Juri L. Pedersen

Hyperalgesia in a human model of acute inflammatory pain : a methodological study

&NA; The aim of the study was to examine reproducibility of primary and secondary hyperalgesia in a psychophysical model of human inflammatory pain. Mild burns were produced on the crura of 12 volunteers with a 50×25 mm thermode (47°C, 7 min). Assessments of (i) cold and warm detection thresholds, (ii) mechanical and heat pain thresholds, (iii) pain to heat (43°C and 45°C, 5 s), (iv) secondary hyperalgesia, and (v) skin erythema were made 1.75 and 0.5 h before, and 0, 1, 2, 4, and 6 h after a burn injury. Sensory thresholds and hyperalgesia to heat and mechanical stimuli were examined by contact thermodes and von Frey hairs, and pain intensity was rated with a visual analog scale (0–100). To describe between‐day reproducibility, the subjects were examined three times at intervals of 21 days. Within‐day comparisons showed that a 20% change could be detected as significant for all variables with fewer than 12 subjects in a cross‐over design (2&agr;=5% and power=80%). Between‐day comparisons demanded up to 25 subjects to detect changes of the same magnitude. The burns caused mild to moderate pain (VAS: mean 29, SD 14) and the subjects (all right‐handed) were more sensitive to heat pain on their left side (P<0.03). Hyperalgesia was induced instantaneously by the burn and outlasted the study period (6 h). However, no spontaneous pain was observed after the injury, and a brief period of hypoesthesia to warm and cold stimuli was induced by the burn. The painful measurements themselves evoked hyperalgesia to heat and mechanical stimuli on the arm, but only to mechanical stimuli on the legs, including secondary hyperalgesia. Hyperalgesia evoked by the measurements was significantly less intense than that induced by injury. Habituation to the painful stimuli was demonstrated by significantly higher pain thresholds and lower pain responses on the second and third day of the study. The burn model is a sensitive psychophysical model of acute inflammatory pain, when cross‐over designs and within‐day comparisons are used, and the model is suitable for double‐blind, placebo‐controlled studies of analgesics. In similar models, we recommend that analgesic and placebo are evenly divided between right and left sides and study days.

Effects of gabapentin in acute inflammatory pain in humans

Background and Objectives The aim of the study was to examine the analgesic effects of the anticonvulsant, gabapentin, in a validated model of acute inflammatory pain. Methods Twenty-two volunteers were investigated in a double-blind, randomized, placebo-controlled cross-over study. Gabapentin 1,200 mg or placebo was given on 2 separate study days. Three hours after drug administration, a first-degree burn injury was produced on the medial aspect of the nondominant calf (12.5 cm2, 47°C for 7 minutes). Quantitative sensory testing (QST) included pain ratings to thermal and mechanical stimuli (visual analog scale [VAS]), assessments of thermal and mechanical detection thresholds, and areas of secondary hyperalgesia. Side effects drowsiness and postural instability were assessed by subjective ratings (VAS). Results The burn injury induced significant primary and secondary hyperalgesia (P < .0001). Gabapentin diminished the decrease in mechanical pain threshold in the burn area (P = .04) and reduced secondary hyperalgesia, but the reduction was not significant (P = .06). Heat pain thresholds, pain during the burn, and mechanical pain in the area of secondary hyperalgesia were not significantly changed by gabapentin (P < .2). Ratings of drowsiness and unsteadiness during walking were significantly higher for gabapentin than for placebo (P < .05). Conclusions The study indicates that gabapentin has no analgesic effect in normal skin, but may reduce primary mechanical allodynia in acute inflammation following a thermal injury. These observations suggest a clinical potential of gabapentin in the treatment of postoperative pain.

Secondary hyperalgesia to heat stimuli after burn injury in man.

