TREATMENT OF POSTOPERATIVE PAIN WITH DICLOFENAC IN UVULOPALATOPHARYNGOPLASTY

Transcription

1 British Journal of Anaesthesia 199; 68: 76-8 REAMEN F PSPERAIVE PAIN WIH DICLFENAC IN UVULPALAPHARYNGPLASY H. EJNELL, R. BJRKMAN, L. WAHLANDER AND J. HEDNER SUMMARY Dilofena sodium suppositories 15- mg day 1 were ompared with plaebo in a double-blind study during the first 3 days after uvulopalatopharyngoplasty in 4 patients with habitual snoring or obstrutive sleep apnoea syndrome. Coumption of resue analgesis (paraetamol suppositories) and pain assessed by a visual analogue sale were signifiantly less in the dilofena group. Bleeding time (modified Ivy's test) and reported side effets did not differ between the two groups. KEY WRDS Analgesis non-steroida/, dilofena. Pain. postoperative Surgery uvulopalatopharyngoplasty Non-steroidal anti-inflammatory drugs (NSAID) are presribed ommonly in mild to moderate pain. he NSAID, dilofena, has been shown to have an analgesi effet in several situatio, suh as postoperative pain after toilletomy [1-3], tooth extration [4] and hip joint surgery [5]. he mehanisms of ation are thought to involve inhibition of prostaglandin synthesis, but other possible mehanisms, suh as an interation with entral opioid systems, have been suggested [7, 8]. Postoperative analgesi treatment of patients with habitual snoring or obstrutive sleep apnoea syndrome (SAS), or both, after uvulopalatopharyngoplasty (UPPP) poses speifi problems. SAS patients have repetitive noturnal respiratory pauses, leading sometimes to severe hypoxaemia aompanied by hyperapnia and sleep fragmentation. Daytime ompliatio inlude hypersomnolene, systemi hyperteion and, in severe ases, pulmonary hyperteion and ardia failure [9]. Moreover, SAS patients may present with a pathologially low ventilatory respoe to hypoxia and hyperapnia [1], possibly as a result of hroni noturnal exposure to alveolar hypoventilation. UPPP is a surgial tehnique to treat habitual snorers or SAS; it inludes onomitant toilletomy and results in peroperative bleeding and postoperative pain [11, 1]. pioid analgesis may be less well tolerated beause of respiratory depressant effets in SAS patients [1]. he aim of this study was to evaluate the use of a non-opioid analgesi drug, dilofena, for treating pain after UPPP. PAIENS AND MEHDS he study omprised a double-blind, plaeboontrolled investigation omparing dilofena sodium suppository (Voltaren) with a plaebo. Paraetamol suppository 5 mg (Panodil) was allowed ad libitum up to a maximum dose of 4 g/4 h as resue mediation during the study period. Patients were studied for 3 days after operation and alloated randomly to eah group using a list of random numbers. After obtaining informed oent, we studied 4 oeutive patients of either sex, aged -75 yr, suffering from severe habitual snoring or previously diagnosed SAS. All patients had undergone an overnight study in the sleep laboratory. Mean desaturation index (number of oxygen desaturatio ^ 4 % per hour of estimated sleep time) was 9.6 (SD 1.7). he study was approved by the Committee of Ethis of the Medial Faulty, University of Goteborg and by the National Board of Health and Welfare. Patients with asthma or known or suspeted seitivity to aetylsaliyli aid or other NSAID, or those reeiving other forms of treatment whih ould affet pain assessment, were exluded from the trial. Patients with signifiant oexisting illness, inluding gastri uler, ardia, hepati or renal disease, a blood or oagulation disorder, and those reeiving treatment with antioagulants or lithium were exluded. ther exlusio inluded a history of alohol or drug abuse or sig of alohol-indued organ damage, mental dysfuntion or other fators limiting the ability to o-operate. Patients were allowed to withdraw from the study at any time for any reason. ne hour before operation, the patient reeived one dilofena suppository (5 mg) or orresponding plaebo, together with morphine.15 mg kg" 1 i.m. and hyosine.6 mg kg" 1 i.m. Anaesthesia was indued with thiopentone 3 mg kg" 1 i.v., followed by panuronium.5-.8 mg/kg body weight (or suxamethonium.5 mg kg" 1 followed by panuronium, when needed). he lungs were ventilated to normoapnia with 5-7% nitrous oxide in oxygen and anaesthesia was supplemented with fentanyl 3 ng kg" 1, i.v. and, in appropriate patients, 1-3 % isoflurane. Per- and post- Pi. EJNELX, M.D., PH.D. CDepartmem of torhinolaryngology); R. B]6RKMAN, B.SC, R.N., L. WAHLANDER, M.SC., J. HEDNER, M.D., PH.D. (Department of Clinial Pharmaology); Sahlgren's University Hospital, S GSteborg, Sweden. Aepted for Publiation: July, 1991.

