Pharmacotherapy for the Prevention of Chronic Pain after Surgery in Adults

An Updated Systematic Review and Meta-analysis

Meg E. Carley, B.Sc.; Luis E. Chaparro, M.D., F.R.C.P.C.; Manon Choinière, Ph.D.; Henrik Kehlet, M.D., Ph.D.; R. Andrew Moore, D.Sc.; Elizabeth Van Den Kerkhof, R.N., Dr.PH.; Ian Gilron, M.D., M.Sc.

Disclosures

Anesthesiology. 2021;135(2):304-325.

Abstract and Introduction

Abstract

Background: Chronic postsurgical pain can severely impair patient health and quality of life. This systematic review update evaluated the effectiveness of systemic drugs to prevent chronic postsurgical pain.

Methods: The authors included double-blind, placebo-controlled, randomized controlled trials including adults that evaluated perioperative systemic drugs. Studies that evaluated same drug(s) administered similarly were pooled. The primary outcome was the proportion reporting any pain at 3 or more months postsurgery.

Results: The authors identified 70 new studies and 40 from 2013. Most evaluated ketamine, pregabalin, gabapentin, IV lidocaine, nonsteroidal anti-inflammatory drugs, and corticosteroids. Some meta-analyses showed statistically significant—but of unclear clinical relevance—reductions in chronic postsurgical pain prevalence after treatment with pregabalin, IV lidocaine, and nonsteroidal anti-inflammatory drugs. Meta-analyses with more than three studies and more than 500 participants showed no effect of ketamine on prevalence of any pain at 6 months when administered for 24 h or less (risk ratio, 0.62 [95% CI, 0.36 to 1.07]; prevalence, 0 to 88% ketamine; 0 to 94% placebo) or more than 24 h (risk ratio, 0.91 [95% CI, 0.74 to 1.12]; 6 to 71% ketamine; 5 to 78% placebo), no effect of pregabalin on prevalence of any pain at 3 months (risk ratio, 0.88 [95% CI, 0.70 to 1.10]; 4 to 88% pregabalin; 3 to 80% placebo) or 6 months (risk ratio, 0.78 [95% CI, 0.47 to 1.28]; 6 to 68% pregabalin; 4 to 69% placebo) when administered more than 24 h, and an effect of pregabalin on prevalence of moderate/severe pain at 3 months when administered more than 24 h (risk ratio, 0.47 [95% CI, 0.33 to 0.68]; 0 to 20% pregabalin; 4 to 34% placebo). However, the results should be interpreted with caution given small study sizes, variable surgical types, dosages, timing and method of outcome measurements in relation to the acute pain trajectory in question, and preoperative pain status.

Conclusions: Despite agreement that chronic postsurgical pain is an important topic, extremely little progress has been made since 2013, likely due to study designs being insufficient to address the complexities of this multifactorial problem.

Introduction

Chronic postsurgical pain has been recognized as a disabling complication that can have a severe impact on patient health and quality of life, with pain that can sometimes last for a significant amount of time after surgery. On average, 10% of patients undergoing common surgical procedures will suffer from chronic pain.^[1–3] Given the difficulty in managing chronic postsurgical pain, many efforts to prevent the transition from acute to chronic pain have been evaluated, including perioperative administration of various systemic pharmacologic interventions. The aim of this review is to synthesize available evidence from placebo-controlled, randomized controlled trials on the effectiveness and safety of systemically administered drugs that aim to prevent the development of chronic postsurgical pain in adults undergoing elective surgeries. This systematic review is the first update of an original review we published in 2013^[4] and it will describe results of an updated search of new studies published since then. The rationale for updating the review is to provide the most current and best available evidence to inform clinical decision-making for this highly relevant issue.

