The origins of colchicine and its history in poisoning can be traced to Greek mythology. Medea was the evil daughter (and a known poisoner) of the king of Colchis, a country that lay east of the Black Sea in Asia Minor. After being betrayed by her husband Jason (of Jason and the Argonauts), she killed their children and her husband’s lover. Medea is often used plants of the Liliaceae family to poison her victims, one of which is Colchicum autumnale.25,144,192 The use of colchicum for medicinal purposes is reported in Pedanius Dioscorides De Materia Medica, an ancient medical text, written in the 1st century a.d.25,144,192 and subsequently in the 6th century a.d. by Alexander of Trallis, who recommended it for arthritic conditions.25,40,181,192,176 However, colchicum fell out of favor, perhaps because of its pronounced gastrointestinal (GI) effects, until it was reintroduced for dropsy and various other nonrheumatic conditions in 1763.25,192 In the late 18th century, a colchicum containing product known as Eau Medicinale reportedly had strong antigout effects.192 Colchicine, the active alkaloidal component in colchicum, was isolated in 1820 and rapidly became popular as an antigout medication.144,192 Benjamin Franklin reportedly had gout and is credited with introducing colchicine in the United States.144 Colchicine is still used in the treatment of gout and has been used in a multitude of other disorders, including amyloidosis, Behçet syndrome, familial Mediterranean fever, chronic pericarditis, arthritis, pulmonary fibrosis, vasculitis, biliary cirrhosis, microcrystalline arthritis, certain spondyloarthropathies, calcinosis, and scleroderma.12,25,133,137 Unfortunately, systematic data supporting the efficacy of colchicine therapy in many of these other diseases are lacking.
Colchicine is derived from two plants of the Liliaceae family, C. autumnale (autumn crocus, meadow saffron, wild saffron, naked lady, son-before-the-father) and Gloriosa superba (glory lily).192 Colchicine is not distributed evenly in the autumn crocus with the highest concentrations found in the bulb and seeds (0.8%) followed by the corm or underground stem (0.6%) and the flowers (0.1%).144,169,181 Colchicine concentrations within the plant peak during the summer months.144 The leaves of C. autumnale closely resemble those of the Allium ursinum or wild garlic and have been mistaken for them.44,45,110 The tubers of G. superba may be confused with Ipomoea batatas (sweet potatoes).192
There is a dearth of epidemiologic data on colchicine poisoning. The American Association of Poison Control Centers records several hundred overall exposures annually (Chap. 136). Most of these exposures are in adults and are categorized as unintentional. Approximately 10% of the cases with a recorded outcome typically have evidence of moderate or major toxicity or resulted in death.41 Although a limited number of cases are due to intentional suicidal ingestions, recent work suggests that therapeutic colchicine administration contributes to adverse health effects and in some cases death among hospitalized patients (probably related to failure to adjust dosing for renal impairment).165 At least 50 adverse events (23 of which were fatalities) are linked to the use of intravenous (IV) colchicine.4 The US Food and Drug Administration announced its intent to stop the marketing of unapproved injectable drug compounds containing colchicine in 2009.4 Although all approved IV formulations in the United States were subsequently withdrawn, it may in theory be obtainable from compounding pharmacies and from other countries. Serious questions remain about the safety of colchicine in light of its extremely narrow therapeutic index.
