TOLERABILITY PROFILE OF TRAMADOL - FINDINGS FROM INTERNATIONAL-STUDIES AND POSTMARKETING SURVEILLANCE DATA

This article presents a summary of drug safety data concerning the use of tramadol hydrochloride and an outline of the specific aspects of t his analgesic, in particular with regard to respiratory depression and dependence potential. Information from phase II to IV clinical studie s, postmarketing surveillance studies (covering safety data from a tot al of more than 21 000 patients) and the spontaneous reporting system have been taken into consideration. The data from the spontaneous repo rting system covers the period between 1977 and 1993, during which mor e than one billion single dose units were distributed throughout the w orld. The phase II to IV studies compare acute intravenous, acute intr amuscular, acute oral and multiple dose oral administration. Postmarke ting surveillance studies provide a picture of everyday use of tramado l in general medical practice. Further analyses were performed to prov ide information about the gender-, age- and dose-related distribution of adverse reactions. The prevalence of side effects was calculated by comparing the number of symptoms with the number of patients. The poo led data from the clinical studies and the postmarketing surveillance studies reveal that the most commonly observed side effects were nause a, dizziness, drowsiness, tiredness, sweating, vomitting and dry mouth , with an overall incidence of between 1 and 6%. In the postmarketing surveillance studies on long term and acute administration, the profil e of adverse events was qualitatively almost identical to that in the phase II to IV studies. However, there were distinct quantitative diff erences in favour of the long term studies. In the postmarketing surve illance study on acute parenteral administration, the incidences of na usea and vomiting were only 4.2 and 0.5% respectively, which is signif icantly lower than the 20.7 and 11.4% in the patient-controlled analge sia studies. Nevertheless, it is important to take into consideration the different conditions in these studies. All the postmarketing surve illance studies were outpatient studies, whereas almost all of the pha se II to IV studies were carried out in hospitals. The studies with in travenous and intramuscular administration were mainly postoperative, which explains the relatively high incidence of nausea and vomiting, 1 7.8 and 7.0%, respectively, with intramuscular administration. The dif ferent conditions in the phase II to IV studies and the postmarketing surveillance studies are also reflected in the occurrence of dizziness and postural hypotension. The incidence of dizziness in the postmarke ting surveillance studies is slightly higher than that observed in the phase II to IV studies. Particularly in the studies with intravenous and intramuscular administration, the patients were confined to bed an d were therefore much less sensitive to dizziness than those in the lo ng term oral and postmarketing surveillance studies, who were all outp atients. On the other hand, postural hypotension played almost no role in the multiple dose studies, in which the oral formulations were use d most frequently. It is interesting to note that diarrhoea, pruritus and gastrointestinal disorders (except nausea and vomiting) are mainly reported in the multiple dose studies in the groups receiving oral tr amadol, and also in thr postmarketing surveillance studies. Once again , the study conditions may well be the explanation. The adverse effect s reported in both clinical and postmarketing surveillance studies are similar to those in the spontaneous reports, The most frequently docu mented adverse effects in clinical and postmarketing surveillance stud ics, i.e. nausea/vomiting, dizziness, drowsiness, tiredness, sweating and dry mouth, are noted very infrequently in spontaneous reports, sin ce in medical practice these side effects are usually known and are de scribed in the product information, Almost all reports referring to ab use/dependence are connected with pain therapy; they give no reason to suspect any problematic developments as regards abuse or drug depende nce. This corresponds with the results of experiments in both animal a nd human pharmacological studies as well as with data from the Substan ce Abuse Warning System in Germany. Another significant number of repo rts concern central and peripheral nervous disorders and general cardi ovascular disorders. Convulsions, which were mentioned mainly in the g roup of central and peripheral nervous disorders, were nor observed in the clinical and postmarketing surveillance studies. However, as it i s generally known that opioids can have an effect on the occurrence of convulsions, convulsions, the possibility that tramadol may induce co nvulsions in rare cases cannot be excluded, particularly if there are other proconvulsant factors present. Spontaneous reports of general ca rdiovascular disorders mainly concerned varying degrees of hypotension /postural dysregulation. This corresponds with the data from the studi es, where the main cardiovascular disorder was postural hypotension (i ncluding circulatory failure), with an overall frequency of 0.7%. Ther e have been some spontaneous reports of allergic and anaphylactic reac tions with tramadol, but the incidence was lower than 0.1%, correspond ing the generally accepted knowledge that the incidence of these react ions is low with opioids. There have been a very small number of spont aneous reports concerning blood dyscrasias, liver disorders and urinar y retention, Although urinary retention cannot be excluded with tramad ol, only extremely rare cases were reported in clinical and postmarket ing surveillance studies (overall incidence below 0.1%), as well as in spontaneous reporting. Respiratory depression is a potentially seriou s opioid effect. Pn comparative : studies with morphine, tramadol show s a more favourable tolerability profile in terms of effect on end-exp iratory CO2 concentrations, respiratory rates and minute volumes, Tram adol was also shown to decrease postoperative oxygen saturation signif icantly less than morphine; this finding is currently being further ex plored, It would appear that the occurrence of respiratory depression is not affected by the route of administration of tramadol. A few case s of respiratory depression have been observed among the spontaneous r eports, In the cases where the cause could be attributed to tramadol, mainly high parenteral doses of up to 1000mg of tramadol had been admi nistered, or the patients had been considerably compromised,