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Understanding the physiology and

pharmacology of epidural and intrathecal
opioids
Christopher M. Bernards MD
Professor of Anesthesiology
University of Washington, Box 356540, Seattle, WA 98195, USA
Epidural and intrathecal opioid administration has become an important part of contemporary
medical practice in a variety of clinical settings. It has been widely assumed that any opioid
placed in the epidural or intrathecal spaces will produce highly selective spinally mediated
analgesia that is superior to that produced by other analgesic techniques. Unfortunately, this is
simply not true. In fact, multiple opioids are currently employed for spinal use despite the fact
that clinical evidence has shown that spinal administration does not produce analgesia with a
selective spinal mechanism or that the analgesia produced is not superior to that produced by
intravenous administration. This chapter presents the basic science and clinical data available
to assist clinicians in identifying which opioids are appropriate for spinal use and which
are not.
Key words: opioids; epidural; intrathecal; analgesia; spinal.
In the 1970s opioid receptors were identi®ed in the spinal cord and shown to produce
potent analgesia without the dose-limiting, supraspinal side-e€ects associated with
systemic opioid administration. Anaesthesiologists rapidly adopted spinal opioid
administration in the belief that it was now possible to separate the desirable analgesic
e€ects of opioids from their untoward side-e€ects.
Unfortunately, it was not until several deaths and near-deaths were reported that
clinicians recognized that spinally administered opioids can reach brainstem sites to
produce the same dose-limiting side-e€ects associated with systemic opioid
administration. Distribution to supraspinal sites occurs either because the opioid
spreads rostrally in cerebral spinal ¯uid or because it is cleared into the bloodstream
from which it is re-distributed to the brainstem.
Fortunately, it is possible to maximize the spinally mediated e€ects of an opioid and
to minimize the risk of supraspinal side-e€ects. To do so requires that we choose the
appropriate spinal route (epidural versus intrathecal), the appropriate opioid, and the
appropriate opioid dose. Thus, the remainder of this chapter will provide the clinician
with the information necessary to make these choices rationally.
Importantly, it is not the intent of this chapter to present a cookbook approach to
providing spinal opioid analgesia; patients, pain states, drug availability from country to
country, and the capabilities of medical facilities are simply too varied to permit a `one
1521±6896/02/$ - see front matter*c
2002 Elsevier Science Ltd. All rights reserved.
Best Practice & Research Clinical Anaesthesiology
Vol. 16, No. 4, pp. 489±505, 2002
doi:10.1053/bean.2002.0255, available online at http://www.idealibrary.com on
2
size ®ts all' approach. In addition, new opioids and new classes of spinal analgesic drugs
will become available in the future and clinicians will need to understand the basic
physiology of spinal drug delivery to best employ these new compounds. Therefore,
the ®rst major section of this chapter will describe what is known about the
physiology of opioid distribution from the epidural and intrathecal spaces to spinal
cord opioid receptors. This `mechanistic' information will allow the reader to
understand why one opioid or route of administration is expected to be better than
another with respect to achieving a selective spinal site of analgesic action. The second
major section of the chapter will present the relevant clinical information that
con®rms what the basic science studies suggest.
THE PHYSIOLOGY GOVERNING THE BIOAVAILABILITY OF
SPINALLY ADMINISTERED OPIOIDS
For the purposes of this discussion, the bioavailability of a spinally administered opioid
refers to the ability of that opioid to distribute from its site of administration (epidural
or intrathecal) to its site of action. The site of action for spinally administered opioids
resides in the grey matter of the spinal cord dorsal horn (principally laminae II), which
is surrounded by a mantle of white matter. Consequently, to reach its intended site of
action, an epidurally administered opioid must traverse, in turn, the contents of the
epidural space, the spinal meninges, the cerebrospinal ¯uid (CSF) and the spinal cord
white matter to ®nally reach lamina II of the dorsal horn. With intrathecal
administration, the tissues that must be traversed are correspondingly reduced.
Consequently, in adults the distance that a spinally administered opioid may need to
travel to reach its site of action can be in the order of tens of millimetres. Contrast this
with the distance the same opioid must travel to reach brainstem opioid receptors
after systemic administration. Because the bloodstream distributes the opioid to within
a few micrometres of the targeted opioid receptor, di€usion distances are, at
minimum, several orders of magnitude less than that following spinal administration. In
addition, the only tissue barrier that systemically administered opioids must traverse is
the capillary of the cerebral vasculature. As we shall see, these di€erences in di€usion
distances and tissue barriers explain the marked di€erences in relative potencies of
opioids when administered spinally compared to systemically.
Epidural space
The epidural space is bounded on its outer edge by the vertebral bodies and the
ligaments running between them and on its inner edge by the spinal meninges. The
human epidural space contains a relatively large volume of fat which is compartmenta-
lized and resides largely in the anterolateral epidural space.
1,2
The epidural venous
plexus also occupies a relatively large volume of the epidural space. This plexus connects
the veins of the pelvis with those of the azygous vein and it drains the epidural fat, the
spinal cord, and the vertebral bodies among other structures.