Colchicine is a potent inhibitor of microtubule formation and function, and thereby interferes with cellular mitosis, intracellular transport mechanisms, and maintenance of cell structure and shape.137,192 The ubiquitous presence of microtubules in cells throughout the body presents a wide variety of targets for colchicine poisoning.137,192 Colchicine accumulates in leukocytes and has inhibitory effects on leukocyte adhesiveness, ameboid motility, mobilization, lysosome degranulation, and chemotaxis.25,51,61,88,95,186, 187, and 188 At doses used clinically, colchicine inhibits neutrophil and synovial cell release of chemotactic glycoproteins.195,218 Colchicine also inhibits microtubule polymerization, which disrupts inflammatory cell-mediated chemotaxis and phagocytosis.199 It reduces expression of adhesion molecules on endothelial and white blood cells and affects polymorphonuclear cell cytokine production.10,26,161 Colchicine also acts as a competitive antagonist at GABAA receptors in a human ex-vivo model.243
Pharmacokinetics and Toxicokinetics
Oral colchicine is rapidly absorbed in the jejunum and ileum and has a bioavailability generally between 25% and 50%.25,203 It is highly lipid soluble19,25,192 with a volume of distribution that ranges from 2.2 to 12 L/kg, which may increase to 21 L/kg in overdose.168,196,197,230 Colchicine binding to plasma proteins approaches 50%.25,137,160,192 Protein binding is principally to albumin, although some binding to α1-glycoprotein acid and other lipoproteins is reported.203 During the first several hours after acute overdose, colchicine is sequestered in white and red blood cells in concentrations five to 10 times higher than in serum.203 Peak serum concentrations after ingestion occur between 1 to 3 hours.137 Toxic effects usually do not occur with concentrations less than 3 ng/mL.89,160,239
Colchicine is primarily metabolized through the liver with up to 20% of the ingested dose excreted unchanged in the urine.230 Colchicine undergoes demethylation by CYP3A4.120,229 Detoxification mainly occurs through deacetylation, demethylation, biliary secretion, and excretion in the stool.201,203 Enterohepatic recirculation of colchicine occurs.3,192
Serum elimination half-lives ranging from 9 to 108 minutes are reported.17,107,192,203,240 However, upon closer examination, these times probably more accurately reflect a rapid initial distribution phase. The drug undergoes a more delayed terminal elimination phase, which ranges from 1.7 to 30 hours, depending on the individual compartment model used to estimate elimination and the amount of colchicine absorbed.3,93,192,197,201,203,230 These values are on the same order as, and probably reflect the tubulin–colchicine complex disassociation time.176 Individuals with stage 5 chronic kidney disease (CKD) and liver cirrhosis may have elimination half-lives that are prolonged up to tenfold.137 Colchicine can remain in measurable tissue quantities for a long time, as evidenced by its detection in white blood cells after 10 days and in urine 7 to 10 days after exposure.88,192 Colchicine can cross the placenta and is secreted in breast milk, but it is not dialyzable.137 Postmortem examination of colchicine-poisoned patients reveals high concentrations within the bone marrow, testicles, spleen, kidney, lung, brain, and heart.196
Colchicine metabolism is susceptible to drug interactions. Because colchicine is metabolized through CYP3A4, serum concentrations are susceptible to xenobiotics that alter the function of this enzyme, such as erythromycin, clarithromycin, and grapefruit juice.53,80,99,137 In particular, coadministration of clarithromycin and colchicine, especially in patients with CKD, increases the risk of fatal interaction.5,119 P-glycoprotein (PGP) expels and clears colchicine; therefore, PGP inhibitors directly affect the amount of colchicine eliminated and hence, toxicity.176 For example, cyclosporine increases colchicine toxicity.85,137,216,217 Coadministration of colchicine with statin or fibrate drugs, nephrotoxins such as nonsteroidal antiinflammatory drugs and angiotensinogen-converting enzyme inhibitors, and fluindione (antivitamin K anticoagulant) can result in colchicine poisoning.233
Microtubules play a vital role in cellular mitosis and demonstrates significant dynamic instability.22,87,127,210 Microtubules are made up of tubulin protein subunits, of which three are known to exist: α, β, and γ.127,154,210 These structures are highly dynamic with α–β-tubulin heterodimers, constantly being added at one end and removed at the other.127,128 Microtubules undergo two forms of dynamic behavior: dynamic instability, in which microtubule ends switch between growth and shortening phases, and tread milling, in which there is a net growth (addition of heterodimers) at one end and a shortening (loss) at the other.30 Assembly and polymerization dynamics are regulated by additional proteins known as stabilizing microtubule-associated proteins (MAPs) and destabilizing MAPs.30 These dynamic behaviors and a resultant equilibrium are needed for multiple cell functions, including cell support, transport, and mitotic spindle formation for cell replication.127 Xenobiotics that bind to specific regions on tubulin can interfere with microtubule structure and function, thereby causing mitotic dysfunction and arrest.154,210 This leads to cellular dysfunction and death.210 Xenobiotics that target microtubules can be generally divided into two categories: polymerization inhibitors (ie, vinca alkaloids, colchicine) and polymerization promoters (ie, taxanes, laulimalides).30
