43 Neuraxial Agents
Robert W. Hurley | Dustin Anderson | Steven P. Cohen
Medication delivery to the spinal cord or the dorsal nerve
roots via the intrathecal or epidural route exploits the
endogenous pharmacology of the neuraxis to relieve pain in
patients. These methods of delivery require a certain degree
of expertise and are commonly used by anesthesiologists
and interventional pain management specialists. In 1885,
Leonard Corning described the first neuraxial administra-
tion of a medication, first in a dog and then in a man suf-
fering from “seminal incontinence.”1 Fourteen years later,
Augustus Bier (Fig. 43.1) reported the first case whereby
cocaine was administered intrathecally to provide surgical
anesthesia for lower limb orthopedic procedures.2 The first
use of a neuraxial technique to treat chronic pain was in
1901 when Sicard administered a local anesthetic epidu­rally
via the caudal route.3 Another significant breakthrough
occurred in 1942 when Manalan used a catheter to continu-
ously administer medication for labor analgesia.4 The epi-
dural injection of steroids for the treatment of sciatica was
first described in 1953.5 Several years after the discovery of
the endogenous opioid receptors and their respective ago-
nists, Wang reported treating cancer pain with intrathecal
morphine.6
This chapter focuses on the current pharmacologic
agents that are administered into the epidural or intrathecal
space to produce antinociception (in animals) or analgesia
(in humans), as well as future potential agents. The out-
comes of neuraxial anesthesia and analgesia on postsurgical
morbidity, as well as long-term neuraxial analgesia either by
intrathecal pump or a tunneled epidural catheter, are cov-
ered elsewhere in this text and, hence, are not addressed in
this chapter.
PERIPHERAL NERVE NEUROTRANSMITTERS
AND THE SPINAL CORD
A variety of mechanical, thermal, or chemical stimuli can
result in the sensation of pain. Information about these
painful or noxious stimuli is carried to higher brain cen-
ters by receptors and neurons that are distinct from those
that carry innocuous somatic sensory information. Small-
diameter A-delta and C fibers primarily transmit nociceptive
information. Neurotransmission by A-delta and C fibers is
accomplished via the release of numerous peptides, includ-
ing substance P, calcitonin gene-related peptide, galanin,
vasoactive intestinal peptide, and somatostatin into the
spinal cord. The excitatory amino acid, glutamate, is also
present within small-diameter primary afferents and can be
released by noxious stimulation, resulting in the activation
of second-order neurons in the dorsal horn of the spinal
cord.7 The presynaptic nerve terminals of primary afferents
582
in the spinal cord are potential therapeutic targets. They
possess numerous receptor systems that can enhance trans-
mission by increasing the release of excitatory amino acids
and other transmitters, activating voltage-gated calcium
channels and purinergic receptors, and inhibiting pathways
involved in the modulation of pain, such as alpha2-adrenergic,
cholinergic, serotonergic, and opioid receptors as well as
gamma-aminobutyric acid (GABA) systems.8-12
Primary afferent neurons release neurotransmitters, acti-
vating postsynaptic receptors on second-order projection
neurons in the spinal cord (Fig. 43.2).13 Second-order neu-
rons in the dorsal horn possess a wide variety of neurotrans-
mitter receptors. A subset of these receptors, including
those involving substance P and the excitatory amino acid
glutamate (e.g., N-methyl-d-aspartate [NMDA] and α-amino-
3-hydroxy-5-methylisoxazole-4-propionic acid [AMPA] kai-
nate, mGluR), can induce depolarization of the neuron,
leading to increased nociceptive transmission. Activation
of other receptors such as opioid, GABAA-ergic and sero-
toninergic incites hyperpolarization of postsynaptic neu-
rons, thereby inhibiting the transmission of noxious stimuli.
Neurotransmission by second-order neurons on bulbar or
thalamic targets is primarily through glutamate, resulting in
depolarization of postsynaptic AMPA and NMDA receptor-
containing neurons.14
NEURAXIAL AGENTS
Medications approved by the Food and Drug Adminis-
tration (FDA) can be used for a multitude of purposes,
including not only the approved indication, but for off-
label indications as well. This practice is common with
systemically delivered medications. Unfortunately, it has
also become common practice to use medications approved
for systemic use in anatomic sites that have not been tested
for safety. These sites include the intrathecal or epidural
compartments that can result in actual or potential risk
to the spinal cord of patients.15 During 2007-2008, the
journals–Anesthesia & Analgesia, Anesthesiology, and Regional
Anesthesiology and Pain Medicine–revised their instructions
to authors to address this concern and established the fol-
lowing policy:16
. Is the drug approved by the FDA for this indication?
1
2. If the drug is not approved, is it widely used off-label
(e.g., in tens of thousands of patients)? [The] editorial
board concluded that if multiple textbooks indicated
that the drug could be safely used in a given manner, this
was a suitable surrogate demonstration that the drug was
widely used for the indication.