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British Journal of Anaesthesia 84 (1): 95–6 (2000) I.v. regional diamorphine for analgesia after foot surgery M. G. Serpell1*, E. Anderson2, D. Wilson2 and N. Dawson2 1Department of Anaesthesia and 2Department of Orthopaedic Surgery, Western Infirmary, Glasgow G11 6NT, UK *Corresponding author Opioids administered to peripheral tissues can have significant analgesic effects in doses which would not be effective centrally. We have assessed the effects of regional diamorphine 2.5 mg i.v. in 14 patients undergoing surgical correction of bilateral arthritic foot deformities in a prospective, randomized, double-blind study. Patients acted as their own controls as only one foot received the active drug. Visual analogue scale (VAS) pain scores and wound tenderness were measured over 72 h. Diamorphine did not improve median VAS area under the curve pain scores during the first 6 h after surgery (33 (95% confidence intervals (CI) 25–46) vs 24 (17–35)). It also did not effect wound hypersensitivity when tested at 72 h after surgery (95 (47–125) vs 90 (50–125) g). There were no significant adverse effects. Br J Anaesth 2000; 84: 95–6 Keywords: analgesics opioid, diamorphine; anaesthetic techniques, regional, i.v.; surgery, orthopaedic Accepted for publication: July 16, 1999 When opioids are applied peripherally to tissues, they can have significant analgesic effects in doses which would not be effective centrally.1 This action may be explained by activation of opioid receptors at peripheral sites located in inflamed tissue. Our previous study failed to show any improvement in analgesia or hyperalgesia after peripheral administration of morphine for bilateral foot surgery.2 We postulated that this may have been because of poor access of morphine to the receptors in the tissues of the foot. Therefore, we have repeated this prospective, randomized, double-blind, placebo-controlled study with a more lipophilic opioid and a larger volume of injectate. Methods and results After obtaining approval from the Hospital Ethics Committee and written informed consent, we studied 14 patients undergoing elective surgery for correction of bilateral arthritic deformities of the feet. Patients were ASA I–II, aged 18–80 yr and weighed 45–90 kg. All anti-inflamatory medication was stopped 72 h before surgery; paracetamol was taken if required for analgesia. Anaesthesia was induced with propofol and maintained with 1–2% enflurane and 66% nitrous oxide in oxygen, with the patient breathing spontaneously via a laryngeal mask. Each foot was cannulated with a 22-gauge i.v. Venflon and exsanguinated using an Esmarch bandage. Tourniquets were applied just above the ankle and inflated to 100 mm Hg above systolic arterial pressure. Patients received 15 ml of 0.9% saline containing diamorphine 2.5 mg into the cannula of one foot and 15 ml of saline into the other over 60 s. This procedure was randomized (Kwickstat 3.01 TexaSoft) and double-blinded. The cannulae were removed and surgery commenced 10 min later on each foot by two operators simultaneously using the same technique. Morphine was administered systemically after commencement of surgery, as required, by i.v. injection. After surgery, the tourniquets were deflated and analgesia was provided in the recovery room by bolus doses of morphine 1–2 mg i.v., as requested, until satisfactory relief was obtained. After 2 h, patients returned to the ward and analgesia was provided by paracetamol 1 g, ibuprofen 400 mg or morphine 7.5–10 mg i.m. Pain scores were measured separately for each foot at 1, 2, 4, 6, 24, 48 and 72 h using a 100-mm visual analogue scores (VAS). At 72 h, sensitivity thresholds were assessed by applying wires to the dominant forearm and to both feet on an area 2 cm lateral to the proximal end of the wound. The six calibrated wires of increasing gauge allowed application of a range of forces to the skin (5, 10, 40, 50, 135 and 230 g). The force values were recorded when touch was first detected and when the stimulus first became uncomfortable, and are expressed as relative thresholds (forearm minus foot) so that each patient acted as their own control. Power analysis indicated that 12 patients would be needed to detect a 50% difference in pain levels with a power of 80% and significance of 0.05 (from area under the curve (AUC) data–SD of 42%).3 4 Data were analysed using Mintab 10.5 for Windows 95. © The Board of Management and Trustees of the British Journal of Anaesthesia 2000 Serpell et al. feet. In support of this, during the pilot phase of the study, when diamorphine 5 mg was given, one patient required naloxone to