Can you provide a data review on IV acetaminophen? Is there any benefit over other routes of administration?

Comment by InpharmD Researcher

Intravenous (IV) acetaminophen (APAP) is an effective analgesic and antipyretic commonly used as part of multimodal analgesia, with evidence suggesting its faster peak plasma and cerebrospinal fluid concentrations than oral (PO) or rectal (PR) routes. Despite these pharmacokinetic advantages, randomized trials and meta-analyses consistently show no clinically significant differences in pain control, opioid reduction, or postoperative outcomes between IV and PO administration in patients able to take oral medications. Studies also indicate that the increased bioavailability of IV APAP does not translate to superior clinical efficacy. In surgical settings such as total joint arthroplasty, both routes similarly reduce pain and opioid use, though recommendations for IV use have been downgraded due to its higher cost. PR APAP appears comparable to PO in antipyretic effect, though it has not been extensively compared to IV. Ultimately, IV APAP may be reserved for cases where PO or PR administration is not feasible.

Background

According to the 2020 Perioperative Anesthesia and Analgesia in Total Joint Arthroplasty Guidelines, the panels recommended using acetaminophen in primary total joint arthroplasty (TJA). The guidelines state that intravenous (IV) or oral (PO) acetaminophen is associated with reduced pain and opioid consumption when used perioperatively during a primary TJA (moderate strength of recommendation). Per current comparative studies, they found the reduction in postoperative pain and/or opioid consumption was similar regardless of the route of administration, either IV or PO. With the concern of a higher cost with IV acetaminophen than the PO, the panel agreed to downgrade the recommendation's strength for IV acetaminophen from strong to moderate. The panel acknowledges that with the approval for marketing a generic IV acetaminophen in December 2020 by the US Food and Drug Administration, the recommendation on IV acetaminophen may be modified in the future. [1]

A 2015 systematic review examined data from six randomized controlled trials to compare the efficacy, safety, and pharmacokinetics of IV vs. PO acetaminophen. Among studies with reported efficacy outcomes, no clinically significant differences were noted between the two groups with unclear risk-of-bias assessments. In one of the examined studies, the authors noted that even though IV acetaminophen was associated with significantly lower use of opioids than the PO, 17.4 ± 7.9 mg vs. 22.1 ± 8.6 mg (p<0.05), respectively, this difference did not provide direct benefits in relief in postoperative nausea and vomiting or pain scores on a visual analog scale (VAS) at any time. In another study, a significant difference was noticed in VAS scores with IV vs. PO 11.6 ± 2.8 mm vs. 30.8 ± 5.8 mm, respectively (p= 0.025) at 50 min after arrival in the recovery units. However, by this time point, one-third of the patients had already been discharged after procedures. [2], [3], [4]

Safety data were not consistently reported among the trials, and none of the noted adverse events were related to acetaminophen use. The authors noted that the increase in bioavailability of IV acetaminophen, with a higher peak concentration and Area Under the Curve (AUC) in cerebrospinal fluid than the PO formulation, does not translate to enhanced clinical efficacy. The authors concluded that no preferential indications were identified for prescribing IV acetaminophen if the patients could tolerate PO medications. Cost, convenience, and associated side effects need to be considered when making clinical decisions. [2], [3], [4]

A 2020 meta-analysis comparing IV and oral acetaminophen found no significant differences in pain (measured via visual analog scale at 24 hours and 48 hours) or opioid use. However, there was a slight decrease in length of stay in favor of intravenous administration (standard mean difference [SMD] = −0.02, 95% confidence interval [CI]: −0.03 to −0.01, p = 0 .0004). However, this significant finding was heavily dependent on one study (see Table 1), and it is unclear if the magnitude of the result of this meta-analysis has clinical significance. [5]

A 2019 meta-analysis compared IV to oral acetaminophen as adjunctive therapy to standard pain management protocols. Two RCTs were identified (See Tables 2 and 3). The analysis did not yield any significant outcomes in terms of pain scores or opioid use. [6]

Regarding oral versus rectal formulations of acetaminophen, a meta-analysis comparing oral versus rectal acetaminophen administration in pediatric patients identified four relevant studies (N= 241). The authors did not find a difference in temperature at one hour, three hours, or maximum temperature decrease for either route. [7]

A 2020 systematic review (14 trials, N= 1,695) compared the efficacy, safety, and costs of IV versus oral perioperative acetaminophen in adults. The review found inconclusive evidence for an effect of acetaminophen, whether given IV or orally, on postoperative pain at 0–2 h (n= 734), 2–6 h (n= 766), 6–24 h (n= 1,115), and >24 h (n= 248 participants). The differences in standardized mean pain scores for IV versus oral were all nonsignificant: −0.17 (95% CI −0.45 to 0.10), −0.09 (95% CI −0.24 to 0.06), 0.06 (95% CI -0.12 to 0.23) and 0.03 (95% CI −0.22 to 0.28), respectively. The route of acetaminophen administration reported no difference in other postoperative outcomes as well (e.g., opioid consumption during the first 24 h; time to first analgesic request or rescue dosage; participant satisfaction; time to discharge; nausea or vomiting; pruritus; sedation). Additionally, the authors noted estimated cost savings of $47,498 with the substitution of oral acetaminophen in half of the patients who were given IV acetaminophen instead. Overall, the authors concluded the quality of evidence was poor. [8]

Despite IV acetaminophen having a higher cost than oral acetaminophen, a 2013 review on the utility of IV acetaminophen in the perioperative period notes that there is evidence that favors the IV formulation over the oral formulation. For instance, the bioavailability of IV acetaminophen in cerebrospinal fluid compared with oral acetaminophen after the administration of 1 g over 6 hours was observed to be 24.9 versus 14.2 mcg•h/mL. The IV route also produces a higher plasma concentration than oral administration and peaks after only 15 minutes compared with > 45 minutes with oral acetaminophen. Notably, early acetaminophen plasma concentrations are highly variable when administered orally and may remain in the subtherapeutic range much longer than when administered via the IV route. The correlation of adequate pain control with cerebrospinal or plasma levels of intravenous and oral agents has not been thoroughly investigated. Intravenous administration also produces less acetaminophen’s toxic metabolite (N-acetyl-p-benzoquinoneimine) than when ingested orally, making IV administration a safer alternative. Intravenous infusion produces a peak acetaminophen concentration in the liver estimated to be 50% less than the equivalent oral dose. [9]

To better understand the optimal route of acetaminophen administration in children, a 2024 network meta-analysis (NMA) aimed to assess the efficacy of different routes of acetaminophen administration for pediatric postoperative pain management. A total of 14 trials comprising 829 participants were included. In these studies, pediatric patients aged 30 days to 17 years who underwent surgical procedures were assessed for postoperative pain outcomes following acetaminophen administration via oral, rectal, or IV routes. For the zero- to two-hour postoperative period, six trials with 496 participants were included in the NMA. There was no evidence of a difference between IV and rectal acetaminophen (difference in means; -0.28; 95% CI -0.62 to 0.06; very low certainty) or between IV and oral administration (difference in means; -0.60; 95% CI -1.20 to 0.01; low certainty). However, oral administration was favored over rectal (difference in means; -0.88; 95% CI -1.44 to -0.31; low certainty). Few trials reported secondary outcomes; among those that did, no difference was found in the incidence of nausea and vomiting between oral and rectal routes (relative risk, 1.20; 95% CI 0.81 to 1.78). Due to these findings, it was suggested that the current evidence regarding the effect of the acetaminophen administration route on postoperative pain in children is very uncertain. Minimal differences were observed between oral and rectal routes in both analgesic efficacy and adverse effects, and further well-designed trials are needed to inform clinical practice better. [10]

A final NMA evaluated the efficacy of oral versus IV acetaminophen for closing a patent ductus arteriosus (PDA) in preterm neonates. Across 21 randomized controlled trials involving infants born before 37 weeks gestation, both routes were effective, with oral acetaminophen ranking higher than IV (low confidence). Neither route showed benefit over no treatment for necrotizing enterocolitis (NEC) or bronchopulmonary dysplasia (BPD), with moderate and low confidence, respectively. Rectal administration was not assessed. Findings suggest oral acetaminophen may improve the odds of PDA closure compared to IV use; however, limitations in study quality and confidence ratings highlight the need for further high-quality trials to confirm these findings. [11]

References:

[1] Fillingham YA, Hannon CP, Erens GA; AAHKS Anesthesia & Analgesia Clinical Practice Guideline Workgroup, Hamilton WG, Della Valle CJ. Acetaminophen in Total Joint Arthroplasty: The Clinical Practice Guidelines of the American Association of Hip and Knee Surgeons, American Society of Regional Anesthesia and Pain Medicine, American Academy of Orthopaedic Surgeons, Hip Society, and Knee Society. J Arthroplasty. 2020;35(10):2697-2699. doi:10.1016/j.arth.2020.05.030
[2] Jibril F, Sharaby S, Mohamed A, Wilby KJ. Intravenous versus Oral Acetaminophen for Pain: Systematic Review of Current Evidence to Support Clinical Decision-Making. Can J Hosp Pharm. 2015;68(3):238-47.
[3] Pettersson PH, Jakobsson J, Owall A. Intravenous acetaminophen reduced the use of opioids compared with oral administration after coronary artery bypass grafting. J Cardiothorac Vasc Anesth. 2005;19(3):306-309. doi:10.1053/j.jvca.2005.03.006
[4] Brett CN, Barnett SG, Pearson J. Postoperative plasma paracetamol levels following oral or intravenous paracetamol administration: a double-blind randomized controlled trial. Anaesth Intensive Care. 2012;40(1):166-171. doi:10.1177/0310057X1204000121
[5] 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;99(50):e23515. doi:10.1097/MD.0000000000023515
[6] Sun L, Zhu X, Zou J, Li Y, Han W. Comparison of intravenous and oral acetaminophen for pain control after total knee and hip arthroplasty: A systematic review and meta-analysis. Medicine (Baltimore). 2018;97(6):e9751. doi:10.1097/MD.0000000000009751
[7] Goldstein LH, Berlin M, Berkovitch M, Kozer E. Effectiveness of oral vs rectal acetaminophen: a meta-analysis. Arch Pediatr Adolesc Med. 2008;162(11):1042-1046. doi:10.1001/archpedi.162.11.1042
[8] Mallama M, Valencia A, Rijs K, et al. A systematic review and trial sequential analysis of intravenous vs. oral peri-operative paracetamol. Anaesthesia. 2021;76(2):270-276. doi:10.1111/anae.15163
[9] O'Neal JB. The utility of intravenous acetaminophen in the perioperative period. Front Public Health. 2013;1:25. Published 2013 Aug 6. doi:10.3389/fpubh.2013.00025
[10] Osorio D, Maldonado D, Rijs K, van der Marel C, Klimek M, Calvache JA. Efficacy of different routes of acetaminophen administration for postoperative pain in children: a systematic review and network meta-analysis. Efficacité des différentes voies d’administration de l’acétaminophène pour la douleur postopératoire chez les enfants : une revue systématique et méta-analyse en réseau. Can J Anaesth. 2024;71(8):1103-1116. doi:10.1007/s12630-024-02760-y
[11] Olowoyeye A, Nnamdi-Nwosu O, Manalastas M, Okwundu C. A Network Meta-Analysis of Intravenous Versus Oral Acetaminophen for Patent Ductus Arteriosus. Pediatr Cardiol. 2023;44(4):748-756. doi:10.1007/s00246-022-03053-1
Literature Review

A search of the published medical literature revealed 18 studies investigating the researchable question:

Can you provide a data review on IV acetaminophen? Is there any benefit over other routes of administration?

