary catecholamine levels that have a high correlation with nociceptive symptoms. In this review, we explored the current evidence in support of the involvement of sympathetic overactivity in CBP. As bladder inflammation often occurs among subgroups of CBP patients, we discuss the possible role of sympathetic nervous system in mastocytosis as well examples examples of animal models that further support the involvement of sympathetic dysfunction in CBP. As there is substantive evidence for cross-organ sensitization in the pelvis can lead to co-morbidity of genitourinary and gastrointestinal dysfunctions, we also include how sympathetic dysfunction may play a role in a number of co-morbid chronic pain syndromes.     

Peripheral mechanisms of somatic pain

In the last two decades, considerable advances have been made in our understanding of the mechanisms of pain. Studies correlating subjective magnitude estimations of pain in man with activity in single nerve fibers in experimental animals, and microneurographic recordings in awake humans, have provided convincing evidence for the role of specific nociceptors and labelled lines for signalling pain sensation in the normal skin. The response properties of the different types of nociceptive afferents, both myelinated and unmyelinated, from skin, muscle, and joints make them ideal candidates for signalling pain sensations. Cutaneous inflammation from any cause results in hyperalgesia. Cutaneous hyperalgesia at the site of an injury, i.e., primary hyperalgesia, can be explained by sensitization of nociceptors. This sensitization is likely due to local release of chemical mediators in the inflamed area. The metabolites of arachidonic acid (eicasonoids) and bradykinin appear to play an important role in the sensitization of nociceptors. Similar inflammation-induced changes in response properties of fine articular afferents might explain the pain of acute arthritis. The neuropeptide substance P released from primary afferents may also play an important role in the pathogenesis of arthritis. The mechanism of hyperalgesia in the region surrounding the injury, i.e., secondary hyperalgesia, is less well understood, and probably results from changes both in the peripheral and central nervous systems. While considerable advances have been made in our understanding of the mechanisms of acute pain, the pathophysiology of most chronic pain states is still unclear. We hope that future studies in experimental animals, and careful psychophysical testing and microneurographic recordings in chronic pain patients, will lead to a better understanding of the pathophysiology of pain.     

Breakthrough pain in opioid-treated chronic non-malignant pain patients referred to a multidisciplinary pain centre: a preliminary study

BACKGROUND: Breakthrough pain (BTP) has not formerly been discussed as such in chronic non-malignant pain patients referred to pain centres and clinics. The purpose of the study was to investigate the prevalence, characteristics and mechanisms of BTP in opioid-treated chronic non-malignant pain patients referred to a pain centre and to assess the short-term effects of pain treatment. METHODS: Patients were assessed at referral (T(0)) and after a treatment period of 3 months (T(3)) using the visual analogue scale (VAS) of the brief pain inventory (BPI) within somatic nociceptive, neuropathic and/or visceral pain conditions, the mini mental state examination (MMSE) and the hospital anxiety and depression scale (HADS). The main treatment intervention from T(0) to T(3) was to convert short-acting oral opioids to long-acting oral opioids and to discontinue on demand and parenteral use of opioids. RESULTS: Thirty-three patients were assessed at T(0) and 27 at T(3). The prevalence of BTP declined significantly from T(0) (90%) to T(3) (70.4%). Worst, least, average and current pain intensities as well as duration of BTP were significantly reduced from T(0) to T(3.) The majority of BTPs were exacerbation of background pain assumed to be of the same pain mechanisms. High average pain intensity (BPI) was significantly associated with high scores for both anxiety and depression (HADS). CONCLUSION: BTP in chronic non-malignant pain patients seems to be surprisingly frequent and severe. Stabilizing the opioid regimen seems to reduce pain intensity in general as well as the intensity and duration of BTP. Average pain intensity was associated with anxiety and depression.     

疼痛灾难化预测术后疼痛的研究进展

疼痛灾难化是患者对疼痛产生的夸大且消极的思维定势。作为与疼痛相关的主要负面心理情绪之一,疼痛灾难化可以通过多种机制调控疼痛体验。因此,疼痛灾难化可能是各种疼痛相关疾病的潜在发病机制和治疗靶点。近年来,由于相对统一的量表出现,越来越多的研究将疼痛灾难化作为术前心理评估项目,探讨术前疼痛灾难化强度预测术后疼痛发生的可能性。全文对疼痛灾难化的相关概念、发生机制、评估手段以及疼痛灾难化对术后急慢性疼痛的预测能力的研究进展进行综述。     

