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M. MORGAN
The prime function of anaesthetists is to relieve by which the efficacy of other analgesic techniques
pain. The technical skills and pharmacological may be assessed by registering the number of
knowledge required to do this during surgery demands for additional analgesia [115]. However,
place them in an ideal position to treat pain in it does require the use of sophisticated and
other situations. Thus anaesthetists have been at relatively expensive apparatus and the maximum
the forefront of developments in the relief of pain dose of drug and minimum time interval between
during labour and devote much attention to the doses are set by the doctor, who must err on the
relief of chronic pain of whatever aetiology. side of safety in these choices. Experience of such
Indeed, active societies exist in both these disci- apparatus has indicated that the patients chose a
plines and have been vigorous in the promotion balance between analgesia and the incidence and
of research and teaching, even though such severity of side effects.
activities are expensive in terms of time and The discovery of opioid receptors in the central
manpower. nervous system, in particular their existence in
Postoperative pain relief, however, has been the spinal cord, came at an opportune time and
sadly ignored [189] and members of the public raised exciting new possibilities in the manage-
[114], and even eminent members of the pro- ment of severe pain.
fession [67,162], have been moved to comment on
the severity of pain after surgery and the lack of
efforts to relieve it. The standard method of HISTORICAL BACKGROUND
prescribing a fixed dose of opioid to be given at The steps leading to the eventual use of spinal
limited time intervals, and with administration opioids in man are shown in table I. In 1976,
being delegated to a nurse, is manifestly a totally Yaksh and Rudy [206] showed, in rats, that
inadequate method of producing postoperative opioids applied directly to the spinal cord and
analgesia. Extradural block with local anaesthetic remaining localized, produced intense analgesia.
agents will abolish postoperative pain, but its use It was suggested [204] that the receptors through
has been limited by anxiety about hypotension, which the drugs were acting were situated pre-
tachyphylaxis, systemic toxicity, the technical synaptically on afferent terminals in the substantia
difficulty of insertion of a catheter into the thoracic gelatinosa and that the effect was to block the
extradural space and the problems of post- release of the neurotransmitter associated with
operative surveillance. Other nerve blocks, par- nociceptive transmission [96]. In this region,
ticularly intercostal [125], can also be very
successful, but their use is restricted by the
feasibility of repeating them in the postoperative TABLE I. Historical background to use of spinal opioids in man
period. 1971 Demonstration of existence of opioid
Patient controlled analgesia was introduced in receptors [82]
an attempt to overcome many of these problems 1973 Demonstration of opioid receptors in the
brain [148]
and has proved to be a successful method after 1976 Demonstration of opioid receptors in the
surgery [39, 182]. It can also be used as a method spinal cord [105]
Demonstration in animals of analgesia
produced by spinally applied opioids [206]
M. MORGAN, M.B., B.S., D.A., F.F.A.R.C.S., Department of 1979 Intrathecal opioids first used in man [193]
Anaesthetics, Royal Postgraduate Medical School, Hammer- Extradural opioids first used in man [18]
smith Hospital, Du Cane Road, London W12 OHS.
166 BRITISH JOURNAL OF ANAESTHESIA
TABLE II. Predicted advantages of spindly applied opioids (1) verify the points documented in table II
Segmental analgesia with no sensory or motor loss.
(2) make some comparison of the available drugs
No autonomic block with consequent absence of (3) assess the merits of the extradural compared
hypotension. with the intrathecal route of administration
No central or respiratory depression. (4) compare extradural and intrathecal opioids
Availability of a large number of drugs. with other methods of analgesia
Existence of a specific antagonist.
(5) assess the nature, incidence and severity of
complications.
opioids have been shown in vivo to antagonize the
release of one putative transmitter, substance P ANALGESIC EFFECTS
[205]. In 1979, morphine was used intrathecally
[193] and extradurally [18] in man, and in small Extradural Opioids
doses produced prolonged analgesia in patients There is no doubt that opioids injected into the
with chronic pain. extradural space produce effective and often
A number of advantages were predicted for this prolonged analgesia. Pethidine 100 mg in normal
new method of analgesia (table II). It was hoped saline 10 ml was first used for postoperative pain
that segmental analgesia would be produced by in seven patients [55]. Onset of analgesia was
only small doses of drug, without loss of any other rapid and complete between 12 and 20 min after
sensory modality or interference with motor injection. At this time, blood concentrations of
function. There should be no autonomic block pethidine were less than those necessary to
and hence no hypotension, which is the main produce analgesia, and concentrations in cere-
factor limiting the use of extradural local anaes- brospinal fluid (CSF) were high. Pain relief
thetics ; there should also be no interference with lasted an average of 6 h and there was no evidence
bladder function. Inadvertent intravascular in- of sensory, motor or autonomic block.
jection would be unlikely to have the serious Morphine, in doses varying from 2 mg [161] to
consequences associated with i.v. local anaes- 0.1 mg kg"1 [195], has been the most widely used
thetics. Above all, was the possibility of divorcing drug. Analgesia tends to be slow in onset, taking
respiratory depression from analgesia with opioid up to 60 min [59,121,195] to develop, but can last
drugs. A range of opioids was available, the for more than 24 h, with many reports mentioning
different durations of action of which would that only one injection was required after
match different clinical situations. Finally, a operation. No evidence of block of any other
specific antagonist was already available in the sensation or of motor power has been revealed by
form of naloxone, thus guaranteeing prompt these studies and hypotension has not been a
antagonism of any unwanted sequelae. problem.
