Could Colchicine Be the New Aspirin?
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Adverse events during oral colchicine use: a systematic review and meta-analysis of randomised controlled trials
January 27, 2020
The benefits of colchicine with regard to cardiovascular end points in COLCOT were at least as large as those of canakinumab in CANTOS.2
In conclusion, among patients with a recent myocardial infarction, colchicine at a dose of 0.5 mg daily led to a significantly lower percentage of patients with ischemic cardiovascular events than placebo.
The main intention-to-treat analysis showed that over a median follow-up of 22.6 months the patients in the colchicine group were at significantly lower risk of experiencing a primary-endpoint event than were those who received placebo (5.5% vs 7.1%; HR 0.77; 95% CI 0.61-0.96). This reduction was also seen in adjusted and per-protocol analyses.
Colchicine was not associated with significant decreases in the individual components of CV death, resuscitated cardiac arrest, or MI. However, the drug did lower the risk of stroke (HR 0.26; 95% CI 0.10-0.70) and urgent hospitalization for angina leading to coronary revascularization (HR 0.50; 95% CI 0.31-0.81).
"The COLCOT results apply to patients who have recently suffered a myocardial infarction. Further research is needed to assess the benefits of colchicine in other high-risk patients," Tardif observed. To meet this knowledge gap, the researchers are launching the COLCOT-T2D trial of 10,000 type 2 diabetes patients without known CAD.
Aruna Pradhan, MD, MPH (Brigham and Women's Hospital, Boston, MA), discussing the results in today's press conference, praised the COLCOT trial: "It was a large, simple, and well-designed event-driven trial which aimed to answer one core question. This will be a landmark study. These results provide confirmation that inflammation management reduces cardiovascular risk and it [stands out] as an example of successful repurposing of a broadly available and relatively safe generic drug for a new application."
But she emphasized the lack of effect on "more robust" hard outcomes like death and MI as well as the "weak" signal for stroke. Pradhan also cautioned that "complete ascertainment of adverse events was not performed in this trial," so there could be unmeasured factors that would limit long-term use. For example, there could be issues in patients with chronic kidney disease, she suggested, seeing as how colchicine is renally cleared.
We performed a randomized, double-blind trial involving patients recruited within 30 days after a myocardial infarction. The patients were randomly assigned to receive either low-dose colchicine (0.5 mg once daily) or placebo. The primary efficacy end point was a composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization. The components of the primary end point and safety were also assessed.
The primary end point occurred in 5.5% of the patients in the colchicine group, as compared with 7.1% of those in the placebo group (hazard ratio, 0.77; 95% confidence interval [CI], 0.61 to 0.96; P=0.02). The hazard ratios were 0.84 (95% CI, 0.46 to 1.52) for death from cardiovascular causes, 0.83 (95% CI, 0.25 to 2.73) for resuscitated cardiac arrest, 0.91 (95% CI, 0.68 to 1.21) for myocardial infarction, 0.26 (95% CI, 0.10 to 0.70) for stroke, and 0.50 (95% CI, 0.31 to 0.81) for urgent hospitalization for angina leading to coronary revascularization.
Colchicine is an inexpensive, orally administered, potent antiinflammatory medication that was initially extracted from the autumn crocus and has been used for centuries. Its mechanism of action is through the inhibition of tubulin polymerization and microtubule generation and, possibly, effects on cellular adhesion molecules, inflammatory chemokines, and the inflammasome.4-6 Colchicine is currently indicated for the treatment of gout, familial Mediterranean fever, and pericarditis.7,8 In the Low-Dose Colchicine (LoDoCo) trial, patients with stable coronary disease treated with colchicine at a dose of 0.5 mg once daily had fewer cardiovascular events than those not receiving colchicine.9 However, that trial enrolled only 532 patients and was not placebo-controlled. Because acute coronary syndromes are associated with higher risks of recurrent events and exacerbated inflammation, we conducted the Colchicine Cardiovascular Outcomes Trial (COLCOT) to evaluate the effects of colchicine on cardiovascular outcomes as well as its long-term safety profile in patients who had recently had a myocardial infarction.
