This review aims to explore and consolidate the therapeutic potential of colchicine, one of the oldest yet still widely used treatments. Colchicine is an alkaloid compound known for its anti-inflammatory and analgesic effects. It has been effectively used to treat conditions such as gout, familial Mediterranean fever (FMF), and Behcet’s disease. The drug’s mechanism of action involves its interaction with tubulin, a structural component of the cytoskeleton, which disrupts neutrophil functions, including adhesion, migration, and chemotaxis. Colchicine specifically inhibits tyrosine phosphorylation, a key process for neutrophil activation, and affects neutrophil deformability, preventing their extravasation. Additionally, it suppresses the production of superoxide and pro-inflammatory cytokines, such as interleukin 1β and IL-6. The drug also inhibits inflammasome activity, hindering caspase-1 activation and interleukin release. Colchicine has attracted attention during the COVID-19 pandemic due to its potential to treat severe cases and reduce mortality. It is a cost-effective and widely accessible drug with a relatively safe profile. However, its metabolism can be influenced by CYP3A4 and P-glycoprotein inhibitors, as well as by renal and hepatic impairments. Common side effects include gastrointestinal disturbances such as diarrhea, nausea, and vomiting.
Colchicine is one of the oldest known treatments, still in use today. It was first documented in 1550 BC in an Egyptian papyrus and was also utilized by physicians from ancient Greece, Byzantium, and Arabia [1]. The structure of colchicine was uncovered through X-ray crystallography in 1952, and its synthetic form was confirmed by 1959 [2]. Colchicine, an alkaloid derived from Colchicum autumnale (autumn crocus), is renowned for its anti-inflammatory and pain-relieving properties. Since its synthesis in the 19th century, colchicine has been used to treat various inflammatory conditions, such as gout, familial Mediterranean fever (FMF), Behcet’s disease, and pericarditis [1]. The anti-inflammatory effects of colchicine are attributed to its interaction with tubulin, a key structural element of the cytoskeleton. Colchicine has also attracted attention during the COVID-19 pandemic, with potential applications for reducing inflammation and improving outcomes in severe cases of the disease [3]. As a widely accessible and affordable medication, colchicine is generally considered safe [4].
This review examines the literature on colchicine and highlights its multiple therapeutic applications.
To gather relevant information, we consulted several medical databases, including PubMed, ScienceDirect, and Google Scholar. Search terms used included “colchicine,” “mechanism of action,” “indications,” and “properties,” either individually or in combination. Only articles written in English were included in this review.
The colchicine molecule is a tricyclic, lipid-soluble compound with the chemical formula C22H25NO6, derived from the amino acid precursors phenylalanine and tyrosine. Its molecular structure consists of three rings: ring A, which carries a trimethoxyl group; a seven-membered ring (ring B); and a tropologic ring (ring C) [5].
Colchicine has a molecular weight of approximately 399.437 g/mol and a melting point of 142-150°C. As a light-sensitive compound, colchicine must be stored in dark containers to prevent exposure to light, which can cause it to darken. This photoisomerization transforms colchicine into lumicolchicine, a compound that is ineffective in binding to tubulin, thus losing its therapeutic properties [6].
Colchicine is primarily absorbed in the small intestine, particularly the jejunum and ileum, with a bioavailability ranging from 25% to 50%. It can be detected in leukocytes for up to 10 days following oral administration. The intravenous form of colchicine has a shorter half-life and is no longer in use due to its potential toxicity [7]. The drug is mainly cleared from the body through P-glycoprotein, which is present in various cells, including those in the liver, intestines, kidneys, and monocytes. The liver metabolizes colchicine via the cytochrome P450 (CYP3A4) enzyme, and some colchicine is excreted by glomerular filtration. This makes colchicine vulnerable to interactions with other drugs that inhibit CYP3A4, such as clarithromycin, calcium channel blockers, certain antifungal and HIV medications, and P-glycoprotein inhibitors like cyclosporine and ranolazine, potentially leading to colchicine accumulation and toxicity [8].
