Introduction: Neuropathic Pain in Long COVID
As the global health system continues to grapple with the long-term consequences of COVID-19, chronic neurological symptoms have emerged as a major challenge for patients and clinicians alike. Among these, neuropathic pain, including burning sensations, tingling, and electric shock-like discomfort, is increasingly recognized in individuals experiencing post-acute sequelae of SARS-CoV-2 infection (PASC), commonly referred to as long COVID.
Estimates suggest that a significant subset of long COVID patients develop small fiber neuropathy (SFN) or related nerve dysfunction, often months after the initial infection. These symptoms are frequently resistant to standard analgesics and may severely impact quality of life. Even in patients who experienced only mild acute infection, lingering symptoms such as paresthesia, burning, and hypersensitivity may develop weeks or months later. These are consistent with small fiber neuropathy (SFN) a disorder of the thin, unmyelinated nerve fibers responsible for pain and temperature sensation.
In this context, medications like gabapentin, traditionally used for diabetic neuropathy and post-herpetic neuralgia, have attracted interest as off-label options for post-COVID neuropathic symptoms.
Though high-quality randomized trials are still limited, early case reports and clinical observations point to potential benefit.
This article explores the mechanisms, current evidence, and practical use of gabapentin in managing neuropathic pain related to long COVID.
Mechanisms of Post-COVID-19 Neuropathic Pain
The pathophysiology of neuropathic pain in long COVID remains an area of active investigation, but current findings suggest a multifactorial process involving both peripheral and central nervous system dysfunction.
SARS-CoV-2 is capable of inducing neuroinflammation, either through direct viral effects or via immune-mediated mechanisms. Even in patients who experienced only mild acute infection, lingering symptoms such as paresthesia, burning, and hypersensitivity may develop weeks or months later. These are consistent with small fiber neuropathy (SFN) a disorder of the thin, unmyelinated nerve fibers responsible for pain and temperature sensation.
Several mechanisms have been proposed:
- Cytokine dysregulation during and after acute infection, particularly involving IL-6, IL-1β, and TNF-α
- Microvascular injury leading to ischemic damage of peripheral nerves
- Autoimmune responses, including molecular mimicry triggering autoantibodies against neural structures
- Autonomic nervous system dysfunction, contributing to both pain and dysesthesias
Additionally, post-COVID patients may experience central sensitization, similar to fibromyalgia, where the pain-processing pathways in the brain become hyper-responsive.
Given this complex pathogenesis, it is unsurprising that conventional analgesics often provide limited relief. This underscores the potential value of neuromodulatory agents like gabapentin, which target neuronal excitability and aberrant pain signaling more directly than NSAIDs or opioids.
Gabapentin: Pharmacology and Mechanism of Action
Gabapentin is a structural analog of gamma-aminobutyric acid (GABA), though it does not bind to GABA receptors or directly influence GABAergic neurotransmission. Instead, its primary mechanism involves binding to the α2δ-1 subunit of voltage-gated calcium channels located on presynaptic neurons in the central nervous system. By modulating these calcium channels, gabapentin reduces the release of excitatory neurotransmitters such as glutamate, substance P, and norepinephrine. This action dampens neuronal hyperexcitability, which is a core feature of neuropathic pain. In effect, gabapentin interrupts aberrant pain signaling at both spinal and supraspinal levels.
In conditions like diabetic neuropathy and postherpetic neuralgia, this mechanism translates into reduced pain intensity, improved sleep, and decreased allodynia.
Given the mechanistic similarities with post-COVID neuropathic pain including central sensitization and peripheral nerve injury gabapentin is a logical candidate for symptom management in this context.
Gabapentin is orally administered and exhibits nonlinear pharmacokinetics. Its absorption depends on a saturable transport system in the gut, meaning higher doses may result in lower bioavailability. Clinically, this supports gradual dose titration to balance efficacy and tolerability.
Its lack of significant hepatic metabolism and minimal drug interactions make gabapentin a relatively safe option for many long COVID patients.
Evidence Base: Gabapentin Use in Post-COVID Neuropathic Pain
While high-quality randomized controlled trials (RCTs) on gabapentin in long COVID are still lacking, a growing body of case reports, observational data, and expert consensus supports its role in managing neuropathic symptoms.
A notable case study published in Neurology Reports (2024) describes a patient with post-COVID small fiber neuropathy (SFN) experiencing severe burning pain in the feet and lower legs. Treatment with gabapentin, titrated to 1,200 mg/day, led to a marked reduction in pain severity and improved sleep within four weeks. This outcome aligns with patterns seen in diabetic and chemotherapy-induced SFN.
The U.S. Pharmacist journal also highlights gabapentin and pregabalin as first-line agents for managing long COVID-related neuropathic pain, particularly when standard analgesics or physical therapy provide insufficient relief. The authors emphasize the value of targeting neuronal excitability in cases where paresthesia and sensory amplification dominate the clinical picture.
An overview in Practical Neurology further supports this view, suggesting gabapentinoids as reasonable off-label options for patients with persistent tingling, limb pain, or fibromyalgia-like presentations following COVID-19.
Importantly, while anecdotal success is encouraging, these findings underscore the need for prospective, controlled studies. Long COVID encompasses a heterogeneous patient population, and not all symptoms are neuropathic in origin. Nonetheless, when small fiber or central sensitization features are present, gabapentin offers a low-risk trial option for targeted neuromodulation. Clinicians should remain cautious, monitor closely, and document symptom trajectories to help guide future treatment frameworks.
