Best evidence topic reports
`
`221
`
`Study type (level of
`evidence)
`
`Pilot study
`
`Prospective
`randomised double
`blind placebo
`controlled trial
`
`Table 2
`
`Author, date
`and country
`
`Miller et al
`1995 USA
`
`Fatovich et al
`1997 Australia
`
`Thel et al
`1997 USA
`
`Allegra
`2001 USA
`
`Patient group
`
`In-hospital cardiac arrest, patients
`in arrest after initial ACLS steps,
`patients with poisoning, minors,
`pregnancy excluded, 62 patients
`included;Pilot study of 5 g MgSO4
`administration and ACLS (n = 29)
`versus standard ACLS (n = 33)
`All victims of out-of-hospital cardiac
`arrest eligible for inclusion, excluded
`if dead, not receiving CPR,
`resuscitated, arrest due to
`non-cardiac etiology; Prospective
`randomised double blind placebo
`controlled trial using high dose 5 g
`of MgSo4 (31 patients)and
`placebo936 patients)
`All patients greater than 18 yrs,
`in-patient in the hospital treated for
`cardiac arrest;Randomised double-
`blind study of 2 g magesium
`sulphate bolus followed by infusion
`of 2 g/24 hours (n = 76) versus
`placebo (n = 80) in hospital
`in-patients, excluded emergency,
`prehospital patients with cardiac
`arrest, diferent rhythms included,
`end points of ROSC, for at least
`1 hour.
`All patients with non-traumatic
`cardiac arrest greater than 18 and
`had VF refractory to 3 electroshocks
`in prehospital set-up. Total of 116
`patients, 58 Mg/58 placebo,
`enrolled between 1992 and 1996.
`109 available for analysis.
`
`T B Hassan,
`C Jagger,
`D B Barnett
`2002 UK
`
`Patients in Cardiac Arrest with
`refractory or recurrent VF treated
`in the prehospital phase by the
`county emergency medical services
`and/or in the A&E department.
`52 given Mg, 53 given placebo.
`
`Randomised
`controlled double-
`blind study
`
`Difference in ROSC
`
`24 hr survival
`
`54% in those who had Magnesium,
`60% no Magnesium,p = 0.44
`43(Mg) vs 50%(no Mg) p = 0.41
`
`survival to discharge
`Karnofsky performance
`index
`
`21 vs 21% p = 0.98
`Higher in Mg group
`
`time to study drug
`administration
`ROSC
`
`Admission
`
`discharge
`
`ROSC
`
`Prospective double
`blind, placebo
`controlled multi-
`center prehospital
`clinical trial;58
`received magnesium
`and 58 placebo
`
`A randomised,
`double blind,
`placebo controlled
`trial
`
`25.5 min for magnesium group,
`30.4 for placebo group
`placebo 18.5 vs Mg 25.5%,
`P = 0.38
`16.7 (placebo)vs 16.4%(Mg)
`P = 1.0
`placebo 3.7% vs Mg 3.6%,
`P = 1.0
`
`17%(Mg) and 13% (placebo)
`(CI-10% to +18%)
`
`Patients alive to discharge
`
`Odds Ratio for ROSC in
`patients treated with Mg
`versus placebo
`
`4%(Mg) and 2% (placebo)
`( CI 27% to +11%)
`1.69 (0.54 to 5.30)
`
`Outcomes
`
`Key results
`
`Study weaknesses
`
`Survival to discharge
`between two groups
`Resuscitation or return of
`spontaneous circulation
`
`1 patient in each group survived
`
`34% (3/33) in patients with ACLS
`and Magnesium versus 21%
`(6/29) only ACLS;p = 0.17
`
`Not a randomised controlled,
`blinded study, pilot study
`In-hospital witnessed arrests, all
`rhythms included
`Small sample size
`
`ROSC
`
`23%(Mg) and 22%(no Mg)
`
`Survival to leave ED
`Survival to leave hospital
`
`13% (Mg)vs 11%(no Mg)
`1 patient (Mg)
`
`Out-of-hospital arrests,
`magnesium administered only
`when in hospital, different rhythms
`included
`Low powered study, no mention of
`randomisation method
`
`Hospital in-patients and witnessed
`cardiac arrests, emergency and
`prehospital excluded, all rhythms
`included
`Low powered study, no allocation
`concealment explained, at the
`time of arrest most patients were
`very ill, in ICU and with malignant
`diseases, time of administration
`not measured, low dose of
`magnesium given.