Colchicine’s primary mechanism of action involves binding to tubulin and disrupting microtubule polymerization, which is essential for cellular functions such as intracellular transport, cell shape, division, and migration. By preventing microtubule elongation, colchicine forms a complex with tubulin, ultimately inhibiting cell division, particularly during metaphase [9].
Colchicine alters neutrophil behavior by reducing chemotaxis, migration, and adhesion through microtubule depolymerization. It alters the function of adhesion molecules, such as E-selectin on endothelial cells, and, at higher concentrations, colchicine promotes shedding of L-selectin on neutrophils, hindering their recruitment to the site of inflammation [10].
Recent findings indicate that colchicine selectively inhibits tyrosine phosphorylation, a process essential for neutrophil activation, and reduces neutrophil extravasation by decreasing their deformability. Additionally, colchicine reduces oxidative stress by limiting calcium influx into neutrophils [11].
Moreover, colchicine prevents the release of pro-inflammatory cytokines, such as interleukin-1β and IL-6, by inhibiting superoxide production and reducing inflammasome activity, thereby suppressing the inflammatory cascade and the release of inflammatory mediators [12, 13].
Colchicine has anti-fibrotic properties, including the inhibition of the caspase-3 pathway, which reduces cell apoptosis and prevents myofibroblast differentiation. This action also reduces the secretion of anti-fibrotic factors, such as TGF-β1 [14].
In cardiovascular protection, colchicine reduces the expression of inflammatory markers, including VEGF, TNF-α, and CRP. It also inhibits vascular smooth muscle proliferation and intimal hyperplasia. When combined with atorvastatin, colchicine enhances nitric oxide production, which contributes to cardiovascular protection. Consequently, colchicine lowers cardiovascular risk markers, including mean platelet volume and β-thromboglobulin [14].
Colchicine interferes with viral replication by targeting tubulin, which is crucial for intracellular viral trafficking in viruses that rely on a microtubule network. By disrupting microtubule polymerization and assembly, colchicine can limit viral replication, particularly in flaviviruses like Zika and dengue [15].
Several RNA viruses, including coronaviruses, exploit the host cell’s membrane for their replication process. This involves the use of microtubules to transport and assemble viral particles. In the case of coronaviruses, their spike proteins interact with tubulin, which facilitates the virus’s entry and replication within the host cell. By inhibiting this process, colchicine effectively prevents viral entry and replication [16].
In addition to inhibiting viral replication, colchicine also suppresses the inflammatory response induced by coronaviruses. These viruses activate the production of pro-inflammatory mediators, such as interleukins (IL-1β and IL-6) and TNF-α, which, in turn, stimulate the NLRP3 inflammasome and trigger an inflammatory cascade. Colchicine reduces the production of these inflammatory molecules, thereby limiting the widespread inflammation caused by the virus [17]. Recent studies have shown that colchicine can reduce mortality in COVID-19 patients [3, 18], although other studies have not found a significant effect on mortality [19, 20]. Furthermore, Lopes et al. [21] observed that colchicine significantly reduced the need for oxygen therapy in COVID-19 patients. These findings highlight colchicine’s potential as a therapeutic option for COVID-19.
Colchicine is an FDA-approved medication used both for preventing and treating gout, as well as for managing familial Mediterranean fever [22]. In recent years, its application has expanded to include treatment for various other conditions, such as osteoarthritis, Behcet’s disease, prevention of post-pericardial syndrome, pericarditis, pseudogout, idiopathic pulmonary fibrosis, hepatic cirrhosis, Paget’s disease, primary biliary cirrhosis, and dermatitis herpetiformis [23].
Colchicine is most commonly taken orally and is available in several forms, including tablets, capsules, oral solutions, and, though rarely used, a gel. The standard doses are 0.6 mg for both tablets and capsules, while the oral solution provides 0.6 mg per 5 mL.
For acute gout flare-ups, the recommended initial dose is 1.2 mg at the onset of symptoms, followed by 0.6 mg one hour later. Prophylactic treatment typically continues 12 hours after the flare, with a recommended dose of 0.6 mg daily or twice daily for adults and children aged 16 and above. The total daily dose should not exceed 1.2 mg [24].
