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NB: Several studies authored by Dr. S. Reuben that have since been retracted were referenced in the previous edition of this text. These references have been removed. All references remaining in which Dr. Reuben was involved that have not been retracted are still referenced.

Peripheral nerve blocks provide many benefits for patients, including superior pain control and reduction in general anesthesia-related side effects. To optimize pain relief while reducing the total dose of local anesthetic, it would be of use to add a drug that both speeds onset and prolongs sensory blockade or analgesic effect. Improvements in our knowledge of peripheral nervous system (PNS) pain mechanisms allow us to develop methods of prolonging analgesia while reducing central and peripherally mediated adverse effects.

In the last 20 years, a number of drugs have been tested, and several have proven clinically useful when added to local anesthetic for peripheral nerve block or when used for local infiltration or intra-articular analgesia. These drugs are known as analgesic adjuvants.

This chapter examines the rationale and current evidence base for use of analgesic adjuvants and summarizes the best strategies for optimizing pain control and reducing adverse effects after surgery under peripheral nerve block, local infiltration, or injection of drugs in the intra-articular space.


Pain transmission in the CNS and PNS involves a complex array of neurotransmitters and pathways that are not easily blocked by one drug type or technique alone. Involvement of several classes of neurotransmitter at the injury site, peripheral nerve, dorsal horn of the spinal cord, and supraspinal sites is responsible for the transmission of nociception. Use of agonists at inhibitory receptors and antagonists at excitatory receptors allows a “multimodal” approach with optimization of pain control and reduction of adverse effects.1

In 1645, Descartes proposed a mechanism for pain transmission, suggesting that a peripheral pain impulse was transmitted directly from the periphery to the brain by a “hardwired” system without any intermediate modulation (Figure 9–1). This theory of pain transmission was widely held as true until as recently as 40 years ago.

Figure 9–1.

Descartes model of pain transmission in the peripheral nervous system.

In 1965, Melzack and Wall proposed their groundbreaking gate control theory of pain that suggested that pain could be modulated or “gated” at a number of points in the pain pathway. Subsequent research identified the dorsal horn (lamina II) of the spinal cord as an important site of potential modulation, and subsequent treatments for acute and chronic pain have utilized this knowledge to good effect. Treatments such as the use of spinal opioids and transcutaneous electrical nerve stimulation (TENS) have been developed in the light of this knowledge. The gate theory also changed many (often unsuccessful) pain management ...

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