Research Paper

Analgesic activity of venlafaxine and its interactions with

tramadol, celecoxib and amlodipine in mice
P. K. Jha, B. Mazumdar, J. D. Bhatt*

ABSTRACT

Department of Pharmacology
P D U Medical College, Rajkot
*Department of Pharmacology
Medical College
Baroda. India
Received: 6.7.2005
Revised: 18.3.2006
Accepted: 20.3.2006
Correspondence to:
P. K. Jha
E-mail: jhapankajku@yahoo.co.in

Objective: To study the analgesic activity of venlafaxine and its interactions with tramadol,

celecoxib and amlodipine.

Materials and Methods: Antinociceptive action of venlafaxine (5, 7.5, 10 and 22.5 mg/kg)

was studied in mice (tail flick and writhing tests). Sub-analgesic doses of venlafaxine,
tramadol, celecoxib and amlodipine were obtained using these methods. A sub-analgesic
dose of venlafaxine was combined with sub-analgesic doses of tramadol, celecoxib and
amlodipine to study their interactions.
Results: The antinociceptive action of venlafaxine was found only at higher doses (10 and
22.5 mg/kg). When a sub-analgesic dose of venlafaxine was combined with sub-analgesic
doses of tramadol, amlodipine or celecoxib, the combination resulted in a significant
antinociceptive effect.
Conclusion: Evidence of analgesic activity, as indicated by increase in tail flick latency
and decrease in number of writhing movements following venlafaxine treatment, suggests
that it could possibly have central as well as peripheral action. The findings indicate that
the potential use of venlafaxine in antidepressant dose could produce marked pain relief.
Thus patients of depression, who are on venlafaxine, may be able to tolerate mild to mod
erate pain without any additional analgesic.
KEY WORDS: Antidepressant, tail flick latency, writhing.

Introduction
[1]

Chronic pain is often accompanied by depression.

Selective serotonin reuptake inhibitors (SSRI) used in the
management of depression, by increasing the serotonin level,
inhibit the release of transmitters carrying the pain sensation
from nerve endings.[2] There is ample evidence to suggest that
descending pain inhibitory pathways involve monoamines such
as noradrenaline (NA) and 5-hydroxytryptamine (5-HT,
serotonin). Spinal inhibition of pain, brought about by inhibiting
NA and 5-HT reuptake, is one of the major mechanisms of
action of opioid analgesics.[3] The release of transmitters,
carrying the pain sensation from nerve endings, is regulated
by intracellular calcium level, which also regulates the
synthesis of prostaglandins.[4] In the absence of any report of
analgesic activity of venlafaxine in animals, the present study
was planned to investigate whether:
a. It has any analgesic activity?
b. And if so, how does it interact with opioid analgesic
tramadol, COX-2 inhibitor celecoxib and calcium channel
blocker amlodipine?

Materials and Methods

The study was carried out on albino mice of either sex
(20-30 g), maintained under standard laboratory conditions.
Venlafaxine (Sun Pharmaceuticals, Baroda, India), amlodipine
(Sarabhai Chemicals, Baroda), tramadol (Sarabhai Chemicals,
Baroda) and celecoxib (Intas Pharmaceuticals, Ahmedabad),
were dissolved in distilled water (DW), dimethyl sulfoxide
(DMSO), isotonic saline (NS) and methyl alcohol (MA),
respectively. All the drugs and vehicles were administered in
a total volume of 0.1 ml, intraperitoneally (i.p.).
The animals were divided into control (saline, administered
15 min prior to the test), vehicle treated (DW, NS or MA were
administered 15 min before, whereas DMSO was given 6.25 h
prior to the test) and drug treated groups, of 6 animals each.
The drugs under investigation were administered 15 min prior
to their individual group tests. However, amlodipine treatment
was given 6.25 h prior to the test.
Determination of analgesic activity
Two different tests were employed to study the analgesic
activity.
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Jha, et al.

