Pharmacological pain management in chronic pancreatitis

Intense abdominal pain is a prominent feature of chronic pancreatitis and its treatment remains a major clinical challenge.Basic studies of pancreatic nerves and experimental human pain research have provided evidence that pain processing is abnormal in these patients and in many cases resembles that seen in neuropathic and chronic pain disorders.An important ultimate outcome of such aberrant pain processing is that once the disease has advanced and the pathophysiological processes are firmly established,the generation of pain can become self-perpetuating and independent of the initial peripheral nociceptive drive.Consequently,the management of pain by traditional methods based on nociceptive deafferentation(e.g.,surgery and visceral nerve blockade)becomes difficult and often ineffective.This novel and improved understanding of pain aetiology requires a paradigm shift in pain management of chronic pancreatitis.Modern mechanism based pain treatments taking into account altered pain processing are likely to increasingly replace invasive therapies targeting the nociceptive source,which should be reserved for special and carefully selected cases.In this review,we offer an overview of the current available pharmacological options for pain management in chronic pancreatitis.In addition,future options for pain management are discussed with special emphasis on personalized pain medicine and multidisciplinarity.     

Pharmacologic treatment of fibromyalgia: Towards chemical neuromodulation

Fibromyalgia is a chronic pathology and its main symptom is pain which usually does not respond to traditional analgesia. Its clinical characteristics and the diverse neurophysiologic findings in these patients point to a central sensitization process of the nociceptive system as the central physiopathologic axis in this disease. The knowledge of the nociceptive system functioning and its behavior in this disease has led, in the past few years, to new possibilities for the therapeutic approach. In that way, drugs with a differential mechanism of action, allowing a modulation of the nociceptive system capable of producing analgesia where other medications have failed are being developed. Different drugs with the capacity increasing the activity of biologically active amines implicated in the nociceptive inhibition process and others which are destined to reduce the excitability of the system through ion channels, are being tested with some benefit in Fibromyalgia patients and may constitute a more rational neuromodulating drug profile for this disease. This article reviews the different pharmacological strategies supported by scientific evidence and points to some future research lines that fortifies the therapeutic change taking place in the treatment approach of these patients.     

Possible mechanisms responsible for silent myocardial ischemia: do patients with silent myocardial ischemia have altered pain thresholds?

There is some evidence that alterations in pain perception are present in patients with coronary artery disease and painless myocardial ischemia, but whether endorphins are implicated is still unclear. Further studies are also needed to document the validity of various theories of the cardiac pain mechanism itself, especially the existence of specific nociceptive sympathetic fibers.     

Diagnosis and pharmacologic management of neuropathic pain among patients with chronic low back pain

Chronic low back pain consists of both nociceptive and neuropathic mechanisms and can be classified as a mixed pain syndrome. Neuropathic component of chronic low back pain has often been under-recognized and under-treated by the physicians. Recent studies have demonstrated that approximately 20%-55% of chronic low back pain patients have neuropathic pain symptoms. An altered peripheral, spinal, and supraspinal processing of pain arising as a result of a lesion affecting the nerves system are the major contributor to neuropathic low back pain. The clinical evaluation is still the gold standard for assessment and diagnosis of neuropathic low back pain. Although diagnosis can be difficult due to the lack of reliable gold standard diagnostic test for neuropathic low back pain, screening tools may help non-specialists, in particular, to identify potential patients with neuropathic low back pain who require further diagnostic evaluation and pain management. Several screening tools for neuropathic pain have been developed and tested with different patient populations. Among the screening tools, the pain DETECT questionnaire and the Standardized Evaluation of Pain are validated in patients with low back pain. The Standardized Evaluation of Pain may lead to more effectivein discriminating between neuropathic and nociceptive pain in patients with low back pain according to the higher rate of sensitivity and its validity in patients with low back pain. However, the most appropriate approach is still to combine findings on physical and neurologic examinations and patient's report in distinguishing neuropathic pain from nociceptive pain. The clinical examination including bedside sensory tests is still the best available tool for assessment and diagnosis neuropathic pain among patients with chronic low back pain. Due to the fact that chronic low back pain consists of both nociceptive and neuropathic mechanisms, a multimodal treatment approach is more rational in the management of patients with chronic low back pain. Therefore, combination therapy including drugs with different mechanisms of action should be given to the patients with chronic low back pain.     

