Alpha₂delta ligands, gabapentin, pregabalin and mirogabalin: a review of their clinical pharmacology and therapeutic use

Abstract

The first two alphadelta ligands - gabapentin (GBP) and pregabalin (PGB) - were initially synthesized as antiepileptics; however, they were later also found to be useful for the treatment of additional conditions. Areas covered: Relevant publications describing potential underlying mechanisms, clinical pharmacokinetics/pharmacokinetics, and clinical efficacy and safety of these drugs in various disease conditions were searched in PubMed and Scopus and included in this review. Expert commentary: GBP and PGB are effective for the treatment neuropathic pain, fibromyalgia and epilepsy; in addition, they may be useful for the reduction of postoperative pain. PGB is also effective for the treatment of generalized anxiety disorder and GBP for the treatment of restless legs syndrome. GBP may be considered a treatment option for pain associated with Guillain-Barré Syndrome and phantom limb and for the management of uremic pruritus. Mirogabalin (MGB), recently developed, is being investigated for the treatment of peripheral neuropathic pain and fibromyalgia, showing promising results in patients with diabetic peripheral neuropathy. Their most frequent adverse reactions are of neuropsychiatric nature and include fatigue, dizziness, sedation, somnolence, and ataxia; peripheral edema and weight gain are also frequently described. Pharmacokinetic interactions are scarce; however, pharmacodynamic interactions have been described in association with drugs with CNS-depressant effects.

Modulation of NMDA Receptor Activity in Fibromyalgia

“…Glutamate reduction in relevant pain-related brain regions in fibromyalgia patients is seen with pregabalin [9,52], with beneficial clinical effects likely to involve changes in NMDAR function in brain and spinal cord due to less synaptic glutamate being available to facilitate receptor activation. Pregabalin also decreases synaptic substance P and noradrenaline, and has other central effects relevant to fibromyalgia management, including improvement in sleep quality and anxiety [53]. The clinical effects of these drugs in fibromyalgia are not the main subjects of this review.…”

Rising pregabalin use and misuse in Australia: trends in utilization and intentional poisonings

“…Gabapentinoids designed were originally as GABA-mimetics [21], but they were not found to directly bind GABA receptors, instead binding the α2-δsubunit of voltage-gated calcium channels. Gabapentinoids designed were originally as GABA-mimetics [21], but they were not found to directly bind GABA receptors, instead binding the α2-δsubunit of voltage-gated calcium channels.…”

Tricyclic Antidepressant and/or γ‐Aminobutyric Acid–Analog Use Is Associated With Fall Risk in Diabetic Peripheral Neuropathy

“…The anticholinergic side effects of TCAs include drowsiness, blurred vision, dizziness, somnolence, and confusion . GABA analogs also increase dizziness and somnolence; however, the mechanism by which this occurs is unknown . Lastly, SNRIs increase somnolence and dizziness in addition to decreasing bone density, resulting in increased risk of falls and fractures, respectively .…”