Colchicine binds to a tubulin dimer at a specific region known as the colchicine-binding domain, which is located at the interphase of the α and β subunits of the tubulin heterodimer.30,111,127,182,210,234 This binding is relatively slow, temperature dependent, and generally irreversible, resulting in an alteration of the secondary structure of the protein.111,127,143,182,204 Colchicine binds at a second reversible but lower-affinity site on tubulin.127,143 The colchicine–tubulin complex binds to the microtubule ends and prevents further growth by sterically blocking further addition of dimers.30 Conformational changes in the tubulin and colchicine complex also result as colchicine concentrations increase, which weakens the lateral bonds at the microtubule end.30,154,196,210 Lateral and longitudinal interactions between dimers within a microtubule help stabilize the structure. The number of tubulin–colchicine dimers incorporated into the microtubule determines the stability of the microtubule ends.30 All of these processes may prevent adequate binding of the next tubulin subunit and result in cessation of microtubule growth.154,210 At low concentrations, colchicine arrests microtubule growth, whereas at high concentrations, colchicine can actually cause microtubule depolymerization through disassociation of tubulin dimers.30
These conformational changes ultimately result in disassembly of the microtubule spindle in metaphase of cellular mitosis, cellular dysfunction, and death.91,111,127,182,204,210 Colchicine also inhibits microtubule-mediated intracellular granule transport.25,137 Some in vitro animal studies also show that colchicine might inhibit DNA synthesis by changing cell regulatory events at a critical time during the mitotic cycle.86,92,113,140
The toxic dose for colchicine is not well established. An early case series suggested that patients who ingested greater than 0.8 mg/kg uniformly died and those who ingested above 0.5 mg/kg but less than 0.8 mg/kg would survive if given supportive care.33 This information was based on a limited series of patients and is not generalizable.166 More recent literature suggests that severe toxicity and even death may occur with doses smaller than 0.5 mg/kg, and patients can survive ingestions reported to be in excess of 0.8 mg/kg.16,81,100,163,166,220 This inability to accurately quantify the toxic dose in humans is likely due in great part to difficulty in dose estimation from the patient’s history and significant advances in supportive care. Furthermore, many comorbid conditions (eg, CKD, liver disease) and other pharmaceuticals, which, when coadministered, can enhance the adverse effects of colchicine, complicating the determination of a minimal toxic dose.
The clinical findings in patients poisoned with colchicine are commonly described as triphasic (Table 36–1).115,150,168,220 GI irritant effects, such as nausea, vomiting, abdominal distress, and diarrhea, occurring within several hours of an overdose8,43,45,71,79,129,150,155,236 and may lead to severe volume depletion.99,118,146,166,168,170,220,242 This first stage usually persists for the first 12 to 24 hours following ingestion.118,150 The second stage is characterized by widespread organ system dysfunction, particularly the bone marrow, and lasts for several days.45,81,166,168,220 The final phase is characterized by recovery or death, and the progression can usually be defined within one week.115,118,150,220
TABLE 36–1.Colchicine Poisoning: Common Clinical Findings, Timing of Onset, and Treatment |Favorite Table|Download (.pdf) TABLE 36–1. Colchicine Poisoning: Common Clinical Findings, Timing of Onset, and Treatment
|Phase ||Timea ||Signs and Symptoms ||Therapy/Follow-Up |
|I ||0–24 hours || |
Nausea, vomiting, diarrhea
Salt and water depletion
Consider GI decontamination
Close observation for leukopenia
|II ||1–7 days || |
Risk of sudden cardiac death (24–48 hours)
Acute kidney injury
Acute respiratory distress syndrome
ICU admission and appropriate resuscitation
Oxygen, mechanical ventilation
Repletion as needed
IV fluids, hemodialysis
|III ||> 7 days || |
Alopecia (may not develop for 2–3 weeks)
Myopathy, neuropathy, or myoneuropathy
Follow-up within 1–2 months
EMG testing, biopsy and neurologic follow-up as needed
After overdose, the hematopoietic effects of colchicine are characterized by an initial leukocytosis, which may be as high as 30,000/mm3. This is followed by a profound leukopenia, which may be lower than 1000/mm3 and is commonly accompanied by pancytopenia, usually beginning 48 to 72 hours after overdose.25,43,93,99,114,150,172 The hematopoietic manifestations occur as a result of the effects of colchicine on bone marrow cell division.40,118,153,196,242 A rebound leukocytosis and recovery of all cell lines occur if the patient survives.
