Br. J. Anaesth.
(1989), 62, 248-252
LOW-DOSE INTRATHECAL DIAMORPHINE ANALGESIA
FOLLOWING MAJOR ORTHOPAEDIC SURGERY
B. A. REAY, A. J. SEMPLE, W. A. MACRAE, N. MACKENZIE
AND I. S. GRANT
Diamorphine is, theoretically, the opioid of choice
for spinal administration. Its high lipid solubility
speeds uptake into neural tissue and leads to
reduced CSF concentrations, thus limiting rostral
spread and the risk of respiratory depression [1].
Furthermore, its action is prolonged by rapid
metabolism in neural tissue to monoacetyl-
morphine and morphine [2].
Clinical studies with extradural diamorphine
5 mg for postoperative analgesia following Caes-
arean section confirmed that it produces effective
prolonged analgesia with a low incidence of
adverse effects [3,4]. Intrathecal administration in
doses of 1.25-2.5 mg also produces effective
prolonged analgesia, but at the price of a high
incidence of nausea, vomiting, urinary retention
and respiratory depression [5].
CSF concentrations of morphine are much
greater after intrathecal than after extradural
administration; this suggests that much smaller
intrathecal doses than used previously may be
effective [6]. This was confirmed in a series of 245
patients given intrathecal diamorphine 0.5-1.0
mg for analgesia after major orthopaedic surgery;
the incidence of adverse effects was acceptable,
while analgesia was prolonged [7].
The present randomized double-blind study
was designed to establish the duration of analgesia
and frequency of side effects following two doses
BARBARA A. REAY*, M.B., CH.B.; ALAN J. SEMPLEf, F.F.A.R.C.S. ;
WILLIAM A. MACRAE, F.F.A.R.C.S.; NEIL MACKENZIE,
F.F.A.R.C.S.; IAN S. GRANT§, F.R.C.P., F.F.A.R.C.S.I.; Depart-
ment of Anaesthesia, Ninewells Hospital, Dundee DD1 9SY.
Accepted for Publication: August 8, 1988.
Present addresses:
* Department of Anaesthesia, Perth Royal Infirmary,
Taymount Terrace, Perth PHI 1NX.
t Department of Anaesthesia, Falkirk and District Royal
Infirmary, Majors Loan, Falkirk FK1 5QE.
§ Department of Anaesthesia, Western General Hospital,
Crewe Road, Edinburgh EH4 2XU.
Correspondence to A.J.S.
SUMMARY
In a randomized double-blind study we exam-
ined the effect of adding diamorphine 0.25 mg
and 0.5 mg to intrathecal bupivacaine anaes-
thesia for major orthopaedic surgery. Duration of
postoperative analgesia was considerably greater
in patients given either doses of intrathecal
diamorphine than in a control group of patients
given bupivacaine alone (P < 0.001). However,
there was no significant difference between the
two diamorphine doses (0.25 mg and 0.5 mg),
each providing prolonged analgesia (10.8 and
9.9 h, respectively). Although there was no
evidence of late respiratory depression, the
frequency of adverse effects, in particular urinary
retention, nausea and vomiting, was high in both
groups receiving intrathecal diamorphine.
of diamorphine, 0.25 mg and 0.5 mg, adminis-
tered intrathecally with bupivacaine spinal anaes-
thesia for major orthopaedic surgery.
SUBJECTS AND METHODS
Sixty patients (ASA categories I or II) scheduled
to undergo major orthopaedic surgery (total hip
or knee replacement) consented to take part in this
study, which was approved by the local Hospital
Ethics Committee.
Premedication consisted of diazepam 5-15 mg
(depending on age and weight) by mouth 60-90
min before induction of spinal anaesthesia. On
arrival in the anaesthetic room, each patient was
allocated randomly to one of three groups: group
A = intrathecal 0.75% bupivacaine 3 ml; group
B = intrathecal 0.75 % bupivacaine 3 ml plus
diamorphine 0.25 mg in 0.9 % sodium chloride
0.5 ml; group C = intrathecal 0.75 % bupivacaine
3 ml plus diamorphine 0.5 mg in 0.9 % sodium
INTRATHECAL DIAMORPHINE
chloride 0.5 ml. Sodium chloride 0.9 % was used
to dissolve diamorphine in order to render the
solution isotonic. Although the manufacturers of
diamorphine (Evans) recommend water as a
