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Three Part Question

In [adults with acute pain] is [intravenous paracetamol more effective than oral paracetamol] at [reducing pain].

Clinical Scenario

A 45-year-old man presents to the emergency department with new onset abdominal pain, and the nurse asks you to quickly prescribe some paracetamol. You wonder if there is any difference in the analgesic effect by route of administration.

Search Strategy

Medline 1968 - 02/2018 using the Ovid interface:
(pain or analgesic or analgesia) AND (intravenous acetaminophen or iv acetaminophen or iv paracetamol or intravenous paracetamol) AND (oral acetaminophen or oral paracetamol or po acetaminophen or po paracetamol)

Search Outcome

Altogether 26 papers were found in Medline and 1 additional paper found through references. Only 9 were found to be relevant for analysis.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Furyk et al. 2017 Australia	87 patients aged ≥18 complaining of moderate to severe pain on presentation to an emergency department were included. Patients must have a pain score corresponding with a visual analogue scale (VAS) ≥40 mm, at least 5 mins after receiving 1 dose of intravenous opioid. Patients were randomly assigned to 2 groups: 1g oral paracetamol (n=40), 1g IV paracetamol (n=47).	Single-centre, randomised, double-blind, double-dummy, active-controlled superiority trial.	Pain score was recorded using a visual analogue scale after 30 mins from administration	There was a statistically significant reduction in VAS scores at 30 mins; oral paracetamol reduction in VAS was 14.6mm (Std Dev. 26.4mm) and 16.0mm (Std Dev. 19.1mm) reduction in the intravenous group. However, there was no significant difference in VAS scores between the groups; difference of -1.4mm (95% CI −11.6 to 8.8, P=0.79).	Study is single-centred, with a narrow cohort by only including patients who have already received 1 dose of IV opioid, therefore is difficult to generalise to patients who are receiving paracetamol as their initial analgesic agent. The study was powered to require 44 patients in each patient group, and unfortunately did not get the required amount in the oral paracetamol group.
Plunkett et al. 2016 USA	66 patients aged ≥18 who were active military personal, veterans or beneficiaries and receiving a laparoscopic cholecystectomy were included for post-operative pain analysis. Both groups were given 1g of paracetamol 1 hour prior to the operation, and again 4 hours post-op. Oral paracetamol group n=28, intravenous paracetamol group n=32.	Double-blinded, prospective, randomised placebo-controlled trial.	Sum of Pain Intensity Differences (SPID) were measured 24 hours post-operation.	There was no statistically significant difference between patient groups. The mean difference in SPID was 11.33 (90% CI= -38.99 – 16.32). There was equally a non-significant difference in the total opioid consumption over the 24 hours.	This study is based on post-operative pain, in a USA military base, and therefore is not particularly comparable with patients presenting in acute pain to a UK practice. Additionally, this study needed 80 patients in each group were required to hit power calculations. Thus this study was not large enough to produce significant differences.
Mahajan et al. 2017 India	150 patients aged 18-35 were equally divided into 3 paracetamol administration groups (oral, rectal and intravenous). Paracetamol was administered for post-operative analgesia in cesarean sections.	Prospective, randomised controlled study.	Time to first rescue analgesia and total rescue analgesia required was recorded.	There was no statistically significant difference in time to, and total dose of rescue analgesia between the oral and intravenous routes of administration. However, there was a significant difference with rectal administration when compared with the other 2 routes (P<0.001).	This was an Indian study based around post-op analgesia for cesarean sections, and therefore has limited generalisation to patients presenting with acute pain to a UK practice. The study used different paracetamol strengths (650mg) to the standard (1g) UK dose, thus further reducing its application to the UK. Additionally the patients were not blinded, allowing for bias to occur.
O'Neal et al. 2017 USA	174 patients aged ≥18 who were undergoing unilateral total knee arthroplasty under spinal anaesthesia were selected. Patients were randomised into 3 groups: 1g IV paracetamol (n=57), 1g oral paracetamol (n=58), and placebo group (n=59). The study medications were administered at the end of the operation.	Single-centre, randomised, double-blinded, placebo-controlled clinical trial.	Pain intensity was measured in the post-anaesthesia care unit at 15 min intervals using a numerical scale. 0= no pain, 10= worst pain imaginable.	There was no statistically significant difference in pain scores across all groups. Scores are as follows (mean ± Std Dev.): IV group (0.56 ± 0.99) compared with oral group (0.67 ± 1.2; P=0.84) and placebo group (0.58 ± 0.99; P=0.71)	This was a post-operative pain study in patients who had also received other forms of local and systemic analgesia, and therefore has limited application in the patient presenting with acute pain.
