Advertisement

Characterisation of tramadol, morphine and tapentadol in an acute pain model in Beagle dogs

      Abstract

      Objective

      To evaluate the analgesic potential of the centrally acting analgesics tramadol, morphine and the novel analgesic tapentadol in a pre-clinical research model of acute nociceptive pain, the tail-flick model in dogs.

      Study design

      Prospective part-randomized pre-clinical research trial.

      Animals

      Fifteen male Beagle dogs (HsdCpb:DOBE), aged 12–15 months.

      Methods

      On different occasions separated by at least 1 week, dogs received intravenous (IV) administrations of tramadol (6.81, 10.0 mg kg−1), tapentadol (2.15, 4.64, 6.81 mg kg−1) or morphine (0.464, 0.681, 1.0 mg kg−1) with subsequent measurement of tail withdrawal latencies from a thermal stimulus (for each treatment n = 5). Blood samples were collected immediately after the pharmacodynamic measurements of tramadol to determine pharmacokinetics and the active metabolite O-demethyltramadol (M1).

      Results

      Tapentadol and morphine induced dose-dependent antinociception with ED50-values of 4.3 mg kg−1 and 0.71 mg kg−1, respectively. In contrast, tramadol did not induce antinociception at any dose tested. Measurements of the serum levels of tramadol and the M1 metabolite revealed only marginal amounts of the M1 metabolite, which explains the absence of the antinociptive effect of tramadol in this experimental pain model in dogs.

