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| Journal of the New Zealand Medical Association,
26-January-2007, Vol 120 No 1248
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Colchicine overdose: the devil is in the
detail
Vikram Jayaprakash, Gillian Ansell, David Galler
“No other pain is more
severe than this, not iron screws, nor cords, not the wound of a dagger, nor
burning fire” (Aretaeus: 2nd century
Greek physician describing gout)
Case reportDay 1—A 39-year-old Samoan man was
admitted to Middlemore Hospital’s Emergency Department (ED) 12 hours after
an apparent accidental overdose of colchicine. He had a history of gout, and
(over an 8–12 hour period) took approximately 30–40 × 600
μg of colchicine tablets and 8 × 50 mg of diclofenac tablets in an
attempt to alleviate the symptoms of his acute attack. He initially presented to
his GP with symptoms of abdominal pain and diarrhoea and was then referred to
hospital.
On presentation he had profuse non-bloody diarrhoea and was
vomiting. He appeared extremely anxious but was fully conscious and alert. He
was tachypnoeic with good gas exchange and clinically dehydrated. In the ED, he
was aggressively resuscitated with intravenous fluids, and an attempt was made
to prevent absorption of any residual drug. He was commenced on repeated doses
of activated charcoal and an enteral purgative before being transferred to the
Intensive Care Unit (ICU). Over the next 4 hours his breathing became more
laboured; his gas exchange worsened, and he subsequently required respiratory
support with facemask continuous positive airway pressure (CPAP).
Day 2—The patient continued to
deteriorate, his chest X-ray worsened (with changes consistent with an acute
lung injury), and hence he was intubated and ventilated. During the course of
the day, he became increasingly hypotensive despite aggressive fluid
replacement, increasing doses of vasopressors, and inotropes. The clinical
picture, confirmed by invasive monitoring (PICCO) and echocardiography, was
initially of a low vascular resistance with a hyper dynamic myocardium.
Day 3—Despite continuous renal
replacement therapy (sustained low efficiency dialysis) to correct his worsening
metabolic status, he continued to deteriorate on all fronts (see Table
1).Profuse bleeding from the nose appeared, and he was given blood products
including fresh frozen plasma, Vitamin K, and recombinant activated factor VII.
Studies and case reports from the mid
1990s7 have suggested benefits in the use of
colchicine-specific Fab (fragment antigen binding) fragments in the treatment of
colchicine overdose, however despite an extensive literature search and a number
of phone calls it appears that none are commercially available.
Despite the most aggressive organ support he steadily and
inexorably deteriorated and died.
Table 1. Blood results
OD=overdose (of colchicine).
Summary of other colchicine overdose casesPatient 1 (KM)—A 15-year-old European
female with a history of depression took a 30 mg overdose of
colchicines—her grandmother’s medications. She presented 22 hours
later with diarrhoea and vomiting. Despite aggressive attempts at
decontamination she deteriorated requiring ventilation, inotropic support, and
haemofiltration. She became increasingly unstable, profoundly coagulopathic, and
died 52 hours post overdose.
Patient 2 (LF)—A 56-year-old Samoan
male presented 24 hours after an accidentally taking 24 mg of colchicine. He was
admitted with symptoms of shortness of breath and diarrhoea. He was immediately
commenced on charcoal. Over the course of his admission, he developed
multi-organ failure with worsening hypoperfusion, hypoxia, and acidaemia.
Despite aggressive support, he had an asystolic cardiac arrest and died.
Patient 3 (TT)—A
59-year-old Tongan male with chronic renal impairment was admitted 18 hours
after taking an accidental overdose of 18 mg of colchicine. On arrival in the ED
he had signs of severe poisoning with shock. Soon after admission, he developed
dysrhythmias and had an asystolic cardiac arrest and died.
Patient 4 (DH)—A 15-year-old European
male was admitted 24 hours after taking an overdose of 18 mg of colchicine. He
presented with diarrhoea and was haemodynamically unstable. Despite aggressive
resuscitation he continued to deteriorate and developed multi-organ failure. He
died 96 hours after ingestion.
Patient 5 (JM)—A 78-year-old European
male, with a history of chronic renal impairment and colchicine ingestion for
gout, presented to hospital with a diagnosis of a right-sided bronchopneumonia.
Over the course of his admission, he continued to deteriorate and became
progressively unwell with generalised abdominal pain, confusion, and agitation.
A diagnostic laparotomy was unremarkable. He was admitted to the ICU and
required full multi-organ support. He became profoundly coagulopathic and
developed a neutropaenia. He died 48 hours post admission. In the absence of a
convincing reason for his progressive deterioration, an overdose of colchicine
was a likely and significant contributor to his death.
