Paracetamol for Multimodal Analgesia

Figures & data

Table 1. Interactions of paracetamol with other analgesics in experimental pain models.

Study, year	Species	Pain test	Drug	Drug class	Interaction	Opioid antagonism
Nociceptive pain
Cabañero and Maldonado, 2021	Mouse	Incision test	Nefopam	Monoamine reuptake inhibitor/glutamate modulator	Synergistic	NT
Dai, 2021	Mouse	Writhing test	Matrine	Opioid	Synergistic	NT
Girard, 2011	Mouse	Writhing test Formalin test	Nefopam	Monoamine reuptake inhibitor/glutamate modulator	Synergistic Additive Synergistic	NT
	Rat	Incision test Carrageenan test
Janovsky and Krsiak, 2011	Mouse	Writhing test	Codeine	Opioid	Synergistic	NT
Li, 2021	Rat	Carrageenan test	Rotigonine	Dopamine agonist	Synergistic	NT
Miranda, 2006	Mouse	Writhing test	Diclofenac Ibuprofen Ketoprofen Meloxicam Metamizol Naproxen Nimesulide Parecoxib Piroxicam	NSAID	Synergistic	No
Miranda, 2021	Mouse	Writhing test	Tramadol	Opioid/monoamine reuptake inhibitor	Synergistic	NT
Sandrini, 2001	Mouse	Formalin test	Morphine	Opioid	Synergistic	Yes
Tomic, 2021	Mouse	Writhing test	Oxcarbazepine	Sodium channel blocker	Synergistic	NT
	Rat	Carrageenan test
Mititelu-Tartau, 2015	Mouse	Tail flick test Writhing test	Pregabalin	Gabapentinoid	Synergistic	NT
Yoshizawa, 2020	Mouse	Freund’s adjuvant	Tramadol	Opioid/Monoamine reuptake inhibitor	Synergistic	Yes
Zapata-Morales, 2018	Mouse	Formalin test	Tapentadol	Opioid/Norepinephrine reuptake inhibitor	Additive Synergistic	Yes
Neuropathic pain
Déciga-Campos and Ortíz-Andrade, 2015	Rat	Streptozotocin diabetes/acetone test/formalin test	N-palmitoylethanolamide	Nuclear factor agonist/ Cyclo-oxygenase inhibitor	Synergistic	NT
Garrido-Suarez, 2021	Rat	Chronic constriction nerve injury/formalin test	Amtryptiline	Monoamine reuptake inhibitor	Synergistic	NT
Gong, 2011	Rat	Streptozotocin diabetes/von Frey test/tail-flick test	Tramadol	Opioid/monoamine reuptake inhibitor	Additive Synergistic
Li, 2021	Rat	Carrageenan test	Rotigonine	Dopamine agonist	Synergistic	NT
Sato, 2020	Rat	Nucleus polposus radicular apposition/von Frey test	Tramadol	Opioid/monoamine reuptake inhibitor	Additive	NT
Shinozaki, 2015	Rat	Tibial neuroma transposition/carrageenan test	Tramadol	Opioid/monoamine reuptake inhibitor	Synergistic	Yes

NT: Not tested.

Table 2. Comparative analgesic efficacy of intravenous and per os paracetamol.

Study, year	Population	Study	Patient number	Outcome
Antill, 2020	Elderly rib fracture	RCT	138	IV = PO: pNRS, ICU LOS
Furyk, 2018	Acute pain	RCT	87	IV = PO: pVAS, MMEs, ED LOS
Charlton, 2020	Abdominal and trauma pain	RETRO	80	IV >PO: pNRS
Furyk, 2018	Acute pain	RCT	87	IV = PO: pVAS, MMEs, LOS
Hansen, 2018	Cholecystectomy	RETRO	61,017	IV >PO: H LOS, costs, MMEs, PONV
Johnson, 2019	Cholecystectomy	RETRO	579	IV = PO: pNRS, MMEs
Marcotte, 2020	Colorectal resection	RETRO	91	IV = PO: pVAS IV >PO: MMEs
Plunkett, 2017	Cholecystectomy	RCT	60	IV = PO: SPID24, MMEs
Wasserman, 2018	Colectomy	RETRO	181,640	IV = PO: MMEs; PO >IV on POD1
Bhoja, 2020	Sinus surgery	RCT	110	IV = PO: pVAS MMEs
Cain, 2020	Gynecologic oncology surgery	RETRO	353	IV = PO: MMEs
Hansen, 2018	Hysterectomy	RETRO	22,828	IV >PO: H LOS
Kor, 2020	Cystoscopy	RETRO	3566	IV = PO: pNRS; PO > IV, MMEs, PONV
Lombardi, 2020	Laparoscopic hysterectomy:	RCT	74	IV = PO: pNRS, MMEs
Wilson, 2019	Cesarean delivery	RCT	141	IV = PO: pVAS, sVAS, MMEs
Hickman, 2018	Total hip/knee arthroplasty	RCT	486	IV = PO: pVAS, MMEs, PACU LOS, H LOS
O’Neal, 2017	Total knee arthroplasty	RCT	174	NO effect of APAP
Pettersson, 2005	Coronary artery bypass graft	RCT	80	IV = PO: pVAS; PO > IV: MMEs
Politi, 2017	Total hip/knee arthroplasty	RCT	120	IV = PO: pVAS, MMEs
Stundner, 2019	Total hip/knee arthroplasty	RETRO	1,039,647	IV = PO
Suarez, 2018	Total knee arthroplasty	RCT	–	IV = PO: pVAS, MMEs
Westrich, 2019	Total hip arthroplasty	RCT	154	IV = PO: pNRS, MMEs, AEs
Wasserman, 2018	Colectomy	RETRO	181,640	IV = PO: MMEs, PO > IV on POD1

