Title: Epidemiologic incidence of rhabdomyolysis in opioid overdose in ICU of

poisoning center in Iran in 2014

Khoshideh Babak1 MD, Arefi Mohammad1 MD, Ghorbani Mazaher2 MD, Akbarpour Samaneh3
PhD, Taghizadeh Fatemeh1 BS.

1
Baharloo Hospital, School of Medicine, Tehran University of Medical Sciences,
Tehran, I.R.Iran.
2
Forensic Medicine Department, School of Medicine, Tehran University of Medical
Sciences, Tehran, I.R.Iran
4
Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of
Medical Sciences, Tehran, Iran

Author’s contribution:

Khoshideh Babak: Data collection and writing the manuscript

Arefi Mohammad: Data collection and writing the manuscript

Ghorbani Mazaher: Data analysis and writing the manuscript

Akbarpour Samaneh: Data analysis and writing the manuscript

Taghizadeh Fatemeh: Data collection and writing the manuscript

A short running title: Epidemiologic incidence of rhabdomyolysis

Addresses of the institutions at which the work was carried out: Baharloo Hospital, School
of Medicine, Tehran University of Medical Sciences, Tehran, I.R.Iran

Corresponding Author: Arefi Mohammad, Baharloo Hospital, School of Medicine, Tehran

University of Medical Sciences, Tehran, I.R.Iran.
Email: armaniair@yahoo.com
Tel: +989123359004

Word count: 1925

Title: Clinical and laboratory findings of rhabdomyolysis in patients with opioid
overdose at Intensive Care Unit (ICU) of poisoning center in 2014 in Iran.

ABSTRACT

Objectives: The aim of this study is to investigate the clinical, demographical characteristics
and some laboratory findings of hospitalized patients with acute opioid toxicity and
rhabdomyolysis.

Methods: In this cross-sectional study, 354 hospitalized patients were investigated at Baharloo
Educational Hospital in Tehran, with acute illicit drug toxicity in 2014. Data was collected by an
investigator-made check lists. The collected data and variations (such as mortality rate,
demographic data, and renal function tests as well as serum biochemical elements) were
analyzed by descriptive statistics and x-square test.

Results: The total number of patients admitted to hospital in 2014 was 354 patients, containing,
291 males and 63 females. The total number of patients with rhabdomyolysis was reported 76
patients (21.46% of total) in which 69 patients (90.7%) were male and 7 (9.3%) were female.
Most cases of rhabdomyolysis were associated with methadone and then Opium abuse. Based on
the reports the highest age range was 30 to 39 years old with methadone and opium as the most
common illicit drug abused. Mean blood urea was 3.8 ± 1 mmol /dl, Mean serum potassium and
sodium was measured, 3.8 ± 0.3 mmol /dL and 140.4 ± 4 mmol /dL respectively. Five patients
passed away due to severe renal failure (6.5%), all the 5 cases were male.

Conclusions: Toxicity caused by opioid is associated with clinical complications and laboratory
disorders such as electrolyte disorders which can lead to lethal and life threatening results in
some cases. Laboratory test error/disorders should be identified in Opioid toxicity in order to
initiate efficient treatment.

Key words: Laboratory findings, Toxicity, Opioid, Rhabdomyolysis

Introduction: Rhabdomyolysis syndrome is defined by degradation of muscle cells and

dissemination of muscle cellular compounds to the bloodstream. This disorder may result in the
release of muscle cells compounds into extracellular and circulatory fluid, which can consist of
potassium, lactate dehydrogenase, uric acid and myoglobin. One of the key elements released is
myoglobin [1]. There are several reasons for rhabdomyolysis, which are widely divided into
three categories: Impacted muscle contraction (for example, crushing syndrome or prolonged
immobilization), extreme physical activities ( in people without hyperthermia, or sympathy) and
non-exertional and non-traumatic causes (drugs or toxins, infection, or electrolyte disorders) [2,
3].

The etiology of rhabdomyolysis: after severe and critical conditions such as muscle contraction
or crash syndrome, coma or post seizure, surgical trauma, extreme physical activities can be
easily detected, but in some other cases, the identification of rhabdomyolysis requires a careful
physical examination, such as history and laboratory evaluation [2-4]. A large number of drug
prescription as well as drug abuse causes rhabdomyolysis [2]. In addition to alcohol, other drugs
including heroin, cocaine, amphetamine, methadone, tramadol, and LSD play significant roles in
development of rhabdomyolysis.