Colchicine toxicity is associated with the development of dysrhythmias and cardiac arrest.40,115,118,150,168 Sudden cardiovascular collapse from colchicine typically occurs between 24 to 36 hours after ingestion.40,52,150,153,166 Profound hypovolemia and shock may contribute to this collapse,25,99,166,168,220 but colchicine also has direct toxic effects on skeletal and cardiac muscle.36,62,148,156,167,237,242
Myopathy,46,47,209,247 neuropathy,13,140 and combined myoneuropathy11,64,72,84,135,136,193,215,253 result from both long-term therapy and acute poisoning.140 Combined myoneuropathy is reported more often, with myopathy dominating the clinical picture.11,64,72,135,136,193,215,253 Myoneuropathy is often initially misdiagnosed as polymyositis or uremic neuropathy (caused by coexistent kidney failure).13,136 Myoneuropathy usually develops in the context of chronic, therapeutic dosing in patients with some baseline CKD,11,64,72,84,134,136,193,215,253 although it may also occur in the presence of normal kidney function.190 Patients may present with proximal limb weakness, distal sensory abnormalities, distal areflexia, and nerve conduction problems consistent with an axonal neuropathy.136,185 A small amount of myelin degeneration is reported on autopsy, which suggests a myelinopathic component.42 The myopathy is characterized by vacuolar changes on biopsy and accompanied by lysosome accumulation.11,84,136,253 An elevated serum creatine kinase concentration is present concurrently with symptoms.136,168 Weakness usually resolves within several weeks of drug discontinuation.136 Myopathy may also occur when hydroxymethylglutaryl–coenzyme A reductase inhibitors are concomitantly used in patients with renal insufficiency.6 Myopathy symptoms typically resolve within 4 to 6 weeks, although it may take up to 6 to 8 months in some patients.247
Acute respiratory distress syndrome occurs with colchicine toxicity.18,71,114,158,208,211 The etiology is not well understood but may result from several factors, including respiratory muscle weakness, multisystem organ failure, and possibly direct pulmonary toxicity.71,150,158,208,228 Other indirect effects of colchicine include acute kidney injury (AKI) and various electrolyte abnormalities resulting from fluid loss and impaired glomerular filtration rate.25,81,99,140,168
Alopecia, which is usually reversible, is a well-described complication that occurs 2 to 3 weeks after poisoning.12,25,93,99,100,118,143,227 Dermatologic complications range in severity from epithelial cell atypia to toxic epidermal necrolysis.9,15,91,98,200 Neurologic effects, including delirium, stupor, coma, and seizures, might be at least partly attributable to the multisystem disease caused by poisoning and not necessarily a direct effect of colchicine.46,172,192,211 The cause of seizures is unclear but it might be partly attributable to antagonism of GABAA receptors.243 Other reported complications of colchicine poisoning include bilateral adrenal hemorrhage,66,224 disseminated intravascular coagulation,118,192,211 pancreatitis,172,232 and liver dysfunction.46,168,192
Although uncommon, poisoning from IV colchicine administration has occurred. Clinical and laboratory manifestations are similar to those that occur after oral exposure including multisystem organ dysfunction and cytopenias.55
Colchicine does not appear to be a significant human teratogen but the limited work on this subject is not definitive.76
Colchicine concentrations in body fluids are not available in a clinically relevant time frame and have no well-established correlation with severity of illness. However, effective steady-state serum concentrations for treatment of patients with various illnesses are reported as 0.5 to 3.0 µg/L.160 Concentrations > 3.0 µg/L can be associated with toxicity depending on the clinical situation and concentrations > 24 µg/L are definitely associated with toxicity.89,160,239,249 Serum concentrations do not correlate well with ingested dose in massive oral overdose settings.75 Initial laboratory monitoring should include a complete blood count (CBC), serum electrolytes, renal and liver function tests, creatine kinase, phosphate, calcium, and magnesium. A prothrombin time, activated partial thromboplastin time, urinalysis, and other focused testing can be considered depending on clinical suspicion for different end-organ injury. The need for other laboratory studies, such as a troponin, arterial or venous blood gas, lactate, fibrinogen, and fibrin split products, should be considered, depending on the clinical situation. Following significant overdose or in any case if cardiac toxicity is present or suspected, serial troponins (every 6–12 hours) should be performed because increasing concentrations may be predictive of cardiovascular collapse.96,237 