Anaesth Intens Care 1998; 26: 137-146

Review
Intrathecal Pethidine: Pharmacology and Clinical
Applications
W. D. NGAN KEE*
Department of Anaesthesia and Intensive Care, Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong

SUMMARY
Pethidine is the only member of the opioid family that has clinically important local anaesthetic activity in the dose
range normally used for analgesia. Pethidine is unique as the only opioid in current use that is effective as the sole
agent for spinal anaesthesia. In lower doses, intrathecal pethidine is also an effective analgesic for treating pain in
labour. This paper reviews the pharmacology of intrathecal pethidine and clinical experience reported to date.
Articles reviewed include those identified by a Medline search using keywords “intrathecal” or “spinal anaesthesia/
anesthesia” and “pethidine” or “meperidine”. Reference lists from identified papers were scrutinized to identify further
relevant articles.
Key Words: ANAESTHETIC TECHNIQUES: spinal, pethidine, meperidine

HISTORY drugs, with molecular weight and pKa in particular

Pethidine was the first synthetic opioid to be used
to provide analgesia in humans. Shortly after its anal-
gesic properties were discovered by Eisleb and
Schaumann in 19391, pethidine was shown also to
have local anaesthetic activity comparable with that
of cocaine2. Subsequently, pethidine has been in-
vestigated for a number of clinical applications,
including peripheral nerve block, intravenous
regional anaesthesia, and intrathecally for spinal
anaesthesia and analgesia. Following initial reports in
animals3, Cousins et al reported the use of intrathecal
pethidine in doses of 10 to 30 mg to treat cancer pain
in humans4. The first report of the use of pethidine as
sole agent for spinal anaesthesia was published in the
French literature by Mircea in 19825 and has been
followed by a number of reports that have used pethi-
dine alone and in combination with conventional
local anaesthetics for spinal anaesthesia for a variety
of different surgical procedures.
PHARMACOLOGY
Pethidine and its derivatives have similar physico-
chemical properties to conventional local anaesthetic
*F.A.N.Z.C.A., Associate Professor.
Address for Reprints: Associate Professor W. D. Ngan Kee, Department
of Anaesthesia and Intensive Care, Chinese University of Hong Kong,
Prince of Wales Hospital, Shatin, Hong Kong.
Accepted for publication on December 23, 1997.
Anaesthesia and Intensive Care, Vol. 26, No. 2, April 1998
being closely related (Table 1). Early investigations of
the pharmacological properties of pethidine ex-
plained its analgesic and local anaesthetic properties
on structural similarities to cocaine and morphine1,2.
A number of in vitro studies have confirmed the
ability of phenylpiperidine opioids to block conduc-
tion in peripheral nerve2,6,7. Gissen et al found that
fentanyl and sufentanil in high concentrations
decreased the amplitude of action potentials after
nerve stimulation7. This effect was not prevented by
pretreatment with naloxone and is evidence that the
effect of the phenylpiperidine derivatives on nerve
conduction is independent of opioid receptors. Power
et al showed that pethidine and fentanyl but not
diamorphine blocked nerve conduction in a similar
nerve preparation6. Pethidine at a concentration of
0.5 mg/ml blocked conduction completely and
reversibly. Fentanyl also blocked nerve conduction
at similar concentrations but these concentrations
are much greater than the commercially available
preparation.
The local anaesthetic activity of pethidine has been
demonstrated in a number of in vivo investigations.
Intradermal injection of pethidine 2% caused a
decrease in sensory perception greater than that
caused by saline and similar to that caused by ligno-
caine 0.5%8. Animal studies confirmed the ability of
perineurally administered pethidine to block nerve
conduction, and also showed motor and sensory block
138 W. D. NGAN KEE

TABLE 1 0.5% and 1.5%14 and this group has suggested that
Physicochemical properties of phenylpiperidine opioids and local mechanisms other than a simple inhibition of sodium
anaesthetics
currents may be responsible for the spinal anaes-
Molecular Weight pKa Octanol: Buffer thesia associated with intrathecal pethidine15. Clinical
Partition Coefficient
reports of spinal anaesthesia using pethidine have
Opioids
used commercially available preparations which have
Pethidine 247 8.5 38.8 a concentration of 50 mg/ml and are preservative-
Fentanyl 336 8.4 813
Sufentanil 287 8.0 1778 free. This solution has a specific gravity of 1.009
Local
which is close to the upper limit of specific gravity of
Anaesthetics cerebrospinal fluid (CSF) and when injected intra-
Lignocaine 234 7.9 366 thecally, pethidine has the properties of a hyperbaric
Prilocaine 220 7.9 129 agent5.
