General Description

Gabapentin is an analgesic medication commonly used for neuropathic pain. It exerts its effects through various mechanisms of action, including the inhibition of voltage-gated calcium channels (VGCCs) and disruption of α2δ-1-NMDAR complexes. By reducing the release of excitatory neurotransmitters and blocking synaptogenesis, gabapentin helps alleviate neuropathic pain. It is approved for conditions like postherpetic neuralgia and diabetic peripheral neuropathy, but its off-label use for non-neuropathic pain management raises concerns regarding its effectiveness. Gabapentin may have side effects, including potential breathing problems, mood changes, and drowsiness. It should be used with caution and not abruptly discontinued without consulting a doctor.

Figure 1. Tablets of gabapentin

Mechanism of action

Gabapentin exerts its analgesic effects through various mechanisms of action. Initially, it was believed that gabapentin acted on neuronal voltage-gated Ca2+ channels (VGCCs) via the α2δ subunit, resulting in reduced release of excitatory neurotransmitters. The α2δ-1 subunit, highly expressed in the dorsal root ganglion (DRG) and spinal dorsal horn, is upregulated in neuropathic pain and correlates with allodynia. This supports gabapentin's clinical use for neuropathic pain. Gabapentin also binds to the α2δ-2 subunit, but its analgesic effect is limited. The α2δ-2 subunit is predominantly expressed in the cerebellum and brainstem and is involved in corticospinal plasticity and regeneration after spinal cord injury. Recent studies challenged the notion that VGCCs are the primary targets of gabapentin. Instead, gabapentin has been found to disrupt the formation of hyperactive α2δ-1-NMDAR complexes, reducing neuropathic pain. These NMDA receptors play a crucial role in synaptic plasticity and neuropathic pain. Additionally, gabapentin inhibits astrocyte-derived thrombospondins (TSPs), which induce the formation of new synapses and contribute to chronic pain after neuronal injury. By inhibiting TSPs via α2δ-1, gabapentin blocks synaptogenesis and reduces excitatory presynaptic input. The effects of gabapentin on synaptogenesis depend on the postsynaptic target and can enhance or reduce analgesia. It's important to note that gabapentin's efficacy may be influenced by other factors and actions. For example, the timing of administration is crucial for blocking TSP4-α2δ-1, and delayed treatment has no effect. Overall, gabapentin's mechanisms of action involve VGCC inhibition, disruption of α2δ-1-NMDAR complexes, and inhibition of TSPs. These multiple targets contribute to its analgesic properties and provide a basis for its use in managing neuropathic pain. ¹

Clinical applications

Gabapentin and pregabalin have a well-established clinical application in treating neuropathic pain. They were approved by the FDA in 2002 and 2004, respectively, for postherpetic neuralgia (PHN) and diabetic peripheral neuropathy (DPN). However, a significant portion of their use is off-label. The opioid crisis and reduced opioid prescribing have led to the substitution of gabapentinoids for non-neuropathic pain management. However, there is currently no clear evidence supporting the medical effectiveness of this policy. The increasing use of gabapentinoids for non-neuropathic pain raises concerns among healthcare professionals. Furthermore, it is important to recognize that gabapentinoids have a significant side effect profile beyond the common symptoms such as dry mouth, nausea, and altered bowel function. Safety concerns arise when they are combined with other drugs, particularly benzodiazepines and opioids. Altered behavior, abuse, misuse, and diversion are also emerging issues associated with gabapentinoid use. In summary, while gabapentin and pregabalin are approved for neuropathic pain, their off-label use for non-neuropathic pain management raises concerns regarding effectiveness. ²

Side effects

Gabapentin, a medication used to treat various conditions, may have certain side effects that should be closely monitored. It is important to note that gabapentin can potentially cause life-threatening breathing problems, particularly if the individual already has a breathing disorder or is using other medications that can induce drowsiness or slow breathing. If very slow breathing occurs, immediate medical attention should be sought. Additionally, some individuals may experience thoughts of suicide while taking gabapentin or other seizure medications. Therefore, it is crucial to remain vigilant for any changes in mood or symptoms. Any sudden alterations in mood or behavior, as well as thoughts of suicide, should be reported to a doctor promptly. Seizures could potentially increase if gabapentin is abruptly discontinued, so it is advisable to consult with a doctor before stopping the medication. Furthermore, until the effects of gabapentin are known, it is recommended to avoid driving or engaging in hazardous activities. Dizziness or drowsiness associated with the medication may lead to falls, accidents, or severe injuries. Lastly, it is important not to discontinue gabapentin suddenly, even if feeling well. ³

Reference

1. Russo M, Graham B, Santarelli DM. Gabapentin-Friend or foe? Pain Pract. 2023 Jan;23(1):63-69.

2. Evoy KE, Sadrameli S, Contreras J, Covvey JR, Peckham AM, Morrison MD. Abuse and Misuse of Pregabalin and Gabapentin: A Systematic Review Update. Drugs. 2021 Jan;81(1):125-156.

3. Bonnet U, Scherbaum N. How addictive are gabapentin and pregabalin? A systematic review. Eur Neuropsychopharmacol. 2017 Dec;27(12):1185-1215.