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Three Part Question

Is [IV morphine 'titrate-to-pain'] a [safe and effective intervention for acute severe pain] in [adult ED patients]?

Clinical Scenario

Your Trust launches an updated Acute Pain Policy which states that IV morphine should be given by a Doctor as a 2mg bolus at 5 minute intervals. Your ED has been using 1-10mg titrated for over 10 years without significant incident but the Trust Risk Management Committee require evidence that what you do is safe and effective. You wonder what the evidence is for your pratice.

Search Strategy

1. MEDLINE, EMBASE, CINAHL & BNI were searched using the NHS Evidence Healthcare portal
2. Google Scholar
Search string: morphine +/- emergency +/-administration +/- intravenous +/- rate
The references of any relevant papers were then searched for further papers
No articles were found that directly addressed the clinical scenario. Ten references that partially addressed aspects of the clinical scenario were identified.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Aubrun et al 2003 France	3045 adult PACU patients with a mean initial VAS pain score of 73mm (±19mm) given IV morphine 2mg (≤60kg) or 3mg (>60kg) bolus at 5 minute intervals	Prospective convenience cohort study	Dose required to achieve pain relief (VAS ≤30mm)	Mean total dose 0.17mg/kg (±0.1mg/kg), median 4 doses (range 1-20)	-PACU not ED -Patients needing rescue analgesics (0.9%) or having ADR’s (2.4%) excluded from analysis therefore may overestimate efficacy/safety
			Pain score-dose relationship	VAS score >70mm associated with need for doses >0.15mg/kg. VAS score vs time depicted as sigmoid curve (i.e. non-linear)
Bektas et al 2009 Turkey	146 ED patients with a working diagnosis of renal colic & a baseline VAS >70mm who were randomised to receive IV morphine 0.1mg/kg, IV paracetamol 1g or placebo	Randomised, double-blind, placebo controlled trial	VAS pain score reduction at 30 minutes	Median VAS reduction not significantly different for morphine vs paracetamol (40mm (95% CI 29-52mm) vs 43mm (95% CI 35-51mm); P=0.74). Both significantly better than placebo (morphine P=0.045; paracetamol P=0.05)	-Does not state how fast morphine was given (assumed to be 15 minutes- so that double-blinding possible) -Only renal colic pain -Only patients aged 18-55 therefore older patients not represented -Excludes patients taking any other analgesia in previous 6 hours including NSAIDs (standard treatment in UK) -Per protocol analysis- not explicit if patients excluded from VAS reduction data if rescue analgesia required before 30 minutes
			Need for rescue analgesia	49% of morphine, 45% of paracetamol & 67% of placebo patients required rescue analgesia at 30 minutes (morphine or paracetamol combined vs placebo P=0.079)
			Presence of ADR	33% of morphine, 24% of paracetamol & 16% of placebo patients had an ADR (morphine or paracetamol combined vs placebo P=0.139)
Bijur et al 2005 USA	119 adult patients attending ED with median NRS pain score 10/10 given 0.1mg/kg IV morphine over 1-2 minutes	Prospective convenience cohort trial	% pts with ineffective analgesia after 30 minutes (<50% decrease in baseline pain score)	67% (95% CI 58-76%) failed to achieve >50% decrease in baseline pain score	-High baseline pain score -Non-Caucasian population -Administration rate appears to be faster than current practice(7mg over 2 minutes for a 70kg pt)
			% patients with ADR (nausea, vomiting, abnormal vital sign)	22% some nausea
Birnbaum et al 2007 USA	Adult patients attending ED with acute pain randomised to receive 0.1mg/kg IV morphine as a single bolus over 4-5 minutes followed 30 minutes later by either placebo (n=138) or 0.5mg/kg IV morphine over 4-5 minutes (n=142)	Randomised, placebo-controlled, double-blind trial	Mean between-group difference in NRS# decrease after 30 & 60 minutes	At 60 minutes: 0.15mg/kg showed a 0.8 (95% CI 0.1-1.5) greater mean decrease than 0.1mg/kg (stat. sig.)	-High baseline pain score -Non-Caucasian population -High levels of pre-morphine nausea & vomiting -Patients with opioid use in past 7 days excluded
			Clinically significant difference in NRS decrease (defined as a reduction ≥1.3)	0.15mg/kg did not achieve a clinically significant difference in NRS decrease compared to 0.1mg/kg