Patient 6 (AP)—A 19-year-old
Māori male was admitted 48 hours after taking an unknown quantity of
colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), augmentin, and
amoxycillin. He was seen in the Emergency Department where he presented with
ongoing vomiting. He was discharged the following day but continued to vomit and
have abdominal pain and diarrhoea. He was re-admitted 12 hours later with a
reduced level of consciousness, severely hypotensive and in acute renal failure
with a worsening acidaemia. He required intubation and ventilation,
resuscitation with volume and inotropes, and renal replacement therapy. Despite
aggressive organ support, the patient became asystolic and died 4 days after his
overdose.
Patient 7 (TT)—A 20-year-old
Māori male took approximately 40 mg of his father’s colchicine
following an argument with his family. He presented to his GP 12 hours later
complaining of increasing abdominal pain and diarrhoea. He was subsequently
transferred to the ED where he received activated charcoal. Over the course of
the next 6 hours he became more tachypnoeic, hypoxic, tachycardic, hypotensive,
and oliguric. He was electively intubated and required escalating doses of
inotropes. He developed a profound coagulopathy and rapidly became
unsupportable. He died 36 hours after ingestion.
Patient 8 (JH)—A 46-year-old European
male presented 36 hours post a purposeful overdose of unknown quantities of
colchicine, Naprosyn (naproxen), and allopurinol. He was initially hypotensive
and had a slight metabolic acidosis both of which responded to fluid boluses.
During the next 48 hours he required some inotropic support, which he was soon
weaned off, and he made a good recovery with normal renal function and
electrolytes.
Table 2: Summary of other colchicine overdose
cases
DiscussionGout is a common form of acute arthritis; it is especially
common amongst the Pacific (mostly Samoans, Tongans, Niueans, and Cook
Islanders) and Māori population in New Zealand.
Gout has been the target of several treatments. With the age
of modern medicine came more effective treatments for gout, such as the drugs
probenecid, allopurinol, steroids, and NSAIDs. Colchicine is the anti-gout agent
in current use with the longest history.
Colchicine was first used over 2000 years ago in the form of
preparations of the meadow saffron Colchicium autumnale (see Figure 1).
It is still thought to be one of the most effective treatments for the symptoms
of gout. Indeed, throughout the years, many historians, physicians, and
pharmacopeias have noted the beneficial effects of colchicum extracts for the
treatment of gout2.
The precise mechanism by which colchicine relieves the pain
of gout is unknown. However, it is believed that the mechanism of pain relief
involves colchicine’s major pharmacological action in binding to the
microtubular protein tubulin. This resultant anti-mitotic activity inhibits
amoeboid motility which in turn prevents macrophage and leukocyte migration and
phagocytosis and this is thought to ameliorate the inflammation and pain of
gout3.
Figure 1. Colchicium autumnale (meadow
saffron)
 Microtubular function is also implicated in many other
cellular functions including cell shape and division, as well as phagocytosis
and motility. The affected cells arrest in the metaphase of cell division and
thus those that show more mitotic activity are most affected and demonstrate
toxic effects most quickly and profoundly. These include the gastrointestinal
epithelial cells, hair follicles, and haematological stem cells. This helps to
explain the various phases of colchicine toxicity (see table 3).
Table 3. Symptoms and signs of colchicine
toxicity
Fatal poisoning has been reported after as little as 7 mg
over 4 days whereas other patients have survived ingestions of up to 60 mg. Up
to 80% of patients on colchicine actually have symptoms of gastrointestinal (GI)
toxicity in therapeutic doses and this has been used as a titration end point
for dosing in the past.
After ingestion, colchicine is rapidly absorbed from the GI
tract. It has a large volume of distribution and binds significantly to plasma
proteins and has rapid distribution. Thus, haemodialysis and haemoperfusion are
ineffective therapies in overdose.
Renal clearance accounts for only 10–20% of its
excretion with the majority of the drug undergoing first pass metabolism and
primary deacetylation. The metabolites then undergo widespread enterohepatic
recirculation before being excreted in bile and faeces. There is therefore a
role for repeat dose activated charcoal in the management of the acute
presentation of colchicine poisoning. The removal of even a small amount from
the GI tract can make a difference to prognosis.
If the patient has liver disease then a larger proportion
will be excreted via the kidneys. Thus the potential for toxicity is greatly
increased in the case of renal and liver dysfunction.
The treatment options for accidental or deliberate overdose
of colchicine remain limited. Those who present with a delay after ingestion,
and those with pre-existing renal or hepatic dysfunction are at higher risk of
toxicity. Decontamination and supportive care are the main readily available
treatment arms.
