Analgesic mechanisms of gabapentinoids and effects in experimental pain models: a narrative review

Abstract

The focus of perioperative pain management should be to attempt to minimise the nociceptive input and reduce the risk of transition to central sensitisation. Gabapentinoids are being increasingly used as adjuncts for management of perioperative pain. Although gabapentinoids are classed as calcium channel blockers, their mechanisms of action are poorly understood. The analgesic effect in neuropathic pain is well evidenced but the role in postoperative pain is less certain. Medline and EMBASE database searches were conducted to identify studies relating to mechanisms of action and effects in experimental animal models of inflammatory and postoperative pain and human models of experimental pain. The effects of gabapentinoids may be attributed to depression of dorsal horn sensitivity through a multitude of mechanisms. They inhibit calcium mediated neurotransmitter release through effects on α2δ-1 subunits. They inhibit forward trafficking of α2δ-1 from the dorsal root ganglion, their recycling from endosomal compartments, thrombospondin mediated processes and stimulate glutamate uptake by excitatory amino acid transporters. Mechanisms not directly related to neurotransmitter release at dorsal horn include inhibition of descending serotonergic facilitation, stimulation of descending inhibition, anti-inflammatory actions, and influence on the affective component of pain. Gabapentinoids are effective analgesics in most animal models of inflammation and postoperative pain but effects in human models are variable.

Preventive use of gabapentin to decrease pain and systemic symptoms in patients with head and neck cancer undergoing chemoradiation

“…22 In addition to its neuromodulator properties, gabapentin has anti-inflammatory effects. 23,24 Because of concerns related to the opioid crisis, researchers are investigating an expanded role for gabapentin by evaluating its potential as an opioidsparing agent in a variety of pain conditions. 25 For example, gabapentin decreases the need for opioid analgesics in the perioperative setting where it is now commonly used.…”

Neuropathic pain: new mechanisms of action of old drugs

“…Inhibition of CNS sensitization causes inhibition of calcium channels after administration of gabapentin and pregabalin (gabapentinoids), which reduce the sensitivity of the posterior horns of the spinal cord through several mechanisms [33]. Drugs from this group inhibit calcium transport, block the release of pronociceptive neurotransmitters by inhibiting the a2d-1 subunit and activate glutamate uptake by excitatory amino acid transporter proteins [34].…”

“…Zahamowanie sensytyzacji OUN powoduje hamowanie kanałów wapniowych po podaniu gabapentyny i pregabaliny (gabapentynoidy), które zmniejszają wrażliwość rogów tylnych rdzenia kręgowego poprzez kilka mechanizmów [33]. Leki z tej grupy hamują transport wapnia i blokują uwalnianie pronocyceptywnych neurotransmiterów poprzez zahamowanie podjednostki a2d-1 i aktywują wychwyt glutaminianu przez białka transporterów aminokwasów pobudzających [34].…”

Co-administration of Pregabalin and Curcumin Synergistically Decreases Pain-Like Behaviors in Acute Nociceptive Pain Murine Models

“…The α2-δ subunits of voltage-gated calcium channels (VGCCs) are distributed and expressed in the peripheral nerves of the dorsal root ganglia and the central nervous system (CNS) [ 5 , 6 ]. The administration VGCC antagonists, such as gabapentin and pregabalin, resulted in behavioral analgesia in both humans and animals [ 7 , 8 ]. In comparison to gabapentin, pregabalin is known to be more effective and has improved pharmacokinetic properties [ 9 ].…”