Pregabalin-induced rhabdomyolysis: a case series and literature analysis

Abstract

Pregabalin is a prescription medicine that has recently been approved for individuals who suffer from fibromyalgia, neuropathic pain, anxiety disorder, or epilepsy. Pregabalin has the side effects of dizziness, sleepiness, and angioedema. Pregabalin-induced rhabdomyolysis has been rarely reported, with only four reports to date. We report two cases of rhabdomyolysis after pregabalin treatment. A man aged older than 90 years presented with exhaustion, muscle aches, and a high serum creatine kinase concentration after taking 75 mg of pregabalin on the first day of treatment. A woman in her 90s with long-term use of pregabalin presented with considerably elevated serum creatine kinase concentrations. Both patients had a long history of taking statins. Pregabalin therapy was stopped, high-volume intravenous fluids were administered, and serum electrolytes were frequently checked. Alkalinisation was performed with excellent outcomes. The Naranjo Adverse Drug Reaction scale and previous research suggest an association between pregabalin and rhabdomyolysis. Clinicians should be alert to the possibility of rhabdomyolysis occurring with the use of pregabalin, especially when taking statins.

Introduction

Pregabalin is a gamma-aminobutyric acid subset, and was approved as an adjunctive therapy for partial epilepsy in the European Union in 2004. In the same year, the US Food and Drug Administration approved pregabalin for the treatment of post-herpetic neuralgia and pain related to diabetes neuropathy. In 2005, pregabalin was approved as an adjuvant therapy for epilepsy by the Food and Drug Administration. ¹ Pregabalin has become a popular medication used to manage fibromyalgia, anxiety disorder, and epilepsy, as well as an adjuvant therapy for epilepsy. Common adverse effects associated with pregabalin are dizziness, sleepiness, angioedema, and weight gain. ² To the best of our knowledge, there have been only four reports of patients with rhabdomyolysis associated with pregabalin have been published in PubMed.^3–6 We report two new cases of rhabdomyolysis caused by pregabalin and review previously reported cases of rhabdomyolysis associated with pregabalin.

Case report

We have de-identified all patients’ details and obtained approval from the Medical Ethics Committee of Chinese PLA General Hospital (approval number: S2024-057-01) for publication. The reporting of this study conforms to the CARE guidelines. ⁷ We obtained informed consent from the patients for treatment and publication.

Case 1

A man aged in his 90s’ experienced searing discomfort within the left clavicle area, and this was later confirmed by a dermatitis eruption. The outbursts began as papules and erythematous patches in the dermatome, and the plaques soon turned into blisters. Through a differential diagnosis, medical professionals determined the presence of herpes zoster. Pregabalin pills (75 mg; Pfizer Pharmaceuticals Limited, New York, NY, USA) were administered once daily.

Unexpectedly, the patient was admitted to the doctor soon after this diagnosis with complaints of weariness, muscle soreness, and dizziness. He had been taking atorvastatin (40 mg daily) for hyperlipidaemia for 30 years, while experiencing less frequently occurring side effects, such as muscle weakness and myasthenia. Additionally, he had experienced prostatic overgrowth, carotid stenosis, twin kidney cysts, and gallstones. His usual medication had not undergone any alterations that included atorvastatin, tolvaptan, spironolactone, trazodone, quetiapine, tamsulosin, finasteride, rivaroxaban, or folic acid, and his physical condition was relatively stable.

Additional laboratory examinations were performed and showed a creatinine kinase (CK) concentration of 908 U/L (normal: 2–200 U/L) and myoglobin concentration of 608 ng/mL (normal: 20–80 ng/mL). Rhabdomyolysis, which was likely caused by the medication, was the physician’s diagnosis on hospitalisation, and atorvastatin and pregabalin therapies were stopped. A 1 L bolus of normal saline was administered and 100 mL/hour of normal saline was then administered intravenously. Fluids were modified to soda (0.45% normal saline with 75 mEq of bicarbonate once at a frequency of 150 mL/hour) to maintain the patient’s urine at an approximately neutral pH, and his acute renal failure was monitored. The symptoms of rhabdomyolysis improved the following day, and his CK and myoglobin concentrations were reduced to 575 U/L and 521 ng/mL, respectively.

After 1 week, his symptoms of weariness, muscle soreness, and dizziness had disappeared. Laboratory test results had returned to normal, with CK and myoglobin concentrations of 60 IU/L and 75 ng/mL, respectively. The patient was recommended to restart atorvastatin, but pregabalin therapy was not restarted because a medical resident disputed its safety. A follow-up clinical visit showed that the patient continued to take atorvastatin and has remained without rhabdomyolysis at follow-up visits and laboratory checks.

