In our hospital, the drug most widely used for moderate post-operative pain relief is a suppository with a combination of acetaminophen and codeine (1000/20 mg; tds or qds). This combination is included in the WHO list of stage II analgesics, positioned between simple analgesics (e.g. acetylsalicylic acid, NSAIDs or acetaminophen alone) on the one side and morphine and other opiates on the other side of the spectrum of systemically applied drugs . Rectal administration has the advantage of being independent of gastrointestinal transport, which may be compromised in the immediate post-operative phase and by the subsequent poor bioavailability of the orally applied drug. However, this combination drug has some drawbacks. Opioids such as codeine, even when administered rectally, may cause constipation, and the commercial availability of such suppositories is limited, at least in the Netherlands. Most hospital pharmacies, therefore produce their own stock, but this involves considerable effort with regard to quality control and costs.
In the early 1990s, another stage II analgesic tramadol, which was originally developed in the 1970s, received new interest [2,3]. Today, the drug is widely available and recent research has revealed an interesting pharmacological profile [3-5]. The commercial preparation contains (±)-tramadol, a racemic mixture. The (+)-enantiomer is a weak μ-receptor agonist and inhibits serotonin uptake. The (−)-enantiomer inhibits noradrenaline uptake thereby stimulating alpha-adrenergic receptors. The alpha-mimetic effect is known to amplify the analgesic effect of μ-receptor agonists . Tramadol might be considered to combine these effects in one molecule.
The significance of these in vitro pharmacological effects was made clear in experiments in humans in which naloxone administration could partly reverse the analgesic action of tramadol and yohimbine administration and almost completely abolish the analgesic properties [3,7]. In clinical studies the drug appeared to be well tolerated, in general, having only minor side effects. The lack of respiratory depression is of particular significance, even in high doses [8,9].
With regard to clinical efficacy, a number of trials in a variety of pain conditions have been conducted . From a clinicians' perspective, the analgesic properties in chronic pain are well appreciated [11,12]. In comparative studies, the drug showed an analgesic potency similar to other weak opiates such as buprenorphine and nalbuphine [13-15]. In post-operative pain, the parenteral and oral administration of tramadol has been well studied [16-19]; however, there are few studies using rectal administration . The properties of tramadol were recently reviewed extensively .
We investigated for the formulary selection in our hospital the properties of rectal tramadol compared with the current drug of choice: acetaminophen/codeine suppositories. As data on rectal administration (PR) were lacking, we intended to perform a double-blind controlled study to establish which preparation might be preferred. An open pilot study served to collect basic data to determine the minimum group size for sufficient statistical power in a blinded trial; however, the results of the pilot study were such that a formal blinded trial was no longer deemed necessary. The result of this pilot study between tramadol suppositories and acetaminophen/codeine suppositories for use in post-operative pain is reported here.
A total of 40 patients (20 per group) were included in this open randomized hospital approved trial (for demographic data see Table 1). Inclusion criteria were: ASA type I or II, undergoing elective surgery for which the patient was not expected to require opiates post-operatively, and with a body weight of 50-125 kg. Surgery mainly comprised reconstructive surgery, usually with a very low incidence of post-operative nausea and vomiting. Exclusion criteria (in addition to ASA III or higher) were: known allergies to the medication; (recent) use of MAO inhibitors; > 75 years of age.
Tramadol suppositories (100 mg) were obtained commercially (Byk Nederland BV, Zwanenburg, the Netherlands). The acetaminophen/codeine (1000/20 mg) suppositories (with Witepsol H15, synthetic saturated triglycerides with a chain length of C12-C18, as the basis) were manufactured in the hospital pharmacy (batch 96C18007; average theoretical weight 99.5%; average content between 95%-105%). The ingredients were obtained via regular commercial suppliers and conformed with the quality requirements in the European Pharmacopoeia.
Treatment and observations
Informed consent was obtained from all patients 1 day prior to surgery. After surgery, the medication was started by the attending anaesthesist at the end of anaesthesia. Subsequently, the dose was administered seven times (every 6 h) by a nurse. Before each dose the patients were asked to grade their pain experience on a validated 100-point Visual Analogue Scale (VAS) scale at rest and a second time while moving (e.g. by turning aside). In addition, the patients were asked to grade their feeling of nausea on a three-point scale (1 = no nausea; 2 = nausea; 3 = nausea and vomiting). In addition, we scanned the daily nurses' report for events in the intervals between doses; two patients required a single dose of morphine at the end of surgery (thus 6 h before the first measurement).
In each group, the median VAS score for each time point was used, both at rest and while moving. Data are presented with their interquartile ranges and were tested for statistical significance (Mann-Whitney U-test). The nausea score includes both the patient score and the remarks recorded in the nurse report. The percentage of patients experiencing at least one episode of nausea was calculated and expressed as a relative risk. The difference in relative risks between both groups was evaluated statistically (χ2-test). A P-value < 0.05 was considered significant. To exclude a possible influence by the type of anaesthesia on the post-operative nausea score, both patient groups were stratified for light (propofol i.v. with oxygen) and intermediate (either propofol i.v. with inhalation of nitrous oxide/oxygen or thiopentone i.v. plus inhalation of isoflurane + nitrous oxide and oxygen) emetogenic type of anaesthesia.
