Pain Profiles: Intravenous vs. Oral Paracetamol

Written by: David Cisewski, MD (@DHCisewski – EM Resident Physician, Icahn School of Medicine at Mount Sinai) // Edited by: Manpreet Singh, MD (@MPrizzleER), Alex Koyfman, MD (@EMHighAK), and Brit Long, MD (@long_brit)

Today’s post in the Pain Profiles series by Dr. David Cisewski evaluates the classic medication paracetamol. Is IV route more effective than PO for analgesia?

Intravenous versus oral paracetamol for acute pain in adults in the emergency department setting: a prospective, double-blind, double-dummy, randomised controlled trial

Furyk J, Levas D, Close B, Laspina K, Fitzpatrick M, Robinson K, 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. Emerg Med J. 2018;35(3):179-84. (link)

One-Liner

IV paracetamol did not demonstrate superiority to oral paracetamol as an opioid adjunct for acute moderate/severe pain relief, ED length of stay, patient satisfaction, or adverse side effects.

Study Characteristics

• Clinical question – Is intravenous paracetamol superior to oral paracetamol as an adjunct to opioids in the management of moderate to severe pain in the ED setting?
• Design– A double-blind, double-dummy, randomized controlled superiority trial.
• Clinical Setting – A single academic tertiary care ED in Australia.
• Patient/Population – Adult patients ≥18 years old presenting with acute,  moderate to severe pain (Visual Analogue Scale (VAS) ≥40 mm at 5 min after receiving at least one dose of IV opioids).  Exclusions included: chronic pain, known or suspected opiate dependence, allergy to paracetamol, any degree of renal or hepatic insufficiency, pregnancy, were currently enrolled in other pain trials, unable to swallow oral medication, or had taken paracetamol within the last 6 hours.
• Intervention: Patients were randomly assigned to receive either 1g intravenous paracetamol  (in 100 cc NS) or 1g (2 x 500 mg pill) oral paracetamol.  Each participant also received a corresponding placebo consistent with the opposing arm of the randomization (double-dummy).  Pain scores were assessed using the Visual Analog Scale (VAS), a validated tool for ED pain research ranging from 0 to 100 (‘0=no pain’ and ‘100=worst possible pain’).
• Patient VAS score was compared between time of medication administration (baseline, t=0) and 30 minutes (primary outcome) and  at regular intervals over the subsequent 3 hours.  Patients were also assessed for secondary outcomes including need for rescue analgesics, length of stay, adverse events, and patient satisfaction with overall pain management ascertained as a percentage (0%–100%) with higher scores representing higher satisfaction, at the conclusion of data collection.

Outcome

• Baseline characteristics were similar in each group.  Mean pain scores at baseline (t=0) were 65.0 (15.8) in the intravenous group and 71.3 (15.6) in the oral group. Mean pain scores at 30 minutes were 51.5 mm (22.9) in the intravenous paracetamol group and 54.2 mm (23.1) in the oral group (ANCOVA analysis; non-significant variance from ANOVA).
• Primary outcome – Both IV and oral paracetamol achieved  clinically significant mean pain score reduction at 30 minutes, with no significant difference between groups (16.0 mm (SD 19.1 mm) in the IV group, 14.6 mm (SD 26.4) in the oral group –  difference −1.4 mm (95% CI −11.6 to 8.8, P=0.79)).
• Secondary outcomes – all outcomes including need for rescue analgesia, patient satisfaction, side effects and ED length of stay did not differ between groups.  There was no difference in pain reduction at time points 60 and 90 minutes.  Rescue opioids were administered in 86.2% of the IV group compared and  84.1% of the oral group (P=0.69).  Patient satisfaction was 100.0% (80.0–100)  in the IV group versus 90.0% (75.0–98.0) in the oral group (P=0.10).

Conclusion

IV paracetamol does not demonstrate superiority to oral paracetamol as an opioid adjunct for acute moderate/severe pain relief, ED length of stay, patient satisfaction, or side effects.

