Gamma-aminobutyric acid analogs

To understand what gamma-aminobutyric acid (GABA) analogs are, we first need to understand what GABA is.

GABA is an amino acid that is one of the most important neurotransmitters (chemical messengers) that we have in our nervous system. It is essential for maintaining the balance between nerve cell excitation and nerve cell inhibition. GABA acts like a brake in a car and slows down nerve cells that are over-excited. Because it calms the nervous system, it is called an inhibitory neurotransmitter.

GABA analogs are medicines that have a very similar structure to GABA but act in a different way, although experts aren’t exactly sure how they work. Most agree they bind to calcium-channels within the nerve cells, improving how well brain cells respond to GABA or making the release of GABA easier.

When we have a problem with GABA in our brain, nerve cells fire more than they should, putting our brain in an excitatory state. This can lead to anxiety and feelings of panic, stress, restlessness, or irritability; a decreased tolerance for pain; a fast heart rate; high blood pressure; insomnia; and occasionally seizures.

GABA analogs were designed because it is difficult to administer GABA itself (previous attempts at developing an intravenous or oral GABA drug have been unsuccessful). To resolve this problem, GABA analogs were developed. These help to restore levels of GABA and calm down nerve firing.

What are GABA analogs used for?

GABA analogs may be used to treat certain conditions associated with rapid nerve firing. Examples include:

• Fibromyalgia
• Nerve pain (neuropathy) resulting from diabetes, amputation, shingles, or another cause
• Restless legs syndrome (gabapentin enacarbil is a treatment option)
• Seizures and epilepsy.

Another GABA analog, acamprosate, may also be used to help restore the balance of neurotransmitters in an alcohol-dependent person who has recently quit drinking.

What are the differences between gamma-aminobutyric acid analogs?

There are differences between the GABA analogs with regards to how fast they work in the body, how they influence GABA, and their effectiveness in treating specific conditions.

Gabapentin enacarbil is a prodrug of gabapentin and was designed to overcome the limitations of gabapentin (gabapentin is poorly absorbed and only lasts for a short duration of time).  Liver enzymes convert gabapentin enacarbil it into its active form, gabapentin. Gabapentin enacarbil may be used for the treatment of restless legs syndrome (RLS) and postherpetic neuralgia (nerve pain that occurs following Shingles). Gabapentin and gabapentin enacarbil are not interchangeable.

Although pregabalin and gabapentin are structurally similar, the way, the extent, and the speed at which they are absorbed are very different, with pregabalin being almost completely absorbed and gabapentin only partially. Both gabapentin and pregabalin are indicated as add-on therapy for partial seizures and postherpetic neuralgia. Pregabalin may also be used for the management of fibromyalgia and diabetic neuropathy and is listed as a Schedule V controlled substance, meaning it has proven potential for abuse and dependence, but at a relatively low level.

Acamprosate is only indicated alongside behavioral modification and counseling in people who have stopped drinking, to reduce the desire to keep drinking.

Are GABA analogs safe?

When taken at the recommended dosage, GABA analogs are considered safe. However, they have been associated with a few serious, potentially fatal severe side effects such as:

• A severe allergic reaction causing anaphylaxis or angioedema. Symptoms include facial and throat swelling, difficulty breathing, and low blood pressure
• An increase in suicidal thoughts or behaviors in people taking these medicines for any relevant condition
• Multiorgan sensitivity (this is known as DRESS or Drug Reaction with Eosinophilia and Systemic Symptoms) and is potentially life-threatening. Symptoms usually include fever, a rash, and swollen lymph nodes; several internal organs may be affected
• Some GABA analogs (eg, gabapentin, pregabalin) have been associated with an increased risk of tumors in animal studies. The significance of these findings in humans is not known
• An increased risk of seizures if GABA analogs are abruptly stopped in people with seizure disorders. GABA analogs should be withdrawn slowly
• Sudden and unexplained death in people with epilepsy, although the incidence is within the range of people with epilepsy not receiving GABA analogs
• Acute kidney failure has been associated with acamprosate use, and this GABA analog should not be used in people with poor kidney function.

What are the side effects of GABA analogs?

Not everybody experiences significant side effects with GABA analogs, although dizziness and drowsiness are common. Other commonly reported side effects include:

• Agitation and other neuropsychiatric reactions (such as behavioral problems, hostility, hyperactivity, restlessness). More commonly reported in children
• Ataxia (a lack of voluntary coordination of muscle movements)
• Anxiety
• Depression
• Dry mouth
• Fatigue
• Gastrointestinal upset (such as diarrhea or constipation, nausea, or vomiting)
• A headache
• Nystagmus (repetitive, uncontrolled eye movements) and other eye disorders
• Pain (including back pain, chest pain, muscle and joint pain, and stomach pain)
• Peripheral edema (swelling of the lower legs and feet)
• Sexual dysfunction (such as reduced desire or erectile dysfunction)
• Teeth grinding
• Tremor
• Weight gain.

For a complete list of side effects, please refer to the individual drug monographs.