Importantly, any drug placed in the epidural space will di€use down its concentration
gradient and into the surrounding tissues. The rate and extent to which a drug moves
into any particular tissue will depend on the volume of that tissue and the tissue's
physicochemical properties relative to the physicochemical properties of the particular
opioid. For example, the laws of thermodynamics dictate that hydrophobic drugs will
preferentially distribute into hydrophobic environments. Consequently, one would
490 C. M. Bernards
expect hydrophobic opioids (e.g. sufentanil, fentanyl) to di€use preferentially into
epidural fat as opposed to CSF. Drug that partitions into fat is no longer bioavailable to
spinal opioid receptors.
Thus, in a very real sense the spinal cord competes with adjacent tissues for the
available opioid. Therefore, choosing an opioid for which uptake by extra-spinal tissues
is minimized will result in more drug reaching the spinal cord target site and less
reaching the systemic circulation. As we shall see, both experimental and clinical data
suggest that the spinal bioavailability of hydrophilic opioids exceeds that of
hydrophobic opioids.
Spinal meninges
Dura mater
Except for the occasional ®broblast, the dura mater is essentially acelluar and is
composed primarily of collagen and elastin ®bres. Surprisingly, given its acellular
nature, the dura mater is quite vascular and in fact has a rich capillary network
apposed to the underlying arachnoid mater.
3±5
Why this avascular tissue has such a
substantial blood supply is unknown but it may be that it is responsible for supplying
nutrients to the adjacent arachnoid mater, which lacks a blood supply of its own.
Whether intended or not, this capillary network also acts to clear some portion of
an opioid dose as it di€uses from the epidural space to the subarachnoid space. Because
hydrophobic molecules are much more permeable across capillary endothelial cells
than are hydrophilic molecules, this is another site at which hydrophobic opioids may
be cleared to a greater extent than are hydrophilic opioids. Further evidence that the
capillary network of the dura mater is an important site for drug clearance comes
from animal studies demonstrating that epidural adrenaline (epinephrine) reduces dura
mater blood ¯ow
6
in parallel with adrenaline's (epinephrine's) ability to reduce
clearance of epidurally administered drugs.
Because the dura mater is by far the thickest of the spinal meninges it has been
suggested that it is the most important permeability barrier to movement of drugs
between the epidural space and the subarachnoid space. However, this is not true.
Experimental data clearly demonstrate that the arachnoid mater is the most important
meningeal permeability barrier.
7
This fact explains why CSF is con®ned to the
subarachnoid space ± that is, because the arachnoid is impermeable to the water,
electrolytes and proteins that make up CSF, thereby con®ning the CSF to the
subarachnoid space and not the subdural space.
Arachnoid mater
The arachnoid mater is composed of six to eight overlapping tiers of ¯attened
epithelium-like cells connected to one another by frequent tight junctions and
occluding junctions.
8,9
It is this cellular architecture that accounts for the very low
permeability of the arachnoid mater. In fact, the arachnoid mater accounts for more
than 90% of the resistance to drug di€usion (Figure 1).
7
Interestingly, the permeability of the arachnoid mater depends on a molecule's lipid
solubility, but not in the way that one might expect. The relationship between
hydrophobic character and arachnoid permeability is biphasic (Figure 2).
10
As lipid
solubility increases, so too does permeability, but only until a moderate octanol :bu€er
distribution coecient of approximately 125. Thereafter, as lipid solubility increases
Epidural and intrathecal opioids 491
further meningeal permeability decreases signi®cantly. Consequently the permeability
of morphine (octanol :bu€er distribution coecient ˆ 1) and sufentanil (octanol: buf-
fer distribution coecient ˆ 1787) is nearly identical. While this might seem unusual,
it is in fact common to all tissues that have been examined. For example, skin, cornea
and even the blood±brain barrier exhibit this same relationship between lipid
solubility and permeability, although the in¯ection point di€ers for di€erent tissues.
The reason for this `biphasic' relationship lies in the fact that drugs crossing the
arachnoid must repeatedly partition into lipid bilayers of the arachnoid mater cells,
di€use across the lipid bilayer and then partition into the aqueous extra- or
intracellular space. Highly lipid-soluble drugs easily partition into the lipid bilayer but
they partition back into aqueous environments with diculty and this slows their
movement through the arachnoid. Hydrophilic drugs have the opposite problem,
which similarly slows their di€usion. Drugs of intermediate lipid solubility, on the
other hand, negotiate the aqueous±lipid interface with greater facility and this results
in more rapid movement through the tissue.
A ®nal aspect of arachnoid physiology to consider is the presence of arachnoid
granulations or villi. These are evaginations of the arachnoid mater in the region of the
spinal nerve root cu€ that lie within epidural veins or, rarely, freely in the epidural
space. These are analogous to the arachnoid villi in the brain that function as sites of
CSF re-absorbtion. It has been suggested that these villi provide a route by which
epidurally administered drugs can move from the epidural space into the CSF.
Figure 1. Permeability of morphine through the individual spinal meninges of the monkey
(Macaca nemestrina). The arachnoid mater accounts for the overwhelming resistance to drug di€usion.
Reproduced from Bernards CM & Hill HF (1990, Anesthesiology 73: 1214±1219) with permission.
492 C. M. Bernards
However, experimental data clearly show that this is not true.
11
In addition, studies of
arachnoid villi function indicate that movement of material through them is by active
transport via pinocytosis, not open pores, and that the direction of movement is from
the CSF outward. Transport into the CSF does not occur.
