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Tapentadol, but not morphine, selectively inhibits disease-related thermal hyperalgesia in a mouse model of diabetic neuropathic pain
Neuroscience Letters 470 (2010) 91–94
Contents lists available at ScienceDirect
Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Tapentadol, but not morphine, selectively inhibits disease-related thermal hyperalgesia in a mouse model of diabetic neuropathic pain Thomas Christoph ∗ , Jean De Vry, Thomas M. Tzschentke Global Preclinical Research and Development, Grünenthal GmbH, Aachen, Germany
a r t i c l e
i n f o
Article history: Received 11 November 2009 Received in revised form 10 December 2009 Accepted 11 December 2009 Keywords: Diabetic neuropathic pain Opioids Tapentadol Animals
a b s t r a c t Neuropathic pain in diabetic patients is a common distressing symptom and remains a challenge for analgesic treatment. Selective inhibition of pathological pain sensation without modification of normal sensory function is a primary aim of analgesic treatment in chronic neuropathic pain. Tapentadol is a novel analgesic with two modes of action, -opioid receptor (MOR) agonism and noradrenaline (NA) reuptake inhibition. Mice were rendered diabetic by means of streptozotocin, and neuropathic hyperalgesia was assessed in a 50 ◦ C hot plate test. Normal nociception was determined in control mice. Tapentadol (0.1–1 mg/kg i.v.) and morphine (0.1–3.16 mg/kg i.v.) dose-dependently attenuated heat-induced nociception in diabetic animals with full efficacy, reaching >80% at the highest doses tested. Tapentadol was more potent than morphine against heat hyperalgesia, with ED50 (minimal effective dose) values of 0.32 (0.316) and 0.65 (1) mg/kg, respectively. Non-diabetic controls did not show significant antinociception with tapentadol up to the highest dose tested (1 mg/kg). In contrast, 3.16 mg/kg morphine, the dose that resulted in full anti-hyperalgesic efficacy under diabetic conditions, produced significant anti-nociception in non-diabetic controls. Selective inhibition of disease-related hyperalgesia by tapentadol suggests a possible advantage in the treatment of chronic neuropathic pain when compared with classical opioids, such as morphine. It is hypothesized that this superior efficacy profile of tapentadol is due to simultaneous activation of MOR and inhibition of NA reuptake. © 2010 Published by Elsevier Ireland Ltd.
Patients with diabetes mellitus often suffer from symptoms of neuropathic pain. About 30% of patients with diabetes mellitus are affected by peripheral neuropathy and 16–26% of diabetic patients experience chronic pain [11]. Only a portion of patients respond to available treatments, which have only limited efficacy and/or are associated with intolerable side effects [23]. Selective inhibition of pathological pain sensation without modification of normal sensory function is a particularly important objective in the management of chronic pain and can be tested in pain models both in animals and in patients. Painful diabetic polyneuropathy (DPN) and postherpetic neuropathy (PHN) are polyneuropathic pain conditions that are commonly used in clinical studies for the assessment of the clinical efficacy of new drugs [1]. In rodents, symptoms of DPN such as thermal or mechanical hyperalgesia or allodynia can be studied after induction of diabetes with streptozotocin (STZ), and analgesic efficacy has been demonstrated in this model for clinically validated analgesic mechanisms, such
∗ Corresponding author at: Department of Pharmacology, Global Preclinical Research and Development, Grünenthal GmbH, Zieglerstrasse 6, 52078 Aachen, Germany. Tel.: +49 241 5692421; fax: +49 241 5692852. E-mail address: [email protected] (T. Christoph). 0304-3940/$ – see front matter © 2010 Published by Elsevier Ireland Ltd. doi:10.1016/j.neulet.2009.12.020
as the ␣2␦-selective Ca2+ channel subunit blocker pregabalin [7] and the noradrenaline (NA)/serotonin (5-HT) reuptake inhibitors duloxetine [14] and venlafaxine [15]. In contrast, the analgesic efficacy of selective -opioid receptor (MOR) agonists, such as morphine, is limited in clinical neuropathic pain conditions [23] and also in rodent STZ diabetes models [12]. Although not directly shown for diabetic rodents, data from mononeuropathic pain models suggest that reduced spinal expression of MOR protein results in limited efficacy of MOR agonists as measured both on the behavioural [18] and on the cellular level [13]. Pain signals are conveyed by several neuro-anatomical pathways and a number of different neurotransmitters. Therefore, a combination of different analgesic mechanisms, targeting different pathways or transmitters, offers the opportunity for increased analgesia with reduced side effects. Synergistic analgesic interaction has been demonstrated both in human [8] and animal studies [2], combining two drugs with different analgesic mechanisms. Tapentadol (3-[(1R,2R)-3-(dimethylamino)-1-ethyl2-methylpropyl]phenol) is a novel analgesic, combining two modes of action, MOR agonism (Ki = 0.1 M for rat MOR binding) and NA reuptake inhibition (Ki = 0.5 M for rat synaptosomal NA reuptake inhibition) in a single molecule [20]. The analgesic efficacy of tapentadol was demonstrated in a wide range of preclinical [20]
