methadone ( mtd ) , as a synthetic opioid with long elimination half - life , is the preferred drug for the treatment of opioid dependence and control of pain in iran .
this drug is available in oral liquid formulation and tablets , has analgesic effects , and can be used in the management of severe chronic pain .
patients who refer after acute overdose are generally those who obtain multiple doses of  take home 
methadone from methadone maintenance therapy ( mmt ) clinics [ 18 ] . in iran ,
it is a colorless liquid usually kept in water bottles at home and accidental acute poisoning with it is extremely common especially in children .
suicidal attempt with mtd syrup has also become so popular within the recent years . delayed or recurrent respiratory depression , ventricular dysrhythmias , acute lung injury , and death are the major complications of mtd overdose .
respiratory arrest is the main cause of mtd - related deaths and usually develops 12 hours after the ingestion of the drug .
additionally , torsade de pointes ( tdp)the arrhythmia induced by qt interval prolongation  may contribute to death [ 11 , 12 ] .
overdose may cause renal failure as a result of rhabdomyolysis and myoglobinuria in prolonged immobilization or coma .
some studies reported a 10-fold increase in mtd toxicity - related fatalities between 2000 and 2003 which could probably be because of its arbitrary use and use in pain clinics [ 13 , 14 ] .
it should be noted that many of mtd intoxication deaths are preventable with cautious prescription , good monitoring , and attention to the signs and symptoms of toxicity and the drug interactions .
it is important to have a broad knowledge about the different epidemiological aspects of mtd usage and overdose .
this study aimed to describe the demographic data of mtd - overdosed patients and compare mtd - intoxicated survivors and nonsurvivors to investigate the possible prognostic factors in this toxicity .
in this retrospective , cross - sectional study , medical data of all mtd - poisoned patients older than 12 years who had been admitted to toxicology ward of loghman hakim hospital between 2007 and 2012 were evaluated .
the diagnosis of mtd poisoning was based on history of its ingestion taken from the patients and/or their relatives , the presence of a minimum of two signs of opioid toxicity including central nervous system depression , respiratory depression , and miosis in physical examination , and the positive urine drug screen test for mtd ( urine was checked twice , once at emergency department [ ed ] and the second time , 8 hours later at ward ) .
all the available information including the demographic data , past medical history , signs and symptoms on presentation , laboratory findings , complications , and outcome was recorded .
the cases with insufficient data , those with background diseases ( i.e. , ischemic heart disease , chronic renal failure , and advanced liver disorders ) , concomitant head trauma , and multidrug toxicity , and those on mtd treatment in mmt program and/or overdosed on other opioids were excluded from the study .
data analysis was performed by statistical package for social sciences ( spss ) version 16 . a p value less than 0.05 was considered to be statistically significant .
finally , the patients were divided into two groups , those with acute toxicity after single ingestion of a dose of mtd for the first time ( suicide attempt or accidental ) and those with acute on chronic toxicity poisoning that were on daily doses of mtd and had ingested it more than the usual dose ( suicide attempt or recreational overdose ) .
the study was performed according to the helsinki declaration and approved by our local ethics committee .
a total of 456 mtd - poisoned patients had been admitted to toxicology ward of loghman - hakim hospital between 2007 and 2012 . of them , 322 patients older than 12 years of age ( mean age : 36.0  15.8 years ) were included .
the male / female ratio was 2.97 and 241 cases ( 74.8% ) were male .
methadone syrup had been used by 129 patients ( 41.4% ) while others had overdosed on mtd tablets .
the mean ingested dose of mtd was 85.91  82.61  mg ( range ; 5 to 500  mg ) .
mean time elapsed between mtd ingestion and admission was 9.41  9.87 hours ( range ; 1 to 72 hours ) . in the first visit at ed ,
 focused on cardinal signs of toxicity  apnea , respiratory depression ( respiratory rate [ rr ] < 10/min ) , and miosis were detected in 23 ( 7.1% ) , 117 ( 36.3% ) , and 177 ( 60.78% ) patients , respectively .
almost 32.5% of the cases were fully conscious on presentation while 59.1% were confused and sleepy , and 3.8% were in comatose status .
based on the mode of toxicity , mtd poisoning had intentionally happened ( suicidal attempt , illicit use , or recreational use ) in 270 patients ( 84.1% ) .
tracheal intubation had been performed in 79 ( 24.5% ) patients at ed or during hospitalization due to respiratory compromise .
the most common complication related to mtd poisoning was renal failure in 16 patients , in eight of whom , concomitant clinical and laboratory signs of rhabdomyolysis were present .
electrocardiographic ( ecg ) findings of 151 patients on admission were available and interpreted by a single cardiologist .
the mean pr , ors , and corrected qt intervals ( qtc ) were 150.3  32.8 ( range ; 80 to 280 ) msec , 92.2  21.6 ( range ; 40 to 150 ) msec , and 446.3  50.7 ( range ; 289 to 584 ) msec , respectively .
a total of 198 patients ( 61.5% ) had intentionally or accidentally ingested mtd for the first time and 12 ( 6% ) of them had died .
acute on chronic poisoning had happened in 123 patients ( 38.2% ) who were users of daily doses of mtd .
of them , 92 ( 28.6% ) were on mmt program and had ingested a higher dose of mtd to suicide or for recreational use and 31 ( 9.6% ) had ingested it without prescription .