Pia mater
The pia mater lies on the surface of the spinal cord and is composed of cells similar to
those of the arachnoid mater. The important di€erence is that the pia is generally only
one cell thick, does not contain occlusive intercellular junctions and is fenestrated.
Consequently, the pia presents very little resistance to drug di€usion.
Cerebrospinal ¯uid
Except for e€ects of baricity and the kinetic energy imparted by injection, opioids that
reach the CSF can be expected to behave identically whether they arrived by direct
injection or by di€usion from the epidural space.
One of the most important clinical factors that distinguish opioids from one another
is their propensity to spread rostrally in the CSF. Importantly, it has been suggested
that hydrophilic opioids spread rostrally more rapidly and to a greater extent than do
hydrophobic opioids. However, this view is only partially correct.
With respect to rostral spread, all opioids move at almost exactly the same rate. To
understand why this is true, consider the two mechanisms by which drugs move in the
CSF ± simple di€usion and bulk ¯ow. The rate of simple di€usion of any molecule in an
Figure 2. The relationship between hydrophobicity (octanol: bu€er distribution coecient) and drug
permeability through the intact spinal meninges of the monkey (M. nemestrina). Note that permeability
initially increases as `lipid solubility' increases but that there is a limit to the e€ect of hydrophobicity. As
hydrophobicity increases beyond an octanol:bu€er distribution coecient of approximately 125, meningeal
permeability actually decreases. Reproduced from Bernards CM & Hill HF (1992, Anesthesiology 77: 750±756)
with permission.
Epidural and intrathecal opioids 493
ideal liquid is proportional to the temperature of the liquid and inversely proportional
to the square root of the molecule's molecular weight. Because CSF temperature is
constant and the square root of the molecular weight of opioid molecules are very
nearly the same (range ˆ 17±20) di€usion cannot explain di€erences in opioid
distribution in CSF. Moreover, di€usion rates are too slow to explain observed rates of
drug spread in CSF.
The principal cause of drug spread in the CSF is movement of the CSF itself.
The energy responsible for CSF movement comes from the pulsatile ¯ow of blood into
the CNS, which transiently increases the volume of the brain (and to a lesser extent
the spinal cord). The pulsing brain acts like a plunger, forcing CSF down the dorsal
surface of the spinal cord and up the ventral surface.
12
As the CSF moves it carries
along any drug molecules suspended in it.
Therefore, given that rates of drug movement by di€usion and by CSF bulk ¯ow are
comparable for all opioids, how can one explain observed di€erences among opioids in
the amount of drug that spreads rostrally over time? The answer is that drugs are
cleared from CSF at di€erent rates. If a drug is cleared relatively rapidly from CSF, then
there will be relatively less drug remaining when the ascending CSF wave front
reaches more rostral sites. The converse is obviously true for drugs that are cleared
more slowly from CSF. For example, sufentanil clearance from human CSF is 27 ml/kg/
minute, which is nearly 10 times the rate for morphine (2.81 ml/kg/minute).
13
The
consequence of slow clearance is that morphine resides in the CSF long enough to
reach brainstem sites in sucient concentration to cause supraspinal side-e€ects (e.g.
sedation, respiratory depression). Rapidly cleared drugs such as sufentanil are in too
low a concentration to cause signi®cant supraspinal side-e€ects by rostral spread in
CSF. However, hydrophobic opioids do cause supraspinal side-e€ects because they are
rapidly cleared into plasma and re-distributed to the brainstem via the bloodstream.
The relevant clinical question with respect to analgesia is not how rapidly a drug is
removed from CSF but, rather, where does it end up once it is cleared. Obviously
drug cleared into the spinal cord dorsal horn has a much greater bioavailability than a
drug cleared into the plasma or epidural space. This issue is discussed in the next
section.
Drug distribution in spinal cord
Opioids suspended in CSF must partition into the spinal cord to reach targeted opioid
receptors. Like the epidural space, the CNS consists of heterogeneous environments
into which opioids can partition. This fact was well demonstrated in a now classic
experiment by Herz and Teschemacher.
14
These investigators administered radio-
labelled morphine, dihydromorphone and fentanyl into the CSF of the lateral cerebral
ventricle of rabbits, and then used autoradiography to measure the distance that the
opioids moved into the substance of the adjacent brain over time. They found that all
three opioids had penetrated approximately 700 micrometres at the earliest time
point (7 minutes) (Figure 3). However, as time progressed fentanyl never penetrated
any deeper into the brain and was completely cleared from the brain by 120 minutes.
In contrast, both morphine and hydromorphone continued to move deeper and
deeper into the brain so that by the end of the study (5 hours) morphine had reached
a depth of 3000 micrometres. Perhaps more important than the di€erential depth of
penetration was the observation that fentanyl demonstrated a `pronounced preference
for ®ber structures' (white matter) while the hydrophilic opioids preferentially
distributed into grey matter.
494 C. M. Bernards
This observation should not be surprising. White matter consists primarily of axonal
plasma membranes, which are, in turn, wrapped by multiple layers of Schwann cell
membranes. Consequently, white matter is approximately 80% lipid, which is a
thermodynamically preferred environment for hydrophobic opioids such as fentanyl
and sufentanil. Because grey matter lacks myelin, it is relatively hydrophilic, which
explains the preferential partitioning of morphine and hydromorphone into grey
matter observed by Herz and Teschemacher.
