K. Budd. The Mornington Clinic. Bradford BD16 1TZ, UK. R. Langford. Anaesthetics ... 21 Russell W. Caudal tramadol for postoperative analgesia in paediatric ...
British Journal of Anaesthesia 82 (4): 493–5 (1999)
Editorial II Tramadol revisited ‘To be great is to be misunderstood’ Ralph Waldo Emerson, 1803–1882 ‘Tis hard to say, if greater want of skill appear in writing or in judging ill’ Alexander Pope, 1688–1744 Since its launch in the UK in 1994, tramadol hydrochloride (Zydol-Searle, Zamadol-Asta, Tramake-Galen) has received a mixed reception in the medical press.1–3 However, more evidence has now accumulated which clarifies both the way in which this interesting compound produces analgesia and its clinical applications. While initially considered to be a weak opioid, the adverse effect profile of tramadol appeared to be atypical of a pure opioid agonist and this led to the discovery of its multimodal mechanisms of action. More complete data have been produced, in both animals and humans, of the effect of tramadol on the release of monaminergic neurotransmitters in the central nervous system and its agonist action at peripheral and central opioid receptors. It is now accepted that in addition to a mu-opioid agonist effect, tramadol enhances the function of the spinal descending inhibitory pathway by inhibition of reuptake of both 5-hydroxytryptamine (5-HT) and norepinephrine, together with presynaptic stimulation of 5-HT release.4 5 Desmoules and co-workers have confirmed in humans that the analgesic effect of tramadol is apportioned between the opioid and monoaminergic components.6 The analgesic effect produced by the racemic mixture that is commercial tramadol is a synergistic interaction of the two enantiomers and their differing modes of action.5 Tramadol is metabolized by the cytochrome P450 enzyme system in the liver to form 11 metabolites, of which M1 (O-desmethyltramadol) predominates and possesses analgesic properties. The O-demethylation to M1 depends on the enzyme sparteine oxygenase, CYP2D6 (P4502D6). The role of M1 in producing analgesia has been evaluated by comparing analgesic efficacy in human volunteers known to be CYP2D6 deficient (as are 8% of Caucasians) with normal subjects who are extensive metabolizers. Tramadol showed measurable but reduced analgesia in the poor metabolizers, suggesting that the M1 metabolite may contribute to analgesic efficacy. This contrasts with complete absence of analgesia in the same group of poor metabolizers after codeine administration.7 The published intraoperative experience with tramadol has been very limited, no doubt because of concerns after the report in 1986 of increased recall of intraoperative events with the use of tramadol administered in the peroperative
period.8 However, this study was based on the now outmoded oxygen–nitrous oxide–opioid anaesthetic technique and more recent studies using sophisticated awareness/ recall and electroencephalographic depth of anaesthesia techniques have shown that tramadol has no clinically significant effect on contemporary, volatile, isoflurane-based anaesthesia.9 10 It would appear, therefore, that in the presence of adequate depth of anaesthesia, as practised currently, intraoperative administration of tramadol does not result in accidental awareness and this is reflected in changes to the UK tramadol data sheet. The role of tramadol as an intraoperative analgesic has been evaluated in both in-patient and day-case studies, showing no instances of intraoperative cardiorespiratory adverse sequelae or accidental awareness. More rapid and complete recovery from general anaesthesia with improved postoperative adverse effect profiles have been reported compared with those studies where tramadol was administered as a loading dose when the patient had regained consciousness. For acute pain of moderate to severe intensity, increasing numbers of studies are showing that tramadol 3 mg kg–1 would appear to be the most suitable initial dose.11–16 A marked reduction in postoperative shivering has also been noted in patients receiving tramadol.14 16 In addition, the significant value of its minimal respiratory depressant effect continues to be emphasized.17 18 The benefit of tramadol