Tetracaine 264 8.5 5822 Several studies have measured concentrations of
Bupivacaine 288 8.1 3420
pethidine in plasma and CSF after intrathecal injec-
tion. Following a dose of 1 mg/kg, plasma concentra-
tions of pethidine reached maximum mean levels
(Cmax) of 107-341 ng/ml16-19 which is less than the
after subarachnoid and epidural administration that reported minimum effective analgesic concentration
was comparable to that achieved with lignocaine9. In (MEAC) of 460 ng/ml20. Mean time to maximum
humans, Beyazova et al investigated the effect of per- concentration (tmax) varied from 45 to 168 min.
ineural injection of pethidine in concentrations of 0.5 Nordberg et al measured plasma concentrations of
to 1.5 mg/ml on conduction in the sural nerve10. pethidine after both intrathecal (25 mg) and epidural
Concentrations of 1.0 and 1.5 mg/ml caused hypo- (100 mg) injection and showed that systemic
algesia and a significant reduction in the amplitude absorption of pethidine was slower after intrathecal
of sensory evoked responses. A concentration of injection (tmax 2.3±1.8 h) compared with epidural
0.5 mg/ml also caused hypoalgesia but the reduction injection (tmax 0.23±0.03 h) but overall systemic
in nerve response amplitude seen did not reach bioavailability was similar21.
statistical significance. Oldroyd et al injected pethi- After intrathecal injection of pethidine, maximum
dine intradermally in concentrations of 0.5, 1 and concentrations of pethidine in CSF were measured at
2 mg/ml and found reduction of sharp sensation 5-10 min after injection21,22. Nordberg et al measured
occurred with the higher two concentrations11. They CSF and plasma concentrations of pethidine after
followed this with injection of 40 ml of pethidine 1 to intrathecal injection of 25 mg of pethidine and found
2 mg/ml by an intravenous regional anaesthetic tech- that the maximum CSF/plasma concentration ratio
nique and found both concentrations caused com- was 6000:45,00021. This compared with a ratio of
plete loss of sharp sensation. Compared with prilo- 26:97 after epidural injection. The volume of distrib-
caine 0.5%, the onset of anaesthesia was slower and ution in CSF was 13±13 ml. Sjöström et al measured
loss of touch sensation and motor block was less com- concentrations of pethidine and morphine in CSF
plete. In a similar study, Armstrong et al found that after intrathecal injection22. Maximum concentrations
intravenous regional anaesthesia was enhanced by in CSF of both drugs were considerably higher
the addition of pethidine 100 mg to prilocaine than concentrations in plasma. Pethidine disappeared
0.25%12. Acalovschi and Cristea found that intra- from CSF faster than morphine which was attributed
venous regional anaesthesia using 40 ml pethidine to the greater lipid solubility of pethidine. After 6 h, a
0.25% gave sensory block that was inferior to that smaller percentage of the dose of pethidine (0.4%)
from lignocaine 0.5% and was associated with more remained in lumbar CSF compared with morphine
side-effects which precluded the authors from recom- (1.6%). The faster elimination of pethidine from CSF
mending pethidine as a sole agent for this technique13. compared with morphine suggested that there was
Intrathecal injection of pethidine produces spinal a higher risk of cephalad spread after intrathecal
anaesthesia that is qualitatively similar to that injection with morphine.
achieved with conventional local anaesthetics. Maurette et al measured concentrations of pethi-
However, the exact mechanism by which this is dine in plasma and ventricular CSF in head-injured
achieved is controversial. Flanagan et al were unable patients after intrathecal injection of pethidine
to demonstrate measurable block of the median 1 mg/kg17. Pethidine was detected in CSF within one
nerve in human volunteers using 5 ml pethidine hour of injection and maximum concentrations in
Anaesthesia and Intensive Care, Vol. 26, No. 2, April 1998
 INTRATHECAL PETHIDINE
CSF were one-third to one-fifth that found in plasma.
