Abstract
OBJECTIVE:
To report a case of acute elevation of hepatic enzyme levels as a probable adverse reaction associated with pregabalin.
CASE SUMMARY:
A 59-year-old man with a history of mantle cell lymphoma developed neuropathic pain and was treated with pregabalin 25 mg daily. Fourteen days after beginning pregabalin therapy, he developed left ankle edema and elevation of liver enzyme levels. Peak values were aspartate transaminase 907 U/L, alanine transaminase 1582 U/L, and γ-glutamyltransferase 510 U/L. Pregabalin was discontinued and hepatic enzyme levels returned gradually (over 4 months) to baseline levels.
DISCUSSION:
Many medications are commonly associated with liver injury; few cases of pregabalin-associated hepatotoxicity have been documented. A MEDLINE search (1966-November 2010) revealed 2 reports of acute liver injury with the initiation of pregabalin. In our patient, with hemosiderosis after hematopoietic cell transplantation, pregabalin worsened the underlying liver injury. The low pregabalin dosage and the short time to elevation of liver enzyme levels suggest an idiosyncratic reaction. According to the Naranjo probability scale and the Council for International Organizations of Medical Sciences probability scale, this reaction was probably due to pregabalin.
CONCLUSIONS:
Prescribers should be alert to the possibility of idiosyncratic hepatotoxicity associated with pregabalin use.
Keywords
Pregabalin is an analogue of the neurotransmitter γ-aminobutyric acid approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for treatment of epilepsia and neuropathic pain. It is also approved by the FDA for the treatment of fibromyalgia. The analgesic activity of pregabalin is mediated through its high affinity binding to the α2-δ subunits of voltage-gated calcium channels in the central nervous system. 1
Idiosyncratic drug-induced liver injury is rare even among individuals who are exposed to drugs that are known to be hepatotoxic. It occurs in 1 in 5000 to 1 in 100,000 individuals who take medication; the risk is lower for some drugs. 2 Pregabalin is generally well tolerated, and hepatic adverse effects were not observed in clinical trials conducted to get the approval from the FDA and the EMA.
We report a case of acute elevation of liver enzyme levels as a probable adverse reaction associated with pregabalin.
Case Report
A 59-year-old man presented to our hospital for persistent fever over 3 days. The patient had been diagnosed with mantle cell lymphoma; he underwent an allogeneic transplantation from matched unrelated donor, with reduced-intensity conditioning 11 months prior to this hospital admission. He received immunosuppressant treatment with tacrolimus and sirolimus that was completed 2 months before presentation. In addition, he had received allopurinol for several years for treatment of gout. Findings on physical examination were unremarkable, with no clinical signs of infectious disease. Laboratory data showed an increase in leukocytes (10,500/μL; reference range 4500-8500), C-reactive protein ([CRP] 7.78 mg/dL; reference range 0-5), lactate dehydrogenase ([LDH] 558 U/L; reference range 240-480), and slightly elevated values of aspartate aminotransferase ([AST] 114 U/L; reference range 1-37) and alanine aminotransferase ([ALT]) 159 U/L; reference range 1-41). The creatinine level was normal (1.09 mg/dL; reference range 0.65-1.35). Urine culture was negative for pathogens, and chest radiographs showed no abnormalities. Results of an abdominal ultrasound were also normal. The patient received the second dose of polio and Haemophilus influenzae vaccines as part of the posttransplantation vaccination schedule 3 days before presentation to the emergency department of our hospital. 3 After the clinical examination was performed and laboratory tests were requested, a single dose of intravenous metamizole 2 g was administered for suspected reactive fever to vaccination. Two days later, liver enzyme levels remained high: AST 81 U/L, ALT 134 U/L, and γ-glutamyltransferase (GGT) 219 U/L (reference range 155); creatinine was normal (0.93 mg/dL). After 6 days of fever without a clinical focus and negative results of blood and urine cultures, oral levofloxacin 500 mg once a day was initiated. Laboratory levels at that time were AST 77 U/L, ALT 133 U/L, LDH 370 U/L, creatinine 1.22 mg/dL, and CRP 9.56 mg/dL.