in day-case surgery was exemplified in a study of 228 patients undergoing surgery through a groin incision. Tramadol administered during and after operation was compared with the combination of intraoperative fentanyl and postoperative co-codamol.12 In these relatively painful procedures, tramadol provided superior analgesia on the day of discharge when pain would likely be maximal. The adverse effect profile in each group was similar but tramadol was responsible for fewer unplanned in-patient admissions than the fentanyl–co-codamol mixture, although this finding was not statistically significant. In moderately painful surgery, tramadol has been shown to be ‘an effective analgesic in postoperative pain’.3 The 18 studies quoted by McQuay and Moore showed that all doses of tramadol were satisfactorily superior to placebo in both post-surgical and dental pain, and there was a significant dose–response effect. Headache, nausea, vomiting, dizziness and somnolence were the most commonly reported adverse events, although they were predominantly of mild intensity. Their occurrence after the treatment of dental surgery pain was significantly higher than that after other types of surgery, possibly related to the ‘acute’ dosing in awake patients and rapid mobilization.3
© British Journal of Anaesthesia
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Paediatric analgesia is seen frequently as a challenge and the use of tramadol has been shown to be beneficial when administered by standard or by less well used routes.19–21 The use of tramadol in children, which is not yet licensed in the UK for those less than 12 yr of age, shows great promise and its potential may be at present underestimated. There is considerable experience with the agent internationally in children greater than 1 yr, and further work is needed to evaluate its true potential. In the treatment of chronic pain, contemporary studies have shown that effective analgesia can be achieved with tramadol in a wide spectrum of painful pathologies, particularly in osteoarthritis, fibromyalgia and diabetic neuropathy, used orally and intra-articularly.22–25 Further benefit has been gained by the introduction of an oral, sustained release formulation of tramadol. Not only is patient compliance improved but the incidence of adverse effects compared with instant release preparations is reduced significantly.26 There would also appear to be a place for tramadol in the field of palliative medicine to the extent that it has been included in the second edition of the WHO recommendations for cancer pain treatment.26–28 The reduced constipating effect of tramadol compared with other opioids is a useful asset in this area of practice.29 While variation in the occurrence of adverse effects from tramadol is wide, patterns of causation, prevention and treatment are emerging. Very early ambulation after i.v., post-surgical tramadol is likely to produce nausea and dizziness while administration of the same dose, well before emergence from anaesthesia, allows the patient to awaken pain free and with a low occurrence of adverse effects.30 As a standard dose, tramadol 3.0 mg kg–1, given at induction of anaesthesia, does not obtund the pressor response31 and onset time is relatively slow.4 30 The optimum time for the initial tramadol loading dose may be immediately after commencement of surgery following the use of a shortacting opioid to cover induction of anaesthesia and surgical incision. To achieve a minimal incidence of adverse effects with chronic oral administration, therapy should be commenced at the lowest dose and increased gradually, titrating patient response against dose.32 33 Commencing treatment with tramadol in this manner appears to result in a low incidence of adverse effects and, should they occur, generate the onset of tolerance to them in the shortest time. It is suggested that the prevention or treatment of the common, opioidlike adverse events can be with phenothiazine derivatives (dopamine antagonists) or 5-HT3 receptor block.34 However, there remain at least three contentious areas: interaction of tramadol with coumarin anticogulants, occurrence of drug-induced seizures and abuse liability. The interaction of tramadol with oral anticoagulants of the coumarin variety with the end result of prolongation of the International Normalized Ratio (INR) has been reported.35 36 However, more recent work has failed to confirm these findings.37 38