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and clinical pain conditions [3,4,9,10,21,22], suggesting a broad analgesic profile, possibly due to the combination of the two mechanisms of action of tapentadol. In addition, reduced opiate-like gastrointestinal side effects were noted in clinical studies as compared with equi-analgesic doses of oxycodone [3,4,9,10,21,22], possibly due to an opiate-sparing effect of the noradrenergic mechanism of action of tapentadol. The aim of this study was to characterize the anti-hyperalgesic potential of tapentadol in a mouse model of DPN pain and compare it with the anti-nociceptive potential in non-diabetic control animals. The effects of the classical MOR agonist morphine were also evaluated. Animal testing was performed in accordance with the recommendations and policies of the International Association for the Study of Pain [24] and the German Animal Welfare Law. Male CD1 mice (18–20 g; Charles River, Germany) were treated i.v. with 200 mg/kg STZ or vehicle (sodium citrate, pH 5). Induction of diabetes was confirmed by blood glucose levels >25 mM 1 week after STZ treatment. One and 2 weeks after treatment, diabetic and non-diabetic control animals were randomly allocated to the different treatment groups (n = 10). Animals were used for a maximum of two tests, with a wash-out period of at least 7 days. For nociceptive and hyperalgesic testing, animals were placed on a 50 ◦ C hot metal plate under a transparent Plexiglas box (13 cm × 13 cm × 10 cm, l × w × h) for periods of 2 min and the number of nocifensive reactions (licking/shaking of the hind paws, licking of the genitals, jumping) was counted 30 min (baseline 1) and 15 min (baseline 2) before and 15, 30, 45 and 60 min after drug or vehicle treatment. Tapentadol (0.1, 0.316, and 1 mg/kg) and morphine (0.1, 0.316, 1, and 3.16 mg/kg) were dissolved in saline and administered i.v. (10 ml/kg). All doses of tapentadol and morphine indicated herein refer to the hydrochloride salts of the compounds. Data are presented as the number of nocifensive reactions occurring within 2 min. Anti-hyperalgesic ED50 values (95% confidence intervals [CIs]) were calculated by linear regression based on % maximal possible effects (MPE), using baseline 2 of diabetic and of non-diabetic controls as 0% and 100% MPE, respectively. Data were analyzed by means of a repeated measures analysis of variance (ANOVA) with post hoc Bonferroni test. Minimal effective dose (MED) was defined as the lowest dose that induced a statistically significant effect (P < 0.05). Although the operators performing the behavioural tests were not formally ‘blinded’ with respect to the treatment, they were not aware of the study hypothesis. One week after STZ treatment, 85% of treated animals developed clear diabetes. Pain reaction toward a heat stimulus was characterized in STZ-treated diabetic and citrate-treated nondiabetic mice to test for diabetes-induced polyneuropathic pain symptoms and compare it with heat nociception in non-diabetic control mice. In non-diabetic control animals the hot plate test resulted in nociception with (mean ± SEM) 18.5 ± 0.5 and 17.5 ± 0.5 nocifensive reactions at baseline 2 for the tapentadol and the morphine groups, respectively. The degree of nociception was stable over 2 weeks and there was no habituation toward the heat stimulus during the test (Fig. 1). Diabetic animals showed significantly increased (P < 0.05 vs. non-diabetic controls) numbers of nocifensive reactions, suggesting development of heat hyperalgesia, with 34.6 ± 0.6 and 36.0 ± 0.6 nocifensive reactions at baseline 2 for the tapentadol and the morphine groups, respectively. The degree of hyperalgesia was stable over 2 weeks and there was no habituation toward the heat stimulus during the test (Fig. 1). Tapentadol (Figs. 1A and 2) showed dose-dependent and significant (P < 0.05 vs. vehicle for 0.316 and 1 mg/kg) anti-hyperalgesic activity in diabetic animals with an MED of 0.316 mg/kg and full efficacy of 82% MPE at 1 mg/kg. Nocifensive reactions of non-
Fig. 1. Effect of tapentadol (A) and morphine (B) on heat hyperalgesia in diabetic mice (closed symbols) and heat nociception in non-diabetic mice (open symbols). Data are presented as number of nocifensive reactions occurring within 2 min (mean ± SEM). *P < 0.05 vs. corresponding vehicle. SEM, standard error of the mean.