solvent, it has been shown that it can be
reconstituted safely in 0.9% sodium chloride [8].
An i.v. infusion was commenced and lumbar
puncture was performed at the L3 space using a
25-gauge needle through which the appropriate
intrathecal drugs were administered. Arterial
pressure and ECG were monitored continuously.
Hartmann's solution 500 ml was administered i.v.
before spinal block was performed; thereafter
fluids were administered as appropriate, depend-
ing on blood loss and cardiovascular parameters.
Ephedrine 7.5 mg i.v. was administered in the
event of undue hypotension (systolic arterial
pressure < 67 % of initial value). During opera-
tion, sedation was provided by increments of
midazolam 1 mg as required. Oxygen 3 litre min"1
was administered throughout the procedure via a
Hudson mask.
After operation, patients were assessed by a
nurse observer at 4, 8, 12 and 24 h after induction
of spinal anaesthesia. Although it was not possible
for the same nurse to carry out all the observations
on any one patient, all the nurses had been
familiarized with the procedure and were drawn
from a small pool of staff covering two orthopaedic
wards. Both patient and nurse were unaware of
the composition of the spinal injection.
Patients were asked to grade the severity of pain
according to a four-point rank pain score (none,
mild, moderate and severe). Independently,
nurses were asked to assess quality of analgesia
using a four-point scale (excellent, good, fair and
poor) and degree of sedation with a three-point
scale (wide-awake = 0, drowsy = 1, very drowsy
TABLE I. Demographic data. * Significant difference from each of the other two groups (Student's t test)
(P < 0.05)
Age (yr)
Analgesic regimen (mean (SEM))
0.75 % Bupivacaine 3 ml 63(2.1)
(n = 20)
0.75 % Bupivacaine 3 ml 73.4(1.7)*
+ diamorphine 0.25 mg
(n = 20)
0.75 % Bupivacaine 3 ml 65.7 (2.8)
+ diamorphine 0.5 mg
(n = 20)
249
= 2). In addition, rate of ventilation and the
presence of adverse effects such as itching, nausea
and vomiting and urinary retention were noted.
The presence of such adverse effects was detected
by observation and direct questioning. All
patients were prescribed diamorphine 5 mg i.m.
for postoperative analgesia and prochlorperazine
12.5 mg for nausea and vomiting. The times and
total doses of both these drugs were recorded.
Results were analysed statistically by Student's
t test, or Chi-squared test with Yates' correction
or for trend, as appropriate.
RESULTS
The mean ages and weights of the patients (20 in
each group) are shown in table I. There was no
significant difference between groups with respect
to dose of midazolam (mean 4—5 mg) or use of
ephedrine. Duration of analgesia as measured by
time from intrathecal injection until first adminis-
tration of postoperative analgesic (table II) was
significantly greater in both the intrathecal dia-
morphine groups than in the control group
(P < 0.001). There was no significant difference
between the two diamorphine groups (0.25 mg
and 0.5 mg), each providing prolonged analgesia
(10.8 and 9.9 h, respectively). Analgesic require-
ments during the first 24 h after operation
(table III) were considerably lower in each of the
intrathecal diamorphine groups than in the control
group (P < 0.01), but there was no significant
difference between the two doses used.
There was no significant difference between the
groups with respect to sedation or quality of
analgesia, as measured by either the patient's rank
pain score or the nurse's independent assessment
(figs 1,2).
Type of operation
Weight (kg) Knee Hip
(mean (SEM)) replacement replacement
74.5 (2.6)* 4 16
66.7 (2.0) 6 14
62.8(3.1) 2 18
250 BRITISH JOURNAL OF ANAESTHESIA
TABLE II. Extent of analgesia assessed by the interval between completion of subarachnoid injection and
first requirement for paremeral postoperative opioid. ^Compared with bupivacaine alone (Student's t test)