			% patients with ADR (nausea, vomiting, itch)	12% some nausea, 5% vomited, 2% itch. No significant difference in incidence of ADRs between groups. No naloxone used
Craig 2011 UK	Adult ED patients with a VAS pain score of 70mm or greater randomised to receive either 10mg IV morphine (n=27) or 1g IV paracetamol (n=28) over 15 minutes	Randomised, double-blind trial	Difference in pain score at 0, 5 15, 30 & 60 mins	No significant difference in pain score between morphine and paracetamol at any time	Non-standard dose & administration of morphine
			Rescue analgesia	No significant difference in patients requiring rescue analgesia
			ADR	Significantly more ADRs in morphine group compared to paracetamol group (8 (29.6%) vs 2 (7.1%); P=0.03)
Fry, M. & Holdgate, A 2002 Australia	349 ED patients with a median VAS score of 8.5cm treated by nurse-initiated IV morphine 2.5mg every 5 minutes until patient ‘comfortable’ or max dose of 0.1mg/kg reached.	Prospective, convenience cohort study	Analgesic efficacy (VAS reduction)	Median reduction of 4.5cm at 1 hour (p,0.001)	End point of ‘patient comfortable’ does not correlate with median VAS at 1 hour of 4/10 (moderate pain).
			ADR	Small but stat. sig. reduction in BP, pulse, O2 sats & RR. 15 (4.3%) adverse events (10 low BP, 5 low sats) only Tx needed was O2. No clinically significant decrease in pulse, RR or GCS
			Time-to-narcotic vs Dr initiated morphine	Median of 52 minutes (Dr) vs 18 minutes (nurse) (26 minutes earlier for nurses)
Galinski et al 2007 France	Adult patients with severe, acute pain in trauma (initial pain score (≥6/10) randomised to receive ketamine 0.2mg/kg (n=33) or placebo (n=32) plus morphine 0.1mg/kg bolus followed by 3mg every 5 minutes	Randomised, placebo-controlled, double blind trial	VAS score at 30 minutes	34.1mm vs 39.5mm (ketamine vs placebo, P= not significant)	Does not state how fast initial IV morphine bolus was given
			Total dose of morphine given	Significantly less morphine given in the ketamine group (0.15mg/kg (0.13-0.17) vs the control group 0.2mg/kg (0.18-0.22) (P= <0.001)
			ADR	No difference in GI (6%), CV (0%) or respiratory ADRs (3%). Significantly more neuropsychiatric ADRs in ketamine group (36% vs 3%; P=0.002)
Kelly et al 2005 Canada	Adult patients attending ED with known history of biliary or renal colic and a suspected recurrence treated with nurse-initiated IV morphine (58) or Dr initiated IV morphine (99)	Retrospective case-note analysis	Median time to 1st opioid	Nurse = 31mins vs Dr = 57mins (P=0.0001)	-Does not state doses or rates just ‘titrated doses at 5-10 minute intervals’ -Does not state any pain scores -Only biliary or renal colic
			ADR	No documented respiratory depression
Mercadante et al 2002 Italy	49 adult cancer patients with severe (≥7/10 on NRS) and prolonged pain administered IV morphine 2mg every 2 minutes until significant reduction in pain intensity or severe adverse event	Prospective convenience cohort study	Mean time to significant decrease in pain	9.7minutes (95% CI 7.4-12.1minutes)	-Chronic cancer pain patients -High level of background opiate use (?more tolerant) -‘Significant’ reduction not explicitly defined but reduction achieved reported as 8 to 3 (9.5-4 when pain on movement) -Some pts may have had more than 1 ADR -Dosing not weight-based
			Mean dose required significant decrease in pain	8.5mg (95% CI 6.5-10.5)
			Number of pts with ADRs at initial relief (%)	2 each (4%) drowsiness, itching, dizziness or vomiting
O'Connor et al 2000 New Zealand	Adult ED patients with pain secondary to suspected renal colic randomised to receive either IV morphine 1 or 2mg, max 10mg, (40 pts) or IV pethidine 10 or 20mg, max 100mg (54 pts) at 3 minute intervals based on and titrated against VAS pain score or adverse effects	Randomised, double-blind, controlled trial	Median pain score at 30 minutes from start	Reduced from 8.05 to 3.8 (morphine) vs. 8 to 3.25 (pethidine). No statistical difference	-Does not state how fast each dose was given -All patients given 10mg metoclopramide which may lead to under-reporting of nausea/vomiting -Doesn’t mention use of NSAIDs (standard treatment in UK -Only renal colic
			Pain score 30 minutes after achieving pain score of <3 or when max dose given	1.5(morphine) vs 1.85 (pethidine)
			ADR	17.5% morphine pts had ADR, 18.5% pethidine pts had ADR, No statistical difference