The present study shows that in patients with stable vascular disease plasma CRP concentration is related to risk of recurrent cardiovascular events, as well as risk of cancer, especially lung cancer. No effect modification by smoking status was observed. A potential relation was observed between CRP and lymphoid/hematopoietic and urinary tract cancer. The relation between plasma CRP and incident cancer was seen for epithelial neoplasms, especially squamous cell neoplasms, irrespective of anatomical location of origin.
Results of the present study support the role of chronic systemic low-grade inflammation as a stimulating factor in cancer development in a cohort of patients with established vascular disease. The observed relation between CRP and cancer risk cannot be explained by reverse causality, meaning that an elevated CRP would simply be a sign of occult cancer, as similar results were observed after exclusion of patients with a diagnosis of cancer within 1, 2, and 5 year(s) after inclusion. Results of the present study correspond to results of the CANTOS trial11,12 and previous prospective cohort studies performed in population-based cohorts or cohorts of apparently healthy people.2-6,9,10 To our knowledge, no previous studies investigated the relation between CRP and incident cancer in patients with established vascular disease specifically. Cancer incidence is higher in patients with established CVD compared to the general population, likely due to common risk factors,20 and the current study shows that systemic low-grade inflammation is a contributing factor in pathophysiology of CVD as well as cancer.
In accordance with previous observational studies,2-6,9,25 and in line with the CANTOS trial results,12 lung cancer risk was especially related to CRP levels. Chronic low-grade inflammation is previously considered to be one of the causal pathways by which smoking leads to lung cancer.15 Epithelial neoplasms and squamous cell neoplasms, irrespective of anatomical location of origin, were mostly respiratory tract cancers; lung carcinomas and carcinomas of the lip, oral cavity, pharynx, and glottis. The elevated systemic inflammatory levels as a risk factor for respiratory tract cancer might reflect a local inflammatory microenvironment caused by smoking26 that contributes to cancer development. It is possible that low-grade inflammation initiated by smoking is not reversed when quitting smoking, emphasizing the importance of smoking abstinence. In the present study, the relation between CRP and total cancer risk in never smokers was uncertain (HR 1.05; 95% CI 0.98-1.13). However, no significant interaction was observed for smoking status (P > 0.05) and the point estimate was the same as in current smokers (HR 1.05; 95% CI 1.01-1.10). The incidence of lung cancer (n = 9) in never smokers was too low for reliable analysis. A previous case-control study nested in population-based cohorts showed no relation between CRP and lung cancer in never smokers.25 However, that higher inflammation levels as a risk factor for cancer are a direct result of smoking is unlikely based on the results of this study. Adjustment for smoking status and pack-years did not mitigate the relation between CRP level and cancer risk, suggesting that other pathophysiological pathway, and possibly other inflammatory pathways, play a role in mechanisms leading from smoking to cancer. Furthermore, the combination of a CRP level in the highest quintile with current smoking, conferred the highest cancer risk, suggesting an additive effect of inflammation and smoking on cancer risk. Potential relations between CRP and lymphoid/haematopoietic and urinary tract cancer should be interpreted with caution, as the relations were not statistically significant in all analyses, but suggest that inflammation could be involved in the pathogenesis of these neoplasms.
The relation between CRP and cancer risk is of great importance for clinical practice. As treatment for CVD has improved substantially over the last decades, more patients survive acute manifestations of CVD and survive long enough to develop cancer. C-reactive protein is a marker for CVD risk and could potentially also serves as a prognostic marker to identify those at high risk of (lung) cancer. Since patients from the third CRP quintile and higher had an increased risk of lung cancer, CRP levels of ≥1.4 mg/L might be indicative of a higher risk of lung cancer. It could even be hypothesized that patients at high cardiovascular risk with high levels of inflammation are those that might benefit from anti-inflammatory treatment to reduce cardiovascular risk as well as risk of (lung) cancer. The CANTOS trial implicated that the IL-1β, IL-6, CRP inflammatory pathway is involved in cancer development.12Results of trials studying other anti-inflammatory treatments could provide additional information on specific inflammatory pathways involved in cancer pathogenesis and the effectiveness of lowering inflammation on reduction of cancer risk, even though cancer was not the primary endpoint in these trials. However, the Cardiovascular Inflammation Reduction Trial (CIRT) was stopped due to ineffectiveness of methotrexate on CRP levels and CVD risk and no data are available yet on cancer incidence.27 The Low Dose Colchicine study (LoDoCo2, EudraCT Number: 2015-005568-40), trialling effect of colchicine on CVD risk is still ongoing and might provide additional information.