After the first reports, there was a surge of Available evidence confirms that analgesia re-
publications attesting to the efficacy of this new sults from a regional rather than a systemic effect,
technique. Winnie [200] commented that never although there may be some initial contribution
before had sophisticated laboratory research from the latter. Pharmacokinetic studies have
moved so rapidly into the clinical field. Un- found no relationship between quality of analgesia
fortunately, many of these initial reports ignored and plasma concentrations of the drug, which
the fundamental principles of properly conducted have been well below reported "analgesic" con-
clinical trials, and claimed complete analgesia of centrations [134, 178, 195, 208]. Indeed, excellent
very prolonged duration with no complications. analgesia may be present with no morphine
One of the main reasons for this was the lack of detectable in the plasma. Experimental work in
any "central" control for the studies that were volunteers also confirms the segmental effect of
being performed, because there was no require- extradural morphine. Torda and colleagues [188]
ment for such control: neither the drugs nor the found that morphine 3 or 4 mg injected into the
techniques were new; it was the application that lumbar extradural space resulted in an increase in
was new [200]. pain threshold in the legs, but not on the forehead,
The purpose of this review is to produce some while i.m. morphine raised the threshold in both
logical conclusions on the use of spinal opioids areas. Similarly, extradural morphine 3.5 or
and consideration will be confined to their use in 7.5 mg markedly delayed the onset of experi-
acute pain. In order to do this it is necessary to: mentally induced ischaemic pain in the lower
USE OF INTRATHECAL AND EXTRADURAL OPIOIDS 167
limbs, but not in the arms. This effect was still were equally effective. Similar results were found
present 6h after injection [185]. Subcutaneous by Lanz, Kehrberger and Theiss [106], who
morphine had no significant effect on the times to found that patients who received 2.0 mg or more
pain perception in either limb and the authors were less likely to require additional analgesia.
concluded that the extradural morphine produced However, they also found that the incidence of
analgesia by a regional effect rather than by urinary retention and pruritis increased dose
systemic absorption. dependently, and recommended 3.0 mg as being
A greater improvement in postoperative pul- the best compromise between analgesia and an
monary function has been found by workers who acceptable incidence of side effects. A dose of
compared extradural opioids with other analgesic 4 mg produced excellent analgesia following hip
techniques. Bromage, Camporesi and Chestnut arthroplasty and major lower limb surgery, but
[27] found that extradural opioids were more 6 mg was required in the thoracic extradural space
effective than i.v. morphine in restoring FEV! after laparotomy or thoracotomy [181].
towards preoperative values. Rybro and col- The majority of workers have used a fixed dose
leagues [168] found that 67% of patients who of morphine to produce analgesia after operation.
received i.m. morphine after upper abdominal In view of the known very wide variation in the
surgery had radiological changes on chest x-ray individual response to opioids, it would seem
on the 2nd day after operation, compared with much more rational to titrate the dose until the
21 % who had received 4-mg doses of morphine desired effect is reached. This approach was used
extradurally. After cholecystectomy, analgesia by Bromage, Camporesi and Chestnut [27] when
with extradural morphine resulted in a smaller comparing three opioids (morphine, hydro-
decrease in peak expiratory flow than was associ- morphone and methadone), extradural local anaes-
ated with either i.m. opioids or intercostal block thetics and i.v. morphine for pain relief after
with bupivacaine [157]. Bonnet and colleagues [24] upper abdominal surgery. They found that the
found lower pain scores with extradural morphine dose of extradural morphine required to produce
than with i.m. injections of the analgesic baral- effective analgesia was very similar to that used
gine, but no difference in VC, FEV, or FRC. A i.v., but that the former route produced much
decrease in postoperative morbidity [177] and more prolonged analgesia with significantly less
possibly mortality [207] has also been reported. central depression. Recently, patient controlled
However, Hjortso and colleagues [89], using a analgesia has been used by the extradural route
mixture of extradural morphine and bupivacaine, [178]. Morphine in increments of 1 mg, with a
found that although pain scores were lower than minimum interval of 30 min between doses, or
with i.m. morphine after abdominal surgery, there pethidine 20 mg, both produced satisfactory anal-
was no difference between the groups in terms of gesia, there being no difference between the
postoperative mortality, pneumonia, arrhythmias, drugs. The authors did comment that large
wound complications, deep vein thrombosis or interindividual variations made it impossible to
convalescence. recommend a standard dose of either drug for
analgesia of predictable duration and with a
Dose of morphine minimum of adverse effects.
Despite the widespread use of extradural mor-
phine there have been few dose finding studies. Other drugs
Morphine 2 mg is effective in relieving pain after Most narcotic analgesics have been used extra-
lower limb orthopaedic surgery [121, 161], but durally in the management of postoperative pain,
ineffective after upper and lower abdominal by either bolus injection or continuous infusion
surgery [57, 167]. However, 5 mg and 10 mg (table III) and effective analgesia has been
produced prolonged analgesia after lower ab- reported after the use of them all. Fentanyl has
dominal operations, although no additional bene- been given using a patient controlled system,
fit resulted from the larger dose [57]. In particular, when no difference was found in fentanyl usage
very prolonged analgesia has been noted to follow between the extradural and i.v. routes [74].