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Table 1. Characteristics of Included Studies
Drug	Surgery	No. of Patients	Allowed Patients with Pain	Follow-up, mo	Preoperative Dose	Intraoperative Dose	Postoperative Dose	Cumulative Dose*	Study ID
Ketamine	Total knee arthroplasty	75	Yes	12	200 μg/kg	120 μg · kg^–1 h^–1	60 μg/kg for 48 h	3,305 μg/kg†	Aveline et al.,¹⁴ 2014 (new)
Ketamine	Cesarean	140	No	12	250 μg/kg	None	None	250 μg/kg	Bilgen et al., ¹⁵ 2012 (new)
					500 μg/kg	None	None	500 μg/kg
					1,000 μg/kg	None	None	1,000 μg/kg
Ketamine	Breast augmentation	106	No	12	420 μg/kg	200 μg · kg^–1 · h^–1	None	820 μg/kg†	Chaparro et al., ²⁸ 2010 (2013 review)
Ketamine	Thoracotomy	77	No	12	100 μg/kg	100 μg/kg for 96 h		9,700 μg/kg	Chumbley et al., ¹⁶ 2019 (new)
Ketamine	Breast	36	Long-term analgesic or anti-inflammatory treatment excluded	3	500 μg/kg	250 μg · kg^–1 · h^–1	None	908 μg/kg†	Crousier et al., ²⁹ 2008 (2013 review)
Ketamine	Major lower back	160	Yes	12	250 μg/kg	250 μg/kg for ~1 h; down to 100 μg/kg until end of postanesthesia care unit stay		900 μg/kg†	Czarnetzki et al., ²⁷ 2020 (new)
Ketamine	Rectal cancer	100	Unclear	12	250 μg/kg	125 μg · kg^–1 · h^–1	None	772 μg/kg†	De Kock et al., ³⁰ 2001 (2013 review)
Ketamine	Rectal cancer	100	Unclear	12	500 μg/kg	250 μg · kg^–1 · h^–1	None	1,595 μg/kg†	De Kock et al., ³⁰ 2001 (2013 review)
Ketamine	Thoracotomy	86	No	4	1,000 μg/kg	1,000 μg · kg^–1 · h^–1	1,000 μg/kg for 24h	3,000 μg/kg†	Duale et al., ³¹ 2009 (2013 review)
Ketamine	Orthopedic	120	Taking psychoactive drugs or opiates excluded	3	150 μg/kg	None	None	150 μg/kg	Dullenkopf et al., ³² 2009 (2013 review)
Ketamine	Orthopedic	120	Taking psychoactive drugs or opiates excluded	3	500 μg/kg	None	None	500 μg/kg	Dullenkopf et al., ³² 2009 (2013 review)
Ketamine	Amputation	45	Yes	6	500 μg/kg	150 μg/kg for 72 h		11,300 μg/kg	Hayes et al., ³³ 2004 (2013 review)
Ketamine	Thoracotomy	81	Taking neuropathic pain drugs, antidepressants, anticonvulsants, NSAIDs, or opioids excluded	6	1,000 μg/kg	120 μg/kg for 72 h		9,640 μg/kg	Hu et al., ¹⁷ 2014 (new)
Ketamine	Nephrectomy	63	No	3	150 μg/kg	100 μg · kg^–1 · h^–1	100 μg/kg for 24 h	22,350 μg/kg†	Jendoubi et al., ¹⁸ 2017 (new)
Ketamine	Thoracotomy	60	No	3	500 μg/kg	180 μg · kg^–1 · h^–1	90 μg/kg for 48 h	5,356 μg/kg†	Joseph et al., ¹⁹ 2012 (new)
Ketamine	Radical prostatectomy	160	Chronic opioid use excluded	6	200 μg/kg	175 μg/kg in 70 min	None	375 μg/kg	Katz et al., ³⁴ 2004 (2013 review)
Ketamine	Radical prostatectomy	160	Chronic opioid use excluded	6	None	200 + 175 μg/kg in 70 min	None	375 μg/kg	Katz et al., ³⁴ 2004 (2013 review)
Ketamine	Thyroidectomy	64	No	3	150 μg/kg	120 μg · kg^–1 · h^–1	None	472 μg/kg†	Lee et al., ²⁰ 2018 (new)