Based on the early appearance of pethidine in
ventricular CSF and the similarity of the concentra-
tion-time curves for pethidine in ventricular CSF and
plasma, they concluded that the potential risk of res-
piratory depression was related mainly to absorption
of pethidine into the systemic circulation and redistri-
bution back into ventricular CSF.
To date, no studies have specifically investigated
the risk of neurotoxicity of intrathecal pethidine. The
large number of reported cases of the use of intra-
thecal pethidine without documented neurological
complications has been cited as evidence for its
safety23,24 and the conduction block induced by pethi-
dine has been shown in vitro to be reversible6.
CLINICAL EXPERIENCE
1. Spinal Anaesthesia
In the first report of spinal anaesthesia using pethi-
dine, Mircea et al described a large series of 713
patients who received intrathecal pethidine in doses
ranging from 0.8 to 1 mg/kg or fixed doses of 50 mg
or 75 mg for abdominal, perineal and lower limb
surgery5. Numerous other reports followed and have
described the use of intrathecal pethidine for
anaesthesia for a variety of surgical procedures,
including surgery on the lower limb and hip5,25-30,
perineal and urological surgery5,16,18,30-36, lower
abdominal surgery5,25,30,37 and caesarean section24,38-42.
Dosage
Doses of pethidine used for spinal anaesthesia have
ranged from 0.5 to 1 mg/kg as well as fixed doses of
50 mg, 60 mg and 100 mg. Because of variation in
patient populations, positioning during injection and
additives used, a wide range of clinical responses to
different doses have been reported. Reports in the
English language are summarized in Table 2. A dose
of 1 mg/kg has been adequate for lower limb, hip,
urological, perineal, and lower abdominal surgery
including caesarean section. Fixed doses of 60 mg
(mean dose 0.79 mg/kg) and 100 mg (mean dose
1.77 mg/kg) have been used for lower limb and lower
abdominal surgery. Lower doses of 0.5 mg/kg were
sufficient for lower limb, hip, perineal and endoscopic
urological surgery and have generally been associated
with fewer side-effects compared with the higher
doses26,27,33.
Few studies have directly compared different doses
of intrathecal pethidine. Nguyen Thi et al investi-
gated addition of pethidine in doses of 0.05 to
0.5 mg/kg to 10 mg hyperbaric bupivacaine 0.5% in
patients having lower limb surgery23. There was no
Anaesthesia and Intensive Care, Vol. 26, No. 2, April 1998
139
correlation between the dose of pethidine and the
duration of sensory block but pethidine caused a
dose-related increase in postoperative analgesia and
a dose-related increase in the duration of motor
block. Grace and Fee compared intrathecal pethidine
0.5 mg/kg with 0.75 mg/kg in patients having
transurethral resection of the prostate gland35. With
the 0.75 mg/kg dose, the median duration of sensory
block was greater (150 vs 120 min) and the median
duration of motor block was greater (105 vs 80 min)
compared with the 0.5 mg/kg dose, but these dif-
ferences were not considered clinically significant.
There was no difference between the two doses in the
quality of intraoperative anaesthesia or the incidence
of side-effects and postoperative analgesia.
Baricity and patient positioning
Pethidine has the properties of a hyperbaric agent
when injected intrathecally5. Therefore, the spread of
anaesthesia can be influenced by the position of the
patient during and immediately after intrathecal
injection. Acalovschi et al described saddle block for
perineal surgery using intrathecal pethidine 0.5
mg/kg43. By injecting the dose with the patient sitting
and maintaining this position for five minutes before
placing the patient supine, sensory block was limited
to the S2-5 dermatomes and permitted early ambula-
tion. Similarly, Patel et al maintained patients having
endoscopic urological procedures in the sitting posi-
tion for ten minutes after intrathecal injection of
pethidine 0.5 mg/kg33. In this study, the spread of
sensory block was somewhat greater, with the highest
dermatomal levels achieved ranging from T8-T11.
Part of the difference in spread might be explained by
differences in the age of the patients studied (mean
age 37 years in the study by Acalovschi et al compared
with 69 years in the study by Patel et al).
Because pethidine has moderately high lipid solu-
bility, it diffuses rapidly into lipid-rich areas of the
spinal cord which reduces its propensity for cephalad
migration in CSF44. However, a certain amount of
time is required for pethidine to “fix”. Thus in studies
where patients were immediately placed supine after
intrathecal injection of pethidine in the lower dose
ranges with the patient sitting, relatively high spread
of the block has been described31,34,35.