`
`Time of administration of study
`drug greater than 25 mins, low
`dose of magnesium administered,
`low powered study.
`Study closed prematurely as it
`became difficult to enroll patients
`when Magnesium became class
`IIB agent in AHA guidelines for VF
`treatment
`Possible that a type II error
`occurred, dose of magnesium
`given during CA may have been
`inadequate. Individual factors
`such as the incidence of bystander
`CPR, the response time to the first
`defibrillatory shock, protocol
`violations and even the
`aggressiveness of care provided
`in hospital both within the A&E
`department and particularly on
`the ICU can have major
`influences.
`Study population is small,
`response time could have been a
`significant factor in magnesium’s
`seeming lack of efficacy in
`treating refractory VF in this study
`population
`
`Thel MC, Armstrong AL, McNulty SE, et al. Randomized trial of magnesium in in-
`hospital cardiac arrest. Lancet 1997 Nov 1;350(9087):1272–6.
`Allegra J, Lavery R, Cody R, et al. Magnesium sufate in the treatment of refractory
`venticular fibrillation in the prehospital setting. Resuscitation 2001 Jun;49(3):
`245–9.
`Hassan TB, Jagger C, Barnett DB. A randomised trial to investigate the efficacy of
`magnesium sulphate for refractory ventricular fibrillation. Emergency Medicine
`Journal 2002 Jan;19(1):57–62.
`
`Intranasal naloxone in suspected
`opioid overdose
`Report by Helen Ashton, Specialist Registrar,
`Emergency Medicine
`Search checked by Ziauddin Hassan, Specialist
`Registrar, Emergency Medicine
`Blackburn Royal Infirmary
`doi: 10.1136/emj.2005.034322
`Abstract
`A short cut review was carried out to establish whether
`intransasal naloxone is effective in suspected opiate overdose.
`
`596 papers were screened, of which eight presented the best
`evidence to answer the clinical question. The author, date
`and country of publication, patient group studied, study type,
`relevant outcomes, results and study weaknesses of these
`best papers are tabulated. The clinical bottom line is that it is
`likely that intranasal Naloxone is a safe and effective first line
`prehospital intervention in reversing the effects of an Opioid
`overdose and helping to reduce the risk of needle stick injury.
`A large, well conducted trial
`into it’s usage is however
`required to confirm this.
`
`Three part question
`In a [patient with a suspected opioid overdose] is the
`[intranasal administration of Naloxone] a safe and effective
`method of [reversing the effects of the overdose]
`
`Clinical scenario
`A 25 year old male is brought into the emergency department
`by ambulance with a history of respiratory arrest following a
`suspected Opioid overdose. One of the paramedics describes
`struggling and failing to achieve peripheral venous access,
`
`www.emjonline.com
`
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`

`

`222
`
`Best evidence topic reports
`
`Outcomes
`
`Key results
`
`Study weaknesses
`
`Table 3
`
`Author, date
`and country
`
`Hussain et al,
`1984, USA
`
`Lorimer et al,
`1992, Pakistan
`
`Study type
`(level of evidence)
`
`Animal study,
`Controlled Trial
`
`Controlled Clinical
`Trial
`
`Patient group
`
`Male rats approximately
`240 g, anaesthetised with
`Phenobarbital, receiving
`30 mcg radiolabelled
`naloxone either IN via
`micropipette (n = 3) or IV
`(n = 3)
`
`30 patients, 22 male opiate
`dependent and 8 male
`controls. Each receiving
`1 mg naloxone (1 mg/
`400 mL) via nasal spray.