Clinical Application: Dosing, Monitoring, and Patient Selection
Gabapentin is typically initiated at low doses to minimize side effects, especially in patients who are already fatigued or sensitive to sedating medications, which are common features in long COVID. A common starting dose is 100–300 mg at bedtime, with gradual upward titration every 3 to 5 days. Most patients with neuropathic pain respond to 900–1,800 mg/day, divided into two or three doses. In some cases, doses up to 3,600 mg/day are used, though benefits plateau and side effects increase at higher ranges.
Monitoring is essential. Sedation, dizziness, and cognitive clouding are the most common adverse effects, particularly during the titration phase. Peripheral edema and ataxia may also occur, especially in older adults or those with autonomic dysfunction.
Gabapentin may be especially useful in patients with documented or suspected small fiber neuropathy, persistent burning pain, tingling, or dysesthesias, after exclusion of other causes (e.g., B12 deficiency, diabetes, autoimmune neuropathies).
Importantly, gabapentin should be tapered gradually when discontinuing to prevent rebound symptoms, including insomnia or anxiety.
Clinical judgment is key, since gabapentin is not universally effective, but when matched to the right symptom profile, it can significantly improve pain control, sleep quality, and daily functioning in patients navigating the prolonged aftermath of COVID-19.
Gabapentin in the Context of Multimodal Therapy
Gabapentin is most effective when integrated into a multimodal treatment approach for long COVID, rather than used in isolation.
Patients with persistent post-COVID symptoms often experience a complex interplay of neuropathic pain, autonomic dysfunction, fatigue, mood disturbances, and cognitive impairment. For this reason, successful management typically involves combining pharmacologic therapy with supportive non-pharmacologic strategies.
Gabapentin may complement physical therapy programs focused on pacing and autonomic regulation, particularly in patients with orthostatic intolerance or post-exertional symptom exacerbation. When pain is accompanied by mood symptoms, it may be used alongside serotonin-norepinephrine reuptake inhibitors (SNRIs) or tricyclic antidepressants. Cognitive-behavioral therapy (CBT), sleep hygiene protocols, and somatic retraining can further enhance pain tolerance and reduce central sensitization.
In patients with fibromyalgia-like presentations, gabapentin’s neuromodulatory effect may help dampen symptom amplification, especially when integrated with mind-body therapies such as breathing regulation or vagal nerve stimulation. The key to success lies in individualizing therapy, aligning drug choice with the dominant pathophysiology, and supporting recovery through a coordinated, interdisciplinary care model. Gabapentin’s safety profile and versatility make it well-suited to this type of integrative framework.
Future Directions & Research Gaps
Despite encouraging early data, the use of gabapentin for post-COVID neuropathic pain remains off-label and under-researched.
Most available evidence comes from case reports and small observational studies, with a notable absence of large, randomized controlled trials (RCTs) specific to long COVID populations.
Future research should prioritize well-designed trials to assess gabapentin’s efficacy across diverse post-COVID symptom profiles, particularly in patients with confirmed small fiber neuropathy or central sensitization. Standardized diagnostic tools such as skin biopsies for nerve fiber density and quantitative sensory testing may help refine patient selection.
Another emerging opportunity lies in the use of digital health tools and wearable neurosensory monitors to objectively track pain response and autonomic function over time. These could help tailor dosing and identify early responders.
Understanding gabapentin’s role within combinatorial regimens alongside anti-inflammatory, antidepressant, or autonomic-targeted therapies will also be key to optimizing care for this heterogeneous patient population.
Conclusion: Practical Role of Gabapentin in Post-COVID Neuropathy
Gabapentin represents a rational, low-risk therapeutic option for managing neuropathic pain symptoms in selected long COVID patients.
Its mechanisms align with the pathophysiology of small fiber neuropathy and central sensitization, and early clinical use suggests meaningful benefit in pain reduction, sleep quality, and functional recovery.
While current evidence is preliminary, gabapentin can be considered as part of a personalized, multidisciplinary treatment plan, especially when standard analgesics fail to address burning, tingling, or sensory disturbances. Cautious dosing, close monitoring, and clear patient education are essential.
Until more robust clinical trials emerge, gabapentin offers a clinically practical tool not as a cure, but as a stabilizing agent in the complex rehabilitation landscape of post-COVID care.
References
- Bisaccia, G., Proietti, L., D’Aprile, M., Pellegrino, F., Ricci, F., & Tartaglia, F. (2023). Strategies for mitigating the neurologic impact of long COVID. U.S. Pharmacist. Retrieved July 24, 2025, from https://www.uspharmacist.com/article/strategies-for-mitigating-the-neurologic-impact-of-long-covid
- Bagella, C. F., Paolucci, L., De Vitis, R., Gagliardi, G., Scalise, A., & Nistri, A. (2024). Gabapentinoids in the treatment of post-COVID-19 small fiber neuropathy: A case-based perspective. Neurology International, 5(2), 24. https://doi.org/10.3390/neurolint5020024
- Prasad, A., & Whetstone, W. D. (2023). Long-term neurologic complications of COVID-19: A practical overview. Practical Neurology. Retrieved July 24, 2025, from https://practicalneurology.com/diseases-diagnoses/imaging-testing/long-term-neurologic-complications-of-covid-19-a-practical-overview/32150/