diabetic control animals were not reduced up to the highest dose tested, even at full anti-hyperalgesic efficacy (P > 0.05 vs. vehicle). Morphine (Figs. 1B and 2) showed dose-dependent and significant (P < 0.05 vs. vehicle for 1 and 3.16 mg/kg) anti-hyperalgesic activity in diabetic animals with an MED of 1 mg/kg and full efficacy of 94% MPE at 3.16 mg/kg. Dose-dependent anti-nociception was seen in non-diabetic controls, the effect being significant at 3.16 mg/kg (P < 0.05 vs. vehicle). Potencies were compared by calculating ED50 values at the time of maximal effect (15 min). Tapentadol showed an ED50 (95% CI) of 0.32 (0.24–0.42) mg/kg while morphine showed an ED50 (95% CI) of 0.65 (0.50–0.84) mg/kg (Fig. 2). Based on the fact that the 95% CI of both ED50 values showed no overlap, the ED50 values were considered to be statistically different. Tapentadol showed potent and selective anti-hyperalgesia in diabetic animals at doses that do not have anti-nociceptive efficacy
Fig. 2. Effect of tapentadol and morphine on heat hyperalgesia in diabetic mice. Data are presented as % MPE (mean ± SEM) at maximal efficacy, 15 min after drug administration. *P < 0.05 vs. corresponding vehicle. MPE, maximum possible effect; SEM, standard error of the mean.
T. Christoph et al. / Neuroscience Letters 470 (2010) 91–94
in normal non-diabetic subjects. This is consistent with previously reported data from the tail-flick test (ED50 4.2 mg/kg i.v.) [21] and implies that higher doses would eventually result in an anti-nociceptive effect in non-diabetic animals in the current setting. In contrast, morphine, which also reduces heat hyperalgesia, showed no separation between anti-hyperalgesia and anti-nociceptive activity as seen in the present study, as well as in published data [21]. Anti-hyperalgesic efficacy of tapentadol (ED50 0.32 mg/kg) in diabetic polyneuropathy was significantly higher than morphine (ED50 0.65 mg/kg), as demonstrated by nonoverlapping 95% CIs. Thus, tapentadol but not morphine shows a feature that is an important objective in the treatment of chronic neuropathic pain (i.e., selective inhibition of disease-related dysfunction). Therefore, tapentadol may allow for a reduction of abnormal pain sensation while maintaining normal sensory function and hence the protective function of the pain transmitting system. STZ-induced diabetes in mice is considered to be an animal model for DPN pain, which is an important clinical pain condition used for the assessment of clinical efficacy of analgesic drugs [1]. Heat hyperalgesia occurs especially in mild DPN and is suggested to be an indicator of early DPN [5]. In STZtreated mice, heat hyperalgesia is seen within 1 week after induction of diabetes. In the current setting, stable and robust heat hyperalgesia for up to 2 weeks was found and repetitive testing did not result in signs of habituation toward the heat stimulus. Comparison of diabetic with non-diabetic control mice allows the description of anti-hyperalgesic (diabetic mice) and anti-nociceptive (non-diabetic mice) efficacy of test compounds. It is suggested that selective inhibition of disease-related thermal hyperalgesia seen with tapentadol is due to the combination of two distinct analgesic mechanisms: MOR agonism and NA reuptake inhibition. Chronic pain is frequently multi-modal in origin (i.e., more than one pathophysiological mechanism is involved) and can therefore be effectively treated by multi-modal analgesic drugs or drug combinations that target different pathophysiological mechanisms. Due to the different nature of these mechanisms, additive contribution to analgesic activity can be expected. Multimodal analgesic combinations may even result in supra-additive (i.e., synergistic) pain