`
`Randomised
`Controlled Trial
`
`Lorimer et al,
`1994, Pakistan
`
`17 male opiate dependent
`patients. Given 1 mg IV
`Naloxone, being
`recommenced on Opium
`then given a further 1 mg
`Naloxone IM (n = 7) or IN
`(1 mg/400 mL) via nasal
`spray (n = 10)
`
`Kelly et al.
`2002 Australia
`
`6 patients with acute heroin
`OD treated in the Emergency
`Department with IN
`Naloxone 0.8 to 2 mg
`
`Case Series
`
`Bioavailability of naloxone
`based on plasma
`concentrations from
`arterial sampling
`Half life of Naloxone
`Time at which peak
`plasma levels occurred
`
`Series of measurements
`from 0 to 30 mins of;
`Severity of withdrawal
`symptoms (Modified
`rating score)
`
`Pulse and BP
`
`Pupillary Response
`
`Series of measurements
`from 0 to 180 mins of;
`Severity of withdrawal
`symptoms (Objective
`Opiate Withdrawal Scale)
`Vital Signs (Pulse/BP)
`
`Pupillary Response
`
`Time to return of
`adequate spontaneous
`respiration
`
`Both methods show 100%
`bioavailability.
`
`Half life same IV and IN.
`Peak plasma levels of IN
`occurred within 3 mins
`
`No difference between groups
`at baseline, significant changes
`between groups and within
`group opiate dependent group
`from 1–30 mins. (P,0.01–
`,0.05)
`No statistically significant
`changes within or between
`groups.
`No change in control group.
`Opiate dependent group
`more constricted at baseline
`and had dilated significantly
`by 10 mins (P,0.01)
`
`Significant changes from
`baseline seen at 1 min IV,
`5 min IN, 15 min IM.
`
`Significant increase in size
`seen at 5 min in IV and IN
`groups. No change seen in
`IM group
`No significant change seen after
`any route of administration
`
`All patients responded within
`2 minutes
`
`37% (n = 11)
`
`10 patients (91% of total
`responders) with average
`response rate of 3.4 min
`One patient responded to IV
`and not IN (has epistaxis)
`
`91% of all Naloxone responders
`did so with IN alone. 64% of all
`patients did not require IV
`placement.
`
`52 patients
`
`43 patients (83% of all
`Naloxone responders)
`7 Patients
`
`9.9 (+/2 4.4SD) Median
`3.0 with IN, 2.8 (+/27.6SD)
`Median 10 with IV
`4.2 (+/22.7SD) Median
`3.0 with IN, 3.7 (+/22.3SD)
`Median 3.0 with IV
`5 of the 9 patients reported to
`have responded to IV and not IN
`
`Need for and response
`to rescue IV Naloxone
`(given if no response to
`IN by the time a secure
`airway/IV)
`Number of IV attempts
`that could be avoided
`
`Response to Naloxone by
`any route (Response =
`‘‘a significant improvement
`in consciousness’’)
`Response to IN Naloxone
`
`Need for further Naloxone
`following initial response
`to IN (due to recurrent
`somnolence)
`Time from initial patient
`contact to response
`
`Time from drug
`administration to
`response
`Nasal Abnormalities
`
`No mention of ethical
`approval, could be considered
`ethically unjustifiable. Results
`may not be reproducible in
`humans
`
`No mention of ethical
`approval; Small numbers
`
`No mention of ethical
`approval; Small, unblinded
`study; Method of
`randomisation not stated;
`Inadequate basic data
`reporting
`
`No mention of ethical
`approval; Very small numbers;
`Definition of acute heroin OD/
`baseline obs. not stated;
`Concentration of Naloxone
`used and administrative
`instrument not stated; Dose of
`Naloxone not standardised;
`Clinical response not well
`defined
`
`Small numbers, Uncontrolled;
`Response not clinically defined;
`Study population appear to be
`part of the population studied
`in the 2005 Barton E D. paper
`
`Small numbers; No baseline
`Obs; Clinical response not well
`defined; 4 of the 9 patients
`reported to have responded to
`IV and not IN, received the IN
`dose ,4 mins after the IN
`dose, allowing limited time for
`the IN dose to take effect.
