Diclofenac- and Pantoprazole-Induced Rhabdomyolysis: A Potential Drug Interaction

Key Points

Introduction

Acute rhabdomyolysis (AR) is a clinical syndrome that occurs when the electrolytes and myoglobin that are released upon skeletal muscle damage enter into the circulation system. There are several ways in which AR may occur [1], one of which is drugs (Fig. 1).

Fig. 1

Etiology of acute rhabdomyolysis and its complications

A comprehensive study was carried out in 2011 using 2004–2009 data of the US Food and Drug Administration (FDA) to reveal which drugs may be associated with rhabdomyloysis. The etiologies of 16,435 drug-induced cases of rhabdomyloysis involved HMG-CoA reductase inhibitors or statins (n = 4325, 26.3 %) as the first suspect. A total of 100 cases were reported for diclofenac and 99 for omeprazole, a proton pump inhibitor, while there were no reports of cases associated with pantoprazole. The cases of drug-induced rhabdomyolysis in previous literature were also associated with statins, and the frequency is similar to that reported in the abovementioned report. That said, drug interactions could not be assessed because the FDA data did not include that level of systematic information [2].

The gastric side effects of non-steroidal anti-inflammatory drugs (NSAIDs) are well known, and their concomitant or subsequent combination with proton pump inhibitors is common. A review of adverse drug reactions, creatinine kinase elevations, and muscle events, including muscle weakness, myopathy, myositis, and polymyositis, analyzed such multiple drug regimens and found that the addition of pantoprazole to a treatment regimen was the cause of all muscle events, aside from myalgia [3].

Case Presentation

A 45-year-old man was referred to hospital complaining of fatigue and extensive body pain. His medical history included stress-induced headaches that had been present for almost the entire previous year, for which he began using diclofenac at 50 mg/day as the frequency of headaches had increased during the prior month. He was referred to a physician for pyrosis, 1 week prior to presenting at the hospital, and was prescribed pantoprazole at 40 mg/day. He continued using diclofenac for the ongoing headaches. He started to experience pain in his leg muscles on the fourth day of the diclofenac and pantoprazole combination regimen and used two 50-mg doses of diclofenac to control the pain. The muscle pain became more widespread on the fifth day, and the patient also developed fatigue.

An examination revealed a blood pressure of 120/80 mmHg and a pulse of 76 bpm, full and rhythmic. Cardiac sounds were normal and the patient had no specific chest pain. Muscular strength was good; however, the patient complained of muscle tenderness upon palpation. Neurological and general system examinations were normal; no abnormal findings were seen in an electrocardiogram; and an abdomen ultrasound revealed no pathology, aside from an abdominal gas distention. A laboratory analysis revealed high levels of muscle destruction products, the foremost of which was creatinine kinase (Table 1). Glucose, urea, creatinine, cholesterol levels, amylase, direct and indirect bilirubin, electrolytes, anti-streptolysin O, C-reactive protein, rheumatoid factor, and thyroid hormones were all within their normal ranges.

A cardiac pathology was excluded because the electrocardiographic assessments and cardiac sounds were normal, and because the patient did not describe any pain that would indicate an infarct, and test results and findings were stable on the following days. Liver and biliary tract pathologies were excluded by ultrasound. AR was considered as a pre-diagnosis, as there was a chronologic alignment between the patient’s clinical representation and the medications he used, and this was supported by the laboratory parameters. Both medications were discontinued and the patient was followed up for 1 week, during which no medical interventions were carried out, aside from a recommendation of general hydration. The AR diagnosis was confirmed because his complaints disappeared, with his laboratory values returning to the normal range, a stable electrocardiogram, and other systemic examinations being found within normal ranges.

Discussion

To date, among the cases involving NSAIDs, two cases were reported that include diclofenac-induced rhabdomyloysis [4, 5]. The patient detailed in this study was referred with extensive pain and fatigue, and represents the third case in which rhabdomyloysis developed while using 100-mg/day diclofenac tablets. The other two cases were induced by diclofenac alone, with no interaction with other drugs. Of these, one patient was admitted with pain that increased after the patient took 200 mg of diclofenac within 2 days (50 mg tablet/twice a day) for joint pain [4]. The other case involved a patient who used diclofenac to ease an acute exacerbation of gout. The patient was referred to a physician on the 13th day of intramuscularly self-administered diclofenac at 75 mg per day for 6 days, followed by 75 mg orally three times a day for 7 days. Unlike the previous case, this patient was referred to the hospital because of erythematous pruritic eruptions that developed on various parts of his body [5].

Conclusion

The FDA recommends that clinicians check CYP-mediated potential drug interactions routinely [14]. In this case report, a case of diclofenac- and pantoprazole-induced AR is evaluated for drug-interaction mechanisms, and different perspectives are presented. While evaluating the patients with side effects of drugs, the CYP and P-gp mechanisms that play roles in drug absorption and distribution should be considered.