Singapore Med J 2001 Vol 42(5) : 193-195
O r i g i n a l A r t i c l e
Role of Tramadol in Reducing Pain on
W H Wong, K F Cheong
5 Lower Kent
W H Wong,
K F Cheong,
Dr K F Cheong
Fax: (65) 777 5702
Propofol is frequently associated with pain on
injection. W e evaluated the effect of tramadol in a
randomised, double-blind study using a tourniquet
venous retention technique. Normal saline
placebo was given intravenously to patients in
Group 1 (n = 30), tramadol 50 mg to Group 2 (n =
30), and lignocaine 50 mg to Group 3 (n = 30). T he
venous retention of drugs was maintained for 1
minute, followed by tourniquet release and
intravenous administration of propofol. Pain
assessment was made immediately after propofol
injection. T here was a significant reduction in the
incidence of pain associated with propofol
administration in patients pretreated with
lignocaine and tramadol (P<0.05). In addition,
pretreatment with tramadol was as effective as
lignocaine in reducing pain on propofol injection.
Keywords: A naesthetics, Intravenous: Propofol,
Narcotics: Tramadol, Anaesthesia, Complications:
Singapore Med J 2001 Vol 42(5):193-195
It is well-known that intravenous injection of propofol
is associated with pain. The incidence ranges from 28%
to 90%(1) and may be recalled as an unpleasant
experience by the patient. Many methods have been
used to reduce the incidence and severity of this
complication with varying success rates(2). Tramadol is
a centrally acting weak mu-receptor agonist and inhibits
noradrenaline re-uptake as well as promotes serotonin
release(3). We postulate that it may have a peripheral
action on the free nerve endings of blood vessels(4) and
proceeded to evaluate its efficacy, in conjunction with
temporary venous occlusion, in reducing pain on
injection of propofol.
PATIENTS AND METHODS
A randomised, double-blind controlled study involving
90 unpremedicated patients of A SA I - II status aged
between 18 and 60-years-old was conducted with ethics
committee approval and patients’ informed consent. The
patients were randomly selected using a coded syringe
method into three groups of 30 each. Group 1 received
5 mls of normal saline as placebo. Group 2 received 5
mls (50 mg) of tramadol as the test drug while Group 3
was administered 5 mls (50 mg) of lignocaine. A 22 G
Venflon cannula was inserted into the largest vein on
the dorsum of the non-dominant hand without
The patient’s arm was elevated for 30 seconds
before a tourniquet was applied at the forearm inflated
to 50 mmHg above baseline systolic pressure. The study
drug was injected and the occlusion released one
minute later. Propofol calculated at 2.5mg kg-1 was then
administered as a bolus dose over 30 seconds.
The patients were informed of the possibility of a
‘burning sensation’ in the forearm during induction of
anaesthesia and were requested to grade the severity
of pain as none, mild or severe at 10 seconds interval.
Limb withdrawal and grimacing were taken to be signs
of severe pain. In the recovery room, the patients
were asked if they could recall any pain at the time of
induction and to grade it. Upon loss of consciousness,
anaesthesia continued as planned.
Post-operatively, all cases of pain and usage of
analgesics in the recovery area as well as patients’ ability
to recall any pain on direct questioning were recorded.
Demographic data between the three groups were
compared using A NOVA . Chi-square test was used to
compare the incidence of pain in the three groups.
R esults were considered significant when p < 0.05.
Power analysis showed that 84 patients were required
for a power of 90% at p < 0.05 for a reduction of pain
incidence from 80% to 40%.
A nalysis of the three groups did not show any
differences in age, sex or weight (Table I). T he
incidence of pain was 30% in the tramadol group as
compared to 27% in the lignocaine group and 83% in
the placebo group (Table II) (P < 0.001, placebo vs
lignocaine and tramadol). There is no significant
difference in the incidence of pain between the
tramadol and lignocaine groups. Severe pain occurred
in 13 patients in the control group as compared to
one in the tramadol and nil in the lignocaine group
(Table II). Post-operative recall of pain was 80% in
the control group, 44% in the tramadol and 37% in
the lignocaine group.
The mechanisms of pain when propofol is given
intravenously have been postulated to be due to either
a direct irritant effect giving rise to an immediate
sensation of pain or an indirect effect via the release of
mediators leading to a delayed onset. The latter theory
involves the release of kininogens when propofol comes
into contact with the vascular endothelium(5).
Furthermore, Klement and A rndt(6) postulated that the
afferent free nerve endings between the media and
intima are the sensors for this pathway.
