The journal of pain : official journal of the American Pain Society
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Formalin (0.25, 0.5, 3, and 5%) injected into the knee joint of rats induced a dose-dependent nociception that was featured by 2 phases of intense guarding behavior of the affected limb, interposed by a period of quasinormal gait (quiescent phase). The guarding behavior during a period of forced gait was measured by the total time the paw of the affected limb was not in contact with the surface of a revolving cylinder (paw elevation time [PET]). Pretreatment with morphine (4 mg/kg, subcutaneously) reduced PET in both nocifensive phases, and naloxone (1 mg/kg, subcutaneously) antagonized morphine's effect. The cyclooxygenase inhibitor diclofenac (5 mg/kg, intraperitoneal) reduced only the second phase of nocifensive responses. A low dose of the benzodiazepine midazolam (0.25 mg/kg, intraperitoneal) significantly reduced only the second phase of response, but a higher dose (1 mg/kg, intraperitoneal) had no effect. A subconvulsant, anxiogenic dose of pentylenetetrazol (30 mg/kg, intraperitoneal) also did not affect the PET increase induced by formalin. The antihistamine meclizine (2.5 mg/kg, intraperitoneal) caused an increase of the response in the second phase, but a higher dose (7.5 mg/kg, intraperitoneal) caused inhibition. The peripheral antihistamine loratadine (5 and 10 mg/kg, intraperitoneal) also caused an increase of the second phase. Neither antihistamine altered the first phase of PET. These results reproduced previous findings with classical analgesics in formalin-induced nociception. However, the pronociceptive effect of antihistamines, and the antinociceptive effect of midazolam observed here suggest that formalin-induced incapacitation introduces new characterists of nociceptive system that may complement the study of analgesics. ⋯ Anxiety is thought to influence pain experience in an opposing manner depending on nociception originates in cutaneous or deep somatic/visceral tissues. The present formalin-induced nociceptive test may help to predict more reliably the pain-killing effect of new pharmacologic strategies, with classical or nonclassical mechanisms, for the treatment of clinically relevant pains, which are generally originated in deep structures.
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Chronic neuropathic pain due to injury or dysfunction of the nervous system remains a formidable treatment challenge in spite of a growing range of medication choices. We review current clinical research supporting the use of ion channel modulators for neuropathic pain states. New modes of local drug delivery, novel Ca2+ channel targets, and increased choices for drugs with activity at Na+channels are transforming this longstanding therapeutic strategy. Clinical decision making is increasingly informed by a more nuanced understanding of the role of voltage-gated Na+channels (VGSCs) and Ca2+ channels (VGCCs) in the pathophysiology of nerve injury. Although holding great promise for the future, mechanism-based approaches to treatment will require greater understanding of the analgesic mechanisms of drug action and of the relationships between pathophysiologic mechanisms and clinical presentation. ⋯ Treatment options for neuropathic pain targeting ion channels have grown rapidly in the past decade. An evolving body of clinical research supports the widespread use of this longstanding therapeutic strategy. Improved efficacy of ion channel modulators hinges upon further elucidation of the relationship between signs and symptoms of pain and underlying pathophysiology.
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Na+ channels are large transmembrane proteins with a voltage-gated central pore capable of selectively passing Na+ ions. They are critical determinants of the electrical excitability of sensory neurons and play a key role in pain sensation by controlling afferent impulse discharge. Injury and disease affecting peripheral nerves induces axonopathy and demyelination. These neuropathic changes, in turn, trigger membrane remodeling in injured afferents and perhaps also in uninjured neighbors. A major consequence of the remodeling is increased cellular excitability. This is due in large part to subtype-selective abnormalities in the expression and trafficking of Na+ channels and perhaps also to altered kinetic properties of unitary channels. Hyperexcitable neurons show enhanced membrane resonance, rhythmogenesis, and ectopic spiking. The resulting excess discharge constitutes a primary neuropathic pain signal. In addition, it triggers and maintains central sensitization. This amplifies residual afferent input, yielding tactile allodynia, and it also amplifies ongoing ectopia that exaggerates spontaneous pain. Membrane-stabilizing Na+ channel ligands suppress neuropathic pain by selectively reducing membrane resonance in injured afferents and hence ectopic hyperexcitability. The clinical usefulness of these peripherally acting drugs might be enhanced by reducing their central side effects. ⋯ Neuropathic pain is a complex outcome of multiple pathophysiological changes that develop in the peripheral nervous system (PNS) and the central nervous system (CNS) following nerve injury or disease. All or most of the CNS changes are thought to be due to abnormal signaling from the PNS, notably electrical hyperexcitability of peripheral sensory neurons. Because hyperexcitability is associated with abnormal sodium channel regulation, this process is a prime target for therapeutic intervention.
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Clinical Trial
Opioid tolerance and hyperalgesia in chronic pain patients after one month of oral morphine therapy: a preliminary prospective study.
There is accumulating evidence that opioid therapy might not only be associated with the development of tolerance but also with an increased sensitivity to pain, a condition referred to as opioid-induced hyperalgesia (OIH). However, there are no prospective studies documenting the development of opioid tolerance or OIH in patients with chronic pain. This preliminary study in 6 patients with chronic low back pain prospectively evaluated the development of tolerance and OIH. Patients were assessed before and 1 month after initiating oral morphine therapy. The cold pressor test and experimental heat pain were used to measure pain sensitivity before and during a target-controlled infusion with the short-acting mu opioid agonist remifentanil. In the cold pressor test, all patients became hyperalgesic as well as tolerant after 1 month of oral morphine therapy. In a model of heat pain, patients exhibited no hyperalgesia, although tolerance could not be evaluated. These results provide the first prospective evidence for the development of analgesic tolerance and OIH by using experimental pain in patients with chronic back pain. This study also validated methodology for prospectively studying these phenomena in larger populations of pain patients. ⋯ Experimental evidence suggests that opioid tolerance and opioid-induced hyperalgesia might limit the clinical utility of opioids in controlling chronic pain. This study validates a pharmacologic approach to study these phenomena prospectively in chronic pain patients and suggests that both conditions do occur within 1 month of initiating opioid therapy.
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A number of experimental studies in animals have suggested that voltage-gated sodium channels may play a crucial role in neuropathic pain. However, it is still difficult to translate the pathophysiological mechanisms identified in animal studies to the clinic and several questions regarding the role of sodium channels in neuropathic pain must therefore be addressed primarily in the clinical setting. Despite providing indirect information, pharmacologic challenge using sodium channel blockers, such as some antiepileptics, local anesthetics and derivatives, is the best way to investigate the role of sodium channels in the various clinical symptoms of neuropathies (eg, spontaneous pain, mechanical or thermal allodynia, and hyperalgesia). Randomized controlled trials have demonstrated the efficacy of these compounds for various neuropathic pain conditions. Recent psychophysical studies in which symptoms and signs are more accurately assessed indicate that these compounds act as antihyperalgesic agents rather than as simple analgesics. They also show that the sensitivity to these drugs is not affected by the aetiology of pain and the peripheral or central location of the nerve lesion. These data emphasize the role of peripheral and central sodium channels in neuropathic pain. Studies using more selective sodium channel blockers are required to gain further insight into the role of the various subtypes of sodium channel in these pain conditions. ⋯ Pharmacological challenge using sodium channel blockers is the best way to translate basic research on sodium channels in human neuropathic pain. To date, the role of sodium channels in neuropathic pain symptoms/signs is mostly documented for mechanical static and dynamic allodynia, and either peripheral or central sodium channels may be involved.