Author(s) and Year

Study Design

Type of Surgery

Timing of Administration

Dose and Duration

Comparison Group(s)

Main Outcomes (Postoperative Pain Relief)

Adverse Effects/Side Effects

Study Conclusions

Khalili et al. (2013) [9]

Randomized, double-blind clinical trial

Lower extremity orthopedic surgery

Preemptive: 30 min before surgery. Preventive: During skin closure

IV acetaminophen 15 mg/kg (both preemptive and preventive); Placebo: IV saline 100 mL

Placebo

Significantly reduced pain scores at 6 h post-surgery (P < 0.001) compared to placebo. Preemptive group required less rescue analgesia within 24 h (P < 0.01). No significant difference in pain scores after 6 h between preemptive and preventive groups.

Not reported.

IV acetaminophen reduce pain and analgesic consumption in lower extremity surgery, with the preemptive group requiring less rescue analgesia within 24 h.

Moon et al. (2011) [10]

Randomized, double-blind, placebo-controlled trial

Abdominal hysterectomy

Preemptive: 30 min before incision.

2 g IV acetaminophen (single dose)

Placebo

Significant reduction in hydromorphone consumption (30% reduction over 24 h; P= 0.013). No significant difference in pain scores.

Lower incidence of PONV in acetaminophen group. (P < 0.05).

Preoperative acetaminophen reduced hydromorphone consumption and opioid-related side effect in patients undergoing abdominal hysterectomy but did not significantly reduce pain intensity.

Jokela et al. (2010) [11]

Randomized controlled trial

Laparoscopic hysterectomy

Preemptive: before induction and incision. Preventive:
then every 6 h.

1 g IV acetaminophen, every 6 h for 24 h; Ondansetron 4mg at the end of surgery

Acetaminophen + placebo (AP), Acetaminophen + ondansetron (AO), Placebo + placebo (PP)

Preemptive IV acetaminophen significantly reduced the total oxycodone dosage required over 24 h (P = 0.031). Ondansetron at the end of surgery had no effect on acetaminophen's analgesic effect (P = 0.723).

Not reported.

IV acetaminophen, compared to placebo, reduces total oxycodone requirements postoperatively in women undergoing laparoscopic hysterectomy. Ondansetron does not affect acetaminophen's analgesic effect.

Hong et al. (2010) [12]

RCT, double-blinded, placebo-controlled

Endoscopic thyroidectomy (robot-assisted)

Preemptive:

1 h before induction. Preventative: then every 6-h for 24 h.

1 g IV 1 h before induction then acetaminophen every 6 h for 24 h

Placebo

Significant reduction in postoperative pain scores at 1, 3, 6 and 24 h post-surgery; Significant reduction in rescue analgesia use (9.5% vs. 65.6% for placebo).

Fewer cases of postoperative nausea (44.3% vs. 22.2%) and vomiting (21.3% vs. 6.3%) in the acetaminophen group compared to placebo.

IV acetaminophen effectively reduced postoperative pain and analgesic rescue use. It was well-tolerated and had fewer adverse effects compared to placebo after gasless robot-assisted endoscopic thyroidectomy.

Hassan et al. (2014) [13]

RCT, randomized, double-blinded, placebo-controlled

Elective cesarean section (CS)

Preemptive:

30 min before induction. Preventative: 30 min before end of surgery.

1 g IV acetaminophen (100 ml)

Preemptive (before induction) vs preventive (at the end of surgery)

Preemptive group showed improved hemodynamic stability; required longer time for next analgesia; fewer postoperative side effects; lower opioid consumption. Preventive group had higher postoperative pain scores at 4 and 8 h.

Fewer postoperative side effects were observed in the preemptive group compared to the preventive group.

IV acetaminophen was more effective in managing pain and reducing opioid use compared to preventive administration during cesarean sections.

Wang et al. (2018) [14]

Randomized, double-blind, placebo-controlled trial

Robotic-assisted laparoscopic prostatectomy (RALP)

Preemptive:

15 min before surgical incision. Preventative: then every 6-h for 24 h.

