Combination Therapy with Flupirtine and Opioid: Studies in Rat Pain Models
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PAIN MEDICINE Volume 9 • Number 7 • 2008 TRANSLATIONAL RESEARCH SECTION Original Research Article Combination Therapy with Flupirtine and Opioid: Studies in Rat Pain Models Downloaded from https://academic.oup.com/painmedicine/article/9/7/928/1861898 by guest on 01 October 2021 Colin S. Goodchild, MA, MBBChir, PhD, FRCA, FANZCA, FFPMANZCA,*† Anton Kolosov, BSc,* Adam P. Tucker, MB, BS, PhD,* and Ian Cooke, PhD† *Department of Anaesthesia and Perioperative Medicine, Monash Institute of Medical Research, Monash University, Clayton, Victoria; †CNSBio Ltd Pty Ltd, Melbourne, Victoria, Australia ABSTRACT Objectives. Flupirtine is an established clinical analgesic for mild to moderate musculoskeletal pain states. It has recently been shown to be a KCNQ2–3 potassium channel opener. These experiments were performed to see if this property could be useful in treating pain states characterized by central sensitization with the drug either given alone or in combination with morphine. Design. Experiments were performed in rats in an observer-blinded fashion with vehicle controls. Nonsedating doses of flupirtine, morphine, and combinations containing both drugs were defined using the rotarod test and open-field activity monitoring. Dose–response relationships were deter- mined for nonsedating doses of both drugs given alone and together in combination in causing antinociception in two nociception paradigms: carrageenan paw inflammation and streptozotocin- induced diabetic neuropathy. Results. Flupirtine and morphine, when given alone at the highest nonsedating doses, caused slight to moderate antinociception in both paradigms. Flupirtine also caused significant increases in morphine antinociception in both models. In carrageenan paw inflammation, complete reversal of carrageenan-induced hyperalgesia was caused by 10 mg/kg flupirtine in combination with 0.4 mg/kg morphine. These doses of the two drugs were ineffective when given alone, but the combination caused complete antinociception in this model of inflammatory pain. In the diabetic neuropathy model, morphine 3.2 mg/kg given alone caused no significant antinociception. However, a lower dose of morphine (1.6 mg/kg shown to be ineffective when it was given alone) given in combination with flupirtine 10 mg/kg caused highly significant antinociceptive effects causing complete reversal of hyperalgesia caused by diabetic neuropathy (P < 0.001, one-way analy- sis of variance). This combination of drugs was not sedating. Conclusions. Flupirtine increases morphine antinociception without causing an increase in sedation. Flupirtine should be investigated as an adjunct analgesic with opioids for the management of patients with pain states involving central sensitization. Key Words. Flupirtine; Morphine; Inflammation; Antinociception; Animal Models; Neuropathic Pain; Diabetes; Streptozotocin; Carrageenan Reprint requests to: Colin S. Goodchild, MA, MBBChir, Introduction PhD, FRCA, FANZCA, FFPMANZCA, 38 Somers euronal potassium channels [KCNQ2–5 or Avenue, Malvern, Victoria, 3144 Australia. Tel: +61 (4) 1456 1401; Fax: +61 (3) 9824 6322; E-mail: N Kv7.2–7.5]) were first described in 1998 [email protected]. after it was discovered that the channel proteins © American Academy of Pain Medicine 1526-2375/08/$15.00/928 928–938 doi:10.1111/j.1526-4637.2008.00514.x Flupirtine–Morphine Combination Therapy: Preclinical Studies 929 shared common sequences with potassium chan- retina [10]. However, binding studies have failed nels found in cardiac tissues [1]. Neuronal KCNQ to show that flupirtine has an affinity for NMDA channels have been found to be molecular sub- recognition sites. The controversy has finally been strates of M channels, and several molecules have solved by the discovery that flupirtine and the been identified as openers or activators of these structurally related analog retigabine bind with channels. The M current has been originally iden- KCNQ receptors and act as potassium channel tified as a membrane hyperpolarizing current cau- openers. As such, these compounds act to increase sed by muscarine [2]. It is the only hyperpolarizing the M current, decreasing neuronal excitability, current that operates around resting membrane and thus decreasing the effect of a number of neu- potential and thus has the possibility of drastically rotransmitters including glutamate (at NMDA Downloaded from https://academic.oup.com/painmedicine/article/9/7/928/1861898 by guest on 01 October 2021 altering neuronal excitability [3]. Involvement of receptors) [11]. KCNQ channels with the M current suggests that Although flupirtine has been available for use drugs acting on neuronal KCNQ channels could as an analgesic in humans for many years, its use