Paracetamol Parenteral Vs. Enteral presented in 11/10 as the 1st lecture of rational drug use series at Al-Mahmoudiya General Hospital

1. Paracetamol: Enteral Vs Parenteral
Alaa F. Hassan (MSc. Pharmacology)

2. Indications
Parenteral
 Mild-moderate pain, moderate-severe
pain with adjunctive opioid analgesics,
fever transient reduction in adults and
children 2 years and older (FDA-approved
since 2010).
 Parenteral analgesics are clinically
recommended for patients with
compromised gastrointestinal (GI)
absorption, unable to take oral analgesics,
&/or when 100% bioavailability is wanted.
Enteral
 Oral & per rectal (PR) forms indicated
for transient reduction of fever and
transient relief of pains, minor aches,
and headaches
 Conversion from IV to PO
administration is recommended when
a patient can take, tolerate and absorb
oral analgesics.

3. Pre/Post-operative pain; approach
 Pre-/post- operative mmultimodal analgesia is currently preferred
approach to treating post-operative pain, utilizing systemic analgesics,
such as NSAIDs, acetaminophen, antidepressants, and α-2 receptor
agonists, as well as local anesthetics besides opioids, which have
traditionally been the mainstay of analgesic therapy for perioperative
patients
 Benefits:
I. Reduce activation of pain receptors and the production or activity of
pain-related neurotransmitters.
II. Results in lower doses of respective agents required to lessen side
effects while providing adequate analgesia.
III. Improve recovery outcomes after surgery, ensuring rehabilitation
while reducing overall costs and expediting discharge to home

4. So which one is preferred?

5. Pharmacokinetics
Parenteral
 Has a rapid onset of action compared to equivalent doses of
oral paracetamol, recommended when the oral or PR route is
unsuitable or ineffective (ex. emesis) or when the high
variability in bioavailability with PR/oral administration is
unacceptable for a particular pt. (ex. Compromised gastric
function i.e. post-operative ileus).
 Time to reach peak plasma concentration (Cmax) for IV
administration is 30 min faster than oral formulation, in peri- &
early post-operative period, high Cp has been achieved within
5 min, and pain relief occurs within (a few) 10-15 min
compared with 1 hr. for oral administration, while significant
fever reduction occurs within 30 min after initiating infusion .
Study results show the Cmax of IV administration is 76%
greater than oral and 256% greater than PR-administration.
Enteral
 Altered gastric emptying changes the absolute
absorption rate of oral medications, especially
postoperatively, oral paracetamol absorption
decreases due to compromised GI function,
the Cmax oral paracetamol concentration is
significantly lower, and oral absorption is
decreased in post nasogastric administration,
specifically on day 1 post-surgery, then oral
paracetamol is commonly used as an analgesic
several days after surgery

6. Pharmacokinetics
Parenteral
 Duration of action appears to be the same between
both formulations (4 to 6 hr), confers the advantage of
intraoperative dosing which can offer a more
prolonged effect into the post recovery period since it
can be given toward the end of surgery. For endotoxin-
induced fever, IV is favored over PO paracetamol in
reducing temperature for up to 2 hours after
administration. After 2 hours, however, there is no
statistically significant difference.
 The peak CSF concentrations are 60% greater with IV
administration than with PO and 87% greater with IV
administration than with PR (easily pass through the
blood-brain barrier-with less variability).
Enteral
 For analgesia duration post
administration of PR versus IV
paracetamol, median time to first
rescue for PR was 10 hrs, compared
with 7 hrs for IV acetaminophen.
 No significant difference is seen
between PO and PR paracetamol
concerning peak CSF concentrations.