For familial Mediterranean fever, the dose range is 1.2-2.4 mg/day for adults and children over 12 years. This dose can be given as one single dose or divided into two doses, with a maximum daily dose of 2.4 mg [25].
Gastrointestinal symptoms, such as diarrhea, vomiting, and nausea, are the most commonly reported side effects of colchicine. However, several less frequent side effects can occur, which are typically reversible once the medication is discontinued. These include sensorimotor neuropathy, alopecia, maculopapular rash, purpura, lactose intolerance, and blood-related issues such as leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia. Additionally, colchicine can cause elevated liver enzymes, myopathy, muscle weakness, pain, rhabdomyolysis, and fertility issues like azoospermia and oligospermia [26].
Colchicine is metabolized primarily by the liver, utilizing the P-glycoprotein transport system and cytochrome P450 (CYP3A4). This process can be significantly affected by CYP3A4 and P-gp inhibitors, as well as by renal and hepatic impairment. CYP3A4 inhibitors, such as ketoconazole, itraconazole, and clarithromycin, and P-gp inhibitors, such as cyclosporine, can reduce colchicine metabolism, leading to dangerous accumulation and toxicity. For individuals with compromised liver or kidney function, dose adjustments or alternative medications are recommended, and colchicine should not be used alongside CYP3A4 or P-glycoprotein inhibitors in these patients [27].
There is no test available to measure colchicine levels in blood, so patients should undergo regular testing, including a complete blood count (CBC) and liver and kidney function tests. This is particularly important for patients taking other medications that interact with colchicine or those with impaired renal or hepatic function. For individuals undergoing regular dialysis, colchicine dosage may need to be reduced, as the drug is not cleared by dialysis [24].
Due to its potential to cause bone marrow suppression, colchicine should be used cautiously in patients with existing blood disorders, particularly if the drug is used for extended periods [28]. Long-term use of colchicine may also increase the risk of neuromuscular side effects, including rhabdomyolysis, and this risk is heightened when colchicine is combined with certain statins or fibrates, such as atorvastatin, simvastatin, or gemfibrozil [29].
Elderly individuals are particularly vulnerable to neuromuscular side effects and rhabdomyolysis, even in the absence of liver or kidney dysfunction. As a result, dose modifications should be considered for this age group to reduce the risk of these adverse effects [29, 30].
Colchicine is classified as a category C medication for pregnant patients, meaning it should only be used when the benefits to the mother outweigh the potential risks to the fetus. Additionally, colchicine is known to be excreted in breast milk. However, no adverse effects have been reported in infants who are breastfed by mothers taking colchicine. The American Academy of Pediatrics has determined that colchicine is generally safe for use in breastfeeding patients [31].
The precise dosage of colchicine that leads to toxicity remains unknown. However, toxicity is typically fatal when more than 0.8 mg/kg is ingested. Symptoms of colchicine toxicity usually appear within 24 hours and primarily include gastrointestinal disturbances and significant fluid loss. Between 24 and 72 hours, severe, life-threatening conditions such as multi-organ failure may develop, ultimately leading to cardiovascular collapse and respiratory failure.
Treatment for colchicine toxicity involves gastric lavage and anti-shock interventions. Since there is no specific antidote and dialysis does not effectively eliminate colchicine, treatment focuses on symptomatic and supportive care [32].
Colchicine, a long-established alkaloid drug, has anti-inflammatory and analgesic properties. It is primarily used to manage inflammatory conditions such as gout, familial Mediterranean fever (FMF), and Behcet’s disease. Recently, it has attracted attention for its potential to treat severe COVID-19 cases and reduce mortality. The drug functions by interacting with tubulin, disrupting neutrophil adhesion, migration, and chemotaxis, while also inhibiting tyrosine phosphorylation, which is vital for neutrophil activation. Additionally, colchicine reduces the production of inflammatory cytokines such as interleukin-1β and IL-6, decreases inflammasome and caspase-1 activation, and reduces superoxide production. While colchicine is widely available and considered safe, it can cause gastrointestinal side effects such as diarrhea, vomiting, and nausea. Its metabolism can be altered by CYP3A4 and P-gp inhibitors, as well as by renal and hepatic impairment.
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