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Rationale: Drug combinations are commonly used in pain management, which can produce potent analgesic effects with reduced dosage and adverse effects. Objective: This study was designed to evaluate the anti-nociceptive effects and adverse effects of new combinations of flupirtine (a Kv7 potassium channel opener) and antihistamines (promethazine, fexofenadine) on acute and chronic pain in mice, and the possible mechanisms behind the synergistic analgesic effects were preliminarily investigated. Methods: In acetic acid writhing test, carrageenan-induced inflammatory pain model, and paclitaxel-induced neuropathic pain model, the interaction indexes (γ) between flupirtine and antihistamines were determined by isobolographic analysis. Furthermore, the Kv7 channel blocker XE991 was used to determine whether the effects of single agents and drug combinations on paclitaxel- and carrageenan-induced mechanical allodynia were mediated by Kv7 channels. Finally, hepatotoxicity markers, liver histopathology, and the rotarod test were used to investigate the adverse effects of drugs in combination doses. Results: The interaction indexes of flupirtine-promethazine and flupirtine-fexofenadine in all the above three pain models were lower than 1. The analgesic effects of flupirtine (13 mg/kg), promethazine (5 mg/kg), fexofenadine (20 mg/kg), and their combinations were antagonized significantly by XE991 (3 mg/kg). And the adverse effects of flupirtine and antihistamines in combination doses were not significantly different from the vehicle group. Conclusions: Flupirtine and antihistamines produced synergistic analgesic effects in all the above pain models. The analgesic effects of antihistamines were partially mediated by Kv7/M channels, and the activation of Kv7/M channels may be partly responsible for the synergistic analgesic effects between flupirtine and antihistamines. [ABSTRACT FROM AUTHOR]

Rationale: Opioid and GABAA receptors are both located in central nociceptive pathways, and compounds that activate these receptors have pain-relieving properties. To date, the interactive effects of concurrent administration of these compounds in preclinical models of pain-like behaviors have not been assessed. Objective: The purpose of this study was to examine the interactive effects of the μ-opioid agonist morphine and the α2GABAA and α3GABAA receptor positive allosteric modulator methyl 8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate (MP-III-024) in preclinical models of mechanical hyperalgesia and thermal nociception. Methods: The antihyperalgesic and antinociceptive effects of morphine and MP-III-024 administered alone were assessed initially, followed by fixed-ratio mixtures of MP-III-024/morphine combinations. Drug interaction data were analyzed using isobolographic and dose-addition analyses. All studies were conducted in male CD-1 mice. Results: In the assay of mechanical hyperalgesia, each compound produced dose-dependent antihyperalgesic effects, whereas only morphine was effective on thermal nociception. Fixed-ratio mixtures of MP-III-024/morphine were also dose-dependently effective in both procedures. These drug combination studies revealed that morphine and MP-III-024 produced supra-additive (synergistic) effects in both assays, depending on their relative proportions. Conclusions: These results demonstrate an interaction between α2GABAA and α3GABAA receptor- and μ-opioid receptor-mediated signals and suggest that combination therapy may be useful for the treatment of pain-related disorders. [ABSTRACT FROM AUTHOR]

Rationale: Acute pain states in the trigeminal region (headaches, dental pain) fall into the most prevalent painful conditions. Standard analgesics (paracetamol/NSAIDs) represent the cornerstone of their treatment, whereas triptans are primarily used in migraine attacks. Due to limited efficacy and/or side effects of current treatments, identifying favorable combinations of available drugs is justified. Objectives: Eslicarbazepine acetate (ESL) is a novel antiepileptic drug whose effectiveness against trigeminal pain was recently demonstrated. Here, we examined the interactions between ESL and several standard/alternative analgesics (paracetamol, propyphenazone, naproxen, zolmitriptan, and metoclopramide) in a model of trigeminal pain. Methods: The antinociceptive effects of orally administered ESL, standard/alternative analgesics, and two-drug ESL-analgesic combinations were examined in the orofacial formalin test in mice. The type of interaction between drugs was determined by isobolographic analysis. Results: ESL, analgesics, and two-drug ESL-analgesic combinations significantly and dose-dependently reduced nociceptive behaviour in the second, inflammatory phase of the test. Isobolographic analysis revealed that ESL interacted additively with paracetamol/propyphenazone/zolmitriptan and synergistically with naproxen/metoclopramide (with about a 4-fold and 3-fold reduction of doses in the ESL-naproxen and ESL-metoclopramide combination, respectively). Conclusions: ESL interacted in a beneficial manner with several analgesics that are used for trigeminal pain treatment, producing synergistic interactions with naproxen/metoclopramide and additive interactions with paracetamol/propyphenazone/zolmitriptan. Our results suggest that combining ESL with analgesics could theoretically enable the use of lower doses of individual drugs for achieving pain relief. [ABSTRACT FROM AUTHOR]