Voltage-gated calcium channels are composed of multi-subunit combinations of a large transmembrane-spanning, pore-forming α subunit, together with accessory β (cytosolic), γ (transmembrane), and α 2δ (transmembrane spanning) subunits ( Fig. However, we now know that both these drugs are likely to exert their mechanisms of action via binding to the α 2δ subunit of the voltage-gated calcium channel ( Rogawski and Brazil 2008, Thorpe and Offord 2010). For many years the pharmacological mechanism of action of these agents was unclear. Gabapentin and pregabalin are both derived from γ-aminobutyric acid (GABA) however, they have no activity against GABA receptors, channels, or transporters.

The follow-on, structurally related molecule pregabalin has now been approved for epilepsy, pain associated with diabetic neuropathy, post-herpetic neuralgia, and more recently, painful symptoms in patients with fibromyalgia ( Taylor 2009). Gabapentin was initially approved as an adjunctive medication for the treatment of partial seizures and subsequently for the treatment of neuropathic pain, including post-herpetic neuralgia. McMahon FMedSci, FSB, in Wall & Melzack's Textbook of Pain, 2013 Anticonvulsants with a Mechanism of Action Against Voltage-Gated Calcium Channels: Gabapentin and Pregabalin The NNTH (withdrawal because of adverse events) was 10 for pregabalin 600 mg/day. The most common adverse events were dizziness (two patients randomized to placebo versus 3, 9, and 14 patients randomized to the increasing doses of pregabalin), peripheral edema (2 versus 5, 9, and 10), and somnolence (1, 5, 4, and 8). In a double-blind, placebo-controlled, parallel-group, 395 adults with post-herpetic neuralgia were randomized to placebo or pregabalin 150, 300, or 600 mg/day (n = 96, 99, 99, and 101) adverse events caused withdrawal in 3, 5, 11, and 13 patients in the respective groups. About 9000 people have been exposed to pregabalin during development. There was weight gain in 14% of patients taking the highest dose, 600 mg/day. The commonest adverse reactions were dizziness (29%), somnolence (21%), ataxia (13%), weakness (11%), and weight gain of more than 7% (10%). In three multicenter randomized, double-blind, placebo-controlled studies in patients with refractory partial epilepsy pregabalin had an antiepileptic effect compared with placebo, as adjunctive therapy, 31–51% of patients having a 50% reduction in seizure frequency. Pregabalin has been evaluated in patients with chronic post-herpetic neuralgia, painful diabetic peripheral neuropathy, generalized anxiety disorder, and fibromyalgia syndrome, and as add-on treatment in refractory partial seizures. The adverse events that most often led to withdrawal of pregabalin were dizziness (2–8%), nausea (1–6%), vertigo (2–3%), and somnolence (0–4%). The most common adverse events in those taking pregabalin were dizziness, peripheral edema, weight gain (not affecting diabetes control), and somnolence. In a 12-week randomized, double-blind, multicenter, placebo-controlled, parallel-group study in patients with chronic post-herpetic neuralgia or painful diabetic peripheral neuropathy, the patients were randomized to placebo (n = 65) or to one of two pregabalin regimens: a flexible schedule of 150, 300, 450, or 600 mg/day with weekly dose escalation based on patients' individual responses and tolerability (n = 141) or a fixed schedule of 300 mg/day for 1 week followed by 600 mg/day for 11 weeks (n = 132). Somnolence was cited as the most common reason for discontinuing pregabalin. Withdrawal rates due to adverse reactions were 11%, 16%, and 32% with pregabalin (5–10% with placebo). The incidences of peripheral edema were 3%, 13%, and 19% with pregabalin (0–2% with placebo). The incidences of somnolence were 15%, 24%, and 25% (7% with placebo).

The incidences of dizziness with pregabalin 150, 300, and 600 mg/day were 12%, 28%, and 28% respectively (12–15% with placebo). Dizziness, somnolence, peripheral edema, headache, dry mouth, and diarrhea were the most common adverse events and were generally mild to moderate. It was generally well tolerated when force-titrated over 1 week to fixed dosages (maximum 600 mg/day) in trials that enrolled mostly elderly patients. Pregabalin was superior to placebo in relieving pain and improving pain-related sleep interference.

The safety of oral pregabalin 150–600 mg/day in three randomized, double-blind, placebo-controlled, multicenter studies in post-herpetic neuralgia lasting 8–13 weeks in a total of 779 evaluable patients has been reviewed. Aronson MA, DPhil, MBChB, FRCP, HonFBPhS, HonFFPM, in Meyler's Side Effects of Drugs, 2016 Neuropathic pain

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