Gabapentin is an anticonvulsive medication primarily used to prevent and control seizures and certain kinds of neuropathic pain, such as nerve pain after shingles and diabetic neuropathy. It was approved by the FDA in 1993 and was initially used to treat muscle spasms before its anticonvulsive properties were discovered.1 In addition to its FDA-approved indications, among which is also moderate to severe restless leg syndrome, the drug has several off-label uses, including in the treatment of bipolar disorder, alcohol withdrawal, anxiety and depression, and as a migraine prophylaxis.1 In anesthesia, gabapentin has been investigated for the management of postoperative pain.2 The pharmacology of gabapentin leads to its multifaceted use.
Gabapentin has a molecular structure similar to that of the neurotransmitter gamma-aminobutyric acid (GABA), which blocks signals in the central nervous system (CNS). However, it does not exert its effects by interacting with GABA receptors. Instead, gabapentin binds to the α2δ subunit of voltage-gated calcium channels in the CNS, which inhibits calcium influx into neurons.1 This in turn reduces the release of neurotransmitters such as glutamate and norepinephrine, thereby diminishing the excitation of neurons. Because neuronal excitability is a key component of conditions like epilepsy and neuropathic pain, gabapentin can limit their effect and duration.
The exact pharmacology of gabapentin’s clinical effects, however, is not fully understood, and the binding of gabapentin to voltage-gated calcium channels appears to be only one of several mechanisms involved in the drug’s activity. Some research suggests that gabapentin affects expression levels of Ca2+/calmodulin-dependent protein kinase II (CaMKII), a protein abundant in the synapses of excitatory neurons.3 In one study, rats undergoing chronic constriction injury were given either gabapentin or saline. Gabapentin not only reduced pain sensitivity but also reduced the expression and phosphorylation of CaMKII in the spinal cord of these rats.4 Gabapentin also has anti-inflammatory effects. In vitro studies of both rat and human cells have shown that gabapentin can counteract the effects of a transcription factor called NF-κB that is involved in the development of inflammation.5 The final known facet of gabapentin’s pharmacology is its interaction with adenosine A1 receptors, a class of receptors involved in the excitement of neurons and neurotransmitter release.5
The use of gabapentin with anesthesia is less well defined. It had once been assumed that gabapentin administered before an operation could lower post-operative pain. In one study, patients receiving gabapentin one hour before abdominal surgery had an enhanced analgesic effect from the pain relief medication tramadol.6 However, a greater body of research seems to suggest that gabapentin is not useful, and potentially harmful, when used in this context. A 2020 review by the Canadian Perioperative Anesthesia Clinical Trials Group conducted a meta-analysis of 281 trials that studied the perioperative use of gabapentin and gabapentin analogues (gabapentinoids).2 The researchers did not find that gabapentin led to a significant analgesic effect, but saw that patients given gabapentin experienced greater rates of dizziness and visual disturbances following surgery. According to a concurrent paper describing the findings of the review, “It is now clear that over the past two decades, evidence of benefit from routine perioperative administration of gabapentinoids has diminished, while evidence of harm has increased.”7
Regardless of its shortcomings in anesthesia, gabapentin is an important medication that may have more indications than currently established, thanks to its pharmacology. Further research can clarify the benefits and risks of its use in different clinical scenarios.

References

1. Gabapentin – StatPearls – NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK493228/.

2. Verret, M. et al. Perioperative Use of Gabapentinoids for the Management of Postoperative Acute Pain: A Systematic Review and Meta-analysis. Anesthesiology 133, 265–279 (2020), DOI: 10.1097/ALN.0000000000003428

3. Rostas, J. A. P. & Skelding, K. A. Calcium/Calmodulin-Stimulated Protein Kinase II (CaMKII): Different Functional Outcomes from Activation, Depending on the Cellular Microenvironment. Cells 12, 401 (2023). DOI: 10.3390/cells12030401

4. Ma, L.-L., Liu, W., Huang, Y.-G., Yang, N. & Zuo, P.-P. Analgesic effect of gabapentin in a rat model for chronic constrictive injury. Chin. Med. J. (Engl.) 124, 4304–4309 (2011), PMID: 22340405

5. Rusciano, D. Molecular Mechanisms and Therapeutic Potential of Gabapentin with a Focus on Topical Formulations to Treat Ocular Surface Diseases. Pharmaceuticals 17, 623 (2024), DOI: 10.3390/ph17050623

6. Parikh, H. G., Dash, S. K. & Upasani, C. B. Study of the effect of oral gabapentin used as preemptive analgesia to attenuate post-operative pain in patients undergoing abdominal surgery under general anesthesia. Saudi J. Anaesth. 4, 137–141 (2010), DOI: 10.4103/1658-354X.71409

7. Kharasch, E. D., Clark, J. D. & Kheterpal, S. Perioperative gabapentinoids: Deflating the bubble. Anesthesiology 133, 251–254 (2020), DOI: 10.1097/ALN.0000000000003394