inhibition [2,8]. Since side effect profiles are usually different for different analgesic mechanisms while pain inhibition through different mechanisms results in a common final effect (i.e., analgesia), it can be argued that multi-modal analgesics will result in increased analgesic potency with reduced overall side effects when compared with equi-analgesic doses of the corresponding uni-modal analgesics. In the case of tapentadol, the noradrenergic mechanism of action results in an opiate-sparing effect (i.e., high potency and full efficacy), despite only moderate activity at the MOR. It is now well established that NA plays an important role in the endogenous descending pain inhibitory system [17], and the relevance of NA reuptake inhibition, in particular for the management of chronic neuropathic pain, has been demonstrated in clinical studies [16,19]. The high efficacy of tapentadol in the present study is also consistent with findings from a phase 3 clinical trial in patients with DPN in which tapentadol has shown good efficacy and tolerability [6]. Thus, in the case of tapentadol, the combination of NA reuptake inhibition with MOR agonism appears to result not only in an opiate-sparing effect (i.e., to less opiate-like side effects) but also in a broad efficacy profile (i.e., high efficacy in acute as well as in chronic/neuropathic pain). In conclusion, the selective inhibition of disease-related hyperalgesia by tapentadol suggests a possible advantage in the management of chronic neuropathic pain compared with classical opioids, such as morphine. It is hypothesized that this attractive
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efficacy profile of tapentadol is due to the simultaneous activation of the MOR and inhibition of NA reuptake. Acknowledgements We thank Elke Schumacher for excellent technical help. Editorial support for this manuscript was provided by Rachel Schulz, MA, ELS, of MedErgy, and was funded by Johnson & Johnson Pharmaceutical Services, L.L.C., and Global Development, Grünenthal GmbH, Aachen, Germany. References [1] R. Baron, T.R. Tölle, U. Gockel, M. Brosz, R. Feynhagen, A cross-sectional cohort survey in 2100 patients with painful diabetic neuropathy and postherpetic neuralgia: differences in demographic data and sensory symptoms, Pain 146 (2009) 34–40. [2] E.E. Codd, R.P. Martinez, L. Molino, K.E. Rogers, D.J. Stone, R.J. Tallarida, Tramadol and several anticonvulsants synergize in attenuating nerve injury-induced allodynia, Pain 134 (2008) 254–262. [3] S. Daniels, E. Casson, J.U. Stegmann, C. Oh, A. Okamoto, C. Rauschkolb, D. Upmalis, A randomized, double-blind, placebo-controlled phase 3 study of the relative efficacy and tolerability of tapentadol IR and oxycodone IR for acute pain, Curr. Med. Res. Opin. 25 (2009) 1551–1561. [4] S.E. Daniels, D. Upmalis, A. Okamoto, C. Lange, J. Haeussler, A randomized, double-blind, phase III study comparing multiple doses of tapentadol IR, oxycodone IR, and placebo for postoperative (bunionectomy) pain, Curr. Med. Res. Opin. 25 (2009) 765–776. [5] P.J. Dyck, P.J.B. Dyck, T.S. Larson, P.C. O’Brien, J.A. Velosa, Patterns of quantitative sensation testing of hypoesthesia and hyperalgesia are predictive of diabetic polyneuropathy: a study of three cohorts. Nerve growth factor study group, Diabetes Care 23 (2000) 510–517. [6] M. Etropolski, D.Y. Shapiro, A. Okamoto, C. Rauschkolb, J. Haeussler, Efficacy and safety of tapentadol ER for diabetic peripheral neuropathic pain: results of a randomized-withdrawal, double-blind, placebo-controlled phase III study, Neurology 72 (11 Suppl. 