Regional Anesthesiaand Pain Medicine23(4): 357-362, 1998
Spinal Anesthesia: Mechanisms, Agents,
Methods, and Safety
Astrid Chiari, M.D. and J.C. Eisenach, M.D.
Transmission of pain from peripheral tissues to
the brain is modulated in the dorsal horn of the
spinal cord. Incoming messages can be enhanced or
attenuated by transmitters derived from either pri-
mary afferent A delta and C-fibers, interneurons, or
descending bulbospinal fibers (1). After noxious
stimulation, excitatory neurotransmitters, such as
excitatory amino acids (glutamate, aspartate) and
peptides (substance P, calcitonin gene-related pep-
tide, somatostatin) are released from afferent fibers.
Compensatory inhibitory neurotransmitters in-
clude norepinephrine (NE), acetylcholine, endor-
phins, and serotonin. Thus, an interplay between
excitatory and inhibitory spinal neuronal systems
determines the message delivered to higher levels
of the central nervous system. Increased under-
standing of spinal processing of pain has led to
development of specific drugs that inhibit pain
transmission without motor block. This article de-
scribes the experimental background and clinical
use of these drugs.
Evaluation of the Safety for New
Intrathecal Drugs
The introduction of new spinal analgesic drugs
must be approached with caution because drugs
that are innocuous intravenously or epidurally are
potentially dangerous when administered into the
subarachnoid space (2,3). Intrathecal (IT) adminis-
tration of drugs close to the spinal cord offers the
advantage of a reduced dose required with fewer
side effects from systemic redistribution, but the
From the Department of Anesthesiology, Wake Forest Univer-
sity School of Medicine, Winston-Salem, NC.
Accepted for publication March 18, 1998.
Supported in part by the Max Kade Foundation.
Reprint requests: J.C. Eisenach, M.D., Department of Anes-
thesiology, Wake Forest University School of Medicine, Medical
Center Boulevard, Winston-Salem, NC 27157-1009.
Copyright © 1998 by the American Society of Regional
Anesthesia.
0146-521X/98/2304-000755.0010
357
dura, known as an effective barrier to the harmful
effects of drugs, is bypassed. To assure the safety of
a new IT drug, preclinical toxicity testing in a large
number of animals of different species is required
before the drug is administered to humans (4).
Local effects of the new agent on the spinal cord
must be examined by assessing animal behavior
and spinal cord histology as well as spinal cord
blood flow. In addition, effects of the new IT drug
on hemodynamics and arterial blood gas tensions
are warranted. Because neurotoxicity can be asso-
ciated with maldistribution after administration
into a restricted area (especially through a fine cath-
eter), it is important that the doses studied in these
animal experiments be far larger than the recom-
mended clinical doses. If toxicity experiments are
negative, phase 1 trials in humans can be per-
formed under standard monitoring conditions
where dosage guidelines and side effect profiles are
established. Controlled clinical trials follow before
the new drug gains widespread use.
Opioids
Intrathecal opioids block transmission of pain-
related information by binding at pre- and postsyn-
aptic receptors in the dorsal horn of the spinal cord
and also at brainstem sites, which they can reach
via cephalad cerebrospinal fluid (CSF) spread. Opi-
oid binding to specific mu, delta, or kappa receptors
increases potassium conductance and hence hyper-
polarizes the nerve membrane. Presynaptic effects
include a reduced release of primary afferent trans-
mitters, such as substance P and glutamate (1).
Postsynaptically, opioids hyperpolarize second-or-
der projecting neurons. Furthermore, activation of
presynaptic mu receptors on primary nerve termi-
nals has been shown to induce the release of spinal
adenosine, which seems to be an important medi-
ator in spinal opioid analgesia (5).
In addition to receptor binding affinity, lipophi-
licity is the most important determinant of onset,
358 Regional Anesthesia and Pain Medicine Vol. 23 No. 4 July-August 1998
spread, and duration of analgesia. Intrathecal mor-
phine, first described in humans in 1979, produces
analgesia with a delayed onset but with a duration
of 12 hours, thus making it suitable for postopera-
tive analgesia (6). Fentanyl and sufentanil are, re-
spectively, approximately 800 and 1,600 times as
lipid soluble as morphine (7) and penetrate the
spinal cord quickly, resulting in rapid onset of an-
algesia. Intrathecal sufentanil provides dose-depen-
dent analgesia (ED95 8,9/,g) for parturients in early
labor without motor block (8) within a few min-
utes, but duration is limited to about 90 minutes. In
parturients, IT opioids alone produce analgesia only
during the first stage and do not produce surgical
anesthesia. If added to bupivacaine, small doses of
fentanyl and sufentanil intensify the spinal anes-
thesia from bupivacaine (9).