Adverse events during oral colchicine use: a systematic review and meta-analysis of randomised controlled trials
Arthritis Research & Therapy volume 22, Article number: 28 (2020)
Colchicine is a widely used drug to treat inflammatory diseases. Due to its long historical use in medicine, controlled clinical trials have been small and there remains some caution with the use of this drug in patients with co-morbidities. The aim of the study is to systematically examine the side effect profile of colchicine in controlled clinical trials across all published indications.
A systematic review was conducted in accordance with PRISMA methodology. The Cochrane Library, MEDLINE and EMBASE were searched for double-blind controlled trials of oral colchicine in adult patients that reported adverse event data. Meta-analyses were used to determine the relative risk (RR) of adverse events in colchicine users compared to comparator groups.
A total of 4915 studies were initially identified and after exclusions, 35 randomised controlled trials with placebo (n = 30) or active comparators (n = 5) were included. The most common diseases studied were gout, liver cirrhosis and pericarditis. There were a total of 8659 pooled participants, 4225 participants were randomised to receive colchicine, 3956 to placebo and 411 to an active comparator. Diarrhoea was reported in 17.9% of colchicine users versus 13.1% in comparator groups (RR 2.4, 95% confidence interval (CI) 1.6, 3.7). Any gastrointestinal event was reported in 17.6% of colchicine users and 13.1% of comparators (RR 1.7, 95% CI 1.3, 2.3). Adverse liver events were reported in 1.9% of colchicine users versus 1.1% in the comparator groups (RR 1.6, 95% CI 0.9, 3.0). Muscle events were reported in 4.2% of colchicine users and 3.3% in the comparator groups (RR 1.3, 95% CI 0.8, 1.9). Haematology events were reported in 0.6% of colchicine users and 0.4% of comparator groups (RR 1.34 (0.64, 2.82). No study reported neuropathy events. Other sensory events were reported in 1.1% of colchicine users and 1.5% of comparator groups (RR 1.4, 95% CI 0.3, 6.7). Infectious events were reported in 0.4% of colchicine users and 2.1% of comparator groups (RR 1.0, 95% CI 0.7, 1.5). No study reported death as an adverse event.
Colchicine increases the rate of diarrhoea and gastrointestinal adverse events but does not increase the rate of liver, sensory, muscle, infectious or haematology adverse events or death.
Colchicine is an anti-inflammatory agent which is widely used for the treatment of gout and also used extensively for familial Mediterranean fever, Behcet's disease and pericarditis. Its use in the management of gout has increased due to the widespread recommendation that it be used as a gout flare prophylaxis when urate-lowering therapy is initiated . It is used continuously for long periods of time in individuals with familial Mediterranean fever and Behcet's disease. However, due to its long historical use in medicine, it has not been subjected to the same registration trials that contemporary medicines require. There remains uncertainty regarding its use in certain risk groups including those with kidney and liver impairment, at higher doses, and with CYP3A4 inhibitors . It has previously been used in an intravenous preparation, but this is no longer used due to the adverse safety profile of this administration method .
Although the adverse event profile of colchicine has been reported in various individual clinical trials and for single indications like pericarditis , it has not been studied systematically to our knowledge. The aim of this study was to examine the adverse events of colchicine reported in randomised controlled trials using a systemic review and meta-analysis methodology.
Characteristics of participants in the included studies are shown in Table 1. A number of disease states were studied including cirrhosis (n = 5 studies) [6,7,8,9,10], pericarditis (n = 4 studies) [26, 27, 29, 31], gout (n = 5 studies) [15, 18, 34, 38, 39], knee osteoarthritis (n = 3 studies) [16, 20, 30], Behcet's syndrome (n = 3 studies) [21, 32, 40], psoriatic arthritis (n = 2 studies) [13, 36], post-pericardiotomy syndrome (n = 2 studies) [25, 28], chronic obstructive pulmonary disorder (n = 1 study) , bare-metal stent restenosis (n = 1 study) , metabolic syndrome (n = 1 study) , lung resection surgery (n = 1 study) , myocardial infarction (n = 1 study) , familial Mediterranean fever (n = 1 study) , asthma (n = 1 study) , primary sclerosing cholangitis (n = 1 study) , aphthous stomatitis (n = 1 study) , allergic rhinitis (n = 1 study)  and low back pain (n = 1 study) . Sample sizes ranged from 11 to 4745, with a pooled sample of 8659 adult participants. Mean age ranged from 27.0 to 69.1 years with most participants being male (73%). The inclusion and exclusion criteria reported by the included studies are shown in Supplementary Table 1.