1 g IV acetaminophen before induction, then every 6 h for 4 doses; Placebo: IV saline 100 mL

Placebo

Median pain scores were not statistically significant slightly lower in the acetaminophen group compared to placebo (P= .055 for the first 24h; P= .13 for the second 24h). Opioid use was similar between groups (P= .64 intraoperatively; P= .16 postoperatively.

Not reported.

IV acetaminophen significantly reduced hospital length of stay by 32% without significantly affecting pain scores or opioid consumption.

Xuan C et al. (2022) [15]

Network meta-analysis of 188 RCTs including 13,769 participants. Data were synthesized from multiple studies evaluating 19 preemptive analgesia regimens.

General surgery (non-specific)

Preemptive

Acetaminophen IV: not specified, duration up to 12 h.

Placebo, NSAIDs (e.g., ibuprofen, lornoxicam), gabapentinoids (e.g., gabapentin, pregabalin), epidural analgesia, etc.

Preemptive IV acetaminophen reduced pain scores, but not significantly more than placebo in some cases. VAS 6h: -11.57, VAS 12h: -10.52. Opioid consumption: Reduced opioid consumption by -0.48 mg IMME (95% CI: -0.89 to -0.08) at 12 h and delayed rescue analgesia slightly compared to placebo.

No significant reduction in PONV incidence compared with placebo.

Preemptive IV acetaminophen significantly reduced opioid consumption and delayed rescue analgesia compared to placebo. Pain reduction was significant but modest, showing less efficacy than NSAIDs like lornoxicam.

Hansen et al. (2016) [16]

Retrospective analysis, Premier Database (2009–2015)

Orthopedic surgery

Preemptive: before induction. Preventative: continued for 2 days post-op.

IV acetaminophen in combination with IV opioids

IV opioids alone

IV acetaminophen combined with opioids led to a significantly shorter length of stay (LOS) and lower hospitalization costs compared to opioid monotherapy.

Not reported.

Compared to opioids alone, managing post-orthopedic surgery pain with the addition of IV acetaminophen administered preemptively is associated with shorter LOS and decreased hospitalization costs.

Arici et al. (2009) [17]

Randomized, placebo-controlled trial

Total Abdominal Hysterectomy

Group I: Preemptive:

30 min before induction.
Group II: Preventative:

before skin closure.

Single dose of 1,000 mg IV paracetamol administered to Groups I and II Group III: saline.

Placebo (saline)

Preemptive and preventive groups showed lower pain scores at rest and with movement compared to placebo.
Group I (preemptive) had significantly lower morphine consumption compared to Group II (preventive).

Intravenous paracetamol intraoperatively and postoperatively did not result in any hemodynamic effects.

Preemptive IV paracetamol 1 g, provides better postoperative analgesia, reduces morphine consumption compared to intraoperative administration or placebo in total abdominal hysterectomy.

Sacha et al. (2022) [18]

Randomized, double-blind, placebo-controlled trial

Oocyte retrieval

Preemptive:

1 h -30 min before surgery.

IV acetaminophen 1 g preoperatively

PO acetaminophen and placebo

No significant difference in postoperative pain scores or time to discharge between groups.

Lower opioid dose requirement in the IV acetaminophen group (0.24 mg IV morphine equivalents vs. 0.59 mg in the other groups). Less constipation in the acetaminophen group (19% vs. 33% and 40%).

Preoperative IV acetaminophen did not reduce postoperative pain scores or time to discharge, but it did reduce opioid use and constipation.

Kinjo et al. (2020) [19]

Randomized, triple-blind, placebo-controlled trial

Gynecological laparotomy

Preemptive: after induction of anesthesia and before surgery.

Preventive: another dose if surgery extended after 4h

IV acetaminophen 15 mg/kg administered over 15 min

Placebo: IV saline

Incidence of severe postoperative shivering significantly lower in the acetaminophen group (22.2%) compared to placebo (73.7%; P = .005).

Core body temperature at 1-h post-observation was slightly lower in the acetaminophen group (P < .001).

Perioperative administration of IV acetaminophen reduced severe postoperative shivering, likely by suppressing the postoperative increase in the body temperature set point.

Ayatollahi et al. (2014) [20]

Randomized, double-blind, placebo-controlled trial

Cesarean Delivery

Preemptive:

20 min prior to incision

1 g IV acetaminophen (single dose); control: saline

Placebo (saline)

IV paracetamol significantly reduced postoperative VAS pain scores, delayed the first analgesic request, and decreased analgesic consumption compared to placebo.