Time to next analgesia (h)

Analgesic regimen mean (SEM) [range]
0.75 % Bupivacaine 3 ml 5.92 (0.34) [3.75-7.83]
(a = 20)
0.75 % Bupivacaine 3 ml 10.85 (1.20) [5.0-24.0] < 0.001
+ diamorphine 0.25 mg
(n = 20)
0.75 % Bupivacaine 3 ml 9.92 (1.14) [4.75-24.0] < 0.01
+ diamorphine 0.5 mg
(n = 20)

TABLE III. Postoperative analgesic requirements for diamor- and vomiting, significantly more than the control
phine 5 mg (during first 24 h). Statistical significance by group, in which the frequency was 40%
Chi-squared test for trend (P < 0.05) (table IV). Urinary retention was a
Group B: Group C: common problem in the diamorphine groups,
Group A: intrathecal intrathecal occurring in 75 % of patients given 0.25 mg and in
intrathecal bupivacaine + bupivacaine + 55 % of those given 0.5 mg. Itching was absent in
No. of doses bupivacaine diamorphine diamorphine the control group; in the combined diamorphine
required alone 0.25 mg 0.5 mg groups the frequency was 30%, but this did not
0 0 2 2 require treatment. No other major adverse effects
1 1 6 5 were reported.
2 7 8 9
§• 7 4 4 DISCUSSION
4 3 0 0
We have demonstrated that small intrathecal
5 1 0 0
6 l 0 0 doses of diamorphine provide good postoperative
P (compared with group A) < 0.001 < 0.005 analgesia for periods up to 24 h and that dia-
morphine 0.25 mg is as effective as 0.5 mg. We
There was no evidence of severe respiratory found no major adverse effects, but the frequency
depression. Sixteen patients (80%) of those of nausea and vomiting was markedly greater in
receiving intrathecal diamorphine 0.5 mg and 14 those receiving intrathecal diamorphine than in
(70%) of those receiving 0.25 mg suffered nausea those receiving bupivacaine alone.

B C A B C
20-

I
Pain scores
18- • None
16-
0 Mild

P
14-
cn H Moderate
c 12-
e
•5 10-
H Severe

|P
a
"5 s-\
i e-
4-
2-
I2h 24 h
0-
FIG. 1. Rank pain scores up to 24 h. No significant difference between groups A (intrathecal
bupivacaine), B (intrathecal bupivacaine plus diamorphine 0.25 mg) and C (intrathecal bupivacaine plus
diamorphine 0.5 mg).
INTRATHECAL DIAMORPHINE 251
TABLE IV. Adverse effects (numbers of patients). *P < 0.05 local cord levels of drug are produced, far beyond
compared with group A those seen in normal pharmacological practice"
Group B: Group C:
[10]. Most intrathecal studies have used morphine
Group A: intrathecal intrathecal which, because of its low lipid solubility, tends to
intrathecal bupivacaine + bupivacaine + linger in the CSF. This potentiates rostral spread
Adverse bupivacaine diamorphine diamorphine and doses in excess of 1 mg seem to be associated
effect alone 0.25 mg 0.5 mg with an unacceptably high incidence of adverse
Nausea and 8 14 16*
effects [11]. Samii, Chauvin and Viars [12]
vomiting compared two doses of intrathecal morphine
Itching 0 7* 5 (0.2 mg kg"1 and 0.02 mg kg"1) and found that,
Urinary 8 15 11 although analgesia was slightly inferior with the
retention lower dose, the frequency of serious adverse
Ventilatory rate 0 0 0
effects, most notably respiratory depression, was
< 10 b.p.m.
considerably reduced. This has been confirmed
[13] in a study using intrathecal morphine 0.25
Although there were differences between the mg and 0.1 mg, which provided prolonged pain
groups, in both age and weight, it is difficult to relief after Caesarean section for 28 h and 18 h,
know if this has influenced the results. However, respectively, with a small frequency of side effects
increasing age has been shown to be associated and absence of respiratory depression.
with increased frequency of respiratory depres- The efficacy of low-dose intrathecal morphine
sion following spinal opioids [9]. Although this in providing analgesia has been confirmed for
serious side effect was notably absent in our study, major vascular surgery [14] and for major ortho-
the greater age of patients in the group receiving paedic surgery [15-17]. However, in the most
diamorphine 0.25 mg may have contributed to the recent retrospective survey from Sweden, three
high incidence of adverse effects (particularly patients developed delayed respiratory depression
urinary retention) in this group. after intrathecal morphine 0.3 mg [18].
In their review of extradural and intrathecal In contrast, lipophilic opioids may be safer for
opioids, Bullingham and his colleagues [10] stated intrathecal use because high drug concentrations
that "The basis of success with intrathecal opioids are not maintained in the mobile CSF phase [1].
is to insert a relatively small dose of opioid into Diamorphine may be the opioid of choice as it is
the CSF, creating a reservoir of drug to provide deacetylated rapidly within the cord to morphine
prolonged analgesia. In so doing, however, high [2].

