eISSN: 1896-9151
ISSN: 1734-1922
Archives of Medical Science
Current issue Archive Manuscripts accepted About the journal Special issues Editorial board Abstracting and indexing Subscription Contact Instructions for authors
SCImago Journal & Country Rank
2/2014
 
Share:
Share:
more
 
 

Clinical research
Naloxone therapy in opioid overdose patients: intranasal or intravenous? A randomized clinical trial

Ali Mohammad Sabzghabaee, Nastaran Eizadi-Mood, Ahmad Yaraghi, Samaneh Zandifar

Arch Med Sci 2014; 10, 2: 309–314
Article file
- naloxone.pdf  [0.07 MB]
 
 

Introduction

As a competitive antagonist of the mu-opioid receptors [1], naloxone can be used for resuscitating patients who have significant respiratory depression and impaired consciousness due to opioid toxicity. Cannulation is a particular difficulty in intravenous drug users (IDUs). Often pre-existing venous damage can delay or even prevent the administration of an antidote. Additionally, IDUs are also at an increased risk of carrying blood borne infections that could be transmitted to healthcare workers through needle stick injuries [2]. Whilst patients with altered mental status or multiple narcotic overdose may require intravenous (IV) access for other reasons, those with isolated narcotic overdose who rapidly respond to intranasal (IN) naloxone may not require IV access at all [3, 4]. The problems with the IV route of naloxone administration have led to efforts to find an effective alternative means of delivery.
The IN route has been shown to be clinically effective for a number of medications including analgesics and sedatives [5, 6]. When used with carefully selected medications, this delivery route has the advantage of rapid onset, high plasma bioavailability, direct transport to the central nervous system across the olfactory mucosa, elimination of first pass metabolism and, perhaps most importantly, elimination of the use of needles [7–13].
Some observational studies have suggested that intranasal naloxone may be safely administered for the reversal of opioid intoxication in the pre-hospital and hospital settings. Unfortunately such studies have suffered from several limitations such as lack of randomization or blinding and reliance on the subjective reporting of paramedics who were required to record times, administer medications and assess appropriate patient responses [4, 14–18].
This study was designed therefore to compare the effect of intranasal administration of naloxone with those of intravenous administration in the treatment of suspected opioid overdose patients in a managed clinical environment referring to the limitations pointed out above in previous studies.

Material and methods

Study design and setting

This randomized trial study was conducted in the Department of Poisoning Emergencies at Noor and Ali Asghar (Peace Be Upon Him) University Hospital. The study protocol was approved by the Ethics Committee of Isfahan University of Medical Sciences. The study was also registered at ClinicalTrials.gov (Reference number identifier: NCT01293058).

Patient selection and treatment protocol

Included in the study were all patients with the age range 15–50 suspected of opioid overdoses. This selection was based upon a history of opioid overdose and the display of clinical manifestations including myotic pupils and loss of consciousness (with or without respiratory depression defined by a respiratory rate of less than 12). One hundred eligible patients were divided into two groups (each group containing 50 patients) in addition to basic life support following clinical practice guidelines [19]. One group was administered 0.4 mg naloxone diluted down to a 2 ml nasal spray (1 ml into each nostril) whilst the other received 0.4 mg IV naloxone as a bolus dose. Normal saline was used as the solvent. The intranasal spray was administered to patients in lying position. All patients who failed to respond within 5 min of the initial naloxone administration were given a further 0.4 mg naloxone by the same administration route (IN or IV). Patients failing to respond to the first 0.4 mg naloxone with an increased level of consciousness or a reversal of respiratory depression were excluded from the study. Naloxone hydrochloride was purchased from Tolid Daru Co, Tehran, Iran.

Data collection

The information collected for this study included patients’ demographics, the type of opioid used and the means of administration, vital signs (blood pressure, heart rate, respiratory rate), level of consciousness measured with descriptive scales (conscious, lethargic, obtundation, stupor, and coma) and the Glasgow Coma Scale (GCS), time to response, arterial blood oxygen (O2) saturation before and 5 min after naloxone administration, side-effects (e.g. agitation) and duration of hospital stay. These data were collected from checklists including information on patient history, clinical assessments and records of treatment administered to the patient.
Trained medical staff prospectively recorded demographic data and clinical features of patients including measurement of the eye, motor, verbal and GCS scores in an appropriate form. The GCS was determined based on three components: eyes (4 – opens spontaneously, 3 – to verbal command, 2 – to pain, 1 – none), verbal (5 – oriented, 4 – disoriented, 3 – inappropriate words, 2 – incomprehensible sounds, 1 – none), and motor (6 – obeys, 5 – localizes pain, 4 – withdrawal, 3 – abnormal flexion, 2 – abnormal extension, 1 – none) [20].