The SBP, DBP, MAP and HR were controlled significantly better in paracetamol group than in placebo group.

Preemptive administration of IV paracetamol effectively decreases hemodynamic responses to tracheal intubation and improved postoperative pain management without neonatal complications in cesarean section.

Towers et al. (2018) [21]

Prospective double-blinded randomized placebo-controlled trial

Cesarean Delivery

Preemptive: 15 min prior to incision

1 g IV acetaminophen

(single dose); control: saline

Placebo

No significant difference in pain scores, postoperative opioid consumption (94.2 mg vs. 90.7 mg morphine equivalents) nor length of stay.

Not mentioned

Preincisional administration of IV acetaminophen did not reduce opioid use, pain scores, or length of stay post cesarean. Acetaminophen cord blood levels were subtherapeutic.

Rindos et al. (2019) [22]

Prospective double-blind randomized study

Laparoscopic Hysterectomy

Preemptive:

at the time of induction of anesthesia and before incision.

Preventive: another dose 6 h later

1 g IV acetaminophen and 6 h later

Placebo

No significant differences in generalized abdominal pain at any time point postoperatively that included 2 h (placebo 3.6±2.5 vs acetaminophen 4.4±2.5; P=.07) and up to 24 h (placebo 3.3±2.4 vs acetaminophen 3.6±2.5; P=.28).

No significant difference in postoperative nausea, satisfaction, or opioid consumption (placebo 1.4±2.0 vs acetaminophen 1.6±2.1; P=.61).

IV acetaminophen showed no benefit in pain relief, high cost; oral alternatives available.

Politi et al. (2017) [23]

Randomized controlled trial

Hip and knee arthroplasty

Preemptive: before surgery

Preventive: after surgery every 6 h for 24 h

1 g IV or PO acetaminophen

Oral acetaminophen

No significant difference in narcotic use or pain scores between IV and oral groups, except for the first 4 h postoperatively (IV: 3.00 vs PO: 3.40, P = .03).

Not mentioned

IV acetaminophen administered preoperatively may reduce immediate postoperative pain but does not provide significant benefit in reducing pain or narcotic use compared to the much less expensive oral form.

Cain et al. (2020) [24]

Retrospective observational study

Open Gynecologic Oncology Surgery

Preemptive:

at the time of induction of anesthesia or 1 h before surgery.

Preventive: after surgery (oral) 1 g every 6 h

1 g IV acetaminophen

1 g Oral Acetaminophen

No significant difference in opioid consumption on POD 0 and POD 1; Pain scores in PACU not reported as significantly different.

Not mentioned

IV acetaminophen showed no advantage over oral acetaminophen in reducing postoperative opioid consumption within an ERAS program for patients undergoing open gynecologic oncology surgery.

Turner et al. (2019) [25]

Double-blind, placebo-controlled, multicenter trial

Pelvic organ prolapse repair

Preemptive: 10 -30 min before incision

1 g IV acetaminophen

Placebo (saline)

No significant difference in pain scores at 24 h post-surgery, opioid use, or patient satisfaction.

Increased urinary retention in the acetaminophen group, potentially due to mannitol suspension. No significant difference in other side effects like nausea.

Preemptive IV acetaminophen did not reduce pain or opioid use and had no effect on satisfaction or quality of life in women undergoing prolapse repair.

Apfel et al. (2013) [26]

Systematic review of RCTs

General Surgery

Preemptive: before surgery Preventative: after surgery, administered before moving to PACU

1 g IV acetaminophen (prophylactic use)

Placebo

Reduced postoperative nausea and vomiting when administered prophylactically, either before surgery or before arrival in the PACU, but not after the onset of pain.

The reduction of nausea correlated with the reduction of pain (OR = 0.66, 95% CI: 0.47-0.93), but not with reduction in postoperative opioids (OR = 0.89, 95% CI: 0.64-1.22).

Perioperative IV acetaminophen reduces postoperative nausea and vomiting, primarily through enhanced pain control, without a significant effect on opioid consumption.

