Gabapentin and pregabalin: How do they help with pain?

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For chronic pain conditions, gabapentinoids (gabapentin & pregabalin) are often first-line treatments because of their effectiveness & safety. They bind to a2d which alters activity of calcium channels on nerves, thereby modulating pain signals before they reach the brain.

Pharmacology of gabapentinoids

The absorption of gabapentin & pregabalin differ.

Gabapentin absorption is slow. Beyond a certain dose, additional gabapentin will not be absorbed & instead pass through the intestine, causing diarrhea. Therefore, it is also inappropriate for patients with gastric bypass.

Pregabalin absorption is faster and does not have a maximum — the more taken, the more absorbed.

Both medications do not chemically interact with the liver or the kidney, and are eliminated via urine. For this reason they are comparatively safer non-opioid pain medications.

Effects of gabapentinoids

  • a2d is a subunit of voltage-gated calcium channels, which consist of one each of a, a2d, b subunits, each of which has at least 4 variants. Gabapentinoids bind to a2d1 and a2d2 and modulate pain intensity. For this reason they are helpful in neuropathic pain, fibromyalgia, post-herpetic neuralgia, restless leg syndrome, and post-surgical pain.
  • Synapse growth appears to be altered by gabapentinoids, independent of calcium channel effects.


  • The most important adverse effect to consider for gabapentinoids is cognitive, typically seen when the medication is started, and when it is taken at large doses. This includes reduced concentration & poor memory. This resolves after stopping the medication.
  • As with many neuropathic pain medications, gabapentinoids could worsened mood, including possibly suicidal thoughts. Patients with a history of mood disorder should be particularly cautious. Epidemiologically, young women are more affected by this.
  • Gabapentinoids sometimes in some patients can cause sedation, leg swelling & weight gain.
  • Patients who have struggled with addiction should note that gabapentinoids have abuse potential.