Key outcome measures

The primary outcome measure was level of consciousness. Secondary outcomes were vital signs, the time interval to response, arterial blood O2 saturation, the frequency of side-effects (e.g. agitation) and the duration of hospital stay.

Statistical analysis

Randomization was carried out using random allocation software (Saghaei, 2004). Quantitative variables were compared using the independent t-test. Qualitative variables were compared using 2 and Mann-Whitney tests. Data were analyzed using SPSS version 17.0 (SPSS Inc, Chicago, IL, USA) with p < 0.05 being considered statistically significant.

Results

Age, gender, opioid agent and route of opioid use before naloxone administration between the two groups were not significantly different (Table I).
The results regarding level of consciousness (including descriptive and Glasgow Coma Scales) after naloxone administration are shown in Table II. The mean response time in the IN group and the IV group was 2.56 ±0.64 min and 1.48 ±0.58 min respectively (p < 0.001). The IN group had a significantly longer time to response to naloxone than the IV group (p < 0.001).
After naloxone administration there was a significant difference in heart rate between the IN and IV groups (p = 0.003). However, blood pressure and respiratory rate were not significantly different between the two groups (p = 0.18, p = 0.17) (Table III).
The mean arterial O2 saturation before IN and IV naloxone administration was 71.4 ±8.3% and 72.7 ±6.3% (p = 0.45) respectively. Arterial O2 saturation following naloxone administration was 94.4 ±1.3 in the IN group and 94.6 ±1.5 (p = 0.32) in the IV group.
The mean length of hospital stay was 1.53 ±0.16 days and 1.2 ±0.15 days in the IN and IV groups respectively (p = 0.15). Agitation after naloxone administration was observed in 12 patients in the IV group. No patient in the IN group were observed to become agitated.

Discussion

Intranasal administration of naloxone has been shown to have many advantages [7–13].
Given the necessity for the rapid administration of naloxone in opioid overdose emergencies, the nasal route can offer immediate safe access and can circumvent the difficulties of having to remove clothing to cannulate. This method has been underutilized to date.
This study showed that among opioid overdose patients, IN naloxone is as effective as IV naloxone at reversing the depressive effects on the central nervous system caused by opioids. Although our results showed no significant clinical difference between the two groups after naloxone administration, level of consciousness was higher in patients administered IN naloxone than those in the IV group. This finding may be because of direct transportation of naloxone to the central nervous system across the olfactory mucosa [7]. Although Dowling et al. [21] in an open-label crossover volunteer study evaluated the pharmacokinetics of intranasal naloxone and reported that the IN route is the least useful due to its poor bioavailability, major differences existed between their subjects and opioid poisoned patients. They administered IN naloxone to alert healthy volunteers who involuntarily swallowed a significant percentage of the administered drug that pooled in the nasopharynx. Due to the high first pass metabolism of naloxone this may have resulted in the very low bioavailability observed. In patients unconscious due to opioid overdose with consequent depressed oropharyngeal reflexes, less nasally administered naloxone may be swallowed, thus increasing the IN absorption and bioavailability.
Merlin et al. [22] reported that the route of administration (IV or IN) of naloxone made no significant difference to its effect on level of consciousness (using GCS). Our findings were incompatible with these results. Previous studies have been criticized for using GCS to quantify the change in level of consciousness following naloxone administration in cases of opioid intoxication [23] but the GCS has previously been used to evaluate non-trauma patients [24–26]. Therefore, in our study we used both descriptive and GCS scores to evaluate the level of consciousness. There is disagreement between physicians over the clinical usefulness of the GCS [27, 28]. The inter-observer variability is high when the scoring systems are not used on a regular basis, thus affecting the accuracy and reproducibility of the data [29–32]. This is potentially relevant in our study, as GCS determination was performed by several different physicians and had not formed a routine part of patient assessment before the study period. We tried to minimize variability by having one person to coordinate the process of data collection and had our anaesthesiologist or toxicologist formally train our emergency physicians in the assessment of GCS prior to the study. All GCS assessments were subsequently made by this group of physicians.
Merlin et al. [22] also reported that the route of naloxone administration (IN or IV) made no difference to the effect on respiratory rate. Our findings supported this conclusion. Our study also showed that there was no difference between the two groups in normalization of blood pressure and arterial O2 saturation after naloxone administration.
There was a difference in the rates of agitation after naloxone treatment between the two study groups, with patients who received IV treatment showing higher rates (n = 12) than those who received IN treatment (n = 0). This may be explained by the difference in rates of naloxone absorption between the two methods of naloxone administration [9] and may be seen as an advantage of the IN route. However, the higher rate of agitation in the IV group may be due to the higher number of addicted patients in this group.
Since opioid abusers frequently have incomplete, inaccessible or non-existent medical histories, it is impossible to establish how many patients in each group were addicted to opioids (and therefore subject to withdrawal with the administration of naloxone).
Whilst the randomization method used in the study should result in an approximately equal addiction rate between the two groups, it remains impossible to state definitely that IN administration results in a lower likelihood of agitation. To further investigate this area, a limited study of patients with a documented history of addiction would be required.
In a review article Kerr et al. [33] demonstrated that there is not enough evidence to support IN naloxone as a first-line intervention by paramedics for the treatment of heroin overdose in the pre-hospital setting. In contrast, in a short-cut review Ashton and Hassan [34] screened 596 papers and concluded that intranasal naloxone is a safe and effective first line, pre-hospital intervention, both in reversing the effects of an opioid overdose and helping to reduce the risk of needle stick injury.
There are also some limitations to our study. Our results should not be extrapolated to other institutions. It is a single-centre study, and may not be representative of all patients. Since not all of the subjects became completely alert after naloxone administration, it remains possible that other toxic agents were present in some patients. However, no toxicological screening was carried out to establish the presence and type of other agents which may have affected the level of consciousness. Alternatively, an insufficient naloxone dosage may have resulted in some of the patients failing to return to full consciousness. In the presented work there was a predominance of male patients – 78% and 74% in the IN and IV groups respectively. Therefore the described results may not be extrapolated to a female population.
In conclusion, IN naloxone is as effective as IV naloxone in reversing both respiratory depression and the depressive effects on the central nervous system caused by opioid overdose. We may therefore suggest using the IN route for administration of naloxone in opioid overdose patients to reverse clinical manifestations with less severe withdrawal, especially in patients with a history of previous addiction.