Altenau et al., 2020 [27]

Double-blind, placebo-controlled, randomized trial

Cesarean Delivery

Preemptive: 30 min before incision Preventative:

Then another dose every 8 h for 48 h

1 g IV acetaminophen every 8 h for 48 h (6 doses total)

Placebo

Reduced oral narcotic consumption (47 mg vs 65 mg of oxycodone; P = .034)

No difference in pain scores between groups before and after study drug administration.

No significant impact on opioid side effects (nausea/emesis, respiratory depression, constipation)

Perioperative IV acetaminophen significantly reduced oral narcotic consumption postoperatively without impacting pain scores.

Kiliçaslan et al. (2010) [28]

Randomized, double-blind, placebo-controlled trial

Cesarean Delivery

Preventative:

15 min before the end surgery and every 6 h for 24 h

1 g IV acetaminophen administered 15 min before surgery ends and every 6 h for 24 h

IV acetaminophen vs. placebo (saline)

IV acetaminophen reduced pain scores, and cumulative tramadol consumption compared to placebo.

No significant difference in sedation or nausea/vomiting scores between groups

Preventive administration of IV acetaminophen effectively reduced post-cesarean pain and tramadol consumption.

Cattabriga et al. (2007) [29]

Single-center, double-blind, randomized, placebo-controlled trial

Cardiac surgery

Preventative:

at skin closure and then 6, 12, 18, and 24 h postoperative

1 g IV acetaminophen

IV acetaminophen vs. placebo

Pain at rest and movement lower in IV acetaminophen group at 12,18, and 24 h compared to placebo; IV acetaminophen required less cumulative morphine compared to the placebo group (48 mg vs. 97 mg).

Not reported.

Preventive administration of IV acetaminophen as part of a multimodal approach in combination with tramadol provides effective pain control in patients undergoing cardiac surgery.

Rizkalla et al. (2018) [30]

Randomized, double-blind study

Posterior spine fusion surgery

Preventative:

at skin closure, then every 6 h for 42 h.

15 mg/kg IV acetaminophen every 6 h for 42 h

IV acetaminophen vs placebo

Lower opioid use in the first 24 h compared to placebo; shorter time to PCA discontinuation (73 h vs. 90 h in the placebo group).

Faster advancement to solid food intake (49 h vs. 69 h in the placebo group).

Preventive administration of IV acetaminophen was associated with reduced postoperative opioid consumption, faster PCA discontinuation, and earlier time to diet advancement.

Kim et al. (2024) [31]

RCT, triple-blinded, placebo-controlled

Posterior spinal fusion (PSF)

Preemptive: after induction of anesthesia and before surgery. Preventative: at the end of surgery just before skin closure.

15 mg/kg IV acetaminophen for preemptive or preventive groups

Placebo

No significant differences in pain scores between preemptive and preventive groups; preventive group had significantly lower opioid consumption than placebo (P = 0.013)

No increase in drug-related adverse effects was observed with preventive administration.

Perioperative IV acetaminophen reduces opioid consumption in pediatric and adolescent patients undergoing PSF without adding significant drug-induced adverse effects.

Mamoun et al. (2016) [32]

Randomized, double-blind, placebo-controlled trial

Cardiac Surgery via Median Sternotomy

Preventive:

Intraoperative (after sternal closure) then every 6 h

Four doses of IV acetaminophen (1 g) every 6 h

Placebo

Reduced pain scores by about 1 point compared to placebo, with an estimated difference of -0.90 on a 0-10 Numeric Rating Scale; it did not significantly reduce opioid consumption.

No significant effect on duration of mechanical ventilation, ICU, or hospital LOS.

Intraoperative administration of IV acetaminophen reduced pain intensity but did not reduce opioid consumption, providing insufficient analgesia alone for patients recovering from median sternotomy.

Subramaniam et al. (2022) [33]

Randomized, double-blind clinical trial

Major abdominal surgery

Preventive: after incision (before wound closure), then every 6 h for 48 h

1 g IV acetaminophen every 6 h for 48 h; Placebo: IV saline 100 mL

Placebo

No significant difference in pain relief between acetaminophen and placebo groups (P = 0.20). Opioid consumption was comparable between groups.

Fewer rescue antiemetics in acetaminophen group (41% vs. 58%, P = 0.02). No major adverse effects reported.

