OVERVIEW

Introduction

Pregabalin is an inhibitor of neuronal activity used for therapy of painful neuropathy and as an anticonvulsant. Therapy with pregabalin is not associated with serum aminotransferase elevations, and clinically apparent liver injury from pregabalin has been reported but appears to be quite rare.

Background

Pregabalin (pre gab' a lin) is a structural analogue of gamma-aminobutyric acid (GABA) but is novel in its activity, having no effects on GABA-A or GABA-B receptors. Instead, the neuronal activity of pregabalin appears to be mediated by its binding to the alpha-2-delta subunit of the presynaptic voltage-gated calcium channel which leads to a decrease in release of neuroexcitatory neurotransmitters by hyperexcited neurons. Pregabalin has been shown to be effective in reducing neuropathic pain from diabetic and postherpetic neuropathy and is an effective anticonvulsant. Pregabalin was approved for use in the United States in 2004. Current indications include diabetic and post-herpetic neuropathy and as adjunctive therapy of partial onset seizures. Pregabalin is also used for fibromyalgia and off-label for generalized anxiety disorders and migraine. Pregabalin is available in capsules in varying concentrations from 25 to 300 mg under the brand name of Lyrica. The recommended initial dose for neuropathic pain is 50 to 75 mg two to three times daily, the maximum dose being 300 mg daily. Higher doses are used in treating seizures. The dose should be increased and tapered gradually. The most common side effects of pregabalin are dose related and include peripheral edema, weight gain, dizziness, somnolence, confusion, headache, blurred vision, tremor and ataxia. Rare but potentially severe adverse events include depression, suicidal ideation and behaviors, angioedema, and hypersensitivity reactions.

Hepatotoxicity

Limited data is available on the hepatotoxicity of pregabalin. In prelicensure clinical trials in diabetic neuropathy and epilepsy, therapy with pregabalin was not associated with an increased frequency of serum aminotransferase elevations or liver toxicity. Since its approval and more wide scale use, however, pregabalin has been linked to rare instances of clinically apparent liver injury. Most cases were mild and frequently without jaundice. The latency to onset of injury was short, symptoms of liver injury arising within 3 to 14 days. Both cholestatic and hepatocellular patterns of injury have been reported. Signs of hypersensitivity (fever, rash, eosinophilia) and autoimmunity were not present. Some cases have been severe and associated with marked jaundice and prolongation of the prothrombin time, but all cases ultimately resolved after the medication was stopped without evidence of residual injury.

Likelihood score: C (probable rare cause of clinically apparent liver injury).

Mechanism of Injury

The low rate of significant hepatotoxicity from pregabalin may be due to its minimal hepatic metabolism and rapid urinary excretion. The injury is clearly idiosyncratic and either immunologic or metabolic causes are possible.

Outcome and Management

The case reports of hepatic injury due to pregabalin were followed by complete recovery without evidence of residual or chronic injury. There is no information about cross reactivity with other compounds having similar structure (gabapentin).

Drug Class: Anticonvulsants

CASE REPORT

Case 1. Mild cholestatic hepatitis attributed to pregabalin therapy.(1)

A 61 year old man underwent laminectomy for spinal stenosis and was started on pregabalin 2 weeks later. Within 2 days he developed dizziness, blurred vision, somnolence and fatigue, which worsened when the dose was increased from 75 to 150 mg/day one week later. Because of persistence of symptoms, blood tests were taken 11 days after starting therapy which revealed moderate enzyme elevations (Table). The patient had a history of hypertension and gout for which he took amlodipine (5 mg/day), candesartan (16 mg/day) and allopurinol (100 mg/day) chronically. Before the laminectomy, serum enzymes were tested and were normal. After surgery, he received metamizole (an NSAID not available in the US) for five days. Physical examination showed no jaundice, rash or signs of chronic liver disease. Tests for hepatitis A, B, C, D, and E, for HIV and for autoantibodies were negative. Abdominal ultrasound and MRCP were normal. Pregabalin was stopped and all symptoms except for mild fatigue, resolved rapidly. Reintroduction of pregabalin a few days later led to an immediate return of symptoms, but blood tests were not taken during the rechallenge. The abnormal enzyme values rapidly improved once pregabalin was stopped and were normal two months later.