When pethidine has been injected intrathecally in
doses greater than 0.5 mg/kg, relatively high blocks
have been described, despite maintaining patients in
the sitting position for variable periods after injec-
tion; however blocks have generally been lower than
those achieved when injection was performed with
the patient lateral (Table 2).
140 W. D. NGAN KEE

TABLE 2
Dosages and characteristics of spinal anaesthesia using intrathecal pethidine
Dose No. Type Duration Position Maximum Onset of Onset of Duration Duration
and of of of During Dermatomal Sensory Motor of Sensory of Motor
References Patients Surgery Surgery Injection Level Block Block Block Block
(min) (min) (min) (min) (min)
1 mg/kg
Famewo31 20 perineal, 39.7±14 sitting T3-T12 6.3±2.7 6.9±2.6 ns 54.5±18.7
inguinal
Cozian32 8 endoscopic ns sitting T6-T12 14.7±2* 5.4±3.2 117.5±53.9 133.7±41
urological
Naguib16 5 perineal ns sitting T7-T12 5.8±2.1 6.2±2.5 77±18.8 47±7.4
Talafre38 26 caesarean ns lateral T5.1±0.24 3.5±0.51 ns 77.6±10.8 67.2±6
section
Spiers28 9 hip ns ns ns ns ns ns ns
Tauzin-Fin18 30 endoscopic 25±12 sitting T7-T12 5.6±2.2* 7.7±2.8 86±24 91.1±22
urological
Lewis34 30 endoscopic ns sitting T4-L3 12.9±5.8* 13.2±10 90±24 66±36
urological
Kafle39 25 caesarean ns lateral T4-T6 7 (5-8) ns 60 (55-70) 50
section
Nguyen Thi24 28 caesarean 66±15 lateral T4-T10 ns ns ns ns
section
Andrivet63 10 lower limb ns sitting/ T4-T12 ns 33.5±14 ns 116
lateral
0.7-0.8 mg/kg
Grace35 20 endoscopic ns sitting T3-T6 20 (11-25)* 20 (15-25) 150 (120- 105 (75-
section 180) 120)
Conway29 14 endoscopic ns lateral T3-L2 17±11 21±6 ns ns
urological
100 mg
Sangarlangkarn25 20 lower limb ns sitting T7.2±3.1 34.2±16.6* 21.3±10.3 76.2±25.2 42.7±20
lower
abdomen
60 mg
Norris37 10 lower ns lateral T3 ns ns ns ns
abdomen
0.5 mg/kg
Acalovschi43 111 perineal ns sitting S2 5.3±1.4* 6-7 141±26.1 ns
Kavuri26 6 hip ns lateral T8-T11 12 ns ns ns
Patel33 22 endoscopic 56 sitting T8-T11 10±2.6 ns 100±13.3 ns
urological
Trivedi27 16 lower limb 58 sitting ns 5.8±1.6 ns 110±5 ns
Grace35 21 endoscopic ns sitting T4-T8 15 (10-20)* 20 (15-30) 120 (105- ns
urological 150)
Data are number, range, mean±standard deviation, or median (interquartile range)
*Time to maximum sensory block
ns=not specified

Additives and mixtures Talafre et al38. However, as the standard preparation

A number of substances have been added to
intrathecal pethidine which can potentially alter the
quality of anaesthesia. Dextrose, which is commonly
added to increase the baricity of local anaesthetics,
was added to pethidine 1 mg/kg by Cozian et al32 and
of pethidine has been shown to behave as a hyper-
baric solution, addition of dextrose may not signifi-
cantly affect the spread and disposition of pethidine
in CSF. Accordingly, the characteristics of the block
attained in the studies where dextrose has been added
Anaesthesia and Intensive Care, Vol. 26, No. 2, April 1998
 INTRATHECAL PETHIDINE
have been similar to those in studies where plain
solution was used (Table 2).