      Conclusions and clinical relevance

      Different breeds of dogs might not or only poorly respond to treatment with tramadol due to low metabolism of the drug. Tapentadol and morphine which act directly on μ-opioid receptors without the need for metabolic activation are demonstrated to induce potent antinociception in the experimental model used and should also provide a reliable pain management in the clinical situation. The non-opioid mechanisms of tramadol do not provide antinociception in this experimental setting. This contrasts to many clinical situations described in the literature, where tramadol appears to provide useful analgesia in dogs for post-operative pain relief and in more chronically pain states.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Veterinary Anaesthesia and Analgesia
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Adams ML
        • Morris DL
        • Brase DA
        • et al.
        Stereoselective effect of morphine on antinociception and endogenous opioid peptide levels in plasma but not cerebrospinal fluid of dogs.
        Life Sci. 1990; 48: 917-924
        • Becker R
        • Lintz W
        Determination of tramadol in human serum by capillary gas chromatography with nitrogen-selective detection.
        J Chromatogr. 1986; 377: 213-220
        • Driessen B
        • Reimann W
        Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro.
        Br J Pharmacol. 1992; 105: 147-151
        • Driessen B
        • Reimann W
        • Giertz H
        Effects of the central analgesic tramadol on the uptake and release of noradrenaline and dopamine in vitro.
        Br J Pharmacol. 1993; 108: 806-811
        • Fairbanks CA
        • Wilcox GL
        Moxonidine, a selective α2-adrenergic and imidazoline receptor agonist, produces spinal antinociception in mice.
        J Pharmacol Exp Ther. 1999; 290: 403-412
        • Friderichs E
        • Becker R
        Correlation of tramadol and M1 serum levels with antinociceptive activity in mice. Abstract no. 36 of the 32nd Spring Meeting, Deutsche Gesellschaft für Pharmakologie und Toxikologie.
        Archives of Pharmacology. 1991; 343
        • Friderichs E
        • Felgenhauer F
        • Jongschaap P
        • et al.
        Pharmacological studies on analgesia, dependence on and tolerance of tramadol, a potent analgetic drug.
        Arzneimittelforschung. 1978; 28: 122-134
        • Frink MC
        • Hennies HH
        • Englberger W
        • et al.
        Influence of tramadol on neurotransmitter systems of the rat brain.
        Arzneimittelforschung. 1996; 46: 1029-1036
        • Gillen C
        • Haurand M
        • Kobelt DJ
        • et al.
        Affinity, potency and efficacy of tramadol and its metabolites at the cloned human mu-opioid receptor.
        Naunyn Schmiedebergs Arch Pharmacol. 2000; 362: 116-121
        • Giorgi M
        • Del Carlo S
        • Saccomanni G
        • et al.
        Biopharmaceutical profile of tramadol in the dog.
        Vet Res Commun. 2009; 33: 189-192
        • Hawley TA
        • Wetmore LA
        Identification of single nucleotide polymorphisms within exon 1 of the canine mu-opioid receptor gene.
        Vet Anaesth Analg. 2010; 37: 79-82
        • Hennies HH
        • Friderichs E
        • Schneider J
        Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids.
        Arzneimittelforschung. 1988; 38: 877-880
        • Johnston SA
        • McLaughlin RM
        • Budsberg SC
        Nonsurgical management of osteoarthritis in dogs.
        Vet Clin North Am Small Anim Pract. 2008; 38: 1449-1470
        • KuKanich B
        • Papich MG
        Pharmacokinetics of tramadol and the metabolite O-desmethyltramadol in dogs.
        J Vet Pharmacol Ther. 2004; 27: 239-246
        • Kukanich B
        • Papich MG
        Pharmacokinetics and antinociceptive effects of oral tramadol hydrochloride administration in Greyhounds.
        Am J Vet Res. 2011; 72: 256-262
        • Mastrocinque S
        • Fantoni DT
        A comparison of preoperative tramadol and morphine for the control of early early postoperative pain in canine ovariohysterectomy.
        Vet Anaesth Analg. 2003; 30: 220-228
        • Mathews KA
        Neuropathic pain in dogs and cats: if only they can tell us if they hurt.
        Vet Clin Small Anim. 2008; 38: 1365-1414
        • McMillan CJ
        • Livingston A
        • Clark CR
        • et al.
        Pharmacokinetics of intravenous tramadol in dogs.
        Can J Vet Res. 2008; 72: 325-331
        • Morgaz J
        • Navarrete R
        • Muñoz-Rascón P
        • et al.
        Postoperative analgesic effects of dexketoprofen, buprenorphine and tramadol in dogs undergoing ovariohysterectomy.
        Res Vet Sci. 2013; 95: 278-282
        • Negus SS
        • Vanderah TW
        • Brandt MR
        • et al.
        Preclinical assessment of candidate analgesic drugs: recent advances and future challenges.
        J Pharmacol Exp Ther. 2006; 319: 507-514
        • Paulson SK
        • Engel L
        • Reitz B
        • et al.
        Evidence for polymorphism in the canine metabolism of the cyclooxygenase 2 inhibitor, celecoxib.
        Drug Metab Dispos. 1999; 27: 1133-1142
        • Pertovaara A
        Antinociception induced by alpha-2-adrenoceptor agonists, with special emphasis on medetomidine studies.
        Prog Neurobiol. 1993; 40: 691-709
        • Poulsen L
        • Arendt-Nielsen L
        • Brøsen K
        • et al.
        The hypoalgesic effect of tramadol in relation to CYP2D6.
        Clin Pharmacol Ther. 1996; 60: 636-644
        • Raffa RB
        • Friderichs E
        The basic science aspect of tramadol hydrochloride.
        Pain Rev. 1996; 3: 249-271
        • Raffa RB
        • Friderichs E
        • Reimann W
        • et al.
        Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an ‘atypical’ opioid analgesic.
        J Pharmacol Exp Ther. 1992; 260: 275-285
        • Rychel JK
        Diagnosis and treatment of osteoarthritis.
        Top Companion Anim Med. 2010; 25: 20-25
        • Saccomanni G
        • Del Carlo S
        • Giorgi M
        • et al.
        Determination of tramadol and metabolites by HPLC-FL and HPLC-MS/MS in urine of dogs.
        J Pharm Biomed Anal. 2010; 53: 194-199
        • Schröder W
        • Vry JD
        • Tzschentke TM
        • et al.
        Differential contribution of opioid and noradrenergic mechanisms of tapentadol in rat models of nociceptive and neuropathic pain.
        Eur J Pain. 2010; 14: 814-821
        • Teixeira RC
        • Monteiro ER
        • Campagnol D
        • et al.
        Effects of tramadol alone, in combination with meloxicam or dipyrone, on postoperative pain and the analgesic requirement in dogs undergoing unilateral mastectomy with or without ovariohysterectomy.
        Vet Anaesth Analg. 2013; 40: 641-649
        • Thomasy SM
        • Moeller BC
        • Stanley SD
        Comparison of opioid receptor binding in horse, guinea pig, and rat cerebral cortex and cerebellum.
        Vet Anaesth Analg. 2007; 34: 351-358
        • Tzschentke TM
        • De Vry J
        • Terlinden R
        • et al.
        Tapentadol hydrochloride. Drug.
        Future. 2006; 31: 1053-1061
        • Tzschentke TM
        • Christoph T
        • Koegel B
        • et al.
        (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel mu-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties.
        J Pharmacol Exp Ther. 2007; 323: 265-276
        • Wu WN
        • McKown LA
        • Gauthier AD
        • et al.
        Metabolism of the analgesic drug, tramadol hydrochloride, in rat and dog.
        Xenobiotica. 2001; 31: 423-441
        • Yoburn BC
        • Lutfy K
        • Candido J
        Species differences in mu- and delta-opioid receptors.
        Eur J Pharmacol. 1991; 193: 105-108