2 PSPERAIVE PAIN AND DICLFENAC 77 ABLE I. Patient harateristis and limal data (frequeny or mean (SD) [range]) Sex (M/F) Age (yr) Body weight (kg) Duration of operation (min) Estimated peroperative bleeding (ml) Dilofena (n = 19) 16/3 47. [-6] 86.3 (15.7) [63-115] 33.3 (6.) [-45] 14.3 (7.) [5-5] Plaebo /1 4.4 [5-58] 84. (8.) [7-97] 33.8 (6.7) [5-45] 14.9 (87.) [5-4] f o Q. (A C 3 -, - 1- _ Day FIG. 1. Mean (SEM) umulative oumption of paraetamol in patients reeiving dilofena ( ; n = 19) or plaebo (; n = 1) on postoperative days, 1 and. *P <.5; **P <.1. operative bleeding was assessed from the volume of blood in the sution devie. Blood loss towards the oesophagus was avoided by tamponade. Bleeding times were assessed with disposable Simplates, using a vertial inision on the volar aspet of the forearm [13] by the same person on all oasio, before operation, 1 h after operation and h after administration of suppository on day 3. A biopsy from reseted uvular tissue was obtained from all patients and frozen at C for subsequent measurement of dilofena onentration [14]. At the same time, a plasma sample was obtained via an indwelling i.v. annula during the operation (1.5.5 h after administration of suppository) for the measurement of serum dilofena onentration. he sample was left at room temperature and, after 1 h, the serum fration was removed and stored frozen until analysis. All patients reeived phenoxymethyl peniillin (1 g twie daily, orally) during the first 7 days after operation. During the postoperative period, dilofena or orresponding plaebo was given as suppositories three times daily (1 mg, 5 mg and 5 mg) at 6:, 1: and :. Pain was assessed using a Visual Analogue Sale (VAS) [15], with a range of -1 indiating "no pain" and "worst possible pain", respetively. n the day of operation, assessments were made immediately after operation and at 14:, 15:, : and 1:. Assessments on day 1 and were made at 6:, 8:, 1:, 14:, : and 1: and on the third day after operation at 6:. After the study was terminated on day 3, all patients were presribed dilofena suppositories 5 mg three times daily for 7 days. Subsequently, the following question was asked: "Whih mediation did you prefer in terms of analgesi effetiveness, the one given in hospital or the one given after the period A I I I I A I I H : Day Day 1 Day Day 3 FIG.. Mean (SEM) pain sores by VAS before and after administration of suppository ( = dilofena 5 mg or plaebo; I = dilofena 1 mg or plaebo) throughout the study period. Numbers on horizontal axis represent time of day at whih VAS evaluatio were made. = Dilofena group; A = plaebo group. *P <.5; **P <.1.