AE: Adverse event; ED: Emergency department; H: Hospital; ICU: Intensive care unit; IV: Intravenous; LOS: Length of stay; MME: Morphine milligram equivalent, opioid consumption; PACU: Post-anesthesia care unit; pNRS: Pain Numerical Rating Scale; PO: per os; POD1: Postoperative day 1; PONV: Postoperative nausea and vomiting; pVAS: Pain Visual Analogue Scale; RCT: Randomized controlled trial; RETRO: Retrospective study; sVAS: Satisfaction Visual Analogue Scale; SPID₂₄: 24-h postoperative sum of pain intensity difference.

Table 3. Analgesic efficacy of paracetamol for multimodal analgesia.

Study, year	Population, time to outcome	Study	Patient number, groups	Treatment doses (mg)	Doses/timing	Outcome
Bondarsky, 2013	Acute musculoskeletal pain, 1 h	RCT	90, 3	IBU 800/ APAP 1000/ IBU 800-APAP 1000	1	No difference
Chang, 2017	Acute extremity pain, 2 h	RCT	411, 4	APAP 1000-IBU 400/ APAP 325-OXY 5/ APAP 300-HYDRO 5/ APAP 300-COD 30	1	No difference
Friedman, 2021	Acute musculoskeletal pain, 2 h	RCT	393, 2	APAP650/ OXY10-APAP 650	1	OXY10-APAP650 >APA650: pNRS OXY 10-APAP 650 <APAP 650: AEs
Gong, 2019	Acute musculoskeletal pain, 1 h	RCT	118, 2	APAP 1000/ APAP 1000-IBU 400-COD 60	1	No difference
Aweke, 2020	Abdominal surgery, 24 h	RCT	63, 3	PreOp PO APAP 1000/ PreOp PO APAP 1000 – IM DICL 75/ PreOP PO APAP 1000 – IV TRAM 100	1	PO APAP- IV TRAM >PO APAP: pNRS, MMEs PO APAP – IM DICL >PO APAP: pNRS. MMEs
Petrikovets, 2019	Pelvic surgery, 24 h	RCT	63, 2	PostOp PO APAP 1000- IV TOR 20-IV HYDRO/ PostOp PO APAP 1000 - PO APAP- PO OXY 5/325 IV HYDRO 0,2	Q6H	AC >PRN: pVAS, sVAS
Reagan, 2017	Pelvic surgery, 7 days	RCT	138, 2	UC/ PreOp-PostOp CELEC-GBP IntraOp-PostOP APAP PRN IBU-NARC	–	MMA >UC: MME
Dinis, 2020	Cesarean section, 4 weeks	RCT	170, 2	APAP 325 - 650 - IBU 600/ APAP 325 - HYDRO 5	Q4–6H Q4H	APAP-IBU >APAP-HYDRO: pNRS
Durmus, 2007	Abdominal hysterectomy, 24 h	RCT	75, 3	PLACEBO/ GPN 1200/ GPN 1200 – APAP 20 mg/kg		GPN-APAP >GPN >PLACEBO: pVAS, MMEs
Daniels, 2019	Bunionectomy, 48 h	RCT	276, 4	PLACEBO/ IBU 300/ APAP 1000/ APAP 1000 – IBU 300	Q6H	APAP 1000 – IBU 300>PLACEBO, IBU 300, APAP 1000: SPID48, MMEs
Gupta, 2016	THA-TKA, 5 days	RCT	76, 2	APAP 1000 – IBU 800/ IBU 800	Q6H	APAP 1000 – IBU 800 >IBU 800: pVAS
Murata-Ooiwa, 2017	TKA, 24 h	RCT	67, 2	APAP 1000/ PLACEBO	Q6H	APAP >PLACEBO: pVAS
Singh, 2021	RCR, 7 days	RCT	57, 3	PostOp APAP 1000 – OXY 5/ PostOp OXY 5/ PreOp- PostOp APAP 1000 OXY 5	Q6H PRN	Preop-postop APAP >preop APAP: pNRS, MME