There has been recent interest in colchicines-specific Fab
fragments7 which have been used with success in
animal models of colchicine poisoning as well as in one case of colchicine
overdose in a patient in France. Of all the treatments Fab fragments seems to
hold the best hope for successful treatment of this otherwise universally fatal
overdose.
The cases above clearly illustrate the consequences
associated with a toxic dose of colchicine; both in its cost of life and also in
financial terms. We feel that there are several issues pertaining to the use and
prescription of colchicine.
This drug has a narrow therapeutic index and severely toxic
side effects. Indeed, in significant overdose, death is nearly universal. It is
very difficult to predict a safe dose or even a toxic dose of this drug, and
when taken in overdose there is no specific antidote currently available.
How effective is this medication compared to existing
medications?
Colchicine has been in use since the age of the Roman
Empire, and although the benefits of the drug have been well documented, there
has still been no study comparing the benefit of colchicine in comparison to any
other treatment for gout.8
Ahern et al did, however, manage to compare the effects of
colchicine versus placebo in a double-blinded controlled
study.1 Whilst this confirmed a symptomatic
benefit in the use of colchicine compared to placebo (>50% had symptomatic
improvement); they did raise some issues with regards to the toxic effects of
this drug. The only side effects that were described were diarrhoea and
vomiting, and these were present in all of the patients in the treatment arm of
the study.
There was no mention of the average dose of colchicine
required to treat the symptoms; but in all these patients, diarrhoea, and
vomiting occurred after a mean dose of 6.7 mg (within the first 12–36
hours). In fact, 91% of the patients taking colchicine had symptoms of diarrhoea
and vomiting before getting any symptomatic benefit for their gout. This raises
the further issue of the cost-benefit ratio in the use of colchicine.
Advice on the dangers of colchicine varies from one source
to the next. Until recently, there was no maximum dose of colchicine stated in
the approved dosage guidelines. There have been published cases of death
occurring after colchicines doses as little as 6 or 7
mg.4 In response, maximum recommended doses
have been reduced to 6 mg (in New Zealand) and 10 mg (in the United Kingdom),
respectively.5 .
Medsafe, New Zealand’s drug safety agency, recently
updated their guidelines (see Table 4) for the prescription of
colchicine.9 In doing so, they have clarified
changes in colchicine usage advice. Specifically, its role in the treatment
hierarchy of gout management and maximum dosing with appropriate allowances made
for age, weight, and other compounding illnesses.
However the risk of death in taking a significant overdose
is not in our view sufficiently highlighted in advice by Medsafe and elsewhere.
Table 4. Medsafe guidelines for prescription of
colchicine
In current practice, any medical practitioner can prescribe
colchicines, and in New Zealand there are currently no limits to the amount that
can be dispensed at any one time. An argument can be made to restrict its
prescribing to a specialist-only approach, however this would raise problems of
access.
An alternative approach might be to limiting the amount
prescribed and dispensed at one time. In the United Kingdom, pharmacists are
only able to dispense a maximum of 6 mg per prescription. This may limit the
possibilities for overdose, especially accidental overdose.
In our view, prescribers, patients, and their families are
not aware of the dangers of this drug in overdose. Whilst this remains the case,
changes to current practice are necessary. Furthermore, appropriate patient
education in the use of colchicine is vital.
A surprisingly large number of our cases were as a
consequence of an accidental overdose. This may illustrate not only a poor
understanding of how the drug should be used but also a lack of awareness of the
side-effects and the consequences of taking too many tablets. This reflects
poorly on the medical profession.
In all cases where the overdose was accidental, the patients
concerned were of Pacific Island or Māori origin. This reflects the more
generic underlying problem of what we tell our patients and what they
understand. And the presence of language barriers and cultural differences make
this all the more difficult.
Given that there are other therapeutic options available in
the treatment of an acute attack of gout and that colchicine is highly toxic in
overdose with a high mortality, it is important for us to consider whether we
can continue to justify the use of colchicine as a treatment modality.
Colchicine cannot cure gout. It only prevents the leucocytes
from functioning; breaking the cycle of ingestion, destruction, release, and
inflammation. The Greek physicians using the raw plant material had to guess the
correct dose. They did not know why the Colchicum treatment worked,
only that the patient would either feel better or die.
In this age of evidence-based medicine, in an age where
medical professionals are held accountable for their decisions, we ask if
colchicine was only discovered today, would it ever be licensed?
Author information: Vikram Jayaprakash,
Gillian Ansell, Intensive Care Registrars; David Galler, Intensive Care
Specialist; Intensive Care Unit, Middlemore Hospital, Otahuhu, Auckland
Correspondence: Vikram Jayaprakash, c/o
Department of Anaesthesia, Middlemore Hospital, Otahuhu, Auckland. Fax:
(09) 367 6813; email: vikram.j@mac.com
References:
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