3 78 BRIISH JURNAL F ANAESHESIA ABLE II. Change in VAS {mm) rating after eah suppository of dilofena or plaebo. Signifianes shown for omparison between groups ompared Day 15:-14: 1:-: Day 1 8:-6: 14:-1: 1:-: Day 8:-6: 14:-1: 1:-: Mean 6 n 4- - X. Dose (mg) Change in VAS (mm) Dilofena Plaebo P Dosing interval (h) FIG 3. Pain sores by VAS before administration of suppository after 6-, 8- or 1-h dosing interval (mea, SEM of aumulated values from the study in the dilofena (Q) and plaebo () groups). *P <.5. in hospital?" he patients were not informed if they had reeived ative or plaebo suppositories until this question had been awered. Adverse drug reatio were sought by ative questioning. Data were analysed for between groups omparison of inteity of pain and number of additional doses of paraetamol using the Wiloxon rank-sum test. Within group ompariso were tested with Wiloxon signed-rank test. P ^.5 was oidered signifiant. RESULS We studied 4 patients of mean age 44.5 yr; 19 reeived dilofena and 1 plaebo. here were no signifiant differenes between the groups in sex, age, weight, duration of operation or peroperative blood loss. Mean apnoea index (SEM) based on estimated sleep time was 9.6 (1.7) (range -^15) (table I). here were no postoperative bleeding or infetive ompliatio. he need for resue analgesis during the three postoperative days differed between the groups; this differene was signifiant (P <.5) on the first two days after operation, with approximately 5% less oumption in the dilofena group. he differene was less pronouned on postoperative day (P <.5) (fig. 1). he average umulative oumption of paraetamol during the three days after operation was 945 mg in the dilofena group and 61 mg in the plaebo group (P <.5). After iertion of the first suppository, there was an average inrease in VAS pain sore of mm in the dilofena group, but a derease of 7 mm in die plaebo group (fig., table II). hereafter, there was always a greater derease in pain sore in the ative than in the plaebo group (P <.1). he pain sore was dependent also on the time elapsed after the last intake of drug in the dilofena group, with a signifiantly greater sore (P <.5) before the morning suppository (1-h mediation interval) ompared with die other dosing times (6- and 8-h mediation intervals, respetively) (fig. 3). Ali patients reeived ative mediation in a singleblind manner after disharge from hospital (day 3 and onwards). Questioning about effiay of the suppositories after disharge ompared widi those given in hospital revealed a tendeny towards a greater preferene for mediation in the follow-up period in the group who reeived plaebo in hospital. he bleeding time was not different between the groups before or 1 h after operation. n day 3, mean bleeding time in the plaebo group (46 s) was signifiantly (P <.5) less than the preoperative value (table III). Mean plasma onentration of dilofena 1- h after suppository administration was 71 (SEM 41) ng ml" 1 ; tissue (uvular) onentration was 13 (3) ng ml" 1. here was a signifiant positive orrelation (P =.6) between plasma and tissue onentratio (fig. 4), but no orrelation between pain sores and plasma or tissue dilofena onentratio (data not shown). In the plaebo group, nine patients experiened a total of 13 symptoms and in the dilofena group 11 patients had 14 symptoms. he frequeny and nature of diese side effets did not differ signifiantly between die two groups (table IV). DISCUSSIN Surgial treatment of snoring and SAS is now ommon [1]. UPPP is assoiated with severe pain in the first week after operation and effiient analgesia is required. Although diret dysfuntion or downregulation of hemoseory mehanisms has not been proven in SAS patients, hyperseitivity to the respiratory depressant effets of opioids has been proposed [1]. Alternative analgesi agents, for example NSAID, without respiratory depressant effets are therefore benefiial in this group of patients. he NSAID, dilofena, was found to provide analgesia in six of seven assessments in the present study. Surprisingly, pain sores 1- h after administration of ative drug were signifiantly different from those after plaebo at the end of day 1 and on day. here may be several explanatio for this observation: (a) he relative hange in VAS sore after