Managing chronic pain with nonopioid analgesics: a multidisciplinary consult

As detailed in this online CME activity (www.cmeaccess.com/AJM/ChronicPain04), determining pain mechanism is an important aspect guiding treatment selection for chronic musculoskeletal pain states. Although broad classifications provide a framework, any combination of mechanisms may be present in a chronic pain patient, and there is growing evidence that pain states generally considered nociceptive may also involve elements of augmented central nervous system pain processing. Nonopioid analgesics, including serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, and alpha-2-delta ligand anticonvulsants, are the treatments of choice for fibromyalgia and other central neuropathic pain states. Additionally, studies have now shown that certain SNRIs can be effective in treating "classic" nociceptive pain states, such as osteoarthritis, and also are effective for low back pain. In addition to considering biological mechanisms, chronic pain management also involves recognizing and evaluating the contribution of psychological and sociocultural factors that can influence pain chronicity and patient prognosis. A multimodal/multidisciplinary approach incorporating pharmacologic and nonpharmacologic therapy into a program that includes more than 1 discipline is important to improve outcomes in patients with chronic pain.     

Fibromyalgia and the complex regional pain syndrome: similarities in pathophysiology and treatment

Although the pain of fibromyalgia usually is not preceded by an injury to the involved tissue, whereas that of the complex regional pain syndrome usually starts at a site of prior trauma or surgery, both disorders may share a common mechanism—pathologic sensitization of brain mechanisms that integrate nociceptive signals—and both apparently respond to treatment with ketamine, an anesthetic-analgesic agent whose actions include blockade of N-methyl-d-aspartate receptors. Ketamine's widespread illegal use as a recreational agent probably precludes developing it as a general treatment of centrally mediated pain disorders; however, its efficacy suggests that related, to-be-discovered agents could be useful.     

Neurosurgical treatments of intractable pain

Intractable pain may require neurosurgical intervention. This review provides a critical update of neurosurgical techniques available to treat this condition. Neurosurgery can affect pain's pathways from the receptor up to the “centers” of its reception and perception, either by destroying or by stimulating them. Early in neurosurgery's development, and still today, ablative procedures are able to suppress or alleviate pain. However, in most cases, such ablations have only remained effective for a few months or, at best, a few years. This is why, from the 1960s on, a better understanding of the mechanism of pain inspired development of electrical and chemical neuromodulation procedures at every level of the nociceptive system (peripheral nerve, cord, thalamic, periventricular/aqueductal gray, and cortical centers). The encouraging outcomes that resulted are attracting increasing attention and interest among clinicians. The indications for undertaking an ablative vs a neurostimulative procedure, as well as selection of the anatomical target, depend largely on whether pain is nociceptive or neuropathic, given that most of these indications overlap to some extent. In addition, because the published outcomes are not based on universal criteria, it is difficult for the attending physician to select the type of procedure most suitable to the pain problem. This brief review surveys the various neurosurgical procedures together with their corresponding indications in the hope that the information provided will help practitioners choose (1) the type of neurosurgical therapy most appropriate to their patients' needs and (2) the neurosurgical group best equipped to implement that choice.     

Comprehensive chronic pain management: improving physical and psychological function (CME multimedia activity)

As shown in this CME online activity (www.cmeaccess.com/AJM/ChronicPain02), chronic, non-cancer pain can arise from a variety of etiologies and can be broadly classified based on its underlying mechanism as nociceptive, inflammatory, neuropathic, or central, with some patients having pain arising from a combination of mechanisms. Chronic pain assessment and treatment involves evaluating not only its biological aspects, but also psychological and sociocultural factors. Beyond neural mechanisms, a patient's perception of chronic pain can be influenced by comorbid mood disorders, such as depression and anxiety; cognitive and affective traits, such as catastrophizing and fear-avoidance; environmental stressors, family relationships, social support, and cultural beliefs. Based on this biopsychosocial model, a multidisciplinary approach to management incorporates pharmacotherapy (opioid, nonopioid, and centrally-acting analgesics, and pain adjuvant medications) with nonpharmacologic physical rehabilitation and psychological and behavioral therapies to address the multifactorial causes of chronic pain, which in turn leads to improvement of physical and psychological function.     

Indication and significance of pharmacological intervention for back pain

Back pain is divided into two phases; acute pain is due to the increased signal from the nociceptive receptors in the nerve endings and chronic pain is resulting from the reconstruction of the new nervous net work during the healing stage. Use of NSAIDs and opioids is indicated for the acute pain that is not eased by taking a rest. NSAIDs is also profitable to control chronic pain, but NSAIDs has complications of renal and digestive functions. Persons with ages of more than 65 are especially liable to those dysfunctions. Pharmacological intervention on back pain may not only give the therapeutic benefits but also it can provide the clues for the elucidation of the mechanism and the new therapeutic interventions.     