Meperidine, an opioid with additional local anes-
thetic properties, enables surgical anesthesia for ce-
sarean delivery (10). However, it has a 30% inci-
dence of nausea and vomiting in addition to other
opioid-related side effects. Less commonly used IT
opioids include the partial-agonist buprenorphine,
alfentanil, which has a short duration of action and
the mixed opioid agonist/antagonist, nalbuphine.
The new ultra-short-acting mu-opioid remifen-
tanil, which is rapidly metabolized by plasma and
tissue esterases, has not yet undergone appropriate
neurotoxicity testing to allow IT administration to
humans, and the currently marketed preparation
contains glycine which could induce pain. Animal
data suggest, however, that IT remifentanil infu-
sions could lead to plasma levels sufficient to pro-
duce a supraspinal redistribution resulting in mea-
surable side effects (l i). Thus, the IT route of
administration of remifentanil does not have an
advantage over commonly used opioids.
Clearly, the IT administration of morphine can
deliver analgesia with fewer systemic side effects
than equivalent doses of systemic morphine. Three
out of the four classic side effects of IT opioids
(pruritus, nausea and vomiting, urinary retention,
and respiratory depression) (7) seem to be related
to cephalad migration of the drug in CSF and sub-
sequent interaction with opioid receptors in the
brainstem (trigeminal nucleus, area postrema, and
ventral medulla, respectively). Although the inci-
dence of pruritus can be decreased by increasing the
baricity of sufentanil, this is associated with a
shorter duration of analgesia (12). The most feared
side effect, respiratory depression, is thought to be
less frequent with the lipophilic opioids, leaving
little drug to ascend cephalad in CSF. However,
early respiratory depression has been reported with
10 /xg IT sufentanil, and rapid rostral spread of
lumbar epidural sufentanil has occurred in dogs
(13,14). Thus, recognition of the possibility of re-
spiratory depression is mandatory for all patients
receiving IT opioids. Most side effects, however, are
dose dependent and less common in patients
chronically exposed to IT opioids. Because of the
profound antinociception obtained and despite the
non-nociceptive side effects, spinal application of
opioids remains very popular and effective for
many pain conditions. In chronic pain and after
prolonged opioid exposure, however, opioids may
become ineffective. Proposed mechanisms include
opioid receptor downregulation, loss of receptors
on afferent terminals after nerve damage, and the
release of specific neurotransmitters after nerve in-
jury which decrease the effectiveness of opioids
(15).
Alpha-2 AdrenergicAgonists
Pain and systemic opioids trigger the release of
endogenous NE from bulbospinal descending neu-
rons, thus stimulating postsynaptic alpha-2 adreno-
ceptors in the spinal cord to produce analgesia.
Intrathecal injection of the alpha-2 adrenergic ago-
nist, clonidine, mimics this effect of NE and pro-
duces analgesia in animals and humans. Spinal
alpha-2 adrenergic-mediated antinociception also
involves a cholinergic interaction, because admin-
istration of clonidine results in increased acetylcho-
line concentration in sheep and in humans ( 16,17).
Clonidine was proved to have a higher analgesic
potency after neuraxial than after systemic admin-
istration, and, in volunteers, a concentration of
clonidine in CSF producing a 95% maximal anal-
gesia to a noxious stimulus in the lower extremity
(130 ng/mL) has been established (18).
Dexmetedomidine, which is more lipophilic and
has a higher affinity for the alpha-2 adrenergic re-
ceptor than donidine, seems to be more associated
with hypotension and does not offer any advantage
over clonidine.
Stimulation of postsynaptic alpha-2 adrenocep-
tors in the brainstem and in the intermediolateral
column of the spinal cord decreases sympathetic
outflow, which causes hypotension and bradycar-
dia (19). Sedation has also been observed with the
administration of alpha-2 adrenergic agonists be-
cause of actions in the locus ceruleus (20). In con-
trast, neuraxial clonidine has not been associated
with respiratory depression or motor block.
If administered intrathecally by itself, clonidine
fails to produce reliable surgical anesthesia (21)
despite a high dose (450 ~g). In contrast, IT
clonidine (150-450 /~g) provides dose-dependent
postoperative analgesia for w o m e n following cesar-

ean delivery (22), lasting up to i4 hours, but asso-
ciated with severe intense sedation and hemody-
namic depression.