4 PSPERAIVE PAIN AND DICLFENAC 79 ABLE III. Pre- and postoperative bleeding time {Ivy's test) (mean (SEM) before and after operation). * P <.5 ompared with before operation CD one o i Dilofena (n = 19) Plaebo (n = 1) E ,.---"""" *' Before op. 39(19) 31() After operation < lh 338(17) 9(15) Day 3 36(1) 75 (14)* Plasma onn (ng ml" 1 ) FIG. 4. Correlation between plasma and tissue (uvular) onentratio of dilofena in 16 patients reeiving ative mediation. Regression line (r =.65; P =.6) and 95 % predition interval. ABLE IV. Adverse reatio and symptoms Dizziness Nausea Headahe Abdominal pain otal number of symptoms otal number of patients with adverse reatio Plaebo (n = 1) * 4 Dilofena (n = 19) dilofena intake was similar throughout the study, indiating signifiant pain relief. Moreover, the lower oumption of resue analgesis in the dilofena group in the latter part of the study, and the greater average VAS soring, may be explained by subjetive adaptation to a lower degree of pain. In other words, the patient had experiened pain relief during ative mediation and therefore sored higher when pain returned. (b) Paraetamol oumption was still signifiantly greater in the plaebo group during the latter part of the study, whih ould result in additional pain relief in the plaebo group in ontrast with the dilofena group. However, the differene in paraetamol oumption between the two groups was even greater on the first day after operation, making this explanation less probable. () he tendeny towards an inrease in pain sore in the dilofena group may follow the natural ourse of pain development in the postoperative period, with more pronouned pain on days and 3. However, there was no similar trend in the plaebo group. In general, it may be argued that onomitant paraetamol mediation may ompliate the interpretation of pain sores in a plaebo-ontrolled study. However, this design was neessary for ethial reaso. Moreover, preferene for the ative mediation after disharge from hospital in the plaebo group indiates that, in spite of a lower pain sore before drug administration in the plaebo group on days and 3, additional pain relief was ahieved with dilofena. he plasma half-life of dilofena has been estimated to be approximately 9 min [16]. hus the dose interval used in the present study (6-1 h) orresponds to approximately four to seven halflives of the drug. herefore, almost omplete washout was allowed between eah administration of dilofena and the pain sore before drug intake may be taken as an index of periods with very low plasma onentratio of ative drug. Interestingly, the subjetively sored pain was greater after the longer dosing interval in the dilofena group. However, this seemingly high individual orrelation between plasma onentration and analgesi effet is in ontrast with large interindividual variation in plasma and tissue onentratio of dilofena after administration of suppository. A high interindividual variation, reported elsewhere [17, 18], may aount for the poor orrelation between plasma drug onentratio and the therapeuti effets of the NSAID. However, the signifiant orrelation between plasma and tissue onentratio of dilofena in the present study indiates a high interindividual otany in distribution to the uvular tissue ompartment. Bleeding ompliatio during and after operation are not unommon in assoiation with UPPP [1]. Several NSAID, for example aspirin [19-1], ibuprofen [], naproxen and indomethain [19, 3], have been reported to inrease bleeding time and may therefore be deleterious in this type of operation. he effet on bleeding time may be related to a dual ation on the formation of thromboxane A in the platelet and prostaylin in vasular endothelial ells [4]. In this study, we found no effet