Quality Assessment

This was a well-conducted randomized control trial conducted which utilized the double-dummy technique in order to further eliminate any potential confounding factors associated with the delivery of each arm of the trial individually.  This studies was conducted using a power calculation which determined that 44 patients were required in each group to achieve 80% power and a significance of 0.05% to detect a clinically significant difference in mean pain scores of 15mm, assuming an SD of 25 mm.  The difference of 15 mm represented a compromise between the commonly cited ‘minimum clinically significant’ difference of 13mm and 20mm (in previously cited literature).

Limitations

• Similar to many RCT’s that rely on pharmacy hours of operation for enrollment, the selected population is a convenience sample of ED patients with acute pain, which may have resulted in selection bias.
• Second, VAS measurements were taken from the time of administration (t=0) rather than time medications were ordered, which might have negated time advantages of more rapid oral medication administration.   Third, this study was conducted at a single center, limiting the  generalisability of the results.  Fourth, only patients who had received opiate analgesia were included in the study, limiting the isolated effect of paracetamol.

The Upshot

Anecdotal evidence has long suggested that IV paracetamol resulted in increased bioavailability, more rapid onset and targeted plasma concentration, and thus increased analgesic efficacy in comparison to its oral form.  However, ED use (and as such, analgesic research) has been hindered by the exorbitant price tag, ranging as high as $40 – $45  per 1-gram vial ($1,019 per 24-pack vials). This has limited its use predominantly to patients in the post-surgical setting.  Currently four patents for IV paracetamol (Ofirmev) exist within the US resulting in these inflated price, but with expirations beginning in April, 2018.  In June, 2016 Perrigo Company announced it received FDA approval for a generic version of Ofirmev (acetaminophen) injection on December 6, 2020.  This announcement has given researchers a window of opportunity to assess the efficacy of IV acetaminophen (paracetamol) for future US in the ED.

To date, this is the first comparison of oral versus intravenous paracetamol as an adjunct to opioid analgesia in the ED setting, the conclusion of which found no superiority of IV paracetamol as an adjunct for pain relief.  As the author states, the increases risks and inconvenience of delivery without added benefit make IV usage difficult to justify.  However, IV use should still be considered a possible delivery mechanism in individuals who can’t tolerate PO medication or who suffer from gastritis/PUD.

It is important to point out that this is an opioid adjunct study and not opioid replacement trial, nor a direct comparison of IV vs oral paracetamol.  Though this study suggests no benefit as an opioid adjunct, further research is needed to assess the efficacy of IV vs oral paracetamol as stand-alone analgesics.

My major concern with the study is the before and after use of opioid analgesia.  With most analgesic research I focus on the question, “does this treatment offer any possibility of an opioid sparing effect?”. As noted, only patients receiving opioid analgesia were enrolled in the study as it was deemed unethical by the researchers to withhold analgesics in a placebo arm.  In addition, an enormous 86% (IV) and 84% (oral) of patients received rescue opioid medications, indicating neither route of paracetamol offers much benefit in an acute moderate/severe emergency setting.  Though the author states a median dose of 5 mg morphine was provided to these patients as rescue medications, we don’t know the severity of the pain in the patients receiving the rescue nor the duration of time lapsed in between receiving the rescue.  This unfortunately limits my utility of IV paracetamol (acetaminophen) in similar-presenting acute pain scenarios.

My personal conclusion is that in a setting of moderate to severe acute pain presentations, acetaminophen has a limited analgesic role.  However, I do find this continued research on IV acetaminophen promising and hope to future work results in alternative uses for IV acetaminophen in an ED setting as it approaches it’s patent deadline.

Further Reading

• The Use of Intravenous Acetaminophen for Acute Pain in the Emergency Department – Sin, B., et al, Acad Emerg Med 23(5):543, May 2016
• Emergency Physicians Monthly article by Richard Bukata, MD – IV APAP Works, So Why Don’t More EPs Use It?
• Emergency Physicians Monthly rebuke of IV Acetaminophen by Richard Bukata, MD following the price hike – IV Acetaminophen: Here Today, Gone Tomorrow
• Reliability of the visual analog scale for measurement of acute pain. Acad Emerg Med. – Bijur PE, Silver W, Gallagher EJ. 2001;8(12):1153-7.