Fenlon et al. 2013 United Kingdom	128 patients aged 18-65 who were undergoing at least one third molar extraction under general anaesthesia were analysed in the trial. Patients were randomised into either oral paracetamol (and IV placebo) or IV paracetamol (and oral placebo) groups. Oral paracetamol was administrated 45 mins before surgery, and IV paracetamol was given at induction of anaesthesia.	Double-blinded, randomised control trial.	Pain scores were recorded using a visual analogue scale (VAS) 1 hour post-operatively.	There was no statistically significant difference in pain scores between either groups. Equally there was no significant difference in the time to rescue analgesia.	This study is looking at the post-operative effect of paracetamol, and therefore is of limited application to a patient presenting in acute pain. Additionally the time of administration of paracetamol differs in each arm, this further reduces its application when considering the patient in front of you in acute pain.
Politi et al. 2017 USA	120 patients undergoing knee and hip arthroplasty were divided into 2 groups: 1g IV paracetamol (n=63) and 1g oral paracetamol (n=63). Both groups received 1 dose preoperatively and then every 6 hours postoperatively for 24 hours, in addition to the standard pain regime.	Prospective, randomised trial.	Pain scores were recorded at 4 hour intervals post-op using a visual analogue scale.	There was a statistically significant difference between the IV and oral groups in the 0-4 hour interval (VAS scores 3.38 and 4.40 respectively, p=0.03). However, from 4-24 hours there was no statistically significant difference between VAS scores.	This was a post-op study, and therefore has limited application to patients presenting in acute pain. Additionally patients were not blinded to the treatment they were receiving, thus allowing for bias.
Nour et al. 2014 USA	45 children aged 5 months-5 years undergoing a cleft palate repair under general anaesthesia were selected. Patients were divided into the following groups: IV paracetamol (n=15), oral paracetamol (n=14) and control (=16). Groups received age appropriate doses of paracetamol prior to the surgery beginning and post-op at 6 hour intervals for 24 hours.	Double-blinded, prospective randomised controlled trial.	Opioid requirements were recorded in the first 24 hours.	There was no statistically significant difference in opioid requirements at 24 hours (p=0.10).	This is a post-op study and therefore has limited application for patients presenting in acute pain. FLACC/ FACES systems were used to assess pain, and these are objective measures, allowing for bias. Additionally this is a very small study size.
Brett et al. 2012 New Zealand	30 patients aged ≥18 undergoing knee arthroscopy were included. Patients were then randomised into 2 groups: 1g IV paracetamol (n=10) and 1g oral paracetamol (n=20). Oral solutions were given ≤60 mins pre-op, and IV solutions were given intraoperatively.	Double-blinded, randomised controlled trial.	Plasma paracetamol levels were measured 30 mins post-op.	There was a significant difference in the mean plasma paracetamol levels, with the greater value being in the IV group (p=0.0005).	This is a post-op pain study, thus has limited application to a patient presenting in acute pain. Additionally the study uses a very small sample size.
			A visual analogue scale was used to measure post-op pain at 10 min intervals.	There was no significant difference between mean pain scores post-op.
Pettersson et al. 2005 Sweden	77 patients undergoing elective coronary artery bypass graft surgery under were included. Patients were randomly assigned to 2 groups: 1g oral paracetamol (n=38) and 1g IV paracetamol (n=39). Patients were given their dose, plus a placebo at 6 hour intervals post-op. Patients also received standard analgesia regime as required.	Prospective, double-blinded, randomised trial.	Pain was assessed using a visual analogue scale post-op.	There was no statistically significant difference in pain scores between the groups.	This is a post-op study, and thus has limited application to patients presenting in acute pain. There was no control group in this study.
			Post-op opioid requirement as rescue analgesia was recorded.	The IV group required less opioid post-op than the oral group (17.4 mg ± 7.9 mg and 22.1 mg ± 8.6 mg (p=0.016), respectively).