Any adverse event
The number of participants with any adverse event was reported by 27 papers (Supplementary Table 2). From this data, 21.1% (95% confidence interval (CI) 19.9, 22.4) of participants using colchicine reported any adverse event compared to 18.9% (95% CI 17.7, 20.1) of participants in comparator groups. A meta-analysis showed the overall estimated risk ratio (RR) (95% CI) of any adverse event in colchicine users compared with pooled comparator groups was 1.46 (1.20, 1.77), P < 0.001 (Fig. 2, Table 2). The difference in RR of any adverse event in colchicine users was not significantly different between placebo and active comparator groups (P = 0.27). After the exclusion of six studies involving participants with liver disease, the RR (95% CI) of any adverse event in colchicine users vs. comparator groups was similar at 1.37 (1.14, 1.65), P < 0.001 (Supplementary Table 3).
Although the sub-group meta-analyses showed a higher relative risk for any adverse event in colchicine users with liver diseases (RR 5.92 (95% CI 2.08, 16.82)), there was no overall significant difference in the relative risk of adverse events between different disease indications (P = 0.11) (Fig. 3). Furthermore, there was no significant difference in relative risk across different durations of drug exposure (P = 0.29) (Supplementary Figure 2), different colchicine daily dose categories (P = 0.70) (Supplementary Figure 3) or different colchicine cumulative dose categories (P = 0.09) (Fig. 4).
The number of participants with diarrhoea was reported by a total of 19 papers (Supplementary Table 2). From this data, 17.9% (95% CI 16.8 19.1) of participants using colchicine reported diarrhoea compared to 13.1% (95% CI 11.9, 14.3) of participants in comparator groups. The meta-analysis showed the overall estimated RR (95% CI) of diarrhoea in colchicine users compared with pooled comparator groups was 2.44 (1.62, 3.69) (P < 0.001) ((Supplementary Figure 4, Table 2). The difference in RR between placebo and active comparator groups was not significant (P = 0.60). After exclusion of 6 studies involving participants with liver disease the RR (95% CI) of diarrhoea in colchicine users vs comparator groups was similar at 2.14 (1.40, 3.26), P < 0.001 (Supplementary Table 3).
The proportion of participants with diarrhoea computed from all 35 studies in this review (in which prevalence was considered 0% if not reported) was 10.8% (95% CI 9.9, 11.7) in colchicine users and 6.1% (95% CI 5.4, 6.8) in comparator groups.
Gastrointestinal adverse event
The number of participants with any gastrointestinal event was reported by 29 papers (Supplementary Table 2) and included diarrhoea, nausea, vomiting, abdominal pain, loss of appetite, bloating, constipation, melena and peptic ulcer (Supplementary Table 4). From these 29 papers, 17.6% (95% CI 16.5, 18.8) of participants using colchicine reported a gastrointestinal event compared to 13.1% (95% CI 12.1, 14.2) of participants in comparator groups. The overall RR (95% CI) of gastrointestinal events in colchicine users compared with pooled comparator groups was 1.74 (1.32, 2.30), P < 0.001 (Fig. 5, Table 2). The difference between placebo and active comparator groups was not significant (P = 0.32). After the exclusion of 6 studies involving participants with liver disease, the RR (95% CI) of any gastrointestinal event in colchicine users vs comparator groups was similar at 1.60 (1.22, 2.10), P < 0.001 (Supplementary Table 3).
The number of participants with liver events was reported by 13 papers (Supplementary Table 2) and included increased liver enzymes, hepatitis, hepatotoxicity and hepatic abnormalities (Supplementary Table 4). Pooled data from these papers showed 1.9% (95% CI 1.2, 2.8) of participants using colchicine reported a liver event compared to 1.1% (95% CI 0.6, 1.8) of participants in comparator groups. The overall RR (95% CI) of liver events in colchicine users did not significantly differ from the pooled comparator groups: 1.61 (0.86, 3.02) (Supplementary Figure 5, Table 2). The difference between placebo and active comparator groups was also not significant. None of the included papers involved participants with liver diseases.