Ketamine	Breast	100	Unclear	6	None	1,000/day for 48 h		2,000 μg/kg	Malek et al., ³⁵ 2006 (2013 review)
Ketamine	Total hip arthroplasty	142	Taking corticosteroids or opioids excluded	3	500 μg/kg	3 μg · kg^–1 · h^–1	None	506 μg/kg†	Martinez et al., ²¹ 2014 (new)
Ketamine	Thoracotomy	66	Unclear	6	None	100 μg/kg for 60 h		6,000 μg/kg	Mendola et al., ²² 2012 (new)
Ketamine	Lumbar fusion	150	Yes	6	500 μg/kg	250 μg · kg^–1 · h^–1	None	1,042 μg/kg†	Nielsen et al., ^23,24 2017; 2019 (new)
Ketamine	Total knee arthroplasty	16	Taking >10 mg morphine equivalent excluded	6	500 μg/kg	240 μg · kg^–1 · h^–1	None	1,002 μg/kg†	Perrin et al., ³⁶ 2009 (2013 review)
Ketamine	Abdominal, thoracic, breast, or inguinal herniorrhaphy	80	No	6	500 μg/kg	250 μg · kg^–1 · h^–1	100 μg/kg for 24h	3,558 μg/kg†	Peyton et al., ²⁵ 2017 (new)
Ketamine	Total hip arthroplasty	160	Taking neuropathic pain drugs or >10 mg morphine equivalent excluded	6	500 μg/kg	120 μg/kg for 24 h		3,380 μg/kg†	Remerand et al., ³⁷ 2009 (2013 review)
Ketamine	Hysterectomy	60	No	6	300 μg/kg h^–1	50 μg · kg^–1 ·	None	363 μg/kg†	Sen et al., ³⁸ 2009 (2013 review)
Ketamine	Hemorrhoidectomy	83	Regular use of opioids excluded	3	350 μg/kg	300 μg · kg^–1 · h^–1	None	452 μg/kg†	Spreng et al., ³⁹ 2010 (2013 review)
Ketamine	Thoracotomy	50	Unclear	6	None	50 μg/kg for 72 h		3,600 μg/kg†	Suzuki et al., ⁴⁰ 2006 (2013 review)
Ketamine	Orthopedic	352	Taking opioids daily for >1 week excluded	6	None	None	1.5 mg‡	1,198 μg/kg§	Sveticic et al., ⁴¹ 2008 (2013 review)
Ketamine	Thoracotomy	125	No	6	500 μg/kg	None	250 μg/kg for 48 h	12,500 μg/kg	Tena et al., ²⁶ 2014 (new)
Pregabalin	Cardiac	150	No	6	150 mg	None	150 mg for 14 days	2,250 mg	Anwar et al., ⁴⁵ 2019 (new)
Pregabalin	Cardiac	101	No	3	75 mg	None	None	75 mg	Bouzia et al., ⁴⁶ 2017 (new)
Pregabalin	Cardiac	101	No	3	150 mg	None	None	150 mg	Bouzia et al., ⁴⁶ 2017 (new)
Pregabalin	Thoracotomy	114	No	3	300 mg	None	300 mg for 4 days	1,500 mg	Brulotte et al., ⁴⁷ 2015 (new)
Pregabalin	Spine	40	Yes	3	300 mg	None	300 mg for 1 day	600 mg	Burke et al., ⁶² 2010 (2013 review)
Pregabalin	Total knee arthroplasty	240	Yes	6	300 mg	None	300 mg for 10 days, 150 mg for 2 days, 100 mg for 2 days	3,800 mg	Buvanendran et al., ⁶³ 2010 (2013 review)
Pregabalin	Spine	120	Yes	6	150 mg	None	300 mg for 3.5 days	1,200 mg	Choi et al., ⁴⁸ 2013 (new)
Pregabalin	Total hip arthroplasty	184	Taking chronic pain medications, >10 mg morphine equivalent, or anticonvulsants excluded	3	150 mg	None	150 mg for 9 days\|\|	1,500 mg	Clarke et al., ⁶⁴ 2015 (new)
Pregabalin	Hysterectomy/myomectomy	80	No	3	450 mg	None	450 mg for 5 days	2,700 mg	Fassoulaki et al., ⁴⁹ 2012 (new)