The patient described neuropathic pain in one foot, and treatment with pregabalin 25 mg twice daily was started. Four days after starting levofloxacin, the patient had no fever and showed clear clinical improvement. Antibiotic therapy was continued for 5 more days (total, 9 days). Fourteen days after starting pregabalin, the patient reported left ankle edema. Laboratory test results revealed a significant increase in liver enzymes (AST 907 U/L, ALT 1582 U/L, GGT 510 U/L), LDH 917 U/L, CRP 0.63 mg/dL, alkaline phosphatase 488 U/L (reference range for men at our institution 80-300), total bilirubin 1.1 mg/dL (reference range 0.1-1), direct bilirubin 0.4 mg/dL (reference range 0.1-0.2), and creatinine 0.95 mg/dL. See Table 1 for biochemical parameters prior to, during, and after pregabalin treatment. An abdominal ultrasound at that time showed no changes. Viral serology testing was negative for hepatitis B and C virus, herpes simplex virus, parvovirus B19, Epstein-Barr virus, and cytomegalovirus. Pregabalin was stopped because it was the only new drug that the patient had been receiving.
Results of Laboratory Tests
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = γ-glutamyltransferase; LDH = lactate dehydrogenase; NR = not reported.
Day 0 represents the start of pregabalin therapy. On day 16, pregabalin was stopped.
Two days after discontinuation of pregabalin, ankle edema decreased and liver enzymes, as well as other markers of hepatic function, were decreasing slightly (AST 710 U/L, ALT 1379 U/L, GGT 511 U/L, LDH 713 U/L, alkaline phosphatase 526 U/L, creatinine 0.87 mg/dL, and international normalized ratio 1.03 [reference range 0.851.35]). Seven days after discontinuation of pregabalin, liver enzyme levels continued to decline (AST 484 U/L, ALT 994 U/L, GGT 523 U/L). Laboratory data to rule out hemosiderosis showed iron 228 μg/dL, ferritin 4267 ng/mL, and saturation index transferrin of 77% (these tests had not been performed before this).
Twenty-six days after pregabalin withdrawal, liver enzymes decreased to AST 93 U/L, ALT 178 U/L, and GGT 338 U/L, and parameters that reflect hemosiderosis also decreased, to iron 152 μg/dL, ferritin 1871 ng/mL, and transferrin saturation 68%.
On a follow-up visit 4 months after pregabalin discontinuation, liver function test results were in the normal range (AST 32 U/L, ALT 36 U/L) with a slightly increased GGT (60 U/L). The iron value was normal (142 μg/dL), but ferritin (1126 ng/mL) and transferrin saturation index (77%) remained high (range 20-50 reference).
Discussion
In general, pregabalin is relatively well tolerated; adverse reactions are usually mild to moderate. The most frequently recognized adverse effects are dizziness and somnolence, which are also the most frequently reported reasons for drug withdrawal. 4 Other common adverse effects are dose-dependent weight gain, ataxia, and peripheral edema.
We conducted a MEDLINE search using the following MeSH terms: pregabalin, drug-induced liver injury, liver failure, hepatic insufficiency, aspartate aminotransferase, alanine aminotransferase, and γ-glutamyltransferase. The search identified 2 references of pregabalin-induced hepatotoxicity. The first was a case report, which classified pregabalin as a probable cause of liver injury. 5 The second mentioned a published case report and 3 other cases reported to the Medical Products Agency in Sweden (these cases were judged to be possible). 6
According to the Naranjo probability scale, the association between pregabalin and increased liver enzyme levels in our patient is probable, but this scale places too much emphasis on rechallenge of the potential offending drug. 7 In addition, we assessed the causality using a specific scale for hepatotoxicity provided by the Council for International Organizations of Medical Sciences. Use of that scale showed pregabalin as a probable cause of hepatotoxicity. 8 There was no alcohol consumption, use of herbal and alternative medications, or hypotension as alternative causes of hepatotoxicity. The patient showed mild preexisting transaminitis prior to pregabalin therapy, so underlying liver injury was taken into account when hepatotoxicity scale was assessed. The low pregabalin dose and the short development time suggest an idiosyncratic reaction, especially in patients with impaired liver function, as in this patient with hemosiderosis after hematopoietic cell transplantation. 9
In addition, AST and ALT levels decreased shortly after discontinuation of pregabalin and returned to baseline within 2 months. Allopurinol treatment was maintained throughout hospitalization and had been administered for several years without adverse affects, ruling out a possible interaction between pregabalin and allopurinol. The pharmacokinetic profile of pregabalin indicates that it should have a very low potential for drug-drug interactions; furthermore, when administered at therapeutic dosages, pregabalin does not affect the cytochrome P450 system. 10
Only a single dose of metamizol was administered, 7 days before pregabalin was started and 3 weeks before the peak hepatic enzyme levels were detected, so it seems unlikely that metamizol played a relevant role in this case of hepatotoxicity
The absence of liver metabolism does not prevent drug-induced hepatotoxicity. 5 Pregabalin is widely used in clinical practice and clinicians must be aware of the occurrence or worsening of hepatotoxicity with pregabalin use.