How do these observations pertain to the bioavailability of spinal opioids? Recall that
opioid receptors lie within the spinal cord grey matter and that grey matter is
surrounded by a mantle of white matter. Hydrophobic opioids present in the CSF will
preferentially partition into the white matter from which they are cleared into plasma.
Partitioning of fentanyl and sufentanil into spinal cord white matter probably explains
the relatively large apparent volume of distribution (VOD) for these two opioids after
intrathecal administration. In contrast, hydrophilic opioids such as morphine will not
partition into white matter to the same extent but will tend to remain in the CSF
(hence morphine's relatively long CSF residence time) or they will di€use through the
aqueous extracellular ¯uid space of the white matter to reach the underlying grey
matter. Consequently, the opioid receptor bioavailabilityof hydrophilic opioids exceeds
that of hydrophobic opioids. This fact was clearly demonstrated in our swine model of
intrathecal opioid distribution.
15
Figure 4 shows opioid concentration over time in the
extracellular ¯uid space of the spinal cord after intrathecal administration of equi-molar
amounts of morphine, alfentanil, sufentanil and fentanyl. Opioid amounts in the
Figure 3. The depth to which morphine, fentanyl and dihydromorphone di€used into the rabbit brain from
the CSF of the lateral cerebral ventricle. Note the much greater depth of penetration and the longer
residence time of the hydrophilic opioids morphine and dihydromorphone. Reproduced from Herz A &
Teschemacher H (1971, in Harper N & Simmonds A (eds) pp 79±117. London: Academic Press) with
permission.
Epidural and intrathecal opioids 495
extracellular ¯uid space are the only clinically relevant drug fractions because this is the
opioid that is freely di€usible and can therefore reach membrane-bound opioid
receptors facing the extracellular ¯uid space. One can clearly see that the bioavailability
of morphine far exceeds that of any of the more lipid soluble opioids (Figure 4).
Additional evidence of the poor bioavailability of hydrophobic opioids comes from
studies by McQuay and colleagues who demonstrated that the analgesic potency of
intrathecal opioids in the rat is inversely related to the drug's hydrophobicity.
16
The preceding discussion makes clear that the overall e€ect of increasing opioid
hydrophobicity is to decrease bioavailability at opioid receptors in the spinal cord
dorsal horn. As described below, this fact explains the relatively greater analgesic
potency of spinally administered morphine compared to more hydrophilic opioids and
the fact that some opioids lack spinal selectivity entirely.
CLINICAL PHARMACOLOGY OF SPINAL OPIOIDS
For the reasons presented above, the clinical pharmacology of opioids varies markedly
among the drugs currently available. With respect to spinal administration, the most
O
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Figure 4. Opioid concentration over time in the extracellular space of the spinal cord following lumbar
intrathecal injection of equimolar doses of each drug. Note that the concentration of morphine over time far
exceeds that of any of the other opioids both at the lumbar site of administration and at the more rostral
thoracic spinal cord segment. Reproduced from Ummenhofer WC et al (2000, Anesthesiology 92: 739±753)
with permission.
496 C. M. Bernards
important di€erences are the degree to which analgesia is spinally mediated. The
following sections describe the clinical data necessary for clinicians to understand
whether an opioid produces analgesia via a predominately spinal or supraspinal
mechanism. This information is summarized in Table 1.
Epidural opioids
Any opioid placed anywhere in the body, from the left ear lobe to the right great toe,
will produce analgesia if for no other reason than that the drug is cleared into the
plasma and re-distributed to brainstem opioid receptors. Thus, the fact that putting an
opioid in the epidural space produces analgesia is not, in and of itself, proof of a
selective spinal site of action. Consequently, the decision to employ a particular opioid
in the epidural space must be based, at a minimum, on appropriate evidence that the
analgesia produced by that opioid is mediated via a spinal site of action.
However, evidence of a spinal site of action is not sucient to justify epidural use of
an opioid. Given the potential risks and the signi®cant expense of epidural opioid
analgesia, it can be justi®ed only by evidence that the technique provides either
superior analgesia, fewer side-e€ects, or both, when compared to less invasive
techniques (e.g. intravenous PCA). In the absence of such evidence, it is dicult to
justify the use of an opioid in the epidural space.
Fortunately, the last two decades have generated a large number of clinical studies
examining the relative ecacyof epidural andparenteral opioids. Workby Kilbride et al
serves as an example of one such study that demonstrates a clinical bene®t to epidural
morphine analgesia.
17
In this study, women who had undergone Caesarean section were
randomized to receive their post-operative analgesia from intramuscular morphine,
intravenous PCA morphine or epidural morphine. These investigators found that over
the 5 days of the study, women who used PCA morphine used 68 mg/day on average
while women receiving morphine epidurally used only 17 mg/day and women receiving
intramuscular morphine used 41 mg/day. Despite using only one-quarter as much
morphine, the women in the epidural group reported signi®cantly better analgesia than
the PCA group who, in turn, reported signi®cantly better analgesia than the
intramuscular group. The fact that women in the epidural group obtained better
analgesia with much less morphine is proof of a spinal site of action for this opioid.
Table 1. Degree of spinal selectivity for opioids used to treat post-operative pain.