Pregabalin	Spine	60	Taking opioids, sedatives, or anticonvulsants excluded	12	300 mg	None	300 mg for 2 days	900 mg	Gianesello et al., ⁶⁵ 2012 (2013 review)
Pregabalin	Cardiac	40	Taking anticonvulsants or antidepressants, or chronic analgesic use excluded	3	150 mg	None	150 mg for 2 days	450 mg	Joshi et al., ⁵⁰ 2013 (new)
Pregabalin	Breast	100	No	3	300 mg	None	150 mg for 9 days	1,650 mg	Khan et al., ⁵¹ 2019 (new)
Pregabalin	Spine	90	Yes	3	75 mg	None	225 mg for 7 days	1,650 mg	Khurana et al., ⁵² 2014 (new)
Pregabalin	Thyroidectomy	99	Taking pregabalin, gabapentin, or opioids excluded	3	150 mg	None	150 mg for 1 day	300 mg	Kim et al., ⁶⁶ 2010 (2013 review)
Pregabalin	Thoracotomy	100	No	9	300 mg	None	300 mg for 5 days	1,800 mg	Konstantatos et al., ⁵³ 2016 (new)
Pregabalin	Total hip arthroplasty	142	Taking corticosteroids or opioids excluded	3	150 mg	None	None	150 mg	Martinez et al., ²¹ 2014 (new)
Pregabalin	Nephrectomy	80	Taking analgesics or sedatives excluded	12	150 mg	None	450 mg for 1 day	600 mg	Myhre et al., ⁵⁴ 2017 (new)
Pregabalin	Cardiac	70	No	3	150 mg	None	150 mg for 5 days	900 mg	Pesonen et al., ⁶⁷ 2011 (2013 review)
Pregabalin	Breast	200	No	6	75 mg	None	150 mg for 7 days	1,125 mg	Reyad et al., ⁵⁵ 2019 (new)
Pregabalin	Brain tumor	100	Yes	3	300 mg	None	300 mg for 3 days	1,200 mg	Shimony et al., ⁵⁶ 2016 (new)
Pregabalin	Thoracotomy	45	No	3	150 mg	None	150 mg for 5 days	900 mg	Sidiropoulou et al., ⁵⁷ 2016 (new)
Pregabalin	Hysterectomy	501	Unclear	6	150 mg	None	150 mg for 28 days	4,350 mg	Singla et al., ⁵⁸ 2015 Post- Hysterectomy (new)
Pregabalin	Hysterectomy	501	Unclear	6	300 mg	None	300 mg for 28 days	8,550 mg	Singla et al., ⁵⁸ 2015 Post- Hysterectomy (new)
Pregabalin	Inguinal hernia repair	425	Unclear	6	50 mg	None	50 mg for 7 days	400 mg	Singla et al., ⁵⁸ 2015 Post-Inguinal hernia repair (new)
					150 mg	None	150 mg for 7 days	1,200 mg
					300 mg	None	300 mg for 7 days	2,400 mg
Pregabalin	Total knee arthroplasty	307	Unclear	6	150 mg	None	150 mg for 42 days	6,450 mg	Singla et al., ⁵⁸ 2015 Post-Total knee arthroplasty (new)
Pregabalin	Total knee arthroplasty	307	Unclear	6	300 mg	None	300 mg for 42 days	12,900 mg	Singla et al., ⁵⁸ 2015 Post-Total knee arthroplasty (new)
Pregabalin	Breast	80	Patients with chronic pain on analgesics or past/current use of gabapentinoids excluded	3	150 mg	None	150 mg for 7 days	1,200 mg	Vig et al., ⁶¹ 2019 (new)
Pregabalin	Total knee arthroplasty	120	Chronic use of gabapentin, pregabalin, or opioids excluded	3	100 mg	None	100 mg for 14 days, 50 mg for 2 days	1,600 mg	YaDeau et al., ⁵⁹ 2015 (new)
					200 mg	None	200 mg for 14 days, 100 mg for 2 days	3,200 mg
					300 mg	None	300 mg for 14 days, 150 mg for 2 days	4,800 mg