In the majority of reports of spinal anaesthesia
using pethidine, the undiluted solution which has a
concentration of 50 mg/ml has been used. However,
Grace and Fee added saline to pethidine 0.5 and
0.75 mg/ml to increase the total injectate volume to
4 ml35. The level of the block that resulted from the
dose of 0.5 mg/kg was the highest that has been
reported from this dose. Further investigation using
standardized patient positioning and speed and site
of injection are required to determine the effect of
injectate volume on the characteristic of the block
from intrathecal pethidine. In another study, Grace
et al added clonidine 75 µg to pethidine 0.75 mg/kg
given intrathecally to patients having total hip joint
replacement45. The characteristics of the spinal block
were similar to those in other reports, and there was
no improvement in postoperative analgesia com-
pared with a control group that received bupivacaine
0.5%. However, the pethidine-clonidine group had a
greater incidence of hypotension and the authors
concluded that this mixture did not have advantages
over bupivacaine.
Substances have been added to intrathecal pethi-
dine in attempts to prolong the duration of spinal
anaesthesia. Bostrom et al reported that the addition
of adrenaline 200 µg to pethidine 0.5 mg/kg in
patients having endoscopic urological surgery did not
prolong the duration of sensory block compared with
controls46. Onset time and the incidence of complica-
tions were similar between groups although more
patients in the control group had complete motor
block. Langerman et al found that the duration of
analgesia and motor block were prolonged in rabbits
when intrathecal pethidine was dissolved in a lipid
solution compared with the standard aqueous solu-
tion47. They attributed this finding to slow release of
pethidine from the lipid phase that effectively served
as a depot of drug in the CSF. Further investigation
of drug formulations based on lipid vehicles was
suggested.
Several reports have investigated mixtures of pethi-
dine with local anaesthetics for spinal anaesthesia.
Addition of pethidine in doses of 0.05 to 0.5 mg/kg to
10 mg hyperbaric bupivacaine 0.5% by Nguyen Thi et
al23 was described above. Tzeng et al reported that
addition of pethidine 0.25 mg/kg to tetracaine 10 mg
increased the speed of onset and duration of
sensory and motor block and improved postoperative
analgesia, but this was at the cost of increased
cardiovascular depression, compared with tetracaine
alone48.
Anaesthesia and Intensive Care, Vol. 26, No. 2, April 1998
141
Conway et al compared haemodynamic effects
of pethidine 0.4 mg/kg plus hyperbaric bupivacaine
7.5 mg with pethidine 0.8 mg/kg and bupivacaine
15 mg29. All groups produced similar reductions in
arterial pressure, systemic vascular resistance and
central venous pressure but there was a high inci-
dence of bradycardia in both groups that received
pethidine that was not seen with bupivacaine. Tauzin-
Fin et al found that addition of prilocaine 0.5 mg/kg
to intrathecal pethidine 1 mg/kg resulted in faster
onset and longer duration of block but enhanced the
systemic absorption of pethidine18. Maurette et al
compared lignocaine 1.6% with lignocaine 1.6% plus
pethidine 1% for continuous spinal anaesthesia in
patients having surgery for fracture of the neck of the
femur49. Addition of pethidine reduced the initial
dose requirement for lignocaine and improved post-
operative analgesia. However, the mixture group had
a high incidence of drowsiness and greater haemo-
dynamic instability and the authors did not recom-
mend the use of this combination in the doses used.
Chen et al reported that addition of pethidine
0.2 mg/kg reduced the incidence of shivering from
56.7% to 16.7% when added to tetracaine 12-16 mg
used for spinal anaesthesia50.
2. Postoperative analgesia
A potential advantage that pethidine has over con-
ventional local anaesthetics as an agent for spinal
anaesthesia is its dual properties of being a both a
local anaesthetic and an opioid receptor agonist. The
opioid effects may persist into the postoperative
period and several studies have shown that post-
operative pain and analgesic requirement were
reduced in patients who had lower abdominal and
lower limb surgery under spinal anaesthesia using
pethidine compared with conventional local anaes-
thetics. Talafre et al found that patients who received
intrathecal pethidine for caesarean section required
less intramuscular pethidine for postoperative anal-
gesia in the first 12 h after surgery compared with
patients who received tetracaine38. Kafle39 and Norris
et al37 compared intrathecal pethidine with lignocaine
for caesarean section and postpartum sterilization
respectively. In both studies, the mean duration of
postoperative analgesia was greater in patients who
received pethidine (6h vs 1h and 448 min vs 83 min).
Sangarlangkarn et al also compared intrathecal pethi-
dine with lignocaine for lower abdominal and lower
limb surgery and found more patients in the pethi-
dine group required only oral analgesia in the first
24h postoperatively, although the number of patients
who were pain-free and required no analgesia was
142 W. D. NGAN KEE
similar between groups25. Nguyen Thi et al showed a
dose-related increase in postoperative analgesia after
lower limb surgery occurred when pethidine 0.05 to
0.5 mg/kg was added to intrathecal bupivacaine
0.5%23.
