FormalPara Key Points

The widespread use of colchicine may expose a large population to potential risk, especially patients with impaired renal function undergoing combination drug therapies that share common metabolic pathways.

Clinicians should be cautious when co-administering colchicine with other drugs, especially in patients with impaired renal function.

Serious neuromuscular adverse events could occur with the concurrent use of colchicine and fluconazole.

Introduction

Colchicine is an ancient therapeutic used to treat gouty arthritis [1]. Although its clinical benefits are well documented, colchicine has been associated with adverse effects secondary to drug–drug interactions. The probable mechanisms of colchicine-induced adverse events include the deterioration of renal function and cytochrome P450 (CYP) 3A4 inhibition, leading to poor drug clearance and increased serum concentrations [2]. Some antibiotic- and cholesterol-lowering drug-related interactions have been reported. Fluconazole is a triazole antifungal agent that inhibits CYP2C19 (strong inhibition), CYP2C9 (moderate inhibition), and CYP3A4 (moderate inhibition) [3]. This is the first reported case of neuromyopathy induced by administration of fluconazole to a patient undergoing long-term colchicine therapy.

Case Report

A 54-year-old woman presented to the emergency department after 2 days of lower limb weakness and bilateral ankle pain. She had a known history of type 2 diabetes mellitus, diabetes mellitus nephropathy with chronic kidney disease, and chronic gouty arthritis. She was orally administered 0.6 mg colchicine once or twice daily for 8 months. She reported no recent traumatic event, alcohol ingestion, or substance abuse.

Four days before visiting our emergency department, the patient was discharged from our nephrology ward after undergoing treatment for a urinary tract infection. During her hospitalization, she was administered intravenous cefazolin for 7 days. Her current maintenance medications including oral colchicine (0.9 mg, once daily) were also prescribed. She still experienced dysuria, urgency, and lower abdominal fullness. Repeated urinalysis revealed the presence of yeast. She was diagnosed with fungal cystitis and administered a 7-day course of oral fluconazole (100 mg) once daily. On day 5 of the course, she was discharged and asked to continue treatment with oral colchicine (0.6 mg, twice daily) and fluconazole to complete the 7-day course.

The initial physical examination revealed an arterial blood pressure of 133/69 mmHg, a pulse rate of 89 beats/min, a respiratory rate of 19 breaths/min, and body temperature of 36.6 °C. She had bilateral tenderness in her ankles with general weakness. Neurological examination revealed marked symmetrical weakness (Medical Research Council grade 4/5). Her sensation and coordination were intact. She had no rash or lymphadenopathy. Her chest plain film showed no active lung lesion and borderline heart size. Cardiac echography revealed preserved left ventricle systolic function without cardiac chamber dilatation. Initial laboratory investigations revealed hyperkalemia (6.2 mmol/L vs. normal: 3.4–4.7 mmol/L), and elevated blood urea nitrogen (181 mg/dL vs. normal: 7–20 mg/dL), serum creatinine (11.16 mg/dL vs. normal: 0.5–1.2 mg/dL), and creatine kinase (CK, 803 U/L vs. normal: 24–120 U/L) levels. Her liver function tests showed elevated alanine aminotransferase (ALT, 112 U/L vs. normal: 0–40 U/L) levels. She had a decreased white blood cell count (2830 cells/mL vs. normal: 4000–9900 cells/mL) and hemoglobin levels (9.7 g/dL vs. normal: 12–16 g/dL). Anemia, indicated by the reduced hemoglobin level, is a common complication of chronic kidney disease. Cholesterol levels, amylase, direct and indirect bilirubin, C-reactive protein, rheumatoid factor, and thyroid hormones were all within their normal ranges.

Motor nerve conduction studies revealed prolonged distal latency, slow nerve conduction velocity, delayed F-wave latency on four limbs, and low compound muscle action potential amplitude in the bilateral peroneal and tibial nerves. Hoffmann’s reflex study showed no response in both lower limbs. Sensory nerve conduction studies revealed slow nerve conduction velocities in bilateral median nerves across the wrist, and relatively low sensory nerve action potential amplitude in four limbs. Needle electromyography demonstrated severely active denervation in both the lower limbs.