Level of evidence

A - Multiple high-quality studies with consistent results  Read more→


Please see Tables 1-18 for your response.

 

Impact of Intravenous Acetaminophen on Lengths of Stay and Discharge Status after Total Knee Arthroplasty

Design

Retrospective, longitudinal study

N= 190,691

Objective

To compare the postoperative outcomes of total knee arthroplasty (TKA) patients who received oral APAP versus IV APAP. Specifically, this study evaluated: the hospital lengths of stay (LOS) and patient discharge disposition

Study Groups

Oral (PO) APAP (n= 134,216)

Intravenous (IV) APAP (n= 56,475)

Inclusion Criteria

Patients who underwent TKA and received either IV or PO APAP

Exclusion Criteria

Patients who received both IV and oral APAP during the study period 

Methods

The Premier Database was used to review patients who underwent TKA from 2012 to 2015. LOS was calculated as the number of days from the date of hospital admission to the date of discharge, and the discharge disposition was categorized as to the home or to a skilled nursing facility (SNF).

The tests were two-tailed and a p-value of less than 0.05 was used as the threshold for statistical significance.

Duration

2012 to 2015

Outcome Measures

Primary: LOS and discharge dispositions

Baseline Characteristics

  

IV APAP

(n= 56,475)

PO APAP

(n= 134,216)

  

Age, years (mean)

  66 67  

Female

 34,660 (61.4%)  89,948 (63.3%)  

White

  45,314 (80.2%)  101,797 (75.9%)  

Results

Endpoint

IV APAP

(n= 56,475)

PO APAP

(n= 134,216)

p-Value

Length of Stay (days)

  2.8  3 <0.001

Patient discharged home (adjusted Odds Ratio)

  1.22  -  

Patient discharged to a skilled nursing facility (SNF) (Odds Ratio)

 0.87 -  

Adverse Events

Common Adverse Events: Not disclosed

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: Not stated

Study Author Conclusions

In conclusion, this study found that patients who underwent TKA and received IV APAP as part of their pain management had a statistically significantly shorter hospital LOS (p < 0.001) and were more likely to be discharged home (p < 0.001) than those who received oral APAP.

InpharmD Researcher Critique

Due to the retrospective nature of the study, it is unclear as to whether the increased instance of discharge to a SNF was due to underlying patient factors. This could also impact LOS. 



References:

Barrington JW, Hansen RN, Lovelace B, et al. Impact of Intravenous Acetaminophen on Lengths of Stay and Discharge Status after Total Knee Arthroplasty. J Knee Surg. 2019;32(1):111-116. doi:10.1055/s-0038-1636908

 

Intravenous vs Oral Acetaminophen as an Adjunct to Multimodal Analgesia After Total Knee Arthroplasty: A Prospective, Randomized, Double-Blind Clinical Trial

Design

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

N= 174

Objective

To compare intravenous (IV) acetaminophen (APAP) to the oral (PO) formulation in a multimodal analgesia regimen 

Study Groups

IV APAP (n= 57)

PO APAP (n= 58)

Placebo (n= 59)

Inclusion Criteria

Age ≥ 18, undergoing unilateral total knee arthroplasty (TKA) under spinal anesthesia

Exclusion Criteria

Failure of spinal anesthesia intraoperatively, pregnancy, history of chronic opiate use, liver disease, hypersensitivity/allergy to APAP or opiates, or used APAP within 24 hours of surgery

Methods

Patients in IV APAP group received 1 gm IV APAP and oral placebo. The PO APAP group was given 1 gm oral APAP and volume-matched IV normal saline (100mL). Patients in the placebo group received oral placebo and volume-matched IV normal saline (100mL). Medications were administered at conclusion of surgery, prior to transfer into post-anesthesia care unit (PACU). Pain intensity was assessed using numeric rating scale, with a range of 0 (no pain) to 10 (worst pain possible) at 15 minute intervals lasting for up to four hours. Every subject was administered opioid pain reliever at end of operation. 

Duration

 Intervention: 24 hours

Outcome Measures

Primary: pain score measured using the NRS

Secondary: total opiate consumption at 6 and 24 hours post-surgery, time to rescue analgesia, time to breakthrough pain, time until ready for PACU discharge

Baseline Characteristics

  

IV (n=57)

PO (n=58)

Placebo (n=59)

  

Age, years

 68 ± 8.3  67 ± 9.0 70 ± 8.8  

Male

 32 (56%) 26 (45%) 25 (42%)  

Results

 

IV (n= 57)

PO (n= 58)

Placebo (n= 59)

p-Value

Average PACU pain score

(IQR)

 0 (0-0.82) 0 (0-0.69) 0 (0-0.82) 0.93 

Max PACU pain score (IQR)

 0 (0-3) 0 (0-3) 0 (0-3) 0.95

Total opiate consumption, HME* (IQR)

6 hours

24 hours

 

0.38 (0-0.75)

0.75 (0.38-1.88)

 

0.38 (0-0.75)

1.14 (0.38-2.25)

 

0.38 (0-0.75)

0.94 (0.38-2.38)

 

0.60

0.48

Time to rescue analgesia, minutes (IQR)

 203 (113-370) 216 (120-325) 175 (111-300) 0.72

Time to breakthrough pain, minutes (IQR)

 170 (118-299) 165 (95-295) 170 (105-260) 0.80

Time to PACU discharge, minutes (IQR)

 165 (129-205) 145 (110-195) 150 (120-210) 0.39

*HME = hydromorphone milligrams equivalents

Adverse Events

 None reported

Study Author Conclusions

Neither intravenous nor oral acetaminophen provides additional analgesia in the immediate postoperative period when administered as an adjunct to multimodal analgesia in patients undergoing TKA in the setting of a spinal anesthetic.

InpharmD Researcher Critique

Although the intention of this study was to observe whether the effect of APAP would vary based on the route of administration, any possible difference in APAP efficacy between PO or IV may have been superseded by the effect of the opioid pain relievers also administered to each patient. To evaluate the efficacy between different forms of APAP, this multimodal analgesic approach must be eliminated or reduced.  



References:

O'Neal JB, Freiberg AA, Yelle MD, et al. Intravenous vs Oral Acetaminophen as an Adjunct to Multimodal Analgesia After Total Knee Arthroplasty: A Prospective, Randomized, Double-Blind Clinical Trial. J Arthroplasty. 2017;32(10):3029-3033. doi:10.1016/j.arth.2017.05.019

 

Randomized Prospective Trial Comparing the Use of Intravenous Versus Oral Acetaminophen in Total Joint Arthroplasty

Design

Single-center, prospective, randomized trial

N= 120

Objective

To compare the effectiveness of intravenous (IV) versus oral (PO) acetaminophen as part of a standard multimodal perioperative pain regimen

Study Groups

IV acetaminophen (n= 63)

PO acetaminophen (n= 57)

Inclusion Criteria

Patients undergoing primary hip or knee replacement

Exclusion Criteria

Known hypersensitivity to acetaminophen, hepatic impairment, or known liver disease

Methods

Patients were randomized to receive 1 gram of IV or PO acetaminophen pre-operatively and post-operatively every 6 hours for 24 hours. All surgeries were performed by a single joint arthroplasty surgeon. Preoperatively, patients received Celebrex 400 mg and Oxycontin 10 mg. Postoperatively, patients received IV Dilaudid every 2 hours as needed, oxycodone 5 mg as needed, Oxycontin 10 mg every 12 hours for 2 doses, and Celebrex 200 mg daily. Patients received Percocet 5/325 mg as needed and meloxicam 7.5 mg daily for pain at discharge with aspirin for deep vein thrombosis prophylaxis. Tot

Duration

10 weeks

Follow-up: 24 hours postoperatively

Outcome Measures

Total narcotic use (hydromorphone equivalent) and visual analog scale (VAS) scores every 4 hours postoperatively for 24 hours

Baseline Characteristics

No baseline characteristics were reported.

Results

Endpoint

IV Acetaminophen (n= 63)

PO acetaminophen (n= 57)

p-value

VAS scores postoperatively

0 hours

4 hours

8 hours

12 hours

16 hours

20 hours

24 hours

Total



3.375

2.814

2.853

2.728

2.754

3.898

2.58

3.01



4.402

3.39

3.14

3.49

2.708

3.225

3.344

3.401



0.033

0.32

0.586

0.134

0.923

0.235

0.11

0.057

Narcotic use postoperatively, mg

0 hours

4 hours

8 hours

12 hours

16 hours

20 hours

24 hours

Total



0.731

0.646

0.588

0.579

0.482

0.581

0.104

3.71



0.675

0.678

0.686

0.534

0.387

0.446

0.078

3.485



0.742

0.866

0.56

0.756

0.447

0.314

0.661

0.756

Adverse Events

Common Adverse Events: N/A

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

The authors support the use of PO acetaminophen over the IV form as an adjunct to a multimodal pain regimen in total joint arthroplasty. The improved quality of life and long-term pain relief obtained by a patient undergoing a hip or knee replacement makes these procedures some of the most successful elective surgical procedures available. Appropriate perioperative pain control remains the cornerstone of providing the total joint population with the best experience possible.

InpharmD Researcher Critique

With no significant differences in pain scores or total opioid consumption following surgery, it is difficult to draw any conclusions regarding the superiority of an acetaminophen formulation. Additionally, due to the study of only surgical patients with no report of baseline characteristics, the generalizability of any significant results would be limited.