Opioid Epidural administration
Intrathecal
administration
Morphine High High
Hydromorphone High High
Heroin High High
Methadone
a
Moderate Moderate
Alfentanil Negligible Unknown
Fentanyl
b
Low Moderate
Sufentanil Negligible Moderate
Meperidine
c
Unknown Unknown
a
Methadone's long plasma half-life results in progressively increasing plasma
concentrations as the duration of administration increases.
b
Spinal selectivity of epidural fentanyl appears to be greater in pregnant women.
c
Meperidine's local anaesthetic e€ect makes it dicult to determine whether
analgesia is mediated by opioid or local anaesthetic, or both.
Epidural and intrathecal opioids 497
This and numerous other studies with similar results provide convincing evidence that
morphine is an appropriate opioid for use in the epidural space.
During the decade of the 1980s, numerous clinical studies were conducted in which
hydrophobic opioids (principally fentanyl and sufentanil) were used in the epidural
space. These studies were predicated on the belief that these drugs would have greater
spinal bioavailability and therefore greater ecacy than morphine because of their
hydrophobic character (N.B. most of the mechanistic studies described above had not
yet been performed). As you would expect, these studies uniformly demonstrated that
epidural fentanyl and sufentanil did produce analgesia.
Unfortunately, the majority of these studies lacked adequate controls to determine
whether the observed analgesic e€ect was spinally mediated. One of the ®rst studies to
question the conventional wisdom regarding the suitability of fentanyl for epidural use
was conducted by Loper et al.
18
These investigators used a double-blind study design
to randomize patients who had undergone open knee reconstructions to receive their
post-operative analgesia via either epidural or intravenous fentanyl infusion. These
investigators found that the quality of analgesia and the amount of fentanyl used were
not di€erent between the two groups nor was the incidence of opioid-mediated side-
e€ects. In addition, when plasma fentanyl concentrations were measured 18 hours
after beginning the drug, there was no di€erence between the two groups (epidural
1.7 + 0.4 ng/ml; intravenous 1.8 + 0.4 ng/ml). These investigators concluded that the
principal analgesic mechanism for epidurally administered fentanyl was systemic uptake
and re-distribution to brain.
Glass and colleagues used a randomized, double-blind, cross-over study design to
compare post-operative analgesia and opioid use when fentanyl was administered via
intravenous PCA and patient-controlled epidural analgesia (PCEA).
19
These investi-
gators found no di€erence in quality of analgesia, amount of fentanyl self-administered
or the incidence of opioid-mediated side-e€ects between the two routes of fentanyl
administration. They concluded that epidural analgesia was mediated by uptake into
plasma and re-distribution to brainstem opioid receptors.
Some have argued that these studies failed to ®nd a signi®cant spinal analgesic e€ect
of epidural fentanyl because this opioid's limited rostral spread necessitates that it be
placed in the epidural space at the spinal level receiving the painful a€erent input. This
issue was addressed in a study by Guinard and colleagues who randomized
thorocotomy patients to receive post-operative analgesia via intravenous fentanyl
PCA, lumbar epidural fentanyl PCEA or thoracic epidural fentanyl PCEA.
20
The study
found that the quality of analgesia at rest and with coughing was the same for all three
routes of administration as was the fentanyl dose and the incidence of opioid-mediated
side-e€ects. Thus, even when fentanyl is placed in the epidural space opposite the
spinal cord segment receiving the painful a€erent input these investigators found no
evidence of a clinically important spinally-mediated analgesic e€ect.
Importantly, the above studies were conducted with fentanyl as the sole analgesic.
While this study design permits quanti®cation of opioid-mediated analgesia it does not
mimic the commonclinical practice of co-administering a local anaesthetic withfentanyl.
However, Berti et al have attempted to determine whether adding fentanyl to epidural
local anaesthetic improves the quality of post-operative analgesia.
21
In this study, two
groups of patients were randomized to receive post-operative analgesia from either
epidural ropivacaine (0.2%) alone or epidural ropivacaine plus 2 mg/ml fentanyl. These
investigators then followed the patients to determine their local anaesthetic use, quality
of analgesia, amount of rescue ketoprofen required and side-e€ects. They found that
addition of fentanyl to epidural ropivacaine resulted in a modest decrease in the amount
498 C. M. Bernards
of local anaesthetic consumed (plain ropivacaine ˆ 230 ml/48 hours; ropivacaine plus
fentanyl ˆ 204 ml/48 hours) but that therewas nodi€erence invisual analog scale (VAS)
painscores, degree of motor block, amount of rescue ketoprofen, number of episodes of
hypotension, number of episodes of bradycardia or duration of gastric stagnation.
However, the fentanyl group had signi®cantly more episodes of oxygen desaturation
(de®ned as SaO
2
5 90%). In short, adding fentanyl to epidural 0.2% ropivacaine
conferred no signi®cant clinical advantages over the use of ropivacaine alone.
Epidural fentanyl in obstetrics
Interestingly, studies of epidural fentanyl in labour do appear to demonstrate a spinal
analgesic e€ect of this opioid. Most convincing is work by D'Angelo and colleagues.