In contrast, studies that have compared intrathecal
pethidine with conventional local anaesthetics for
endoscopic urological surgery have not shown a dif-
ference in postoperative pain or analgesic require-
ment. This may be related to there being less post-
operative pain associated with these procedures.
Furthermore, Grace et al compared intrathecal pethi-
dine 0.75 mg/kg plus clonidine 75 µg with bupi-
vacaine 13.75 mg and bupivacaine 13.75 mg plus
morphine 0.5 mg for total hip joint replacement45.
They found that 24h postoperative analgesic require-
ment in the pethidine-clonidine group was similar to
that in the bupivacaine group and significantly more
than that in the bupivacaine-morphine group. They
concluded that the postoperative analgesic effects of
intrathecal pethidine are relatively short-lived.
Investigations of the addition of pethidine to con-
ventional local anaesthetic for spinal anaesthesia for
caesarean section have shown that early postopera-
tive analgesia is improved. Feldman et al found that
addition of pethidine 10 mg to bupivacine 12 mg
resulted in lower pain scores and reduced require-
ment for supplementary analgesia at 2 h compared
with saline control51. Increasing the dose of pethidine
to 20 mg caused more side-effects without improving
analgesia. A subsequent study from the same centre
showed that a combination of pethidine 10 mg with
morphine 0.15 mg added to intrathecal bupivacaine
resulted in better early postoperative analgesia com-
pared with morphine alone or fentanyl52.
3. Analgesia In Labour
The introduction of small-gauge, atraumatic spinal
needles, microcatheters and combined spinal-
epidural techniques has increased the popularity of
intrathecal opioids in labour. Advantages of this tech-
nique include rapid onset of analgesia and preserva-
tion of motor function53. A variety of different drugs
have been used, alone and in combination with local
anaesthetics. The efficacy of intrathecal pethidine
for analgesia was investigated by Norris et al54 and
Swayze et al55. In both these studies, intrathecal pethi-
dine 10 mg was injected via spinal microcatheters.
Norris et al found that eight of 10 parturients
obtained dramatic reduction in pain within five
minutes, although two patients required a second
dose to obtain adequate pain relief54. One patient
developed pruritus, two patients vomited and two
patients required ephedrine for treatment of
hypotension. Swayze et al administered a bolus of
intrathecal pethidine 10 mg to 20 parturients at their
first request for analgesia with subsequent doses of
7 mg as required55. Effective analgesia with high level
of patient satisfaction was obtained with a mean
pethidine consumption of 12.96 mg/hr. Following the
initial dose, mean onset time for analgesia was
3.9 min (range 2 to 12 min) and mean duration of
83 min (range 38 to 120 min). No patients developed
hypotension, and only two patients (10%) developed
slight motor block. Eight patients (40%) complained
of nausea, three (15%) had pruritus and two (10%)
became drowsy. In five cases a transient fetal brady-
cardia was noted, two within 15 min of a dose of
pethidine, but none required operative delivery and
there were no adverse fetal outcomes. Plasma con-
centrations of pethidine in maternal and umbilical
cord blood ranged widely with maximum recorded
values of 250.4 and 157.5 ng/ml respectively. Honet
et al also used a spinal catheter technique in a com-
parison of intrathecal pethidine, fentanyl and sufen-
tanil for analgesia in labour56. They found that the
drugs gave similar onset and duration of analgesia but
patients receiving pethidine had lower pain scores
once cervical dilatation progressed beyond 6 cm. The
incidence of side-effects in all groups was low, but
patients receiving pethidine experienced more
nausea. In a review of complications of epidural and
combined spinal-epidural analgesia in labour, Norris
et al found patients who received intrathecal pethi-
dine had less pruritus but more frequent nausea and
hypotension compared with patients who received
sufentanil57.
4. Adverse effects
Although the use of intrathecal pethidine has been
recommended to reduce the risk of haemodynamic
fluctuations in high risk patients58, analysis of reports
of its use indicates that pethidine can cause haemo-
dynamic instability that is equal to or greater than
that associated with conventional local anaesthetic
drugs38,59. Furthermore, intrathecal pethidine is
associated with a number of other adverse effects
(Table 3). However, the incidence of side-effects is
less when the dose is limited to 0.5 mg/kg. Following
a dose of 0.5 mg/kg, the reported incidence of
hypotension ranged from 0 to 17% compared with an
incidence of 3.3 to 64% in doses of 0.75 mg/kg and
greater.