She was diagnosed with neuromyopathy based on clinical presentation and laboratory studies. On admission, her anti-inflammatory drugs were changed to corticosteroids for gouty arthritis, and colchicine was withdrawn. Ten days after the cessation of colchicine, her laboratory values returned to the normal range (potassium 4.1 mmol/L; ALT 41 U/L; white blood cell count 5540 cells/mL), with the exception of the hemoglobin level (9.6 g/dL). Her weakness disappeared gradually.

Discussion

We searched the PubMed electronic database for literature from 1987 to 2013, using the keywords colchicine, myopathy, neuromyopathy, rhabdomyolysis, and myotoxicity. We limited the search to case reports published in English involving adult patients. We identified 114 articles in which colchicine-induced neuromyopathy was reported. Both authors scanned titles and abstracts for initial selections. Forty-three articles were not associated with drug interactions, and were therefore excluded. Fifty-one articles were excluded because the mentioned drug–drug interactions were not related to myopathy. Finally, we extracted the following data from 20 articles describing 24 different cases (Table 1) [4–23]: baseline demographic characteristics (age, sex); colchicine dose and duration of use; recent concomitant drug dose; symptom presentation after concurrent drug use; time from concomitant drug dose to symptoms; CK, aspartate transaminase (AST), and ALT levels, electromyography findings; and time to resolution.

Table 1 Characteristics of included case reports
Full size table

The mean age of the patients who experienced drug interaction-induced myopathy was 58 ± 15 years, 83 % were men, and most had underlying comorbidities (chronic kidney disease, dyslipidemia, or solid organ transplantation). The duration of concomitant drug use with colchicine therapy ranged from 3 to 28 days (mean ± standard deviation, 13 ± 7 days), with a mean cumulative daily dose of 1.27 ± 0.6 mg. The mean time to resolution after drug discontinuation was 17 ± 12 days. Most patients in this case series presented with proximal muscle weakness. As in our report, CK, ALT, and AST levels were significantly elevated. Hyperkalemia is caused by the release of potassium from damaged myocytes. The blood potassium level may increase rapidly, but it decreases as it is eliminated in the urine. Elevated levels of AST and ALT may be caused by hepatic inflammation, which occurs in approximately 25 % of patients with rhabdomyolysis or myopathy. The possible mechanism for this inflammation is related to the proteases released from the injured muscle [24].

Colchicine is primarily cleared from the body via bile, the intestinal tract and, to a lesser extent, renal excretion. In one study in normal healthy subjects, 14–40 % of the unchanged drug and 4–14 % of its metabolites were recovered in the urine [25]. The impaired renal function in the present case was a risk factor for colchicine toxicity, but not the primary mechanism, as she had been orally administered 0.6 mg colchicine one to two times daily for 8 months prior to this event. Previous reports have suggested that numerous drugs, including clarithromycin, pravastatin, simvastatin, fluvastatin, atorvastatin, gemfibrozil, and cyclosporine, contribute to neuromyopathy associated with drug–drug interactions following colchicine administration. The possible mechanisms of interaction were inhibited demethylation of colchicine in the liver before excretion, which is dependent on CYP3A4, concurrent administration of CYP3A4 substrates, and interference with P-glycoprotein-mediated transport [26]. Co-administration of these drugs impairs the metabolism of colchicine, which leads to decreased colchicine clearance, and increased plasma colchicine concentrations. The high plasma concentrations may have also caused myelosuppression and leukopenia in two reported cases [27]. Furthermore, co-administration can impair axonal transport in peripheral nerves, thereby altering the microtubule-dependent cytoskeleton necessary for the normal lysosome movement in cells [28]. To our knowledge, this is the first case of neuromyopathy induced by concomitant use of colchicine and fluconazole. We have used the Drug Interaction Probability Scale to evaluate our patient’s case [29]. A score of 5 was calculated, indicating that the drug–drug interaction was the probable cause of neuromuscular toxicity. Based on the well-documented pharmacokinetic mechanism and similar drug interactions with other CYP3A4 substrates or inhibitors, it is strongly suspected that a drug–drug interaction induced the neuromyopathy.

Conclusion

We presented a case of a patient who developed neuromyopathy secondary to concomitant use of colchicine and fluconazole. The use of colchicine in the treatment of gouty arthritis may be associated with neuromuscular adverse events. The widespread use of this medication may expose a large population to potential risk, especially patients with impaired renal function undergoing combination drug therapies that share common metabolic pathways. Physicians should be cautious when co-administering colchicine with other drugs, and carefully monitor patients for symptoms of myotoxicity.