In clinical practice, however, IT clonidine is
mainly administered in conjunction,with local an-
esthetics. Clinical studies confirm that clonidine
prolongs sensory and motor block from IT local
anesthetics (23,24) and reduces tourniquet pain
(25) without further decreasing blood pressure.
Although synergistic interactions between spinal
alpha-2 adrenergic agonists and opioids have been
observed in rodents (26), this does not seem to be
true in humans. The EDso of epidural donidine in
postoperative analgesia is markedly reduced in hu-
mans when combined with fentanyl, but this inter-
action is only additive, not synergistic (27). When
sufentanil and clonidine are combined spinally dur-
ing labor in small doses as well as in large doses,
duration of analgesia is prolonged, but the inci-
dence of hypotension limits the clinical usefulness
(28,29).
Because IT alpha-2 adrenergic agonists produce
analgesia through a different mechanism than IT
opioids, patients suffering from chronic pain toler-
ant to opioids can receive analgesia from alpha-2
adrenergic agonists alone or combined with opioids
(30-32).
Cholinergic Drugs
Spinal alpha-2 adrenergic receptor activation--
either through endogenous NE or spinally admin-
istered clonidine--involves spinal cholinergic path-
ways and transmitters to produce analgesia (16,17).
Spinally administered neostigmine causes anal-
gesia in animals and humans by preventing the
breakdown of synaptically released acetylcholine,
which acts on muscarinic and also nicotinic recep-
tors in the spinal cord. Because it is a quaternary
amine, neostigmine is unable to cross the blood-
brain barrier and therefore has to be administered
spinally to reach the spinal cord.
When injected intrathecally in volunteers,
neostigmine produces dose-dependent analgesia
but also severe nausea and vomiting, probably be-
cause of cephalad spread and action in the brain-
stem (33). This side effect can be reduced by inject-
ing the drug in a hyperbaric solution and by
keeping the head of the bed elevated. Because al-
pha-adrenergic agonists and neostigmine act
through the same mechanism, additive analgesic
enhancement has been observed with the combi-
nation of IT neostigmine and epidural clonidine
(34) in volunteers. In addition, neostigmine in-
creases sympathetic outflow, thus counteracting
New Spinal Analgesics • Chiari and Eisenach 359
the hypotension of IT local anesthetics and
clonidine (35 ).
In the clinical setting, IT neostigmine (25-100
/xg) coadministered with bupivacaine for spinal an-
esthesia revealed a dose-independent reduction in
postoperative rescue analgesic consumption; how-
ever, severe nausea and vomiting limited its useful-
ness (36). In obstetrics, IT neostigmine alone failed
to show any analgesic effect, but it increased the
analgesia from IT sufentanil (37). These studies sug-
gest that IT neostigmine might become a future
adjunctive spinal analgesic.
Although analgesic actions of acetylcholine have
been attributed mainly to actions on muscarinic
cholinergic receptors in the spinal cord (38), there is
also recent evidence that stimulation of spinal nic-
otinic receptors can produce analgesia. In rodents,
the specific nicotinic acetylcholine receptor ]igand
ABT-594 provided analgesia equal in efficacy to
morphine but without inducing physical depen-
dance in the animals with repetitive treatment (39).
Despite these promising data in animals, because of
species differences, the pharmacologic properties
might be different in humans. Therefore, after ap-
propriate neurotoxicity testing, controlled studies in
humans will be performed in the future.
N-MethyI-D-Aspartate Antagonists
Acute painful stimuli induce the release of neu-
rotransmitters (mainly excitatory amino acids) at
the first synapses within the dorsal horn of the
spinal cord which stimulate postsynaptic alpha-
amino-3-hydroxy- 5-methyl-4-isoxazole-propioic
acid (AMPA) receptors and lead to a brief neuronal
firing (15). If the painful stimulus continues, spi-
nally released peptides and glutamate can cooperate
to activate the N-methyl-D-aspartate (NMDA) re-
ceptor. Once the NMDA complex is activated, mas-
sive neuronal depolarizations occur with amplifica-
tion and prolongation of the response. This switch
from low-level activity to a much higher level has
been termed "wind up," which is characteristic of
centrally mediated hyperalgesia.
