Pain
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Randomized Controlled Trial Clinical Trial
Transdermal clonidine compared to placebo in painful diabetic neuropathy using a two-stage 'enriched enrollment' design.
Because a variety of mechanisms may generate pain in neuropathic pain syndromes, conventional clinical trial methods may fail to identify some potentially useful drugs; a drug affecting just a single mechanism may work in too few patients to yield a statistically significant result for the trial. To test a previous clinical observation that approximately one-quarter of patients with painful diabetic neuropathy appear responsive to clonidine, we conducted a formal clinical trial of transdermal clonidine in painful diabetic neuropathy patients using a 2-stage enriched enrollment design. In the first stage (study 1), 41 patients with painful diabetic neuropathy completed a randomized, 3-period crossover comparison of transdermal clonidine (titrated from 0.1 to 0.3 mg/day) to placebo patches. ⋯ In study II, however, the 12 apparent responders from study I had 20% less pain with clonidine than placebo (95% confidence interval (CI): 4-35% pain reduction; P = 0.015), confirming that their pain was responsive to clonidine. None of the 3 consistent clonidine responders who were tested with the alpha-adrenergic blocker phentolamine had relief of pain, suggesting that clonidine's pain relief is not mediated by a decrease in sympathetic outflow. A post-hoc analysis of many variables suggested that patients who described their pain as sharp and shooting may have a greater likelihood of responding to clonidine.(ABSTRACT TRUNCATED AT 250 WORDS)
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Rats in which the sciatic nerve is partially transected develop hyperalgesia which is relieved by sympathectomy. We carried out experiments using this model of experimental peripheral neuropathy to examine the peripheral mechanisms underlying sympathetically maintained pain. Subcutaneous injection of noradrenaline (NA) into the affected paw exacerbated the hyperalgesia but had no effect in control animals. ⋯ Following a chemical sympathectomy, hyperalgesia was eliminated and injection of NA into the hyperalgesic paw had no effect on pain thresholds. We concluded that NA exacerbates hyperalgesia in this experimental model by acting on alpha 2-adrenoreceptors which are located on post-ganglionic sympathetic terminals. Our results are consistent with the proposal (Levine et al. 1986) that activation of these adrenoreceptors brings about an increased release of prostaglandins which sensitises nociceptors.
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Randomized Controlled Trial Comparative Study Clinical Trial
The hypoalgesic effect of imipramine in different human experimental pain models.
In a randomized, placebo-controlled, double-blind, cross-over study, the hypoalgesic effect of a single oral dose of 100 mg imipramine was investigated in 12 healthy volunteers. Test procedures performed before, 3, 6, and 9 h after medication included determination of (1) pain detection and tolerance thresholds to heat and pressure; (2) the thresholds of quadriceps femoris muscle withdrawal reflex to single and repeated electric stimulation of the sural nerve; (3) amplitude of the reflex evoked by 1.5 times the premedication reflex threshold; and (4) continuous pain rating during the cold pressor test. Imipramine significantly increased pain tolerance thresholds to heat (P = 0.03) and pressure (P = 0.01), and both the psychophysical pain tolerance threshold and the reflex threshold to single electric stimulation (P = 0.02 and P = 0.03, respectively). ⋯ Pain detection thresholds to heat and pressure, the amplitude of the reflex to single suprathreshold stimulation, and pain ratings during the cold pressor test were unaltered by imipramine. It is concluded that imipramine has a differential hypoalgesic effect on different human experimental pain tests. This provides new possibilities of assessing the differential effect of different tricyclic antidepressants on different pain modalities and intensities.