Topiramate in nociceptive pain - experimental analgesia study

Introduction The complex pharmacodynamic mechanism of topiramate is currently approved for only two major diseases: epilepsy, mono or combined therapy, and preventing episodes of migraine. However, there are many other studies that emphasize other potential clinical effects deriving from its complex action and leading to its use in acute nociceptive pain and neuropathic pain management. Topiramate inhibits the action potential generated by repeated depolarization of neurons through blockage of sodium channels(Shank et al 1994; Perucca 1997) and some voltagedependent L-type calcium channels, inhibiting calcium current (Shank et al 1994; Shank et al 2000). Studies have shown that lower concentrations of topiramate selectively inhibits kainate receptor-mediated synaptic currents containing the GluR5 subunit (GLUK1) and also inhibits, reducing the effectiveness, the postsynaptic transmission of the action potential by blocking the glutamate AMPA receptor (Braga et al 2009). Glutamate action on kainate receptors, facilitating transmission of excitatory potential, leads to the inhibition of GABA release, so topiramate inhibition of kainate receptors will favor GABA release and increase GABA(A) receptor-mediated inhibitory current (Braga et al 2009; Gryder et al 2003). Topiramate inhibits carbonic anhydrase, CA-II and CA-IV isoenzymes, but this mecanism is unlikely to explain its anticonvulsant and antinociceptive action (Wieczorkiewicz-Płaza et al 2004). Studies suggest that topiramate can be used to alleviate pain caused by diabetic neuropathy and migraines, in lower doses than those used to treat epilepsy (Spina et al 2004; Naegel et al 2010). Its normothymic stabilizing effect also occurs at lower doses than it does with anticonvulsant doses. Therefore, initially used as anticonvulsant, topiramate is currently used by psychiatrists to treat bipolar disorder, anxiety disorders, ADHD and substance abuse (Marcotte 1998; Maidment 2002). The purpose of this study is to assess the action of topiramate on experimental models of nociceptive pain, with acute, subacute and chronic administration. Abstract. Objective: The aim of this study is to assess the action of topiramate on experimental models of nociceptive pain, with acute, subacute and chronic administration within 30 days. Material and methods. We used 50 male Wistar white rats as experimental animals, randomized into 5 groups: a group treated with saline solution, a group treated with metamizole (50 mg/kg), a group treated with tramadol (10 mg/kg), and two groups treated with topiramate (TPM) in different concentrations (10 mg/kg and 50 mg/kg). The following tests have been performed at baseline and after injection (intraperitoneal administration of 0.5 ml/100 g), at specific time points: mechanical paw pressure test, hot plate test and tail-flick test. Results. After a single dose, TPM shows statistically significant antinociceptive effects compared to the values obtained at baseline during various testing times, while performing the hot plate test (p<0.05). The use of the paw pressure test and the tail-flick test showed no statistically significant increased pain threshold compared to the values obtained at baseline. Both doses of TPM determine a statistically significant increased pain threshold (p=0.001) one hour after administration, compared to the control group and the groups treated with conventional analgesics, and the effect is maintained for up to 24 hours. Increased pain tolerance after TPM administration for 14 days stays high (p<0.05) and is obvious in comparison to the control group at all testing times. Antinociceptive profile of TPM after 30 days of administration shows that it increases baseline pain threshold after the first dose, with maximum effect after 14 days, followed by a stable period, without significant increases compared to the baseline. Conclusions. TPM dose of 50 mg/kg has a predominant supraspinal central and prolonged analgesic effect in acute nociceptive pain. TPM dose of 10mg/kg has a predominant spinal analgesic effect (revealed in tail-flick test) and is prolonged in acute nociceptive pain. TPM analgesic effect is superior to the control group and to conventional analgesics tested in acute pain and throughout the entire testing period.