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In This Article
   Abstract
   Introduction
   Materials and Me...
   Results
   Discussion
   Acknowledgments
   References
   Article Tables

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RESEARCH PAPER
Year : 2006  |  Volume : 38  |  Issue : 3  |  Page : 181-184
 

Analgesic activity of venlafaxine and its interactions with tramadol, celecoxib and amlodipine in mice


1 Department of Pharmacology, P D U Medical College, Rajkot, India
2 Department of Pharmacology, Medical College, Baroda, India

Correspondence Address:
P K Jha
Department of Pharmacology, P D U Medical College, Rajkot
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0253-7613.25804

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  Abstract 

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 moderate pain without any additional analgesic.


Keywords: Antidepressant, tail flick latency, writhing


How to cite this article:
Jha P K, Mazumdar B, Bhatt J D. Analgesic activity of venlafaxine and its interactions with tramadol, celecoxib and amlodipine in mice. Indian J Pharmacol 2006;38:181-4

How to cite this URL:
Jha P K, Mazumdar B, Bhatt J D. Analgesic activity of venlafaxine and its interactions with tramadol, celecoxib and amlodipine in mice. Indian J Pharmacol [serial online] 2006 [cited 2019 Oct 18];38:181-4. Available from: http://www.ijp-online.com/text.asp?2006/38/3/181/25804



  Introduction Top


Chronic pain is often accompanied by depression.[1] 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 Top


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.

1. Tail flick test: Analgesic activity was measured by the tail flick method, using the analgesiometer as described by D'Armour 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 mean±SEM. One-way ANOVA followed by either Dunnett's 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 Top


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 - 3]A

(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 - 3]A

(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 - 3]A

(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 - 3]A

Drug combinations

Sub-analgesic dose of venlafaxine (7.5 mg/kg) was combined with sub-analgesic doses of tramadol (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 - 3]B

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 [Table - 3]B

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 - 3]B


  Discussion Top


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 Ca 2+ channels, particularly the latter, are important in controlling the release of neurotransmitters from peripheral and central terminals.[16] Blockers of N-type Ca 2+ 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 Top


The authors acknowledge the support and valuable suggestions provided by Dr. J.G. Buch, in preparing the manuscript.

 
  References Top

1.Rafieian-Kopaei M, Sewell RDE. Newer antidepressants: analgesic and relative monoamine reuptake inhibitory potency. J Pharm Pharmacol 1994;46:1088.  Back to cited text no. 1    
2.Guyton AC, Hall JE. Medical physiology. 9th ed. Philadelphia: WB Saunders Co.; 1996.  Back to cited text no. 2    
3.Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE. Opioid and non-opioid components independently contribute to the mechanism of action of tramadol, an 'atypical' opioid analgesic. J Pharmacol Exp Ther 1992;260: 275-85.  Back to cited text no. 3    
4.Lin LL, Lin AY, Knopf JL. Cytosolic phospholipase A2 is coupled to hormonally regulated release of arachidonic acid. Proc Natl Acad Sci USA1992;89: 6147-151.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]
5.D'Armour FE, Smith DL. A method for determining loss of pain sensation. J Pharmacol Exp Ther 1941;72:74-9.  Back to cited text no. 5    
6.Ramabadran K, Bansinath M. A critical analysis of the experimental evaluation of nociceptive reactions in animals. Pharmaceutical Res 1986;3:263-70.  Back to cited text no. 6    
7.Jung AC, Staiger T, Sullivan M. The efficacy of selective serotonin reuptake inhibitors for the management of chronic pain. J Gen Intern Med 1997;12: 384-9.  Back to cited text no. 7    
8.Singh VP, Jain NK, Kulkarni SK. On the antinociceptive effect of fluoxetine, a selective serotonin reuptake inhibitor. Brain Res 2001;915:218-26.  Back to cited text no. 8    
9.Kiayias JA, Vlachou ED, Lakka-Papadodima E. Venlafaxine HCl in the treatment of painful peripheral diabetic neuropathy. Diabetes Care 2000;23:699.  Back to cited text no. 9    
10.Pernia A, Mico JA, Calderon E, Torres LM. Venlafaxine for the treatment of neuropathic pain. J Pain Symptom Manage 2000;19:408-1.  Back to cited text no. 10    
11.Rang HP, Dale MM, Ritter JM. Pharmacology. 4th ed. Edinburgh: Churchill Livingstone; 1999.  Back to cited text no. 11    
12.Hopwood SE, Owesson CA, Callado LF, McLaughlin DP, Stamford JA. Effects of chronic tramadol on pre- and post-synaptic measures of monoamine functions. J Psychopharmacol 2001;15:147-53.  Back to cited text no. 12    
13.Driessen B, Reimann W, Giertz H, Grunenthal G. Effects of the central analgesic tramadol on the uptake and release of noradrenaline and dopamine in vitro. Br J Pharmacol 1993;108:806-11.  Back to cited text no. 13    
14.Burnett FE, Scott LV, Weaver MG, Medbak SH, Dinan TG. The effect of naloxone on adrenocorticotropin and cortisol release and evidence for a reduced response in depression. J Affect Disord 1999;53:263-8.   Back to cited text no. 14    
15.Markowitz JS, Patrick KS. Venlafaxine-tramadol similarities. Med Hypotheses 1998;51:167-8.  Back to cited text no. 15    
16.Dray A, Urban L. New pharmacological strategies for pain relief. Annu Rev Pharmacol Toxicol 1996;36:262.  Back to cited text no. 16    
17.Murakami M, Nakagawasai O, Fujii S, Kameyama K, Murakami S, Hozumi S, et al . Antinociceptive action of amlodipine blocking N-type Ca2+ channels at the primary afferent neurons in mice. Eur J Pharmacol 2001;419:175-81.   Back to cited text no. 17    


    Tables

[Table - 1], [Table - 2], [Table - 3]

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