Retigabine, known by its U.S. brand name Ezogabine and European name Trobalt, was an anticonvulsant medication. It received approval from the European Medicines Agency in March 2011 and the U.S. Food and Drug Administration (FDA) in June 2011. Developed as an additional treatment option for adults with specific types of seizures, it was globally withdrawn from the market in June 2017.
Mechanism of Action
Brain neurons communicate via electrical signals, regulated by ion channels. These specialized proteins control the flow of charged particles, like potassium ions, across cell membranes. Retigabine uniquely opened specific potassium channels, primarily targeting the KCNQ (Kv7) family (KCNQ2-5), abundant in neurons.
This made retigabine the first medication of its kind to function as a neuronal potassium channel opener for epilepsy treatment. It worked as a positive allosteric modulator, binding to a specific site on the channel to stabilize its open form and shift voltage dependence.
By keeping these potassium channels open, retigabine enhanced the brain’s natural inhibitory forces. This stabilized the resting membrane potential of neurons, making them less excitable. The drug prevented the excessive and rapid firing of electrical signals, known as epileptiform activity, that can lead to seizures.
Clinical Application and Efficacy
Retigabine was approved as an adjunctive therapy for adults with partial-onset seizures. It was used in combination with other anti-epilepsy medications, not as a standalone treatment. It targeted patients aged 18 or older with drug-resistant partial seizures who had not responded to or tolerated other therapies.
Clinical trials demonstrated its effectiveness in reducing seizure frequency. One study showed a median reduction of 23% to 35% in monthly seizure frequency for retigabine patients (600-1200 mg/day), versus 13% for placebo. Another trial reported a 44.3% median reduction for retigabine-treated patients compared to 17.5% for placebo.
The proportion of patients experiencing at least a 50% reduction in seizure frequency, known as the responder rate, showed positive results. Responder rates for retigabine ranged from 23% to 33% depending on dose, compared to 16% for placebo. A separate trial reported a 44.4% responder rate for retigabine versus 17.8% for placebo.
Adverse Effects and Safety Concerns
Retigabine was associated with several adverse effects, both common and serious. Common side effects included dizziness, drowsiness, confusion, fatigue, speech disorder, blurred vision, tremor, and coordination problems. These central nervous system effects were often dose-dependent.
More concerning were the unusual and serious adverse effects that prompted significant safety warnings. Retigabine could cause a distinctive blue-gray discoloration of the skin, lips, and nails. Additionally, it was linked to pigmentary abnormalities in the retina, the light-sensitive tissue at the back of the eye, which raised concerns about potential vision loss. The FDA issued a black box warning, the most stringent safety warning, in 2013 to highlight these risks.
The drug also carried a risk of acute urinary retention, a condition where the bladder cannot empty completely. This issue was observed in clinical trials, with urinary or renal symptoms reported in approximately 25% of patients receiving the highest dose of retigabine, compared to about 13% in the placebo group. Monitoring for urological symptoms was advised, especially for patients with pre-existing bladder conditions or those taking certain other medications.
Market Withdrawal and Legacy
Retigabine was voluntarily withdrawn from the market worldwide by GlaxoSmithKline (GSK) in June 2017. The primary stated reasons were commercial, citing limited usage and declining new patient initiations. While efficacious, its serious side effects significantly impacted its commercial viability and widespread adoption.
The blue-gray skin discoloration, retinal pigment changes, and the risk of urinary retention necessitated intensive monitoring for patients, which contributed to its limited use. Despite the manufacturer’s statement that the withdrawal was not for reasons of efficacy or safety, the safety concerns played a role in the low commercial prospects. The requirement for extensive monitoring and the black box warning made it a less attractive option for both prescribers and patients.
Despite its market failure, retigabine left a notable legacy by validating a novel therapeutic target for epilepsy. Its unique mechanism of action, specifically the opening of potassium channels, demonstrated a new approach to controlling neuronal excitability. This proof-of-concept has inspired ongoing research into developing safer and more selective potassium channel openers for the treatment of epilepsy and other neurological conditions, such as neuropathic pain and tinnitus.