morphine 5 mg after Caesarean section [202]. Meptazinol 90 mg was found by Verborgh, Van
Martin and colleagues [121] compared five doses Der Awera and Camu [191] to produce effective
of morphine (0.5-8.0 mg) after orthopaedic sur- analgesia, but others found smaller doses to be
gery and found that doses of 2.0 mg and greater ineffective and did not recommend its use [22,
168 BRITISH JOURNAL OF ANAESTHESIA
76]. Lofentanil produces very prolonged anal- been few, but it is unlikely that there will be any
gesia, but because of its extreme potency and very differences in analgesic efficacy between the drugs,
strong receptor binding characteristics, concern but only in rate of onset, duration of action and
has been expressed that antagonism might be incidence and severity of side effects. A major
difficult [21]. problem in comparing agents will be in choosing
It would seem more sensible to use the shorter equipotent doses, because equivalent doses for
acting drugs like fentanyl by continuous infusion, systemic administration may well not apply to the
particularly after upper abdominal surgery, where extradural route. This has been shown to be the
it produces effective, but short lasting analgesia case for morphine and pethidine [178]. Thus
when given by bolus injection [167]. Welchew and Torda and Pybus [187] compared extradurally
Thornton [198] found that an extradural infusion administered morphine 6 mg, methadone 6 mg,
of fentanyl at a rate of 60 ug h"1 provided pain pethidine 60 mg and fentanyl 60 ug—doses which
relief superior to that obtained with i.m. papa- are regarded as being equipotent when given
veretum. An infusion rate between 80 and 130 ug parenterally. There was no difference in the
h"1 was necessary to maintain adequate analgesia quality of analgesia, but the respective durations
after abdominal aortic aneurysm surgery [19]. were 12.3 (SD 7.69) h, 8.7 (SD 5.89) h, 6.6 (SD
These authors commented that the short duration 3.32) h and 5.7 (SD 3.72) h. No difference in the
of action of fentanyl actually aided bed man- quality of analgesia was found between morphine
agement in the intensive care unit, since it was not and diamorphine [194].
necessary to keep patients in the unit for so long
after the last injection. Alfentanil would probably Timing of injection
be an even better choice, and has been shown to The efficacy of extradural morphine might be
produce excellent analgesia after major abdominal increased if it is given before the onset of pain
surgery, although experience with its use is [106]. The time to the first administration of an
limited [47, 48]. Despite its long duration of analgesic after surgery was almost twice as long in
action, continuous infusions of morphine have patients who had received extradural bupivacaine
been used to manage postoperative pain in doses containing morphine 10 mg for the operative
varying from 100 to 400 ugh" 1 [58, 72, 73, 111]. procedure than when bupivacaine was used alone
Comparisons between the different opioids have [41]. In contrast, extradural morphine given for
USE OF INTRATHECAL AND EXTRADURAL OPIOIDS 169
the first time on the day after surgery failed to lumbar level [132]. In contrast, a lipid soluble
produce useful analgesia. It has also been noted drug would rapidly enter the CSF and be more
that morphine 5 mg given after chloroprocaine rapidly absorbed into the spinal cord and would
with adrenaline had been used for Caesarean be expected to produce a more sharply segmental
section had a slower onset and provided poorer analgesia. Controlled studies have not been per-
analgesia than when plain chloroprocaine was formed to verify this hypothesis, and few have
used [150]. This resulted from the greater acidity compared the effects of thoracic v. lumbar
of the local anaesthetic combined with adrenaline, extradural morphine for upper abdominal sur-
resulting in a greater degree of ionization of the gery. Asari and colleagues [10] found that the
morphine. Others have found that morphine [86, analgesia produced by thoracic morphine was
166] and diamorphine [137] given extradurally significantly superior to that given in the lumbar
before surgery reduced opioid requirement in the region. In contrast, a retrospective study [78]
immediate postoperative period. found no difference between the two routes in the
number of patients requesting additional anal-
Effect on the stress response gesia, but there was a considerable discrepancy in
Neither morphine [166] nor diamorphine [137] the numbers (92 thoracic v. 30 lumbar) and such
administered extradurally influences the meta- studies cannot give any indication of the quality of
bolic and hormonal responses to surgery, although analgesia. Similarly, Larsen and colleagues [109]
cortisol concentrations were lower than controls reported no difference between thoracic and
in the postoperative period, probably reflecting lumbar morphine 5 mg after upper abdominal
the better pain relief. Extradural local anaesthetics surgery, but the first assessments were not made
suppress the increase in catecholamine concen- until 6 h after injection.
trations noted in the immediate postoperative
period, whereas extradural morphine can only
suppress this response later on, indicating that Intrathecal Opioids
pain might be a factor in the production of the Intrathecal opioids also produce satisfactory and
stress response [166]. prolonged relief of postoperative pain [131].