Opioid receptors are found in the dorsal root-
ganglia, the central terminals of primary afferent
nerves(7,8) and peripheral sensory nerve fibres and their
terminals(9). E ndogenous or exogenous opioids after
activating those receptors will increase potassium
currents and decrease calcium currents in sensory
neuron cell bodies leading to inhibition of signal
transmission(10). Opioids can also inhibit the release of
excitatory and proinflammatory compounds from
sensory nerve endings(11).
With the above proposed mechanisms in mind,
various authors have tried different pharmacological
agents and methodologies to decrease the incidence
and severity of pain including the use of lignocaine
and tourniquet(12), opioids(13,14) and different sites
L ignocaine has been shown to be successful
especially when used with a tourniquet. Mangar and
Holak(12) found that lignocaine given after a tourniquet
was inflated to 50 mmHg virtually abolishes this pain.
Trials with opioids such as fentanyl, alfentanil and
pethidine however showed mixed results. Fletcher
et al(16) found that intravenous alfentanil 1 mg given
15 seconds before administration of propofol was
efficacious in reducing the incidence and severity of
pain. Similarly, Nathanson et al(13) demonstrated that
the incidence of pain was reduced with alfentanil
(24%) compared to placebo (67%). However, Wrench
et al(14) failed to show any peripheral action by
alfentanil in reducing pain and concluded that there
was no difference between placebo and the study
drug. These authors used a tourniquet with cuff
pressure of 50 mmHg above arterial pressure for
30 seconds together with intravenous alfentanil.
The amount of propofol used on per kg basis was
similar to our study. While the differences between
this study and ours lie in the study drug (tramadol vs
alfentanil) and the time of tourniquet applied
(1 minute versus 30 seconds), we felt that the longer
time allowed for tramadol to act locally on the
peripheral opioid receptors may have succeeded in
inhibiting pain signal transmission from the free nerve
endings in the vascular endothelium.
Not only is tramadol effective in attenuating pain
on propofol injection, we feel that it is also useful for
intra and post-operative analgesia when relatively
minor operations are undertaken. Nine patients in
the tramadol group underwent cone biopsy, dilation
and curettage or hysteroscopic procedures but only
one needed additional analgesics post-operatively.
Tramadol has the same analgesic potency as pethidine
and 1/10 that of morphine. In patients who had
undergone hysterectomy, it was demonstrated that i.v.
tramadol 50 mg was as effective as i.v. morphine 5 mg
in treating moderate pain(17). In another study
comparing i.v. tramadol and epidural morphine for
post thoracotomy analgesia, the two methods were
found to be equally effective(18). It may be useful to
increase the dose of i.v. tramadol from 50 to 100 mg
in future studies to determine if there is a further
reduction in perioperative analgesic needs and if the
number of patients complaining of propofol induced
pain will be decreased. There were yet no reports of
clinically relevant respiratory depression as a result
of treatment with tramadol. Vickers et al(19) compared
patients breathing spontaneously under general
anaesthesia when given i.v. tramadol 0.5 - 2 mg kg-1
versus i.v. morphine 0.143 mg kg-1. It was found that
apnea or clinically relevant respiratory depression
was present in those given morphine but none with
Table I. Demographic data: Values are expressed as
(n = 30)
(n = 30)
(n = 30)
Age (yrs)39.3 (15.8) 37.4 (15.1) 36.2 (12.9)
Sex (M : F)14 : 1615 : 15 17 : 13
Weight (kg)59.9 (10.1) 64.1 (12.4)65.2 (10.5)
Table II. Incidence and grade of pain on propofol injection
Results expressed as number (%)
(n = 30) (n = 30)
(n = 30)
None 5 (17)21 (70)*22 (73)*
Mild 12 (40)8 (27)8 (27)
Severe 13 (43)1 (3)* 0 (0)*
* P<0.05 compared to placebo.
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Singapore Med J 2001 Vol 42(5) : 195
tramadol. It was thus not surprising that there were
no episodes of apnea detected in our patients given
tramadol. Interestingly, although tramadol has not
been reported to cause histamine release, one patient
in our study developed urticaria and itchiness localised
to the forearm after it was injected with tramadol.
One problem that we encountered in this study
was that of discomfort in the forearm during the
period of tourniquet though it had only occurred in
less than 5% of the patients. This may be avoided if a
simple tourniquet with a Vacro strap is used instead
of one using a sphygmomanometer pumped to 50
mmHg above systolic pressure.