The haemodynamic changes associated with
intrathecal pethidine were examined in detail by
Cozian et al32 and Conway et al29. Cozian et al found
Anaesthesia and Intensive Care, Vol. 26, No. 2, April 1998
 INTRATHECAL PETHIDINE 143

TABLE 3
Adverse effects associated with intrathecal pethidine
Reference Dose Hypotension Bradycardia Nausea/ Pruritus
Vomiting
Famewo31 1 mg/kg 15% 20% 30% 25%
Cozian32 1 mg/kg ns ns 12.5% 62.5%
Naguib16 1 mg/kg 20% 20% nil 60%
Talafre38 1 mg/kg 50% ns 40% 38%
Spiers28 1 mg/kg ns ns ns ns
Tauzin-Fin18 1 mg/kg 1 (3.3%) nil nil nil
Lewis34 1 mg/kg 10% 3.3% 6.7% 13.3%
Kafle39 1 mg/kg 32% 0 8% 32%
Nguyen Thi24 1 mg/kg 36% 0 32% 10.7%
Grace35 0.75 mg/kg 5% ns 10% 35%
Grace35 0.5 mg/kg 4.8% ns 15% 15%
Conway29 0.8 mg/kg 9 (64%) 6 (42.8%) 6 (42.8%) nil
Sangarlangkarn25 100 mg 2 (10%) ns 55% 10%
Norris37 60 mg ns ns ns ns
Acalovschi43 0.5 mg/kg nil nil 4.5% 6.3%
Kavuri26 0.5 mg/kg 17% ns 0 33%
Patel33 0.5 mg/kg 14% ns 0 4.5%
Trivedi27 0.5 mg/kg 0 0 6.3% 6.3%
ns=not specified

intrathecal pethidine 1 mg/kg caused reductions in
mean arterial pressure, right atrial pressure, mean
pulmonary artery pressure and pulmonary capillary
wedge pressure32. Cardiac index was unchanged and
there was a small reduction in systemic vascular
resistance index. The changes in mean arterial pres-
sure correlated with changes in systemic vascular
resistance index. There was a small decrease in heart
rate, and although the change was not statistically sig-
nificant, it was considered clinically significant since
the reduction in arterial pressure would normally be
expected to cause a baroreceptor-mediated increase
in heart rate. Bradycardia after intrathecal pethidine
has been observed in a number of other reports.
Conway et al reported that bradycardia requiring
atropine occurred in six of 14 (43%) elderly patients
who received pethidine 0.8 mg/kg for urological
surgery and four of 14 (29%) who received a mixture
of pethidine 0.4 mg/kg plus bupivacaine 7.5 mg29.
Patients in that study did not receive intravenous fluid
preload and bradycardia only occurred when the
upper level of the block was T7 or higher. The inci-
dence of bradycardia in other reports has ranged
from 0 to 20% (Table 3). Shimai and Yokohama re-
ported atrioventicular block that occurred after a
young patient who received intrathecal pethidine
45 mg had bradycardia treated with intravenous
atropine60.
Other adverse effects that are associated with
intrathecal pethidine include nausea and vomiting,
pruritus, sedation and respiratory depression. Several
Anaesthesia and Intensive Care, Vol. 26, No. 2, April 1998
comparative studies have shown that the incidence of
these side-effects is greater with pethidine compared
with conventional local anaesthetics although this
may be dose-dependent25,29,37,39. In the first report of
spinal anaesthesia using pethidine, Mircea et al
described a syndrome of hypotension, bradycardia
and hypoxaemia that occurred in 0.55% of patients5.
Subsequently, the incidence of these adverse effects
has varied considerably between studies although the
incidence appears greater with doses greater than
0.5 mg/kg. Treatment of these side-effects responds to
standard methods although amelioration of pruritus
associated with intrathecal pethidine using low-dose
propofol has been described61. Reactivation of herpes
simplex type I after intrathecal pethidine has been
reported although other factors may also have been
contributory in this case62.