Comment(s)

There are no documented studies that directly address the question of titrated IV morphine in the ED which clearly state the dose, interval and/or rate of administration. A literature review published by Patanwala et al in 2010 describes the evidence for several opioids used for acute pain in the ED but does not describe in detail the administration process. A consensus of the data from published studies indicates that doses in the region of 0.1-0.15mg/kg (7-10mg for a 70kg patient) are most commonly used, that there is wide variability in the rate of administration (1-20 minutes) and that there is wide variability in the incidence of adverse drug reactions (ADRs) (4-33%). Most studies however indicate that ADRs are not serious and require no more intervention than the administration of supplemental oxygen or anti-emetics. This would be expected and is easily managed by prudent prescribing of anti-emetics to those patients at highest risk of opioid-induced nausea & vomiting. Neither intervention are reason preclude the use of IV morphine in acute severe pain.

Clinical Bottom Line

IV morphine is a safe and effective intervention for acute severe pain. There are no studies which adequately describe titrated administration. Further research on this is recommended.

References

1. Aubrun et al Relationships between Measurement of Pain Using Visual Analog Score and Morphine Requirements during Postoperative Intravenous Morphine Titration Anesthesiology 2003; 98:1415–21
2. Betkas et al Intravenous Paracetamol or Morphine for the Treatment of Renal Colic: A Randomized, Placebo-Controlled Trial Annals of Emergency Medicine 2009;54:568-574
3. Bijur et al Intravenous Morphine at 0.1 mg/kg Is Not Effective for Controlling Severe Acute Pain In the Majority of Patients Annals of Emergency Medicine 2005;46:362-367
4. Birnbaum et al Randomized Double-Blind Placebo-Controlled Trial of Two Intravenous Morphine Dosages (0.10 mg/kg and 0.15 mg/kg) in Emergency Department Patients With Moderate to Severe Acute Pain Annals of Emergency Medicine 2007;49:445-453
5. Craig et al Randomised comparison of intravenous paracetamol and intravenous morphine for acute traumatic limb pain in the emergency department Emerg Med J 2012;29:37-39
6. Fry, M. & Holdgate, A Nurse-initiated intravenous morphine in the emergency department: Efficacy, rate of adverse events and impact on time to analgesia. Emergency Medicine 2002;14:249-254
7. Galinski et al Management of severe acute pain in emergency settings: ketamine reduces morphine consumption The Amercian journal of Emergency Medicine 2007;25,385-390
8. Kelly et al Nurse-initiated, titrated intravenous opioid analgesia reduces time to analgesia for selected painful conditions Can J Emerg Med 2005;7,149-154
9. Mercadante et al Rapid Titration with Intravenous Morphine for Severe Cancer Pain and Immediate Oral Conversion Cancer 2002;95,203-208
10. O'Conner A comparison of the efficacy and safety of morphine and pethidine as analgesia for suspected renal colic in the emergency setting J Accid Emerg Med 2000;17:261–264