22
These investigators randomized women in labour to receive analgesia with patient-
controlled epidural 0.125% bupivacaine plus a separate constant infusion of epidural
fentanyl (20 mg/hour), intravenous fentanyl (20 mg/hour), or intravenous plus epidural
saline. They found that the dose of bupivacaine required to produce equivalent
analgesia was modestly lower in the epidural fentanyl group (11.5 + 4.6 ml/hour)
compared to the intravenous fentanyl group (15.9 + 4.5) and the saline control group
(16 + 5.9 ml/hour). However, there were no signi®cant di€erences in the incidence of
hypotension, motor block, nausea, vomiting or pruritus.
The fact that the epidural fentanyl group obtained equivalent analgesia despite using
modestly less bupivacaine indicates a spinal site of epidural fentanyl analgesia in labour.
However, given that greater bupivacaine use in the saline group was not associated
with a signi®cantly higher incidence of side-e€ects raises the question of whether
adding epidural fentanyl provided any clinically important advantage.
In a similar study, Lee and colleagues recently randomized women in labour to
receive analgesia from 0.1% plain ropivacaine, 0.1% ropivacaine plus 2 mg/ml fentanyl or
0.2% plain ropivacaine. Initial sensory block was established with 0.2% ropivacaine
prior to infusing the study solution at 10 ml/hour. Women requiring additional
analgesia were given `top-ups' of 5 ml 0.2% ropivacaine. Women receiving 0.2% plain
ropivacaine consumed more ropivacaine than the other two groups (21.1 mg/hour
versus 11.5 mg/hour in the 0.1% plain ropivacaine group and 10.8 mg/hour in the 0.1%
ropivacaine plus fentanyl group). Analgesia was modestly better and equivalent in the
0.2% plain ropivacaine and the 0.1% ropivacaine plus fentanyl groups (VAS pain scores
of 0±10 mm out of 100) compared to the plain 0.1% ropivacaine group (VAS pain
scores of 20±30 mm). However, the number of requests for additional analgesia in the
form of a `top-up' dose was not di€erent among the three groups nor was the degree
of patient satisfaction or midwife satisfaction. Degree of motor block, nausea, vomiting,
sedation and pruritus were not di€erent among the groups. Hypotension was
signi®cantly more common in the 0.2% ropivacaine group but use of ephedrine was not
di€erent among the three groups.
In short, adding fentanyl to dilute local anaesthetics for labour does reduce the
amount of local anaesthetic necessary to produce equivalent analgesia but it does not
improve patient satisfaction or reduce side-e€ects to an important degree. Given that
patient satisfaction is, arguably, the most important outcome it is reasonable to
question whether the spinally mediated analgesic e€ect of epidural fentanyl in labour
confers any clinical advantage from our patients' perspective.
Why women in labour should respond di€erently to epidural fentanyl than post-
operative patients is unclear but there are several potential explanations. Multiple
studies in humans and other mammals have shown that endogenous analgesic systems
Epidural and intrathecal opioids 499
are activated by labour and these endogenous systems may decrease the amount of
exogenous analgesic necessary to produce an observable analgesic e€ect. For example,
endogenous opioids are elevated in women in labour
23,24
so that the amount of
fentanyl that needs to reach the cord to produce an incremental increase in analgesia
would be expected to be signi®cantly less than if fentanyl were the only opioid
present. Also, pregnant women have been shown to be more sensitive to local
anaesthetics than are non-pregnant women
25
(and presumably men); consequently the
amount of spinal opioid necessary to produce additional analgesia in the presence of a
local anaesthetic may well be less than in non-pregnant humans.
Epidural sufentanil
Because it is signi®cantly more hydrophobic than fentanyl, sufentanil was suggested by
sometobea betterchoicethanfentanyl for post-operativeepidural analgesia. Moreover,
as one would expect, placing sufentanil in the epidural space does produce analgesia.
However, the analgesic e€ect is mediated by systemic uptake and re-distribution of
sufentanil tobrainstemopioid receptors. This was convincingly demonstrated by Miguel
et al
40
who double-blindly randomized patients having abdominal surgery to receive
their post-operative analgesic via intravenous sufentanil or low thoracic epidural
sufentanil. They found that the sufentanil dose required, the VAS pain scores achieved
(at rest and with coughing), the incidence of opioid-mediated side-e€ects and the plasma
sufentanil concentrations maintained throughout the 48 hours of the study were not
di€erent between the two routes of administration. These investigators concluded that
epidurally administered sufentanil produces analgesia by uptake into plasma and
re-distributiontothe brain. Todate, nostudy has demonstrateda spinal site of actionfor
epidurally administered sufentanil; consequently, such use of sufentanil is probably
unwarranted.
Epidural alfentanil
Multiple human studies have demonstrated that epidurally administered alfentanil
produces analgesia by uptake into plasma and re-distribution to the brain. In one such
study, Coda andcolleagues usedanexperimental painmodel toassess painperceptionin
hand and foot after intravenous or epidural alfentanil infusion.
26
This study was elegant
in that the investigators gave each subject an intravenous alfentanil bolus and
determined each subject's individual alfentanil pharmacokinetics. The subjects then
received alfentanil epidurally and the investigators measured pain perception as well as
alfentanil plasma concentrations over time. The investigators then used a computer-
driven infusion pump and each subject's individual alfentanil pharmacokinetics to
produce a tailored intravenous alfentanil infusion that produced exactly the same
alfentanil plasma concentration that resulted from that subject's epidural alfentanil
infusion. The investigators found that the VAS pain reports and opioid-mediated side-
e€ects were identical whether alfentanil was infused intravenously or epidurally. In
addition, analgesia was the same in the hand and the foot, indicating a complete lack of
the segmental distribution of analgesia that would be expected if analgesia resulted from
spinal mechanism.
