The journal of pain : official journal of the American Pain Society
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The development of more effective methods of relieving pain associated with burn injury is a major unmet medical need. Not only is acute burn injury pain a source of immense suffering, but it has been linked to debilitating chronic pain and stress-related disorders. Although pain management guidelines and protocols have been developed and implemented, unrelieved moderate-to-severe pain continues to be reported after burn injury. One reason for this is that the intensity of pain associated with wound care and rehabilitation therapy, the major source of severe pain in this patient population, varies widely over the 3 phases of burn recovery, making it difficult to estimate analgesic requirements. The effects of opioids, the most commonly administered analgesics for burn injury procedural pain, are difficult to gauge over the course of burn recovery because the need for an opioid may change rapidly, resulting in the overmedication or undermedication of burn-injured patients. Understanding the mechanisms that contribute to the intensity and variability of burn injury pain over time is crucial to its proper management. We provide an overview of the types of pain associated with a burn injury, describe how these different types of pain interfere with the phases of burn recovery, and summarize pharmacologic pain management strategies across the continuum of burn care. We conclude with a discussion and suggestions for improvement. Rational management, based on the underlying mechanisms that contribute to the intensity and variability of burn injury pain, is in its infancy. The paucity of information highlights the need for research that explores and advances the identification of mechanisms of acute and chronic burn injury pain. ⋯ Researchers continue to report that burn pain is undertreated. This review examines burn injury pain management across the phases of burn recovery, emphasizing 3 types of pain that require separate assessment and management. It provides insights and suggestions for future research directions to address this significant clinical problem.
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In the present study, the adrenergic receptor (AR) subtype mediating adrenergic augmentation of P2X(3) receptor-mediated nociceptive responses on sensory nerve endings was examined by using selective AR receptor agonists and antagonists in Sprague Dawley rats in the uninjured state. Local administration of alphabeta-methyleneATP (ligand for P2X3/P2X2/3 receptors) into the plantar hind paw produced few pain behaviors when given alone in this strain of rats; combination with adrenaline (alpha1- and alpha2-AR agonist) and phenylephrine (alpha1-AR agonist) but not clonidine or UK 14,304 (alpha2-AR agonists) increased flinching behaviors. Flinching produced by noradrenaline (NA)/alphabeta-methyleneATP was suppressed by low doses of prazosin (alpha1-AR antagonist), and this reduction was selective compared with yohimbine (alpha2-AR antagonist). Prazosin also reduced flinching produced by phenylephrine/alphabeta-methyleneATP. Using thermal threshold determinations, adrenaline and phenylephrine but not clonidine or UK 14,304, mimicked the action of NA in augmenting reductions in thermal thresholds produced by alphabeta-methyleneATP. Terazosin (another alpha1-AR antagonist) inhibited hyperalgesia produced by NA/alphabeta-methyleneATP. These results provide evidence for alpha1-AR involvement in adrenergic augmentation of P2X3/P2X2/3 receptor-mediated responses on sensory nerve endings in the uninjured state in Sprague Dawley rats. ⋯ This study indicates the alpha1-adrenergic receptor subtype mediates adrenergic augmentation of the activation of sensory nerves by purinergic P2X3 receptors (respond to ATP) in the periphery. Observations are potentially relevant to chronic pain conditions in which sympathetic nerves influence sensory nerves.
