Oxycodone is a strong μ-opioid receptor agonist, quite similar in analgesic potency to morphine , and it is used orally for cancer pain  and parenterally for post-operative pain [3,4]. We have recently shown that the analgesic efficacy of oxycodone and morphine in intravenous patient-controlled analgesia (PCA) after plastic reconstructions of the breast and major operations of the vertebrae was similar .
Tramadol is a centrally acting analgesic drug with a low affinity for μ-opioid receptors. It has been shown to be about 1/6-1/10 as potent an analgesic as morphine when both intensity and duration of the effect were considered . The low risk of respiratory depression [6-8] makes it potentially suitable for analgesic use with PCA, which is a popular method for post-operative pain management. Therefore, in a prospective, randomized and double-blind study, we examined the effects of tramadol and oxycodone administered by patient-controlled analgesia, which enables comparison of potency, efficacy and side effects of the opioids in analgesia after surgery. We also wanted to evaluate whether tramadol is suitable for pain relief after maxillofacial surgery.
Patients and methods
This randomized and double-blind study protocol was approved by the Ethics Committee of the Helsinki University Central Hospital. After obtaining informed consent, 54 ASA I-II patients between the age of 12 and 54 years undergoing maxillofacial surgery (osteotomies) were randomly (sealed envelope method) assigned to the tramadol or oxycodone group. Before the operation patients were instructed in the use of the PCA apparatus (Abbott Pain Management Provider APM, Abbott Laboratories, North Chicago, IL, USA). The patients were advised to demand opioid from the PCA-pump frequently so that they would be pain-free.
All patients received general anaesthesia according to a standardized regimen. Oral diazepam (approximately 0.2 mg kg−1) was given as premedication 1 h before surgery. Before induction of anaesthesia, the patients received intravenous glycopyrrolate (0.2 mg) and alcuronium (2-3 mg) for precurarization. Anaesthesia was induced with propofol 2 mg kg−1 and alfentanil 0.5-1 mg, and suxamethonium (1.5 mg kg−1) was administered to facilitate tracheal intubation. Muscle relaxation was maintained with vecuronium and the degree of relaxation was monitored with a peripheral nerve stimulator. Anaesthesia was maintained with 65% nitrous oxide in oxygen and 1% isoflurane and alfentanil 0.5 mg i.v. was given for analgesia if the systolic arterial pressure increased 20% from the basic value. At the end of anaesthesia, residual neuromuscular block was reversed with neostigmine 2.0 mg, preceded by glycopyrrolate 0.4 mg.
Every patient was given dexamethasone 8 mg twice a day, from the evening before the operation to the first post-operative day, to diminish post-operative oedema. Before incision and at the end of anaesthesia diclofenac sodium 1 mg kg−1 was given i.m.
The intensity of pain following surgery was assessed at rest and during activity (mouth opening). Pain was assessed with a verbal rating scale (VRS) where 0 = no pain, 1 = slight pain, 2 = moderate pain, 3 = severe pain. In addition a 50-cm visual analogue scale (VAS) for assessment of pain was used (0 = no pain, 50 = worst possible pain) . Patients were also asked to indicate their satisfaction with regard to the PCA pain relief (0 = no pain relief, 1 = partial pain relief, 2 = good pain relief, 3 = excellent pain relief).
In the recovery room when the patient felt pain, the anaesthetist gave either tramadol 10 mg or oxycodone 1 mg intravenously in double-blinded fashion every 2 min until the patient was pain-free or fell asleep (loading). Maximum doses of loading were tramadol 100 mg and oxycodone 10 mg. Then the PCA apparatus was connected to the intravenous line with a one-way (anti-reflux) valve. Patients were randomly assigned to receive a drug solution that contained either 6 mg mL−1 tramadol or 0.6 mg mL−1 oxycodone. The PCA apparatus was set to deliver a bolus dose of 300 μg kg−1 tramadol or 30 μg kg−1 oxycodone with a lockout interval of 5 min. Maximum dosage was tramadol 4 mg kg−1 or oxycodone 0.4 mg kg−1 in 4 h. The rescue analgesic was oxycodone i.m. Start time, the time of each bolus dose, the number of demands and the cumulative tramadol and oxycodone requirements were recorded. VAS scores, VRS for pain and the satisfaction of pain relief were measured in the recovery room before and after loading, at 2 h after commencing PCA and on the ward at 21.00 hours and at 09.00 hours the next morning by one of the investigators.
Adverse reactions, such as sedation, nausea, vomiting, pruritus and urinary retention were sought by active questioning and recorded on a 4-point verbal scale (none, slight, moderate, severe). Droperidol (10 μg kg−1) was given intravenously in the case of prolonged emesis or vomiting.
Student's t-test was used for the comparison of differences between mean values of demographic data. χ2-Test and Mann-Whitney U-test were used as appropriate. A P-value less than 0.05 was considered statistically significant.
The patient groups were similar with respect to age, gender, weight, height, loss of blood, type of surgery and duration of operation (Table 1). Total peroperative alfentanil administration during the operation did not differ between the groups (Table 1).
