Rhabdomyolysis has been defined by the American College of Cardiology, the American Heart Association, and the National Heart, Lung, and Blood Institute as muscle symptoms with marked creatine phosphokinase (CPK) elevations of more than 10 times the upper limit of normal (ULN) with creatinine elevation, usually with brown urine and urinary myoglobin.1
Myoglobinuria is the most significant consequence in patients with rhabdomyolysis, leading to acute renal failure in 15% to 33% of patients, as a result of muscle necrosis.2
The mortality rate is approximately 5%.3
Rhabdomyolysis can be caused by various drugs and toxins4
as well as by mechanical, viral, bacterial, metabolic, and environmental factors.3
Statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) are associated with higher rates of rhabdomyolysis outside of the clinical trial setting and with higher rates of myopathy or rhabdomyolysis when used either alone or in combination with fibrates.4
Pregabalin (Lyrica, Pfizer) is similar in structure to gamma-aminobutyric acid (GABA); it is also similar structurally and chemically to gabapentin (Neurontin, Pfizer). Pregabalin exhibits analgesic, anxiolytic, and antiepileptic properties.5
Although it is similar to GABA, pregabalin does not exhibit GABA-mimetic effects; however, it does result in increased neuronal GABA levels and generates dose-dependent glutamic acid decarboxylase activity.
The drug’s effect on neuropathic pain, anxiety, and other pain syndromes probably results from a reduction in neuronal calcium trafficking in alpha2-delta calcium channels and/or by reducing calcium currents. Pregabalin does not bind to benzodiazepine or opiate receptors or to GABAA or GABAB receptors, and it has no effect on cyclooxygenase activity. It does not inhibit serotonin, norepinephrine, or dopamine reuptake, and it is inactive at these receptors.
The FDA has approved pregabalin for the treatment of diabetic peripheral neuropathic pain (DPN), postherpetic neuralgia (PHN), as adjunctive therapy for adults with partial-onset seizures, fibromyalgia, and neuropathic pain associated with spinal cord injury.6
The recommended dosage of pregabalin for DPN is 50 mg three times daily. This dose can be increased to 100 mg three times daily within a week according to its effectiveness and the patient’s tolerability.
Pregabalin has negligible hepatic metabolism and does not bind to plasma proteins. It is excreted primarily unchanged in the urine (90%–98%) with its renal clearance proportional to the creatinine clearance (CrCl) in patients not receiving hemodialysis. A dose reduction may be required in patients with renal dysfunction or failure.
The drug’s oral bioavailability is about 90% independent of the dose, and the elimination half-life is about 6 hours.6
Common adverse reactions include central nervous system (CNS) depression, dizziness and drowsiness.
Pregabalin is classified as a federally controlled substance (C-V) and therefore may cause some physical or psychological dependence. Suicidal ideation in association with this agent was the topic of an initial FDA alert in January 2008.7
Angioedema, peripheral edema, dry mouth, blurred vision, weight gain, difficulty in concentration, and hypersensitivity reactions have also been reported.
A 70-year-old male patient presented to the emergency department (ED) with generalized extremity weakness. He was mentally disoriented and unable to stand up, and his legs were atonic. His right side and all four extremities were twitching, and he had slurred speech. The patient had experienced these symptoms when he was at home, and emergency medical services was called. In the ED, his medical history was significant for type-2 diabetes mellitus, peripheral neuropathy, hypercholesterolemia, and chronic low back pain (a disc had been removed in the early 1980s). He had no family history of stroke or coronary artery disease. In addition, he stated that he is functional and walks his dog four or five blocks every day.
According to the patient’s medication reconciliation file, his home regimen included the following oral medications: lisinopril (e.g., Zestril, AstraZeneca) 5 mg daily, amitriptyline 25 mg in the morning, amitriptyline 50 mg at bedtime, simvastatin (Zocor, Merck) 20 mg daily (started 4 days earlier), pregabalin (Lyrica) 100 mg three times daily, oxycodone HCl controlled-release (OxyContin, Purdue Pharma) 80 mg every 8 hours, oxycodone HCl immediate-release (generic) 30 mg every 4 hours as needed, and metformin (Glucophage, Bristol-Myers Squibb) 500 mg twice daily.
