Gabapentinoids-Duloxetine Combination Therapy for Chronic Pain: A Mechanisms Oriented Rational to Bridge Theoretical Knowledge and Real Life Setting

  1. Stefania Nobili
  2. Maurizio Evangelista
  3. Elena Lucarini
  4. Elena Giulia Giugliano
  5. Carla Ghelardini
  6. Laura Micheli
  7. Lorenzo Di Cesare Mannelli

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Abstract

Chronic pain represents a complex debilitating condition that extends beyond the protective function of physiological pain, often persisting as an independent disease entity. 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, a 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, while duloxetine restores descending noradrenergic inhibition and alleviates comorbid symptoms. Clinical trial and meta-analyses highlight their individual efficacy in diabetic peripheral neuropathy, postherpetic neuralgia, and fibromyalgia. Among gabapentinoids, pregabalin exhibits a favorable pharmacokinetic profile that allows rapid titration and demonstrates effectiveness against anxiety-related sleep disorders. Importantly, emerging evidence suggests that their combination may yield superior pain relief and functional improvement compared with monotherapy, particularly in patients with residual pain. This review provides a proof of concept by bridging theoretical knowledge and real-life clinical settings aiming to develop treatment protocols based on predominant pain mechanisms that can effectively control hypersensitivity and improve quality of life.

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  1. PREreview

    This Zenodo record is a permanently preserved version of a Structured PREreview. You can view the complete PREreview at https://prereview.org/reviews/17418098.

    Does the introduction explain the objective of the research presented in the preprint? Yes The objective is explained by stating that the review aims to evaluate the mechanistic rationale and clinical evidence supporting the combined use of gabapentinoids and duloxetine for chronic pain management. This includes bridging theoretical knowledge and real-life clinical settings to develop treatment protocols based on predominant pain mechanisms. The review also discusses the potential application of this combination in chemotherapy-induced peripheral neuropathy.
    Are the methods well-suited for this research? Highly appropriate The methodology of summarizing and synthesizing mechanistic rationale and clinical evidence is well-suited to the objective of evaluating the combination therapy of gabapentinoids and duloxetine. The paper aims to evaluate the role of this combination in managing pathological pain by presenting pivotal clinical trials and bridging theoretical knowledge with real-life clinical settings
    Are the conclusions supported by the data? Highly supported The review concludes that gabapentinoids and duloxetine are important therapeutic options, which is supported by numerous randomized trials and meta-analyses demonstrating their efficacy as single agents in conditions like painful diabetic peripheral neuropathy (DPN), postherpetic neuralgia (PHN), and fibromyalgia
    Are the data presentations, including visualizations, well-suited to represent the data? Neither appropriate and clear nor inappropriate and unclear The sources are excerpts from a narrative review. They present data findings through text, summarizing results and reporting statistics from cited clinical trials. No figures, graphs, or tables are included in the paper.
    How clearly do the authors discuss, explain, and interpret their findings and potential next steps for the research? Very clearly a. Mechanistic Rationale: They clearly explain that the combination is supported by the drugs acting on distinct yet complementary targets: gabapentinoids modulate calcium channel activity, while duloxetine restores descending noradrenergic inhibition b. Clinical Efficacy: They interpret the clinical evidence to conclude that the combination may offer potential improvements in pain relief and non-pain symptoms (like mood and sleep disorders) by leveraging these complementary mechanisms. They note that existing studies generally show the superiority of combination therapy over single agents, particularly in patients with residual pain
    Is the preprint likely to advance academic knowledge? Highly likely The authors specifically identify areas for future research, such as defining the optimal treatment regimens, doses, and administration to maximize efficacy and limit side effects, which means that the current work lays the foundation for subsequent studies
    Would it benefit from language editing? Yes
    Would you recommend this preprint to others? Yes, it's of high quality The authors clearly discuss the complementary mechanisms and suggest the combination may offer potential improvements in pain relief and non-pain symptoms. They also identify necessary next steps for future research, such as defining an optimal treatment regimen
    Is it ready for attention from an editor, publisher or broader audience? Yes, after minor changes

    Competing interests

    The author declares that they have no competing interests.

    Use of Artificial Intelligence (AI)

    The author declares that they did not use generative AI to come up with new ideas for their review.

  2. Version published to 10.20944/preprints202510.0209.v1