doi: 10.1111/ijun.

12011 RESEARCH PAPER

Intraurethral tramadol alleviates rigid

cystoscopy-related pain in men
Mohammadreza Khajavi, Reza Shariat Moharari, Atabak Najafi, Hamed Kazemi,
Afshin Ostovar and Patricia Khashayar

ABSTRACT
Considering the effectiveness of tramadol in alleviating pain following major operations, trauma, labour and
even chronic neuropathic pain, this study was designed to evaluate the efficacy of intraurethral administration
of the drug in alleviating cystoscopy-related pain in men. Sixty male candidates of diagnostic cystoscopy, aged
between 20 and 50 years, in ASA physical status I or II were included in the study. Patients were randomized
into intervention [who received tramadol (100 mg) and lidocaine gel] or control group (in whom distilled water
and lidocaine was administered) based on a permuted block randomization method. The severity of pain and
the incidence of adverse effects were measured during and following the cystoscopy. The urologist’ satisfaction
was also assessed. Total pain score in the intervention group was significantly lower than the control group
(P = 0·037). The urologist was more satisfied with the ease and convenience of performing the cystoscopy
in the intervention group. No significant side effect was reported in either group. Adding 100 mg tramadol to
lidocaine gel is more effective than using lidocaine gel alone in alleviating the pain associating with male rigid
cystoscopy.
Key words: Intraurethral injection • Lidocaine gel • Rigid cystoscopy • Tramadol

INTRODUCTION et al., 1989). Since the 1920s, numerous synthetic

Cystoscopy is one of the most common examinations
performed in urologic outpatient clinics. There is an
increasing body of literature showing that the diag-
nostic procedure is painful (Pliskin et al., 1989). Many
believe reducing the pain associating such procedure
can not only increase patient compliance but also lower
the number of those requiring sedation or anaesthesia.
Intraurethral cocaine has been the first drug used
to alleviate the cystoscopy-related pain; the drug,
however, was not reported to be effective (Pliskin
Authors: M Khajavi, MD, Associate Professor of Anesthesiology, Tehran
University of Medical Sciences, Tehran, Iran ; RS Moharari, MD, Associate
Professor of Anesthesiology, Tehran University of Medical Sciences,
Tehran, Iran ; A Najafi, MD, Associate Professor of Anesthesiology, Tehran
University of Medical Sciences, Tehran, Iran ; H Kazemi, MD,
Anesthesiologist, Tehran University of Medical Sciences, Tehran, Iran;
A Ostovar, MD, Resident of Epidemiology, Tehran University of Medical
Sciences, Tehran, Iran ; P Khashayar, MD, General Practitioner,
Endocrinology and Metabolism Research Center, Tehran University of
Medical Sciences, Tehran, Iran
Address for correspondence: RS Moharari, Sina Hospital, Hassan
Abad Square, 11367-46911 Tehran, Iran
E-mail: moharari@tums.ac.ir
topical anaesthetic agents, including lidocaine,
tetracaine, tripelennamine, silicone and dyclonine
have been introduced. From among these agents,
topical lidocaine gel has emerged as the anaesthetic
agent of choice based on its simultaneous role as a
lubricant and local anaesthetic. The anaesthetic value
of lidocaine gel, however, is debated. Several reports
have pointed out that periurethral lidocaine gel is at
best of no benefit and at worst, causes more pain
when compared to plain lubricant (Burke et al., 2002;
Schede and Thoruff, 2006). Tramadol, the synthetic
analogue of 4-phenylpiperidine is a centrally acting
analgesic used in treating moderate to moderately
severe pain without causing any major adverse effects
on the respiratory and cardiovascular system (Grond
and Sablotzki, 2004).
Considering the peripheral local anaesthetic effects
of tramadol, this study was designed to evaluate the
efficacy of intraurethral administration of tramadol in
alleviating cystoscopy-related pain in men (Kaabachi
et al., 2009; Khajavi et al., 2009). The final objective
was to develop a new method to perform outpatient
cystoscopy with the least pain possible.