The only recent modifications to the regimen were the additions of lisinopril 5 mg and simvastatin 20 mg and an increase in the pregabalin dose from 50 mg three times daily 4 days earlier; it was not known how long the patient had used the lower pregabalin dose. He denied smoking, drinking alcohol, or using recreational drugs, and he had no known drug allergies or a history of trauma.
The patient’s initial vital signs were as follows: temperature, 97.6 °F; heart rate, 71 beats/minute; blood pressure, 110/60 mm Hg; and respiratory rate, 14 breaths/minute. Oxygen saturation was recorded at 99% on room air. The physical examination findings were normal except for the musculoskeletal system, which showed more weakness in the legs than in the arms. Upper-limb strength was 5/5 (normal), but lower-limb strength was 3/5 (movement possible against gravity but not against resistance by the examiner). A muscle twitch was also observed in the right lower and upper extremities.
Laboratory test results were significant for elevated CPK levels of 1,391 IU/L, a creatine phosphokinase–muscle band (CPK–MB) of 234 ng/mL (MB 1%), serum creatinine (SCr) of 1.5 mg/dL, and a fingerstick glucose reading of 117 mg/dL. The patient was awake, alert, and oriented to person, place, and time, although he stated that he felt very tired.
The patient displayed no slurred speech or acute distress. According to his wife, he was back to his baseline mental status, which included being mentally oriented to person, place, and time. The stroke team was activated. A neurologist stated that the patient’s history did not suggest a cerebrovascular accident. Computed tomography (CT) of the head was negative for an infarct or a hemorrhage.
Additional laboratory tests were within normal limits. Total bilirubin was 0.5 mg/dL, direct bilirubin was zero, alkaline phosphatase was 78 units/L, aspartate aminotransferase (AST) was 39 units/L, and alanine aminotransferase (ALT) was 24 units/L. The prothrombin time was 10 seconds, the activated partial thromboplastin time was 28.7 seconds, the International Normalized Ratio (INR) was 1, and glycosylated hemoglobin (HbA1c) was 6.2%. His lipid panel was also within normal limits. It was not evident whether he had received previous treatment for hypercholesterolemia or, if so, which agent or agents had been previously prescribed. Additional laboratory tests throughout his hospitalization are presented in .
The patient was admitted with a diagnosis of rhabdomyolysis, which was probably a result of statin therapy. It was also thought that he might have had a seizure disorder, but this was ruled out following a normal electroencephalogram. Simvastatin was discontinued. The patient was initially given a 1-liter normal saline (NS) bolus, followed by intravenous (IV) NS at 100 mL/hour. His acute renal failure was monitored, and the fluids were changed to bicarbonate (0.45% NS with 75 mEq of bicarbonate at a rate of 150 mL/hour) to keep the urine pH at approximately 7. Serial troponin levels were used to rule out acute coronary syndromes.
On the second hospital day, CPK peaked at 14,191 units/L and SCr peaked at 1.6 mg/dL. The patient had received one dose of pregabalin and lisinopril that morning but not simvastatin. His mental status had improved, and he was able to follow commands. Pregabalin, lisinopril, and metformin were discontinued in the afternoon. The patient received 5,000 units of heparin sodium subcutaneously every 12 hours for deep vein thrombosis prophylaxis, sliding-scale (short-acting) insulin, and 10 units of insulin glargine (Lantus, Sanofi) at bedtime for diabetes.
The next day, leg pain and chronic low back pain were the same as at baseline; he was able to take slow walks and bear weight. His strength, balance, and coordination improved, and his mental status continued to improve. His CPK and SCr values began to fall; CPK was 4,605 units/L, and SCr was 1.0.
It was recommended that the patient restart lisinopril and metformin upon discharge. However, the safety of pregabalin was questioned by the medical resident, and pregabalin and simvastatin were not restarted. The patient has not been readmitted to New York Downtown Hospital.