• M Cossmann, C Kohnen, R Langford, and C McCartney.
• Département de Pharmacovigilance et d'Information, Grünenthal GmbH, Stolberg, Allemagne.
• Drugs. 1997 Jan 1;53 Suppl 2:50-62.

AbstractThis article presents a summary of drug safety data concerning the use of tramadol hydrochloride and an outline of the specific aspects of this analgesic in particular with regard to respiratory depression and dependence potential. Information from phase II to IV clinical studies, postmarketing surveillance studies (covering safety data from a total of more than 21,000 patients) and the spontaneous reporting system have been taken into consideration. The data from the spontaneous reporting system covers the period between 1977 and 1993, during which more than one billion single dose units were distributed throughout the world. The phase II to IV studies compare acute intravenous, acute intramuscular, acute oral and multiple dose oral administration Postmarketing surveillance studies provide a picture of everyday use of tramadol in general medical practice. Further analyses were performed to provide 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 pooled data from the clinical studies and the postmarketing surveillance studies reveal that the most commonly observed side effects were nausea, dizziness, drowsiness, tiredness, sweating, vomiting and dry mouth, with an overall incidence of between 1 and 6%. In the postmarketing surveillance studies on long term and acute administration, the profile of adverse events was qualitatively almost identical to that in the phase II to IV studies. However, there were distinct quantitative differences it favour of the long term studies. In the postmarketing surveillance study on acute parenteral administration, the incidences of nausea and vomiting were only 4.2 and 0.5% respectively, which is significantly lower than the 20.7 and 11.4% in the patient-controlled analgesia studies. Nevertheless, it is important to take into consideration the different conditions in these studies. All the postmarketing surveillance studies were outpatient studies, whereas almost all of the phase II to IV studies were carried out in hospitals. The studies with intravenous and intramuscular administration were mainly postoperative, which explains the relatively high incidence of nausea and vomiting, 17.8 and 7.0%, respectively, with intramuscular administration. The different 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 postmarketing 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 and were therefore much less sensitive to dizziness than those in the long term oral and postmarketing surveillance studies, who were all outpatients. On the other hand, postural hypotension played almost no role in the multiple dose studies, in which the oral formulation were used most frequently. It is interesting to note that diarrhoea, pruritus and gastrointestinal disorder (except nausea and vomiting) are mainly reported in the multiple dose studies in the groups receiving oral tramadol, and also in the postmarketing surveillance studies. Once again, the study conditions may well be the explanation. The adverse effects reported in both clinical and postmarketing surveillance studies are similar to those in the spontaneous reports. The most frequently documented adverse effects in clinical and postmarketing surveillance studies, i.e. nausea/vomiting, dizziness, drowsiness, tiredness, sweating and dry mouth, are noted very infrequently in spontaneous reports, since in medical practice these side effects are usually known and are described in the product information. Almost all reports referring to abuse/dependence are connected with pain therapy; they give no reason to suspect any pro

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