Department of Surgical Gastroenterology, Hvidovre University Hospital, Kettegaard Allé 30, DK-2650 Hvidovre, Denmark
Accepted for publication: January 25, 2000
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Abstract |
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Br J Anaesth 2000; 85: 22832
Keywords: analgesia; pain; analgesics, morphine; analgesics, opioid
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Introduction |
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The analgesic effect of intra-articular opioid administration in the knee cavity has been studied extensively, and it has been concluded that intra-articular morphine may have some effect in reducing postoperative pain intensity, but final conclusions were hindered by flaws in designs and samples sizes of the studies.5 Peripheral analgesic effects of opioids applied at extra-articular sites have been difficult to demonstrate, and a recent review concluded on the basis of 26 trials with data from 952 patients that there was no evidence for a clinically relevant peripheral analgesic effect of opioids in acute extra-articular pain.6
However, in the view of the clinical potential, there is a need for further human studies investigating the analgesic effects of peripheral morphine. The aim of our study was to examine the antinociceptive effect of morphine infiltrated subcutaneously (s.c.) in a human model of acute inflammatory pain. One trial has previously tested morphine in a similar burn model, but with limited sensory assessments and without systemic morphine as control.7
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Methods |
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The study used a randomized, double-blind, placebo-controlled, three-way crossover design. Each volunteer received either morphine (2 mg, 5 ml) s.c. in the burn injury area (local), morphine in the corresponding area on the opposite leg (systemic), or saline (0.9%, 5 ml) in both legs (placebo) on three study days separated by 2 weeks. When subjects received morphine, they received saline in the opposite leg. The order of the study days was randomized en bloc, so the treatments were equally distributed over the three study days. Morphine or placebo (saline) was injected after baseline measurements and measurements were repeated thereafter. The burn was induced on the non-dominant leg 1 h after the injections, and measurements were made at 0, 1 and 2 h after the burn. Subjects received naloxone (0.2 mg, 5 ml) in both areas, 2 h and 25 min after the burn injury, and measurements were repeated 30 and 90 min after the naloxone injections. The order and duration of the different measurements has been described previously.8 All testing was performed by two experimenters in a quiet room at a temperature of 2326°C. All subjects were tested by the same experimenter at the same time of the day on the three study days. The subjects were resting in a relaxed position and instructed to keep their eyes closed during all measurements.
All injections were given using a needle, 40 mm long with an external diameter of 0.4 mm. Morphine (SAD, Copenhagen, Denmark) was used at the concentration of 0.4 mg ml1 (pH 4.1), naloxone (Du Pont Pharma, Meda AS, Copenhagen, Denmark) at the concentration of 0.04 mg ml1 (pH 4.3). In all injections the volume was 5 ml. The injections were given from opposite corners of the 50x25-mm drawn rectangles, 2.5 ml from each corner, injected in a fan-like manner, in order to distribute the volume evenly in the rectangle. The injections were made in the most superficial part of the s.c. tissue. A person not involved in the testing administered the injections and prepared the morphine and placebo. Subjects were asked to evaluate the pain associated with each injection, using a visual analogue scale (VAS 0100).
Burns were produced on the medial part of the non-dominant distal leg with a 50x25-mm thermode (Thermotest, Somedic A/B, Stockholm, Sweden).8 The burns were induced in the same area on the three study days. The thermode (47 C) was applied to the skin for 7 min under standardized pressure (6.9 kPa). This caused redness without blistering.
The pain was rated with a VAS at the start and every minute during the burn injury. The scale was anchored by the descriptors, no pain (0) and worst pain imaginable (100). Verbal descriptors were added at 2 mm (weak pain), 8 mm (mild pain), 18 mm (moderate pain), 39 mm (intense pain) and 74 mm (very intense pain) to make the scale more comprehensible.8 The subjects rated the pain with a slider on a plastic device that was pulled along a 10 cm line between the end points. The numeric value of the rating was read on the back of the device by the experimenter.