References:

Politi JR, Davis RL 2nd, Matrka AK. Randomized Prospective Trial Comparing the Use of Intravenous versus Oral Acetaminophen in Total Joint Arthroplasty. J Arthroplasty. 2017;32(4):1125-1127. doi:10.1016/j.arth.2016.10.018

 

Randomized Trial of Oral Versus Intravenous Acetaminophen for Postoperative Pain Control

Design

Single-center, randomized, placebo-controlled, equivalence trial

N= 486

Objective

To determine if preoperative oral (PO) acetaminophen is equivalent to intravenous (IV) acetaminophen administered in the operating suite in controlling pain and minimizing opioid use in the immediate 24-hour postoperative period in a population of patients undergoing total hip or total knee joint arthroplasty

Study Groups

PO APAP (n= 241)

IV APAP (n= 245)

Inclusion Criteria

Age ≥ 18, weight > 50 kg

Exclusion Criteria

Requirement of trauma or other emergent surgery, acetaminophen allergy, inability to use a numeric pain scale, unable to swallow oral capsules, pregnant or breastfeeding, hepatic impairment or failure

Methods

Patients in PO group were administered two 500-mg capsules of APAP and placebo IV infusion of 100 mL 0.9% sodium chloride injection. Patients in IV group were administered IV infusion of acetaminophen 1,000 mg/100 mL and two oral placebo capsules. Oral study medication was administered preoperatively and IV study medication was administered in the operating suite. Opioid use was documented in morphine milligram equivalents (MMEs). Patient-rated pain score recorded on scale of 0 (no pain) to 10 (worst pain). All patients were undergoing one of two elective procedures: total hip arthroplasty (THA) or total knee arthroplasty (TKA).

Duration

January 1, 2015 to March 31, 2016

Outcome Measures

Primary: opioid use in the first 24 hours postoperatively

Secondary: patient-rated pain in the first 24 hours postoperatively, time from PACU admission to first use of postoperative pain medication, length of PACU stay, length of hospital stay, documented nausea or vomiting, and hours to ambulate 10 feet postoperatively

Baseline Characteristics

  

PO APAP (n= 241)

IV APAP (n= 245)

  

Age, years (IQR)

67 (59.5-73.0) 

 67 (60.0-72.5)  

Male

 93 (38.6%) 105 (42.9%)  

White

 234 (97.9%)

230 (93.9)

  

Procedure type

THA

TKA

 

73 (30.3%)

168 (69.7%)

 

75 (30.6%)

170 (69.4%)

  

Results

 

PO APAP (n= 241)

IV APAP (n= 245)

p-Value

Opioid use in first 24 hours postoperatively, MME (IQR)

 21.7 (12.5-33.6) 21.7 (11.3-34.4) 0.60

Pain score in first 24 hours postoperatively

3.6 (2.4-5.0)

 3.4 (2.1-4.8) 0.22 

No statistically significant difference in other outcome measures including time from PACU admission to the first use of postoperative pain medication, length of PACU stay, length of hospital stay, documented nausea or vomiting, and hours to ambulate 10 feet postoperatively

Adverse Events

 Acetaminophen specific events not specified, opioid-related events include postoperative nausea (21.2%), postoperative vomiting (7.9%)

Study Author Conclusions

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 24-hour postoperative period. Additionally, IV acetaminophen was not superior to preoperative 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.

InpharmD Researcher Critique

One of the limitations apparent in this study was a relatively homogenous subject population, all of whom were recruited from the same hospital and underwent one of only two different elective surgical procedures. However, due to the large sample size and adequate power of the study, the results may be more generalizable across other patients and situations. Results from this study were consistent with other studies. 



References:

Hickman SR, Mathieson KM, Bradford LM, Garman CD, Gregg RW, Lukens DW. Randomized trial of oral versus intravenous acetaminophen for postoperative pain control. Am J Health Syst Pharm. 2018;75(6):367-375. doi:10.2146/ajhp170064

 

Intravenous vs. Oral Acetaminophen as a Component of Multimodal Analgesia After Total Hip Arthroplasty: A Randomized, Blinded Trial

Design

Single-center, parallel-group, double-blinded, randomized, controlled trial

(N= 154)

Objective

To evaluate if intravenous (IV) acetaminophen would reduce pain with activity, opioid usage, or opioid-related side effects, compared to oral acetaminophen after total hip arthroplasty (THA)

Study Groups

IV acetaminophen (n= 77)

Oral acetaminophen (n= 77) 

Inclusion Criteria

Age ≥ 18 to 90 years with scheduled elective primary unilateral THA

Exclusion Criteria

History of opioid abuse or daily use of opioids for one month before surgery, chronic pain management, hypersensitivity or contraindication to protocol medication, abnormal hepatic or renal function tests, planned general anesthesia or to receive preoperative medication or a periarticular injection, rheumatoid arthritis, THA with additional procedures and/or hardware removal, bodyweight < 50 kg

Methods

Enrolled patients were randomized (1:1) to receive either IV 1 g acetaminophen (100 mL of solution) infused over 15 mins plus oral placebo or oral 1 g acetaminophen (in two capsules) plus IV placebo. First doses were given 30 minutes after admission to the post-anesthesia care unit. IV or oral acetaminophen were given every 6 hours for three full days after surgeries or until discharge. 

Postoperatively, patient-controlled epidural analgesia was used with bupivacaine 0.06% and clonidine 1 mcg/mL, at 2 mL/h basal rates with a 4 mL patient-controlled bolus (20 mL max/hour). At 7 AM postoperative day (POD) 1, the basal rate was decreased to 0, and the epidural was discontinued at noon. Patients also received IV ketorolac 15-30 mg every 8 hours for a total of 6 doses, followed by oral meloxicam 7.5-15 mg (7.5 mg if age > 70 years or weight < 60 kg) until POD 3 or until discharge. Oral tramadol 50 mg (for mild pain), tramadol 100 mg (for moderate pain), or oxycodone 5 mg (for severe pain and up to 10/15 mg) were given to the patient's request. IV 2 mg hydromorphone could be used as rescue analgesia. 

Duration

Enrollment: between February 2017 and May 2018

Follow-up: POD 3 or until discharge 

Outcome Measures

Primary outcomes: pain with activity on POD 1 (patient-reported pain during physical therapy), cumulative opioid usage between POD 0 and POD 3 (mg of oral morphine equivalents [OME]), and opioid-related side effects on POD 1 (Opioid-Related Symptom Distress Scale [ORSDS]) 

Secondary outcomes: pain at rest and with physical therapy (POD 0, 2, 3), daily opioid use, American Pain Society Patient Outcome Questionnaire (also termed PainOUT or APS-POQ-R), discharge time, and Confusion Assessment Method (CAM) score, daily opioid side effects 

Baseline Characteristics

  

IV acetaminophen (n= 77)

Oral acetaminophen (n= 77)

 Standardized Difference 

Mean age, years

63 ± 10

 65 ± 10 - 0.121

Female

49 (63.6%) 42 (54.5%) - 0.186

Mean BMI, kg/m2

29.4 ± 5.9

29.0 ± 4.7

0.068

Race 

Amerian Indian and Alaskan native

Black 

White

 

3 (3.9%)

4 (5.2%)

69 (89.6%)

 

0

4 (5.2%)

70 (90.9%)

 

--

--

--

Pain at rest (numerical rating scale), mean

3.9 ± 2.6

 4.2 ± 2.6 - 0.095

Pain with ambulation (NRS), mean

 6.5 ± 2.5 6.7 ± 2.4

- 0.053

Surgical time (min), median (Q1, Q3)

 69 (60, 83) 72 (62, 86)

- 0.206 

Cemented hip

7 (9.1%)

 10 (13%)

- 0.125

Results

Primary Outcomes 

IV acetaminophen

Oral acetaminophen

 Difference in means (98.3% CI); p-value

Pain with physical therapy

(n= 76) 3.9 ± 2.4

 (n= 75) 3.6 ± 2.4 0.3 (0.6 to 1.2); 0.999

POD 0 to POD 3 opioid consumption, mg OME

 (n= 61) 121 ± 71 (n= 65) 108 ± 63

13 (16 to 42); 0.831

POD 1 Opioid side effects (ORSDS score) 

 (n= 75) 0.3 ± 0.3 (n= 74) 0.4 ± 0.3  

- 0.1 (- 0.2 to 0.1); 0.636

Secondary Outcomes 

 IV acetaminophen Oral acetaminophen

Effect size (95% CI); p-value

Median time to hospital discharge, hrs (Q1, Q3)

 (n= 77) 49 (47, 58) (n= 77) 50 (47, 53)

Hazard ratio 0.82 (0.59 to 1.14); 0.233

Mean PainOUT POD 2, or n (%) “No”

Worst pain

How often in severe pain 

Sleep interference

Nausea

Drowsiness

Itching 

 

5.6 ± 2.7

19.2% ± 20.1%

1.7 ± 2.8

1.6 ± 3.1

2.4 ± 3.3

0.5 ± 1.6

 

5.7 ± 2.7

15.8% ± 14.7%

1.6 ± 2.5

1.2 ± 2.6

2.6 ± 3.3

0.6 ± 1.8

Difference in means 

- 0.1 (- 1 to 0.8); 0.796

3.4% (2.5% to 9.2%); 0.256

0.2 (- 0.7 to 1.0); 0.712

0.4 (- 0.6 to 1.4); 0.428

- 0.2 (- 1.3 to 0.9); 0.733

- 0.1 (- 0.6 to 0.5); 0.802

No significant differences were noted in any of the pre-specified secondary outcomes. 

CAM, Confusion Assessment Method; CI, confidence interval; NRS, numerical rating scale; OME, oral morphine equivalents; ORSDS, Opioid-Related Symptom American Pain Society Patient Outcome Questionnaire; SD, standard deviation; SPMSQ, Short Portable Mental Status Questionnaire.  

Adverse Events

Daily opioid side effects were reported under the secondary outcomes session. 

Study Author Conclusions

In conclusion, no benefits were found from using IV acetaminophen for postoperative analgesia after THA compared to oral acetaminophen. Because the oral formulation is less invasive to administer and less costly, the study supports the routine use of oral acetaminophen for these patients.

InpharmD Researcher Critique

The study results may not be readily generalized to other institutions where different postoperative pain management protocols or agents are used. Opioid consumption is mainly based on patients' requests per study protocol, which may introduce potential bias on this particular outcome between the two groups. 



References:

Westrich, Geoffrey H et al. “Intravenous vs Oral Acetaminophen as a Component of Multimodal Analgesia After Total Hip Arthroplasty: A Randomized, Blinded Trial.” The Journal of arthroplasty vol. 34,7S (2019): S215-S220. doi:10.1016/j.arth.2019.02.030

 

Intravenous vs. Oral Acetaminophen as a Component of Multimodal Analgesia After Total Hip Arthroplasty: A Randomized, Blinded Trial

Design

Single-center, parallel-group, double-blinded, randomized, controlled trial

(N= 154)

Objective

To evaluate if intravenous (IV) acetaminophen would reduce pain with activity, opioid usage, or opioid-related side effects, compared to oral acetaminophen after total hip arthroplasty (THA)

Study Groups

IV acetaminophen (n= 77)

Oral acetaminophen (n= 77) 

Inclusion Criteria

Age ≥ 18 to 90 years with scheduled elective primary unilateral THA

Exclusion Criteria

History of opioid abuse or daily use of opioids for one month before surgery, chronic pain management, hypersensitivity or contraindication to protocol medication, abnormal hepatic or renal function tests, planned general anesthesia or to receive preoperative medication or a periarticular injection, rheumatoid arthritis, THA with additional procedures and/or hardware removal, bodyweight < 50 kg

Methods

Enrolled patients were randomized (1:1) to receive either IV 1 g acetaminophen (100 mL of solution) infused over 15 mins plus oral placebo or oral 1 g acetaminophen (in two capsules) plus IV placebo. First doses were given 30 minutes after admission to the post-anesthesia care unit. IV or oral acetaminophen were given every 6 hours for three full days after surgeries or until discharge. 