`Potential conflict of interest
`declared (one of authors is Vice
`President and Medical Director
`of company supplying the
`atomizer device)
`
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`
`Case Series
`
`Response to Naloxone
`by any route
`Response to IN Naloxone
`
`Barton et al,
`2002, USA
`
`30 patients presenting pre-
`hospital with Altered Mental
`Status (AMS) n = 11, Found
`Down (FD) n = 7 or
`Suspected Opiate OD)
`(OD) n = 12. Given
`2 mg (1 mg/ml) IN
`Naloxone via atomizer,
`followed by IV rescue
`dose if required.
`
`Barton ED et al
`2005 USA
`
`Case Series
`
`95 Patients presenting pre-
`hospital with Altered Mental
`Status (AMS) n = 40, Found
`Down (FD) n = 20 or
`Suspected Opiate OD (OD)
`n = 38. (NB 3 patients listed
`in 2 categories) Given 2 mg
`(1 mg/ml) IN Naloxone via
`atomizer, followed by IV
`rescue dose if no response to
`IN by the time a secure
`airway/IV established.
`
`www.emjonline.com
`
`

`

`Best evidence topic reports
`
`Table 3 Continued.
`
`Study type
`(level of evidence)
`
`Randomised
`Controlled Trial.
`
`Author, date
`and country
`
`Kelly et al,
`2005,
`Australia
`
`Patient group
`
`155 patients with suspected
`opiate OD who were un-
`rousable with RR,10.
`Randomised to receive
`2 mg Naloxone IM (n = 71)
`or IN (0.4 mg/ml) via
`atomizer (n = 84)
`pre-hospital.
`
`Robertson et al,
`2005, USA
`
`154 patients with suspected
`narcotic overdose in the
`pre-hospital setting.
`104 given IV and 50 IN
`Naloxone.
`
`Retrospective Case
`Note Review (before
`and after introduction
`of IN Naloxone into
`pre-hospital protocols)
`(poster presentation)
`
`223
`
`Outcomes
`
`Key results
`
`Study weaknesses
`
`Time to regain RR.10
`
`Patients with spontaneous
`resps at 8 min
`Patients with GCS .11 at
`8 min
`
`Patients requiring rescue
`Naloxone
`
`Patients in IN group
`requiring additional
`therapy.
`Adverse events
`
`Time from medication
`administration to Clinical
`Response (defined as
`increase in RR or
`GCS.6)
`Time from patient contact
`to Clinical Response
`
`Patients requiring rescue
`doses by same route
`
`Clinical Response
`(Defined as increase in
`RR or GCS.6)
`
`Faster in IM group (mean
`6 min vs. 8 min, P = 0.006)
`Greater in IM group (82% vs.
`63%, P = 0.0163)
`No statistical difference between
`groups. (72% IM vs. 57%IN,
`P = 0.0829)
`No statistical difference between
`groups. (13%IM vs. 26%IN,
`P = 0.0558)
`26%
`
`More agitation/irritation in IM
`group (13% vs. 2%, P = 0.0278)
`
`Significantly longer in IN group
`(8.1 vs. 12.9 min, P = 0.02)
`
`No significant difference in
`response times (20.3 IV vs.
`20.7 min IN, P = 0.9)
`No statistical difference (18%
`IV vs 34% IN, P = 0.05.) NB.
`3 patients in IN group required
`IM or IV rescue
`IV group 56%, IN Group
`66%
`
`Unblinded study; Adequate
`sample size not achieved;
`Statistics not based on intention
`to treat (3 patients excluded
`because of technical problems
`with nasal administration);
`GCS used in non-trauma
`patients
`
`Small study; No mention of
`ethical approval; Patient
`baseline obs not verified.
`Dose/Concentration of
`Naloxone and administrative
`instrument not verified. GCS of
`6 and un-quantified rise in RR
`not clinically useful endpoints.