The most common drugs cause rhabdomyolysis, are as follow: antipsychotics, statins, selective
serotonin inhibitors, zidovudine, colchicine, lithium, antihistamines [3]. Acute intoxication with
opioid and other abusive drugs are routine and common daily occurrence in the emergency
department and intensive care unit, and that is the reason for many deaths due to overdose.
Mortality due to overdose among opioid users and other similar compounds is so high. On the
other hand, acute poisoning with these drugs not only leads to severe and fatal complications
during admission, but also creates permanent sequels. Rhabdomyolysis can be occurred after
poisoning, which is often not diagnosed. Opium is rapidly metabolized in the liver, which reduce
the duration of their activity, even when they take over dosage.

As a result of heavy and debilitating of rhabdomyolysis, acute renal damage and failure in opioid
poisoning, it is required to have an accurate evaluation, diagnostic procedure and therapeutic
method, which can assist to reduce mortality rate among mentioned patients.

In addition, the studies which have been conducted in this field are not sufficient. Therefore,
special focus and concentration are necessary in this field
The aim of the study is about demographical characteristics, clinical characteristics and some
laboratory findings in patients with acute opium abuse admitted to Baharloo hospital. We hope
the result of this study assist the other analytical and empirical studies to find appropriate
solutions for a clinical and laboratory examination in detection of this problem.

Method: This cross-sectional study was carried out at Baharlo Hospital. The selected patients
were hospitalized in the ICU of the Baharlo Hospital in 2014 in Tehran, due to drug poisoning
such as Methadone, Tramadol, Opium, Heroin, and other opioid drugs, (pure opium or opioid
and not the other drugs). They had a Creative phosphokinase (CPK) of over 1,500, without
trauma, sepsis and the other drug poisoning. For instance, if someone had a fall from a building
or infe

The diagnosis of rhabdomyolysis was based on dark urine without other symptoms or an acute
neuromuscular illness, plus an acute elevation in serum creatine kinase (CK). The diagnosis of
rhabdomyolysis was defined as five times the upper limit of normal for CK (greater than 5000
international units/L).

Information was collected from biographies, physical examinations, written nursing reports, and
patient laboratory exams. Information such as age and type of drug, urine culture and tests like
CPK, kidney and LDH, were extracted from patient records files.

In clinical examinations, attention was paid to issues such as fever, stiffness, muscle swelling,
and urine discoloration, and attempts were made to exclude other causes of elevated creatine
phosphokinase (such as heart attack and brain injury).

The design and method of this study were approved by the Institutional Review Board (IRB) of
Tehran University of Medical Sciences; and all participants provided written informed consent.

The data of this study was entered in SPSS in order to verify the linkage between quantitative
means in qualitative groups in the case of normal distribution from t-test and anova, and to
determine the relationship between qualitative variables Chi-square.:

Results: The total number of admitted patients from the beginning to the end of 2014 was 354 in
Baharloo Hospital, of whom 291 (82.2%) were male and 63 (17.8%) female. The age of
youngest patient was 14 and the oldest was 83. Range of age was 37.69± 5.87. The most
common age group was 20 to 29 years old (33.3%), followed by the group of patients aged 30 to
39 years old. The most commonly used drugs were opium (36%), tramadol (33%) and
methadone (29%) respectively, but in patients with rhabdomyolysis disease, the most drug use
was methadone (Table 1)

Table 1

The total number of patients with rhabdomyolysis was reported 76 (Rhabdomyolysis incidence
rate was 21.46%): 69 patients (90.7%) were male and 7 (9.3%) were female. The number of
patients with red urine was 18 (23.6%) and patients with clear urine were 35 (46%). As it is
illustrated in Table 2, the most commonly reported nephrotoxicosis is methadone intake and then
related to opium, 5 patients (6.5%) , (all men), passed away during the study. 35.4 ± 13.8 . The
age average among males was 35.4 ±13.8 and among females was 18.4 ±34.

The average of laboratory variables is shown in table 3.