Chronic post-thoracotomy pain: a retrospective study

BACKGROUND: Chronic pain is common after thoracotomy. The primary goal of this study was to investigate the incidence of chronic post-thoracotomy pain. The secondary goal was to identify possible risk factors associated with the development of chronic post-operative pain. METHODS: We contacted 255 patients who had undergone a classic postero-lateral thoracotomy at our institution in the period between January 2001 and December 2003. All patients received a letter requesting participation; a questionnaire was included with the letter. One week later patients were contacted by telephone to obtain the answers to the questionnaire. RESULTS: We ultimately obtained results from 149 patients (58% of all thoracotomies, 84% of survivors). The overall incidence of chronic post-operative pain was 52% (32% mild, 16% moderate and 3% severe chronic post-operative pain). Patients with chronic post-operative pain reported acute post-operative pain more frequently than those without (85% vs. 62%, P = 0.01), had more severe acute post-operative pain (P = 0.0001), underwent more extensive surgical procedures (P = 0.01), had more constant acute pain (vs. fluctuating pain or pain in attacks) (P = 0.0004) and reported less absence of pain during the first post-operative week (P = 0.0001). There was no significant decrease in chronic pain with time after thoracotomy. CONCLUSION: Our study confirms that chronic post-thoracotomy pain is a common problem. The results from our study suggest that chronic post-thoracotomy pain may be associated with more intensive and extensive nociceptive input due to thoracic surgery.     

The anatomy of pain

Pain is a sensory and emotional experience that is personal and unique to an individual. Nociception is different from pain and considers the neural process of encoding and processing noxious stimuli. Anatomically noxious stimuli are transduced by nociceptors to an electrical signal carried by first-order neurons to the dorsal horn of the spinal cord. From the spinal cord second-order neurons project in tracts to the thalamus, where third-order neurons continue to higher cerebral centres. There is no known primary pain processing centre in the brain, instead multiple different areas activate and interact in response to noxious stimuli. The brain centres associated with pain perception overlap with those involved in depression. The brain regulates the nociceptive information it receives and can exert both anti- and pro-nociceptive influence. Pathology in the peripheral and central nervous systems can contribute to nociception and pain, as can changes in the interaction of higher cerebral centres. Appreciating the anatomical structures involved in pain and nociception affords an understanding of where different therapies may be applied to alleviate pain.     

Translational medicine: cancer pain mechanisms and management

Cancer-induced bone pain (CIBP) is a major clinical problem with up to 85% of patients with bony metastases having pain, often associated with anxiety and depression, reduced performance status, and a poor quality of life. Malignant bone disease creates a chronic pain state through sensitization and synaptic plasticity within the spinal cord that amplifies nociceptive signals and their transmission to the brain. Fifty per cent of patients are expected to gain adequate analgesia from palliative radiotherapy within 4-6 weeks of treatment. Opioid analgesia does make a useful contribution to the management of CIBP, especially in terms of suppressing tonic background pain. However, CIBP remains a clinical challenge because the spontaneous and movement-related components are more difficult to treat with opioids and commonly used analgesic drugs, without unacceptable side-effects. Recently developed laboratory models of CIBP, which show congruency with the clinical syndrome, are contributing to an improved understanding of the neurobiology of CIBP. This chronic pain syndrome appears to be unique and distinct from other chronic pain states, such as inflammatory or neuropathic pain. This has clear implications for treatment and development of future therapies. A translational medicine approach, using a highly iterative process between the clinic and the laboratory, may allow improved understanding of the underlying mechanisms of CIBP to be rapidly translated into real clinical benefits in terms of improved pain management.     

Drugs able to prevent chronic pain

Using drugs that follow anatomical pathways and act on receptors to treat acute pain and prevent its transformation into chronic pain is an appealing idea. The challenge consists of providing personalized treatment based on risk factors, pain and surgery type, and the type of rehabilitation program to minimize complications and optimize the pain treatment to prevent chronic pain. Clinical practice has started to understand the pathophysiological mechanisms and various neurochemical receptors involved in the transformation of acute pain into chronic pain. Unfortunately, the clinical reality differs greatly from the theory and no studies based on medical evidence show that using drugs to prevent chronic pain is a real possibility, nor what kinds of pain can actually be prevented with the use of preventive drugs. This article examines what kinds of pain are most commonly referred to chronic pain centers, looks at which drugs can be used to prevent chronic pain, and aims to establish a preventive treatment algorithm based on the type of postoperative pain. There is growing interest in providing therapeutic patient education, which consists of health professionals transferring knowledge to patients. In the model proposed in this article, therapeutic patient education acts as a connecting thread to different factors and enables patients to become more responsible for and proactive in the healing process. Prevention should be comprehensive, and not just pharmacologic.