Postoperatively, patient-controlled epidural analgesia was used with bupivacaine 0.06% and clonidine 1 mcg/mL, at 2 mL/h basal rates with a 4 mL patient-controlled bolus (20 mL max/hour). At 7 AM postoperative day (POD) 1, the basal rate was decreased to 0, and the epidural was discontinued at noon. Patients also received IV ketorolac 15-30 mg every 8 hours for a total of 6 doses, followed by oral meloxicam 7.5-15 mg (7.5 mg if age > 70 years or weight < 60 kg) until POD 3 or until discharge. Oral tramadol 50 mg (for mild pain), tramadol 100 mg (for moderate pain), or oxycodone 5 mg (for severe pain and up to 10/15 mg) were given to the patient's request. IV 2 mg hydromorphone could be used as rescue analgesia. 

Duration

Enrollment: between February 2017 and May 2018

Follow-up: POD 3 or until discharge 

Outcome Measures

Primary outcomes: pain with activity on POD 1 (patient-reported pain during physical therapy), cumulative opioid usage between POD 0 and POD 3 (mg of oral morphine equivalents [OME]), and opioid-related side effects on POD 1 (Opioid-Related Symptom Distress Scale [ORSDS]) 

Secondary outcomes: pain at rest and with physical therapy (POD 0, 2, 3), daily opioid use, American Pain Society Patient Outcome Questionnaire (also termed PainOUT or APS-POQ-R), discharge time, and Confusion Assessment Method (CAM) score, daily opioid side effects 

Baseline Characteristics

  

IV acetaminophen (n= 77)

Oral acetaminophen (n= 77)

 Standardized Difference 

Mean age, years

63 ± 10

 65 ± 10 - 0.121

Female

49 (63.6%) 42 (54.5%) - 0.186

Mean BMI, kg/m2

29.4 ± 5.9

29.0 ± 4.7

0.068

Race 

Amerian Indian and Alaskan native

Black 

White

 

3 (3.9%)

4 (5.2%)

69 (89.6%)

 

0

4 (5.2%)

70 (90.9%)

 

--

--

--

Pain at rest (numerical rating scale), mean

3.9 ± 2.6

 4.2 ± 2.6 - 0.095

Pain with ambulation (NRS), mean

 6.5 ± 2.5 6.7 ± 2.4

- 0.053

Surgical time (min), median (Q1, Q3)

 69 (60, 83) 72 (62, 86)

- 0.206 

Cemented hip

7 (9.1%)

 10 (13%)

- 0.125

Results

Primary Outcomes 

IV acetaminophen

Oral acetaminophen

 Difference in means (98.3% CI); p-value

Pain with physical therapy

(n= 76) 3.9 ± 2.4

 (n= 75) 3.6 ± 2.4 0.3 (0.6 to 1.2); 0.999

POD 0 to POD 3 opioid consumption, mg OME

 (n= 61) 121 ± 71 (n= 65) 108 ± 63

13 (16 to 42); 0.831

POD 1 Opioid side effects (ORSDS score) 

 (n= 75) 0.3 ± 0.3 (n= 74) 0.4 ± 0.3  

- 0.1 (- 0.2 to 0.1); 0.636

Secondary Outcomes 

 IV acetaminophen Oral acetaminophen

Effect size (95% CI); p-value

Median time to hospital discharge, hrs (Q1, Q3)

 (n= 77) 49 (47, 58) (n= 77) 50 (47, 53)

Hazard ratio 0.82 (0.59 to 1.14); 0.233

Mean PainOUT POD 2, or n (%) “No”

Worst pain

How often in severe pain 

Sleep interference

Nausea

Drowsiness

Itching 

 

5.6 ± 2.7

19.2% ± 20.1%

1.7 ± 2.8

1.6 ± 3.1

2.4 ± 3.3

0.5 ± 1.6

 

5.7 ± 2.7

15.8% ± 14.7%

1.6 ± 2.5

1.2 ± 2.6

2.6 ± 3.3

0.6 ± 1.8

Difference in means 

- 0.1 (- 1 to 0.8); 0.796

3.4% (2.5% to 9.2%); 0.256

0.2 (0.7 to 1.0); 0.712

0.4 (0.6 to 1.4); 0.428

- 0.2 (- 1.3 to 0.9); 0.733

- 0.1 (- 0.6 to 0.5); 0.802

No significant differences were noted in any of the pre-specified secondary outcomes. 

CAM, Confusion Assessment Method; CI, confidence interval; NRS, numerical rating scale; OME, oral morphine equivalents; ORSDS, Opioid-Related Symptom American Pain Society Patient Outcome Questionnaire; SD, standard deviation; SPMSQ, Short Portable Mental Status Questionnaire.  

Adverse Events

Daily opioid side effects were reported under the secondary outcomes session. 

Study Author Conclusions

In conclusion, no benefits were found from using IV acetaminophen for postoperative analgesia after THA compared to oral acetaminophen. Because the oral formulation is less invasive to administer and less costly, the study supports the routine use of oral acetaminophen for these patients.

InpharmD Researcher Critique

The study results may not be readily generalized to other institutions where different postoperative pain management protocols or agents are used. Opioid consumption is mainly based on patients' requests per study protocol, which may introduce potential bias on this particular outcome between the two groups. 



References:

Westrich, Geoffrey H et al. “Intravenous vs Oral Acetaminophen as a Component of Multimodal Analgesia After Total Hip Arthroplasty: A Randomized, Blinded Trial.” The Journal of arthroplasty vol. 34,7S (2019): S215-S220. doi:10.1016/j.arth.2019.02.030

 

Comparison of Clinical Outcomes of Acetaminophen IV vs PO in the Perioperative Setting for Laparoscopic Inguinal Hernia Repair Surgeries: A Triple-blinded, Randomized Controlled Trial

Design

Prospective, triple-blind, randomized, controlled trial

N= 100

Objective

To determine the non-inferiority of oral (PO) acetaminophen to intravenous (IV) acetaminophen for ambulatory surgery patients

Study Groups

PO acetaminophen (n= 56)

IV acetaminophen (n= 44)

Inclusion Criteria

Patients 18 to 75 years old presenting for laparoscopic hernia repair under general anesthesia. American Society of Anesthesiologists (ASA) physical status 1-3

Exclusion Criteria

Known allergy or contraindication to acetaminophen, unable to tolerate oral medication, pregnant, weight < 50 kg, surgery anticipated to last > 3 hours, history of chronic opioid use, undergoing emergency surgery, anesthetic plan included a regional technique during surgery

Methods

Patients were randomized to receive either pre-operative PO acetaminophen 975 mg administered approximately 15 minutes prior to entering the operating room with 100 mL of normal saline given after induction of general anesthesia or intraoperative IV acetaminophen 1,000 mg in 100 mL after standard induction of general anesthesia with Vitamin C placebo pills given preoperatively. Intraoperative opioids could be given at the discretion of the anesthesiologist. Ten mL of 0.25% bupivacaine was used for port site injection prior to and during the closure of the incision site. Intraoperative non-steroidal anti-inflammatory drugs (NSAIDs) administration was based on physician preference. Pain scores were assessed using the numerical pain rating scale. Patient satisfaction in regards to overall pain management was recorded on a 0 to 10 scale.

Post-operative opioids were administered according to a standard post-operative order set, and patients were discharged with an opioid prescription. Opioid consumption was evaluated using morphine milligram equivalents (MME).

The post-operative opioid protocol included the following: oxycodone 5 mg for mild pain (1-3), oxycodone 10 mg for moderate pain (4-6), fentanyl 25 mg for severe pain (7-10), hydromorphone for breakthrough pain, and discharge with a prescription for oxycodone 5 mg with instructions to take 1 to 2 tablets as needed every 4 hours for pain.

Duration

Enrollment: July 2017 to December 2018

Outcome Measures

 

Primary outcomes: PACU pain scores at arrival, 1 hour post-op, 6 hours post-op, and at discharge; total opioid use intraoperatively and in PACU

Secondary outcomes: PACU length of stay, patient-reported total opioid use 24 hours post-discharge, pain scores at 24 hours post-op, and patient satisfaction

Baseline Characteristics

   IV acetaminophen (n= 56) PO acetaminophen (n= 44) p-value

Age, years

 52.52 ± 15.1 53.93 ± 13.37  0.623

Weight, kg

 80.18 ± 19.49 81.07 ± 18.55 0.818

Height, in

 67.81 ± 4.11 69.11 ± 5.93 0.199

Body-mass index, kg/m2

 26.37 ± 4.76 26.35 ± 5.14 0.98

Results

Endpoint

IV acetaminophen (n= 56)

PO acetaminophen (n= 44)

95% confidence interval; p-value

Pain score

On arrival to PACU

1 hour after arrival to PACU

Discharge from PACU

6 hours post-op

24 hours post-op

 



1.52 ± 2.44

2.41 ± 2.21

1.59 ± 1.44

4.27 ± 1.74

4.16 ± 1.83



2.13 ± 2.72

2.88 ± 2.74

1.45 ± 1.51

3.82 ± 2.28

3.64 ± 2.26



-1.64 to 0.44; 0.173

-1.47 to 0.54; 0.544

-0.45 to 0.74; 0.586

-0.37 to 1.27; 0.234

-0.31 to 1.35; 0.133

Total MME requirement

Intraoperative

PACU

Home



57.24 ± 29.2

9.83 ± 11.99

17.56 ± 17.42



63.75 ± 21.33

11.33 ± 17.1

14.06 ± 14.02



-16.95 to 3.93; 0.096

-4.53 to 7.53; 0.96

-2.74 to 9.73; 0.336

Time in PACU, minutes

 64.05 ± 33.13  82.93 ± 55.79 -36.71 to -1.06; 0.15

Overall patient satisfaction

 6.2 ± 3.01 5.05 ± 2.18 0.06 to 2.23; 0.067

Adverse Events

Common Adverse Events: N/A

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

There are no statistically significant clinical differences between pain scores, opioid consumption and patient satisfaction in oral versus intravenous acetaminophen. The use of PO acetaminophen is non-inferior to IV acetaminophen.

InpharmD Researcher Critique

Administration times were implemented to mimic the pharmacokinetic profile of each formulation, which allowed peak effects to generally occur around the same time. However, the onset of action and duration of effect may differ between patients. This study did not adjust for certain confounders including the use of NSAIDs such as ketorolac, which could have largely effected patients' pain scores. With no significant findings between the two groups and multiple confounders present, no conclusions can be drawn regarding a more efficacious formulation.