Originally, doses of morphine as large as 15-20 mg
Site of extradural injection were used [170], but although analgesia is sig-
It was originally stressed that the segmental nificantly longer with these large doses, the
nature of the analgesia produced by extradural incidence of side effects is also significantly higher
opioids demanded the use of thoracic injection [169].
after thoracic and upper abdominal surgery. The Most workers inject morphine intrathecally
thoracic approach is more difficult anatomically before the surgical procedure and have found
than the lumbar and potentially more dafigerous similar results. When 0.8 mg was given intra-
[135], but there are numerous reports of the thecally before cholecystectomy, less papa-
lumbar route providing satisfactory analgesia after veretum was required in the first 24 h after
upper abdominal and thoracic surgery [84, 134, operation than in a control group [69]. O'Neill
136, 197]. However, Sandier, Chovaz and and colleagues [139] found that intrathecal mor-
Whiting [171] commented on the long latency phine 1 mg resulted in a significant decrease in the
between the injection of lumbar morphine and need for postoperative analgesia after spinal
pain relief in the thoracic dermatomes. This may surgery. Intrathecal morphine 0.8 mg provided
lead to additional doses of drug being given before analgesia during aortic aneurysm surgery that was
they are necessary, so that complications are more indistinguishable from moderate doses of par-
likely to occur. Caudally administered morphine enteral opioids and was no more effective in
has provided satisfactory analgesia after perineal attenuating the autonomic responses during the
[25, 151] and even cardiac surgery [165]. procedure [61]. The principal advantage was the
The explanation may lie in the properties of avoidance of irregular and inadequate analgesia in
morphine. It enters the CSF but, being of low the early and the most painful part of the
lipid solubility, does not rapidly enter the spinal postoperative period. Isaacson and colleagues [92]
cord; it may thus spread widely and produce found that patients given morphine 0.5-1.0 mg
diffuse analgesia. After thoracic extradural mor- intrathecally before abdominal aortic surgery
phine, the drug quickly appears in the CSF at could be extubated earlier in the postoperative
170 BRITISH JOURNAL OF ANAESTHESIA
period and had significantly shorter stays in the approaching the systemic dose. Extradural fen-
intensive care unit and in hospital. Others have tanyl 150-200 ug produced excellent pain relief
confirmed that earlier extubation is possible after until the late first stage, but was inadequate
major abdominal surgery when intrathecal mor- during the latter part of the first stage and during
phine has been used, and also that its use is the second, when pain was at its worst [38].
consistent with a stable perioperative haemo- Addition of fentanyl 80 ug to the test dose of
dynamic state [44]. After coronary artery bypass bupivacaine resulted in more rapid and complete
surgery, patients who had received morphine analgesia compared with a control group [99].
0.5 mg intrathecally required significantly less Pethidine 50 mg alone did not produce as effective
sodium nitroprusside and fewer i.v. supplements analgesia as pethidine with adrenaline [146, 147].
of morphine; there was, however, no difference in Alfentanil, however, was unsatisfactory [88].
pain score [190]. Intrathecal administration has proved to be
The dose of morphine used by this route has much more satisfactory in labour (fig. 1). Ex-
been decreasing gradually. Recently, doses of 0.1 cellent analgesia, often lasting several hours, has
mg and 0.25 mg have been shown to produce been reported after morphine 0.5-2 mg given for
excellent and prolonged analgesia (18.6 and the first stage of labour, although the effects were
27.7 h, respectively) after Caesarean section [1]. much less marked during the second stage [3, 15,
However, there is a lack of information on the 175]. The incidence of side effects, even though
optimum dose of intrathecal morphine. A com- classified as "minor", was distressingly high [3].
parison of 0.3, 1.0 and 2.5 mg found that the low It is possible to decrease these with naloxone
dose was associated with an inconsistent duration without affecting the degree of analgesia [29], but
of analgesia and irritating side effects [93]. The this complicates what should be a simple tech-
larger doses provided excellent analgesia, but also nique. Despite the simplicity and efficacy of using
a high incidence of respiratory depression. intrathecal opioids in labour, Crawford [56] has
Diamorphine [16, 144] and buprenorphine [37] warned that the potential for respiratory de-
have also been used intrathecally with good effect. pression always exists and makes routine use of
Pethidine is the only drug that has been used the technique in obstetrics difficult to accept.
successfully intrathecally as the sole anaesthetic Apnoea has now been reported some 7 h after
agent, for genito-urinary [130] and lower ab- intrathecal morphine 1 mg given to a mother in
dominal and lower limb surgery [172]. The doses labour [4].
were 0.1 mg kg"1 and 100 mg, respectively; the In view of the high incidence of side effects,
effects may have been related to the local intrathecal morphine in labour would best be
anaesthetic properties of pethidine. reserved for those situations in which it is essential
to avoid the unwanted effects of local anaesthetics,
Specialist Applications particularly hypotension, for example in patients
with congenital heart disease [5].
Obstetric analgesia
Although extradural local anaesthetics will Paediatric use
abolish the pain of labour, their use is associated There are few reports of the use of spinal
with a number of problems. They are relatively opioids in children. Jones and colleagues [98]
short acting and so require repeated injection or a found that postoperative analgesia lasted more
continuous infusion; hypotension is an ever than 24 h in 22 of 56 children given intrathecal
present risk and accidental i.v. or intrathecal morphine before the surgical incision. Fifteen
injection can have major consequences. The children required additional analgesia at 22 h,
possibility of producing prolonged analgesia with while in the remainder pain relief lasted approxi-
small doses of opioids was therefore exciting. mately 13 h. The initial 27 children received a
However, extradural morphine has proved to dose of 0.03 mg kg"1, but six of these developed
be disappointing. Husemeyer and colleagues [91] respiratory depression an average of 4.4 h after
found 2 mg to be totally ineffective in relieving the morphine and required naloxone. The re-
the pain of the first stage of labour. Others found maining children were given 0.02 mg kg"1 and
that 2.0 and 5.0 mg did not produce satisfactory three of these required naloxone to antagonize
pain relief, whereas 7.5 mg did during the first, respiratory depression.