3) (2009) A217–A218. [7] M.J. Field, S. McCleary, J. Hughes, L. Singh, Gabapentin and pregabalin, but not morphine and amitriptyline, block both static and dynamic components of mechanical allodynia induced by streptozocin in the rat, Pain 80 (1999) 391–398. [8] J. Filitz, H. Ihmsen, W. Gunther, A. Troster, H. Schwilden, J. Schuttler, W. Koppert, Supra-additive effects of tramadol and acetaminophen in a human pain model, Pain 136 (2008) 262–270. [9] M. Hale, D. Upmalis, A. Okamoto, C. Lange, C. Rauschkolb, Tolerability of tapentadol immediate release in patients with lower back pain or osteoarthritis of the hip or knee over 90 days: a randomized, double-blind study, Curr. Med. Res. Opin. 25 (2009) 1095–1104. [10] C Hartrick, I. Van Hove, J.-U. Stegmann, C. Oh, D. Upmalis, Efficacy and tolerability of tapentadol immediate release and oxycodone HCl immediate release in patients awaiting primary joint replacement surgery for end-stage joint disease: a 10-day, phase III, randomized, double-blind, active- and placebocontrolled study, Clin. Ther. 31 (2009) 260–271. [11] T.S. Jensen, M.M. Backonja, J.S. Hernandez, S. Tesfaye, P. Valensi, D. Ziegler, New perspectives on the management of diabetic peripheral neuropathic pain, Diab. Vasc. Dis. Res. 3 (2006) 108–119. [12] J. Kamei, Y. Ohhashi, T. Aoki, N. Kawasima, Y. Kasuya, Streptozotocin-induced diabetes selectively alters the potency of analgesia produced by -opioid agonists, but not by ␦- and -opioid agonists, Brain Res. 571 (1992) 199–203. [13] T. Kohno, R.R. Ji, N. Ito, A.J. Allchorne, K. Befort, L.A. Karchewski, C.J. Woolf, Peripheral axonal injury results in reduced opioid receptor pre- and postsynaptic action in the spinal cord, Pain 117 (2005) 77–87. [14] A. Kuhad, M. Bishnoi, K. Chopra, Anti-nociceptive effect of duloxetine in mouse model of diabetic neuropathic pain, Indian J. Exp. Biol. 47 (2009) 193–197. [15] F. Marchand, A. Alloui, E. Chapuy, A. Hernandez, T. Pelissier, D. Ardid, A. Eschalier, The antihyperalgesic effect of venlafaxine in diabetic rats does not involve the opioid system, Neurosci. Lett. 342 (2003) 105–108. [16] M.B. Max, S.A. Lynch, J. Muir, S.E. Shoaf, B. Smoller, R. Dubner, Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy, N. Engl. J. Med. 326 (1992) 1250–1256. [17] M.J. Millan, Descending control of pain, Prog. Neurobiol. 66 (2002) 355–474. [18] M.H. Ossipov, Y. Lopez, M.L. Nichols, D. Bian, F. Porreca, Inhibition by spinal morphine of the tail-flick response is attenuated in rats with nerve ligation injury, Neurosci. Lett. 199 (1995) 83–86. [19] T.O. Staiger, B. Gaster, M.D. Sullivan, R.A. Deyo, Systematic review of antidepressants in the treatment of chronic low back pain, Spine 28 (2003) 2540–2545. [20] T.M. Tzschentke, T. Christoph, B. Kögel, K. Schiene, H.-H. Hennies, W. Englberger, M. Haurand, U. Jahnel, T.I. Cremers, E. Friderichs, J. De Vry, (−)(1R, 2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties, J. Pharmacol. Exp. Ther. 323 (2007) 265–276.
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[21] T.M. Tzschentke, J. De Vry, R. Terlinden, H.H. Hennies, C. Lange, W. Strassburger, M. Haurand, J. Kolb, J. Schneider, H. Buschmann, M. Finkam, U. Jahnel, E. Friderichs, Tapentadol HCl, Drugs Future 31 (2006) 1053–1061. [22] T.M. Tzschentke, U. Jahnel, B. Kogel, T. Christoph, W. Englberger, V.J. De, K. Schiene, A. Okamoto, D. Upmalis, H. Weber, C. Lange, J.U. Stegmann, R. Kleinert, Tapentadol hydrochloride: a next-generation, centrally acting analgesic with
two mechanisms of action in a single molecule, Drugs Today (Barc) 45 (2009) 483–496. [23] A. Veves, M. Backonja, R.A. Malik, Painful diabetic neuropathy: epidemiology, natural history, early diagnosis, and treatment options, Pain Med. 9 (2008) 660–674. [24] M. Zimmermann, Ethical guidelines for investigations of experimental pain in conscious animals, Pain 16 (1983) 109–110.