The proportion of participants with any liver event computed from all 32 studies in this review (in which prevalence was considered 0% if not reported) was 0.5% (95% CI 0.3, 0.7) in colchicine users and 0.3% (95% CI 0.2, 0.5) in comparator groups.
The number of participants with muscle events was reported by nine studies (Supplementary Table 2) and included myalgia, muscle cramps, elevated creatine phosphokinase and muscle weakness (Supplementary Table 5). Rhabdomyolysis was not mentioned in any study. All nine studies involved placebo comparator groups. Pooled data from these studies showed 4.2% (95% CI 3.0, 5.7) of participants using colchicine reported a muscle event compared to 3.3% (95% CI 2.3, 4.7) of participants in placebo groups. The meta-analysis showed an overall non-significant RR (95% CI) of muscle events in colchicine users of 1.25 (0.80, 1.93) (Fig. 6, Table 2). None of the studies involved participants with liver diseases.
The proportion of participants with muscle events computed from all 35 studies in this review (in which prevalence was considered 0% if not reported) was 0.8% (95% CI 0.6, 1.1) in colchicine users and 0.6% (95% CI 0.4, 0.9) in comparator groups.
The number of participants with haematology events was reported by eight studies (Supplementary Table 2) and included anaemia, bone marrow toxicity, leukopenia and purpura (Supplementary Table 4). All studies involved placebo comparator groups. Pooled data from these studies showed 0.6% (95% CI 0.3, 0.9) of participants using colchicine reported a haematology event compared to 0.4% (95% CI 0.2, 0.7) of participants in placebo groups. The occurrence of haematology events in colchicine or comparator groups was reported by three studies [21, 23, 37]. The meta-analysis showed an overall non-significant RR (95% CI) of haematology events in 1.34 (0.64, 2.82) (Supplementary Figure 6, Table 2). None of the studies involved participants with liver diseases.
The proportion of participants with a haematology event computed from all 35 studies in this review (in which prevalence was considered 0% if not reported) was 0.4% (95% CI 0.2, 0.6) in colchicine users and 0.3% (95% CI 0.1, 0.4) in comparator groups.
No studies mentioned neuropathy-related adverse events. However, two studies involving placebo comparator groups reported other sensory events (Supplementary Table 2) which included dysthesia in the legs and paresthesia (Supplementary Table 5). From this data, the pooled prevalence of sensory events was 1.1% (95% CI 0.2, 3.4) in colchicine users and 1.5% (95% CI 0.4, 4.0) in placebo groups. The meta-analysis showed an overall non-significant RR (95% CI) of sensory events in colchicine users of 1.35 (0.27, 6.74) (Supplementary Figure 7, Table 2). None of the included papers involved participants with liver diseases.
The proportion of participants with any sensory events computed from all 35 studies in this review (in which prevalence was considered 0% if not reported) was 0.04% (95% CI 0.0, 0.1) in colchicine users and 0.07% (95% CI 0.0, 0.2) in comparator groups.
Seven studies reported various infectious events (Supplementary Table 2), including urinary tract infection, parotiditis, shingles, upper respiratory tract infection, nasopharyngitis and sinus congestion (Supplementary Table 5). From these papers, 0.4% (95% CI 0.2, 0.6) of participants using colchicine reported an infectious event compared to 2.1% (95% CI 1.6, 2.7) of participants in comparator groups. The overall RR (95% CI) of infectious events in colchicine users compared with pooled comparator groups was non-significant: 1.03 (0.70, 1.51) (Supplementary Figure 8, Table 2). The difference between placebo and active comparator groups was not significant (P = 0.94). No study involved participants with liver diseases.
The proportion of participants with any infectious event computed from all 35 studies in this review (in which prevalence was considered 0% if not reported) was 2.4% (95% CI 2.0, 2.9) in colchicine users and 2.8% (95% CI 2.4, 3.4) in comparator groups.
Death related to adverse events was specifically reported in three studies (Supplementary Table 2). No study reported deaths related to an adverse event.
Miscellaneous adverse events reported by the included studies are summarised in Supplementary Table 6. These events were not meta-analysed but contributed to the 'any adverse event' category.