reverse respiratory depression which occurred immediately after deflation of the tourniquet. These systemic effects did not occur with the dose of 2.5 mg. Similarly, the dose of morphine given systemically and paracetamol and ibuprofen analgesic consumption would have had a central analgesic effect which would be equal for both feet and may have attenuated any potential differences. However, it would have been unethical to withhold these drugs as optimal analgesia must remain a priority for patients after surgery. Analgesia has been reported with morphine 1 mg administered arthroscopically1 but the area is relatively avascular and so the drug is likely to remain localized when the tourniquet is deflated. Consequently, application of opioids into the knee joint seems to be beneficial while other peripheral routes of administration do not.6 The main analgesic effect would be expected to occur in the early postoperative period and we doubt the clinical significance of the 24-h VAS recording. The lower pain thresholds in the feet are indicative of secondary hyperalgesia which can result from both peripheral and central sensitization. The fact that diamorphine was not effective despite being administered peripherally and before surgery was commenced, supports a larger role for central sensitization in this phenomenon. We used a sensitive model for this investigation.3 Patients were their own controls and therefore differences in the comprehension and reporting of pain, and the pharmacodynamic and kinetic profile of any drug, would not be responsible for differences seen in either foot. In summary, i.v. regional diamorphine 2.5 mg had no beneficial effect on pain scores or wound hypersensitivity during the first 72 h after surgical correction of arthritic foot deformities. Fig 1 Median, interquartile and full range of visual analogue scale (VAS) pain scores for the diamorphine and control groups at various individual postoperative times. *P⫽0.05 (Wilcoxon sign rank test). One patient was withdrawn from the study because the injectate leaked from the Venflon. There were no differences between groups in operator seniority or tourniquet time. Relative median pain thresholds were 95 (95% confidence intervals (CI) 47–125) g and 90 (50–125) g for the diamorphine and control groups, respectively. Mean doses of systemic morphine given during and after operation were 6.5 (SD 3) and 9.3 (7.9) mg, respectively. VAS values at individual times are presented in Figure 1. Median (interquartile) scores tended to be higher in the diamorphine group but this only just reached significance at 24 h (42 (18–59) vs 21 (9–36), respectively; P⫽0.05 Wilcoxon sign rank test). AUC pain scores for the first 6 h were not significantly different (median 33 (95% CI 25– 46) for diamorphine and 24 (17–35) for controls). The only adverse effect noted was flushing of the foot which occurred in one patient in each group. Comment Diamorphine did not appear to have an effect on postoperative pain or secondary hyperalgesia. Diamorphine may have failed to gain access to the peripheral receptors. Some leakage of drug into the general circulation can occur through both intraosseous and other veins, but we took steps to prevent this by ensuring that the tourniquet completely encircled the lower calf, that exsanguination was performed and the injection was given slowly. We did not observe any seepage of the injectate from the wound during surgery. Diamorphine is lipophilic and would be expected to have high tissue uptake and gain access to the peripheral receptors in the nerve and joint tissue.5 However, when the tourniquet is deflated, the drug may be washed out rapidly and any peripheral effect of the opioid could then be obscured by the central effects which would produce analgesia of both References 1 Stein C, Comisel K, Haimerl E, et al. Analgesic effect of intraarticular morphine after arthroscopic knee surgery. N Engl J Med 1991; 325: 1123–6 2 Serpell MG, Marshall S, Anderson E, Cullen T, Abernethy J. Intravenous regional morphine for analgesia after foot surgery. Analgesia 1995; 1: 719–22 3 McQuay H, Weir L, Porter B, et al. A model for comparison of local anesthetics in man. Anesth Analg 1982; 61: 418–22 4 du V Florey C. Sample size for beginners. BMJ 1993; 306: 1181–4 5 Sawynok J. The therapeutic use of heroin: a review of the pharmacological literature. Can J Physiol Pharmacol 1986; 64: 1–6 6 McQuay HJ, Moore RA. Pain relief with intra-articular morphine after knee surgery and analgesic efficacy of peripheral opioids. In: McQuay HJ, Moore RA, eds. An Evidence-Based Resource for Pain Relief. Oxford: Oxford University Press, 1988; 147–63 96