of dilofena on bleeding time. We have no explanation for the signifiant derease in bleeding time in the plaebo group. ACKNWLEDGEMENS he study was supported by grants from the Swedish Medial Researh Foundation, grants 464 and 86 and by grants from he CIBA-Geigy Researh Foundation. he dilofena measurements were performed by Dr Lars Abrahamsson, Department of Clinial Chemistry, Central Hospital, Uddevalla. REFERENCES 1. Bone ME, Fell D. A omparison of retal dilofena with intramusular papaveretum or plaebo for pain relief following toilletomy. Anaesthesia 1988; 43: Dommerby H, Rasmussen R. Dilofena (Voltaren). Painrelieving effet after toilletomy. Ada tolaryngologia 1984; 98:

5 8 BRIISH JURNAL F ANAESHESIA 3. Watters CH, Patterson CC, Mathws HM, Campbell W. Dilofena sodium for post-toilletomy pain in hildren. Anaesthesia 1988; 43: Henrikson PA, hilander H, Wahlander LA. Voltaren as an analgesi after surgial removal of a lower wisdom tooth. International Journal of ral Surgery 1985; 14: Lindgren U, Djupsjd H. Dilofena for pain after hip surgery. Ata rthopaedia Sandinavia 1985; 56: Menasse R, Hedwall PR, Kraetz J, Periin C, Riesterer L, Sallmon A, Ziel R, Jaqus R. Pharmaologial properties of dilofena sodium and its metabolites. Sandinavian Journal of Rheumatology (Suppl.) 1978; : Bjorkman R, Hedner J, Hedner, Henning M. Central, naloxone-reversible antinoieption by dilofena in the writhing test in rats. Naunyn-Shmiedeberg's Arkwes of Pharmaology 199; 34: Vesovi P, Passeri M, Gerra G, Grossi E. NaJoxone inhibits the early phase of dilofena analgesia in man. Pain Clini 1987; 1: Guilleminault C. bstrutive sleep apnoea. Medial Clinis of North Ameria 1985; 69: Berthon-Jones M, Issa FG, Sullivan CE. Aute upward shift in ventilatory respoe to C, after reversal of obstrutive sleep apnoea by pneumati splinting. Australian and New Zealand Journal of Mediine 198; 1: Fujita S, Conway W, Zorik F, Roth. Surgial orretion of anatomi abnormalities in obstrutive sleep apnoea syndrome : Uvulopalatopharyngoplasty. tolaryngology Head and Nek Surgery 1981; 89: Colman MF. Risk management in UPPP. Limitatio, pitfalls and risk management in palatopharyngoplasty. In: Fairbanks NF, Fujita S, Ikematsu, Simmo FB, eds. Snoring and bstrutive Sleep Apnoea. New York: Raven Press, 1987; Babson SR, Babson Al*. Development and evaluation of a disposable devie for performing simultaneous dupliate bleeding time determinatio. Amerian Journal of Clinial Pathology 1978; 7: 46-^ Godbillon J, Gauron S, Metayer JP. High-performane liquid hromatographi determination of dilofena and its monohydroxylated metabolites in biologialfluids.chromatography 1985; 338: Huskisson EC. Measurement of pain. Lanet 1974; : John VA. he pharmaokinetis and metabolism of dilofena sodium (Voltarol) in animals and man. Rheumatology and Rehabilitation (Suppl.) 1979; : Wallis WJ, Simkin PA. Antirheumati drug onentratio in human synovia! fluid and synovial tissue. bservatio on xtravasular pharmaokintis. Clinial Pharmaokinetis 1983;8: Wollheim FA, Stenberg P, Nilsson B, Mllbin G. Clinial and methodologial studies on intramusular ketoprofen in postoperative rheumati pain. European Journal of Climal Pharmaology 1981; : 43-^ Lind SE. Prolonged bleeding time. Amerian Journal of Mediine 1984; 77: Mielke CH, Kaneshiro MM, Maher IA, Weiner JM, Rapaport SI. he standardized normal ivy bleeding time and its prolongation by aspirin. Blood 1969; 34: Stage J, Jeen JH, Bonding P. Post-toilletomy haemorrhage and analgesis. A omparative study of aetylsaliyli aid and paraetamol. Clinial tolaryngology 1988; 13: Mlntyre BA, Philip RB, Inwood MJ. Effet of ibuprofen on platelet funtion in normal subjets and hemophilia patients. Climal Pharmaology and herapeutis 1978; 4: de Gaetano G, Doneti MB, Garartini S. Drugs affeting platelet funtion tests. hrombosis, Diathermy and Haemorrhage 1975; 34: Seymour RA, Williams FM, Ward A, Rawli MD. Aspirin metabolism and effiay in postoperative dental pain. British Journal of Clinial Pharmaology 1984; 17: