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Colchicine Toxicity: An Exaggerated Reality?

      To the Editor:
      With great interest, we read the review article entitled “Colchicine: Old and New” by Slobodnick et al.
      • Slobodnick A.
      • Shah B.
      • Pillinger M.H.
      • Krasnokutsky S.
      Colchicine: old and new.
      The authors reviewed the general pharmacokinetic properties of colchicine, as well as registered and emerging indications for clinical use. When one searches medical indexes with the keyword “colchicine,” an abundance of case reports are encountered, describing the catastrophic consequences of colchicine use. A closer look unveils that most of the time, these toxicities result from intentional or inadvertent high doses and use of conventional doses in patients with renal impairment or interaction with certain medications. Most commonly used drug guides recommend “avoid” or simply state “no data available” for the use of colchicine in patients with end-stage renal disease. The significance of renal function in the context of colchicine use stems from 2 facts. First, indications for colchicine use, such as gout, familial Mediterranean fever, and cardiovascular diseases, are also risk factors for concomitant renal disease. Second, most of the reported toxicity cases have underlying impaired renal function as the major contribution to colchicine toxicity. Thus, patients who are candidates for colchicine use for the aforementioned indications are more likely to have impaired kidney function.
      Slobodnick et al
      • Slobodnick A.
      • Shah B.
      • Pillinger M.H.
      • Krasnokutsky S.
      Colchicine: old and new.
      did not thoroughly evaluate this situation in their article, possibly because of the scope of the article and page restrictions. They briefly mentioned chronic colchicine toxicity in patients with diminished kidney function according to an article published in the 1980s.
      • Kuncl R.W.
      • Duncan G.
      Chronic human colchicine myopathy and neuropathy.
      However, recent studies by us and other groups
      • Solak Y.
      • Atalay H.
      • Biyik Z.
      • et al.
      Colchicine toxicity in end-stage renal disease patients: a case-control study.
      • Wason S.
      • Mount D.
      • Faulkner R.
      Single-dose, open-label study of the differences in pharmacokinetics of colchicine in subjects with renal impairment, including end-stage renal disease.
      continue to investigate the effect of level of kidney function on the toxicity of colchicine. To our knowledge, we reported the largest study to date examining patients undergoing maintenance hemodialysis and concomitantly using normal to high doses of colchicine on a chronic basis. What our study showed was that despite high doses of colchicine use, these patients had no signs or symptoms of chronic colchicine toxicity. Although it is not possible to exclude the selection bias with certainty, the results are remarkable for a drug for which the literature describes many catastrophic toxicity cases.
      Colchicine is a strong candidate for more common use in the future, considering an ever-expanding indication range. The advent of studies showing the beneficial effects of colchicine in coronary artery disease and myocardial infarction
      • Nidorf S.M.
      • Eikelboom J.W.
      • Thompson P.L.
      Colchicine for secondary prevention of cardiovascular disease.
      particularly may increase the number of patients who use colchicine, along with potential toxicities. Thus, the inconsistencies regarding dose adjustments in patients with kidney disease should be clarified with elaborate studies rather than single case reports before mass use of the drug.

      References

        • Slobodnick A.
        • Shah B.
        • Pillinger M.H.
        • Krasnokutsky S.
        Colchicine: old and new.
        Am J Med. 2015; 128: 461-470
        • Kuncl R.W.
        • Duncan G.
        Chronic human colchicine myopathy and neuropathy.
        Arch Neurol. 1988; 45: 245-246
        • Solak Y.
        • Atalay H.
        • Biyik Z.
        • et al.
        Colchicine toxicity in end-stage renal disease patients: a case-control study.
        Am J Ther. 2014; 21: e189-e195
        • Wason S.
        • Mount D.
        • Faulkner R.
        Single-dose, open-label study of the differences in pharmacokinetics of colchicine in subjects with renal impairment, including end-stage renal disease.
        Clin Drug Investig. 2014; 34: 845-855
        • Nidorf S.M.
        • Eikelboom J.W.
        • Thompson P.L.
        Colchicine for secondary prevention of cardiovascular disease.
        Curr Atheroscler Rep. 2014; 16: 391

      Linked Article

      • Colchicine: Old and New
        The American Journal of MedicineVol. 128Issue 5
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          Although colchicine has been a focus of research, debate, and controversy for thousands of years, the US Food and Drug Administration just approved it in 2009. Over the past decade, advances in the knowledge of colchicine pharmacology, drug safety, and mechanisms of action have led to changes in colchicine dosing and to potential new uses for this very old drug. In this review, we discuss the pharmacologic properties of colchicine and summarize what is currently known about its mechanisms of action.
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      • The Reply
        The American Journal of MedicineVol. 128Issue 8
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          We thank Solak et al for their important insights. We agree that when prescribed appropriately, colchicine is a safe and effective medication. The situation is in some ways analogous to that of acetaminophen—safe in the recommended range, with potential for significant toxicity in the setting of excessive overdose. In contrast to acetaminophen, however, colchicine is subject to more drug-drug interactions and is affected by declining renal function. Prudent and sound management—but certainly not fear and irrational avoidance—are therefore warranted.
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