Sedation after intrathecal pethidine has been
reported frequently and there have been some
reports of respiratory depression which may be dose-
related5. Several patients in the initial report by
Mircea et al required assisted ventilation and the
authors recommended that the dose of pethidine
should not exceed 1 mg/kg5. Andrivet et al reported
that two of 10 patients who received intrathecal
pethidine 1 mg/kg for orthopaedic surgery developed
respiratory depression and required treatment with
naloxone63. Sangarlangkarn et al gave a fixed dose of
pethidine 100 mg intrathecally that was equivalent to
a mean dose of 1.8 mg/kg and found that one patient
required assisted ventilation25. Ong and Segstro
144 W. D. NGAN KEE
reported respiratory depression in two patients who
received a fixed dose of 50 mg64. The first patient was
an 81-year-old woman who weighed 73 kg and who
had received premedication of diazepam 10 mg. She
had an upper sensory level of T8 and required
naloxone. The second patient was a 24-year-old
woman who weighed 70 kg who became hypoxaemic
and required oxygen and verbal stimulation in the
recovery room. She had received midazolam 2 mg
intraoperatively. Brownridge et al reported a 24-year-
old parturient who required assisted ventilation and
naloxone after accidental intrathecal injection of
pethidine 50 mg in 10 ml saline injected through an
epidural catheter that was subsequently shown radio-
logically to be in the subarachnoid place65.
Delayed respiratory depression after intrathecal
pethidine has not been reported.
5. Cost and availability
Intrathecal pethidine may have advantages when
cost and availability are considered. In the author’s
institution, the cost of a single dose of pethidine is 13
to 14 times less than the equivalent cost for the stan-
dard preparations of bupivacaine. In addition, pethi-
dine provides an alternative in developing countries
when local anaesthetics are not available24,66.
Intrathecal pethidine can also be considered in the
presence of allergy to conventional local anaesthetic
drug41,67.
CONCLUSIONS
Pethidine is unique amongst the opioids in possess-
ing local anaesthetic activity sufficient for its use as
sole agent for spinal anaesthesia. Intrathecal pethi-
dine is effective for providing spinal anaesthesia for
endoscopic urological procedures and surgery of the
lower limb, perineum and lower abdomen including
caesarean section. The combination of opioid and
local anaesthetic activity confers the ability to provide
surgical anaesthesia that is comparable to that
achieved with conventional local anaesthetic agents
and early postoperative analgesia that may be
superior. In low doses, intrathecal pethidine provides
effective analgesia in the first stage of labour and is
more effective than intrathecal fentanyl and sufen-
tanil as labour advances. However, the incidence of
side-effects is greater with pethidine compared with
the other commonly used intrathecal opioids.
Adverse effects that have been reported after
intrathecal pethidine include hypotension, brady-
cardia, sedation, respiratory depression, nausea and
pruritus. The risk of these occurring increases with
dose. Respiratory depression should be treated with
assisted ventilation and naloxone. Other side-effects
should be managed as for conventional spinal anaes-
thesia. Pethidine appears to have a therapeutic index
that is lower than that of conventional local anaes-
thetics used for spinal anaesthesia, particularly for
doses of 1 mg/kg or greater. In order to minimize
side-effects, the dose should be limited to 0.5 mg/kg
for perineal procedures and 0.5 to 1.0 mg/kg for lower
limb and lower abdominal procedures. Because
pethidine behaves like a hyperbaric agent, patient
posture can be manipulated to control spread of
spinal block. Undiluted pethidine in a concentration
of 50 mg/ml is effective for spinal anaesthesia.
Increasing injectate volume may increase the extent
of the block. There is no evidence that addition of
dextrose or adrenaline has significant advantages.
Careful postoperative monitoring is mandatory with
the use of intrathecal pethidine and concurrent use of
sedatives should be avoided.
With the current techniques, intrathecal pethidine
has not been established as a first-line agent for
routine use. However it has the advantage of being
inexpensive and it is a good alternative for patients
with allergy to amino-linked and ester-linked local
anaesthetics or in developing countries where these
drugs are not available or resources are limited. With
controversy currently surrounding the use of ligno-
caine for spinal anaesthesia68 there is a need for
alternative short-acting spinal anaesthetic agents.
Further investigation is warranted to determine
whether pethidine can fill this gap.
ACKNOWLEDGEMENT
I wish to thank Professor Tony Gin for reviewing
the manuscript.
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