The data on recall of pain shows that a greater
percentage of patients who received placebo had
recall of pain during the recovery period. Seven of
the 12 patients in the placebo group who reported
mild pain had recall compared to three in eight for
the patients given tramadol. A ll 13 who complained
of severe pain in the former and the sole patient who
had severe pain in the latter did remember the
There have been many studies done with various
pharmacological and non-pharmacological means to
reduce the incidence of pain on propofol injection. The
most effective method appears to be that of lignocaine
with an application of a tourniquet. This method
however does not provide for any perioperative
analgesia for the patient. We have found intravenous
tramadol to be equally effective in relieving pain
associated with propofol injection compared to
lignocaine in addition to the possibility of it providing
good analgesia for mild to moderate perioperative pain
as evidenced by previous studies(17,18).
In conclusion, we have found tramadol to have a
peripheral site of action and it is as effective as
lignocaine in reducing the incidence and severity
of pain on propofol injection. Future studies with
different doses of tramadol may be useful to
determine if there is a dose-dependent effect on the
incidence and severity of pain on propofol injections
as well as perioperative pain relief.
1. Stark Rd, Binks SM, Dutka VN, O’Connor KM, Arnstein MJ, Glen JB: A
review of the safety and tolerance of propofol (‘Diprivan’). Postgrad Med
J 1985; 61 (Suppl.3):152-6.
2. Tan CH, Onsiong MK. Pain on injection of propofol. Anaesthesia 1998,
3. Hennies HH, Friderichs E, Wilsmann K, Flohe L. Effect of the opioids
analgesia tramadol on inactivation of norepinephrine and serotonin.
Biochem Pharmacol 1982; 31:1654-55.
4. Stein C. The control of pain in peripheral tissue by opioids. New England
J Med 1995 Jun 22; 332 (25):1685-90.
5. Scott RP, Saunders DA, Norman J. Propofol: clinical strategies for
preventing pain on injection. Anaesthesia 1988; 43:492-4.
6. Klement W, Arndt JO. Pain on intravenous injection of some anaethetic
agents is evoked by the unphysiological osmolality or pH of their
formulations. Br J Anaesth 1991; 66:189-5.
7. Lamotte C, Pert CB, Synder SH. Opiate receptor binding in primate spinal
cord; distribution and changes after dorsal root section. Brain Res 1976;
8. Fields HL, Emson PC, Leigh BK, Gilbert RF, Iversen LL. Multiple opiate
receptor sites on primary afferent fibres. Nature 1980; 284:351-3.
9. Stein C, Hassan AHS, Przewlocki R, Gramsch C, Peter K, Herz A. Opioids
from immunocytes interact with receptors on sensory nerves to inhibit
nociception in inflammation. Proc Natl Acad Sci USA 1990; 87:5935-9.
10. Russell NJ, Schaible HG, Schmidt RF. Opiates inhibit the discharges of
fine afferent units from inflamed knee joint of the cat. Neurosci Lett 1987;
11. Yaksh TL. Substance P release from knee joint afferent terminals:
modulation by opioids. Brain Res 1988; 458:319-24.
12. Mangar D, Holak EJ Tourniquet at 50 mmHg followed by intravenous
lignocaine diminishes hand pain associated with propofol injection. Anesth
Analg 1992; 74:250-2.
13. Nathanson MH, Gajraj NM, Russell JA. Prevention of pain on injection
of propofol. A comparison of lidocaine and alfentanil. Anesth Analg 1996;
14. Wrench IJ, Girling KJ, Hobbs GJ. Alfentanil-mediated analgesia during
propofol injection: no evidence for a peripheral action. Br J Anaesth 1996;
15. Briggs LP, White M. The effects of premedication on anaesthesia with
propofol (‘Diprivan’). Postgrad Med J 1985; 61 (Suppl. 3):35-7.
16. Fletcher JE, Seavell CR, Boweri DJ. Pretreatment with alfentanil reduces
pain caused by propofol. Br J Anaesth 1994; 72:342-4.
17. Houmes RJ, Voets MA, Verkaaik A, Erdmann W, Lachmann B. Efficacy
and safety of tramadol versus morphine for moderate and severe
postoperative pain with special regard to respiratory depression. Anesth
Analg 1992; 74:510-4.
18. James MFM, Heijke SAM, Gordon PC. Intravenous tramadol versus
epidural morphine for post thoracotomy pain relief - a placebo-controlled
double-blind trial. Anesth Analg 1996; 83:87-91.
19. Vickers MD, O’Flaherty, Szekely, Read M, Yoshizumi J. Tramadol : Pain
relief by an opioid without depression of respiration. Anaesthesia 1992;