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Three Part Question

[In an adult in moderate to severe pain] does [intravenous paracetamol] [reduce the need for morphine analgesia, its side-effects and enhance pain relief and patient satisfaction]

Clinical Scenario

A 35 year old male is brought to the emergency department with severe pain due to a fractured humerus. Intravenous access is available, and you wonder whether the use of intravenous paracetamol would decrease the amount of morphine analgesia he will need and provide better pain relief with less potential adverse effects.

Search Strategy

Medline 1966-05/09 using the Ovid interface
([paracetamol.ti,ab. OR acetaminophen.ti,ab. OR propacetamol.ti,ab.] AND morphine.ti,ab., AND [anlages$.ti,ab. OR pain treatment.ti,ab]
Cochrane database of systematic reviews 2009 [intravenous and paracetamol] – no completed review. One study in protocol stage.

Search Outcome

188 papers were found. Two studies were meta-analysis, one incorporating seven and the other incorporating ten prospective randomised controlled trials, PRCTs,(of which seven are the same as the first meta-analysis). 3 other studies not included in these meta-analysis were also obtained.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Remy, C et al. 2005 France	7 PRCTs, 265 patients with PCA morphine plus paracetamol vs. 226 patients with PCA morphine alone	Meta-analysis	Morphine use	24 hour mean reduction of 9 mg (95% CI, -15 to -3 mg; P=0.003) Paracetamol reduced morphine consumption by 20%.	Meta-analysis of post-operative patients on PCA morphine. Thus different scenario to the emergency department. This meta-analysis may lack power because it included too few patients, however all 7 trials had a methodology of high quality. 1 trial used oral paracetamol 6g daily. The side-effects reported may have been attributed to other post-operative causes rather than morphine
			Morphine side-effects	Paracetamol did not decrease the incidence of morphine side-effects
			Patient analgesia & satisfaction	Satisfaction scores were comparable in both groups. Only two studies showed a significant decrease in VAS scores 24 h after surgery, and four studies show no significant differences.
Elia, N et al. 2005 Switzerland	10 PRCTs. 379 PCA morphine plus IV paracetamol vs 334 with PCA morphine alone	Meta-analysis	Morphine Use	24 hour weighted mean difference of -8.31mg [95% CI of -10.9 to -5.72]	Meta-analysis of post-operative patients on PCA morphine. In controls, 24-h morphine consumption was considerable. Thus different scenario to the emergency department. The study also analysed nonsteroidal anti-inflammatory drugs, and selective cyclooxygenase-2 inhibitors with a total of 52 randomised placebo-controlled trials, 10 of which considered paracetamol alone. 2 trials used rectal route. 1 trial used oral route with 6g daily dose and reported largest decrease in pain intensity (still not significant). In control groups, the average VAS was less than 3 cm; therefore, it may be difficult to demonstrate an additional benefit with an analgesic when baseline pain is low and pain intensity at rest only could be analyzed
			Morphine Side-effects	Paracetamol did not significantly decrease the incidence of respiratory depression, nausea and vomiting, urinary retention, or sedation
			Patient analgesia	5 trials (175 active vs 180 control) reported no significant reduction in VAS (visual analogue score). Mean difference -0.29 [-0.71 to 0.14]
Aubrun, F et al. 2003 France	550 post-op patients receiving 4 hourly morphine s.c., 275 with propacetamol vs 275 with placebo	PRCT	Morphine Use	Morphine requirements over 24 hours were only decreased by 6.5mg in the propacetamol group (21 vs 14.5 mg, P<0.001) Patients in moderate pain (n=395), morphine requirements decreased by 37% (P<0.001) and the percentage of patients requiring no morphine was greater (21 vs 8%, P=0.002) in the propacetamol group. Patients in severe pain (n=155), morphine requirements decreased by 18% (P=0.04) in the propacetamol group and the number of patients who did not require morphine (3 vs 8%) did not differ significantly	Post-operative study. Blinding – possibly single. >20% of patients had received NSAIDs in addition to paracetamol. Subcutaneous morphine doses (fixed 5-10mg 4 hourly prn) administered were low – median subcutaneous dose of morphine was 10 mg in the control group.
			Morphine Side-effects	Morphine-related adverse effects did not differ between groups (42 vs 46%, not significant).
Van Aken, H et al. 2004 Belgium	95 patients after surgical removal of 3rd molar teeth under GA. 31 received IV propacetamol, 30 received 10 mg IM morphine. 34 placebo	PRCT	Need for rescue morphine medication	21of 34 in placebo 6 of 31 in propacetamol group (p<0.0009) 4 of 30 in morphine group (p<0.027)	Post-operative study. IM morphine used which is much less strong analgesic than its equivalent given through intravenous route. Dental surgery post-op patients in mild to moderate pain evaluated. Study may not have had adequate power to identify real differences between propacetamol and morphine in this model due to low number of patient in study. No Confidence Interval analysis. External validity of study thus uncertain.
			Adverse events	Adverse events were significantly less frequent in the propacetamol group than in the morphine group (P <0.027). No CI stated
			Patient analgesia	No statistically or clinically significant differences were found between propacetamol and morphine for any sum or peak measures of analgesia
Cakan, T et al. 2008 Turkey	40 post-op patients. 20 received paracetamol iv vs 20 placebo	PRCT	Morphine Use	Morphine consumption was not statistically significantly different between the groups (P>0.05).	Post-operative study. Only 40 patients in study. No Confidence Interval analysis. External validity of study thus uncertain.
			Side-effects	Vomiting in placebo group was significantly higher (14 vs 7) (P=0.027).
			Analgesia	Significantly more patients in the paracetamol group rated their pain management as excellent (45% vs. 5%). Pain scores at rest and on movement at the 12th, 18th, and 24th hours were significantly lower in paracetamol group (P<0.001)

