nurses routinely encounter by many stressful working conditions . a well - defined stress factor for nursing caregiver
this clinical condition ( agitation ) is also an early symptom of the acute withdrawal syndrome , especially following inappropriate use of naltrexone in addicted people , which may jeopardize health status of the addicts and also their close relatives .
naltrexone is a well - known drug for the prevention of drug re - abuse in addicts , which competitively antagonizes opium euphoria due to its role in - and -receptor antagonism .
the drug has a 10-h half - life and should be used 7 - 10 days after opium quit and 10 - 14 days after the last dose of methadone .
severe withdrawal syndromes will appear if naltrexone is used accidentally or earlier than the above because of acute block of opioid receptor .
agitation , delirium , yawning , severe muscular pain , tachycardia , diarrhea , and vomiting are common in this case , which may be much more dangerous in geriatric patients and also patients with underlying ischemic heart disease . in our setting , there are many admissions of addicts referred to the department of clinical toxicology just due to inappropriate use of naltrexone having severe agitation . as it is mentioned before , this agitation is so dangerous that the patient may hurt himself / herself or the health care professionals , and it can be managed by sedation .
clonidine and propofol are believed to have a role in controlling these patients but using propofol needs icu admission and intubation .
in addition , clonidine has a limited efficacy , which is not appropriate for acute and critical status of these patients .
benzodiazepines are among the safest sedative drugs which their efficacy in similar situations are documented elsewhere .
midazolam and diazepam are both available in parental dosage form , and both are used in acute - care settings in our department routinely .
midazolam is a short - acting benzodiazepine with about 2 h half - life , which metabolizes in the liver and is used regularly for relieving preoperation anxiety and also agitation in critically ill patients .
the onset of action of midazolam is about 2 min and is physically compatible with dextrose 5% and saline on administration .
diazepam is a long - acting benzodiazepine with a 1 - 2 days half - life .
one of the common causes of agitation in our department is misusing naltrexone in addicted patients .
the routine medication in our department is diazepam bolus dose and infusion . although the different medications have been used for agitation induced by naltrexone in addicted patients , none of them had an acceptable efficacy on admission control of agitation .
therefore this study was conducted to have a comparative evaluation of these two drugs for controlling agitation due to inappropriate use of naltrexone in addict patients .
this double - blind randomized controlled clinical trial was carried out in 2005 in the department of clinical toxicology at noor general teaching hospital affiliated with isfahan university of medical sciences ( iran ) .
eligible patients were naltrexone used agitated adult addicts who were not given or used any type of benzodiazepines in any dosage form ( oral , parenteral , or rectal ) , not on systematic central nervous system depressant drugs ( eg , tricyclic antidepressants , phenothiazines , buterophenones ) , without any known hypersensitivity to diazepam , midazolam , or any other component of their formulation . patients who required the endotracheal intubations were excluded .
patients who were discharged from the ward with their own written consent were also excluded from the study due to ethical issues .
families of eligible patients or their legally eligible companions were informed by one of the investigators about the whole study , and it was optional for the patients to take part in the investigation .
so , all the included patients had a written informed consent form , which was signed without any hesitation after the interview .
the consent form was in concordance with helsinki ii declaration and also tehran declaration for ethics in human researches .
the study protocol was approved by isfahan university of medical sciences board of human studies .
using ncss - pass ( jerry hintze , utah , 2004 ) the minimum patient number for at least 10% of difference in efficacy scoring of therapy (  = 0.05 ) and for a power of 80% , was calculated as 21 for each arm of the study ( diazepam and midazolam ) . assuming a dropout of about 20% of patients ( eg , if they met the exclusion criteria ) the total patient number needed for the study was at least 48 . in this study , 51 patients were included , from which 42 completed full course of study .
patients were randomly allocated in 2 groups ( a and b ) , using the random number table after primary supportive measures .
group a received an intravenous stat dose of 0.1 mg / kg diazepam and group b received 0.1 mg / kg stat dose of midazolam and 0.1 mg / kg / h of the drugs was infused in dextrose water 5% as the maintenance dose .
patients were kept blinded using two types of coded vials , code 1 for midazolam vials and code 2 for diazepam vials .
agitation was evaluated and scored by an attending physician who was unaware of the type of treatment groups . the patient s agitation score was measured using richmond agitation sedation scale .
each patient was evaluated individually and was scored on admission at 30 , 60 , and 120 min . direct observation and judgment
were needed to confirm and add up the results using the following definitions to describe the severity of agitation : mildly agitated ( score 1 - 3 ) , patient was quite calm and there was no need for any physical restriction ; moderate agitation ( score 4 - 6 ) , patient was more or less calm , muscular fasciculation was faded but he / she needed physical restriction ; severe agitation ( score 7 - 9 ) , patient was slightly sleepy after benzodiazepine administration with muscular fasciculation , and physical restriction was needed .
finally , very severe agitation ( score 10 ) was observed when the patient was completely cooperative and had frequent involuntary organ movement and was firmly restricted to the bed .
mann - whitney u test , student s t test , and t paired test were performed for statistical analysis using spss 11 statistical software .
from 42 eligible patients ( 38 male and 4 female ) , 26 had taken naltrexone as 50 mg oral tablet and 3 patients were not sure about the naltrexone dosage form strength , but drug utilization was documented .
