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Chronic primary and secondary pain syndromes reflect a multifaceted continuum involving nociceptive, neuropathic and nociplastic mechanisms. The maladaptive plasticity of the peripheral and central nervous system (encompassing the ascending and descending pain pathways) sustains hypersensitivity and correlates with comorbid alterations in mood, cognition, sleep and fatigue, underpinned by functional reorganization of brain networks. In this scenario, traditional analgesics frequently demonstrate limited efficacy, while current guidelines recommend antiepileptic agents and antidepressants, particularly gabapentinoids and duloxetine, as first line pharmacological options. This review explores the mechanistic rationale and clinical evidence supporting the combined use of gabapentinoids and duloxetine in chronic pain management. These agents act on distinct yet complementary targets: gabapentinoids reduce excitatory neurotransmission via modulation of calcium channel activity, whereas duloxetine restores descending noradrenergic inhibition and alleviates comorbid symptoms. Clinical trial and meta\u2010analyses highlight their individual efficacy in diabetic peripheral neuropathy, postherpetic neuralgia and fibromyalgia. Among gabapentinoids, pregabalin exhibits a favourable pharmacokinetic profile that allows rapid titration and demonstrates effectiveness against anxiety\u2010related sleep disorders. Importantly, emerging evidence suggests that their combination may offer additional benefit, particularly in patients with residual pain despite monotherapy, though evidence remains limited to small, short\u2010term studies. This review provides proof of concept by bridging theoretical knowledge and real\u2010life clinical settings aiming to develop treatment protocols based on predominant pain mechanisms that can effectively control hypersensitivity and improve quality of life.<\/jats:p>","DOI":"10.1002\/bcp.70689","type":"journal-article","created":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T02:36:09Z","timestamp":1784946969000},"page":"3333-3353","source":"Crossref","is-referenced-by-count":0,"title":["Gabapentinoids\u2010duloxetine combination therapy for chronic pain: A mechanism oriented rational to bridge theoretical knowledge and real life setting"],"prefix":"10.1002","volume":"92","author":[{"given":"Stefania","family":"Nobili","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child Health University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Evangelista","sequence":"additional","affiliation":[{"name":"Institute of Anesthesia, Resuscitation and Pain Therapy Catholic University of Sacred Heart  Rome Italy"},{"name":"Department of Clinical and Experimental Medicine (DIMED) University of Messina  Messina Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3459-2660","authenticated-orcid":false,"given":"Elena","family":"Lucarini","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child Health University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena G.","family":"Giugliano","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child Health University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Ghelardini","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child Health University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Micheli","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child Health University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Di Cesare Mannelli","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child Health University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000001384"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics15041165"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(21)00393\u20107"},{"key":"e_1_2_11_5_1","unstructured":"International Association for the Study of Pain.Terminology|International Association for the Study of Pain (IASP). 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