Clinical studies have similarly failed to ®nd evidence of a spinal site of action for
epidurally administered alfentanil. Using a double-blind study design, van den
Nieuwenhuyzen et al randomized patients to receive their post-operative analgesia
from 0.125% bupivacaine infusions combined with either epidural alfentanil or
500 C. M. Bernards
intravenous alfentanil infusions (both at 0.36 mg/hour). They found no di€erence in
quality of analgesia, opioid-mediated side-e€ects, amount of `rescue' intravenous
morphine used or alfentanil plasma concentrations between the two groups.
27
Given that in vitro animal studies have shown alfentanil to be the most permeable
opioid through the spinal meninges, why then is it not clinically e€ective when used in
the epidural space? The answer lies in the fact that alfentanil's intermediate lipid
solubility makes it very permeable through many tissues so that it is cleared very
rapidly into the plasma from both the epidural space and spinal cord.
Other opioids for epidural use
All clinically available opioids have been used in the epidural space for analgesia.
Unfortunately, not all have been appropriately studied to determine whether their
analgesic e€ects are spinally mediated ± nor does space permit a detailed discussion of
each drug's suitability for epidural use. However, in general hydrophobic opioids, for
example, hydromorphone, heroin, can be expected to produce spinally mediated
analgesia when used in the epidural space. Epidural meperidine is a special case because
its demonstrable local anaesthetic e€ects make it dicult to distinguish whether
analgesia is the result of a spinal cord opioid e€ect or a local anaesthetic e€ect, or both.
Regardless of the analgesic mechanism, the potential for accumulation of the toxic
metabolite, normeperidine, makes meperidine unsuitable for anything but short-term
epidural use. Methadone is another opioid that has been shown to have moderate spinal
selectivity after epidural administration. However, the very long plasma half-life of this
opioid results in its accumulation in plasma and greater supraspinal e€ects over time.
Intrathecal opioids
All opioids injected intrathecally can be expected to produce analgesia, at least in part,
by a spinal mechanism. The principal di€erence among opioids is in their duration of
analgesic action, speed of re-distribution to brainstem sites and the mechanism by
which the drug reaches brainstem sites. In general, hydrophobic opioids produce short
durations of action (1±3 hours), which makes them unsuitable for `single-shot' post-
operative analgesia but attractive for short-term pain states such as labour. In addition,
hydrophobic opioids produce supraspinal side-e€ects (sedation, respiratory depression)
much earlier than do hydrophilic drugs. Early supraspinal side-e€ects occur with
hydrophobic opioids because the doses that must be administered are relatively large;
consequently, plasma concentrations rapidly reach clinically signi®cant levels.
The interesting issue with intrathecally administered opioids is how much of their
analgesic e€ect is spinally versus supraspinally mediated, when does the supraspinal
e€ect occur, and whether the supraspinal e€ect is a necessary component of the
observed analgesia. These issues are well illustrated by the clinical pharmacology of
intrathecal sufentanil and morphine.
Morphine should be considered the `gold-standard' for spinally selective analgesia
following intrathecal administration. Morphine doses of only 100 to 200 mg produce
potent analgesia lasting as long as 24 hours.
28
Clearly, this profound, long-lasting
analgesia could not be achieved by intravenous injection of the same morphine dose
thereby `proving' a spinal mechanism. It is dicult, however, to explain morphine's
prolonged duration of action. Human studies have reported the terminal elimination
half-life of intrathecally administered morphine to be 73±140 minutes, which would
result in the drug being completely eliminated from lumbar CSF in approximately
Epidural and intrathecal opioids 501
6±12 hours.
29±31
Thus, one must explain why analgesia persists well after morphine's
CSF concentrations would be expected to be negligible. One obvious explanation is
that CSF pharmacokinetics do not re¯ect e€ect site pharmacokinetics and that
morphine persists at spinal cord opioid receptors much longer than in the CSF.
However, another intriguing explanationfollows fromthe fact that morphine spreads
rostrally in CSF to reach brainstem opioid receptors. While clinicians are under-
standably concerned about the side-e€ects resulting from morphine's rostral spread, it
may very well be that rostral spread is an important component of morphine's duration
of action. For example, multiple animal studies have demonstrated that a supra-additive
or synergistic analgesic e€ect results from simultaneous stimulation of spinal and
supraspinal opioid receptors.
32±34
Whether this synergy occurs in humans is unknown;
however, if it does occur, then spinal/supraspinal synergy could explain the unusually
long duration of analgesia produced by such small doses of intrathecal morphine.
Speci®cally, waning analgesia at the spinal level may be e€ectively `supplemented' by
drug reaching the brainstem.
While morphine clearly produces a selective spinal analgesic e€ect, at least early after
administration, the analgesic e€ect of intrathecally administered hydrophobic opioids
may not be as spinally selective. Consider, for example, the work of Lu et al.