Case 2

A woman aged older than 90 years was hospitalised owing to worsening asthma, and her medical history included hypertension, coronary heart disease, stable angina pectoris after percutaneous intervention, acute kidney injury, pericardial effusion, type 2 diabetes, right renal artery stenosis after right renal artery stent implantation, varicose veins of the lower extremities, herpes zoster, chronic anaemia, arrhythmia, ventricular premature beat, and chronic gastritis. Her medications included acarbose, rivaroxaban, benidipine, amlodipine, rosuvastatin, tolvaptan, and pregabalin for herpes zoster. She had no drug allergies or a history of trauma. The patient reported generalised myalgia and joint pain after using pregabalin for 22 days. A laboratory examination showed that her CK concentration was considerably elevated at 8627 U/L (43 times the upper reference limit from normal), and serum creatinine, blood urea nitrogen, and blood myoglobin concentrations were 140 mol/L, 11.70 mmol/L, and >500 ng/mL, respectively.

Rhabdomyolysis caused by drug administration was diagnosed, and pregabalin was stopped owing to the possible relationship between its use and adverse effects. Hyperhydration, alkalinizing urine, and correcting electrolyte turbulence were the main treatments used. After 7 days, CK and creatinine concentrations were 114 U/L and 106 mol/L, respectively. The abnormal blood test results steadily decreased once pregabalin was discontinued, and the findings became routine 2 weeks following cessation of therapy. The patient has remained in good health. After resuming the use of rosuvastatin, there were no symptoms of rhabdomyolysis.

Discussion

Rhabdomyolysis involves the degradation of skeletal muscle tissue leading to the release of cellular components, such as CK and myoglobin, into the circulation. ⁸ An elevated serum CK concentration is the most important indicator of rhabdomyolysis. ⁹ Rhabdomyolysis occurs after various acute muscle damage, muscle necrosis, release of contents from muscle cells into the circulation, mild to asymptomatic elevation of serum CK, severe to extreme elevation of enzymes, electrolyte disorders, and acute kidney injury, which can be life-threatening. Myalgia, diffuse muscle discomfort, weariness, weakening, and increased CK concentrations are signs of rhabdomyolysis in patients. Rhabdomyolysis can be caused by many factors, and statins, fibrates, diuretics, benzodiazepines, and traditional Chinese medicine are the most frequent causes. Pregabalin is also an agent that causes rhabdomyolysis despite being rarely reported.

Our patients were diagnosed with rhabdomyolysis when they appeared fatigued, and had muscle pain, oliguria, and a marked increase in CK and myoglobin concentrations after taking pregabalin. They were cured after discontinuation of pregabalin and statins, hydration, alkalisation, and diuresis. The patients were not recommended to take pregabalin because of its major side effects, but resumed lipid-lowering therapy with statins as soon as CK concentrations returned to normal, and the primary symptoms of the patients’ rhabdomyolysis did not return.

Although rhabdomyolysis is usually an adverse reaction associated with statins, we believe that pregabalin was the likely cause in our cases. Pregabalin was considered the cause of myopathy in our patients for the following reasons: (a) the patients did not have any muscle weakness before initiating pregabalin, (b) the patients recovered quickly after pregabalin was stopped; (c) the patients did not develop recurrent myopathy after their statins were reverted; and (d) pregabalin is eliminated via the kidneys with little metabolic activity and has no major interactions with prescription drugs. ¹⁰ Furthermore, we applied the Naranjo probability scale to our cases and found a possible association between pregabalin and rhabdomyolysis (previous conclusive reports on this reaction [+1], the adverse event appeared after the suspected drug was administered [+2], and the adverse reaction improved when the drug was discontinued [+1]; Naranjo score = 4).