&NA; The aim of the study was to examine the presence of hyperalgesia to heat stimuli within the zone of secondary hyperalgesia to punctate mechanical stimuli. A burn was produced on the medial part of the non‐dominant crus in 15 healthy volunteers with a 50×25 mm thermode (47°C, 7 min), and assessments were made 70 min and 40 min before, and 0, 1, and 2 h after the burn injury. Hyperalgesia to mechanical and heat stimuli were examined by von Frey hairs and contact thermodes (3.75 and 12.5 cm2), and pain responses were rated with a visual analog scale (0–100). The area of secondary hyperalgesia to punctate stimuli was assessed with a rigid von Frey hair (462 mN). The heat pain responses to 45°C in 5 s (3.75 cm2) were tested in the area just outside the burn, where the subjects developed secondary hyperalgesia, and on the lateral crus where no subject developed secondary hyperalgesia (control area). The burns decreased pain thresholds and increased pain responses to both thermal and mechanical stimuli within the burn (P<10−5). Further, the burns induced secondary hyperalgesia (mean 89 cm2) to punctate mechanical stimuli (P<10−5), and increased the pain response to mechanical stimuli in the areas of secondary hyperalgesia (P<10−5). The pain response to heat stimuli increased over time in the area of secondary hyperalgesia (P<10−5), and so did the pain response to heat on the lateral part of the crus (P<10−3). However, the heat pain response increased more (P=0.006) and was more intense (P=0.001) within the zone of secondary hyperalgesia than on the lateral part of the crus. Further, the heat pain response was more intense in the zone of primary hyperalgesia than in the zone of secondary hyperalgesia (P=0.004), in contrast to the mechanical pain response, which was not significantly different between the two zones of hyperalgesia. In conclusion, secondary hyperalgesia in man is not restricted to mechanical stimuli, as significant hyperalgesia to heat developed within the zone of secondary hyperalgesia to punctate mechanical stimuli. The data, combined with other evidence, suggest differences in the mechanisms accounting for primary hyperalgesia to heat and mechanical stimuli, whereas secondary hyperalgesia to heat and mechanical stimuli may be explained by a common central mechanism.

Peripheral Analgesic Effects of Ketamine in Acute Inflammatory Pain

Background This study examined the analgesic effect of local ketamine infiltration, compared with placebo and systemic ketamine, in a human model of inflammatory pain. Methods Inflammatory pain was induced by a burn (at 47 [degree sign]C for 7 min; wound size, 2.5 x 5 cm) on the calf in 15 volunteers on 3 separate days with 7‐day intervals. They received either (1) subcutaneous infiltration with ketamine in the burn area (local treatment) and contralateral placebo injections, or (2) subcutaneous ketamine contralateral to the burn (systemic treatment) and placebo in the burn area, or (3) placebo on both sides. The study was double‐blinded and the order of the treatments was randomized. Hyperalgesia to mechanical and heat stimuli was examined by von Frey hairs and contact thermodes (3.75 and 12.5 cm2), and pain was rated using a visual analog scale (0–100). Results The burns produced significant hyperalgesia. Local ketamine infiltration reduced pain during the burn injury compared with systemic treatment and placebo (P <or= to 0.01). Heat pain thresholds were increased by local ketamine treatment compared with placebo immediately after injection (P <or= to 0.03), and so were the mechanical pain thresholds (P = 0.02). Secondary hyperalgesia and suprathreshold pain responses to heat and mechanical stimuli were not significantly affected by local ketamine. No difference between local ketamine and placebo could be detected 1 h and 2 h after the burn. Conclusions Ketamine infiltration had brief local analgesic effects, but several measures of pain and hyperalgesia were unaffected. Therefore, a clinically relevant effect of peripheral ketamine in acute pain seems unlikely.

