Superior postoperative analgesic efficacy of a continuous infusion of tramadol and dipyrone (metamizol) versus tramadol alone
Introduction
A variety of options for the management of postoperative pain is currently available: peripheral or regional nerve blocks, intramuscular opioids on an “as needed” basis that is considered inappropriate nowadays, and intravenous patient-controlled analgesia (PCA). Strong opioids have been recognised and used as potent and effective analgesics for a long time, but side effects, such as respiratory depression, pruritus, sedation, nausea, vomiting and constipation do occur more or less frequently when PCA is used [1], [2]. Especially after abdominal surgery, the constipation inevitably produced by strong opioids is undesirable. Moreover, the administration of small doses of morphine at the patients’ request rarely produces sufficient analgesia, especially during movement. Last but not the least, the PCA pump, which is a rather expensive device, cannot be provided to every patient after surgery. PCA devices can also cause some safety problems [3]. As has been shown, the combination of classic, non-steroidal anti-inflammatory drugs (NSAID) or other non-opioid analgesics (acetaminophen, dipyrone) with opioids may lead to a reduction of postoperative pain and of the required total dose of opioids [4], [5], [6]. Consequently, a reduction of opioid-related side effects has been reported by use of such an analgesic combination [7], [8], [9]. The risk of developing severe NSAID side effects does not seem to be clinically relevant during short-term use in postoperative pain management [10], [11]. Because of the known additive analgesic effects of such combinations, it is tempting to speculate that the replacement of the strong opioid by a so-called weak opioid should also better work than each drug alone without strong opioid-related side effects [12]. The only weak opioid applicable in parenteral form is tramadol which is used for postoperative pain, at least in Europe, for more than 20 years [13], [14]. Tramadol is a centrally acting analgesic which binds to opioid receptors and also activates monoaminergic spinal inhibition of nociception by inhibition of both norepinephrine and 5-hydroxytryptamine (5-HAT) re-uptake into the neuron and by facilitation of 5-HAT release [15]. Intravenous clinical doses of the weak opioid tramadol do not cause a respiratory depression, but even in high doses it has been shown to be insufficient in some postoperative patients [16], [17], [18]. Dipyrone (a water soluble pyrazolone derivative) is an old-established potent non-opioid drug with good analgesic, antipyretic and spasmolytic properties. In contrast to classic NSAIDs, dipyrone primarily acts on the periaqueductal grey matter and produces its antinociceptive effects via descending central pathways [19]. Dipyrone is characterised by low gastrointestinal and renal toxicity, although there was some concern on the potential risk of the development of agranulocytosis [18], [20], [21], [22]. Despite some very recent reports from Sweden on the quite high risk of dipyrone-induced agranulocytosis, the so-called Boston study could show that the risk to develop this rare but severe adverse effect is extremely low [23], [24], [25]. This opinion has been proved by some other papers [26], [27], [28]. Therefore, dipyrone has been safely used for several decades in many countries for the treatment of mild to moderate postoperative pain [6], [12], [18], [29], [30], [31], [32], [33]. In particular, the effectiveness of dipyrone in the therapy of visceral pain is well documented [30], [33], [34]. Thus, it is not surprising that the combined infusion of these two drugs (tramadol and dipyrone) has been proposed and is widely used as a therapeutic option for postoperative pain management, although its efficacy was never shown in a prospective, controlled, randomised trial [12].
The rationale for combining a non-opioid with a weak opioid drug, such as tramadol, is to reduce the common side effects of strong opioids and to provide better analgesia than with each component alone. Thus, the aim of the present prospective, randomised, placebo-controlled, double-blind study was to test the hypothesis that the continuous infusion of tramadol combined with dipyrone is not only safe, and superior to placebo, but also provides better analgesia than tramadol alone in postoperative patients.
Section snippets
Study design
After approval by the Institutional Ethics Committee and informed consent, 90 patients (American Society of Anesthesiologists (ASA) physical status I–III, 18–70 years of age) scheduled for elective abdominal surgery for neoplasm under general anaesthesia were enrolled into the study. Patients with allergies, peptic ulcers or bleeding problems, renal or haematological disorders, known or suspected alcohol or drug abuse were excluded. Inability to operate a PCA device was also considered an
Results
There were no drop-outs or cases of violation of protocol. The three study groups did not significantly differ in their demographic and preoperative biometric data (age, gender, weight, ASA-classification) (Table 1). Also the types of surgical procedures and their distribution between the groups has been shown in Table 1. The duration of surgery were comparable in each of the three groups.
Arterial blood pressure, heart rate and oxygen saturation were indistinguishable between the groups during
Discussion
Because of the availability of the morphine PCA rescue medication, it was not surprising that a significant pain relief occurred in each patient group during the 24 h study period, both at rest and during the standard movement.
The significantly lower pain scores observed in group 2 (tramadol combined with dipyrone) already 1 h after start of the test infusion showed that the onset of a sufficient therapeutic effect occurred much faster with the combination of the two analgesics than with tramadol
Acknowledgements
The authors thank the medical staff and nurses of the Department of Anaesthesiology, The Maria Sklodowska-Curie Memorial Cancer Centre—Institute of Oncology in Warsaw, Poland for their excellent co-operation.
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