`
`IN, intranasal; IV, intravenous
`
`sustaining a needle stick injury in the process. The paramedic
`describes proceeding to administer a total of 800 mcg of
`Naloxone intramuscularly to which the patient’s response
`has been slow. You wonder whether the administration of
`Naloxone intranasally, would have been effective in both
`reversing the effects of the overdose and eliminating the need
`to use needles in the prehospital environment in a patient at
`high risk of having both limited peripheral venous access and
`potentially contractible blood-borne viruses.
`
`Search strategy
`Medline 1966-11/2005 using Ovid Interface.
`Embase 1980 to 2005 Week 53 using Ovid Interface.
`
`Search details
`[(exp ADMINISTRATION, INTRANASAL OR Intranasal$.mp.
`OR exp NOSE OR exp NASAL MUCOSA OR exp NASAL
`CAVITY OR Nasal.mp. OR Pernasal$.mp. OR Transnasal$.mp.
`or exp MUCOUS MEMBRANE or Transmucosal$.mp.) AND
`(Naloxone.mp. OR exp NALOXONE OR Narcan.mp. OR
`Nalone.mp OR Naloxon.mp OR Narcotic Antagonist$.mp.
`OR
`exp
`NARCOTIC
`ANTAGONISTS
`OR
`Opioid
`Antagonist$.mp. OR Opioid Receptor Antagonist$.mp.
`OR
`Opiate
`Antagonist$.mp.
`OR
`Opiate
`Receptor
`Antagonist$.mp.)] LIMIT to English Language.
`Plus Google Search for Intranasal Naloxone.
`
`Search outcome
`280 papers were identified on Medline of which five were
`relevant and 416 papers were identified on Embase of which
`an additional 2 were relevant. One further relevant paper/
`poster presentation was identified on a Google Search.
`
`Comments
`The evidence from the above papers is weak and there are
`conflicting results
`regarding the efficacy of
`intranasal
`compared to iontravenous and intramuscular routes of
`Naloxone administration.
`It does seem, however,
`that
`
`intranasal Naloxone is safe and has significant efficacy in
`reversing the effects of an opioid overdose.
`The intranasal route of administration may be a potentially
`useful first line intervention in managing Opioid OD in the
`community, as it reduces the need for needles to be used in an
`often hostile prehospital environment, in patients who are often
`poor candidates for peripheral venous cannulation and at
`increased risk of carrying blood-borne pathogens. The option of
`being able to administer rescue intravenous or intramuscular
`Naloxone, would however need to remain in place.
`One problem with efficacy was highlighted in patients who
`didn’t respond to intranasal Naloxone due to nasal abnorm-
`ality
`(epistaxis/trauma/deformity/mucous). Other nasal
`pathology and prior use of intranasal drugs such as Cocaine
`could therefore potentially also lead to treatment failure.
`At present Naloxone remains unlicenced for IN use and is not
`available in the UK at a concentration greater than 0.4 mg/ml.
`
`c CLINICAL BOTTOM LINE
`It is likely that intranasal Naloxone is a safe and effective first
`line prehospital intervention in reversing the effects of an
`Opioid overdose and helping to reduce the risk of needle stick
`injury. A large, well conducted trial into it’s usage is however
`required.
`
`Hussain A, Kimura R, Huang C-H, et al. Nasal Absorption of Naloxone and
`Bu prenorphine i n Rats
`Intern ati on al
`Jo urn al of Pha rm aceu tics
`1984;21(2):2332237.
`Loimer N, Hofmann P, Chaudhry H R. Nasal Administration of Naloxone for
`Detection of Opiate Dependence. Journal of Psychiatric Research 1992
`Jan;26(1):39243.
`Loimer N, Hofmann P, Chaudhry H R. Nasal Administration of Naloxone is as
`Effective as the Intravenous Route in Opiate Addicts. International Journal of the
`Addictions 1994 Apr;29(6):819227.
`Kelly A M, Koutsogiannis Z. Intranasal Naloxone for Life Threatening Opioid
`Overdose. Emergency Medicine Journal 2002;19(4);375.