but not the second stage of labour [90]; this is Extradural morphine behaves in a similar way
USE OF INTRATHECAL AND EXTRADURAL OPIOIDS 171
2 3 4
Time after injection (h)
FIG. 1. Maternal pain relief (before delivery), after extradural administration of 0.5% bupivacaine
10 ml (X), extradural administration of morphine 7.5 mg (O) or intrathecal injection of morphine 0.5 mg
and 1.0 mg (0). (Reproduced by kind permission of Dr T. K. Abboud and her colleagues [3] and the
editor of the British Journal of Anaesthesia.)
w 8
X
cc
4-
10 30
4 4 4
12-1
cc 4- K
cc CC
to CO
10 20 30
44 4
CC
K
TABLE VI. Respiratory depression after extradural opioids other than morphine
623 patients (1 in 156, 0.6%) reported by Ready Three of 12 patients given extradural diamorphine
and colleagues [160] and four of 128 (1 in 32, 5.5 mg had ventilatory rates of less than 8 b.p.m.
3.1%) in a Canadian multicentre trial [202]. In between 20 and 90 min later [194], while all
another large series [181], the incidence of patients given 10 mg into the thoracic space had
respiratory depression was 0.9 % in patients who evidence of respiratory depression some 2 h later
received morphine 4-6 mg with a tendency for [137].
more frequent occurrence after thoracic extra- There may possibly be an association between
dural injection. Apart from isolated case reports, the appearance of respiratory depression after
many studies investigating the analgesic effects of extradural administration which has been com-
extradural and intrathecal morphine, and con- plicated by previous dural puncture [53, 196].
taining relatively few patients, have reported Radiological evidence exists of injectate into the
instances of respiratory depression, occasionally extradural space passing through a previous
with alarming frequency. Thus three of six accidental dural puncture hole into the sub-
patients given morphine 1.0 mg intrathecally arachnoid space [110].
developed profound, delayed respiratory depres- More sinister delayed respiratory depression
sion [60]. After morphine 5 mg by the thoracic can also occur. Extradural diamorphine 3 mg
route, eight of 30 patients gradually lost con- resulted in apnoea at 4.5 h in a patient who had
sciousness with respiratory depression 30-73 min also had a spinal anaesthetic [53]. Respiratory
after the injection, the general anaesthetic having depression occurred 4 h after lumbar extradural
contained no opioid analgesic [72]. methadone given after thoracic surgery [197].
It should be noted that the Swedish studies Hydromorphone 1.0 mg, which is much more fat
were retrospective, which have several problems soluble than morphine, caused apnoea 4.5 h later
of data retrieval. Also, many of the patients were in a patient who had not received any other opioid
being treated for chronic pain conditions and in the previous 10 h [203].
these patients are known to be resistant to the Theoretically, respiratory depression should
respiratory depressant effects of opioids [54]. occur less frequently with the more fat soluble
Respiratory depression can also follow use of opioids as they will enter the spinal cord more
the more fat soluble opioids (table VI). When rapidly and will not remain in the CSF. There are
occurring soon after injection it can be ascribed to far fewer cases reported, but the frequency of use
systemic absorption. Scott and McLure [174] of these agents compared with morphine is not
reported two patients who developed severe known. Few experimental studies have been
depression within 30 min of extradural pethidine performed. Diamorphine 5 mg either i.m. or into
50 mg, while Brownridge, Wrobel and Watt- the thoracic extradural space depressed respir-
Smith [32] reported a patient who became ation maximally within 30 min of injection and,
increasingly drowsy with gasping ventilation after although statistically significant, its clinical im-
pethidine 50 mg given into a catheter that was portance was slight [120]. Ahuja and Strunin [6]
accidentally placed intrathecally. It is pertinent to investigated the respiratory effects of a bolus
note with regard to this case that the nurse had injection of fentanyl l.Sugkg" 1 followed by a
actually left the patient's room, but fortunately continuous infusion into the thoracic extradural
the husband drew attention to the problem. space. The bolus injection resulted in a significant
Extradural sufentanil has been followed within a decrease in rate of ventilation and a non-sig-
few minutes by respiratory depression [23, 192]. nificant increase in end-tidal carbon dioxide
USE OF INTRATHECAL AND EXTRADURAL OPIOIDS 179
concentration within minutes, which was similar
TABLE VII. Factors predisposing to the development of
to the findings of others [112]. The changes were respiratory depression [54]
accentuated by prior parenteral administration of
morphine. A continuous infusion of fentanyl Advanced age.
50-100 ug h"1 commenced 1 h after the bolus Use of water soluble opioids.
injection and continued for 18 h had no further Concomitant use of parenteral opioids or other
central nervous system depressants.
effect on the end-tidal carbon dioxide concen- Lack of tolerance to opioids.
tration or ventilatory rate, despite a gradually Increased intrathoracic pressure.
increasing plasma concentration of fentanyl. Intrathecal opioids.
Molke-Jensen and colleagues [123] were dis- Large doses.