Effect of Preemptive Nerve Block on Inflammation and Hyperalgesia after Human Thermal Injury

Background Postoperative pain relief may be improved by reducing sensitization of nociceptive pathways caused by surgical trauma. Such a reduction may depend on the timing and efficacy of analgesia and the duration of the nociceptive block versus the duration of the nociceptive input. We examined whether a prolonged nerve block administered before a superficial burn injury could reduce local inflammation and late hyperalgesia after recovery from the block. Methods The effects of a preemptive saphenous nerve block on primary and secondary hyperalgesia, skin erythema, and blister formation, were compared to the opposite unblocked leg for 12 h after bilateral thermal injuries (15 x 25 mm, 49 degrees C for 5 min) in 20 healthy volunteers. Recovery from the block was identified by return of sensation to cold. Results Six subjects were excluded because of insufficient initial block (2 subjects) or because the block lasted beyond the study period (4 subjects). The remaining 14 subjects experienced significantly reduced primary (P = 0.005) and secondary hyperalgesia (P = 0.01) in the blocked leg after return of cold sensation compared to the unblocked leg. Erythema intensity and blister formation were not significantly affected by the blockade (P = 0.94 and P = 0.07, respectively). Conclusions These data suggest that a prolonged, preemptive nerve block reduced late hyperalgesia after thermal injury, whereas the erythema and blister formation were not significantly affected.

Multimodal pain stimulations in patients with grade B oesophagitis

Aim: To obtain a better understanding of nociceptive processing in patients with oesophagitis. Patients and methods: Eleven patients with grade B oesophagitis were compared with an age and sex matched group of 16 healthy subjects. A probe was positioned in the lower part of the oesophagus. After preconditioning of the tissue, painful mechanical stimuli were applied as distensions with a bag using an impedance planimetric method. Distensions were done before and after pharmacological impairment of distension induced smooth muscle contractions. Thermal stimulation was performed by recirculating water at 1 and 60°C in the bag. The area under the temperature curve (AUC) represented caloric load. The referred pain area (being a proxy for the central pain mechanisms) to the mechanical stimuli was drawn at maximum pain intensities. Results: Patients were hyposensitive to mechanical stimuli, as assessed by the distending volume (F = 8.1, p = 0.005). After relaxation of smooth muscle with butylscopolamine, the difference between the two groups was more evident (F = 27.4, p<0.001). AUC for cold stimulation was 1048.6 (242.7) °C×s in controls and 889.8 (202.6) °C×s in patients (p = 0.5). For heat stimuli, AUC values were 323.3 (104.1) and 81.3 (32.3) °C×s in controls and patients, respectively (p = 0.04). The referred pain area to the mechanical stimulations was larger and more widespread in patients (49.3 (6.2) cm2 compared with controls 23.9 (7) cm2; p = 0.02). Conclusions: The data indicate that peripheral sensitisation of heat sensitive receptors and pathways combined with facilitation of central pain mechanisms may explain the symptoms in patients with oesophagitis.

Hyperalgesia and temporal summation of pain after heat injury in man

&NA; Temporal summation of pain occurs when repeated stimuli become increasingly painful in spite of unchanged stimulus intensity. Summation can be quantified as the difference in pain between the first and the last stimulus in a train of stimuli. The aim of the study was to compare temporal summation of pain in normal skin with summation of pain in skin with primary and secondary hyperalgesia evoked by a heat injury. A heat injury was produced on the crus of 12 volunteers with a 50×25 mm thermode (47°C, 7 min). Measurements were made before, and 0, 1, 2, and 4 h after the heat injury, in three areas: primary and secondary mechanical hyperalgesia induced by the heat injury, and in a mirror image of the injury on the opposite leg. Temporal summation of pain was induced by repeated electrical stimuli (five stimuli at 2 Hz) and assessed by visual analog scale (VAS). Primary hyperalgesia was evaluated by von Frey hairs and electrical stimuli, and the areas of secondary hyperalgesia with a rigid von Frey hair (314 mN). Significant primary (P<0.000001) and secondary (P<0.00006) mechanical hyperalgesia were evoked by the heat injury. The pain threshold to single electrical stimuli was reduced within the injury (P<0.03), but not outside. The pain responses to single and repeated electrical stimuli were not significantly altered by the injury. Temporal summation of pain occurred in 418 stimulus trains out of 576 (73%), but no significant changes in summation developed in skin with primary or secondary mechanical hyperalgesia compared with normal skin (baseline measurements). Temporal summation at high stimulus intensities was more pronounced than at lower intensities (P<0.0002). We found no correlation between either temporal summation and area of secondary hyperalgesia, or temporal summation and pain intensity during the induction of heat injury. We conclude that the development of primary and secondary mechanical hyperalgesia after heat injury in man was not associated with changes in temporal summation of painful electrical stimuli.

