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Original Article

Analgesic activity of fixed dose combinations of paracetamol

with diclofenac sodium and paracetamol with tramadol on
different pain models in healthy volunteers - A randomized
double blind crossover study
Sachidanand Tripathi, Rima Shah, D C Sharma1
Department of Pharmacology, SBKS Medical Institute and Research Center, Sumandeep Vidyapeeth, Piparia, 1GMERS Medical College, Gotri,
Vadodara, Gujarat, India

Abstract
Aim: To evaluate and compare the analgesic activity of fixed dose combinations (FDC) of Paracetamol with Diclofenac sodium
and Paracetamol with Tramadol on different human pain models in healthy human volunteers.
Materials and Methods: Arandomized double blind crossover study was carried out in 30healthy human volunteers using
three pain models; cold-water stress test, radiant heat method, and BP cuff inflation method. The subjects were randomized into
two groups of 15 each, groupA received FDC of Paracetamol 500mg with Diclofenac sodium 50mg and groupB was given a
FDC of Paracetamol 375 mg and Tramadol 50 mg. All the volunteers were tested on three pain models. Observations for pain
tolerance were recorded at baseline and at the interval of 30, 60, 120, and 180minutes after drug administration. Crossover
was done after a washout period of 7days. The results of both the study periods were analyzed using an independent t-test.
Results: Mean age of the participants was 231years and the male:female ratio was 2:1. In the radiant heat method,
paracetamol with tramadol combination treatment showed a significant increase in pain tolerance at 2hours and 3hours (P
0.028 and 0.055 respectively) compared to paracetamol with diclofenac combination. Other two pain models did not show any
significant difference in the study groups.
Conclusion: Paracetamol with tramadol combination was more effective than paracetamol with diclofenac sodium combination
on the radiant heat model. In human pain models, there is an incomplete understanding of mechanisms and activated pathways
are not precisely determined that needs further evaluation.
Key words: Evaluation of analgesics, human pain models, healthy volunteers, paracetamol and diclofenac sodium combination,
paracetamol and tramadol combination

Introduction
Pain is the most common clinical complaint and causes
considerable human suffering. [1] In the United States
alone, approximately 100 million people suffer from
moderate to severe pain during any given year.[1] Analgesic
Address for correspondence: Dr.Rima Shah, Department of
Pharmacology, SBKS Medical Institute and Research Center, Piparia,
Vadodara, Gujarat, India.
E-mail:rima_1223@yahoo.co.in
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DOI:
10.4103/0970-9185.101912

pharmacotherapy with drugs, such as acetic acid derivatives,

nonsteroidal anti-inflammatory drugs (NSAIDS), and
opioids, has made significant advances to date. NSAIDS
are most commonly prescribed drugs for acute and chronic
pain or for long-term anti-inflammatory therapy. They inhibit
the cyclo-oxygenase enzyme, reduce prostaglandin synthesis
(particularly PGE1 and PGE2 that promote inflammation),
and other inflammatory agents.[2] Opioid analgesics block
mu receptors in CNS and relieve pain.[2] However, these
medications are not devoid of side effects. In fact, some drugs
have been associated with serious adverse drug reactions and
dependence liability. Of the total number of patients seeking
treatment for pain, 50% are not satisfied with the available
pharmacological options.[3-6]
Developing an ideal pain model to evaluate analgesics in
healthy human volunteers is difficult. Various established
pain models are used for evaluating analgesic action. The

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Tripathi, etal.: Evaluation of analgesics using human pain models