Neuroplasticity--an important factor in acute and chronic pain

The nociceptive system is not just a system for the conduction of pain impulses from the periphery to the brain. We now know that plastic changes can take place in the periphery, the spinal cord and also in higher brain centres following injury or inflammation. These changes may increase the magnitude of the perceived pain and may contribute to the development of chronic pain syndromes. Although our knowledge is growing, we are now almost more confused as to how we should intervene in order to attenuate or inhibit neuroplasticity. The present review examines the current knowledge on mechanism, clinical significance and prevention of neuroplastic changes.     

Trypsin mediates nociception via the proteinase-activated receptor 2: a potentially novel role in pancreatic pain

BACKGROUND & AIMS: The pathogenesis of pain in pancreatitis remains poorly understood. We hypothesized that trypsin, a key inflammatory mediator in this condition, can also activate nociceptive neurons via the proteinase-activated receptor 2. METHODS: Double immunohistochemical staining of T8 to T12 dorsal root ganglia sections was performed with antibodies against proteinase-activated receptor 2 and vanilloid receptor 1, a marker for primary nociceptive neurons. In vivo nociceptive activity was measured by FOS immunoreactivity in thoracic spinal dorsal horn segments after intrapancreatic administration of proteinase-activated receptor 2 agonists. Pain behavior was assessed by visceromotor reflex activity in response to noxious stimulation of the pancreas with proteinase-activated receptor 2 agonists. RESULTS: Proteinase-activated receptor 2 was expressed by virtually all nociceptive neurons in thoracic dorsal root ganglia. Intraductal trypsin, in subinflammatory concentrations, activated spinal dorsal horn neurons in a dose-dependent manner, as measured by FOS expression. Both trypsin and a proteinase-activated receptor 2-specific peptide agonist induced a behavioral pain response when infused into the pancreatic duct of awake rats. Preinfusion of the pancreatic duct with proteinase-activated receptor 2-specific activating peptide desensitized the response to trypsin. CONCLUSIONS: Our findings suggest a novel proteinase-activated receptor 2-mediated role for trypsin in the pathogenesis of pancreatic pain and one that is independent of its inflammatory effect.     

IMMUNOHISTOCHEMICAL DEMONSTRATION OF NOCICEPTORS IN THE CAPSULE AND SYNOVIAL FOLDS OF HUMAN ZYGAPOPHYSEAL JOINTS

Substance P, a physiologically potent neuropeptide, is consideredto participate in nociceptive transmission of nerve impulses.Substance P immunofluorescent nerves are demonstrated in theinferior joint recess capsule and its synovial folds in humanlumbosacral zygapophyseal joints. This may have clinical significancein spinal pain. KEY WORDS: Low back pain, lumbar spine, synovial folds, nociceptors, immunohistochemistry, substance P.     

Reactive oxygen species are second messengers of neurokinin signaling in peripheral sensory neurons

Substance P (SP) is a prominent neuromodulator, which is produced and released by peripheral damage-sensing (nociceptive) neurons; these neurons also express SP receptors. However, the mechanisms of peripheral SP signaling are poorly understood. We report a signaling pathway of SP in nociceptive neurons: Acting predominantly through NK1 receptors and G(i/o) proteins, SP stimulates increased release of reactive oxygen species from the mitochondrial electron transport chain. Reactive oxygen species, functioning as second messengers, induce oxidative modification and augment M-type potassium channels, thereby suppressing excitability. This signaling cascade requires activation of phospholipase C but is largely uncoupled from the inositol 1,4,5-trisphosphate sensitive Ca(2+) stores. In rats SP causes sensitization of TRPV1 and produces thermal hyperalgesia. However, the lack of coupling between SP signaling and inositol 1,4,5-trisphosphate sensitive Ca(2+) stores, together with the augmenting effect on M channels, renders the SP pathway ineffective to excite nociceptors acutely and produce spontaneous pain. Our study describes a mechanism for neurokinin signaling in sensory neurons and provides evidence that spontaneous pain and hyperalgesia can have distinct underlying mechanisms within a single nociceptive neuron.     

Fibromyalgia pain: do we know the source?

PURPOSE OF REVIEW: Fibromyalgia Syndrome (FMS) is a chronic pain condition of unknown origin. Multiple abnormalities have been described, including peripheral tissue and central nervous system changes. The relation of these mechanisms, however, is likely bidirectional. FMS pain clearly depends on peripheral nociceptive input as well as abnormal central pain processing. This review will focus on the role of peripheral nociceptive input for pain in FMS. RECENT FINDINGS: There is strong evidence for abnormal central pain processing in FMS. Sensitized spinal cord neurons in the dorsal horn are responsible for augmented pain processing of nociceptive signals from the periphery. In addition, glial activation, possibly by cytokines and excitatory amino acids may play a role in the initiation and perpetuation of this sensitized state. SUMMARY: Nociceptive input clearly plays an important role in FMS. Acute or repetitive tissue injury has been associated with FMS pain. Cytokines related to such injuries may be responsible for long-term activation of spinal cord glia and dorsal horn neurons, thus resulting in central sensitization. A better understanding of these important neuro-immune interactions may provide relevant insights into future effective therapies.     