Perioperative administration of IV acetaminophen did not improve postoperative pain relief or characteristics of postoperative recovery in patients undergoing major abdominal surgery within an ERP (enhanced recovery protocol) but reduced the need for rescue antiemetics.

Deng et al. (2017) [34]

Retrospective comparative cohort study

Spine surgery

Preventative:

after incision (at skin closure)

1 g IV acetaminophen (single dose)

IV acetaminophen group vs no IV acetaminophen group

IV acetaminophen group had lower VAS scores shortly after surgery at 60 min. However, no consistent VAS differences across all procedures or timepoints.

No difference was found for other secondary outcomes between groups.

Intraoperative administration of IV acetaminophen did not consistently improve pain scores or exhibit opioid-sparing effects.

Hickman et al. (2018) [35]

Randomized, placebo-controlled, equivalence trial

Total Hip/Knee Arthroplasty (THA/TK)

Group 1 (oral)

Preemptive

Acetaminophen. Group 2 (IV)

Preventative:

After incision:

1 g PO acetaminophen, preoperatively; 1 g IV acetaminophen, intraoperatively

PO vs IV acetaminophen

No significant differences in postoperative opioid use (MMEs) or pain scores over 24 h between oral and IV acetaminophen groups.

No significant differences in postoperative nausea/vomiting, ambulation time, PACU length of stay, or hospital length of stay.

Timing (preoperative vs. intraoperative) did not impact outcomes in THA/TKA. Preoperative PO acetaminophen and intraoperative IV acetaminophen. provided equivalent pain control; IV acetaminophen was not superior to oral acetaminophen.

Huang et al. (2018) [36]

Retrospective review

Primary Total Knee Arthroplasty (TKA)

Preventative:

After surgery then every 6 h for 24 h

1 g IV acetaminophen every 6 h for 24 h

IV acetaminophen group vs. no additional intervention group

Significantly reduced overall opioid consumption (37.6 vs 18.6 morphine milligram equivalents). Reduced VAS pain scores between 16 and 24 h postoperatively; no significant difference in LOS (at 3.3 days in the control group and 2.9 days in the intervention group).

Not reported.

Postoperative administration of IV acetaminophen significantly reduced opioid consumption and improved pain scores in the first 24 h following primary TKA.

Aksoy et al. (2023) [37]

Prospective, double-blind, placebo-controlled, randomized trial

Cesarean Delivery

Preventative:

After surgery then every 6 h for 24 h

1 g IV acetaminophen every 6 h for 24 h; SC bupivacaine

IV acetaminophen vs. SC bupivacaine vs. placebo

IV acetaminophen and SC bupivacaine both significantly reduced VAS pain scores (at rest and during coughing) and decreased opioid consumption compared to placebo.

Not reported.

Postoperative administration of IV acetaminophen is as effective as SC bupivacaine in reducing pain and opioid consumption compared to placebo; bupivacaine is superior to IV acetaminophen at 15 min.

Wilson et al. (2019) [38]

Prospective, three-arm, randomized clinical trial

Cesarean Delivery

Preventative:

First dose at PACU then every 8 hs for 3 doses

IV acetaminophen: 1 g every 8 h for 3 doses; oral acetaminophen: 1 g every 8 h for 3 doses

IV acetaminophen vs. PO acetaminophen vs. no acetaminophen

Reduced opioid consumption and pain scores compared to no acetaminophen. However, there was no significant difference between IV and oral acetaminophen in opioid consumption or pain scores.

Not reported

IV acetaminophen administered postoperatively Postoperative IV or oral acetaminophen decreased opioid consumption and pain scores compared to no acetaminophen but did not outperform oral acetaminophen.

Takeda et al. (2019) [39]

Prospective, open-label randomized control study

Total Hip Arthroplasty (THA)

Preventative:

After surgery, then every 6 h for 24 h

1 g IV acetaminophen every 6 h for 24 h; Control: standard pain control

IV acetaminophen vs. control group

IV acetaminophen significantly reduced pain scores at rest 24 h after surgery and decreased total fentanyl citrate consumption.

Not reported.

Postoperative administration of IV acetaminophen as part of multimodal significantly reduced pain scores and opioid use after THA.