Patient demographic data is given in Table 1. Both groups were comparable regarding gender, age and body weight. However, the duration of anaesthesia in the acetaminophen/codeine treated patients was on average 30 min longer than in the tramadol-treated group. In both groups, one patient was lost to follow-up for reasons not related to post-operative pain management (one patient had diarrhoea post-operatively, and the other patient had unexpected complications during surgery).
Median pain scores (with interquartile ranges) are shown in Fig. 1 (at rest) and Fig. 2 (while moving). As expected, the average VAS scores while moving are slightly higher than those at rest. Although the median VAS score in the patients treated with tramadol is lower than in the acetaminophen/codeine treated group (particularly in the first 12-18 h postoperatively) the difference is not significant (all P>0.3) due to the large interindividual variation.
Distribution of the type of anaesthesia with regard to emetogenic potential is given in Table 2, together with the episodes of nausea experienced by these patients. It can be seen that 16 of the 19 patients (84%) treated with tramadol experienced at least one episode of nausea, compared with only 6 of the 19 (31%) treated with acetaminophen/codeine. The relative risk of experiencing nausea with tramadol is therefore 2.7 (95% confidence interval: 1.3-5.3; P = 0.0001). Analysis of the emetogenic strata (light or intermediate) did not influence this overall result. In the tramadol-treated patients, eight (42%) required additional antiemetic therapy compared with only three patients (16%) in the other group.
This study showed a significantly higher incidence of nausea and vomiting in patients receiving tramadol (84%) than in the paracetamol/codeine treated group (31%). No difference in analgesic potency was evident between the two preparations in both study groups. The apparantly higher mean pain score in the acetaminophen/codeine treated group during the first 12 h post-operatively was not statistically significant (P>0.3) as compared with the tramadol treated group.
The type of anaesthesia can influence the incidence of post-operative nausea and vomiting, the patients were therefore stratified with respect to the type of anaesthesia used. Gender, body weight, age, type and duration of surgery were similar in both groups. Thus, it appears that the observed difference in the incidence of nausea and vomiting was indeed due to the different post-operative analgesics used.
In trials that report the post-operative analgesic properties of acutely administered tramadol, the reported frequency of nausea ranges from about 5-50% [10, 13] and for vomiting on average less than 15% . In a recent paper, Crighton et al. reports a frequency of nausea and vomiting of almost 40% in patients receiving oral tramadol on demand (average dose: 210 mg day−1). Our results agree with the frequency of nausea and vomiting after paracetamol/codeine with that reported. The greater frequency after tramadol observed in our study can be explained in that we use almost twice the dose. In the case of chronic pain, these values are usually lower . This may be explained by the gradual increase in dose. In post-operative pain, the drug has to be effective immediately, therefore maximal doses are usually administered. We question why is there a discrepancy between reported data and the high frequency of nausea observed in our study? We noticed that close monitoring of our patients over 48 h contributed considerably to the nausea score. Moreover, our results include the cumulative data of 6-hourly scoring by the patient and information drawn from the nurses' reports. It is likely that with less stringent monitoring a short episode of nausea (and even vomiting) could be missed. In addition, the episodes of nausea recorded in our tramadol group occurred after the first post-operative day. In most other studies of this kind, it is usual for only the first 12 or 24 h to be monitored.
Tramadol has a far lower affinity for the emetogenic μ-receptor than morphine. An explanation must therefore be sought for the high incidence of nausea and vomiting observed with tramadol, higher than that usually observed with parental morphine. In the present study, the frequency of these undesired side effects was higher than that usually observed with parenteral morphine. The demethylated tramadol metabolite has a higher affinity for this receptor than the parent compound. Pharmacological studies have shown that tramadol also has reuptake-blocking properties for 5-HT [3,6]. From studies with 5HT re-uptake blockers (e.g. clomipramine, fluvoxamine and fluoxetine) it is clear that gastrointestinal side effects are very common; this pharmacological effect may contribute to this undesirable property of tramadol.
It can be argued that an open study is prone to bias with respect to efficacy and side effects. However, both nursing staff and patients were informed in advance about our hypothesis: i.e. that the drug of study would be likely to have fewer side effects. In this respect, any bias would be in favour of tramadol.
Adverse effects such as nausea and vomiting represent a significant disadvantage for a post-operative analgesic and can be more troublesome than moderate pain. We therefore conclude that for this group of patients rectal tramadol does not offer any advantage over the drug currently in use: acetaminophen/codeine suppositories. It was therefore decided not to conduct the planned randomized comparison and not to include tramadol in our hospital formulary.
We thank the nursing staff of the Department of Plastic Surgery and the Department of Orthopedics for their cooperation in this trial. The support of Drs B. H. Graatsma, head of the Hospital Pharmacy, Dr J. Danser, Department of Pharmacology, Erasmus University Rotterdam and Prof. Dr W. Erdmann, head of the Department of Anaesthesiology, is greatly appreciated. The statistical advice from Prof. Dr D. E. Grobbee, Department of Epidemiology, Erasmus University Rotterdam is gratefully acknowledged.
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