The mechanical pain threshold within the injury area was determined by pinprick with nine progressively rigid von Frey hairs (Senselab Aesthesiometer, Somedic A/B, Stockholm, Sweden) numbered onenine (force of hairs: hair 1=6 mN, 2=9 mN, 3=17 mN, 4=27 mN, 5=46 mN, 6=77 mN, 7=118 mN, 8=228 mN, 9=314 mN). Suprathreshold pain responses to mechanical stimuli were assessed using the VAS following stimuli with a von Frey hair (314 mN). The area of mechanical hyperalgesia to punctate stimuli that developed around the burn area was assessed using a rigid von Frey hair (428 mN).8
Thermal thresholds were determined using a computerized contact thermode (Somedic A/B, Stockholm, Sweden).8 All thresholds were assessed using a 25x50-mm thermode, and determined as the average of three trials performed at 9-s intervals, from a baseline temperature of 32°C, and with a rate of change of 1°C s1. The upper cut-off limit was 52°C. The pain response (VAS 0100) to heat was evaluated with a heat stimulus (15x25-mm thermode) of 45°C lasting 5 s, preceded by a temperature rise from 40 to 45°C over 5 s.
The subjects completed a questionnaire at the end of each day concerning the presence (yes/no responses) of euphoria, nausea, bluntness, headache, dizziness, confusion, feeling drunk, itching and restlessness. When side effects were present, these were rated as weak, moderate or marked.
Normality of raw data and differences between groups were evaluated using the ShapiroWilks W-test.9 Data are presented as means or medians dependent on the distribution (normal or skewed), and comparisons were made using the Students t-test for a paired design, when the differences showed normal distributions,11 whereas differences showing non-normal distributions were analysed using the Wilcoxon matched-pairs test. If baseline assessments differed significantly between groups, changes from baseline assessments were compared. Comparisons of more than two groups, such as changes over time, were performed using parametric analysis of variance (ANOVA) for repeated measurements (one-way), or the Friedman ANOVA, as appropriate. The smallest differences between placebo and local morphine detectable with a power of 80% and a type I error of 5% were calculated for all measurements at all time points. P-values below 0.05 were considered statistically significant.
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Results |
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All side effects (euphoria, nausea, bluntness, headache, dizziness, confusion, feeling of being drunk, itching and restlessness) were reported except headache. However, most side effects were reported by only onethree subjects out of 18 and were rated as weak. One exception was itching which was reported by seven subjects of which two rated the intensity of itching as moderate and one rated it as marked. When saline was injected only one subject reported dizziness. No other side effects related to saline were reported.
The smallest differences between placebo and local morphine detectable at single time points are presented in Table 1. The values are the means of seven observation times (baseline, post-drug, 0, 1 and 2 h after heat injury, and 30 and 90 min after naloxone injection).
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Discussion |
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Our results may have been influenced by the pH of the morphine solution. The pH of morphine was 4.1, naloxone 4.3 and saline 5.6. Injection of morphine induced a significantly higher pain score compared with saline injections (P<0.02), which may be explained by the lower pH. The acidic morphine solution may be local irritating and increased sensitization of nociceptors in the burn area, thereby counteracting the possible antinociceptive effect of morphine. However, the morphine solution used was the one generally applied for clinical use. Further, we cannot exclude a minor analgesic effect of morphine, as we were able to detect an 40% difference between the overall mean of measurements between treatments and with a power of 80% for most measurements.
Our results are not contradictory to the clinical studies wherein extra-articular administration of opioid had no relevant effect,6 or the studies of intra-articular administration which have shown variable effects.5 However, our results do not exclude a late (e.g. >8 h) analgesic effect of peripheral morphine.10 In other experimental human pain models (capsaicin,11 thermal stimulation,12 propofol injection pain13), the peripheral analgesic effects of opioids have also been debatable, as only the capsaicin model showed a peripheral analgesic effect.11
In conclusion, our results cannot verify acute antinociceptive effects of peripheral morphine in this model of acute inflammatory pain.
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Acknowledgements |
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Footnotes |
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References |
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