After 2 yr availability of tramadol in the UK, 27 reports of convulsions, possibly caused by tramadol, had been reported to the Committee on Safety of Medicines (CSM), a reporting rate of 1 in 7000. The majority of these patients were receiving epileptogenic agents in addition to tramadol and several of the others had received large i.v. doses of tramadol.39 Data from the UK-based General Practice Research Database identified 10 916 patients who had received more than 30 000 prescriptions for tramadol over a 22-month period, the most frequent dose being 50 mg 3–4 times daily. The study identified 17 patients who experienced idiopathic incident seizures (11 had definite seizures and six were possible cases). All (17) had received other drugs in addition to tramadol in the previous 90 days: opioids (eight patients), tramadol and opioids (five), other analgesics (three) or no analgesic (one). The conclusion was that there was no risk of idiopathic seizures associated with tramadol therapy alone.40 However, tramadol should not be used in epileptics and should be used with caution in patients on concomitant medication which lowers seizure threshold. The abuse potential of tramadol requires more data for an accurate picture to emerge. In the USA, 247 instances of abuse were described out of an estimated 16.5 million patient exposures to tramadol in 2.5 yr (1995–1997), equivalent to 1.5 per 100 000. By late 1997, the rate had declined to less than 1:100 000.41 However, Federal Drug Administration (FDA) values were somewhat higher; in 1996, there were 1203 reports of abuse but a proportion of these may have included cases of opioid withdrawal. UK figures for 1994–5 detailed five reports of drug dependence and 28 of withdrawal.39 Tramadol is now established in several clinical roles, usefully blending a reasonable, dose-related efficacy with a relative lack of respiratory depression, major organ toxicity or abuse potential. It is of particular value in NSAIDintolerant patients, the elderly and for those undergoing daycase surgery. Although the literature concerning tramadol continues to grow apace, not all questions have been answered. Further evaluation, especially in contentious areas, needs to be forthcoming. Its role in the longterm management of persistent pain also remains to be demarcated accurately. K. Budd The Mornington Clinic Bradford BD16 1TZ, UK
R. Langford Anaesthetics Laboratory St Bartholomew’s Hospital London EC1A 7BE, UK
References
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1 Eggers KA, Power I. Tramadol. Br J Anaesth 1995; 74: 247–9 2 Duthie DJR. Remifentanil and tramadol. Br J Anaesth 1998; 81: 51–7
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3 McQuay HJ, Moore RA. Oral tramadol versus placebo, codeine and combination analgesics. In: McQuay HJ, Moore RA, eds. An Evidence Based Resource for Pain. Oxford: Oxford University Press, 1998; 138–46 4 Raffa RB, Friderichs E. The basic science aspect of tramadol hydrochloride. Pain Rev 1996; 3: 249–71 5 Bamigbade TA, Davidson C, Langford RM, Stamford JA. Actions of tramadol, its enantiomers and principal metabolite, Odesmethyltramadol, on serotinin (5-HT) efflux and uptake in the rat dorsal raphe nucleus. Br J Anaesth 1997; 79: 352–6 6 Desmoules JA, Piquet V, Collart L, Dayer P. Contribution of monoaminergic modulation to the analgesic effect of tramadol. Br J Clin Pharmacol 1996; 41: 7–12 7 Poulsen L, Arendt-Nielsen L, Brosen K, Sindrup SH. The hypoalgesic effect of tramadol in relation to CYP2D6. Clin Pharmacol Ther 1996; 60: 636–44 8 Lehmann KA, Horrichs G, Hoeckle W. Tramadol as an intraoperative analgesic. A randomised double-blind study with placebo. Anaesthetist 1985; 34: 11–19 9 Coetzee JF, Maritz JS, du Toit JC. Effect of tramadol on depth of anaesthesia. Br J Anaesth 1996; 76: 415–18 10 Bamigbade TA, Paes M, Gayles R, Foster JMG, Langford RM. Does tramadol lighten anaesthetic depth during isoflurane anaesthesia? 