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The present study was undertaken to determine the role of P2X3 receptor (P2X3R) on heat hyperalgesia in a newly developed rat model of trigeminal neuropathic pain. The unilateral infraorbital nerve (IoN) was partially ligated by 6-0 silk. To assess heat sensitivity, a vibrissal pad (VP) was placed on a hot plate and the latency until the rats withdrew their head was measured. Mechanical sensitivity of VP was also assessed by the use of von Frey filament. Both heat and mechanical hyperalgesia were observed at the VP ipsilateral to the IoN ligation. The latency to heat stimuli was prolonged after subcutaneous administration of pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS, P2X1,2,3,5,7,1/5,2/3R antagonist) and 2',3'-O-(2,4,6-trinitrophenyl) adenosine 5'-triphosphate (TNP-ATP, P2X1,3,2/3,1/5R antagonist). The latency was shortened after administration of alpha,beta-methylene ATP (alpha,beta-meATP, P2X1,3,2/3R agonist), although no changes appeared after administration of beta,gamma-methylene-L-ATP (beta,gamma-me-L-ATP, P2X1R agonist). The protein gene product-9.5 and calcitonin gene-related peptide immunoreactive nerve fibers significantly decreased in the VP skin of ipsilateral to the IoN ligation. In the ipsilateral trigeminal ganglion, the number of P2X3-immunoreactive neurons significantly increased in the small cell group. In this study, we developed an experimental model of trigeminal neuropathic pain by partial ligation of IoN, which produced heat and mechanical hyperalgesia in the VP. Pharmacological and immunohistochemical studies revealed that the P2X3R plays an important role in the heat hyperalgesia observed in this model. ⋯ The study describes the development of a novel model of trigeminal neuropathic pain. Heat hyperalgesia in this model was inhibited by peripheral injection of P2XR antagonists. The results suggest that P2X3R is a potential target for development of a novel therapy for trigeminal neuropathic pain.
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The antidepressant amitriptyline is used as an adjuvant in the treatment of chronic pain. Among its many actions, amitriptyline blocks Na+ channels and nerves in several animal and human models. As perioperative intravenous lidocaine has been suggested to decrease postoperative pain, amitriptyline, because of its longer half-life time, might be more useful than lidocaine. However, the use of intravenous amitriptyline is not approved by the US Food and Drug Administration. We therefore investigated the adverse effects of preoperative intravenous amitriptyline in a typical phase 1A trial. After obtaining written Food and Drug Administration and institutional review board approval, we obtained written consent for preoperative infusion of amitriptyline in an open-label, dose-escalating design (25, 50, and 100 mg, n=5 per group). Plasma levels of amitriptyline/nortriptyline were determined, and adverse effects were recorded in a predetermined symptom list. Infusion of 25 and 50 mg amitriptyline appears to be well tolerated; however, the study was terminated when 1 subject in the 100-mg group developed severe bradycardia. Intravenous infusion of amitriptyline (25 to 50 mg over 1 hour) did not create side effects beyond dry mouth and drowsiness, or dizziness, in 2 of our 10 otherwise healthy participants receiving the 25- to 50-mg dose. An appropriately powered future trial is necessary to determine a potential role of amitriptyline in decreasing postoperative pain. ⋯ Amitriptyline potently blocks the persistently open Na+ channels, which are known to be instrumental in various pain states. As this occurs at very low plasma concentrations, a single preoperative intravenous infusion of amitriptyline could provide long-lasting pain relief and decrease the incidence of chronic pain.
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The primary goal of this paper was to present a comprehensive picture of substance use disorders in a sample of patients receiving opioid therapy from their primary care physician. A second goal was to determine the relation of positive urine screens and aberrant drug behaviors to opioid use disorders. The study recruited 801 adults receiving daily opioid therapy from the primary care practices of 235 family physicians and internists in 6 health care systems in Wisconsin. The 6 most common pain diagnoses were degenerative arthritis, low back pain, migraine headaches, neuropathy, and fibromyalgia. The point prevalence of current (DSM-IV criteria in the past 30 days) substance abuse and/or dependence was 9.7% (n=78) and 3.8% (30) for an opioid use disorder. A logistic regression model found that current substance use disorders were associated with age between 18 and 30 (OR=6.17: 1.99 to 19.12), severity of lifetime psychiatric disorders (OR=6.17; 1.99 to 19.12), a positive toxicology test for cocaine (OR=5.92; 2.60 to 13.50) or marijuana (OR=3.52; 1.85 to 6.73), and 4 aberrant drug behaviors (OR=11.48; 6.13 to 21.48). The final model for opioid use disorders was limited to aberrant behaviors (OR=48.27; 13.63 to 171.04) as the other variables dropped out of the model. ⋯ This study found that the frequency of opioid use disorders was 4 times higher in patients receiving opioid therapy compared with general population samples (3.8% vs 0.9%). The study also provides quantitative data linking aberrant drug behaviors to opioid use disorders.