A B C A B A B C
201
18 Quality scores

16 CD Excellent
14 Y7X Good
CO
ca 12 H Fair

H Poor
o 8
2 6-
4-
2-
0- 24 h
12 h

FIG. 2. Quality of analgesia scoring up to.24 h. No significant difference between groups A (intrathecal
bupivacaine), B (intrathecal bupivacaine plus diamorphine 0.25 mg) and C (intrathecal bupivacaine plus
diamorphine 0.5 mg).
252 BRITISH JOURNAL OF ANAESTHESIA
Using diamorphine 1.25 mg and 2.5 mg in D, Cole A. Spinal fluid kinetics of morphine and heroin.
combination with intrathecal cinchocaine for Clinical Pharmacology and Therapeutics 1984; 35:
40-45.
patients undergoing major orthopaedic surgery, 2. Way EL, Kemp JW, Young JM, Grassetti DR. The
Paterson and colleagues [5] demonstrated a ceiling pharmacologic effects of heroin in relationship to its rate
effect and no significant benefit from use of the of biotransformation. Journa/ of Pharmacology 1960; 129:
greater dose. Adverse effects were frequent and 144-154.
four patients required naloxone to antagonize 3. Macrae DJ, Munishankrappa S, Burrow LM, Milne MK,
Grant IS. A double-blind comparison of extradural
respiratory depression [5]. Comparing the anal- diamorphine, extradural phenoperidine and intramuscular
gesic effects of four different doses of intrathecal diamorphine analgesia following Caesarean section.
diamorphine (0.25 mg, 0.75mg, 1.5 mg and 2.5 British Journal of Anaesthesia 1987; 59: 354-359.
mg), Jacobsen, Kokri and Pridie found a similar 4. Semple AJ, Macrae DJ, Munishankrappa S, Burrow LM,
quality of analgesia in all groups [19]. Although Milne MK, Grant IS. Effect of the addition of adrenaline
to extradural diamorphine analgesia following Caesarean
duration of analgesia was increased with the larger section. British Journal of Anaesthesia 1988; 60: 632-638.
doses, the higher incidence of adverse effects, 5. Paterson GMC, McQuay HJ, Bullingham RES, Moore
particularly nausea and vomiting, was a dis- RA. Intradural morphine and diamorphine. Anaesthesia
advantage. However, in some patients even the 1984; 39: 113-117.
higher doses did not provide "adequate" anal- 6. Jorgensen BC, Anderson HB, Enquist A. CSF and plasma
morphine after epidural and intrathecal application.
gesia and they concluded that "sufficient quanti- Anesthesiology 1981; 55: 714-715.
ties of opioid necessary to ensure both spinal and 7. Barron DW, Strong JE. The safety and efficacy of
supraspinal effects may be required to provide the intrathecal diamorphine. Pain 1984; 18: 279-285.
superior analgesia attributable to intradural 8. Hain WR, Kirk B. Stability of diamorphine-sodium
opioid therapy". In 245 patients undergoing chloride solutions. Anaesthesia 1985; 40: 1241.
9. Gustafssbn LL, Schildt B, Jacobsen KJ. Adverse effects
major orthopaedic surgery, the use of low dose of extradural and intrathecal opiates: Report of a nation-
intrathecal diamorphine 0.5 mg-1.0 mg provided wide survey in Sweden. British Journal of Anaesthesia
