A Hybrid for Pain, I.e. Bifunctional Analgesics in Neuropathy

The need of developing new neuropathic pain therapies results from limited potency of currently available treatments, which is underlain by low efficacy of conventional analgesics, complex etiology and pathogenesis of neuropathy, diversity of its symptoms, as well as heightened side effects risk that accompanies the polypharmaceutical strategy, employed commonly to improve the therapeutic outcomes. Designing hybrid compounds, i.e. multimodal molecules that present the affinity to more than one receptor target, offers a promising perspective in this context. The multimodal approach allows to increase the analgesic efficacy of a given compound thanks to aiming at the very pathomechanisms specific for neuropathic pain, and to optimize the pharmacological profile of the drug. Thanks to the hybrid structure, analgesic properties of its moieties can be maximized, even if their action as separate pharmacophores tends to be limited or inconsistent under nerve injury conditions, such as in the case of opioid agonists. The present review discusses selected targets of hybrid compounds in the view of potential neuropathic pain therapy, along with the gains, limitations and challenges related to the use of hybrid compounds.