Acknowledgments

We would like to thank all the staff nurses of the Poisoning Emergency Department of Noor and Ali Asghar (PBUH) University Hospital for their invaluable help. The help and support of academic faculty members of the Anaesthesiology and Intensive Care Department and members of the Research Committee of Isfahan University of Medical Sciences is greatly appreciated. This research is a result of a medical internship project and was financially supported by the vice-chancellery of research at the Isfahan University of Medical Sciences (Project Registration Number 386083, 2008).

References

1. Goodman & Gilman’s the pharmacological basis of therapeutics. McGraw-Hill, Health Professions Division, New York 1996; 549-51.
2. Dore GJ, Thomas DL. Management and treatment of injection drug users with hepatitis C virus (HCV) infection and HCV/human immunodeficiency virus coinfection. Semin Liver Dis 2005; 25: 18-32.
3. Barton ED,  Ramos J, Colwell C, Benson J, Baily J, Dunn W. Intranasal administration of naloxone by paramedics. Prehosp Emerg Care 2002; 6: 54-8.
4. Barton ED, Colwell CB, Wolfe T, et al. Efficacy of intranasal naloxone as a needleless alternative for treatment of opioid overdose in the prehospital setting. J Emerg Med 2005; 29: 265-71.
5. Dale O, Hjortkjaer R, Kharasch ED. Nasal administration of opioids for pain management in adults. Acta Anaesthesiol Scand 2002; 46: 759-70.
6. Lahat E, Goldman M, Barr J, Eshel G, Berkovitch M. Intranasal midazolam for childhood seizures. Lancet 1998; 352: 620.
7. Hussain AA, Kimura R, Huang CH. Nasal absorption of testosterone in rats. J Pharm Sci 1984; 73: 1300-1.
8. Loimer N, Hofmann P, Chaudhry HR. Nasal administration of naloxone is as effective as the intravenous route in opiate addicts. Int J Addict 1994; 29: 819-27.
9. Loimer N, Hofmann P, Chaudhry HR. Nasal administration of naloxone for detection of opiate dependence. J Psychiatr Res 1992; 26: 39-43.
10. Ugwoke MI, Exaud S, Van Den Mooter G, Verbeke N, Kinget R. Bioavailability of apomorphine following intranasal administration of mucoadhesive drug delivery systems in rabbits. Eur J Pharm Sci 1999; 9: 213-9.
11. Wermeling DP. Opioid harm reduction strategies: focus on expanded access to intranasal naloxone. Pharmacotherapy 2010; 30: 627-31.
12. Scaglione F, Scanni A, Tomirotti M, Dimaiuta M, Ferrari P, Fraschini F. Pharmacokinetics and bioavailability of metoclopramide nasal spray versus metoclopramide intravenous in healthy volunteers and cancer patients. Arzneimittelforschung 1993; 43: 986-8.
13. Dobryakova YV, Dubynin VA, Ivleva YA, Belyaeva YA, Kamenskii AA. Effect of opioid antagonist naloxone on maternal motivation in albino rats. Bull Exp Biol Med 2005; 140: 10-2.
14. Glaser A, Arakaki D, Chan GM, Hoffman RS. Randomised trial of intranasal versus intramuscular naloxone in prehospital treatment for suspected opioid overdose. Med J Aust 2005; 182: 427.
15. Kerr D, Kelly AM, Dietze P, Jolley D, Barger B. Randomized controlled trial comparing the effectiveness and safety of intranasal and intramuscular naloxone for the treatment of suspected heroin overdose. Addiction 2009; 104: 2067-74.
16. Kelly AM, Koutsogiannis Z. Intranasal naloxone for life threatening opioid toxicity. Emerg Med J 2002; 19: 375.
