Pregabalin and Duloxetine in Patients with Non-Nociceptive Pain: A Narrative Review Exploring the Pharmacological Effects of This Combination

Both neuropathic and nociplastic pain (non-nociceptive pain) are characterized by a similar pattern of clinical symptoms, including numbness, dysesthesia, tingling, and pricking. Whereas nociplastic pain results from altered nociception without indication of tissue damage or a somatosensory system lesion, neuropathic pain is caused by a disease or lesion affecting the somatosensory system. The available therapeutic options consist of antiepileptic drugs, antidepressants, and muscle relaxants. Unfortunately, symptoms are often refractory, and increasing drug dosage may lead to adverse events. In this narrative review, we searched PubMed, MEDLINE, Cochrane, and EMBASE databases from their inception up to 26 July 2025, using the key words “duloxetine,” “pregabalin,” and then ‘‘combination,’’ “nociplastic pain,” “neuropathic pain,” “efficacy,” “safety,” “pharmacology,” “pharmacokinetic,” and “pharmacodynamic.” We evaluated the role of combination therapy with duloxetine, a serotonin–norepinephrine reuptake inhibitor, and pregabalin, an antiseizure medication that acts on voltage-gated calcium channels α2δ subunit, in patients with neuropathic or nociplastic pain. The literature data indicate that combination therapy has synergistic effects, leading to fewer adverse events in specific categories of patients. Available evidence showed that combination therapy is generally not inferior to monotherapy, with slight differences in safety outcomes depending on supplementation, drug labels, and titration. These results indicate that even if not superior, combination therapy may be an alternative to monotherapy in selected patients: those who experience side effects from higher dosages of duloxetine or pregabalin and for whom symptom relief from dose reduction alone is not possible; those who use medications that interact with duloxetine; those who suffer from anxiety–depression, where pain is closely linked to mental symptoms; and those who have central neuropathic pain (often refractory).