a 72.8% of the patients had used opioid less than 10 h of admission and 27.3% of them 11 - 15 h before admission in hospital [ table 1 ] .
intoxication and toxicologic characteristics of the study patients both groups had the agitation score of 10 on admission and 30 min after administrating benzodiazepines . comparing the mean agitation scores in midazolam and diazepam
groups did not show a significant difference at 0 , 30 , and 60 min after medication administration .
however , the difference was significant at 120 min ( p = 0.04 , table 2 ) .
comparison of the mean agitation score in midazolam and diazepam groups the difference between the mean onset of action in the midazolam group ( at 67 min ) and diazepam group ( at 81 min ) was statistically significant ( p = 0.04 ) .
correlation between the agitation score and naltrexone dose was not significant ( p = 0.020 ) .
there was a negative and significant correlation ( r = - 0.09 p = 0.02 ) between agitation score and time interval from opioid used to taking naltrexone [ figure 1 ] .
furthermore , there was a negative correlation between agitation score and time elapsed from naltrexone administration to admission .
since many years , addict patients are considered as special population of ill people who need particular nursing care .
nurse practitioners in the emergency wards all round the world are more or less familiar with the agitated addicts with withdrawal syndrome who need special nursing care .
drug therapy is still considered as part of the treatment in these patients . to the best of our knowledge ,
this is the first comparative study on efficacy of midazolam and diazepam for controlling the agitation precipitated following naltrexone misuse .
the results [ tables 1 and 2 ] showed that diazepam can not reduce agitation , and its mean onset of action is lower than midazolam , so midazolam acts more efficiently for controlling agitation , but on the base of our data and other studies , none of the drugs are suitable choices for controlling agitation because agitation management is important during first minutes that it is severe and patients may hurt himself / herself , companions , or medical staff .
although propofol is a suitable alternative to benzodiazepines in severe acute withdrawal syndrome but has side effects , such as hypoventilation , causing atelectasis and respiratory arrest .
our results indicate that , there is no relationship between naltrexone dose and the agitation score in the study patients .
however , elongation of time elapsed between opioid usage and taking naltrexone , leads to a better response to treatment and lower agitation score , because of reduction of naltrexone half - life . based on our data [ tables 1 and 2 ]
it is clear that severity of agitation depends on the amount of undetoxified opioid and it is in concordance with the results from other studies .
only one patient responded to treatment very quickly , but it was confirmed that he had received a single dose of morphine in another clinic prior to the admission .
it seems that that co - administration of benzodiazepines and a dose of morphine were effective in the management of agitation due to naltrexone inappropriate usage in that patient .
a limitation of our study was the different number of males and females in the study sample .
sex differences may influence the substance use disorders , response to opioid withdrawal , and rate of the response to the treatment or required dose of the drugs .
also the type of the opioid that addicts had used was not mentioned in this study .
opioids such as heroin and morphine have generally a short half - life , whereas methadone has a long one , and this issue can affect onset and severity of symptoms of withdrawal and also rate of the response to agitation treatment .
further studies are needed to test the efficacy of combination therapy of benzodiazepines with opioid agonists , and also other sedative drugs , such as ultra - short - acting barbiturates ( eg , thiopental ) for controlling and management of agitation in these patients . regarding the increased reports of acute opioid withdrawal , which are precipitated by naltrexone , adequate patient counseling and family awareness seem to be necessary . in conclusion ,
the present study showed that despite the induction of sedation by midazolam and diazepam in their usage for the agitation due to inappropriate use of naltrexone , these agents are not drugs of choice in this issue .
authors had no conflict of interest - including personal or financial relationships with organizations that might inappropriately influence , or be perceived to influence the work .
this research was the result of a medical internship thesis project , which was supported financially by the vice chancellery for research and technology at the isfahan university of medical sciences .
 background : agitation is an early symptom of the acute opioid withdrawal syndrome in addicts that may start by inappropriate use of naltrexone 
 . the current drug interventions are not efficient or need critical care as well . 
 this study compares the clinical role of midazolam and diazepam for the management of agitation due to inappropriate use of naltrexone.materials and methods : in this double - blind randomized controlled clinical trial , 44 agitated addicts , who did not use any type of benzodiazepine , not on systematic central nervous system depressant drugs , without any known hypersensitivity to diazepam , midazolam , or any other component of their formulation and had no evidence for the need of critical care , were enrolled . 
 an i.v . 
 stat dose of 0.1 mg / kg diazepam and 0.1 mg / kg stat dose of midazolam and a 0.1 mg / kg / h infusion of these drugs were administered for different groups of patients , respectively . 
 agitation scores were recorded at 30 , 60 , 120 min after the start of drug administration using richmond agitation sedation scale score.results:a significant difference between the mean onset of agitation control in midazolam group ( at 67 min ) and diazepam group ( at 81 min ) was recorded . 
 the difference of mean agitation score in the midazolam and diazepam group was only significant at 120 min . 
 there was a negative correlation between agitation score and time elapsed from naltrexone administration to admission.conclusion:midazolam and diazepam may not be considered suitable and perfect pharmacologic agents for the initial controlling of agitation induced by naltrexone . 
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