1. Tail flick test: Analgesic activity was measured by the

tail flick method, using the analgesiometer as described by
DArmour and Smith.[5] For each animal, the tail flick latency
was obtained thrice before drug administration, and mean was
used as pre-drug latency. The tail flick latencies were measured
at 0, 0.25, 0.5, 1, 1.5, 2 and 3 h after administration of vehicle
or drug(s). For animals that did not respond within the cut-off
time of 10 seconds, the value of the cut-off time was considered
as latency period for that animal.[6]
2. Writhing test: Writhing was induced in mice by
intraperitoneal administration of 0.1 ml of 1% acetic acid. The
number of writhing movements was counted for 20 minutes.
The writhing test was performed after the administration of
the vehicle or drug.
Statistical analysis
Group results are expressed as meanSEM. One-way
ANOVA followed by either Dunnetts or Tukey-Kramer, post
hoc tests of significance was applied for multiple comparisons
amongst different groups. P<0.05 was regarded as statistically
significant.
Results
Analgesic activity of individual drugs
(a) Venlafaxine
Venlafaxine in doses of 5 and 7.5 mg/kg did not have any
effect on tail flick latency. However, doses of 10 and 22.5
mg/kg, produced dose dependent antinociceptive effect. The
antinociceptive effect started at 0.5 h, reached peak at 1 hour
and persisted for 2 h and it disappeared at the end of 3 h.
[Table 1]
Venlafaxine in the dose of 10.0 mg/kg produced significant
decrease in the number of writhes suggesting its
antinociceptive effect. The lower doses of venlafaxine (5.0 and

7.5 mg/kg) failed to produce any decrease in the number of

writhes. [Table 3A]
(b) Tramadol
Tramadol, at 10 mg/kg did not have any antinociceptive
effect when tested by tail flick test. The antinociceptive effect
was noted with 22.8 mg/kg with onset at 1.0 h, peak at 1.5 h
and it persisted throughout the 3 h of study. [Table 1]
Tramadol in the doses of 5.0 mg/kg and 10.0 mg/kg
produced a marked decrease in the number of writhes as
observed over a test period of 20 min, which suggests a strong
antinociceptive effect. However, 2.5 mg/kg dose of tramadol
did not produce any significant effect. [Table 3A]
(c) Celecoxib
In the tail flick test, antinociceptive effect of celecoxib was
observed only at a dose of 30 mg/kg, with latency of 1 h. Peak
effect was seen at 2 h and it persisted for entire duration of
3 h. Lower dose (15 mg/kg) of celecoxib did not produce any
change in the latency period. [Table 1]
Celecoxib in the dose of 15.0 mg/kg, produced significant
decrease in the number of writhes. Celecoxib 7.5 mg/kg failed
to produce any effect. [Table 3A]
(d) Amlodipine
In tail flick test, with a dose of 3.5 mg/kg of amlodipine,
significant antinociceptive effect was observed 6.25 h after
the treatment, reaching peak at 7.0 h after amlodipine
administration and the effect significantly persisted for the
entire test period. [Table 1]
Significant antinociceptive effect was however observed
with amlodipine at a lower dose (3 mg/kg) in the writhing test.
[Table 3A]
Drug combinations
Sub-analgesic dose of venlafaxine (7.5 mg/kg) was
combined with sub-analgesic doses of tramadol

Table 1
Effects of different doses of venlafaxine (V), tradamol (T), celecoxib (Cz), amlodipine (A) and their different combinations
on tail flick latency in mice
Tail flick latency in seconds
Post drug time (h)
Group (mg/kg)
V (5)
V (7.5)
V (10)
V (22.5)
T(10)
T (22.8)
C (15)
C (30)

0.25

0.5

4.33 0.06
4.36 0.06
3.73 0.03
3.41 0.06
3.38 0.04
4.50 0.07
3.98 0.03
3.20 0.04

4.36 0.03
4.48 0.07
3.85 0.02
3.58 0.08
3.40 0.04
4.66 0.08
4.05 0.03
3.25 0.05

4.38 0.03
4.510.04
5.180.07**
4.710.06**
3.360.06
4.830.10
4.050.02
3.300.03

4.40 0.03
4.50 0.04
5.66 0.06**
5.86 0.05**
3.41 0.04
6.86 0.10**
4.08 0.04
4.08 0.07**

1.5

One-way ANOVA
2

4.40 0.03
4.480.04
4.550.05**
5.310.06**
3.410.06
8.430.11**
4.080.03
5.580.04**

4.33 0.02
4.33 0.02
4.45 0.05
4.41 0.04
4.31 0.04** 3.81 0.03
4.60 0.09** 3.53 0.07
3.41 0.01
3.41 0.02
6.00 0.06** 4.86 0.15*
4.5 0.02
4.08 0.02
5.35 0.06** 4.26 0.04**

7.5
4.500.07
6.450.09**

8
4.48 0.12
5.65 0.07**

F
0.92
0.35
261.5
196.2
0.203
215.9
1.6
414.7

df

6,35
6,35
6,35
6,35
6,35
6,35
6,35
6,35

0.495
1.165
0.0001
0.974
0.974
0.0001
0.1764
0.0001

9
4.46 0.07 0.238 6,35
5.03 0.02** 446.9 6,35

0.9606
0.0001

Post drug time (h)

A (3)
A (3.5)

0
4.40 0.07
3.50 0.04

6.25
4.41 0.06
4.23 0.07**

6.5
4.480.01
5.230.08**

7
4.46 0.09
8.46 0.12**

Values are mean+SEM. n=6 in each group. * P<0.05 ** P <0.001 significantly different from their corresponding value at 0 hour.