, it was not clear if the overdose was due to the first - time use or he was an abuser .
methadone is a synthesized opioid with excellent oral bioavailability of 70% to 90% and a long plasma half - life ( 15 to 52  h ) . with many drug interactions ,
tablets or syrup of mtd are broadly prescribed for treatment of opioid dependency in iran , and therefore , mtd - related death has increased in this country within the recent decades .
profound hypoxia due to respiratory depression or arrest can lead to acute lung injury or acute respiratory distress syndrome ( ards ) , brain injury , and renal or liver impairment .
some mtd - intoxicated patients need endotracheal intubation and artificial ventilation because of central hypoventilation and inability to protect airways .
dangerous tdp dysrhythmia is another uncommon cause of death in these patients . in our study ,
the mortality rate was significantly less in those who had ingested mtd for the first time ( p = 0.04 ) .
this means that acute toxicity is more dangerous in the patients who are on mmt program .
reviewing the literature shows different but increasing rates of mtd - related fatalities in different parts of the world .
for instance , in western australia , vermont , ontario , and zurich , a total of 84 ( 19931999 ) , 76 ( 20012006 ) , 54 ( 2004 ) , and 146 ( 19982007 ) deaths have been reported due to mtd overdose [ 1518 ] .
our study is one of the first reports on mtd - related deaths from the capital of iran .
the results showed that mean age of nonsurvivors was more than survivors ( 46.2.21.2 versus 35.0  14.9 years , resp . ;
p = 0.01 ) . it can be concluded that mtd poisoning can contribute to more complications in older ages and surely needs more medical attention in them .
the mean age of our patients was similar to a norwegian study ( 36  15 versus 36  10 years , resp . ) . according to our results
also , against our expectation , the mean ingested dose was lower in nonsurvivors whose possible cause is their delayed hospital presentation . on the other hand ,
factors including older ages , acute on chronic toxicity , severe loss of consciousness , and decreased mean arterial pressures on admission were significantly associated with poorer outcomes .
it should be noted that , in our cases , respiratory rate was significantly more in nonsurvivors . since acute lung injury , ards , and pneumonia [ table 4 ] may occur and accompany a higher respiratory rate , it can be suggested that tachypnea can be a predictor for poor prognosis in mtd poisoning . although no statistically significant difference was detected in the level of creatinine phosphokinase ( cpk ) between the survivors and nonsurvivors , cpk was less in those who survived ( 1691  3457 versus 16058  31749 ) .
acute renal failure was a poor prognostic factor for mtd toxicity - related deaths since eight dead cases had acute renal failure due to rhabdomyolysis and acute tubular necrosis .
the frequency of endotracheal intubation , duration of hospitalization , lactate dehydrogenase ( ldh ) , blood urea nitrogen ( bun ) , creatinine ( cr ) , aspartate transaminase ( ast ) , and alanine transaminase ( alt ) were significantly higher in the nonsurvivors , while mean platelet count was significantly lower in this group .
arterial ph and hco3 were lower and pco2 was higher in nonsurvivors . although the differences were not significant , these findings are due to central respiratory depression and profound hypoxia in severe mtd toxicity .
prolongation of pr ( > 200  msec ) , qrs widening ( > 120  msec ) , and prolongation of qtc interval ( > 450  msec ) were seen in 3.3% , 7.9% , and 45% of the patients , respectively .
previous studies had defined a qtc interval greater than 450 msec as a risk factor for cardiac dysrhythmia ( such as tdp ) , syncope , and cardiac sudden death [ 10 , 12 , 19 ] .
qtc interval was reported to be 472.72  18.5  msec in iranian causalities receiving mmt and prolonged in 25% of the 100 studied patients .
mean dose of mtd had a significant relationship with the mean qtc interval ( p = 0.009 ) .
there are different reports about the relationship between the mean dose of mtd and qtc interval ; some show significant and others nonsignificant relationships [ 20 , 21 ] .
according to the literature , sudden death due to cardiac arrhythmia and especially qtc interval can occur in a wide range of doses of mtd , even in daily doses of less than 30  mg / day .
higher numbers of acute renal failure , rhabdomyolysis , aspiration pneumonia , hepatic failure , sepsis , and disseminated intravascular coagulation in nonsurviving patients suggest that these patients have serious complications which can lead to death . in a study performed in london in 2004 ,
reduced respiratory rate , aspiration , pulmonary edema , bronchopneumonia , and heart and renal problems were reported as factors causing death in mtd abusers .
delayed hospital presentation , severe loss of consciousness , acute toxicity in patients who were on daily dose of mtd ( acute on chronic toxicity ) , need for early endotracheal intubation , tachypnea ( as a sign of acute lung injury or aspiration pneumonitis ) , acute renal failure , and rhabdomyolysis can be assumed as early poor prognostic factors for mtd - related death .
 
 background . delayed or recurrent profound respiratory depression , 
 ventricular dysrhythmias , acute lung injury , and death are the major complications of mtd overdose . 
 we aimed to clarify the prognostic factors in mtd toxicity . 
 materials and methods . retrospectively , medical files of all patients poisoned by mtd and older than 12 years of age who had presented to loghman hakim poison center between 2007 and 2012 were evaluated . 
 the data was compared between survivors and nonsurvivors . 
 results . 
 twenty - eight out of 322 patients died ( mortality rate = 8.7% ) . 
 mtd - related death was higher in patients with acute on chronic toxicity who were on daily dose of mtd and had ingested higher doses ( in comparison to those with acute toxicity due to first - time exposure ; 13% versus 6% ) . 
 renal failure was the most common medical complication related to deaths due to mtd toxicity . 
 conclusions . based on previous researches , the most common cause of mtd overdose - related deaths is respiratory impairment ; however , in our study , acute renal failure with or without rhabdomyolysis was the main delayed cause of deaths in mtd - poisoned patients . 
 antidotal therapy , early recognition , and treatment of hemodynamic compromise and rhabdomyolysis can be life - saving in these patients . 