Thoracic extradural opioids.
appointed to find that the very fat soluble
buprenorphine in an extradural dose of 0.15 mg
produced prolonged and biphasic depression of profound respiratory depression can occur in the
the carbon dioxide response, with respiratory young [60,203]. The water soluble drug morphine
depression being significant between 2 and 4 h has been most frequently implicated, although
and again at 8-10 h. No clinical reports of it does occur with the more lipophilic drugs
respiratory depression after the drug have yet (table V).
been reported. The mixed agonist-antagonist The residual effects of other central depressants
butorphanol 2—4 mg given extradurally depressed are frequently quoted as being contributory to the
the ventilatory response to carbon dioxide for respiratory depression produced by spinal opi-
12 h [2]. oids. Severe respiratory depression, resistant to
Thus all the narcotic analgesics have the naloxone, but antagonized with physostigmine,
propensity to produce respiratory depression, but has been reported in a patient who received
there is no doubt that it is more common after droperidol 1.25 mg i.v. for nausea after delivery,
morphine. Fentanyl may be the least problematic, followed later by extradural hydromorphone
although the frequency of its use is not known. 1.25 mg [50]. Lack of tolerance to opioids is
Profound central nervous system and respiratory another important factor and there does not
depression has followed just over 1 h after 100 (ig appear to be a problem, even when very large
given extradurally, but the patient had also doses are given extradurally to patients with
received i.v. midazolam, droperidol and nal- intractable pain who have usually received large
buphine to counteract pruritis [199]. An infusion doses of a variety of drugs for some time [9]. The
of naloxone was necessary to maintain respiration. respiratory depressant effects of extradural mor-
Respiratory depression has been reported 4 h phine can be seen 16 h or more after ad-
after fentanyl 100 |ig with adrenaline, the defini- ministration [36] and further depressant drugs, by
tion of respiratory depression being a rate of any route, at this time may result in significant
ventilation less than 10 b.p.m. or a venous carbon respiratory depression.
dioxide partial pressure more than 1.33 kPa Increased intrathoracic pressures, caused by
greater than control [142]. The rate of ventilation artificial ventilation, coughing or the grunting
in this patient was 16 and the venous Pco2 respiration associated with pain may serve to
1.47 kPa greater than control. This occurred in accelerate passage of drug containing CSF cepha-
one of two patients given this dose of fentanyl and lad. This is well illustrated in the case reported by
hardly justifies the claim of a 50 % incidence of Kafer and her colleagues [100]. The incidence is
respiratory depression with this drug [152]. more common after intrathecal opioids [87, 153]
and, although it has been reported after extradural
Predisposing factors administration after accidental dural puncture
The factors that may predispose to the de- [53, 196], the number of such cases is too few to
velopment of respiratory depression are shown in draw any firm conclusions. The large doses of
table VII. Most patients are elderly, 77% in the morphine (10 mg) that may be required to
recent nationwide survey in Sweden being older produce satisfactory analgesia after upper ab-
than 65 yr. It is in these elderly patients, who dominal surgery are associated with a higher
frequently have concomitant cardiopulmonary incidence of respiratory depression than 2—4 mg
disease, that good analgesia with minimal central [159]. It is also more common after intrathecal
depression is so often required. Nevertheless, doses greater than 1 mg [79, 93]. The thoracic
180 BRITISH JOURNAL OF ANAESTHESIA
extradural approach also is associated with a extradural morphine O.lmgkg" 1 . There was a
higher reported incidence [87, 181]. trend towards decreased analgesia with all three
A wide spectrum of factors are involved in the rates of infusion of naloxone and side effects
development of this complication, so much so that occurred in all groups. They concluded that a
the most predictable thing that can be said about naloxone infusion was not an appropriate tech-
its appearance is that it is unpredictable. This has nique for reducing side effects while maintaining
important implications for the management of analgesia after extradural morphine.
patients who have received spinal opioids. The partial opioid agonist nalbuphine also has
been used to prevent respiratory depression [68].
Prevention A bolus dose of 0.2 mg followed by an infusion of
It has been suggested that patients receiving 0.05 mg kg"1 h"1 resulted in lower arterial carbon
spinal opioids should be nursed in the semi- dioxide tensions than in a control group. Naloxone
sitting position, in the hope of preventing res- was required in the latter patients. The results of
piratory depression. It has been suggested that giving a partial agonist in the presence of an
intrathecal opioids should be used in hyperbaric agonist may be additive or antagonistic, depend-
solution [170], but supporting evidence for these ing on the relative concentrations of two drugs
views have not been forthcoming. Respiratory [35], and it would be wiser to avoid such a drug
depression has followed hyperbaric morphine combination.
1.0 mg in a patient kept in the head-up position [4].
McCaughey and Graham [113] found a consistent FEASIBILITY OF USE OF SPINAL OPIOIDS FOR
pattern of respiratory depression after extradural POSTOPERATIVE PAIN RELIEF
morphine 2 mg in patients kept supine. In the Intrathecal and extradural opioids produce ex-
sitting position the same degree of respiratory cellent analgesia with much smaller doses of drug
depression was not observed, although there was than is achieved via other routes. There is
considerable individual variation. Others have therefore less central depression and greater
found that the 45° elevated position offered no patient mobility and co-operation, with all the
protection with regard to the incidence or degree attendant benefits. A major advantage over extra-
of respiratory depression after lumbar extradural dural local anaesthetics is the lack of autonomic
morphine 4mg [124]. The head down position block and absence of hypotension. However, there
should be avoided. Severe respiratory depression is no doubt that their use is associated with a high
has occurred after only 0.4 mg of hyperbaric incidence of complications, the most sinister of
morphine given intrathecally in such circum- which is delayed respiratory depression.