`Barton E D, Ramos J, Colwell C, et al. Intranasal Administration of Naloxone by
`Paramedics. Prehospital Emergency Care 2002 Jan2Mar;6(1):5428.
`Barton E D, Colwell C B, Wolff T, et al. Efficacy of Intranasal Naloxone as a
`Needleless Alternative for Treatment of Opioid Overdose in the Prehospital Setting.
`Journal of Emergency Medicine 29(3);2652271.
`
`www.emjonline.com
`
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`224
`
`Best evidence topic reports
`
`Intranasal versus
`Kelly A M, Kerr D, Dietze P, et al. Randomised Trial of
`Intramuscular Naloxone in Prehospital Treatment For Suspected Opioid Overdose.
`Medical Journal of Australia 2005 Jan;182(1):2427.
`
`Robertson T M, Hendey G W, Stroh G, et al. Versus Intravenous Naloxone for
`Prehospital Narcotic Overdose. Academic Emergency Medicine 2005 May;12(5)
`suppl 1:1662167.
`
`Table 4
`
`Author, date,
`and, country
`
`Holdgate A
`& Pollock T,
`2004, UK.
`
`Patient group
`
`448 patients taken from 5
`prospective, double-blind,
`randomised control trials.
`
`Adults aged 16–79 who
`were diagnosed with acute
`renal/uretertic colic were
`randomised to receive either
`IV NSAID or IV Opiate.
`Patients in whom calculi
`could not be diagnosed;
`those who had already
`taken analgesics; those
`who passed the offending
`stone; and those with
`common CI’s to NSAID’s
`were excluded.
`
`Study type
`(level of evidence)
`
`Meta-analysis
`
`Outcomes
`
`Effectiveness
`
`Study 1:
`
`(based on pain relief
`scores and/or
`reduction of
`
`Key result
`
`Study 1:
`
`Ind = Peth
`
`Study weakness
`
`Randomisation details were
`unclear in Studies 1, 2, and 4.
`
`Only Study 5 performed
`intention-to-treat analysis
`
`(Lehtonen at al, 1983)
`
`Study2:
`
`Pain intensity scores
`20–30 min after
`dministration of 1st
`dose of drug)
`
`(NSAID was still more
`efficacious than Opiate at
`30 min, P,0.001).
`
`Indometacin Vs
`
`Pethidine
`
`Study 2:
`(Jonsson et al, 1987)
`
`Indomethacin Vs
`Oxycone/Papaverine
`
`Study 3:
`(Curry and Kelly, 1995)
`
`Tenoxicam Vs Pethidine
`
`Study 4:
`(Al-Sahlawi and Tawfik, 1996)
`
`Indomethacin Vs
`Aspirin Vs Pethidine
`
`Study 5:
`(Cordell et al, 1996)
`Ketorolac Vs
`Meperidine
`
`Studies 1–4 lack statistical
`analysis of the differences in
`additional analgesia
`requirement & adverse effects
`between the various groups
`of drugs
`
`Ind = Oxy/Pap
`
`Study3:
`Ten = Peth
`
`Study 4:
`Ind . Asp
`(P = 0.05),
`Peth . Asp
`(P = 0.01),
`Ind = Peth
`Study 5:
`Ket . Mep
`(P,0.001)
`
`Study 1:
`Ind 21%
`Peth 26%
`
`Study 2:
`Ind 54%
`Oxy/Pap 73%
`Study 3:
`Ten 18%
`Peth 17%
`Study 4:
`Ind 4%
`Asp 26%
`Peth 0%
`Study 5:
`Ket 64%
`Mep 89%
`(p = 0.04)
`Study 1:
`Ind 27%
`Peth 55%
`Study 2:
`Ind 60%
`Peth 73%
`Study 3:
`Ten 0%
`Peth 18%
`Study 4:
`Ind 4%
`Asp 0%, Peth 0%
`Study 5:
`Ket 37%
`Mep 55%
`(p = 0.07)
`
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