be useful in treating a variety of clinical conditions has been limited and confined to monotherapy; it caused by neuronal hyperexcitability such as has not been described in combination therapies. epilepsy, acute pain, and neuropathic pain [4]. It is reported to be less effective for severe pain Although this theoretical property has been sug- compared with morphine or pethidine but as gested, it has not been tested by experiment. effective an analgesic as codeine or pentazocine However, there are experimental observations that with a similar side-effect profile [7]. It is the dose- might suggest how this property might be used in related side effects of somnolence, dizziness, and antinociception and analgesia. Activation of the M hallucinations that have limited its use (as mono- current by openers of KCNQ channels decreases therapy) to mild or moderate musculoskeletal the release of a number of neurotransmitters pain syndromes. known to be involved with such neuronal hyper- In the light of the new evidence on its mode of excitability such as excitatory amino acids [5]. It is action, it is appropriate to consider flupirtine again well established that glutamate is involved with but for the treatment of pain states that involve central sensitization states such as neuropathic neuronal hyperexcitability. Furthermore, a drug pain in which it targets the N-methyl-d-aspartate that controls neuronal hyperexcitability via the M (NMDA) subtype of excitatory amino acid recep- current, and thus NMDA receptor activation, is tor. Compounds inhibiting this action, such as likely to have synergistic or additive interactions NMDA antagonists, are active as antinociceptive with other analgesics, particularly opioids such as agents to some extent when given alone but more morphine. The latter provides for the possibility potently when combined with opioids such as of a more effective treatment for these pain states morphine. Unfortunately, the compounds devel- using smaller doses of the constituent drugs in a oped as NMDA antagonists have an unfavorable combination and thus reducing the likelihood of therapeutic effect/side-effect profile. Perhaps dose-limiting side effects. This would only be another method of invoking this mechanism, for useful, of course, if there was no similar synergy example, KCNQ channel openers, might have less between them with respect to sedating properties problems with therapeutic ratio. or other undesirable side effects. Flupirtine is a centrally acting nonopioid anal- This article describes experiments performed gesic that has been used clinically in Germany using two rat models of inflammatory and neuro- since 1984. It has been used for the treatment of a pathic pain investigating the antinociceptive ac- variety of pain states, but it has not been advocated tivity of flupirtine given alone and also in for the treatment of neuropathic pain. Despite its combination with morphine at low doses, less than long history of clinical use, the exact mode of those causing side effects of central nervous system action of flupirtine as an analgesic has remained depression. unknown until recently. In early studies, it has been found that flupirtine does not appear to Methods interact with serotonin, dopamine, nicotine, or adrenoceptors [6,7]. Subsequently, flupirtine has All experiments were carried out with the approval been found to decrease spinal polysynaptic reflexes of Monash University Standing Committee on mediated by NMDA receptors [8] and a2 adreno- Animal Experimentation and in all experiments, ceptors [9], and to antagonize NMDA-induced attention was paid to ethical guidelines for the changes on g-aminobutyric acid (GABA) in the investigation of experimental pain in conscious 930 Goodchild et al. animals [12]. All experiments reported in this the minimum speed for two training sessions of article were performed on male Wistar rats 1–2 minutes separated by an interval of 30–60 (weight 150–200 g for experiments investigating minutes. After this conditioning period, an intra- sedation and antinociception using the carrag- peritoneal injection of vehicle, drug, or drug com- eenan inflammation paradigm and weight 65–80 g bination was given. Five minutes later, the animals for experiments evaluating sedation and antinoci- were placed onto the rotarod at a constant speed of ception using the diabetic neuropathy model). 4 rpm. As the animal took grip of the drum, the The experiments were performed in an observer- accelerator mode was selected on the treadmill, blinded fashion with parallel saline vehicle treat- i.e., the rotation rate of the drum was increased ment controls. All drug solutions and vehicle were linearly at the rate of 20 rpm every minute there- Downloaded from https://academic.oup.com/painmedicine/article/9/7/928/1861898 by guest on 01 October 2021 given intraperitoneally