Etiopathogenetic mechanisms of fibromyalgia syndrome

Fibromyalgia syndrome (FMS) is a common chronic condition of widespread pain with causal mechanisms that are largely unknown. It is characterized by moderate to severe musculoskeletal pain and allodynia, but its pathogenesis appears confined to the nociceptive structures of the central nervous system. FMS is often triggered by negative environmental influences, especially if they occur in childhood. In a fetus, these environmental triggers may influence the development of the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal axis (HPA). Increasing evidence supports the comorbidity of psychological conditions including depression, panic disorders, anxiety, and post-traumatic stress disorder (PTSD). Recent evidence suggests that genetic factors may play a role in the pathogenesis of FMS. Central sensitization has long been associated with FMS pain. It describes enhanced excitability of dorsal horn neurons, which leads to transmission of altered nociceptive information to the brain. Understanding of pathogenetic pathways in FMS has advanced beyond observing patient responses to neurophysiologically targeted therapies and basic research.     

Cannabinoid and opioid system in the mechanisms and control of pain

Opium and Hashish have been classically employed for the control of pain. The pharmacologic rationale for the use of these substances lies in the fact that they are able to modulate the endogenous opioid and cannabinoid systems respectively. Both systems, which depress the central nervous system (CNS), are capable of producing analgesia both in experimental animals and in humans by interfering with the transmission of pain signals (nociceptive) from the periphery to the superior centers of the CNS. We will review the main theories that explain the peripheral effects on both systems and its possible interest from the treatment of musculoskeletal pain standpoint.     

Role of Functional Brain Imaging in Understanding Rheumatic Pain

Rheumatic pain and, in particular, rheumatoid arthritis, osteoarthritis and fibromyalgia, are common and debilitating chronic pain syndromes. Recently, human functional neuroimaging, for example EEG, fMRI, and PET has begun to reveal some of the crucial central nervous system mechanisms underlying these diseases. The purpose of this review is to summarise current knowledge on the brain mechanisms of rheumatic pain revealed by functional neuroimaging techniques. The evidence suggests that two mechanisms may be largely responsible for the clinical pain associated with these rheumatic diseases: abnormalities in the medial pain system and/or central nervous system sensitisation and inhibition. If we can understand how functioning of the central nociceptive system becomes altered, even in the absence of peripheral nociceptive input, by using functional neuroimaging techniques, in the future we may be able to develop improved, more effective treatments for patients with chronic rheumatic pain.     

Fibromyalgia: Present to future

There has been a dramatic increase in our understanding of fibromyalgia throughout the past 14 years since the publica-tion of the 1990 American College of Rheumatology classi-fication criteria. Before 1990, and for most of the 20th century, fibromyalgia was considered to be predominantly a muscle disorder; now the critical abnormality is described as "central sensitization." However, central sensitization has to have an initial genesis and nociceptive stimuli from painful foci in muscle are increasingly recognized as being relevant to the development of fibromyalgia. Clinicians also recognize an association between the initiation of fibromy-algia and chronic psychologic stressors and inflammatory disorders. It has been more difficult to understand how two such apparently diverse events could affect central pain physiology. However, some clues are emerging from the role of diverse stimuli in activating glial cells and the role of disordered cytokine networks. Some predictions about future developments in fibromyalgia are ventured based on the current state of knowledge.     

Leading symptom of angina pectoris. Psychophysiologic mechanisms of pain perception in chest pain complaints

Anginal chest pain represents an important cardiac symptom which proved to have a high pretest probability for the existence of potential heart disease. The occurrence of clinically unapparent or atypically exposed myocardial ischemia, as well as discrepancies in effort angina, provide evidence that the release of a nociceptive stimulus does not guarantee pain perception of the same proportion. The connections between sequential nociceptive nerve impulses at different central nervous regions and particularly at non-specified thalamic nuclei allow learning processes in the development of pain perception. The intensity of pain may be altered to a great extent by the anxiety level. The patient might develop habits of vigilance for low threshold abnormal signals generated from the interior of the body; he might, however, also reach a stage of complete pain suppression by centrifugal control of the nociceptive input. Heart pain is probably one of the moderators in a more complex warning system.