7. Pharmacokinetics
Parenteral
 Decreases hepatic exposure to the
drug by nearly half (50%) because of
avoiding first-pass metabolism through
portal circulation, which reduce the
potential for hepatic injury.
Enteral

8. Common Adverse Drug reactions
Parenteral
 More serious reactions are liver injury,
anaphylaxis, serious skin reactions (SJS & TEN),
and hypersensitivity reactions, while associated
risks include infection, phlebitis & local irritation.
 Most common side effects are similar to oral
nausea and vomiting, headache, and insomnia.
 Others include time needed for IV
administration, inconvenience to patients, and
the increased costs (particularly IV form of
paracetamol has a higher cost and longer
administration time [15 min] than oral form).
Enteral
 Potential reactions include liver toxicity,
leukopenia, increased serum bilirubin,
anemia, reduced serum bicarbonate,
pancytopenia, skin rash, decreased serum
calcium and sodium, hyperchloremia,
hyperuricemia, increased serum glucose,
renal toxicity generally with chronic
overdose, neutropenia, increased serum
alkaline phosphatase, and kidney disease.

9. Contraindications
Parenteral
 Hypersensitivity reactions
 Severe liver damage
 Active severe liver disease
Enteral
 Avoid use with any other medications
that contain acetaminophen as an
ingredient
 Allergic reaction to acetaminophen

10. Safety
Parenteral
 IV paracetamol could be administered
safely at doses of 1000 mg (pt. wt. > 50
kg), with a maximum daily limit of 4000
mg& at dose of 15 mg/kg (pt. & children
over 2 years wt. <50mg).
 Given its favorable first pass effects, the
theoretical risk of hepatotoxicity with IV
acetaminophen is believed to be low.
enteral

11. WHAT RESEARCHES SAY ABOUT
PARENTERAL VS ENTERAL PARACETAMOL

12. Jibril F. et al., Teng et al. & Alopi P. et al.
 No superiority of IV paracetamol over oral paracetamol & no strong evidence exists that IV
acetaminophen should replace any form of standard care in patients undergoing surgeries,
whenever the patient has a functioning gastrointestinal tract and is able to take oral
formulations, IV formulations are not indicated, also indicates that IV formulation could
function as an adjunctive agent in patients unable to take oral forms.
 Teng et al stated that “IV paracetamol was not found to be superior to oral paracetamol in
patients undergoing TKA (total knee arthroplasty) in terms of VAS scores at 24 hours,
48hours, and total morphine consumption at 24hours”.
 Alopi P. et al concluded that “In the ambulatory surgery population the efficacy of oral and
intravenous acetaminophen is equivalent” (their study includes pre-operative setting for
laparoscopic inguinal hernia repair surgeries).

13. Skip R. H. et al., BHOJA ET AL
 Skip R. H. et al. “In patients undergoing hip or knee arthroplasty, oral acetaminophen
given preoperatively was equivalent to IV acetaminophen administered in the
operating suite in controlling pain in the immediate postoperative period. I.V.
acetaminophen was not superior to oral acetaminophen in reducing postoperative
nausea and vomiting, time to ambulation, time to first dose of as-needed pain
medication, length of PACU stay, or total length of hospital stay”.
 BHOJA ET AL. in their comparative efficacy trial of oral vs IV paracetamol for sinus
surgery stated that “There was no significant difference in pain scores at 1 or
24 hours postoperatively, and no difference in postoperative opioid use. Intravenous
acetaminophen offers no apparent advantage over oral acetaminophen in patients
undergoing sinus surgery”.

14. Furyk J, Levas D, Close B, et al. & Another review study,
don’t ask me whom et el. Since I got lost
 Furyk J, Levas D, Close B, et al Stated that “In adults in the emergency department
setting, No superiority was demonstrated in this trial with IV paracetamol compared
with oral paracetamol in terms of efficacy of analgesia and no difference in length of
stay, patient satisfaction, need for rescue analgesia or side effects”.
 Pharmacokinetic outcome evaluation of paracetamol found that oral dosage forms
of paracetamol were associated with high bioavailability, with only 13% to 21% dose
being lost during absorption & bioavailability of paracetamol tablet dosage forms
increased from 63% to 89% after 500- & 1000-mg doses respectively.
 “Such bioavailability at doses used in the clinical setting may indicate dose
equivalency between IV and oral dosage forms, which enhances interchangeability in
the absence of efficacy differences”.
 “In a direct comparison trial, no significant differences in intraoperative or post-
operative pain measures were identified between 1000 mg of oral versus IV
acetaminophen”.