Comment(s)

Currently there is limited research considering the use of IV vs oral administration of paracetamol for patients presenting in acute pain, with most research focusing on postoperative analgesia. Out of the 9 papers analysed there was only 1 paper that demonstrated a statistically significant reduction in pain scores; with this occuring within the initial treatment period, but this difference diminished as the study time progressed. Several studies suggest a trend towards IV paracetamol providing better analgesia, but this is never statistically significant. Some studies demonstrated that IV paracetamol may provide an opiate sparing effect. However, this does not result in a corresponding reduction in pain scores. Further research must be conducted to compare the use of IV and oral paracetamol in patients presenting with acute pain. The Furyk et al study in 2017 is currently the closest study to answering this clinical question. Additionally many studies discuss the resource cost comparison between IV and oral preparations - with oral preparations being markedly cheaper in all.

Clinical Bottom Line

Currently there is minimal evidence to suggest that IV paracetamol is superior to oral paracetamol. However, consideration must be taken to patients with impaired gastrointestinal function.

References

1. Furyk et al. Intravenous versus oral paracetamol for acute pain in adults in the emergency department setting: a prospective, double-blind, double-dummy, randomised controlled trial Emergency Medicine Journal 2017 Dec; Pages 179-184
2. Plunkett et al. A Preliminary Examination of the Comparative Efficacy of Intravenous vs Oral Acetaminophen in the Treatment of Perioperative Pain Pain Medicine 2016 December, Volume 18, Issue 12, Pages 2466-2473
3. Mahajan et al. Study to Compare the Effect of Oral, Rectal, and Intravenous Infusion of Paracetamol for Postoperative Analgesia in Women Undergoing Cesarean Section Under Spinal Anesthesia Anesthesia: Essays and Researches 2017; Issue 3, Volume 11, Pages 594-598
4. O'Neal et al. Author: Intravenous vs Oral Acetaminophen as an Adjunct to Multimodal Analgesia After Total Knee Arthroplasty: A Prospective, Randomized, Double-Blind Clinical Trial The Journal of Arthroplasty 2017;32(10):3029-3033.
5. Fenlon et al. Oral vs intravenous paracetamol for lower third molar extractions under general anaesthesia: is oral administration inferior? British Journal of Anaesthesia 2013;110(3):432-437
6. Politi et al. Randomized Prospective Trial Comparing the Use of Intravenous versus Oral Acetaminophen in Total Joint Arthroplasty The Journal of Arthroplasty 2017;32(4):1125-1127.
7. Nour et al. Analgesic effectiveness of acetaminophen for primary cleft palate repair in young children: a randomized placebo controlled trial Pediatric Anesthesia 2014;24(6):574-581.
8. Brett et al. Postoperative plasma paracetamol levels following oral or intravenous paracetamol administration: a double-blind randomised controlled trial. Anaesthesia and intensive care 2012; 40: 166-I71
9. Pettersson et al. Intravenous Acetaminophen Reduced the Use of Opioids Compared With Oral Administration After Coronary Artery Bypass Grafting Journal of Cardiothoracic and Vascular Anesthesia 2005;19(3):306-309.