References:

Patel A, Pai B H P, Diskina D, Reardon B, Lai YH. 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. J Clin Anesth. 2020;61:109628. doi:10.1016/j.jclinane.2019.109628

 

Comparison of Antipyretic Efficacy of Intravenous (IV) Acetaminophen versus Oral (PO) Acetaminophen in the Management of Fever in Children

Design

Observational, single-dose study 

N= 400

Objective

To evaluate the antipyretic efficacy of intravenous (IV) acetaminophen versus oral (PO) acetaminophen in the management of fever in children

Study Groups

Intravenous (IV) acetaminophen (n= 200)

Oral (PO) acetaminophen (n= 200)

Inclusion Criteria

All admitted or out-patient patients with fever more than 103° F

Exclusion Criteria

Having received other antipyretic agents within 48 hours of admission, having hypersensitivity to acetaminophen or other non-steroidal anti-inflammatory drugs (NSAIDs), having evidence of clinically significant liver and renal disease

Methods

Patients were randomized to receive IV acetaminophen 15 mg/kg/dose versus PO acetaminophen 15 mg/kg/dose over 6 hours at a tertiary care center in New Delhi. Children were monitored for the primary efficacy outcome following the administration of the drug. The temperature was recorded with a mercury thermometer every 30 minutes for six hours. Children were monitored for any evidence of intolerance.

Duration

 Intervention: 6 hours

Outcome Measures

 Mean temperature reduction, need for an additional dose

Baseline Characteristics

  

All cases (N= 400)

 

  

Age, years

 6.8 ± 2.7    

Male

 71%    

Weight, kg

 23.3 ± 6.4    

Vitals

Heart rate, min

Respiratory rate, min

 

118.4 ± 9.3

23.9 ± 2.8

    

Results

Endpoint

IV acetaminophen (n= 200)

PO acetaminophen (n= 200)

p-value
Additional dose required 10 (5%) 6 (3%) 0.31

There was a statistically significant difference in the weighted sum of temperature differences in 180 minutes (p < 0.004) between the groups in favor of the IV acetaminophen group compared to PO acetaminophen. There was no significant difference beyond four hours in between the two groups.

Adverse Events

Common Adverse Events: constipation (4% vs 0%), dry mouth (4% vs 0%), allergic reaction (rash, itching) (3.5% vs 0%)

Study Author Conclusions

A single dose of intravenous acetaminophen is safe and effective in reducing fever where patients are unable to tolerate oral administration or when rapid reduction of temperature is desirable.

InpharmD Researcher Critique

Given the observational nature of the study, confounding factors are not likely to be completely eliminated, which decreases the generalizability of the study results.
References:

Roy S, Simalti AK. Comparison of Antipyretic Efficacy of Intravenous (IV) Acetaminophen versus Oral (PO) Acetaminophen in the Management of Fever in Children. Indian J Pediatr. 2018;85(1):1-4. doi:10.1007/s12098-017-2457-3

 

Intravenous Versus Oral Acetaminophen in Ambulatory Surgical Center Laparoscopic Cholecystectomies: A Retrospective Analysis

Design

Single-center, retrospective, non-inferiority study

N= 579

Objective

To compare postoperative pain scores in patients undergoing laparoscopic cholecystectomy and receiving intravenous (IV) or oral (PO) acetaminophen (APAP) as part of a multimodal analgesic regimen to examine whether PO APAP is non-inferior to IV APAP

Study Groups

IV APAP (n= 319)

PO APAP (n= 260)

Inclusion Criteria

Patients aged 18 to 70 years old undergoing laparoscopic cholecystectomy in an ambulatory surgical center (ASC) who received 1,000 mg IV APAP intraoperatively or 1,000 mg PO APAP preoperatively, American Society of Anesthesiologists (ASA) physical status I-III

Exclusion Criteria

Patients who underwent additional procedures, received < 1,000 mg APAP, received a transverse abdominal plane block, or underwent surgery during a three-month transition from IV to PO APAP where overlap of the two formulations may have occurred

Methods

Patients received general endotracheal anesthesia with IV fentanyl administered at induction and throughout the procedure at the discretion of the operating team. Surgical incisions are infiltrated with 0.2% ropivacaine during closure. Intravenous ketorolac and dexamethasone administration is strongly encouraged by surgical protocol, however, intraoperative administration of long-acting opioids (i.e. hydromorphone and morphine) is discouraged.

Postoperative analgesia with IV morphine or hydromorphone 0.2 mg every 15 minutes (max of 1 mg) is used for moderate (4-6) or severe (7-10) pain scores, and oral hydrocodone can be administered when the patient is tolerating fluids by mouth.

Pain scores were evaluated using the numeric rating scale (NRS) or Wong-Baker FACES pain scale. One pain-scale point was used as the non-inferiority margin.

Duration

June 2015 to June 2017

Outcome Measures

Primary outcome: difference in median end-pain scores before discharge from the post-anesthesia care unit (PACU), at PACU admission, and at 15, 30, 45, and 60 minutes

Secondary outcomes: intraoperative and PACU opioid and non-opioid analgesic consumption, PACU length of stay, time from APAP administration to PACU admission, time to first PACU rescue opioid

Baseline Characteristics

   IV APAP (n= 319)

PO APAP (n= 260)

 p-value  

Age, years

 41.06 ± 10.6 41.73 ± 11.51 0.46  

Female

294 (92%) 241 (93%) 0.81  

Hispanic

 294 (92%) 237 (91%) 0.66  

Body-mass index, kg/m2

 29.43 ± 4.91 30.75 ± 5.25 0.002  

ASA physical status

1

2

3



74 (23%)

217 (68%)

28 (9%)



43 (16%)

184 (71%)

33 (13%)

0.07

 

 

 

  

Results

Endpoint

IV APAP (n= 319)

PO APAP (n= 260)

p-value

Upper limit of confidence interval compared to non-inferiority margin

Median pain scores

Initial

15 minutes

30 minutes

45 minutes

60 minutes

End



n= 318; 0 (0 to 0)

n= 292; 4 (0 to 7)

n= 290; 5 (2 to 7)

n= 250; 3 (0 to 5)

n= 241; 2 (0 to 4)

n= 319; 2 (0 to 3)



n= 260; 0 (0 to 0)

n= 244; 5 (0 to 7)

n= 250; 5 (2 to 7)

n= 240; 4 (0 to 5)

n= 195; 2 (0 to 4)

n= 260; 2 (0 to 3)





Upper limit of CI ≤ 1

Upper limit of CI ≤ 1

Upper limit of CI ≤ 1

Upper limit of CI ≤ 1

Upper limit of CI ≤ 1

Upper limit of CI ≤ 1

Median PACU length of stay, minutes

 79 (66 to 95) 80 (66 to 94.5) 0.89  

Median time from APAP administration to PACU admission, minutes

 62 (51 to 82) 150.5 (114 to 188.5) < 0.001  

Median time to first PACU rescue opioid, minutes

n= 240

21 (14.5 to 26)

n= 199

23 (16 to 30)

 0.014  

Intraoperative analgesic consumption

Ketorolac

Fentanyl

Hydromorphone equivalent

 

212 (66%)

319 (100%)

28 (9%)

 

188 (72%)

260 (100%)

11 (4%)

 

0.13

-

0.03

  

PACU analgesic consumption

Hydromorphone equivalent

Hydrocodone



240 (75%)

305 (96%)



199 (77%)

248 (95%)



0.72

0.9

  

Amount of intraoperative analgesic consumption

Ketorolac, mg

15

30

Median fentanyl, mcg

Median hydromorphone equivalent, mg



-

13 (6%)

199 (94%)

200 (100 to 250)

0.5 (0.5 to 1.25)



-

4 (2%)

184 (98%)

150 (100 to 200)

1 (0.5 to 1.5)



0.48

-

-

< 0.001

0.24

  

Amount of PACU analgesic consumption

Median hydromorphone equivalent, mg

Hydrocodone, mg

5

7.5

10



0.5 (0.35 to 0.8)

-

197 (65%)

59 (19%)

49 (16%)



0.5 (0.4 to 0.9)

-

188 (76%)

48 (19%)

12 (5%)



0.66

< 0.001

-

-

-

  

Adverse Events

Common Adverse Events: N/A

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

Single-dose PO APAP is non-inferior to IV APAP for postoperative analgesia in ASC laparoscopic cholecystectomy patients. The value of single-dose IV APAP in this population should be further explored.

InpharmD Researcher Critique

Due to the retrospective design, lack of control group, variation of protocol following, and use of two different pain scales it is difficult to determine the clinical applicability of these results. Additionally, these results may not be generalizable to non-surgical patients.

 

References:

Johnson RJ, Nguyen DK, Acosta JM, O'Brien AL, Doyle PD, Medina-Rivera G. Intravenous Versus Oral Acetaminophen in Ambulatory Surgical Center Laparoscopic Cholecystectomies: A Retrospective Analysis. P T. 2019;44(6):359-363.

 

Oral Versus Intravenous Acetaminophen within an Enhanced Recovery after Surgery Protocol in Colorectal Surgery

Design

Retrospective observational study

N= 175

Objective

To evaluate the role of intravenous (IV) versus oral (PO) acetaminophen within an established enhanced recovery after surgery protocol in colorectal surgery

Study Groups

IV group (n= 91)

PO group (n=84)

Inclusion Criteria

Patients undergoing elective colorectal resection procedure

Exclusion Criteria

None reported

Methods

Patients underwent treatment following multimodal pain management strategy involving both opioid and nonopioid analgesics. In IV acetaminophen group patients were given only IV acetaminophen 1000 mg/dose. Patients in PO group were given single dose of intraoperative IV acetaminophen followed by subsequent PO acetaminophen 975 mg/dose. Data was documented through 72 hours postoperatively or until discharge. Pain scores taken every eight hours according to the Visual Analog Scale (VAS). Opioid doses were documented as oral morphine equivalents (OME). 

Duration

Procedures performed between November 1, 2015 to September 30, 2016 and November 1, 2017 to October 31, 2017

Outcome Measures

 Average pain scores, opioid use through 72 hours postoperatively, postoperative outcomes (e.g., length of hospital stay, return of bowel function, complications, readmissions, reoperations, nausea and vomiting, etc.)