This systematic review and meta-analysis of randomised controlled trials indicate that overall, colchicine increases the rate of adverse events compared to both placebo and active comparators. Analysis of individual events demonstrated an increased risk for diarrhoea and gastrointestinal events in colchicine users, but no increase in the rate of other commonly cited adverse events, including liver, muscle, haematology, sensory or infectious events.
The mechanism by which colchicine induces diarrhoea and other gastrointestinal symptoms is not exactly known, but can be attributed to an increase in prostaglandin synthesis, intestinal secretion and gastrointestinal motility with this drug . Although these symptoms can be clinical features of colchicine toxicity, they are usually mild, short-lived and reversible with dose reduction . Serious adverse events associated with colchicine use, including neuropathy, myotoxicity and death were not reported in any trial included in the current analysis. These events may be more readily observed in less controlled environments evident in case reports involving colchicine over-dose, chronic renal diseases, interaction with concomitant medications and intravenous administration [42,43,44,45,46,47,48,49].
Analysis of adverse events in colchicine users showed no difference across different disease indications. Although overall, adverse events were numerically higher in patients with liver diseases, this risk was not significantly different from other disease indications. Furthermore, the sub-analysis excluding participants with liver disease showed similar adverse events rates to the main analysis. Although dose reduction is generally recommended when colchicine is used continuously in those with severe renal impairment, accurate conclusions regarding adverse events in this population could not be drawn from the current analysis.
There was notable heterogeneity across the clinical trials included in this review with regards to intervention methodology, including colchicine dose and treatment duration. However, sub-group analyses concluded that differences in drug use duration, daily dose or cumulative dose categories had no effect on the risk for adverse events. This contrasts with trials assessing the treatment of acute gout which report that high-dose colchicine results in a greater risk-to-benefit ratio. The paper reporting the AGREE trial included in the current analysis by Terkeltaub et al. , which directly compared two different doses of colchicine, found differences in adverse event rates between low and high dose groups, with 36% and 81% of participants having any adverse event, respectively. However, the short duration of treatment (1 to 6 h) meant that the cumulative drug doses in both groups were low in the context of the other papers included in the meta-analysis, resulting in a non-significant effect of dose in the meta-analysis. The difference in adverse event rates between the two arms of this AGREE trial may relate to better surveillance of adverse events in this trial compared to previously reported trials, or the relatively high dose (4.8 mg over 6 h) of the high-dose colchicine group. This is the only published trial comparing two differing doses of colchicine so conclusions on the reason for this disparity are difficult to be definitive about.
The limitations of this study include the inability in assessing the occurrence of rarer adverse events when only short duration controlled clinical trials were included. Different methodology is required to assess the frequency of rarer adverse events. Furthermore, the aims of the majority of the included studies were not primarily to assess safety, resulting in limited availability of adverse event data for extraction. As only studies which specifically reported an adverse event as being present or absent were included in the meta-analyses, it is possible that the pooled results may have over-estimated the true occurrence of adverse events which were not reported in all papers. In addition, it is also possible that the pooled results may have under-estimated the true occurrence of adverse events which were not assessed (e.g. those requiring blood tests). There were few included participants with severely impaired renal function, so the ability to assess for safety in this group was limited. Clinical trials often recruit patients in a highly selective manner, including excluding those with co-morbidities, and therefore the results are not necessarily generalizable to a general patient population. In addition, the included studies spanned over 20 years and it is likely that participants in earlier studies are not representative of patients treated with colchicine in clinical practice today. Other limitations include the screening of titles, abstracts and full-texts being undertaken by a single reviewer, and the exclusion of non-English language publications.
The strengths of this study include the strict inclusion of only placebo or active comparator blinded trials which reduces the potential for bias; although the occurrence of diarrhoea in participants can lead to at the least the suspicion of being in the colchicine group. In addition, there was a wide range of included indications such as gout, familial Mediterranean fever, Behcet's disease and pericarditis, which leads to increased generalisability of the study results.
This meta-analysis provides reassurance that common adverse events with colchicine use are limited to diarrhoea and gastrointestinal events. Whilst these are not benign side effects in some individuals, they will settle on dose reduction or drug discontinuation. More serious adverse events during colchicine use, including liver and haematological changes, muscle toxicity, neuropathy and death are very infrequent in clinical trials.