182

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Analgesic activity of venlafaxine

Table 2
Effects of combined treatments on tail flick latency in mice
Tail flick latency in seconds
Post drug time (h)
Drug (mg/kg)
V (7.5)
T (10)
C (15)
V (7.5) + T (10)
V (7.5) + C (15)

0
4.36 0.06
3.38 0.04
3.98 0.03
3.55 0.06a
3.83 0.06a

0.25

0.5

4.48 0.07
3.40 0.04
4.05 0.03
4.28 0.04*b
3.86 0.07a

4.51 0.04
3.360.06
4.050.02
5.330.04* ab
3.880.07a

1.5

4.50 0.04
3.41 0.04
4.08 0.04
6.76 0.06* ab
3.96 0.06a

4.48 0.04
3.410.06
4.080.03
5.310.04* ab
4.160.06* a

One-way ANOVA
2

4.45 0.05
4.41 0.04
3.41 0.01
3.41 0.02
4.05 0.02
4.08 0.02
4.46 0.04*b 3.48 0.04a
4.06 0.04* a 4.01 0.05a

df

0.35
0.203
1.6
617.6
4.02

6,35
6,35
6,35
6,35
6,35

P
1.165

0.974

0.1764

0.0001

0.0035

Post drug time (h)

A (3)
V (7.5) + A (3)

6.25

4.40 0.07
3.110.03ac

4.41 0.06
4.11 0.4*ac

6.5

7.5

4.48 0.01
4.46 0.09
4.50 0.07
5.350.06* ac 8.28 0.04* ac 10.000.0*ac

4.48 0.12
4.46 0.07 0.23 6,35 0.9606

9.68 0.06* ac 7.68 0.07* ac 296.7 6,35 0.0001

Values are mean+SEM. n=6 in each group. * P<0.05 significantly different from their corresponding value at 0 hour (n=6 in each group). aP<0.05 as compared
to venlafaxine (7.5 mg/kg) treated mice. bP <0.05 as compared to tramadol (10 mg/kg) treated mice. cP<0.05 as compared to amlodipine (3 mg/kg) treated
mice. V-Venlafaxine; T-Tramadol; C-Celecoxib; A-Amlodipine.

Table 3A

Table 3B

Effects of different doses of venlafaxine (v), tramadol (t),

celecoxib (c) and amlodipine(a) on number of writhes in mice

Effects of combined treatments on number writhes in mice

Group

Number of writhes

One-way ANOVA

(mg/kg)

(MeanSEM)

df

Control (DW)
V (5)
V (7.5)
V (10)
Control (NS)
T (2.5)
T (5)
T (10)
Control (MA)
C (7.5)
C (15)
Control (DMSO)
A (2.5)
A (3)

44.50 1.08
44.33 1.05
44.50 1.08
25.83 0.54*
44.50 1.08
43.00 0.93
31.83 0.74*
21.83 0.83*
36.00 0.73
34.66 0.42
19.66 0.61*
55.33 0.66
55.33 0.76
33.66 0.61*

92.968

3,20

0.0001

137.67

3,20

0.0001

228.31

2,15

0.0001

314.87

2,15

0.0001

Group

Number of writhes

One-way ANOVA

(mg/kg)

(MeanSEM)

df

Control (DW+NS)
V (7.5)
T (2.5)
V (7.5)+T (2.5)
Control
(DW+MA)
V (7.5)
C (7.5)
V (7.5)+C (7.5)
Control
(DW+DMSO)
V (7.5)
A (2.5)
V (7.5)+A (2.5)

44.50 1.08
44.50 1.05
43.00 0.93
34.60 0.98**ab

21.79

3, 20

0.0001

36.00 0.73
44.50 1.05
34.66 0.42
32.00 1.03* a

3.875

3, 20

0.0246

55.33 0.66
44.50 1.05
53.66 0.76
32.16 0.74**ac

188.03

3, 20

0.0001

* P <0.001 indicates significant difference from their corresponding control

value (i.e. vehicle treated group) (n=6 in each group). DW-Distilled water treated;
NS-Normal saline treated; MA-Methyl alcohol treated; DMSO-Dimethyl
sulfoxide treated.