parameters recorded in these models are pain threshold

(time between the stimulus applied and the feeling of pain
sensation) and pain tolerance (time interval from feeling
of pain to unbearable pain causing withdrawal of hand away
from painful stimulus).[6]
World Health Organization (WHO) has suggested a pain
management protocol which states that simple analgesics
should be selected first and in case the patient does not
respond to that, one can choose any other nonsteroidal
anti-inflammatory drug (NSAID) and thereafter give a
combination of NSAID with opioid analgesic. There is no
place for fixed dose combination (FDC) of two NSAIDs in
it. Currently FDC of diclofenac with paracetamol are available
in Indian market and are widely used for pain relief.[7,8] Two
drugs having the same mechanism of action are ideally not
combined in a FDC, as they serve no added advantage and
their adverse drugs reactions are additive, which may increase
the potential of developing serious consequences.[9] However,
limited data show that addition of NSAID to paracetamol
may confer additional analgesic and anti-inflammatory activity
compared to paracetamol alone.[10] The FDC of tramadol
hydrochloride 50mg with paracetamol 375mg are also in
use as the drugs act by different mechanism and synergism
is proven.[9] This FDC is effective in acute postoperative
pain of dental,[11] orthopedic and abdominal surgery,[12]
fibromyalgia,[13] low back pain,[14-16] migraine,[17] and as addon therapy for osteoarthritis[18] and rheumatoid arthritis.[19]
The efficacy of fixed-dose combination of tramadol with
paracetamol in the management of moderate to severe pain
has been reported.[20] Therefore, the objective of this study
was to compare the analgesic activity of fixed dose combination
of paracetamol + diclofenac sodium and paracetamol +
tramadol on different human pain models in healthy volunteers.

Materials and Methods

A randomized double blind crossover study carried out in the
clinical pharmacology unit of Department of Pharmacology
after prior approval from Institutional Ethics Committee. The
participants were explained the nature, purpose, and risks
and benefits involved in the study and a written informed
consent obtained. Before entering the study, a full medical
history taken and a qualified physician performed clinical
examination to declare the participant healthy. Thirty healthy
volunteers aged between 19 and 35years of either sex were
included in the study. Exclusion criteria for the study were
regular use of any medication; participation in any clinical
trial in the preceding 2weeks or during the study; history
of hypersensitivity to the trial drug or to chemically similar
drugs; history or presence of gastrointestinal, pulmonary,
liver or kidney diseases; any conditions known to interfere
466

with pharmacokinetics of study drugs; and pregnancy and/or

breast-feeding. Subjects were asked to abstain from alcohol,
nicotine, and caffeinated drinks during the study period.
All the volunteers were exposed to three pain models for
evaluation of analgesic activity.[2,6] Details of these pain models
were as under:

Cold stress test[2,6]

Volunteers were asked to immerse their nondominant hand

up to a specific mark just above the wrist joint into container
of warm water (34.5--35.5c) for 2minutes. The hand was
then immediately transferred and immersed in to another
container of cold ice water (0.5--1.5c) until the pain was
tolerated (pain tolerance). The time of onset of pain and the
pain became intolerable were recorded in seconds before and
after drug administration.

Radiant heat method[2,6]

The instrument for delivering the radiant heat (drier, Bajaj

Electronics) was kept at a fixed distance of 25cm from the
nonhairy marked skin surface of the middle of the forearm.
Hypersensitivity was checked initially. The subjects indicated
the time of pain threshold and maximum pain tolerance. The
volunteers withdrew the forearm away from the apparatus
as soon as the pain became intolerable. Observations were
recorded before and after drug administration.

Blood pressure (BP) cuff inflation method[2,6]

In this method, an adult BP cuff was tied to the middle of the

arm keeping a cap of a cold drink bottle under the cuff with
its edges facing to skin. The cuff was inflated till the pain was
felt. The cuff pressure was maintained till the pain became
unbearable. The cuff deflated. The time was noted at the
onset of pain, and when it became intolerable.
The eyes of the subjects remained covered with eye shield
during experiment to avoid time clues and visual distraction.
Volunteers were advised to take adequate overnight sleep and
light morning breakfast preferably 2hours before on the days
of experiments.
The study was a randomized, double-blind balanced twoway crossover trial. The sequence of study sessions balanced
for the overall study population. The dextrality effect of the
dominant and nondominant side was avoided in the trial.
Each of the two study sessions consisted of two study days as
shown in Figure1.
The subjects were randomized into two groups, A and B,
of 15 each by using a computer-generated random number
table. Treatment assigned was not revealed to the subject or to

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Tripathi, etal.: Evaluation of analgesics using human pain models

Statistical analysis of the data was done using SPSS software

version14. The independent t-test was applied for analysis
of analgesic efficacy for the two groups before and after drug
administration. The chi-square test was used to analyze
adverse drug reactions in two groups. APvalue<0.05 was
considered significant.