Baseline Characteristics

  

IV (n= 91)

PO (n= 84)

  

Age, years

 62.4 ± 13.1

58.9 ± 11.9

  

Male

48 (52.7%) 

34 (40.5%)

  

Body Mass Index (BMI)

 30.8 ± 7.9

30.1 ± 7.4

  

Results

 

IV (n= 91)

PO (n= 84)

p-Value

Pain score, average

0-24 hours

24-48 hours

48-72 hours

 

2.87 ± 1.75

4.16 ± 2.16

3.37 ± 1.85

 

 

3.39 ± 1.97

4.02 ± 1.81

3.71 ± 1.73

 

 

0.0645

0.6499

0.2222

 

Opioid use at 72 hours, (oral morphine equivalents) 

 68.5 ± 34.5 93.7 ± 35.0 0.0001

Postoperative nausea and vomiting, n (%)

 30 (33%) 41 (48.8%) 0.0449

Difference in other postoperative outcomes not statistically significant

Adverse Events

 Adverse events specific to acetaminophen not reported. However, the incidence of possible opioid-related nausea and vomiting was higher in PO acetaminophen group. 

Study Author Conclusions

Restriction of IV acetaminophen was associated with increased opioid use, greater need for opioid patient-controlled analgesia, and increased incidence of postoperative nausea and vomiting. Intravenous acetaminophen may be superior to oral acetaminophen in the early postoperative setting.

InpharmD Researcher Critique

Reported average pain score was disproportionately higher between the 0 and 24-hour interval in the PO group vs. the IV group as compared to the other intervals. Although the difference turned out to be statistically insignificant, it may invoke more research into the potential of using a hybrid approach in which acetaminophen may be administered intravenously in the early postoperative phase and then later transition to oral. However, time-based intervals were not conducted for the statistically significant outcomes of opioid use and postoperative nausea and vomiting. 



References:

Marcotte JH, Patel KM, Gaughan JP, et al. Oral Versus Intravenous Acetaminophen within an Enhanced Recovery after Surgery Protocol in Colorectal Surgery. Pain Physician. 2020;23(1):57-64.

 

Acetaminophen for Analgesia Following Pyloromyotomy: Does the Route of Administration Make a Difference?

Design

Retrospective review

N= 68

Objective

To compare the efficacy of intravenous (IV) and rectal acetaminophen for postoperative analgesia in infants undergoing laparoscopic pyloromyotomy

Study Groups

IV acetaminophen (n= 34)

Rectal acetaminophen (n= 34) 

Inclusion Criteria

Infants undergoing pyloromyotomy over a 3 year period

Exclusion Criteria

Received opioids intraoperatively

Methods

Patient records were reviewed retrospectively to determine infants who could be included for analysis and demographic data. The intraoperative anesthetic record was used to determine the route of administration and the dose of acetaminophen in addition to other perioperative data. Postoperative pain scores were evaluated using the Faces, Leg, Activity, Cry, and Consolability (FLACC) scale.

Duration

June 2014 to August 2016

Outcome Measures

Pain scores, time in the post-anesthesia care unit (PACU), time to hospital discharge, need for supplemental analgesic agents in the PACU and during the postoperative period

Baseline Characteristics

  

IV acetaminophen (n= 34)

Rectal acetaminophen (n= 34)

Age, days

 34.2 ± 14.5 37.8 ± 16.5

Female

 5 (14.7%) 5 (14.7%)

Weight, kg

 4.01 ± 0.8 3.87 ± 0.71

Dose of acetaminophen, mg/kg

 8.6 ± 3.9 30.7 ± 6.3

Results

Endpoint

 IV acetaminophen (n= 34)

Rectal acetaminophen (n= 34)

FLACC pain scores

Average in PACU

Final in PACU

Initial postoperative in the ward

Average postoperative



0.3 ± 0.6

0 ± 0

0.6 ± 1.6

0.5 ± 0.5



0.6 ± 0.1

0.1 ± 0.3

1.6 ± 3

0.5 ±0.5 

Length of stay

PACU, minutes

Hospital, days



48 ± 19.9

1.7 ± 1.9



50.4 ± 12

1.5 ± 1.4

Required acetaminophen supplementation

31 (91.2%)

27 (79.4%)

Acetaminophen supplementation, doses

 4.4 ± 5.6 3.5 ± 3.7

Opioids received postoperatively

 0 2 (5.9%)

No difference was seen regarding pain scores, time spent in the PACU, time spent in the hospital, or perioperative complications. 

Adverse Events

Common Adverse Events: N/A

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

For patients undergoing laparoscopic pyloromyotomy, this preliminary data suggests that there is no clinical advantage with the use of IV compared with rectal acetaminophen. Pain scores, acetaminophen supplementation, PACU discharge time, length of hospital stay, and nonsurgical complications were similar in both groups (IV versus rectal acetaminophen). Given the superficial nature of the surgical incision sites, infiltration with a local anesthetic agent may play a bigger role in controlling postoperative pain than the acetaminophen formulation.

InpharmD Researcher Critique

The retrospective nature of this study allows for inevitable human error and missing data from patient records. It appears effective analgesia was achieved in both groups, but with no significant differences between the groups. Additionally, with varying pharmacokinetic parameters in regards to drug administration in infants, these results may prove different for an adult population.



References:

Yung A, Thung A, Tobias JD. Acetaminophen for analgesia following pyloromyotomy: does the route of administration make a difference?. J Pain Res. 2016;9:123-127. Published 2016 Mar 8. doi:10.2147/JPR.S100607

 

Oral vs. intravenous paracetamol for lower third molar extractions under general anesthesia: is oral administration inferior?

Design

Single-center, randomized, controlled, non-inferiority trial

(N= 130)

Objective

To investigate whether oral acetaminophen is inferior in clinical effect to intravenous (IV) acetaminophen with a consistent pain model 

Study Groups

IV acetaminophen (n= 63)

Oral acetaminophen (n= 65)

Inclusion Criteria

Age ≥ 18 to 65 years, having at least one lower third molar extraction under general anesthesia

Exclusion Criteria

Analgesic medication administered in the previous 24 hours, had caffeine in the previous 6 hours, could not swallow tablets, allergic to the trial medications, history of liver or renal dysfunction, drug or alcohol abuse, pregnant or breastfeeding

Methods

Enrolled patients were randomized (1:1) at a hospital in England to receive either 1 g oral acetaminophen and IV placebo (100 ml 0.9% saline) or 1 g IV acetaminophen and oral placebo. Oral preparations were given at least 45 minutes before surgery versus IV preparations after induction of anesthesia. The pain was assessed by a 100 mm visual analog scale (VAS) one hour before the end of surgery. Rescue analgesia was given on request (IV diclofenac 50 mg). Satisfactory pain relief was defined as VAS scores of ≤30 mm one hour after the operation. The study was designed to show whether oral acetaminophen is inferior to IV acetaminophen, with an inferiority margin of 20%.

Outcome Measures

Primary outcome: proportion of participants reporting satisfactory pain relief in each group

Secondary outcome: mean of postoperative VAS scores at one hour in each group

Baseline Characteristics

  

Oral (n= 65)

 IV (n= 63)    

Age, years

 18.1 to 57.7  18.7 to 54.4    

Female,n

 51 43    

Mean BMI

 24.4 ± 4.3 24.5 ± 5    

Mean preoperation VAS

 0.35 ± 0.99 0.22 ± 0.71    

Mean length of surgery, min

 17.8 ± 8.9 18.1 ± 11.5    

 Surgical difficulty

1

2

3

 

24

26

15

 

24

16

23 

    

Patient aware of route of administration

8

8

    

Results

Endpoint

 Oral (n= 65) IV (n= 63)

Difference in proportions

90% Confidence Interval (CI)

Achieved meaningful analgesic effect at one hour, (95% CI)

15/65

23.1% (14 to 35) 

17/63

27% (17 to 40) 

 – 0.039  – 0.17 to 0.09

Mean VAS by study arm

 5.2 ± 2.2 4.7 ± 2.2  Mean difference 0.5 – 0.11 to 1.2

Median time to request rescue analgesia within the first hour, min (95% CI)

54.3 (51.2 to 57.4)

 57.2 (55.4 to 59.2) --

--

Adverse Events

Common Adverse Events: N/A

Study Author Conclusions

In this lower third molar extraction study, oral acetaminophen is not inferior to IV for postoperative analgesia.

InpharmD Researcher Critique

The result of the study may be subject to bias since there was a tendency for more difficult dental extractions to happen in the IV group.



References:

Fenlon S, Collyer J, Giles J, et al. Oral vs intravenous paracetamol for lower third molar extractions under general anaesthesia: is oral administration inferior?. Br J Anaesth. 2013;110(3):432-437. doi:10.1093/bja/aes387

 

Effectiveness of Novel Adjuncts in Pain Management Following Total Knee Arthroplasty: A Randomized Clinical Trial

Design

Single blinded, prospective, randomized clinical trial

N= 156

Objective

To compare the effectiveness of three different pain management modalities after total knee arthroplasty (TKA) that included (1) our standardized knee injection cocktail and oral acetaminophen, (2) liposomal bupivacaine periarticular injection and oral acetaminophen, and (3) our standardized knee injection cocktail and intravenous acetaminophen

Study Groups

Oral (PO) acetaminophen (APAP) + standard knee injection cocktail (n= 52)

PO APAP + liposomal bupivacaine (LB) periarticular injection (n= 52)

Intravenous (IV) APAP + standard knee injection cocktail (n= 52)

Inclusion Criteria

Age 18-85, undergoing primary TKA

Exclusion Criteria

Undergoing revision or bilateral TKA, contraindications to study-related medications, chronic opioid or alcohol use, advanced renal disease (GFR < 30) or severe liver disease

Methods

In PO APAP + standard knee injection and PO APAP + LB injection group, four 1 gm doses of APAP were given PO every six hours, with first dose given immediately preoperatively. In IV APAP + standard knee injection group, four 1 gm IV doses were given every six hours, again with first dose given immediately preoperatively. 

All patients received four 15 mg postoperative doses of IV ketorolac (30 mg for patients aged < 65 years). Rescue opioids were ordered on an as needed basis including oral oxycodone, tramadol, hydrocodone, and IV morphine

Duration

October 2015 - December 2016

Outcome Measures

Primary: visual analog scale (VAS) pain score, total morphine equivalents (TME), opioid-related symptoms distress scale (OR-SDS) at 24 and 48 hours postoperatively

Secondary: hospital length of stay, discharge disposition, postoperative knee range of motion, and complications

Baseline Characteristics

  

PO APAP + LB (n= 52)

IV APAP + standard injection (n= 52)

 PO APAP + standard injection (n= 52)  

Age, years

  68.1 ± 8.2 66.6 ± 8.9   67.3 ± 7.4  

Female

33 (63.5%)   24 (46.2%)  26 (50%)  

ASA Class

1

2

3

 

1 (1.9%)

30 (57.7%)

21 (40.4%)

 

 

3 (5.8%)

30 (57.7%)

19 (36.5%) 

 

0

34 (65.4%)

18 (34.6%) 

  

ASA: American Society of Anesthesiologists 

Results

 

PO APAP + LB (n= 52)

 IV APAP + standard injection (n= 52)

PO APAP + standard injection (n= 52)

  p-Value

24 hours postoperatively

VAS

 2.75 2.21 2.37 0.488

TME

 51.51  31.05  30.03  0.040*

OR-SDS

 0.27  0.17  0.3  0.09

48 hours postoperatively
VAS

3.57

 3.21 3.59 0.831
TME

41.47

 33.82 50.34 0.174
OR-SDS

0.26

 0.32 0.35 0.417

*Post Hoc analysis for TME at 24 hours postoperatively revealed significant difference between LB group compared to other groups but not between IV APAP and PO APAP group; no significant difference between groups in any secondary outcome measures.