Comment(s)

Due to the lack of studies regarding intravenous paracetamol use in the emergency setting, post-operative studies of its use were used to evaluate its efficacy. Extrapolation of the results to other clinical scenarios as in the emergency department should be done with caution. The use of propacetamol 2g iv is equivalent to 1 g paracetamol iv.

Editor Comment

DH

Clinical Bottom Line

Studies in the emergency department are needed to quantify its effect on patients in moderate to severe pain. There is no clear added benefit of using paracetamol 1g iv in addition to morphine for analgesia in patients in moderate to severe pain.. The use of intravenous paracetamol 1g 6 hourly over 24 hours has a small morphine sparing effect of 8-9mg but does not significantly reduce the frequency of morphine related adverse events, patient analgesia or satisfaction. In moderate pain its use may be of more benefit but in such cases oral medications may be more suited and cost-effective.

References

1. C. Remy, E. Marret, F. Bonnet Effects of acetaminophen on morphine side-effects and consumption after major surgery: meta-analysis of randomized controlled trials British Journal of Anaesthesia (2005) 94 (4): 505-513
2. Elia, Nadia; Lysakowski, Christopher; Tramèr, Martin R. Does Multimodal Analgesia with Acetaminophen, Nonsteroidal Antiinflammatory Drugs, or Selective Cyclooxygenase-2 Inhibitors and Patient-controlled Analgesia Morphine Offer Advantages over Morphine Alo Anesthesiology Volume 103(6), December 2005, pp 1296-1304
3. Aubrun F, Kalfon F, Mottet P, Bellanger A, Langeron O, Coriat P, Riou B. Adjunctive analgesia with intravenous propacetamol does not reduce morphine-related adverse effects. British Journal of Anaesthesia 2003; 90 (3): 314-319.
4. Van Aken H, Thys L, Veekman L, Buerkle H. Assessing analgesia in single and repeated administrations of propacetamol for postoperative pain: comparison with morphine after dental surgery. Anesthesia & Analgesia 2004; Jan;98(1):159-65
5. Cakan T, Inan N, Culhaoglu S, Bakkal K, Başar H. Intravenous Paracetamol Improves the Quality of Postoperative Analgesia but Does not Decrease Narcotic Requirements Journal of Neurosurgical Anesthesiology 2008; Jul;20(3):169-73