Local cooling does not prevent hyperalgesia following burn injury in humans

&NA; One of the oldest methods of pain relief following a burn injury is local application of ice or cold water. Experimental data indicate that cooling may also reduce the severity of tissue injury and promote wound healing, but there are no controlled studies in humans evaluating the anti‐inflammatory or anti‐hyperalgesic potential of early cooling after thermal injury. Twenty‐four healthy volunteers participated in this randomized, single‐blinded study. Following baseline measurements, which included inflammatory variables (skin temperature, erythema index) and sensory variables (thermal and mechanical detection thresholds, thermal and mechanical pain responses, area of secondary hyperalgesia), first degree burn injuries were induced on both calves by contact thermodes (12.5 cm2, 47°C for 7 min). Eight minutes after the burn injury, contact thermodes (12.5 cm2) were again applied on the burns. One of the thermodes cooled the burn (8°C for 30 min) whereas the other thermode was a non‐active dummy on the control burn. Inflammatory and sensory variables were followed for 160 min after end of the cooling procedure. The burn injury induced significant increases in skin temperature (P<0.0005), erythema index (P<0.0001), thermal pain responses (P<0.0005), mechanical pain responses (P<0.005) and secondary hyperalgesia, and significant decreases in heat pain threshold (P<0.0005) and mechanical pain threshold (P<0.0005). There were no post‐cooling effects on skin temperature (P>0.5), erythema (P>0.9), heat pain threshold (P>0.5), thermal or mechanical pain responses (P>0.5) or the development of secondary hyperalgesia (P>0.4) compared with the control burn. However, a significant, albeit transient, increase in cold detection threshold was observed on the cooled burn side (P<0.0001). In conclusion, cooling with 8°C for 30 min following a first degree burn injury in humans does not attenuate inflammatory or hyperalgesic responses compared with a placebo‐treated control burn.

Effect of sympathetic nerve block on acute inflammatory pain and hyperalgesia.

Background Sympathetic nerve blocks relieve pain in certain chronic pain states, but the role of the sympathetic pathways in acute pain is unclear. Thus the authors wanted to determine whether a sympathetic block could reduce acute pain and hyperalgesia after a heat injury in healthy volunteers. Methods The study was made as a randomized, single‐blinded investigation, in which the volunteers served as their own controls. A lumbar sympathetic nerve block and a contralateral placebo block were performed in 24 persons by injecting 10 ml bupivacaine (0.5%) and 10 ml saline, respectively. The duration and quality of blocks were evaluated by the sympathogalvanic skin response and skin temperature. Bilateral heat injuries were produced on the medial surfaces of the calves with a 50 x 25 mm thermode (47 degrees C, 7 min) 45 min after the blocks. Pain intensity induced by heat, pain thresholds to thermal and mechanical stimulation, and secondary hyperalgesia were assessed before block, after block, and 1, 2, 4, and 6 h after the heat injuries. Results Of the 24 volunteers, eight were excluded because of somatic block or incomplete sympathetic block. The study revealed no significant differences between sympathetic block and placebo for pain or mechanical allodynia during injury, or pain thresholds, pain responses to heat, or areas of secondary hyperalgesia after the injury. The comparisons were done for the period when the block was effective. Conclusion Sympathetic nerve block did not change acute inflammatory pain or hyperalgesia after a heat injury in human skin.