To conduct a more thorough investigation and gain a better understanding of the patients’ characteristics, risk factors, clinical management, and prognosis of the inhibitory effect of pregabalin, we searched the PubMed database for reports of rhabdomyolysis caused by pregabalin combination therapy. The relevant studies reported in the English language literature were searched from onset to 20 May 2022 using the following terms: pregabalin, myalgia, and rhabdomyolysis. To the best of our knowledge, four cases of pregabalin-induced rhabdomyolysis have been documented.^3–6 Kaufman and Choy reported a case of rhabdomyolysis for the first time in 2012. ³ After discontinuing simvastatin, the patient’s creatinine and CK concentrations continued to rise, leading to the cessation of pregabalin use and improved symptoms. These findings suggest that rhabdomyolysis may be an adverse reaction associated with pregabalin. Gunathilake et al. reported a case of fatal rhabdomyolysis in a patient who had been taking atorvastatin 40 mg daily for 5 years without any adverse effects. The patient developed rhabdomyolysis after starting pregabalin 75 mg twice daily for 2 days. ⁴ After discontinuing statins, these two cases still showed elevated levels of rhabdomyolysis markers, and thus pregabalin was stopped and the patients received active fluid resuscitation. Two other case reports have described rhabdomyolysis in patients who took pregabalin. One case of rhabdomyolysis with purpura was caused by a drug interaction between pregabalin and azithromycin ⁵ and a case of pregabalin-induced myopathy in a double lung transplant recipient was reported. ⁶ Both of these patients were not administered statins. Table 1 contains a summary of all clinical and laboratory data of these four cases. There were two men and two women, and pregabalin-induced rhabdomyolysis did not appear to differ by sex. Rhabdomyolysis was more common in patients with an older age or with hyperlipidaemia, hypertension, chronic renal failure, and/or hypo-immunity. Therefore, these factors may be potential risk factors for rhabdomyolysis associated with pregabalin monotherapy. The time when a reaction started varied between 1 day and 3 months. Most patients could be cured by discontinuation of pregabalin or with combination therapy of hydration, alkalinisation, and diuresis. The clinical presentation had a good prognosis, and most patients recovered and improved. Based on this previous literature, we speculate that pregabalin is a factor involved in rhabdomyolysis.

Table 1.

Data of previously reported cases of pregabalin-induced rhabdomyolysis.

Reference	Year	Patient		Statin use	Acute kidney injury	Myalgias	Peak CK (IU/L)	Duration of pregabalin use	Treatment	Time of recovery
		Age (y)	Sex
Kaufman and Choy 3	2012	70	Male	Yes	No	Yes	14,191	Unknown	Pregabalin and simvastatin were discontinued, and hydration and alkalinisation were performed	Unknown
Gunathilake et al. 4	2013	66	Female	Yes	Yes	Yes	14,050	2 days	Pregabalin and atorvastatin were discontinued	7–8 days
Kato et al. 5	2016	75	Female	No	No	Yes	1250	3 months	Pregabalin was discontinued	3 weeks
Hegde et al. 6	2020	36	Male	No	No	Yes	1700	2 months	Pregabalin was discontinued	Within 1 month

CK, creatine kinase.

The pathological mechanism of pregabalin induced rhabdomyolysis remains unclear. There have been three premarketing reports of severe rhabdomyolysis associated with pregabalin, but the mechanism was not discussed. ¹¹ Research suggests that a drug-induced sustained elevation in cytosolic calcium concentrations and a reduction in myoplasmic ATP content may be a common mechanism shared by some drugs that induce muscle toxicity.^12–16 By studying a new generation of antiepileptic drug-related rhabdomyolysis cases, Deng et al. found that rhabdomyolysis caused by the antiepileptic drug levetiracetam may be due to the presence of receptor SV2A protein in muscle fibres. ¹⁷ Intracellular calcium has a high affinity for pregabalin because of widespread distribution of the voltage-dependent calcium channel α 2/δ1 subunit in the brain and skeletal muscle. ¹⁸ The role of α 2/δ1 subunits in the observed adverse effects of pregabalin treatment on skeletal muscle needs to be investigated in future research.^19,20 Bin Dayel et al. found that pregabalin had a strong inhibitory effect on cellular oxidative phosphorylation, directly inhibiting electron transfer chain activity and inducing mitochondrial dysfunction, and preventing the synthesis of ATP. ²¹

Conclusions

Our cases and previous cases highlight the importance of awareness that pregabalin, especially when used with statins, may occasionally cause rhabdomyolysis. Therefore, clinicians should be aware of this uncommon adverse reaction to pregabalin, especially in the first phase of treatment. After starting pregabalin therapy, we advise careful monitoring of CK concentrations and fluid balance. If CK concentrations are noticeably high, we advise considering the cessation of pregabalin therapy to prevent kidney damage. Patients experiencing pregabalin-induced rhabdomyolysis can obtain satisfactory results with an accurate diagnosis and efficient treatment.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605241257776 - Supplemental material for Pregabalin-induced rhabdomyolysis: a case series and literature analysis

Supplemental material, sj-pdf-1-imr-10.1177_03000605241257776 for Pregabalin-induced rhabdomyolysis: a case series and literature analysis by Wenjing Zhai, Hao Liu, Jinrui Li and Haili Xin in Journal of International Medical Research