35
These
investigators examined the e€ect of intrathecal sufentanil on pain thresholds for tibial
pressure in women volunteers. The investigators determined baseline pain thresholds
and then administered 12.5, 25 or 50 mg sufentanil and repeated the pain threshold
measurement. They found that all three intrathecal sufentanil doses increased pain
thresholds to a comparable degree but that they also produced signi®cant respiratory
depression as determined by arterial P
a
CO
2
. Moreover, the time course of the
respiratory depression exactly paralleled that of the analgesic e€ect. Given that
respiratory depression is clearly a supraspinal e€ect it is reasonable to assume that some
portion of the analgesia was supraspinally mediated. In addition, all three doses
produced sufentanil plasma concentrations that exceeded the minimum concentration
shown to produce analgesia in humans.
36
This is not to suggest that the observed analgesia is entirely mediated by systemic
uptake of sufentanil and re-distribution to brain, but it is probable that some portion
of the analgesic e€ect is supraspinally mediated. While we typically administer opioids
spinally to prevent supraspinal e€ects it may actually be an advantage in this situation.
Speci®cally, if spinal±supraspinal synergy exists in humans, then intrathecal sufentanil
may well produce better analgesia because of supraspinal re-distribution than could be
obtained if the drug were restricted to the spinal cord. In fact, it is possible that the
ecacy of intrathecal sufentanil for labour analgesia is due in part to sufentanil's rapid
redistribution to the brainstem. Unfortunately this rapid re-distribution to the
brainstem also explains the multiple case reports of early respiratory depression in
labouring women receiving intrathecal sufentanil.
37±39
The question of whether supraspinal opioid e€ects contribute to analgesia from
intrathecal opioids is yet to be resolved. However, the potential for synergy makes
addressing this question important. If synergy does exist in humans then clinicians will
need to re-think the prohibition of administering systemic opioids to patients who are
simultaneously receiving spinal opioids.
Another interesting aspect of intrathecal opioid pharmacology is the fact that lipid-
soluble opioids are relatively less potent than are their more hydrophilic counterparts.
For example, when administered intravenously fentanyl is approximately 100 times
more potent than morphine and sufentanil is roughly 1000 times more potent.
However, to produce signi®cant spinal analgesia, intrathecal fentanyl is typically
502 C. M. Bernards
administered in doses of 25 to 50 mg, which is only two to four times the dose of
morphine that is typically used intrathecally. Thus, there is an approximately 25-fold
decrease in the relative potency of fentanyl compared to morphine when the drugs are
administered intrathecally instead of intravenously. More striking is the relative
decrease in sufentanil's potency. Typical intrathecal morphine doses of 100 mg produce
analgesia that is similar in magnitude (although much longer in duration) to that
produced by 10 mg sufentanil. Thus, intrathecal sufentanil is only 10 times more potent
than morphine, which represents a 100-fold decrease in their relative potency when
administered intravenously.
As discussed above, the presumed explanation for the relative low potency of
intrathecally administered hydrophobic opioids is that they partition into hydrophobic
environments and, therefore, are not readily bioavailable at spinal opioid receptors.
The clinical signi®cance of the reduced potency of hydrophobic opioids is that
relatively large doses must be administered to produce measurable analgesia, which
explains why hydrophobic, but not hydrophilic, opioids produce clinically signi®cant
peak plasma concentrations after intrathecal administration.
SUMMARY
It is hoped that the clinician has recognized that the mere fact of placing an opioid in
the epidural or intrathecal spaces is not a guarantee of a spinal site of analgesic action.
Consequently, spinal opioid administration is not necessarily superior to systemic
opioid administration in all cases. Appropriate use of spinal opioids necessitates
understanding which opioids produce selective spinal analgesia and which do not. In
short, spinal selectivity is greatest for hydrophilic opioids and least for hydrophobic
opioids. These di€erences result from inherent di€erences in the bioavilability of
opioids at spinal cord opioid receptors. Bioavailability di€ers because hydrophobic
Practice points
. the spinal cord bioavailability of hydrophobic drugs is less than that of hydrophilic
opioids
. morphine is probably the most spinally selective opioid currently used in the
intrathecal and epidural spaces
. epidurally administered sufentanil and alfentanil appear to produce analgesia by
systemic uptake and re-distribution to brainstemopioid receptors. There appears
to be little reason to use these drugs in the epidural space
. epidural administration of fentanyl o€ers little or no bene®t over the intravenous
route of administration except in obstetrics where it does appear to produce
modestly selective spinal analgesia
. all intrathecally administered opioids produce at least some of their analgesic
e€ect via a spinal mechanism; however, for hydrophobic drugs uptake into plasma
with subsequent re-distribution to the brain may contribute signi®cantly to the
observed analgesia
. for intrathecal morphine, early analgesia is clearly the result of a selective spinal
mechanism; however, late analgesia may result in part from rostral spread in
cerebrospinal ¯uid (CSF) to brainstem sites
Epidural and intrathecal opioids 503
drugs are more rapidly cleared into plasma than hydrophobic drugs; consequently they
produce more early supraspinal side-e€ects and have a considerably shorter duration of
analgesic action.
Because future directions for spinal analgesics cannot be predicted, it is hoped that
the reader will be able to employ the information presented when evaluating new
opioids and new classes of analgesics proposed for spinal administration.
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