Contents lists available at ScienceDirect
Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Tapentadol, but not morphine, selectively inhibits disease-related thermal hyperalgesia in a mouse model of diabetic neuropathic pain Thomas Christoph ∗ , Jean De Vry, Thomas M. Tzschentke Global Preclinical Research and Development, Grünenthal GmbH, Aachen, Germany
a r t i c l e
i n f o
Article history: Received 11 November 2009 Received in revised form 10 December 2009 Accepted 11 December 2009 Keywords: Diabetic neuropathic pain Opioids Tapentadol Animals
a b s t r a c t Neuropathic pain in diabetic patients is a common distressing symptom and remains a challenge for analgesic treatment. Selective inhibition of pathological pain sensation without modification of normal sensory function is a primary aim of analgesic treatment in chronic neuropathic pain. Tapentadol is a novel analgesic with two modes of action, -opioid receptor (MOR) agonism and noradrenaline (NA) reuptake inhibition. Mice were rendered diabetic by means of streptozotocin, and neuropathic hyperalgesia was assessed in a 50 ◦ C hot plate test. Normal nociception was determined in control mice. Tapentadol (0.1–1 mg/kg i.v.) and morphine (0.1–3.16 mg/kg i.v.) dose-dependently attenuated heat-induced nociception in diabetic animals with full efficacy, reaching >80% at the highest doses tested. Tapentadol was more potent than morphine against heat hyperalgesia, with ED50 (minimal effective dose) values of 0.32 (0.316) and 0.65 (1) mg/kg, respectively. Non-diabetic controls did not show significant antinociception with tapentadol up to the highest dose tested (1 mg/kg). In contrast, 3.16 mg/kg morphine, the dose that resulted in full anti-hyperalgesic efficacy under diabetic conditions, produced significant anti-nociception in non-diabetic controls. Selective inhibition of disease-related hyperalgesia by tapentadol suggests a possible advantage in the treatment of chronic neuropathic pain when compared with classical opioids, such as morphine. It is hypothesized that this superior efficacy profile of tapentadol is due to simultaneous activation of MOR and inhibition of NA reuptake. © 2010 Published by Elsevier Ireland Ltd.
Patients with diabetes mellitus often suffer from symptoms of neuropathic pain. About 30% of patients with diabetes mellitus are affected by peripheral neuropathy and 16–26% of diabetic patients experience chronic pain [11]. Only a portion of patients respond to available treatments, which have only limited efficacy and/or are associated with intolerable side effects [23]. Selective inhibition of pathological pain sensation without modification of normal sensory function is a particularly important objective in the management of chronic pain and can be tested in pain models both in animals and in patients. Painful diabetic polyneuropathy (DPN) and postherpetic neuropathy (PHN) are polyneuropathic pain conditions that are commonly used in clinical studies for the assessment of the clinical efficacy of new drugs [1]. In rodents, symptoms of DPN such as thermal or mechanical hyperalgesia or allodynia can be studied after induction of diabetes with streptozotocin (STZ), and analgesic efficacy has been demonstrated in this model for clinically validated analgesic mechanisms, such
∗ Corresponding author at: Department of Pharmacology, Global Preclinical Research and Development, Grünenthal GmbH, Zieglerstrasse 6, 52078 Aachen, Germany. Tel.: +49 241 5692421; fax: +49 241 5692852. E-mail address: [email protected] (T. Christoph). 0304-3940/$ – see front matter © 2010 Published by Elsevier Ireland Ltd. doi:10.1016/j.neulet.2009.12.020
as the ␣2␦-selective Ca2+ channel subunit blocker pregabalin [7] and the noradrenaline (NA)/serotonin (5-HT) reuptake inhibitors duloxetine [14] and venlafaxine [15]. In contrast, the analgesic efficacy of selective -opioid receptor (MOR) agonists, such as morphine, is limited in clinical neuropathic pain conditions [23] and also in rodent STZ diabetes models [12]. Although not directly shown for diabetic rodents, data from mononeuropathic pain models suggest that reduced spinal expression of MOR protein results in limited efficacy of MOR agonists as measured both on the behavioural [18] and on the cellular level [13]. Pain signals are conveyed by several neuro-anatomical pathways and a number of different neurotransmitters. Therefore, a combination of different analgesic mechanisms, targeting different pathways or transmitters, offers the opportunity for increased analgesia with reduced side effects. Synergistic analgesic interaction has been demonstrated both in human [8] and animal studies [2], combining two drugs with different analgesic mechanisms. Tapentadol (3-[(1R,2R)-3-(dimethylamino)-1-ethyl2-methylpropyl]phenol) is a novel analgesic, combining two modes of action, MOR agonism (Ki = 0.1 M for rat MOR binding) and NA reuptake inhibition (Ki = 0.5 M for rat synaptosomal NA reuptake inhibition) in a single molecule [20]. The analgesic efficacy of tapentadol was demonstrated in a wide range of preclinical [20]