Adverse Events

   PO APAP + LB (n= 52) IV APAP + standard injection (n= 52) PO APAP + standard injection (n= 52)  

Hematoma

Arthrofibrosis

Deep vein thrombosis

Surgical site infection

Surgical site blisters

Intubated due to aspiration

during surgery

0 (0.0%)

2 (1.3%)

0 

0 

0 

1 (0.66%)

1 (0.66%)

0 

1 (0.66%)

1 (0.66%)

1 (0.66%)

0 

0

0 

0

0

0

0

  

Adverse events documented for duration of six weeks postoperatively; no significant difference between any group

Study Author Conclusions

The use of intravenous acetaminophen or liposomal bupivacaine did not provide an advantage in terms of pain relief or decreased narcotic consumption in our study population. Based on our findings, we do not recommend their use in routine TKA. Further research in at risk populations is recommended.

InpharmD Researcher Critique

This was a single blind study and thus may have been subject to selection bias. All patients were from the same institution and underwent an identical surgical procedure, TKA. 



References:

Suarez JC, Al-Mansoori AA, Kanwar S, et al. Effectiveness of Novel Adjuncts in Pain Management Following Total Knee Arthroplasty: A Randomized Clinical Trial. J Arthroplasty. 2018;33(7S):S136-S141. doi:10.1016/j.arth.2018.02.088

 

Plasma and Cerebrospinal Fluid Pharmacokinetic Parameters After Single-Dose Administration of Intravenous, Oral, or Rectal Acetaminophen

Design

Single-center, open-label study

N= 7

Objective

To determine plasma and cerebrospinal fluid (CSF) acetaminophen time-concentration profiles over 6 hours and pharmacokinetic (PK) parameters after administration of a single-dose of intravenous (IV), oral (PO), or rectal (PR) acetaminophen

Study Groups

IV 1,000 mg (N= 7)

PO 1,000 mg (N= 7)

PR 1,000 mg (N= 7)

PR standardized to 1,000 mg (N= 7)

Inclusion Criteria

Healthy nonsmoking men 18 to 45 years old, body mass index (BMI) between 19 and 25 lbs/in2, ≥ 50 kg, negative drug and alcohol screens, negative antibody tests for hepatitis and human immunodeficiency viruses

Exclusion Criteria

Use of medications or supplements ≤ 7 days prior to the first clinic dose acetaminophen; history of excessive bleeding, recent infection, lumbar spine deformities, elevated intracranial pressure, or other neurological conditions; allergy to acetaminophen

Methods

Patients served as their own control and received separate treatment periods of acetaminophen IV 1,000 mg 15-minute infusion, PO 1,000 mg, or PR 1,300 mg. A 20-gauge spinal catheter was placed on admission to the clinic for CSF sampling, and a 24-hour washout period was implemented between acetaminophen doses. The concentration results from the 1,300 mg PR dose were standardized to 1,000 mg for better comparison to the IV and PO administration routes. Acetaminophen levels were taken at T0 (predose), 0.25, 0.5, 0.75, 1, 2, 3, 4, and 6 hours following administration. Concomitant medication use was not allowed during the treatment and assessment period. 

Duration

 Three days

Outcome Measures

Mean maximum concentration (Cmax), median time to maximal concentration (Tmax), mean elimination half-life (t1/2), mean area under the curve (AUC) from T0 to 6 hours, clearance

Baseline Characteristics

  

Total (N= 7)

Age (range), years

 29.4 (19 to 44)  

Male

 7 (100%)  

Race

Caucasian

African-American



5 (71.4%)

2 (28.6%)

Results

Endpoint

IV 1,000 mg (N= 6)

PO 1,000 mg (N= 7)

PR 1,300 mg (N= 6)

PR standardized to 1,000 mg (N= 6)

Plasma PK parameters

Cmax, μg/mL

Median Tmax, hours

t1/2, hours

AUC0-6, μg·hours/mL

AUC0-∞, μg·hours/mL

Clearance/bioavailability, L/hours



21.6 ± 17.9

0.25 (0.25 to 0.25)

2.17 ± 20

42.5 ± 16.5

50 ± 18.7

20.7 ± 19.8



12.3 ± 45.2

1 (0.5 to 2)

N= 6; 2.53 ± 19.3

29.4 ± 52.3

N= 6; 44.4 ± 35.4

N= 6; 24.6 ± 28.9



7.9 ± 49

2.5 (2 to 4)

N= 2; 3

31.9 ± 29.2

N= 2; 41.3

N= 2; 32.5



6.07 ± 49

2.5 (2 to 4)

N= 2; 3

24.5 ± 29.2

N= 2; 31.8

N= 2; 32.5

CSF PK parameters

CSFmax, μg/mL

Median Tmax, hours

AUC0-6, μg·hours/mL

N= 6

5.94 ± 18.4

2 (1 to 4)

24.9 ± 17.4

N= 7

3.72 ± 39.1

4 (0.75 to 6)

14.2 ± 52.1

N= 5

4.13 ± 25.6

6 (3 to 6)

13.4 ± 24.6

N= 5

3.18 ± 25.6

6 (3 to 6)

10.3 ± 24.5

 

The mean Cmax was significantly higher for the IV route compared to the PO (p= 0.0004) or PR (p < 0.0001) routes. The mean CSFmax was significantly higher with the IV route than the PO (p < 0.0001) and PR (p < 0.0001) routes.

The IV group had a significantly shorter Tmax compared to the PO (p= 0.0018) and the PR (p= 0.0025) groups. The IV CSF Tmax was significantly shorter than the PR route (p= 0.0195).

The IV CSF AUC0-6 was significantly higher than PO (p= 0.0099) and PR (p= 0.0004). 

Adverse Events

 It was reported that three patients experienced 12 adverse events that were all mild to moderate in severity with headache being the most common, and it was determined that none of the events were treatment-related adverse events.

Study Author Conclusions

IV acetaminophen shows significantly better CNS penetration compared with PO or PR routes, and these results, in conjunction with the typical gastric stasis and poor oral absorption that occurs perioperatively because of fasting or opioid administration, may justify use of IV acetaminophen preoperatively through the immediate postoperative period.

InpharmD Researcher Critique

A 24-hour washout period between each dose was appropriate in helping to prevent confounding. However, the small sample size is a significant limitation of this study. Additionally, the men included in this study were healthy and were not allowed to receive concomitant medications, which is not generalizable to a population of patients in a hospital.



References:

Singla NK, Parulan C, Samson R, et al. Plasma and cerebrospinal fluid pharmacokinetic parameters after single-dose administration of intravenous, oral, or rectal acetaminophen. Pain Pract. 2012;12(7):523-532. doi:10.1111/j.1533-2500.2012.00556.x

Onset of acetaminophen analgesia: comparison of oral and intravenous routes after third molar surgery

Design

Randomized, double-blind, placebo-controlled trial 

N=175

Objective

To determine the time of analgesia onset after administering acetaminophen via bolus injection, IV, or oral, compared to placebo in patients receiving a third molar surgery with patients with moderate to severe pain 

Study Groups

IV Acetaminophen (n=50)

Oral Acetaminophen (n=50)

Bolus injectable acetaminophen (n=50)

Placebo (n=25)

Methods

Inclusion criteria: 18-50 years old, classified as ASA I-II, scheduled for removal of impacted mandibular third molar under local anesthesia, experiencing moderate to severe pain within 4 hours of surgery

Exclusion criteria: psychiatric or medical disorder that could affect compliance, history of lack of response to acetaminophen or ibuprofen, gastric or peptic ulcer disease, inflammatory bowel disease, blood coagulation abnormalities, pancreatic disease within the past 12 months, impaired liver function

In a triple-dummy fashion, patients were randomized into four parallel groups: 2 grams of acetaminophen as a 2 minute IV bolus; 2 grams as a 15 minute IV infusion; 1 gram of oral acetaminophen; or a placebo. Prilocaine 3% was also used for local anesthesia and a standard procedure was used for third molar surgery. 

Using the double click stopwatch method, researchers can measure the time onset of analgesia. Each patient had two watches placed by their bedside. When they felt the medication start to work, they stopped one watch. Then, they stopped the other watch when they were sure that the drug was working. Patients were given rescue analgesia if needed (ibuprofen 600 mg orally), but patients were requested to wait at least one hour before asking for it. 

Duration

Short-term follow-up: 6 hours after medication

Outcome Measures

 Primary Endpoint: Time to onset of analgesia

Secondary enpoints: pain relief, pain intensity, patients global evaulation and duration of analgesia

Baseline Characteristics

  

Bolus (n=50)

 Infusion (n=50)

Oral (n=50)

Placebo (n=25)

P-value

Age, years (range)

 25.6 (20-42)  24.2 (18-39) 24.4 (20-29) 23.4 (20–29) 0.024 

Male

 38% 46% 38%

44%

 0.806 

Baseline pain intensity level, score (0-100)

Mild

Moderate

Severe

59.9±14.9

4%

80%

16%

58.1±16.9

2%

80%

18%

58.2±17.4

2%

80%

18%

60.6±20.1

4%

76%

20%

0.894

0.997

 

 

Results

 

Bolus (n=50)

Infusion (n=50)

Oral (n=50)

Placebo (n=25)

 P-value 

Primary endpoint, minutes (95% CI)

Time to onset of analgesia

Time to a meaningful response

Time to rescue medication request

 

3 (2-3)

4 (3-5)

180 (121-237)

 

5 (4-7)

8 (6-13)

171 (138-525)

 

11 (7-19)

37 (24-44)

278 (178->360)

 

13 (3->120)

14 (8-?)

68 (60-90)

 

<0.001

<0.001

0.023

Secondary endpoints

Maximum pain relief score

Maxmium pain score difference 

 

2.66±1.02

39.86±19.35

 

2.70±0.86

39.55±18.25

 

2.64±1.17

39.70±24.18 

 

1.44±1.04

21.48±21.78

 

<0.001

<0.001

Adverse Events

Common Adverse Events: dizziness, nausea, malaise, and cold, clammy skin were more common among those receiving the I.V or injection rather than the oral and placebo groups. Injection site pains and reactions were also more commonly found in the infusion and even more so in the injection group than the oral or placebo.

