Pregabalin (Lyrica)

Pregabalin (brand name Lyrica) is a gabapentinoid, a compound from the same family as gabapentin. Chemically it is a derivative of the amino acid GABA. That name misleads people all the time: pregabalin does not bind GABA receptors and does not behave like a GABA agent in any other way either. It was developed as the successor to gabapentin with one clear goal, getting rid of gabapentin's unpredictable absorption.

Clinically, pregabalin is approved in the EU for neuropathic pain, as add-on for focal seizures and for generalized anxiety disorder. In the US it is additionally approved for fibromyalgia. Its defining feature, though, is not the breadth of indications but the pharmacokinetics: linear, fast and liver-free. In a research context that is why pregabalin often serves as the reference gabapentinoid.

This entry covers pregabalin as a tablet with 50, 300 or 450mg of active ingredient, in blisters of 10 (50 and 300mg) or 15 tablets (300 and 450mg).

This information is for research and educational purposes only. No medical advice.

Pregabalin binds the alpha-2-delta subunit of voltage-gated calcium channels located at nerve terminals. That subunit helps govern how many channels sit in the membrane and how much calcium enters during an action potential. Less calcium influx means less release of excitatory messengers such as glutamate, noradrenaline and substance P. Pregabalin and gabapentin share this mechanism (Bockbrader et al. 2010).

The effect is largest where neurons fire in an overexcited state: in sensitized pain pathways, in an epileptic focus or in anxiety circuits. In a quiet system little happens. That also explains why the effect on pain or anxiety is not there after an hour, even though plasma levels already are, but builds over days.

What pregabalin does not do: it does not bind GABA-A or GABA-B, does not alter GABA uptake and is not a sodium channel blocker. The sedation many people experience comes from dampened excitatory transmission, not from a benzodiazepine-like mechanism.

Bockbrader and colleagues (Clinical Pharmacokinetics 2010) put the two gabapentinoids side by side. Gabapentin is absorbed through a saturable transporter, its absolute bioavailability falls from 60 to 33 percent as the daily dose rises from 900 to 3600mg. Peak concentration arrives only after 3 to 4 hours. Pregabalin reaches its plasma peak within about an hour and absorption is linear. Bioavailability stays at 90 percent or more no matter the dose. Double the dose, double the level.

• Plasma proteins: no binding.
• Liver: no metabolism, no inhibition or induction of CYP enzymes. Interactions via the hepatic route practically do not exist.
• Food: can be taken with or without a meal, total absorption does not change.
• Elimination: renal, unchanged, elimination half-life around 6 hours. Levels are therefore stable after one to two days of steady dosing.

The flip side of pure renal elimination was measured by Randinitis and colleagues (Journal of Clinical Pharmacology 2003) in 38 people across the range of kidney function plus 12 dialysis patients: total and renal clearance fall in proportion to creatinine clearance. Area under the curve and half-life rise accordingly. Hemodialysis removes a large share of the drug. If you do not know your kidney function, you do not know your actual exposure.

The densest evidence is in neuropathic pain. Derry and colleagues (Cochrane 2019) analysed 45 randomized, double-blind trials with 11,906 participants at 150, 300 and 600mg per day. In postherpetic neuralgia, 50 percent on 300mg achieved at least a 30 percent pain reduction versus 25 percent on placebo; on 600mg it was 62 versus 24 percent. At 300mg, roughly four participants corresponded to one additional person with a noticeable benefit (NNT 3.9). In painful diabetic neuropathy the effect was far smaller (47 versus 42 percent on 300mg). In HIV neuropathy there was no benefit. The authors' summary: some derive substantial benefit, more derive moderate benefit and many get nothing or discontinue. Serious adverse events were no more frequent than on placebo in the trials.

In generalized anxiety disorder, Generoso and colleagues (International Clinical Psychopharmacology 2017) pooled eight randomized trials with 2,299 participants. Pregabalin beat placebo with a Hedges g of 0.37, a small to moderate effect size, with no sign of publication bias and no meaningful heterogeneity between trials. Dropout rates did not differ from placebo. In clinical response pregabalin sat roughly level with benzodiazepines, with fewer dropouts.

Bockbrader and colleagues (2010) rank the analgesic potency such that 450mg pregabalin per day corresponds roughly to the predicted maximum effect of gabapentin. They see a possible edge for pregabalin as an antiepileptic. Honest summary: the kinetics are what set pregabalin apart from gabapentin. The effect sizes are solidly documented but moderate. They depend heavily on whether someone belongs to the responders.

• Dizziness and somnolence: the two most common reports, clearly dose-dependent. In the Cochrane review for postherpetic neuralgia, 29 percent dizziness and 16 percent somnolence on 300mg, 35 and 25 percent on 600mg, versus 8 and 6 percent on placebo. Strongest in the first days and after every increase. Reaction time and fitness to drive are directly affected.
• Weight gain and fluid retention: regularly reported in the registration data, rising with dose. Swollen ankles are not a reason for diuretics but a hint about the dose.
• Blurred vision, dry mouth, trouble concentrating: common, mostly mild and receding.
• Abuse and dependence: Evoy and colleagues (Drugs 2017) reviewed 59 studies. In the general population the prevalence of gabapentinoid abuse was 1.6 percent, among opioid users between 3 and 68 percent. An international database counted 11,940 reports between 2004 and 2015, more than three quarters of them from 2012 onwards. Risk factors are psychiatric comorbidity and a substance history, especially with opioids. Pregabalin is increasingly found in post-mortem toxicology.
• Combination with opioids, benzodiazepines and alcohol: the depressant effects add up, as far as respiratory depression. That is the route by which gabapentinoids feature in fatalities. Drug regulators have warned explicitly about it since 2019.
• Withdrawal: after an abrupt stop, insomnia, nausea, headache, restlessness, sweating and diarrhea are described. Taper over at least one week.
• Mood: as for all antiepileptics there is a class warning about suicidal thoughts. New or worsening low mood is a reason to reconsider use.
• Kidney function: because elimination is almost entirely renal, exposure multiplies with impaired kidneys unless the dose is adjusted. See dosing.
• Pregnancy and breastfeeding: per the prescribing information only to be used if clearly necessary. Pregabalin passes into breast milk. Malformation data are sparse and contradictory. A small additional risk cannot be ruled out.
• Legal status: classified as a controlled substance in the UK since 2019 and in the US, prescription-only in Germany. Check the situation where you live.

Rare but documented: angioedema and hypersensitivity reactions, with a higher risk in combination with ACE inhibitors. Swelling of the face, mouth or throat is a reason to stop immediately and seek medical assessment.

Store dry, at room temperature and protected from light. Leave tablets in the blister until you need them and keep them out of reach of children. Pregabalin is chemically stable, but use split tablets promptly rather than leaving halves around for weeks.