Results

Figure1: Study protocol

the person administering the drug until the study period was
complete. GroupA received a FDC of paracetamol 500mg
with diclofenac sodium 50 mg (Unison Pharmaceuticals,
Ahmedabad) and groupB received a FDC of paracetamol
375mg with tramadol 50 mg (Biochem Pharmaceuticals,
Mumbai) orally as a single dose with 200ml of water. All
the volunteers were tested for all the three pain models.
Baseline observations were recorded for pain threshold and
pain tolerance before the administration of the drugs. After
drug administration, test readings were taken at the interval
of 30, 60, 120, and 180minutes. Both groups were given a
washout period of 7days. Crossover was done and the abovementioned procedure repeated.
The results were analyzed as under:

Efficacy analysis
Primary end point -- an increase in the pain tolerance as
denoted by the increase in time interval for which the subject
can withstand the pain.

Safety analysis
Identification, analysis and reporting of adverse drug reactions
occurred during the study were done. All the reported adverse
drug events were analyzed for causality by using the World
Health Organization-Uppsala Monitoring Centre (WHOUMC) scale.[21] A physician gave appropriate treatment for
the adverse drug reactions.

Out of 30 participants, 29 completed the trial. One volunteer

could not come for the crossover because of malarial infection.
Mean age of participants was 231years. Twenty participants
were male and 10 were female having a male:female ratio
of 2:1 [Table 1]. The results of the cold-water stress test
were analyzed by an independent t-test [Table 2]. There
was no significant difference between the two groups in
both sessions (Pvalue>0.05). The results of the radiant
heattest suggested that paracetamol with tramadol treatment
significantly increased pain tolerance at 2hours and 3hours
(P 0.02 and 0.05 respectively) compared to the paracetamol
with diclofenac combination group [Table3]. The results of
the BP cuff inflation method revealed no significant difference
between the two groups in both the sessions (P>0.05) as
shown in Table4, though this model is considered specific
for evaluation of anti-inflammatory action.
In the paracetamol with tramadol FDC group, four volunteers
complained of sedation and one developed rash over the
forearm. None of the volunteer receiving a FDC of paracetamol
with diclofenac combination developed any adverse drug
reactions during the study period. The difference between
the two groups was statistically significant (P<0.05). All
the reactions were in the category of probable according to
WHO-UMC criteria of causality assessment.

Discussion
This study is conducted with the main objective of evaluating and
comparing the analgesic activity of a FDC of paracetamol with
diclofenac sodium and a FDC of paracetamol with tramadol
on different human pain models in healthy volunteers. Human
experimental pain models for the evaluation of analgesic
efficacy use different algesic stimuli like heat, cold, pressure,
ischemia, electricity, etc. for pain production. Mechanical,

Table: 1 Genderwise distribution of participants (n=30)

Gender of
participants
Male
Female
Total

Group
Paracetamol with diclofenac (A)
No. (%)
12 (80.0)
3 (20.0)
15 (100)

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Paracetamol with tramadol (B)

No. (%)
8 (53.3)
7 (46.7)
15 (100)

Total no.
(%)
20 (66.7)
10 (33.3)
30 (100)
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Tripathi, etal.: Evaluation of analgesics using human pain models
Table 2: Analysis of the cold-water stress test (n=30)
Time
Group
Pain tolerance
P value
(minutes)
(seconds)
(t-test)
Mean SEM
0
A
60.26 23.76
0.37
B
103.93 42.44
30
A
88.26 43.81
0.51
60
120
180

B
A
B
A
B
A
B

129.66 45.41
61.26 35.05
119.73 56.66
55.73 30.89
27.93 29.05
46.53 14.88
58.33 25.64

0.38
0.51
0.69

Table 3: Analysis of the radiant heat method: (n=30)

Time
Group
Pain tolerance
P value
(minutes)
(seconds)
(t-test)
Mean SEM
0
A
109.00 60.43
0.83
B
94.20 38.25
30
A
111.13 46.64
0.97
B
113.06 30.63
60
A
199.86 38.09
0.24
B
121.06 33.21
120
A
88.33 31.59
0.02*
B
286.66 79.75
180
A
79.53 30.31
0.05*
B
224.53 65.63
Table 4: Analysis of the BP cuff inflation method (n=30)
Time
Group
Pain tolerance
P value
(n=30)
(seconds)
(t-test)
Mean SEM
O minute
A
133.86 33.64
0.10
B
73.60 11.10
30 minutes
A
89.86 17.79
0.69
B
104.13 31.70
60 minutes
A
176.80 51.33
0.85
B
164.00 46.73
120 minutes
A
90.06 26.20
0.09
B
171.26 38.93
180 minutes
A
95.26 38.65
0.43
B
139.46 40.45