Serious Adverse Events: 1 severe adverse event in the IV group (post-operative hemorrhage-not related to treatment)

Study Author Conclusions

IV acetaminophen, given as a 15-minute infusion, is a faster acting analgesic compared to oral administration. It is more effective for the onset of pain when comparing the two drug administration routes. The bolus injection had a quicker onset of action than the infusion, but it had more significant adverse reactions such as injection site pain/reactions.

InpharmD Researcher Critique

It should be noted that each group asked for rescue medication, the difference between each group amount of time it took to ask for the ibuprofen. Although the IV route was proven to be the better method in dealing with onset pain, oral acetaminophen was better when it came to the time difference between the meaningful pain relief and time to the breakthrough medication.

 

 
References:

Moller PL, Sindet-Pedersen S, Petersen CT, Juhl GI, Dillenschneider A, Skoglund LA. Onset of acetaminophen analgesia: comparison of oral and intravenous routes after third molar surgery. Br J Anaesth. 2005;94(5):642-648. doi:10.1093/bja/aei109

Study to Compare the Effect of Oral, Rectal, and Intravenous Infusion of Paracetamol for Postoperative Analgesia in Women Undergoing Cesarean Section Under Spinal Anesthesia

Design

Prospective, randomized, controlled study 

N=150

Objective

To compare the efficacy of oral, rectal, and intravenous acetaminophen in postoperative analgesia for a cesarean section

Study Groups

Oral Acetaminophen (n=50)

IV Acetaminophen (n=50)

Rectal Acetaminophen (n=50)

Methods

Inclusion criteria: women 18-35 years of age in ASA class I and II, scheduled for cesarean section under spinal anesthesia

Exclusion criteria: bleeding diathesis or coagulation disorders, those unable to rate their pain on pain scales used due to psychiatric or rother reasons; hepatic, renal, cardiovascular, or pulmonary disease; central or peripheral nervous system disease, chronic abdominal pain or on the treatment with analgesics and anticoagulants

Women were randomly assigned to three groups. The oral acetaminophen group received 650 mg 20 minutes before going into the operating room. The rectal acetaminophen group received a suppository of 35-45 mg/kg immediately after spinal anesthesia. The IV group received an infusion of 10-15 mg/kg over 15 minutes 20 minutes before the operation was finished.

Duration

 Up to 8 hours post-surgery

Outcome Measures

Primary Outcome: Duration of Analgesia

Secondary outcome: Time to first rescue analgesia, total dosage, and number of doses of rescue analgesia taken in 24 hours

Baseline Characteristics

  

Oral (n=50)

Rectal (n=50)

IV (n=50)

      

Age, years

 25.84±2.90 25.88±2.77   25.24±3.03      

ASA status

Grade I

Grade II

 

42 (84%)

8 (16%)

 

42 (84%)

8 (16%)

 

45 (90%)

5 (10%)

 

    

Results

  

Oral (n=50)

Rectal (n=50)

IV (n=50)

P-value oral vs rectal

 P-value oral vs IV

P-value rectal vs IV

Duration of analgesia

321.50±89.541

533.60±79.866

314.10±88.449

<0.001

0.903

<0.001

Time to first rescue analgesia, minutes

322.50±90.369

536.20±80.734

315.80±88.042

<0.001

0.829

 <0.001

Total dosage of rescue analgesia, mg

174.00±35.34

118.50±40.34

118.50±40.08

<0.001

0.829

<0.001

Total number of doses of rescue analgesia 

2.32±0.471

1.58±0.538

2.38±0.530

<0.001

0.921

<0.001

Adverse Events

Common Adverse Events: No significant adverse effects were noted in each group

Serious Adverse Events: No significant adverse effects were noted in each group

Study Author Conclusions

 Acetaminophen, when given rectally, improves the quality and duration of postoperative analgesia to a greater extent as compared to oral and intravenous route of acetaminophen without any side effects.

InpharmD Researcher Critique

 This study is limited to use in women after cesarean section, which may limit its external validity. The duration of follow-up is also relatively sure.

 

 
References:

Mahajan L, Mittal V, Gupta R, Chhabra H, Vidhan J, Kaur A. Study to Compare the Effect of Oral, Rectal, and Intravenous Infusion of Paracetamol for Postoperative Analgesia in Women Undergoing Cesarean Section Under Spinal Anesthesia. Anesth Essays Res. 2017;11(3):594-598. doi:10.4103/0259-1162.206872

A Randomized Study of the Efficacy and Safety of Intravenous Acetaminophen Compared to Oral Acetaminophen for the Treatment of Fever
Design

Randomized, double-blind, double-dummy, single-dose, parallel-group study

N=81
Objective

To assess the safety and dynamics of the onset of antipyretic efficacy of intravenous (IV) acetaminophen versus oral (PO) acetaminophen in the treatment of endotoxin-induced fever
Study Groups

PO acetaminophen (n=36)

IV acetaminophen (n=45)
Methods

Inclusion criteria: healthy males aged between 18-75 years old; BMI 19-45; no physical, mental, or medical conditions that the principle investigator (WS) deemed could have confounded study participation

Exclusion criteria:  treated with any medication having antipyretic effects within 2 days of clinic admission; known hypersensitivity or contraindication to receiving endotoxin, acetaminophen; known or suspected recent history of alcohol or drug dependence; history of nasal polyps, angioedema, or significant or actively treated bronchospastic disease; active infection or condition that might cause abnormal alterations in body temperature; or impaired liver function; females were excluded from study participation due to the known fetotoxic effects of endotoxin

After an overnight admission to ensure the subjects were afebrile, subjects were administered a test dose of IV reference standard endotoxin (1 ng/kg ) to verify the absence of a medically significant allergic or exaggerated systemic response. Subjects were then administered IV reference standard endotoxin 4 ng/kg. The threshold temperature for antipyretic administration was 38.6°C.

Once the threshold temperature was exceeded and it appeared that a peak fever response was present, subjects were randomized 1:1 to receive either IV acetaminophen 1 g (100 mL; given as a 15‐minute IV infusion) or PO acetaminophen 1 g.
Duration

Follow-up: up to 6 hours
Primary Outcome Measure The weighted sum of temperature differences from baseline at time 0 through 120 minutes
Baseline Characteristics  

PO (n = 36)

 IV (n = 45)
Age, years 32.1 ± 9.07 33.8 ± 11.60
Weight, lbs 191.9 ± 48.96 192.3 ± 38.65
Temperature prior to randomization, °C 38.7 ± 0.08 38.7 ± 0.06
Temperature prior to study drug administration, °C 38.8 ± 0.14 38.8 ± 0.13
Results

Statistically significant results favoring IV acetaminophen were observed for the primary endpoint (weighted sum of temperature differences over 120 minutes; P = 0.0039), although the maximum mean observed temperature difference was only 0.3°C. 
Adverse Events Common Adverse Events: Not reported
Study Author Conclusions

A single dose of IV acetaminophen is as safe and effective in reducing endotoxin‐induced fever as PO acetaminophen. IV acetaminophen may be useful where patients are unable to tolerate PO intake or when an earlier onset of action is desirable.
InpharmD Researcher Critique

The results of this study show a minimum clinical different between IV and PO acetaminophen for fever reduction. It is worth noting that 9/54 (17%) and 15/51 (29%) of the IV and PO groups were excluded due to vomiting <2 hours post-dose.

Other limitations of this study include only including healthy males in a simulated setting.

 

 
References:

Peacock WF, Breitmeyer JB, Pan C, Smith WB, Royal MA. A randomized study of the efficacy and safety of intravenous acetaminophen compared to oral acetaminophen for the treatment of fever. Acad Emerg Med. 2011;18(4):360-366.

Randomized controlled trial of duration of analgesia following intravenous or rectal acetaminophen after adenotonsillectomy in children

Design

Prospective, randomized, controlled trial 

N=46

Objective

To compare the duration and efficacy of analgesia after having an adenotonsillectomy after being given acetaminophen rectally or intravenously

Study Groups

Rectal acetaminophen (n=23)

IV acetaminophen (n=23)

Methods

Inclusion Criteria: 2-5 years old with an American Society of Anesthesiologists physical status of I-II, <30 kg, scheduled to undergo elective adenoidectomy or adenotonsillectomy

Exclusion Criteria: emergency surgery, history of seizures, history of chronic pain or analgesic use, neurological or neuromuscular disorders, history of active and severe renal, hepatic, respiratory, or cardiac disease

Patients were randomized to receive either 15 mg/kg of IV or 40 mg/kg of rectal acetaminophen. After surgery, the patient's vitals were monitored continuously. Pain intensity, emergence agitation, and Aldrete score was recorded every 10 minutes until a score <8 was achieved. Behavior after the operation was evaluated using a 4 point agitation scale.

Postoperative pain was also evaluated every 15 minutes in the recovery room, every 2 hours during the first 6 hours of surgery, and every 4 hours after that by the nursing staff using the Children and Infants Postoperative Pain Scale (CHIPPS). If CHIPPS score >4, the child could receive rescue analgesia as a bolus of fentanyl 0.5 µg/kg. After discharge, any child with a CHIPPS score >4 received acetaminophen 20 mg/kg rectally. After discharge home, the child's parents were contacted via telephone to assess comfort at home.

Duration

N/A

Outcome Measures

Primary outcome: The time to first rescue analgesia(defined as the time from tracheal extubation to the first request or indication of rescue medication due to a CHIPPS score >4)

Baseline Characteristics

  

Rectal acetaminophen (n=23)

IV acetaminophen (n=23)

  

Age, months 

 48.9±6.8 46.9±9.3  

Female

 12 (52%) 8 (35%)  

Weight, kg

 19±3 18±3  

Significant postoperative agitation

 8 (35%) 11 (48%)  

Surgery time, minutes

 17±8 22±12  

Wake-up time, minutes

 18±8 14±6  

Results

 

Rectal acetaminophen (n=23)

IV acetaminophen (n=23)

P-value 

The time to first rescue analgesia, hours (IQR)

 10 (9-11) 7 (6-10) 0.01

Few children needed rescue analgesia before 6 hours, but 98% of all children received a rescue bolus of fentanyl within 13 hours of surgery.

There was no difference between the IV group and rectal group when it came to discomfort at home (61% vs.78%; P=0.3).

Adverse Events

Postoperative agitation (35% vs 48%)

Study Author Conclusions

Rectal acetaminophen 40 mg/kg provided a longer duration of analgesia then IV acetaminophen 15 mg/kg in children for moderately painful procedures. 

InpharmD Researcher Critique

All children were given dexamethasone before surgery which provided some analgesic effect that could have confounded the results. Also, another confounding variable could be that an adenoidectomy is less painful than an adenotonsillectomy, but the study showed that no children required rescue medication during the first 6 hours after the adenoidectomy. 

 

 
References:

Capici F, Ingelmo PM, Davidson A, et al. Randomized controlled trial of duration of analgesia following intravenous or rectal acetaminophen after adenotonsillectomy in children. Br J Anaesth. 2008;100(2):251-255. doi:10.1093/bja/aem377