Electrocardiography and chest radiography should also be obtained. Serial CBCs are indicated (at least every 12 hours) to evaluate for the development of depression in cell lines. Bile appears to be the biologic matrix of choice for postmortem testing, probably due to normal postmortem biologic processes that can increase blood colchicine concentration.28,171 One colchicine-associated fatality who had a premortem blood colchicine concentration of 50 μg/L, also had a postmortem femoral blood concentration of 137 μg/L and a bile concentration above 600 μg/L.249 Another reported a postmortem blood concentration of 60 µg/L.2 Two IV colchicine-associated fatalities had postmortem blood colchicine concentrations of 32 µg/L and 44 µg/L.55
Treatment for patients with colchicine toxicity is mainly supportive, which includes IV fluid replacement, vasopressor use, hemodialysis (as indicated for acute kidney injury), antibiotics for suspected secondary infection, colony-stimulating factors, and adjunctive respiratory therapy (endotracheal intubation, positive end-expiratory pressure), as necessary. Consultation with nephrologists and hematologists may be useful. In severe poisoning, intraaortic balloon pump therapy and extracorporeal membrane oxygenation therapy may be of help but there is no proof of clinical benefit.179
Because most patients with an acute oral colchicine overdose present several hours after their ingestion, vomiting has already begun, and the utility of GI decontamination is inadequately defined. However, given the extensive morbidity and mortality associated with colchicine overdose, orogastric lavage should be considered in patients who present within 1 to 2 hours of ingestion and are not already vomiting.1,35,235 A dose of activated charcoal (AC) should be administered after lavage, or in its place if lavage is not appropriate or possible in the judgment of the physician. Since limited evidence suggests that colchicine undergoes some enterohepatic recirculation, administration of a single dose of AC to a patient presenting to a health care facility beyond 2 hours following ingestion can be considered if no contraindications exist. Multiple-dose AC (MDAC) can also be considered in these patients for the same reason.3,192 The delay in presentation to a health care facility coupled with the fact that patients often have GI symptoms such as vomiting limits the potential benefit of using MDAC. However, antiemetic medications can be given to control emesis and facilitate AC administration (Antidotes in Depth: A1).
Experimentally, colchicine-specific antibodies can restore colchicine-affected tubulin activity in vitro and were successfully used in a single case of severe colchicine poisoning.21 The administration of Fab fragments was temporally associated with a dramatic improvement in clinical and hemodynamic status. This improvement was also associated with a significant increase in serum colchicine concentrations, which suggests a redistribution of drug into the intravascular space.21 Unfortunately, this therapy is not commercially available.
Granulocyte-colony stimulating factor (G-CSF) is useful in the treatment of patients with colchicine-induced leukopenia and thrombocytopenia.69,109,131,252 The dose of G-CSF, the dosing frequency, and the route of administration were variable in the reported cases.69,109,131,252 G-CSF should be started if the patient develops leukopenia. Dosing should be in accordance with the manufacturer’s instructions.
Hemodialysis and hemoperfusion are not viable options to enhance colchicine clearance based on its large volume of distribution, but hemodialysis may be required if AKI is severe.24,31,32,196,197,230,242 Whole blood and plasma exchange have been suggested for cases presenting with lethal-dose colchicine exposures, but evidence of efficacy is lacking, and therefore these procedures are not recommended at this time.179
Because of the significant morbidity and mortality associated with colchicine toxicity, all symptomatic patients with suspected or known overdoses should be admitted to the hospital for observation. Because these patients have a risk of sudden cardiovascular collapse within the first 24 to 48 hours166 intensive care unit monitoring is recommended for at least this initial time period. Troponin should be checked every 6 to 12 hours during this period because increasing results may suggest an increased risk of cardiotoxicity and cardiovascular collapse.96,237 CBCs should be followed at least daily to evaluate for cytopenias. Poisoned patients manifest GI signs and symptoms within several hours of ingestion and should be observed for at least 8 to 12 hours. Patients who do not manifest GI signs and symptoms within that time period after ingestion are unlikely to be significantly poisoned.