Gabapentin vs Pregabalin: Two Nerve Pain Medicines, One Real Difference

Both drugs are members of a small group of drugs known as gabapentinoids. Both work by binding to the alpha-2-delta subunit of the calcium channels on the membranes of nerve cells, which reduces the release of the chemical messengers that overactive nerves use to send pain signals.

The names of both drugs suggest that they work on GABA, the brain's main chemical messenger that has a calming effect on the brain. They do not. The product information for gabapentin in the UK states quite clearly that gabapentin has no affinity for either of the types of GABA receptors, and does not affect the metabolism of GABA. The names are an accident of chemistry, and any website that compares the two drugs and states that they boost GABA has copied this error.

Neither of these drugs is an opioid, nor does either work in the same way as paracetamol. Both of them act upon the nerves that have been damaged, which helps with the burning, shooting, electric-type pain that ibuprofen does nothing for.

The licences for both drugs are not the same, and this represents the first point of genuine difference between the two drugs.

Gabapentin is licenced in the EU and the UK for the treatment of epilepsy with focal seizures, both in combination with other anti-epileptic drugs and as a drug used on its own, as well as for the treatment of peripheral neuropathic pain in adults, such as painful diabetic neuropathy or the pain that lingers after shingles.

Pregabalin has a broader licence than gabapentin. Pregabalin is licenced for both peripheral and central neuropathic pain, meaning that it also covers nerve pain that originates within the brain or spinal cord. Pregabalin is also licenced as an add-on drug to treat focal seizures, as well as for the treatment of generalised anxiety disorder in adults. Gabapentin, however, does not have a licence for anxiety in the EU or the UK.

Here is the part worth understanding, because everything practical follows from it.

Gabapentin's entry into the bloodstream depends on a transporter in the gut that can only carry so much at a time. Increasing the dose saturates the transporter, limiting the fraction of the tablet that gets absorbed. The American label puts numbers on this: about 60 percent of a 900 mg daily dose is absorbed, dropping to about 27 percent at 4,800 mg a day. Doubling the dose does not double the amount absorbed. Two patients taking the same dose can absorb quite different amounts of the drug.

Pregabalin takes a different route into the bloodstream and is absorbed almost completely. The bioavailability of pregabalin is at least 90 percent of the dose, regardless of the dose amount. Blood levels of pregabalin rise in line with the dose. Pregabalin is also absorbed quickly, reaching the peak concentration in the bloodstream in about an hour when taken on an empty stomach, as opposed to gabapentin's two to three hours.

Pregabalin is the more potent molecule as well. Pregabalin is roughly two to six times stronger on a milligram for milligram basis depending on the measure used; a pharmacokinetic study indicated that the plasma-based figure was around two and a half times stronger. That is why pregabalin doses look small next to gabapentin doses. A 300 mg pregabalin capsule is considered to be a high dose. A 300 mg gabapentin capsule is a starting one.

Gabapentin for treating nerve pain begins with a three-day climb in the dosage; 300 mg once on the first day, twice on the second day, three times on the third day, and then the dose can be increased as needed up to a maximum of 3,600 mg per day in three divided doses. It can take several weeks for the gabapentin dose to provide relief to the patient with nerve pain, which is one of the reasons why patients give up on gabapentin before it has a chance to show its effectiveness. The familiar gabapentin 100mg and gabapentin 300mg capsule strengths exist for exactly this stepwise build.

Pregabalin starts at 150 mg daily, divided into two or three doses, but can go as high as 600 mg daily. Because the absorption of pregabalin is complete and predictable, the starting dose is the active dose for some individuals and the dose climb is shorter. Taking it twice a day is also easier than three times a day.

Both drugs leave the body in the same way. Neither is metabolised by the liver; both are excreted in the same form by the kidneys. This means that lower doses are required by individuals with reduced kidney function, and they are less likely to interact with other medications. Neither drug should be stopped abruptly; the product information for both requires a taper over at least one week, whatever it was prescribed for.

The side effect profiles are near twins. The European product information for pregabalin lists dizziness and somnolence as its very common effects, with weight gain and peripheral swelling as common ones; the SmPC for gabapentin lists the same four, dizziness, drowsiness, weight gain and oedema, at comparable frequencies.

There are plenty of articles that compare gabapentin and pregabalin and claim that the weight gain and swelling in the ankles that some people experience with pregabalin are problems that gabapentin does not cause. The labels of both drugs disagree. The difference in practice is mostly in timing: pregabalin's side effects arrive faster because the drug does, and for most people both settle after the first weeks at a steady dose.

In the UK both became Class C controlled drugs in April 2019, on the same day. In the United States, however, pregabalin is a federal Schedule V controlled substance while gabapentin remains unscheduled at the federal level, though some states have implemented their own controls over the drug.

Pregabalin attracts the tighter handling in part because of its rapid rate of absorption by the body. Pregabalin reaches its peak concentration in the blood more quickly than gabapentin, leading to greater potential for misuse of the drug. Published reviews of misuse confirm this, especially in individuals who also use opioids. In December 2019, the American regulator mandated the inclusion of warnings regarding breathing difficulties that can result from the combination of either drug with opioids or other sedating medicines, or from either drug being taken by people who already have breathing problems. Neither drug carries a boxed warning in the United States, whatever some pages claim, but the breathing risk is real, printed on both labels, and shared by both drugs.

There is no honest headline winner. Cochrane reviews of each drug in nerve pain find that both provide good relief for only a minority of those who take them, moderate relief for some more, and no worthwhile relief for over half of those who try either one. There are no head-to-head trials that demonstrate either drug as superior to the other, and the trials that have been undertaken of each drug measured different aspects of pain relief.

The choice between the two drugs is made according to the details outlined above. For instance, pregabalin may be preferred for those with central pain or anxiety, since gabapentin does not have a licence to treat those conditions. Gabapentin's slower build suits some patients fine, and it is less costly in many countries. Those who do not find relief from one drug may be switched to the other by their prescriber. That switch is a prescriber's job, not a self-directed experiment.