92
T. Christoph et al. / Neuroscience Letters 470 (2010) 91–94
and clinical pain conditions [3,4,9,10,21,22], suggesting a broad analgesic profile, possibly due to the combination of the two mechanisms of action of tapentadol. In addition, reduced opiate-like gastrointestinal side effects were noted in clinical studies as compared with equi-analgesic doses of oxycodone [3,4,9,10,21,22], possibly due to an opiate-sparing effect of the noradrenergic mechanism of action of tapentadol. The aim of this study was to characterize the anti-hyperalgesic potential of tapentadol in a mouse model of DPN pain and compare it with the anti-nociceptive potential in non-diabetic control animals. The effects of the classical MOR agonist morphine were also evaluated. Animal testing was performed in accordance with the recommendations and policies of the International Association for the Study of Pain [24] and the German Animal Welfare Law. Male CD1 mice (18–20 g; Charles River, Germany) were treated i.v. with 200 mg/kg STZ or vehicle (sodium citrate, pH 5). Induction of diabetes was confirmed by blood glucose levels >25 mM 1 week after STZ treatment. One and 2 weeks after treatment, diabetic and non-diabetic control animals were randomly allocated to the different treatment groups (n = 10). Animals were used for a maximum of two tests, with a wash-out period of at least 7 days. For nociceptive and hyperalgesic testing, animals were placed on a 50 ◦ C hot metal plate under a transparent Plexiglas box (13 cm × 13 cm × 10 cm, l × w × h) for periods of 2 min and the number of nocifensive reactions (licking/shaking of the hind paws, licking of the genitals, jumping) was counted 30 min (baseline 1) and 15 min (baseline 2) before and 15, 30, 45 and 60 min after drug or vehicle treatment. Tapentadol (0.1, 0.316, and 1 mg/kg) and morphine (0.1, 0.316, 1, and 3.16 mg/kg) were dissolved in saline and administered i.v. (10 ml/kg). All doses of tapentadol and morphine indicated herein refer to the hydrochloride salts of the compounds. Data are presented as the number of nocifensive reactions occurring within 2 min. Anti-hyperalgesic ED50 values (95% confidence intervals [CIs]) were calculated by linear regression based on % maximal possible effects (MPE), using baseline 2 of diabetic and of non-diabetic controls as 0% and 100% MPE, respectively. Data were analyzed by means of a repeated measures analysis of variance (ANOVA) with post hoc Bonferroni test. Minimal effective dose (MED) was defined as the lowest dose that induced a statistically significant effect (P < 0.05). Although the operators performing the behavioural tests were not formally ‘blinded’ with respect to the treatment, they were not aware of the study hypothesis. One week after STZ treatment, 85% of treated animals developed clear diabetes. Pain reaction toward a heat stimulus was characterized in STZ-treated diabetic and citrate-treated nondiabetic mice to test for diabetes-induced polyneuropathic pain symptoms and compare it with heat nociception in non-diabetic control mice. In non-diabetic control animals the hot plate test resulted in nociception with (mean ± SEM) 18.5 ± 0.5 and 17.5 ± 0.5 nocifensive reactions at baseline 2 for the tapentadol and the morphine groups, respectively. The degree of nociception was stable over 2 weeks and there was no habituation toward the heat stimulus during the test (Fig. 1). Diabetic animals showed significantly increased (P < 0.05 vs. non-diabetic controls) numbers of nocifensive reactions, suggesting development of heat hyperalgesia, with 34.6 ± 0.6 and 36.0 ± 0.6 nocifensive reactions at baseline 2 for the tapentadol and the morphine groups, respectively. The degree of hyperalgesia was stable over 2 weeks and there was no habituation toward the heat stimulus during the test (Fig. 1). Tapentadol (Figs. 1A and 2) showed dose-dependent and significant (P < 0.05 vs. vehicle for 0.316 and 1 mg/kg) anti-hyperalgesic activity in diabetic animals with an MED of 0.316 mg/kg and full efficacy of 82% MPE at 1 mg/kg. Nocifensive reactions of non-
Fig. 1. Effect of tapentadol (A) and morphine (B) on heat hyperalgesia in diabetic mice (closed symbols) and heat nociception in non-diabetic mice (open symbols). Data are presented as number of nocifensive reactions occurring within 2 min (mean ± SEM). *P < 0.05 vs. corresponding vehicle. SEM, standard error of the mean.