Table 2
 Table 3

Discussion: One of the most common complications of acute poisoning due to alcohol,
narcotics and psychotropic drugs is the phenomenon of rhabdomyolysis, which can lead to acute
renal failure and death in patients. Therefore, in order to reduce complications and associated
death with this phenomenon, early diagnosis and clinical suspicion are significant. . Awareness
of symptoms and early treatment play significant role indeed. Rhabdomyolysis has been reported
as a clinical problem in previous studies, but the results of recent studies showeda higher
incidence of this disorder [5]. This is one of the main causes of acute renal failure[3, 6]. However,
the number of comprehensive studies conducted in this field is not sufficient. In many studies,
alcohol abuse has been recognized as the main cause of rhabdomyolysis [7, 8], however, other
studies have also examined the relationship between drug and alcohol abuse. For instance in Iran
the results of Mousavi's [9] and Talaie [7] reviews of the etiology of rhabdomyolysis have been
indicated opioid overdose. Also, in Koffler [10], Gabow [11] and Taheri [12] studies, alcohol
and opium abuse were reported as the main cause of rhabdomyolysis. The results of the studies
showed a high prevalence of rhabdomyolysis in their observed patients (21.4%). In other studies,
the incidence was reported from 7% in Lai [13] article to 79% in Talaie [7] In present studies,
the most frequent age range was reported, 21-30 years old (33.3%), and the highest frequency
of gender has happened among men (82.2%), which is similar to previous studies., The most
commonly narcotic drug reported in this study was tramadol (35.8%), which was not the same
as Jebel Ameli’s study, in which the most opioid type was opium (60.4%), This could be due to
an increase in the prevalence of tramadol use among young people and the change in drug abuse
trends. In the recent years [14], Islambulchic [15], In his study, which was conducted on 1,342
poisoned patients , came to conclusion that 5.4% of all hospital admissions were poisoned
patients. In the aforementioned study, opioid abuse was the most common cause of poisoning
(60.8%). Subsequently, benzodiazepines (40.31%), antidepressants (31.98%) were afterward. In
the Talaie’s study [7], opium poisoning was the most common cause of rhabdomyolysis (23.3%)
and the subsequent causes included benzodiazepines, phenobarbital, propranolol, aluminum
phosphide, alcohol and co poisoning.

Various studies on drug poisoning have often focused on demographic and clinical
manifestations, and only a few cases of narcotic poisoning have been documented in laboratory
disorders, on the other hand, in most of the articles laboratory abnormalities caused by narcotics
was studied in laboratory animals, and limited studies is available to reveal laboratory findings
in human poisoning.

The mean urea level of patients with rhabdomyolysis was also measured at 3 ± 1 mmol / dL. The
mean serum potassium was 3.8 ± 0.3 mmol / dL and the mean serum sodium was 140.4 ± 3.4
mmol / dL. In other words, patients with rhabdomyolysis did not have hyperkalemia, but sodium
was observed in the upper limit of the patients. In our study, five patients out of 76 patients
passed away due to renal insufficiency. (6.5%), all of them were male.

In the Kouros study which tracked changing serum parameters in patients after taking opium and
heroin showed that fasting blood glucose and potassium levels decreased significantly [12]. In
recent case studies of methadone abuse, morphine infusion, and the use of tramadol in different
parts of the world have shown hyperglycemia (490 mg / dL), hyperkalemia (8.1 mmol / l),
hypoglycemia and hyponatremia [16-18]. In the study of Karam et al., the effect of opium on
biochemical parameters in addicts with non-insulin dependent diabetes mellitus (NIDDM),
increased potassium and serum glucose [19].

In the same study, the effect of opium on glucose, potassium and sodium in male and female
was investigated. Sodium, potassium and glucose were significantly increased in all mice
compared to the control group [20]. In the study of Talaei et al [7], the prevalence of 13%
myoglobinuria was found in the patients, which can be related to the lower incidence of
rhabdomyolysis in this study. On the other hand, myoglobin rapidly filters out kidneys, and urine
sampling time can also alter the results of myoglobin in the catheter.

According to the results of this study as well as results obtained from the present and similar
studies, it seems that the onset and other electrolyte disorders due to rhabdomyolysis can be also
occurred in the next days of admission, and therefore the need for preventive and therapeutic
procedures such as adequate hydration and patient movement out of the bed at the first time is a
good opportunity to prevent serious complications due to electrolyte disorder and
rhabdomyolysis which is associated with acute renal failure and death of patients.

Conclusion: Based on the results of this and previous studies, rhabdomyolysis is more
commonly associated with poisoning in younger patients and can lead to serious and fatal
complications, such as progressive renal failure. Therefore, due to high prevalence of mortality
as a result of poisoning in young people, it is necessary to pay more attention to early diagnosis
and treatment of these patients. Future studies are recommended to be conducted on following
areas: prevalence of rhabdomyolysis in different centers and locations, accurate determination
of prevalence and risk factors, efficacy of treatment, chemical and molecular evaluation of toxins;
and a better understanding of the relationship between the toxic substance and the phenomenon
of rhabdomyolysis is required.