17. Wolfe TR, Bernstone T. Intranasal drug delivery: an alternative to intravenous administration in selected emergency cases. J Emerg Nurs 2004; 30: 141-7.
18. Kelly AM, Kerr D, Dietze P, Patrick I, Walker T, Koutsogiannis Z. Randomised trial of intranasal versus intramuscular naloxone in prehospital treatment for suspected opioid overdose. Med J Aust 2005; 182: 24-7.
19. Shannon MW, Borron SW, Burns MJ (eds.). Haddad and Winchester’s clinical management of poisoning and drug overdose. Saunders/Elsevier, Philadelphia 2007.
20. Barsic B, Marton E, Himbele J, Ravlić Z. Evaluation of the Glasgow Coma Scale score in critically ill infectious disease patients. Infection 1996; 24: 297-300.
21. Dowling J,  Isbister GK, Kirkpatrick CM, Naidoo D, Graudins A. Population pharmacokinetics of intravenous, intramuscular, and intranasal naloxone in human volunteers. Ther Drug Monit 2008; 30: 490-6.
22. Merlin MA, Saybolt M, Kapitanyan R, et al. Intranasal naloxone delivery is an alternative to intravenous naloxone for opioid overdoses. Am J Emerg Med 2010; 28: 296-303.
23. Duchěne D, Ponchel G. Nasal administration: a tool for tomorrow’s systemic administration of drugs. Drug Development and Industrial Pharmacy 1993; 19: 101-22.
24. Fulton JA, Greller HA, Hoffman RS. GCS and AVPU: the alphabet soup doesn’t spell “C-O-M-A” in toxicology. Ann Emerg Med 2005; 45: 224-5.
25. Walther SM, Jonasson U, Gill H. Comparison of the Glasgow Coma Scale and the Reaction Level Scale for assessment of cerebral responsiveness in the critically ill. Intensive Care Med 2003; 29: 933-8.
26. Weir CJ, Bradford AP, Lees KR. The prognostic value of the components of the Glasgow Coma Scale following acute stroke. QJM 2003; 96: 67-74.
27. Holdgate A, Ching N, Angonese L. Variability in agreement between physicians and nurses when measuring the Glasgow Coma Scale in the emergency department limits its clinical usefulness. Emerg Med Australas 2006; 18: 379-84.
28. Gill MR, Reiley DG, Green SM. Interrater reliability of Glasgow Coma Scale scores in the emergency department. Ann Emerg Med 2004; 43: 215-23.
29. Eizadi-Mood N, Saghaei M, Alfred S, et al. Comparative evaluation of Glasgow Coma Score and gag reflex in predicting aspiration pneumonitis in acute poisoning. J Crit Care 2009; 24: 470 e9-15.
30. Polderman KH, Jorna EM, Girbes AR. Inter-observer variability in APACHE II scoring: effect of strict guidelines and training. Intensive Care Med 2001; 27: 1365-9.
31. Polderman KH, Thijs LG, Girbes AR. Interobserver variability in the use of APACHE II scores. Lancet 1999; 353: 380.
32. Sabzghabaee AM, Eizadi-Mood N, Gheshlaghi F, Adib N, Safaeian L. Is there a relationship between admission blood glucose level following acute poisoning and clinical outcome? Arch Med Sci 2011; 7: 81-6.
33. Kerr D, Dietze P, Kelly AM. Intranasal naloxone for the treatment of suspected heroin overdose. Addiction 2008; 103: 379-86.
34. Ashton H, Hassan Z. Best evidence topic report. Intranasal naloxone in suspected opioid overdose. Emerg Med J 2006; 23: 221-3.
Copyright: © 2014 Termedia & Banach. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
Quick links
© 2017 Termedia Sp. z o.o. All rights reserved.
Developed by Bentus.
PayU - płatności internetowe