satisfactory analgesia; 40% required no other 1982; 54: 479-486.
analgesia and there was a low incidence of adverse 10. Bullingham RES, McQuay HJ, Moore RA. Extradural
effects [7]. and intrathecal narcotics. In: Atkinson RS, Langton
Hewer C, eds. Recent Advances in Anaesthesia and
In the present study we have shown that small Analgesia, 14th Edn. London: Churchill Livingstone,
doses of intrathecal diamorphine produce effective 1982: 141-156.
11. Gjessing J, Tomlin PJ. Postoperative pain control with
analgesia for major orthopaedic surgery and that intrathecal morphine. Anaesthesia 1981; 36: 268-276.
diamorphine 0.25 mg provides a duration of 12. Samii K, Chauvin M, Viars P. Postoperative spinal
analgesia similar to that of diamorphine 0.5 mg. analgesia with morphine. British Journal of Anaesthesia
This concurs with the findings of Paterson and 1981; 53: 817-820.
colleagues [5] who concluded that "increasing 13. Abboud TK, Dror A, Mosaad P, Zhu J, Mantilla M,
Swart F, Gangolly J, Silao P, Makar A, Moore J, Davis H,
intrathecal opiate doses above a certain level has Lee J. Mini-dose intrathecal morphine for the relief
little additional analgesic benefit". of post-Cesarean section pain: Safety, efficacy and
Although no major adverse effects were encoun- ventilatory responses to carbon dioxide. Anesthesia and
tered in our study, the frequency of minor effects Analgesia 1988; 67: 137-143.
14. Davis I. Intrathecal morphine in aortic aneurysm surgery.
was surprisingly high in the diamorphine groups Anaesthesia 1987; 42: 491^197.
despite the use of low doses. This differs markedly 15. Glass PSA, Biagi B, Sischy S, Camporesi E. Analgesic
from the low incidence of adverse effects found in action of very low dose intrathecal morphine (0.1 mg) as
the larger study by Barron and Strong [7] (20 % compared to higher doses (0.2-0.4 mg). Anesthesiology
vomiting; 20% urinary retention) using intra- 1985; 63: A236.
16. Bengtsson M, Lofstrom JB, Merits H. Postoperative pain
thecal diamorphine in doses of 0.5 mg and 1.0 mg. relief with intrathecal morphine after major hip surgery.
Although we found no evidence of late respiratory Regional Anesthesia 1983; 8: 139-143.
depression, we feel that the high frequency of 17. Kalso E. Effects of intrathecal morphine, injected with
"minor" adverse effects, particularly nausea and bupivacaine, on pain after orthopaedic surgery. British
vomiting, precludes the routine use of this Journal of Anaesthesia 1983; 55: 415-422.
technique, despite the prolonged analgesia it 18. of Rawal N, Arner S, Gustafsson LL, Allvin R. Present state
extradural and intrathecal opioid analgesia in Sweden.
provides. British Journal of Anaesthesia 1987; 59: 791-799.
19. Jacobson L, Kokri MS, Pridie AK. Intrathecal
REFERENCES diamorphine: Efficacy, duration, optimal dose and
1. Moore A, Bullingham R, McQuay H, Allen M, Baldwin side effects. Anesthesia and Analgesia 1987; 66: S89.