15. References
 IV, PO, and PR Acetaminophen: A Quick Comparison. Pharmacy times August 19, 2016. Available from: https://www.pharmacytimes.com/view/iv-po-and-pr-
acetaminophen-a-quick-comparison
 Harricharan S, Frey N. Intravenous Acetaminophen for the Management of Short-Term Post-Operative Pain: A Review of Clinical Effectiveness and Cost-Effectiveness
[Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2018 Oct 12. Available from: https://www.ncbi.nlm.nih.gov/books/NBK538274/
 Jibril, F., Sharaby, S., Mohamed, A., & Wilby, K. J. (2015). Intravenous versus Oral Acetaminophen for Pain: Systematic Review of Current Evidence to Support Clinical
Decision-Making. The Canadian Journal of Hospital Pharmacy, 68(3), 238-247. https://doi.org/10.4212/cjhp.v68i3.1458
 Teng Y, Zhang Y, Li B. Intravenous versus oral acetaminophen as an adjunct on pain and recovery after total knee arthroplasty: A systematic review and meta-analysis.
Medicine (Baltimore). 2020 Dec 11;99(50):e23515. https://doi.org/10.1097/MD.0000000000023515 PMID: 33327295; PMCID: PMC7738014.
 Alopi Patel, Poonam Pai B.H., Dina Diskina, Brittany Reardon, Yan H. Lai, Comparison of clinical outcomes of acetaminophen IV vs PO in the peri-operative setting for
laparoscopic inguinal hernia repair surgeries: A triple-blinded, randomized controlled trial, Journal of Clinical Anesthesia, Volume 61, 2020, 109628, ISSN 0952-8180,
https://doi.org/10.1016/j.jclinane.2019.109628
 Skip R. Hickman, Kathleen M. Mathieson, Lynne M. Bradford, Casey D. Garman, Richard W. Gregg, Douglas W. Lukens, Randomized trial of oral versus intravenous
acetaminophen for postoperative pain control, American Journal of Health-System Pharmacy, Volume 75, Issue 6, 15 March 2018, Pages 367–375,
https://doi.org/10.2146/ajhp170064
 Bhoja, R, Ryan, MW, Klein, K, et al. Intravenous vs oral acetaminophen in sinus surgery: A randomized clinical trial. Laryngoscope Investigative Otolaryngology. 2020; 5:
348–353. https://doi.org/10.1002/lio2.375
 Jahnavi Gollamudi & Sean Marks. FAST FACTS AND CONCEPTS #302 ORAL VS INTRAVENOUS ACETAMINOPHEN. Palliative Care Network of Wisconsin 2023,
https://www.mypcnow.org/fast-fact/oral-vs-intravenous-acetaminophen/
 Furyk J, Levas D, Close B, et al Intravenous versus oral paracetamol for acute pain in adults in the emergency department setting: a prospective, double-blind, double-
dummy, randomised controlled trialEmergency Medicine Journal 2018;35:179-184. http://dx.doi.org/10.1136/emermed-2017-206787
 Needleman SM. Safety of rapid intravenous of infusion acetaminophen. Proc (Bayl Univ Med Cent). 2013 Jul;26(3):235-8. doi: 10.1080/08998280.2013.11928969. PMID:
23814378; PMCID: PMC3684285. https://doi.org/10.1080/08998280.2013.11928969
 Needleman SM. Safety of rapid intravenous of infusion acetaminophen. Proc (Bayl Univ Med Cent). 2013 Jul;26(3):235-8. https://dx.doi.org/10.1080/08998280.2013.11928969

16. THANK YOU