© 2013 John Wiley & Sons Ltd. and BAUN Int J of Urol Nurs 2013 1
 Tramadol alleviates cystoscopy pain
PATIENTS AND METHODS
After being approved by the Ethical Board Committee
of Tehran University of Medical Sciences, this parallel
group, double blind, randomized controlled clinical trial
was conducted on male candidates of diagnostic rigid
cystoscopy. After explaining different aspects of the
study, a written informed consent was obtained from
all the patients enrolled in the study.
Sixty male candidates of diagnostic cystoscopy,
aged between 20 and 50 years, in American Society
of Anesthesiologists (ASA) physical status I or II
who were candidates of diagnostic cystoscopy were
included in the study (Moharari et al., 2010). Those
who had experienced repeated cystoscopy or needed
open surgery once after cystoscopy were excluded.
Other exclusion criteria were patient refusal, urethral
stricture, a history of urinary tract infections, pres-
ence of underlying cardiac diseases or uncontrolled
hypertension, any drug hypersensitivity, any history of
seizure or substance abuse.
Patients were randomized into intervention or con-
trol group based on a permuted block random-
ization method. Blocks of four were used for this
purpose.
In the intervention group, 100 mg of tramadol
solution (Tramadol; Tehran Shimi, Iran) (2 cc) was
added to 18 cc lidocaine (Lidocaine Hydrochloride;
Astra Zeneca) 2% gel, which was administered into
the urethra using a syringe in patients undergoing
cystoscopy. This was performed 15 min prior to
the diagnostic cystoscopy; thereafter, the glans was
clamped for 15 min to keep the drug in the lumen.
For the patients in the control group 2 cc of distilled
water (as placebo) was added to the 18 cc of lidocaine
2% gel. pH values of each solution, tramadol and
lidocaine, as well as that of the combination solution
was also measured. Diagnostic cystoscopy was done
by an experienced urologist, similarly in the two groups.
Cystoscopy was performed using a 17.5F Olympus
rigid cystoscope under video-camera guidance. Sterile
saline irrigation was used at a pressure of 40 cm H2 O
during cystoscopy. The patients, anaesthesiologists
and urologist were blind regarding the type of
performed intervention. The solutions were prepared
by another person unaware of the hypothesis of the
study. Primary outcome measure of the study was pain
assessed through an 11-point numerical scale, rated
from no pain (zero) to the worst pain. In both groups,
sedation was not expected and drowsiness, defined
as having a Ramsey Sedation Score (RSS) level of
equal or greater than 3 (responds to commands only),
was considered as a complication. The occurrence
of nausea, vomiting and seizure-like movements was
recorded.
2 © 2013 John Wiley & Sons Ltd. and BAUN
Systolic and diastolic blood pressures as well as
arterial oxygen saturation were monitored during the
cystoscopy using pulse oximetry up to 60 min after
termination of the procedure. All outcomes were
measured at the baseline, during the instrument
insertion, 5 and 10 min after the initiation of cystoscopy,
at the end of the procedure, and 10 and 60 min after
cystoscopy. A 0·75 mcg/kg intravenous fentanyl was
prescribed whenever the patient reported intolerable
pain or Numerical Rating Scale (NRS) higher than
6. The need for opioid during the procedure was
recorded. We also asked the urologist who performed
the procedure after the end of cystoscopy whether or
not he was satisfied with the ease and convenience
of the procedure. The urologist’s satisfaction rate was
assessed at the end of the procedure based on whether
the procedure had been completed easily or with
difficulty. The incidence of adverse effects such as
headache, nausea, vomiting and dizziness was also
recorded.
Statistical analysis
The sample size for this study was calculated based
on our previous study on the effect of ketamine
and lidocaine on reducing pain during cystoscopy
(Chitale et al., 2008). We assumed a power of
80% at the significant level of 0·05 to detect a
mean difference of 1·5 for the pain numerical score
between the two groups. The standard deviation of
numerical pain score was assumed equal to 2·0.
Demographic characteristics, pain scores and mean
arterial blood pressure were compared between two
groups at the baseline by calculating means and
standard deviations. Mean arterial blood pressure
was calculated as systolic blood pressure plus two
times diastolic blood pressure divided by three. To
compare pain scores between two groups in each
time point, we used non-parametric Wilcoxon rank
sum (Mann–Whitney) test. We also calculated total
pain score as sum of the pain scores after the
insertion of cystoscope. Then, total pain score was
compared between two groups using independent
two sample t tests. Independent two sample t tests
were also used to compare differences of mean
arterial blood pressures from baseline between two
groups in each time point. We also calculated
medians and their confidence intervals for the pain
scores of both groups in each time point during
the study. We used χ 2 test to compare rate of
opioid use, satisfaction of urologist and also rate
of adverse effects between intervention and control
group.