diabetic control animals were not reduced up to the highest dose tested, even at full anti-hyperalgesic efficacy (P > 0.05 vs. vehicle). Morphine (Figs. 1B and 2) showed dose-dependent and significant (P < 0.05 vs. vehicle for 1 and 3.16 mg/kg) anti-hyperalgesic activity in diabetic animals with an MED of 1 mg/kg and full efficacy of 94% MPE at 3.16 mg/kg. Dose-dependent anti-nociception was seen in non-diabetic controls, the effect being significant at 3.16 mg/kg (P < 0.05 vs. vehicle). Potencies were compared by calculating ED50 values at the time of maximal effect (15 min). Tapentadol showed an ED50 (95% CI) of 0.32 (0.24–0.42) mg/kg while morphine showed an ED50 (95% CI) of 0.65 (0.50–0.84) mg/kg (Fig. 2). Based on the fact that the 95% CI of both ED50 values showed no overlap, the ED50 values were considered to be statistically different. Tapentadol showed potent and selective anti-hyperalgesia in diabetic animals at doses that do not have anti-nociceptive efficacy
Fig. 2. Effect of tapentadol and morphine on heat hyperalgesia in diabetic mice. Data are presented as % MPE (mean ± SEM) at maximal efficacy, 15 min after drug administration. *P < 0.05 vs. corresponding vehicle. MPE, maximum possible effect; SEM, standard error of the mean.
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in normal non-diabetic subjects. This is consistent with previously reported data from the tail-flick test (ED50 4.2 mg/kg i.v.) [21] and implies that higher doses would eventually result in an anti-nociceptive effect in non-diabetic animals in the current setting. In contrast, morphine, which also reduces heat hyperalgesia, showed no separation between anti-hyperalgesia and anti-nociceptive activity as seen in the present study, as well as in published data [21]. Anti-hyperalgesic efficacy of tapentadol (ED50 0.32 mg/kg) in diabetic polyneuropathy was significantly higher than morphine (ED50 0.65 mg/kg), as demonstrated by nonoverlapping 95% CIs. Thus, tapentadol but not morphine shows a feature that is an important objective in the treatment of chronic neuropathic pain (i.e., selective inhibition of disease-related dysfunction). Therefore, tapentadol may allow for a reduction of abnormal pain sensation while maintaining normal sensory function and hence the protective function of the pain transmitting system. STZ-induced diabetes in mice is considered to be an animal model for DPN pain, which is an important clinical pain condition used for the assessment of clinical efficacy of analgesic drugs [1]. Heat hyperalgesia occurs especially in mild DPN and is suggested to be an indicator of early DPN [5]. In STZtreated mice, heat hyperalgesia is seen within 1 week after induction of diabetes. In the current setting, stable and robust heat hyperalgesia for up to 2 weeks was found and repetitive testing did not result in signs of habituation toward the heat stimulus. Comparison of diabetic with non-diabetic control mice allows the description of anti-hyperalgesic (diabetic mice) and anti-nociceptive (non-diabetic mice) efficacy of test compounds. It is suggested that selective inhibition of disease-related thermal hyperalgesia seen with tapentadol is due to the combination of two distinct analgesic mechanisms: MOR agonism and NA reuptake inhibition. Chronic pain is frequently multi-modal in origin (i.e., more than one pathophysiological mechanism is involved) and can therefore be effectively treated by multi-modal analgesic drugs or drug combinations that target different pathophysiological mechanisms. Due to the different nature of these mechanisms, additive contribution to analgesic activity can be expected. Multimodal analgesic combinations may even result in supra-additive (i.e., synergistic) pain inhibition [2,8]. Since side effect profiles are usually different for different analgesic mechanisms while pain inhibition through different mechanisms results in a common final effect (i.e., analgesia), it can be argued that multi-modal analgesics will result in increased analgesic potency with reduced overall side effects when compared with equi-analgesic doses of the corresponding uni-modal analgesics. In the case of tapentadol, the noradrenergic mechanism of action results in an opiate-sparing effect (i.e., high potency and full efficacy), despite only moderate activity at the MOR. It is now well established that NA plays an important role in the endogenous descending pain inhibitory system [17], and the relevance of NA reuptake inhibition, in particular for the management of chronic neuropathic pain, has been demonstrated in clinical studies [16,19]. The high efficacy of tapentadol in the present study is also consistent with findings from a phase 3 clinical trial in patients with DPN in which tapentadol has shown good efficacy and tolerability [6]. Thus, in the case of tapentadol, the combination of NA reuptake inhibition with MOR agonism appears to result not only in an opiate-sparing effect (i.e., to less opiate-like side effects) but also in a broad efficacy profile (i.e., high efficacy in acute as well as in chronic/neuropathic pain). In conclusion, the selective inhibition of disease-related hyperalgesia by tapentadol suggests a possible advantage in the management of chronic neuropathic pain compared with classical opioids, such as morphine. It is hypothesized that this attractive
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