*P<0.01, **P<0.001 as compared to their corresponding control value (n=6

in each group); a P<0.05 as compared to venlafaxine (7.5 mg/kg) treated
mice; bP<0.05 as compared to tramadol (2.5 mg/kg) treated mice; cP<0.05
as compared to amlodipine (2.5 mg/kg) treated mice. DW-Distilled water;
V -Venlafaxine; NS-Normal saline; T-Tramadol; MA-Methyl alcohol; CCelecoxib; DMSO-Dimethyl sulfoxide; A-Amlodipine.

(10 and 2.5 mg/kg), celecoxib (15 and 7.5 mg/kg) and
amlodipine (3.0 and 2.5 mg/kg) for tail flick test and writhing
test respectively.
Venlafaxine in combination with tramadol produced a
significant increase in tail flick latency as compared to control
or either of the treatment alone. [Table 2]
The combination also decreased number of writhes as
compared to control value or either of the treatment alone.
[Table 3B]
Similarly venlafaxine in combination with amlodipine was
also found to have significant antinociceptive action in both

the tests when they were combined in the sub-analgesic doses

as compared to control value or either of the treatment alone.
[Table 2 and 3B]
In tail flick latency test, combination of the sub-analgesic
doses of celecoxib and venlafaxine failed to achieve significant
antinociceptive effect throughout the study, except at 1.5 and
2.00 h when they marginally increased the duration of tail flick
latency. [Table 2]
However the combination produced significant decrease
in number of writhes as compared to control or either of the
treatment alone. [Table 3B]
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Jha, et al.

Discussion
Pain is an unpleasant sensation, with a large subjective
component. It is often accompanied by depression and a feeling
of hopelessness.[1]
Several antidepressants are known to possess intrinsic
analgesic acitivity. [7,8] Venlafaxine, a widely used newer
generation antidepressant, has been cited as a promising drug
for neuropathic pain control.[9,10] We also found venlafaxine to
have an analgesic effect in both the tail flick and the writhing
tests. There is ample evidence to suggest the involvement of
monoamines such as NA and 5-HT in descending pain
pathways.[11] Antidepressants such as venlafaxine mainly block
reuptake of the above neurotransmitters. This could be the
mechanism of its analgesic action. However, the possibility of
other mechanisms cannot be ruled out. Extensive research,
over the past two decades, has revealed the pivotal roles of
serotonergic and noradrenergic neurotransmitter systems in
nociception and analgesic action of opioids.[12,13] In addition,
there is sufficient data to suggest that opioid pathways may
play a significant role in the mechanism of action of
antidepressant drugs.[14] Studies have shown that tramadol
activates monoaminergic spinal inhibition of pain by inhibiting
noradrenaline and serotonin uptake and, to a lesser extent,
dopamine uptake.[3,13] Antinociception produced by SSRIs has
been shown to be blocked by naloxone.[1,8]
Venlafaxine bears a close structural similarity to tramadol
and thus shares a number of its molecular and pharmacological
features.[9,15] In confirmation of these, our findings suggest that
if an opioid analgesic is combined with an SSRI, analgesia can
be achieved at sub-analgesic doses of each.
L and N types of Ca2+ channels, particularly the latter, are
important in controlling the release of neurotransmitters from
peripheral and central terminals.[16] Blockers of N-type Ca2+
channels can prevent nociceptive signaling.[17] In order to see
the interaction between venlafaxine and amlodipine, a
combination of sub-analgesic doses of both were used. This
produced a significant increase in the tail flick latency and
decrease in the number of writhing movements, implying an
additive effect.
There have been no reports so far about the use of COX-2
inhibitors along with SSRIs for pain relief. Since our study has
demonstrated the analgesic potential of venlafaxine, we
ventured to study a possible interaction. Sub-analgesic doses
of venlafaxine and celecoxib, when combined, produced a
significant antinociceptive effect in the writhing test. However,
the results were not convincing in the tail flick test.
From this study, we conclude that venlafaxine, a selective
serotonin reuptake blocker, can produce dose dependent

antinociceptive action per se, and additive antinociceptive

effect when combined with tramadol, amlodipine and celecoxib.
Observations from these animal studies need to be tested in
clinical trials.
Acknowledgments
The authors acknowledge the support and valuable suggestions provided by
Dr. J.G. Buch, in preparing the manuscript.

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| June 2006 |

Vol 38

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