stance [80]. The proposition of a single injection given at
Naloxone antagonizes all the unwanted effects the time of surgery and providing long lasting
of spinal opioids, although repeated doses may be analgesia is very attractive. A single intrathecal
necessary to maintain adequate ventilation. An- injection of morphine has been shown to be
algesia is not usually affected, and this has led to beneficial to patients undergoing abdominal aortic
attempts to reduce the incidence of side effects by and coronary artery surgery. Significantly less
concomitant administration of naloxone. Thind, parenteral analgesia is required after operation,
Wells and Wilkes [184] found that naloxone 2 mg the time spent in the intensive care unit is
given by infusion over 12 h after extradural shortened [92] and significantly less hypotensive
morphine 4 mg did not affect analgesia and agents are required after cardiac surgery [190].
reduced the severity, but not the incidence of side However, these types of patient are nursed in an
effects. There was no respiratory depression. intensive care unit and their lungs are usually
Rawal and colleagues [155] used 5 and 10 ng kg"1 ventilated artificially after operation. It would
h~J after extradural morphine 4 mg and found certainly be feasible to perform a single intrathecal
that the larger dose decreased the duration of injection for the majority of patients undergoing
analagesia by about 25%. The naloxone also surgery, but repeat administration in the post-
reduced the incidence of side effects and a dose operative period would not be possible, there
related stimulatory effect on ventilation was seen. being few anaesthetists prepared to maintain a
These findings are contrary to those of Gowan catheter in the subarachnoid space for several
and colleagues [84], who used three bolus doses days. Performing an extradural injection is tech-
and infusion rates of naloxone in patients given nically more difficult, is more time consuming and
USE OF INTRATHECAL AND EXTRADURAL OPIOIDS 181
would not be a feasible proposition for as many In a nationwide survey in Sweden [153], it was
patients. An extradural injection does have the reported that 33% of anaesthetic departments
advantage that catheter techniques are routinely kept patients under close surveillance in an
practised, so that top up doses or continuous intensive care unit for 12-24 h after extradural
infusions are perfectly feasible. The incidence of morphine, 40% kept the patients under close
complications is also lower after extradural opi- surveillance for up to 12 h, and 18% returned the
oids than intrathecal. patients to an ordinary ward with no special
The biggest constraint on the use of spinal observations. The incidence of respiratory de-
opioids is the nature and incidence of the pression in this survey was 0.09%, which, is
associated complications. Pruritis, nausea and considerably lower than that reported by others
vomiting and urinary retention are common. The with reasonably large series (table VI).
last of these is probably the most troublesome Recently, the development of an Acute Pain
complication and must be taken into account Service for the management of postoperative pain
when considering the technique for postoperative has been described. This allows use of patient
analgesia in the majority of patients who will not controlled analgesia and extradural opioids in
routinely have urinary catheters. However, the general wards as well as in areas of close
most serious problem is respiratory depression. surveillance [160]. Others have also described
Although more common after morphine, it does their experiences of using extradural opioids on
occur after other drugs and it is the unpredict- general surgical and medical wards [34]. Ready
ability of its appearance that makes it so danger- and colleagues [160] stressed both that the service
ous. Large comparative series have not been must be available on a 24-h basis, and the
performed to indicate the frequency of occurrence importance of a joint educational programme with
with the different opioids. the nursing staff. Standard procedures are issued,
Because of the problem of respiratory depres- the nurses give the opioid (usually morphine)
sion, the majority of workers recommend that through the extradural catheter and have instruc-
these patients be kept in areas where there is a tions on the treatment of complications. Criteria
higher degree of surveillance than can be provided are laid down for the use of mechanical respiratory
on an ordinary ward, and for up to 24 h after the monitors, and for the circumstances in which they
last injection, certainly with morphine. Some are not to be used. Both groups require naloxone
form of respiratory monitoring is mandatory and to be immediately available.
probably most easily provided by the constant Bursch and Stedman [34] have used this
supervision of the nursing staff. Respiratory approach since 1984. They analysed retro-
inductance plethysmography is not practical as a spectively data from 125 patients and reported a
routine, and although apnoea alarms have been low incidence of complications and no respiratory
used [7], apnoea is the very problem that it is depression. Because the analysis was retrospec-
hoped to prevent. End-tidal carbon dioxide tive, they were unable to comment on the quality
measurements can be valuable, while trans- of analgesia. Ready and colleagues [160] reported
cutaneous carbon dioxide electrodes still await that, after 18 months of operation, their service
critical analysis in a large series of patients. Pulse continues to grow and is popular with patients
oximetry may also prove useful, but choosing the and surgeons. Extradurals have been used in 623
correct saturation below which intervention be- patients. Delayed respiratory depression occurred
comes necessary will depend on the individual in four, all of whom were high risk patients who
patient. Respiratory depression usually comes on had undergone prolonged surgery and who were
gradually, often indicated by a slowing of the rate being cared for in an intensive care unit.
of ventilation [181], and it is the trend indicated The policy of how and where to manage patients
by the respiratory monitoring equipment that who are in receipt of spinal opioids must rest with
must be taken into account. Hourly monitoring of individual anaesthetists and their departments.
ventilatory rate is totally unacceptable. Use of The programmes mentioned above are time
continuous infusions of naloxone, although suc- consuming and require much manpower. It is
cessful in reducing the severity of complications difficult to see, given the facilities that exist in the
(but possibly also analgesic efficacy [84]), adds to U.K. at the moment and the commitments of
the complexity of the procedure and mitigates nursing and medical staff, how such patients can
against widespread use of the method. be safely managed on an ordinary ward. The
182 BRITISH JOURNAL OF ANAESTHESIA
spectrum of occurrence of respiratory depression development of guidelines so that the technique
after extradural opioids is wide [203] and close can be extended to the majority of patients
surveillance is necessary for up to 24 h after undergoing surgery.
administration. It is therefore difficult to justify
returning these patients directly to an ordinary
RATIONAL USE OF EXTRADURAL AND INTRATHECAL
ward.