Table 1 Demographic and baseline characteristics of the intervention and
control groups
Intervention (n = 30)
Age (year)∗ 41·9 (9·1)
Weight∗ 76·5 (10·3)
SBP∗ 126 (10·5)
DBP∗ 80·4 (6·6)
MAP∗ 95·6 (7·4)
Intervention group: 18 cc lidocaine 2% gel plus 100 mg tramadol. Control
group: 18 cc lidocaine 2% gel plus 2 cc distilled water as placebo.
Results are shown as mean (SD).
DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood
pressure.
∗ the associating pain.
There was no significant difference between the variables of the intervention
and variable group.
RESULTS
pH of the used agents
The pH value of the used tramadol and lidocaine
solutions was 6 and 7, respectively. The combination
solution had a pH of 6·5.
Patients
No clinically significant difference was found in
the demographic characteristics or the baseline
measurements of the patients between the two study
groups (Table 1). Mean cystoscopy time was 10 min.
Pain
Median values of pain numerical rating score were
significantly lower in the intervention group at the
time of insertion of probe of cystoscope, 10 min
after the insertion of the cystoscope, and at the
end of cystoscopy (Table 2). Total pain score in
the intervention group was significantly lower than
the control group (mean total pain score ± standard
error was 35·5 ± 1·57 in the control group compared to
29·4 ± 2·39 in the intervention group; P = 0·037).
Mean arterial pressure (MAP)
There was no significant difference between baseline
values of mean arterial blood pressure and that
measured at eight-time points in neither of the two
groups (Table 2).
Other outcomes
Eight out of thirty patients in the control group and
only one patient in the intervention group needed
opioid during the study period (P = 0·01). The urologist
reported the procedure to be easy in 28 patients in
the intervention group and 22 in the control group
(P = 0·038).
© 2013 John Wiley & Sons Ltd. and BAUN
Tramadol alleviates cystoscopy pain
Adverse effects
None of the patients had seizure like movements.
There was no impairment in the level of consciousness
Control (n = 30) in either group. We recorded nausea and vomiting in
39·7 (8·5) four cases in the intervention group and one case in
76·9 (8·4) the control group (P-value = 0·10).
120·8 (8·8)
77·4 (6·7)
91·9 (7·2) DISCUSSION
This prospective clinical trial, designed to assess
the analgesic effect of intraurethral administration
of tramadol in rigid cystoscopy in men showed that
adding 100 mg tramadol to lidocaine gel is more
effective than using lidocaine gel alone in alleviating
Cystoscopy-related pain is more severely felt at the
times the probe is manipulated, mainly during its inser-
tion or removal. This study showed that the individuals
in the intervention group felt less pain at these two
intervals. Considering the fact that cystoscopy in our
centre generally lasts no longer than 10 min, it could
be concluded that a considerable reduction of the pain
intensity was noted just at the end of the procedure.
Moreover, the total pain score was significantly lower
in the intervention group. In view of the fact that the
participants in the both groups had received lidocaine,
there was no clinically significant difference between
the reported pain scores. Further studies designed to
compare the efficacy of tramadol with that of placebo
may result in more considerable differences.
While the efficacy of lidocaine gel 2% in alleviating
pain following intraurethral instrumentation is not yet
confirmed, the gel is commonly prescribed in patients
undergoing cystoscopy (McFarlane et al., 2001; Palit
et al., 2003; Schede and Thoruff, 2006; Aaronson
et al., 2009). In other words, many studies, including
several meta-analyses, have questioned the efficacy
of intraurethral lidocaine gel in this regard (Grond and
Sablotzki, 2004; Kobayashi et al., 2004). Possible
reasons for this lack of efficacy include difficulty in
identifying the optimal regimen and conditions for its
use and the adequate amount of the drug needed for
anesthetizing the sphincter (Herr and Schneider, 2001;
McFarlane et al., 2001; Chen et al., 2005).
Considering the above mentioned findings, scien-
tists are seeking other medication and compound to
substitute the futile lidocaine gel, aiming to turn cys-
toscopy into a more tolerable procedure. In a study
conducted by Choe et al., lidocaine spray and lido-
caine gel were reported to have similar anaesthetic
effects in women undergoing rigid cystoscopy (Choe
et al., 2008).
Compared to lidocaine hydrochloride gel alone,
the combination of dimethyl sulfoxide (DMSO) and
3
 Tramadol alleviates cystoscopy pain

Table 2 Median pain numerical score, mean arterial blood pressure and mean heart rate in intervention and control groups at the baseline, time of insertion of
cystoscope, 5 min after insertion, 10 min after insertion, end of cystoscopy, 10 min after the end of cystoscopy and 60 min after the end of cystoscopy

5 min after 10 min after End of 10 min after 60 min after

Baseline Insertion time insertion insertion cystoscopy cystoscopy cystoscopy

NRS∗ Intervention (n = 30) – 6 (5·03–6·97) 5 (4·06–5·94) 4 (3·10–4·90) 5 (4·04–5·96) 3 (1·94–4·06) 1 (0·12–1·88)