Takeda, 2019	THA, 24 h	RCT	97, 2	PCA-FENT-PostOp APAP 1000/ PCA-FENT	–	PostOp APAP >PCA-FENT: pNRS
Thybo, 2019	THA, 24 h	RCT	556, 4	APAP 1000 – IBU 400/ APAP 1000 – PLACEBO/ IBU 400 – PLACEBO/ APAP 500 – IBU 200	Q6H	APAP 1000 – IBU 400 >APAP 1000: pVAS APAP 1000 – IBU 400 = IBU 400: pVAS
Atkinson, 2015	TME, 24 h	RCT	159, 4	PLACEBO/ APAP 250/IBU 75/ APAP 500/IBU 150/ APAP 1000/IBU 300	Q6H	Dose effect: SPID 24
Daniels, 2011	TME, 12 h	RCT	669, 5	PLACEBO/ APAP 500/IBU 200/ APAP 500/IBU 400/ APAP 500/COD 15/ IBU 200/COD 12.2	1	APAP 500/IBU 200 highly effective: pVAS
Kellstein and Leyva, 2020	TME, 12 h	RCT	394, 5	PLACEBO/ IBU 400/ IBU 200/APAP 500/ IBU 250/APAP 500/ IBU 300/APAP 500	1	IBU/APAP >PLACEBO on SPRID0–8 IBU/APAP = IBU on SPRID0–8
Mehlisch, 2010	TME, 8 h	RCT	678, 8	PLACEBO/ IBU 200/ IBU 400/ APAP 500/ APAP 1000/ IBU 100/APAP 250/ IBU 200/APAP 500/ IBU 400/APAP 1000	1	IBU 200–400/APAP 500–1000 > PLACEBO, IBU, APAP on SPRID0–8
Searle, 2020	TME, 12 h	RCT	568, 4	PLACEBO/ APAP 650/ IBU 250/ APAP 500 - IBU 250	1	APAP 500-IBU 250 >IBU 250, APAP 650, PLACEBO: pNRS
Pereira, 2017	Keratectomy, 72 h	RCT	80	PLACEBO/ APAP 500/COD 30	Q4H	APAP 500/COD 30 >PLACEBO: pNRS
Doherty, 2011	Chronic knee pain, 13 weeks	RCT	892	IBU 400/ APAP 1000/ IBU 200-APAP 500/ IBU 400-APAP 1000	Q8H	IBU 200-APAP 500, IBU 400-APAP 1000 >IBU: WOMAC >APAP: WOMAC
Mullican, 2001	Chronic pain, 4 weeks		462	APAP 300/COD 30/ APAP 325/TRAM 37.5	–	APAP 300/COD 30 = APAP 325/TRAM 37.5: PR

AE: Adverse event; APAP: N-acetyl-para-aminophenol, paracetamol; COD: Codeine; DICL: Diclofenac; FENT: Fentanyl; GPN: Gabapentin; HYDRO: Hydromorphone; IBU: Ibuprofen; IV: Intravenous; MED: Morphine equivalent dosing; MME: Morphine milligram equivalent; OXY: Oxycodone; pNRS: Pain Numerical Rating Scale; PACU: Post-anesthesia care unit; PreOP: Preoperative; PR: Pain relief; PRN: Pro re nata; pVAS: Pain Visual Analog Scale; Q2H Q6H Q8H: Quaque secunda sixta octa hora, every 2, 6, 8 h; RCR: Rotator cuff repair; RCT: Randomized controlled trial; sVAS: Satisfaction Visual Analogue Scale; SPID _{24 48}: 24–48 h postoperative sum of pain intensity difference; SPRID_0–8: Sum of pain relief and pain intensity difference scores from 0 to 8 hTHA, total hip arthroplasty; TKA: Total knee arthroplasty; TME: Third molar extraction; TRAM: Tramadol; UC: Usual care; WOMAC: Western Ontario and McMaster University.