Pain
-
The present study was designed to identify the neuronal mechanisms causing cardiac baroreflex inhibition associated with thermal nociception in rats. Under urethane-anesthesia, noxious thermal stimuli > or = 48 degrees C were found to inhibit the cardiac baroreflex, whereas noxious stimuli < or = 46 degrees C had no effect. Using double immunohistochemical labeling, noxious stimuli > or = 48 degrees C were found to evoke primarily a strong expression of Fos protein (Fos) encoded by c-fos gene in serotonergic neurons of lateral paragigantocellular reticular nucleus (LPGi). ⋯ Local blockade of neuronal activity by bilateral microinjections of fluorescent muscimol (a GABA(A) receptor agonist tagged with a fluorophore that allowed visualization of the injections) into both the LPGi and the raphe magnus nucleus prevented the inhibitory effect of noxious stimuli > or = 48 degrees C on the cardiac baroreflex. Bilateral microinjections of granisetron (a 5-HT(3) antagonist) within the nucleus tractus solitarius also prevented the inhibition of cardiac baroreflex elicited by noxious stimuli > or = 48 degrees C. These results show that activation of serotonergic cells in the LPGi is critical to trigger nucleus tractus solitarius-mediated cardiac baroreflex inhibition elicited by intense thermal noxious stimuli.
-
Review Meta Analysis
A systematic review of adverse events in placebo groups of anti-migraine clinical trials.
In analgesic clinical trials, adverse events are reported for the painkiller under evaluation and compared with adverse events in the placebo group. Interestingly, patients who receive the placebo often report a high frequency of adverse events, but little is understood about the nature of these negative effects. In the present study, we compared the rates of adverse events reported in the placebo arms of clinical trials for three classes of anti-migraine drugs: NSAIDs, triptans and anticonvulsants. ⋯ For example, anorexia and memory difficulties, which are typical adverse events of anticonvulsants, were present only in the placebo arm of these trials. These results suggest that the adverse events in placebo arms of clinical trials of anti-migraine medications depend on the adverse events of the active medication against which the placebo is compared. These findings are in accordance with the expectation theory of placebo and nocebo effects.
-
Randomized Controlled Trial Multicenter Study
A randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of ABT-594 in patients with diabetic peripheral neuropathic pain.
ABT-594 is a neuronal nicotinic acetylcholine receptor (NNR) agonist that exhibits potent analgesic activity in preclinical models of acute, chronic, and neuropathic pain. The purpose of this phase 2, randomized, multicenter, double-blind, placebo-controlled study was to evaluate the safety and analgesic efficacy of ABT-594 in patients with diabetic peripheral neuropathic pain (DPNP). A total of 266 DPNP patients were randomized 1:1:1:1 to receive placebo, ABT-594 150 microg BID, ABT-594 225 microg BID, or ABT-594 300 microg BID. ⋯ However, adverse event (AE) dropout rates were significantly higher in all three ABT-594 treatment groups (28% for 150 microg BID, 46% for 225 microg BID, and 66% for 300 microg BID) than for the placebo group (9%). Consistent with the expected side-effect profile of NNR agonists, the most frequently reported AEs were nausea, dizziness, vomiting, abnormal dreams, and asthenia. This study establishes proof of concept for NNR agonists as a new class of compounds for treating neuropathic pain.
-
Randomized Controlled Trial
Duloxetine, a centrally acting analgesic, in the treatment of patients with osteoarthritis knee pain: a 13-week, randomized, placebo-controlled trial.
Pain is a common cause of disability in osteoarthritis. Duloxetine, a serotonin and norepinephrine reuptake inhibitor (SNRI), has demonstrated analgesic effects in diabetic peripheral neuropathy and fibromyalgia. Considering its central mechanism of action, duloxetine may be effective in other pain states with evidence of central sensitization. ⋯ Duloxetine was superior to placebo on the primary efficacy measure (weekly mean 24-h pain scores) beginning at Week 1 and continuing through the treatment period (P < or = .05). There was also a significant improvement in the WOMAC physical functioning subscale and several other secondary outcomes. Adverse-event rates did not differ significantly between treatment groups (49.5% for duloxetine 60-120 mg/day, and 40.8% for placebo).
-
An essential component of the interpretation of results of randomized clinical trials of treatments for chronic pain involves the determination of their clinical importance or meaningfulness. This involves two distinct processes--interpreting the clinical importance of individual patient improvements and the clinical importance of group differences--which are frequently misunderstood. In this article, we first describe the essential differences between the interpretation of the clinical importance of patient improvements and of group differences. ⋯ The clinical importance of individual patient improvements can be determined by assessing what patients themselves consider meaningful improvement using well-described methods. In contrast, the clinical meaningfulness of group differences must be determined by a multi-factorial evaluation of the benefits and risks of the treatment and of other available treatments for the condition in light of the primary goals of therapy. Such determinations must be conducted on a case-by-case basis, and are ideally informed by patients and their significant others, clinicians, researchers, statisticians, and representatives of society at large.