8th World Congress on Pain. IASP Press, Seattle, 1996; abstract 261 11 James MFM, Heijke SAM, Gordon PC. Intravenous tramadol versus epidural morphine for post-thoracotomy pain relief: a placebo-controlled double-blind trial. Anesth Analg 1996; 83: 87–91 12 Bamigbade TA, Langford RM, Blower AL, et al. Pain control in day surgery: tramadol compared to standard analgesia. Br J Anaesth 1998; 80: 558–9 13 Coetzee JF, van Loggerenberg H. Tramadol administration prior to wound closure. Br J Anaesth 1998; 81: 737–41 14 Reitman GW, de Witte J, Deloof T. Tramadol reduces the sweating, vasoconstriction and shivering thresholds. Anesth Analg 1997; 84: S536 15 Stamer UM, Maier C, Grond S, Veh-Schmidt B, Klaschik E, Lehmann KA. Tramadol in the management of post-operative pain: a double-blind, placebo- and active drug-controlled study. Eur J Anaesthesiol 1997; 14: 646–54 16 De Witte J, Rietman GW, Vandenbroucke G, Deloof T. Postoperative effects of tramadol administered at wound closure. Eur J Anaesthesiol 1998; 15: 190–5 17 Langford RM, Bakhshi KN, Moylan S, Foster JMG. Hypoxaemia and pain relief after lower abdominal surgery: comparison of tramadol and morphine. Int J Acute Pain Manage 1998; i: 7–12 18 Trakkila P, Tuominen M, Lindgren L. Comparison of respiratory effects of tramadol and pethidine. Eur J Anaesthesiol 1998; 15: 64–8 19 Bosenberg AT, Ratcliffe S. Respiratory effects of tramadol in children under halothane anaesthesia. Anaesthesia 1998; 53: 960–4 20 Prosser DP, Davis A, Booker PD, Murray A. Caudal tramadol for postoperative analgesia in paediatric hypospadias surgery. Br J Anaesth 1997; 79: 293–6
21 Russell W. Caudal tramadol for postoperative analgesia in paediatric hypospadias surgery. Br J Anaesth 1998; 80: 408–9 22 Roth SH. Efficacy and safety of tramadol hydrochloride in breakthrough musculoskeletal pain attributed to osteoarthritis. J Rheumatol 1998; 25: 45–54 23 Harati Y, Gooch C, Swenson M, et al. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology 1998; 50: 1842–6 24 Biasi G, Manca S, Manganelli S, Marcolongo R. Tramadol in the fibromyalgia syndrome: a controlled clinical trial versus placebo. Int J Clin Pharmacol Res 1998; 18: 13–19 25 Budd K. The analgesic effect of tramadol hydrochloride when administered intra-articularly. 8th World Congress on Pain. IASP Press, Seattle, 1996; abstract 229. 26 Nossol S. Treatment of pain with sustained release tramadol. Int J Clin Pract 1998; 52: 94–126 27 Cancer Pain Relief, 2nd Edn. Geneva: World Health Organization, 1997 28 Aurer I, Kovacevic-Metelko J, Radman I, Labar B. Treatment of plasmacytoma related bone pain with tramadol. Exp Haematol 1997; 25: 851 29 Wilder-Smith CH, Hill L, Osler W, O’Keefe S. The effect of tramadol and morphine on pain and gastrointestinal motor function in patients with chronic pancreatitis. Gastroenterology 1999 (in press) 30 Bamigbade TA, Langford RM. The clinical use of tramadol hydrochloride. Pain Rev 1998; 5: 155–83 31 Van den Berg AA, Halliday E. Attenuation of vasomotor responses to tracheal intubation. Comparison of tramadol, pethidine, nalbuphine and placebo. Br J Anaesth 1998; 80: A65 32 Price PM, Budd K. Tramadol in the treatment of spinal pain. Br J Med Economics 1995; 9: 17–20 33 Dalgin PH. Use of tramadol in chronic pain. Clin Geriatr 1995; 3: 1–6 34 Vickers MD. The efficacy of tramadol in the treatment of postoperative pain. Rev Contemp Pharmacother 1995; 6: 499–506 35 Jensen K. Interaction between tramadol and oral antocoagulants. Ugeskr Laeg 1997; 159: 785–6 36 Madsen H, Rasmussen JM, Brosen K. Interaction beween tramadol and phenprocoumon. Lancet 1997; 350: 637 37 Boeijinga JK, van Meegan E, van den Ende R, Schook CE, Cohen AF. Is there interaction between tramadol and phenprocoumon. Lancet 1997; 350: 1552 38 Boeijinga JK, van Meegan E, van den Ende R, Cohen AF. Lack of interaction between tramadol and coumarins. J Clin Pharmacol 1998; 38: 966–970 39 Committee on Safety of Medicines/Medicines Control Agency. Curr Probl Pharmacovigilance 1995; 21: 2 40 Jick H, Derby LE, Vasilakis C, Fife D. The risk of seizures associated with tramadol. Pharmacotherapy 1998; 18: 607–11 41 FDA Committee. FDC Reports (Pink Sheet) Prescription Pharmaceuticals and Biotechnology 1998; 60: 4–5
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