Key Points

Laboratory Values

Comment

Other causes of acute liver disease were excluded. The rechallenge was somewhat convincing, but the role of pregabalin in causing liver injury was not completely proven because of the lack of testing immediately before and after the two day rechallenge (on days 13-14 after starting). Based on the “R” value, the pattern of enzyme elevations was “mixed,” but the subsequent values and GGT elevations suggest that the injury was cholestatic. Most published cases of liver injury attributed to pregabalin have been marked by a short latency (3 to 14 days) and a rapidly resolving, self-limiting course.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Pregabalin – Generic, Lyrica®

DRUG CLASS

Anticonvulsants

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

CITED REFERENCE

1.
Crespo Pérez L, Moreira Vicente V, Manzano Fernández R, García Aguilera XA. Med Clin (Barc). 2008;130:157–8. [Cholestasis associated with pregabalin treatment] Spanish. [PubMed: 18279637]

ANNOTATED BIBLIOGRAPHY

References updated: 30 July 2020

Abbreviations used: DRESS, drug rash with eosinophilia and systemic symptoms; SJS/TEN, Stevens-Johnson syndrome and toxic epidermal necrolysis.

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    (61 year old man with neuropathic pain after laminectomy developed symptoms of dizziness and fatigue within 2 days, and liver test abnormalities at 11 days after starting pregabalin [bilirubin 1.2 mg/dL, ALT 307 U/L, Alk P 476 U/L], symptoms recurring with rechallenge, and all signs of injury resolving within 2 months of stopping: Case 1).
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    (61 year old man developed nausea followed by jaundice 8 days after starting pregabalin [bilirubin 10.7 mg/dL, ALT 35 times ULN, INR 3.8], resolving completely within 24 weeks).
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    (Pooled data from 7 trials of pregabalin given for 5-13 weeks vs placebo in 1510 patients; common side effects were edema, weight gain, dizziness and somnolence with “…no clinically meaningful changes in laboratory values from baseline.”).
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    (40 year old man developed fever, rash and facial swelling 2 weeks after starting pregabalin for post-herpetic neuralgia [bilirubin normal, ALT 250 U/L, Alk P normal], resolving on oral prednisolone and within a few months of stopping pregabalin).
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    (Review of adverse event reports to the FDA between 2014 and 2018 identified ~2.9 million reports, 1034 for SJS/TEN, the most common class of drugs being anticonvulsants with 17 of 34 having at least one report, those most frequently linked being lamotrigine [n=106], carbamazepine [22], levetiracetam [14], phenytoin [14], valproate [9], clonazepam [8], zonisamide [7], gabapentin [4] and pregabalin [4]; no mention of accompanying liver injury or whether attribution was as a single agent or one of several).
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    (76 year old woman developed jaundice 15 days after starting pregabalin for back pain [bilirubin 6.0 mg/dL, ALT 2030 U/L, Alk P 650 U/L], with recovery 1-3 months after stopping).
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  • Markman J, Resnick M, Greenberg S, Katz N, Yang R, Scavone J, Whalen E, et al. Efficacy of pregabalin in post-traumatic peripheral neuropathic pain: a randomized, double-blind, placebo-controlled phase 3 trial. J Neurol. 2018;265:2815–24. [PMC free article: PMC6244661] [PubMed: 30242745]
    (Among 539 adults with post-traumatic neuropathic pain treated for 15 weeks with pregabalin or placebo, there were no differences in improvements in pain scores between the two groups while adverse events more common with pregabalin were dizziness [15% vs 4%] and somnolence [10% vs 3%]; no mention of ALT elevations or hepatotoxicity).
  • Salehifar E, Janbabaei G, Hendouei N, Alipour A, Tabrizi N, Avan R. Comparison of the efficacy and safety of pregabalin and duloxetine in taxane-induced sensory neuropathy: a randomized controlled trial. Clin Drug Investig. 2020;40:249–57. [PubMed: 31925721]
    (Among 82 patients with post-taxane chemotherapy neuropathy treated with pregabalin or duloxetine for 6 weeks, response rates were 93% for pregabalin vs 38% for duloxetine and adverse events were mild-to-moderate, dizziness and somnolence more common with pregabalin, nausea and vomiting with duloxetine; no mention of ALT elevations or hepatotoxicity).