Animal studies suggest that activation of NMDA
receptors is involved in the development of chronic
pain caused by inflammation and nerve injury
(neuropathic pain). Intrathecally applied NMDA
antagonists to animals do not abolish pain, but
rather prevent or block central hypersensitive states
(40) which makes this substance class have promise
for treating patients suffering from neuropathic
pain. Spinal cord neurotoxicity studies of the IT use
of NMDA antagonists show evidence for neurotox-
icity of ketamine in large doses which might be
360 Regional Anesthesia and Pain Medicine Vol. 23 No. 4 July-August 1998
related to the preservative benzethonium chloride
(41). In addition, ketamine produces antihyperal-
gesic actions only at doses that impair motor func-
tion (40), and frequent psychomimetic side effects
represent another drawback of the substance class.
However, in patients with terminal cancer pain, IT
ketamine potentiated the analgesic effect of IT mor-
phine (42), while decreasing side effects and im-
proving the quality of life. Intrathecal injection of
the more potent, competitive NMDA antagonist
3-(2-carboxypiperacin-4-yl)propyl- 1-phosphonic
acid (CPP) alleviated intractable neurogenic pain in
a patient, but phychomimetic effects caused by ros-
tral spread limited its usefulness (43).
Although NMDA-receptor antagonism plays an
important role in the treatment of chronic pain,
neurotoxicologic data are not yet sufficient to per-
mit the use of either IT ketamine of CPP in clinical
practice.
Other Pharmacological Agents
Endogenous somatostatin is released from intrin-
sic spinal cord interneurons in the dorsal horn of
the spinal cord and induces an inhibitory effect on
nociceptive neurons. Intrathecally administered so-
matostatin relieves pain in animals and produces
effective analgesia in humans suffering from cancer
pain tolerant to opioids (44). Somatostatin has been
shown to be clearly more effective in neuropathic
than in somatic pain states (45). Although no pa-
tient showed any evidence of neurologic deficit af-
ter the somatostatin treatment, postmortem spinal
cord histopathologic studies revealed neuropatho-
logic changes in those patients who had received
the highest dose of somatostatin (3,000 /zg/d). In
animal studies using large doses, somatostatin can
produce neurotoxicity and a reduced spinal cord
blood flow, which is dose and species related
(46,47). Another difficulty is that somatostatin is an
unstable peptide that is degraded rapidly by en-
zymes in the central nervous system and is there-
fore not suited for long-term infusion. Intrathecal
octreotide, a stable analog of somatostatin, was
shown to be a powerful analgesic for cancer pain
with continuous infusion over several months (48).
However, it was less effective than clonidine in
relieving pain in a rat model of neuropathic pain
(49). In the face of existing animal toxicity data, IT
somatostatin administration seems to be only justi-
fied in selected patients with terminal cancer in
w h o m pain remains unrelieved despite large doses
of opioid analgesics.
The hormone calcitonin, which is secreted by the
thyroid gland, acts peripherally in controlling the
serum calcium concentration but is also thought to
have an analgesic effect in various chronic pain
states, possibly involving a serotonergic mechanism
(50). Intrathecally administered calcitonin, which is
normally present in the CSF in small amounts, pro-
duces pain relief for cancer patients (51,52) and in
the postoperative setting (53), but it also produces
nausea and vomiting. Animal toxicity studies of IT
calcitonin describe impaired motor coordination in
rats and respiratory distress in dogs and baboons
(54). Although no toxicity was observed in the
small number of patients studied, the safety of IT
calcitonin must be demonstrated in animals prior to
further administration in humans.
Because pain transmission in the spinal cord is
linked to the activation of voltage-sensitive calcium
channels of the N-type, selective calcium channel
blockers can potentially produce analgesia. In a ro-
dent model of neuropathic pain, the IT administra-
tion of SNX 111 produces antinociceptive effects
without producing tolerance (55). Its suitability for
IT use in humans is currently being investigated.
Summary
Recent advances in our understanding of neuro-
transmitter and receptor pharmacology in the spi-
nal cord have provided new directions for the
development of novel analgesic compounds. Al-
though IT opioids provide effective analgesia for
most patients, limited duration of action, tolerance,
and side effects represent a limitation. Nonopioids
such as alpha-2 adrenergic and cholinergic agonists
may be more suited as adjuvants rather than sole
analgesic agents. N-methyl-D-aspartate antagonists
could be used to treat centrally mediated hyperal-
gesia, although ketamine might have a neurotoxic
potential. The role of other agents in pain manage-
ment, such as somatostatin analogs, calcitonin, and
calcium channel blockers, which all act by different
pathways, remains to be determined. It is essential
that appropriate animal neurotoxicity studies fol-
lowed by controlled clinical trials are performed
before widespread spinal administration of new
drugs.
The combined use of low doses of drugs with
separate but synergistic mechanisms of analgesia
can reduce the required dose as well as unwanted
side effects.
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