The journal of pain : official journal of the American Pain Society
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Vanilloid receptor subunit 1 (TRPV1) is an integrator of physical and chemical stimuli in the peripheral nervous system. This receptor plays a key role in the pathophysiology of inflammatory pain. Thus, the identification of receptor antagonists with analgesic and anti-inflammatory activity in vivo is an important goal of current neuropharmacology. Here, we report that [L-arginyl]-[N-[2,4-dichlorophenethyl]glycyl]-N-(2,4-dichlorophenethyl) glycinamide (H-Arg-15-15C) is a channel blocker that abrogates capsaicin and pH-evoked TRPV1 channel activity with submicromolar activity. Compound H-Arg-15-15C preferentially inhibits TRPV1, showing marginal block of other neuronal receptors. Compound H-Arg-15-15C acts as a noncompetitive capsaicin antagonist with modest voltage-dependent blockade activity. The compound inhibited capsaicin-evoked nerve activity in afferent fibers without affecting mechanically activated activity. Notably, administration of compound H-Arg-15-15C prevented the irritant activity of a local administration of capsaicin and formalin and reversed the thermal hyperalgesia evoked by injection of complete Freund's adjuvant. Furthermore, it attenuated carrageenan-induced paw inflammation. Compound H-Arg-15-15C specifically decreased inflammatory conditions without affecting normal nociception. Taken together, these findings demonstrate that compound H-Arg-15-15C is a channel blocker of TRPV1 with analgesic and anti-inflammatory activity in vivo at clinically useful doses and substantiate the tenet that TRPV1 plays an important role in the etiology of chronic inflammatory pain. ⋯ This study reports the design of a potent TRPV1 noncompetitive antagonist that exhibits anti-inflammatory and analgesic activity in preclinical models of acute and chronic pain. This compound is a lead for analgesic drug development.
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The present study investigated the role of central metabotropic glutamate receptors (mGluRs) in interleukin-1beta (IL-1beta)-induced mechanical allodynia and mirror-image mechanical allodynia in the orofacial area. Experiments were carried out on male Sprague-Dawley rats weighing 230 to 280 g. After administration of 0.01, 0.1, 1, or 10 pg of IL-1beta into a subcutaneous area of the vibrissa pad, we examined the withdrawal behavioral responses produced by 10 successive trials of an air-puff ramp pressure applied ipsilaterally or contralaterally to the IL-1beta injection site. Subcutaneous injection of IL-1beta produced mechanical allodynia and mirror-image mechanical allodynia in the orofacial area. Intracisternal administration of CPCCOEt, a mGluR1 antagonist, or MPEP, a mGluR5 antagonist, reduced IL-1beta-induced mechanical allodynia and mirror-image mechanical allodynia. Intracisternal administration of APDC, a group II mGluR agonist, or L-AP4, a group III mGluR agonist, reduced both IL-1beta-induced mechanical allodynia and mirror-image mechanical allodynia. The antiallodynic effect, induced by APDC or L-AP4, was blocked by intracisternal pretreatment with LY341495, a group II mGluR antagonist, or CPPG, a group III mGluR antagonist. These results suggest that groups I, II, and III mGluRs differentially modulated IL-1beta-induced mechanical allodynia, as well as mirror-image mechanical allodynia, in the orofacial area. ⋯ Central group I mGluR antagonists and groups II and III mGluR agonists modulate IL-1beta-induced mechanical allodynia and mirror-image mechanical allodynia in the orofacial area. Therefore, the central application of group I mGluR antagonists or groups II and III mGluR agonists might be of therapeutic value in treating pain disorder.
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The objective of this retrospective study was to test the validity and reliability of a scoring tool (the DIRE Score), for use by clinicians, that predicts which chronic noncancer pain patients will have effective analgesia and be compliant with long-term opioid maintenance treatment. DIRE scores were assigned to 61 cases from the pain center's databases. These cases were abstracted into vignettes that were reviewed and scored by 6 physicians. Repeat scoring was carried out on a subset of 30 vignettes after 2 weeks. The main outcome measures were: global impression of compliance and efficacy as indicated in the medical record and by interview with the patient's treating clinician; and final disposition, ie, whether or not opioids were continued or discontinued at the time of last clinical documentation. Internal consistency of the factors making up the DIRE Score was high (Cronbach's alpha = .80). Sensitivity and specificity of the DIRE Score for predicting patient compliance were 94% and 87%, respectively. For efficacy, sensitivity and specificity were 81% and 76%. For disposition, the sensitivity and specificity were 86% and 73%. Intraclass correlation was 0.94 for interrater reliability and 0.95 for intrarater reliability. ⋯ Public controversy about the use of long-term opioids for chronic pain fuels physician ambivalence about the prescribing process. In this initial retrospective study, validity and reliability of the DIRE Score are demonstrated. The score correlated well with measures of patient compliance and efficacy of long-term opioid therapy.
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Randomized Controlled Trial Comparative Study
A comparison of conventional pain coping skills training and pain coping skills training with a maintenance training component: a daily diary analysis of short- and long-term treatment effects.
Pain coping skills training (PCST) has been shown to produce immediate improvements in pain and disability in rheumatoid arthritis (RA). However, some patients have difficulty maintaining these gains. This study compared a conventional PCST protocol with a PCST protocol that included maintenance training (PCST/MT). Patients with RA (n = 167) were randomly assigned to either conventional PCST, PCST/MT, arthritis education control, or standard care control. Daily data were collected on joint pain, coping, coping efficacy, and mood. Multilevel analyses showed that at posttreatment, conventional PCST was superior to all other conditions in joint pain, coping efficacy, and negative mood, whereas PCST/MT was superior to all other conditions in emotion-focused coping and positive mood. At 18 months follow-up, both PCST conditions were superior to standard care in joint pain and coping efficacy. Interpretation of follow-up outcomes was limited by higher dropout rates in the 2 PCST groups. For RA, a maintenance training component does not appear to produce significant improvements over conventional PCST. ⋯ This article reports a trial evaluating a conventional pain coping skills training protocol and a similar protocol that included a maintenance training component. Overall, results indicate similar results for both the conventional and the modified protocols.
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Chronic pain following breast cancer surgery is associated with decreased health-related quality of life and is a source of additional psychosocial distress in women who are already confronting the multiple stresses of cancer. Few prospective studies have identified risk factors for chronic pain following breast cancer surgery. Putative demographic, clinical, and psychosocial risk factors for chronic pain were evaluated prospectively in 95 women scheduled for breast cancer surgery. In a multivariate analysis of the presence of chronic pain, only younger age was associated with a significantly increased risk of developing chronic pain 3 months after surgery. In an analysis of the intensity of chronic pain, however, more invasive surgery, radiation therapy after surgery, and clinically meaningful acute postoperative pain each independently predicted more intense chronic pain 3 months after surgery. Preoperative emotional functioning variables did not independently contribute to the prediction of either the presence or the intensity of chronic pain after breast cancer surgery. These findings not only increase understanding of risk factors for chronic pain following breast cancer surgery and the processes that may contribute to its development but also provide a basis for the development of preventive interventions. ⋯ Clinical variables and severe acute pain were risk factors for chronic pain following breast cancer surgery, but psychosocial distress was not, which provides a basis for hypothesizing that aggressive management of acute postoperative pain may reduce chronic pain.