Ten patients (4 female, 6 male) aged 34-67 years suffering from peripheral neuropathic pain participated in a double-blind placebo-controlled study where ketamine or magnesium chloride were administered by a 10 min bolus infusion (ketamine: 0.84 mumol/kg = 0.2 mg/kg, magnesium: 0.16 mmol/kg) followed by a continuous infusion (ketamine: 1.3 mumol/kg/h = 0.3 mg/kg/h, magnesium: 0.16 mmol/kg/h). Ongoing pain determined by VAS score, area of touch-evoked allodynia, detection and pain thresholds to mechanical and thermal stimuli were measured before and during drug infusion. Ketamine produced a significant reduction of spontaneous pain (57%) and of the area of allodynia (33%). Magnesium chloride reduced pain (29%) and area of allodynia (18%) insignificantly. Following ketamine there was a significant correlation between the reduction in ongoing pain and reduction in area of touch-evoked allodynia. Detection and pain thresholds to mechanical and thermal stimuli were not significantly changed by the drugs. These findings suggest that both ongoing pain and touch-evoked pain (allodynia) in neuropathic pain are inter-related phenomena, which may be mediated by the same mechanism and involving a N-methyl-D-aspartate receptor.
The non-competitive NMDA-antagonist, Ketamine, was infused (i.v.) in healthy volunteers to study the effect on central excitability with the presence of cutaneous hyperalgesia. Hyperalgesia was established experimentally on the dorsum of the foot by topical application of capsaicin (1%). Different thermal and mechanical conditioning stimuli were applied to the primary and secondary hyperalgesic areas to modulate the central nociceptive excitability monitored by the nociceptive reflex. When the elicited reflex was combined with an activation of the secondary hyperalgesic area by continuous, non-painful, electrical stimulation, a facilitation of the reflex was observed. This indicates that summation of activity in non-nociceptive and nociceptive afferents can occur under mild pathological conditions. Conditioning thermal stimuli of the primary hyperalgesic area were employed to intensify the allodynia prior to testing this interaction between tactile and nociceptive activity. The same reflex facilitation was inhibited by Ketamine. Furthermore, Ketamine decreased the pain intensity associated with the stimuli eliciting the reflex. Psychophysical measures to single and repeated electrical and thermal (laser) stimuli applied within the hyperalgesic areas were also obtained. The intensity of pain sensations produced by single, painful, electrical stimuli applied to the primary hyperalgesic region was reduced after Ketamine infusion. Finally, five repeated, electrical stimuli applied to the secondary hyperalgesic area were used to assess the temporal summation threshold. Ketamine caused an increase in the summation threshold compared to the placebo treatment. In conclusion, these results demonstrate that (1) summation of activity in non-nociceptive and nociceptive afferents occurs under hyperalgesic conditions and, (2) this summation can be inhibited by NMDA-antagonists. Therefore, the study shows an apparent involvement of NMDA-receptors in some of the central mechanisms underlying secondary hyperalgesia.
The aim of this study was to demonstrate the effect of intra-articular morphine following knee arthroscopy performed in infiltration analgesia. Fifty-two healthy patients were randomized to receive either 1 mg of morphine or placebo. The pain was assessed 2, 4, 8 and 24 h after the procedure by (1) a VAS scale and (2) the amount of acetaminophen consumed. Demographic data in the 2 groups were similar. The pain scores at 8 and 24 h and the acetaminophen consumption after 8 h were lower in the morphine group (P < 0.05). Our results support the hypothesis of peripherally distributed opioid receptors. Stratifying data in therapeutic versus diagnostic arthroscopy indicated additional effect of morphine in patients undergoing therapy (P < 0.1), an aspect supporting the hypothesis of peripherally administered morphine as a potential suppressor of the substance P-mediated cytokine cascade and the peripheral leukocyte activity. Intra-articular morphine (1 mg) after knee arthroscopy offers efficient analgesia lasting more than 24 h. The method is devoid of side effects and deserves wider recognition.
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