OPIOIDS
THE FUTURE
The pharmacokinetic and pharmacodynamic
The introduction of spinal opioids has been an effects of spinal opioids have been extensively
exciting and significant advance in the man- investigated, but more work is necessary before
agement of acute and chronic pain. The incidence the chapter can be finally closed on this new
of side effects, however, is high. Morphine is still technique of analgesia. From the knowledge that
the drug most commonly used worldwide, but the exists at the moment, it is possible to suggest
more fat soluble opioids are more popular in the recommendations for their logical use in the
U.K., although exact figures are not available. management of acute pain.
The search will continue for drugs with a more Choice of drug. Morphine has been the most
specific analgesic action at cord level, in the hope widely used and studied drug and, although its
of removing the possibility of respiratory de- use has been defended [152], the incidence of
pression. Midazolam has been used extradurally complications are such that its routine use is
[163] and intrathecally [83] and is effective in difficult to accept. The lipophilic drugs are a
relieving somatic, but not visceral pain. Perhaps much more logical choice, but large trials are
the analgesic actions of benzodiazepines can be necessary to identify the drug of choice.
developed without associated central effects. Choice of dose. There is a wide variation in
Endogenous peptides have been used and individual susceptibility to opioids and conse-
prolonged analgesia has been reported after quently in dose requirements. It is not logical to
intrathecal P-endorphin [140]. An infusion of give afixeddose to everyone, as has been done for
somatostatin after a 250-ng bolus provided com- many years with i.m. opioids with totally in-
plete analgesia after surgery and was not influ- adequate results. The dose should be titrated
enced by the administration of naloxone [46]. against the patient's needs and more use should be
Modification of endogenous peptides might be made of patient controlled analgesia. It is possible,
possible and result in compounds with long lasting however, to achieve adequate analgesia more
analgesic properties. Calcitonin has produced easily with spinal opioids by giving a fixed dose of
prolonged analgesia when injected intrathecally in drug, but this does not allow for the patient whose
patients with intractable pain [75] and was needs are greater than average.
associated with significantly less postoperative Choice of route of administration. Although it is
pain when given together with lignocaine intra- more logical to use the intrathecal route, the
thecally for spinal analgesia [122]. The manu- logistical problems of giving repeat injections and
facturers of salmon calcitonin, however, have in particular the high incidence of complications,
warned of its possible serious effects when used in do not make this the route of choice. Arguments
this way [176]. For long term use in patients with have been made for routinely using the lumbar
intractable pain, drug combinations with the a2- extradural route even after upper abdominal and
agonist clonidine or the synthetic opioid D-ala, D- thoracic surgery. Adequate analgesia does occur
leu-enkephalin (DADL) may help in those de- with morphine, and the incidence of respiratory
veloping tolerance to opioids [52]. Droperidol has depression is probably lower, but it is slow in
been used extradurally for this purpose, with onset, which might result in repeated doses being
benefit [13]. given in belief that the original dose was too small
The future will also see more use of patient to be effective. With the lipophilic opioids,
controlled analgesia given by the extradural route theoretical considerations would suggest that they
and the development of sophisticated infusion should be given at the appropriate spinal level.
pumps for long term self-administration of opi- Studies are required to confirm or refute this
oids. Above all, what are needed are extensive, hypothesis.
controlled, comparative trials to identify the most Precautions and surveillance. Because of the
suitable drug for use in acute pain and the complications, the degree of surveillance that is
USE OF INTRATHECAL AND EXTRADURAL OPIOIDS 183
required cannot be provided on an ordinary ward. Epidural morphine in children: pharmacokinetics and
At the moment, close observation is recommended CO2 sensitivity. Anesthesiology 1986; 65: 590-594.
12. Austin KL, Stapleton JV, Mather LE. Relationship
for 24 h, especially after morphine, although this between blood meperidine concentrations and analgesic
period might safely be shortened for other drugs response: a preliminary report. Anesthesiology 1980; 53:
once information becomes available. It is im- 460-^66.
perative that nursing staff and resident medical 13. Bach V, Carl P, Ravlo O, Crawford ME, Werner M.
staff be educated in their use, are instructed on the Potentiation of epidural opioids with epidural droperidol.
A one year retrospective study. Anaesthesia 1986; 41:
treatment of complications and are able to recog- 1116-1119.
nize the circumstances when urgent adminis- 14. Bailey PM, Sangwan S. Caudal analgesia for perineal
tration of naloxone is required. surgery. A comparison between bupivacaine and dia-
Extradural and intrathecal opioids have been morphine. Anaesthesia 1986; 41: 499-504.
15. Baraka A, Noveihid R, Hajj S. Intrathecal injection of
widely accepted by anaesthetists and have proved morphine for obstetric analgesia. Anesthesiology 1981;
a valuable asset in the management of all types of 54: 136-140.
pain. It would be a pity if one publicized disaster 16. Barron DW, Strong JE. Postoperative analgesia in major
were to set back the technique by 20 years. orthopaedic surgery: epidural and intrathecal opiates.
Anaesthesia 1981; 36: 937-941.
17. Beeby D, Macintosh KC, Bailey M, Welch DB.
Postoperative analgesia for Caesarean section using
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