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Table 1: Comparing characteristics of the patients with and without rhabdomyolysis

With rhabdomyolysis Without of Total p-value

rhabdomyolysis

Age (mean and SD) 35.45 (4.82) 39.78 (6.31) 37.69 (5.87) 0.034
Sex
Male 69 (90.79) 222 (79.86) 291(82.20) 0.023
Female 7 (9.21) 56 (20.14%) 63 (17.8)
Type of drug
Heroin 4 (5.27%) 0 4 (1.1%) 0.021
Cocaine 2 (2.63%) 3 (1.08%) 5 (1.42%)
Opium 24 (31.57%) 93 (33.45%) 117 (33.05%)
Tramadol 21 (27.64%) 106 (38.13%) 127 (35.88%)
Methadone 25 (32.89%) 76 (27.34%) 101 (28.54%)

Table 1: Number of hospitalized patients with rhabdomyolysis in ICU according to type of drugs
and age groups in 2014.

Age group* Heroin Cocaine Opium Tramadol Methadone Total

11-19 0 0 0 5 1 6

20-29 0 0 3 14 5 22
30-39 1 1 10 2 8 22

40-49 1 1 6 0 6 14

50-59 0 0 4 0 5 9

60-69 1 0 0 0 0 1

70-79 1 0 0 0 0 1

80-89 0 0 1 0 0 1

The beginning
day**
First day 2 1 14 17 18 52

Next days 2 1 10 4 7 24

* No patients with age <10 years old

**Rhabdomyolysis incidence based on the onset of ICU Poisoning

Table 2: Average laboratory variables in patients with rhabdomyolysis

minimum maximum average ±SD

LDH 161 3266 921.5 511.8
Urea 2 7.2 3.8 1
K 2.8 5 3.8 0.3
Na 134 150 140.4 3.4
Ca 0.6 7.4 1.4 1.1
P 9 207 40.8 35.5
Dear Editor,

Following is our manuscript “Epidemiologic incidence of rhabdomyolysis in opioid overdose in

ICU of poisoning center in Iran in 2014” for consideration for publication by the Epidemiology
and Health journal. We believe that this paper will be very interesting to the readers of
Epidemiology and Health journal, as it evaluates the incidence of rhabdomyolysis in opioid
overdose. The authors would like to advise that all authors listed have contributed to the work.
There is no conflict of interest in this study to declare. All authors have agreed to submit the
manuscript. No part of the work has not been published or submitted for publication elsewhere
before.

Arefi Mohammad
Table 1: Comparing characteristics of the patients with and without rhabdomyolysis

With rhabdomyolysis Without of Total p-value

rhabdomyolysis

Age (mean and SD) 35.45 (4.82) 39.78 (6.31) 37.69 (5.87) 0.034
Sex
Male 69 (90.79) 222 (79.86) 291(82.20) 0.023
Female 7 (9.21) 56 (20.14%) 63 (17.8)
Type of drug
Heroin 4 (5.27%) 0 4 (1.1%) 0.021
Cocaine 2 (2.63%) 3 (1.08%) 5 (1.42%)
Opium 24 (31.57%) 93 (33.45%) 117 (33.05%)
Tramadol 21 (27.64%) 106 (38.13%) 127 (35.88%)
Methadone 25 (32.89%) 76 (27.34%) 101 (28.54%)

Table 1: Number of hospitalized patients with rhabdomyolysis in ICU according to type of drugs
and age groups in 2014.

Age group* Heroin Cocaine Opium Tramadol Methadone Total

11-19 0 0 0 5 1 6

20-29 0 0 3 14 5 22

30-39 1 1 10 2 8 22

40-49 1 1 6 0 6 14

50-59 0 0 4 0 5 9
60-69 1 0 0 0 0 1

70-79 1 0 0 0 0 1

80-89 0 0 1 0 0 1

The beginning
day**
First day 2 1 14 17 18 52

Next days 2 1 10 4 7 24

* No patients with age <10 years old

**Rhabdomyolysis incidence based on the onset of ICU Poisoning

Table 2: Average laboratory variables in patients with rhabdomyolysis

minimum maximum average ±SD

LDH 161 3266 921.5 511.8
Urea 2 7.2 3.8 1
K 2.8 5 3.8 0.3
Na 134 150 140.4 3.4
Ca 0.6 7.4 1.4 1.1
P 9 207 40.8 35.5