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Multimodal analgesia was popularized in 1993 by Kehlet and Dahl and described as “combined analgesic regimens” in order to achieve “sufficient analgesia due to additive or synergistic effects between different analgesics, with concomitant reduction of side effects.”1 Through the past 20 years, many patients have benefitted from practical implementation of this concept. By modulating multiple receptor-ligand systems involved in the transduction and sensation of pain, we have also appreciated the ability for certain agents to reduce acute postoperative pain and, therefore, reduce the incidence of persistent postsurgical pain. Several individual medications have been identified, although precise dosage, timing, and route of administration have yet to be completely understood. Additionally, there are techniques available, which if used in the perioperative phase, may prevent development of chronic pain after surgery.


Many analgesic combinations have been shown to demonstrate synergistic analgesia when used in combination, as opposed to the analgesic effects of those agents used individually. Examples include combinations of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), N-methyl D-aspartate (NMDA)–receptor antagonists, anticonvulsants, and corticosteroids. Other mechanisms of analgesia include the use of regional anesthesia and local wound infiltration.

The sum of these efforts can result in a postoperative course that allows patients undergoing some of the more painful surgical procedures, even total knee arthroplasty, to meet discharge criteria and be discharged the same day as surgery.2,3

Surgical stimuli produce a multitude of mediators—leading to inflammation, sensitization, and pain.4,5 The process begins with tissue damage and the production of prostaglandins (PGs), particularly PGE2.4 Other mediators include histamine, bradykinin,5 substance P, and the excitatory neurotransmitters (glutamate and aspartate).6 Nociceptors become sensitized as a result of the expression of the c-fos, nitric oxide (NO) synthase, and cyclooxygenase (COX) genes augmenting the sensation of pain and perhaps beginning the process of developing persistent postsurgical pain. By using a multimodal approach to treating acute surgical pain, the various mediators or their targets, optimal pain relief can be achieved both acutely and chronically.


Acetaminophen, (paracetamol), produces its analgesic effect by inhibiting central prostaglandin synthesis with minimal inhibition of peripheral prostaglandin synthesis.7,8 Often labeled as an NSAID, the two substances have some important differences. This includes acetaminophen’s weak anti-inflammatory effect9 and its generally poor ability to inhibit COX in sites of inflammation.10 Unlike NSAIDs, acetaminophen does not have an adverse effect on platelets11 or the gastric mucosa.10

The use of acetaminophen in the perioperative setting had been limited until intravenous (IV) acetaminophen became available for use. The IV formulation has some benefits over enteral routes of administration; bioavailability is 100% and shorter time peak effect; the onset of ‘meaningful’ pain relief is less than 30 minutes after administration.12 In addition, the IV formulation of ...

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