For the initial post-operative analgesia (loading) the mean tramadol consumption was 38 mg and the mean oxycodone consumption was 3 mg. The mean cumulative consumption of tramadol and oxycodone during the study were 200 mg and 26 mg, respectively (Table 2). One patient in the tramadol group demanded tramadol over the 4-h limit of the apparatus. One patient in the oxycodone group was given ketorolac because of intensive pain despite of PCA-oxycodone and was excluded from the study. The PCA treatment was discontinued because of intractable pruritus in one patient in the oxycodone group. She was given promethazine hydrochloride and was withdrawn from the study.
There was no significant difference between the groups in the VAS scores for pain (Fig. 1). Before loading the median VAS scores at rest were 20 (range 0-40) in the tramadol group and 21 (range 2-40) in the oxycodone group. After loading the median VAS scores at rest were 16 (range 0-28) in the tramadol group and 10 (range 0-22) in the oxycodone group. The highest median VAS scores during the study were 13 in the tramadol group and 15 in the oxycodone group. However, there was great interindividual variation and at rest two patients in both groups scored > 20 at 21.00 hours. The corresponding numbers at 09.00 hours on the following morning were three in the tramadol group and one in the oxycodone group. VRS scores were similar in both groups at rest and during activity (Fig. 2a,b). One patient in both the tramadol and the oxycodone groups did not use the PCA apparatus at all during the study.
No serious side effects occurred in either group. During the study period 12 patients in the tramadol group (44%) and seven patients in the oxycodone group (28%) had nausea (NS) (Table 3). The incidence of other side effects was similar in both groups (Table 3). During or immediately after loading four patients in the tramadol group but none in the oxycodone group needed droperidol because of nausea. Later in the recovery room, four patients in the tramadol group, but none in the oxycodone group still needed droperidol. On the surgical ward four patients in the tramadol group and two patients in the oxycodone group needed droperidol until the end of the study period. One patient in the tramadol group received droperidol three times during the first night.
No respiratory depression (respiratory rate < 10 bpm) was identified. There was no difference in the incidence of other minor adverse events (Table 3). Three patients in the tramadol and two patients in the oxycodone group including the one mentioned above had pruritus. One patient in the tramadol group had a generalized transient rash, the origin of which remained uncertain. Dry mouth and fatigue were general side effects in both groups.
All patients, except one in the oxycodone group, were satisfied with their pain therapy. This patient could not express his opinion about the quality of analgesia and the apparatus.
In the present study tramadol was shown to be as good an analgesic as oxycodone over a 24-h period after maxillofacial surgery. The measurements of pain indicated that the analgesia regimen was relatively good. Thus, the median VAS scores were 3-15 (6-30%), which may be considered to be adequate pain relief . None of patients had severe pain after the initial loading of analgesics and the number of patients expressing moderate pain was low (Fig. 2a,b).
The amount of opioids delivered via a PCA device is considered to be an objective method for the assessment of the efficacy of different opioids, when the pain scores in two analgesic groups are quite similar . In our study the potency ratio of tramadol to oxycodone was found to be approximately 8:1. This was within the expected ratio range of 6:1-12:1, which is based on comparisons of tramadol with morphine [5,12].
In this study all the patients were given i.m. diclofenac sodium at the beginning and at the end of anaesthesia as a part of the overall balanced analgesia . The role of nonsteroidal anti-inflammatory drugs (NSAID) in reducing the need for opioids has been verified in several studies [14,15]. After maxillofacial surgery the anti-inflammatory action of the NSAIDs may also effectively reduce inflammatory tissue swelling around the operative area.
The diminishing effect of a single i.m. pre-operative injection of a corticosteroid on post-operative swelling and associated pain, has also been shown to be impressive , so our patients were given dexamethasone i.v. during the study according to a routine surgical protocol. It can be assumed that the patients benefited from both the nonsteroidal and the steroidal anti-inflammatory drugs and, thus, all but one patient could control their pain by using the PCA apparatus.
In the present study nausea and vomiting were more common in the tramadol group than in the oxycodone group. This observation is in accordance with a previous study which reported that nausea is the most common side effect during pain control with morphine and tramadol, and slightly worse with tramadol .
Vickers and co-workers  have shown that an equianalgesic dose of tramadol has much less effect on the respiratory centre than morphine. In our study no respiratory depression, based on counting respiratory rates and clinical observation, was recorded. This might be due to appropriate dose selection, but also because the respiratory depressant effect (μ-opioid receptor agonist action) of tramadol is less than oxycodone . However, in the case of maxillofacial surgery, in which swelling of tissues surrounding the upper airways may hamper respiratory function, the risk of opioid-induced hypoxaemia in the immediate post-operative period is greater than usual. In this regard tramadol might be a better choice than oxycodone (or morphine) after maxillofacial surgery. Fortunately, respiratory depression and hypoxaemia are quite rare post-operative complications after adequate opioid administration and adequate supervision .
In conclusion, in patients who routinely received peri-operatively diclofenac and dexamethasone, tramadol by the PCA principle was found to provide safe opioid analgesia after maxillofacial surgery without risk of respiratory depression. However, nausea and vomiting which frequently occurred are disturbing side effects of tramadol.
We thank most sincerely Dr Mikko Pitkänen for valuable advice on the preparation of the manuscript and for assistance in drawing the figures.
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