A good understanding of peripheral and central nociceptive transmission mechanisms offers a variety of ways to manage acute pain efficiently. Pharmacological therapies range from monotherapy with commonly used analgesics, such as antiinflammatory agents, nonopioid analgesics, such as paracetamol, weak and strong opioids, local anaesthetics, N-methyl-D-aspartate blocking agents, and ion channel blockers, to any combination of these as multimodal therapy. In the present issue of the Journal, Rasmussen et al.1 provide an interesting example of what an analgesic cocktail might look like when the concept of multimodal analgesia in clinical practice is taken seriously. This begs the question as to whether such a cocktail is always advantageous or whether combining such diverse chemical substances constitutes an additional risk.
The ‘pros’ of combining analgesics would be to improve efficacy, reduce toxicity and achieve an optimal efficacy/toxicity ratio. On the other hand, the ‘con’ of analgesic combination would be the potential for harmful pharmacokinetic or pharmacodynamic interactions. Rational combination should, therefore, fulfil certain pharmacokinetic and pharmacodynamic criteria.
In most instances, unwanted interactions affecting absorption, distribution, metabolism or elimination of one or more of these drugs will lead to decreased analgesic efficacy. Similarly, the use of drugs acting on the same receptor should be avoided and the combination should be at least additive or ideally synergistic with each component contributing significantly to the analgesia observed. The use of additive or synergistic combinations should allow for lower doses of each substance and, therefore, result in an overall improved safety profile.
When given postoperatively, one reason for using nonopioid analgesics is opioid sparing, with an associated reduction in opioid-related adverse effects. The analgesic synergy between opioids and other classes of analgesics (such as ketamine, clonidine, gabapentin, nonsteroidal antiinflammatory drugs and paracetamol) is evident in the published findings of controlled experimental studies. However, validation of multimodal drug regimens and identification of clear benefits to patients remain to be demonstrated in clinical practice.
Despite this, current perioperative clinical pain management recommendations promote the use of the multimodal approach to reduce the need for opioids and improve the quality of analgesia, at least in theory. Unfortunately, meta-analysis based on randomized controlled trials investigating the use of paracetamol or nonsteroidal antiinflammatory drugs as adjuvant analgesics failed to recognize a clinically significant opioid-related adverse event sparing effect.2 Furthermore, the inappropriate use of drugs acting on the same target has been demonstrated for the combination of tramadol with morphine. This combination had a less than additive effect in relieving postoperative pain.3
Using available data on the dose–effect relationship to optimize efficacy of a single administration, Rasmussen et al.1 investigated dexamethasone, gabapentin and ketamine in a preemptive role. They chose this combination because it held promise of additive effects. Patients undergoing arthroplasty were randomized to receive this cocktail or placebo preoperatively, together with paracetamol, and at the end of surgery ketorolac was given together with patient-controlled morphine. Analysis of postoperative data from the first 24 h showed significant but marginal improvement in analgesia as well as a trend to reduced opioid consumption. However, it is impossible to identify which of these three drugs, dexamethasone, gabapentin or ketamine, contributed to this improvement. Furthermore, the short-term benefit and risk analysis provided (0–24 h) by the authors potentially underestimates the risk of late adverse events expected with a multimodal approach. Czarnetzki et al.,4 while investigating the efficacy of a single dose of a glucocorticosteroid in the prevention of emesis in children undergoing tonsillectomy, recently reported that the addition of dexamethasone perioperatively was associated with an increased risk of late (>24 h) postoperative bleeding.
Identifying the best additive and synergistic drug combinations requires complex, time-consuming and costly experimental designs. Experienced clinicians often apply individualized single centre multimodal analgesic approaches without strong scientific support. Analgesic monotherapy is not a dogma, but well designed controlled trials are still urgently needed to justify our use of every day multimodal regimens. A rational step-by-step approach to multimodal strategies that avoids unwanted pharmacokinetic or dynamic interactions remains essential.
1 Rasmussen ML, Mathiesen O, Dierking G. Multimodal analgesia with gabapentin, ketamine and dexamethasone in combination with paracetamol and ketorolac after hip arthroplasty: a preliminary study. Eur J Anaesthesiol 2010; 27:324–330.
2 Elia N, Lysakowski C, Tramèr MR. Does multimodal analgesia with acetaminophen, nonsteroidal antiinflammatory drugs, or selective cyclooxygenase-2 inhibitors and patient-controlled analgesia morphine offer advantages over morphine alone? Meta-analyses of randomized trials. Anesthesiology 2005; 103:1296–1304.
3 Marcou TA, Marque S, Mazoit JX, Benhamou D. The median effective dose of tramadol and morphine for postoperative patients: a study of interactions. Anesth Analg 2005; 100:469–474.
4 Czarnetzki C, Elia N, Lysakowski C, et al
. Dexamethasone and risk of nausea and vomiting and postoperative bleeding after tonsillectomy in children: a randomized trial. JAMA 2008; 300:2621–2630.