Treating the pain of ambulatory surgical patients can be problematic. Concerns over the safety of analgesics often lead physicians to use small doses of these drugs with consequent sacrifices in efficacy. In particular, the respiratory depression, together with the prevalent nausea and vomiting, caused by opioids severely limit their value in this setting. However, other groups of analgesics are limited in terms of strength and duration of effect. One established approach to circumventing these problems is to use combinations of analgesics in single formulations. However, until recently, such combination formulations of analgesics have generally proved to be disappointing in practice, especially in treating moderate-to-severe pain.

Summary

Background and objective: The growth of ambulatory surgical procedures is limited by severe postoperative pain. After particularly painful operative procedures, moderate-to-severe pain is estimated to occur in approximately 30% of patients. Inadequate analgesia may delay or prevent discharge, or result in readmission. Severe postoperative pain also causes extreme discomfort and can prevent sleep, thus contributing to postoperative fatigue. Moreover, postoperative pain limits mobility at home and delays the return to normal activities. The development of effective analgesia for postoperative pain is therefore a priority of modern medicine.

Results: The pain experienced during the first days spent at home is related to the magnitude of pain experienced at the hospital. Aggressive analgesic treatment at the hospital is therefore of key importance. This includes pre- and intraoperative administration of analgesics to reduce the pain in the immediate postoperative period, and the use of multimodal, balanced analgesia throughout recovery. Clinical studies have shown that patients who receive both pre- and postoperative analgesia experience greater pain relief than those who receive postoperative analgesia alone. Multimodal analgesia, including the use of anaesthetics, is increasingly important in attempts to avoid the prescription of single strong opioids postoperatively. The use of a non-steroidal anti-inflammatory drug (NSAID) plus an anaesthetic perioperatively has also been shown to be more effective than anaesthetic alone.

Conclusions: Postoperative pain is the most commonly reported complication of ambulatory surgery. Although the number of analgesic techniques seems more limited in outpatient than in inpatient surgery, the combination of analgesic regimens in a multimodal approach may improve postoperative analgesia and functional outcome after ambulatory surgery. The combination of acetaminophen plus tramadol is a useful formulation to prescribe if acetaminophen or NSAIDs alone are ineffective.

Summary

Background and objective: Oral fixed drug combination analgesics have potential advantages over monotherapy, but these can only be attained through careful design.

Results: The main reasons for developing combination analgesics are to gain efficacy and to reduce toxicity. Analgesic combinations interact pharmacokinetically, or pharmacodynamically, or both, in positive or negative terms. The tmax value for both enantiomers of tramadol occur two hours following administration, and that for the active, (+)-M1 metabolite occurs after three hours. Thus, pairing tramadol with acetaminophen, a rapid-onset analgesic, represents a pharmacokinetically rational combination. Analgesic combinations should satisfy two important pharmacodynamic criteria: the components of the combination should display additive or synergistic analgesia; and this interaction should allow lower doses of each substance to be used in combination, resulting in an improved safety profile. Clinical studies of the pharmacodynamic between oral tramadol and acetaminophen in third molar extraction and cold pressor models have provided evidence that this combination provides better efficacy than either individual component of the combination.

Conclusions: In summary, combination analgesics can play a valuable role in pain management. However, dubious combinations (directed against the same targets or with unwanted interactions) and ‘old fashioned’ fixed-dose multiple analgesic agent combinations should be avoided. Fixed-dose combination analgesics are of value only when they have been developed according to rational pharmacokinetic and pharmacodynamic criteria, and when claims for their benefits have been supported by evidence-based data and well-designed clinical studies.

Summary

Background: Combinations of analgesic drugs provide the opportunity for better efficacy with less overall morbidity than provided by single analgesic agents. This article discusses the rationale, efficacy and safety for a novel analgesic combination: tramadol and acetaminophen (paracetamol).

Methods: Data supporting the rationale of combining tramadol and acetaminophen to provide pain relief will be reviewed in addition to clinical data demonstrating the efficacy and safety of this combination in acute and chronic pain states.

Results: Tramadol and acetaminophen are a rational combination product in that their mechanisms of action do not overlap and that in preclinical studies this combination acts synergistically. Also, this combination would be expected to provide more rapid pain relief than tramadol alone, and more persistent pain relief than acetaminophen alone. Moreover, each compound is broken down along separate metabolic pathways. Acute dental pain studies showed that pain relief and improvements in pain intensity associated with tramadol 75 mg plus acetaminophen 650 mg are superior to placebo, or tramadol or acetaminophen alone. This combination provided a rapid onset of action, identical to that achieved with acetaminophen alone, but the pain relief was also sustained, as for tramadol alone. Tramadol/acetaminophen also had the same adverse event profile as tramadol monotherapy. A chronic low back/osteoarthritic pain study showed that the drug combination can also be used similarly to codeine/acetaminophen combinations in treating benign chronic pain. The safety profile of the tramadol/acetaminophen combination is at least as favourable as that of codeine/acetaminophen, and is well tolerated with long-term use.

Conclusions: Tramadol/acetaminophen combination is a new preparation that is effective in acute or chronic moderate-to-moderately severe pain. It benefits from the complementary actions of the constituent analgesics, having the rapid onset of acetaminophen and the sustained effect of tramadol. The analgesic efficacy of this combination is comparable to that of positive controls, and its adverse event profile is in line with that of its single components.

Summary

Background and objective: Trials in acute postoperative pain are usually small. Pooling homogenous data from a number of trials in a meta-analysis enables a truer estimate of efficacy. The aims of the present meta-analysis were to assess the analgesic efficacy and adverse effects of single-dose oral tramadol plus acetaminophen (paracetamol) in acute postoperative pain, and to demonstrate the efficacy of the combination formulation compared with its components.

Methods: Individual data from >1400 adult dental or gynaecologic/orthopaedic patients with moderate-to-severe pain were taken from seven randomised, double-blind, placebo controlled trials of tramadol (75 mg or 112.5 mg) plus acetaminophen (650 mg or 975 mg) with identical methods. The primary outcome measure was the number of patients needed to be treated (NNT) for one patient to obtain at least 50% pain relief. Information on adverse effects was also collected and the number needed to harm (NNH) was estimated.

Results: The tramadol/acetaminophen combination was more effective than either of its two components administered alone. For dental patients, who formed the bulk of the population, the combination formulation also had a significantly lower (better) NNT (≈3) than the components alone (≈8–12), comparable to ibuprofen 400 mg. The adverse effects associated with tramadol/acetaminophen were similar to those associated with the components alone. The commonest were dizziness, drowsiness, nausea, vomiting and headache.

Conclusions: Meta-analysis confirmed the analgesic superiority of the combination treatment over its components, without additional toxicity. Combination analgesic formulations are an important and effective means of pain relief, and should prove useful in treating elderly and other groups of patients who often cannot tolerate non-steroidal anti-inflammatory drugs, including the newer COX-2 inhibitors.