Control (n = 30) – 7 (6·23–7·73) 6 (5·32–6·68) 5 (4·27–5·73) 6 (5·28–6·72) 3 (2·37–3·63) 2 (1·61–2·39)
P-value† – 0·0386 0·1101 0·0440 0·0028 0·4625 0·1661
MAP∗∗ Intervention (n = 30) 95·6 (7·4) 100·3 (6·6) 98·0 (8·3) 96·0 (6·2) 96·9 (6·0) 94·2 (5·9) 93·4(6·4)
Control (n = 30) 91·9 (7·2) 96·2 (7·9) 94·1 (7·4) 91·6 (6·0) 92·4 (6·1) 90·2 (5·9) 89·2 (6·2)
P-value‡ – 0·8000 0·9047 0·6326 0·5771 0·8425 0·7712
∗
Numerical rating score; results are shown as medians (confidence interval).
∗∗ Mean arterial blood pressure; results are shown as mean (SD).
† Two-sample Wilcoxon rank-sum (Mann–Whitney) test.
‡
Two-sample t test with equal variances for the difference of the value in each time point from the baseline

lidocaine gel, similarly, was reported to cause less
discomfort in men undergoing such procedures. The
combination is believed to take less time to act and
reduce pain perception (Demir et al., 2008).
Moharari et al. also revealed that instillation of
lidocaine gel in conjunction with ketamine in the
urethra could decrease pain perception, helping men
undergo outpatient rigid cystoscopy more comfortably
(Chitale et al., 2008).
Opioids have long been the mainstay for
post-operative pain relief. Recent studies have
similarly shown the efficacy of localized opioids such
as tramadol, a drug with a centrally acting analgesic
selective for μ-receptors and local anaesthetic actions
on peripheral nerves which can activate both opioid
and non-opioid (descending monoaminergic) systems
mainly involved in the inhibition of pain, in lowering
a patient’s need for analgesics (Mert et al., 2002;
Unlugenc et al., 2003; Altunkaya et al., 2004). The
effect of the non-opioid component of tramadol is
mediated through α2 agonistic and serotonergic activ-
ities by inhibiting the reuptake of the norepinephrine
and 5-hydroxytryptamine, and possibly by displacing
stored 5-hydroxytryptamine from nerve endings (Hille,
1977). Khajavi et al. reported that subcutaneous
wound infiltration with tramadol following pyelolitho-
tomy is associated with a lower incidence of nausea
and vomiting, reduced need for meperidine, decrease
in VAS scores and lower RSS level (Khajavi et al.,
2009).
Alkalinizing the environment would improve the
action of lidocaine on node of Ranvier, the 1-μm-wide
gaps formed between myelin sheath cells long the
axons, through increasing the local anaesthetic neutral
free base. The more rapid onset of action for lidocaine
in these patients can be secondary to the reduced
acidity following the consumption of tramadol. As the
combination of tramadol and lidocaine had a pH lower
than that of lidocaine per se, it seems impossible
that the analgesic properties of the combination
solution would be secondary to the improved action of
lidocaine.
This study suffered from several limitations. First
of all, the difference in the intensity of pain in the
two groups is not significant from the clinical point
of view. Tramadol has never been used alone for
analgesic purposes in cystoscopy; as a result, we
were not able to compare the efficacy of tramadol
alone with that of lidocaine due to ethical purposes.
However, as lidocaine was applied in both groups, even
this small difference in pain scores can be clinically
significant. Moreover, considering the nature of the
main outcome (the intensity of pain) and the use of a
subjective tool for measuring it (VAS), non-parametric
tests were used to analyze the difference between the
two groups. The consistency in the findings of study
outcomes (pain, opioid use, urologist satisfaction) can
also show the clinical importance of these results.
The link between the blood concentrations of tramadol
and the resulting analgesic effects were not evaluated
in this study. Further studies are also needed to
compare the effectiveness of tramadol alone with
that of the commonly used lidocaine and ketamine
which its efficacy was reported in previous studies in
men undergoing rigid cystoscopy. Despite all these
limitations, this study shows that tramadol can be used
for analgesic purposes in cystoscopy.
CONCLUSION
This study, which was to assess the analgesic effects
of intraurethral tramadol, showed the efficacy of adding
100 mg tramadol to lidocaine gel in lowering rigid
cystoscopy-related pain in men.

4 © 2013 John Wiley & Sons Ltd. and BAUN

 Tramadol alleviates cystoscopy pain

WHAT IS KNOWN ABOUT THIS TOPIC

• Cystoscopy is one of the most painful examinations performed in urologic outpatient clinics.
• Many believe reducing the pain associating such procedure can not only increase patient compliance but also lower the number of those
requiring sedation or anaesthesia.
• Since the 1920s, numerous synthetic topical anaesthetic agents have been used in this regard.

WHAT THIS PAPER ADDS

• Intraurethral tramadol not only alleviates total pain in the patients but also is more effective compared with lidocain gel.
• The urologist was also more satisfied with the ease and convenience of performing the cystoscopy after the consumption of intraurethral
tramadol.
• This comes while the new technique does not cause any significant side effects in the consumers.

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