chemical, thermal, freezing, and ultraviolet A or B radiation

are used to study the analgesic effect of NSAID.[22] Electrically
induced pain models are able to discriminate the effect of
diclofenac from placebo. It also differentiates the gender effect
in response to ibuprofen.[22] In a laser-induced pain model
paracetamol shows significant analgesic activity compared to
placebo. However, paracetamol is less effective compared to
the combined effect of paracetamol plus codeine.[22]
In the present study, three different pain models are used.
The parameter taken to evaluate the analgesic efficacy of
468

study drugs is pain tolerance. The wide difference in the pain

tolerance at the baseline, though not statistically significant,
can be because of individual variations in pain perception.
Results of the cold-water stress test show no statistically
significant difference between the efficacies of two groups in
both the sessions possibly because of lack of inflammation
or hyperalgesia in this model leading to inconsistent and
unreliable results.[2] A cold-pressure test is known to activate
the diffuse noxious inhibitory control system, which is
a system of descending neuronal pathways arising in the
brain stem that exerts negative feed-back control on the
incoming activity to the spinal cord.[23] Other have also shown
inconsistent analgesic effects of several NSAID in the coldwater stress pain model.[23]
In the radiant heat method, paracetamol with tramadol
treatment significantly increased pain tolerance at 2 hours
and 3hours (P 0.028 and 0.055 respectively) compared to
that of the paracetamol with diclofenac group. In this model
there is rapid skin heating (more than 1C/s) which activates
A- fibers that evoke pain sensation within 0.4 seconds
and is called first pain.[19] Slow heating less than 1C/s
preferentially activates C-fibers to cause second pain.
It is thought to be due to activation of peripheral opioid
receptors and is considered best for evaluation of the opioid
analgesics. Radiant heat delivers fast heat so the evaluation
of the second pain is not possible with this model. Lasers
probably stimulate A- fibers giving a pricking pain followed
by C-fiber mediated second pain. Compared to heat pain, the
neuronal activation after cold pain is not completely described
but it probably involves a mosaic of primary afferent input with
a definite involvement of C-fibers.[23]
Results of the BP cuff inflammation method did not show
statistically significant difference between the efficacies of two
groups in both the sessions. This is an established method for
evaluating inflammatory component of the pain. AFDC of
paracetamol with diclofenac sodium has been justified stating
that diclofenac sodium adds the anti-inflammatory component
to the combination. Our results show that there is no superior
efficacy of the FDC of paracetamol with diclofenac in the
inflammatory pain model in this study.
Concerns over the marketing of increasing number of drug
combinations by pharmaceutical companies, particularly
in the developing countries, have been raised. Avariety
of NSAID combinations are available, often as over the
counter products.[24] These FDC are an easy way to sell two
drugs when one (or even none) may be needed. These FDC
have become the largest selling antiinflammatory/analgesic/
antipyretic products[24-26] and single drugs have almost
become redundant and old fashioned. Combination of

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Tripathi, etal.: Evaluation of analgesics using human pain models

two drugs acting by same mechanism is not synergistic.

Combining two NSAIDs or NSAID with analgesics like
paracetamol does not improve the efficacy of treatment but
imposes unnecessary financial burden, increases adverse effects
leading to hospitalization, and deteriorate quality of life.[27]

13.

14.

In conclusion, the FDC of paracetamol with tramadol is

more effective than the FDC of paracetamol with diclofenac
sodium on the radiant heat model but the cold stress and blood
pressure cuff inflation models did not show any difference
between the two.

15.

Acknowledgments

16.

The authors thank Dr.Hetal Pandya, Department of Medicine,

for clinical examination of the volunteers. We are thankful to
Mr.Diwakar for helping us in statistical analysis. The authors
would also like to thank all the residents in the Department of
Pharmacology for their technical assistance in carrying out the study.

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How to cite this article: Tripathi S, Shah R, Sharma DC. Analgesic activity
of fixed dose combinations of paracetamol with diclofenac sodium and
paracetamol with tramadol on different pain models in healthy volunteers - A
randomized double blind crossover study. J Anaesthesiol Clin Pharmacol
2012;28:465-9.
Source of Support: Nil, Conflict of Interest: None declared.

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