Pregabalin	Spine	105	Use of opioids, pregabalin, or gabapentin within past 2 weeks excluded	12	300 mg	None	300 mg for 1 days	600 mg	Zarei et al., ⁶⁰ 2016 (new)
Pregabalin	Spine	105		12	300 mg	None	300 mg for 14 days	4,500 mg	Zarei et al., ⁶⁰ 2016 (new)
Gabapentin	Breast	150	Taking antidepressants, anticonvulsants, NSAIDS, or opioids excluded	6	300 mg	None	300 mg for 9 days	3,000 mg	Amr et al., ⁷⁸ 2010 (2013 review)
Gabapentin	Thyroidectomy	50	No	6	1,200 mg	None	None	1,200 mg	Brogly et al., ⁷⁹ 2008 (2013 review)
Gabapentin	Total hip arthroplasty	126	Taking chronic pain medications excluded	6	600 mg	None	None	600 mg	Clarke et al., ⁸⁰ 2009 (2013 review)
Gabapentin	Total hip arthroplasty	126	Taking chronic pain medications excluded	6	None	None	600 mg	600 mg	Clarke et al., ⁸⁰ 2009 (2013 review)
Gabapentin	Total knee arthroplasty	179	Taking chronic pain medications excluded	3	600 mg	None	600 mg for 4 days	3,000 mg	Clarke et al., ⁷¹ 2014 (new)
Gabapentin	Breast	75	Taking analgesics, sedatives, hypnotics, or antidepressants excluded	3	1,200 mg	None	1,200 mg for 9 days	12,000 mg	Fassoulaki et al., ⁸¹ 2002 (2013 review)
Gabapentin	Thoracotomy	104	No	6	1,200 mg	None	600 mg for 1 day, 900 mg for 1 day, 12,00 mg for 3 days	6,300 mg	Grosen et al., ⁷² 2014 (new)
Gabapentin	Thoracotomy, total hip arthroplasty, total knee arthroplasty, or breast	422	Yes	24	1,200 mg	None	1,800 mg for 3 days	6,600 mg	Hah et al., ⁷³ 2018 (new)
Gabapentin	Spine	90	Yes	3	300 mg	None	900 mg for 7 days	6,600 mg	Khurana et al., ⁵² 2014 (new)
Gabapentin	Thoracotomy	146	No	3	600 mg	None	None	600 mg	Kinney et al., ⁸² 2011 (2013 review)
Gabapentin	Total knee arthroplasty	300	Taking gabapentinoids, antiepileptics, anxiolytics, antidepressants, systemic glucocorticoids, or opioids excluded	3–4 yr	900 mg	None	400 mg for 1 day, 1300 mg for 6 days	9,100 mg	KjaerPetersen et al., ⁷⁴ 2018 (new)
Gabapentin	Total knee arthroplasty	300		3–4 yr	600 mg	None	300 mg for 1 day, 900 mg for 6 days	6,300 mg	KjaerPetersen et al., ⁷⁴ 2018 (new)
Gabapentin	Caesarean	46	Taking analgesics in previous week excluded	3	600 mg	None	None	600 mg	Moore et al., ⁸³ 2011 (2013 review)
Gabapentin	Amputation	46	Yes	6	None	None	300 mg for 1 day, 900 mg for 3 days, 1,200 mg for 2 days, 1,500 mg for 2 days, 1,800 mg for 2 days, 2,100 mg for 2 days, 2,400 mg for 18 days	75,600 mg	Nikolajsen et al., ⁸⁴ 2006 (2013 review)
Gabapentin	Inguinal hernia repair	100	Yes	24	300 mg	None	600 mg for 1 day, 900 mg for 1 day	1,800 mg	Quail et al., ⁷⁵ 2017 (new)
Gabapentin	Carpal tunnel	40	Yes	6	600 mg	None	None	600 mg	Sadatsune et al., ⁷⁶ 2016 (new)
Gabapentin	Hysterectomy	60	No	6	1,200 mg	None	None	1,200 mg	Sen et al., ³⁸ 2009a (2013 review)
Gabapentin	Inguinal herniorrhaphy	60	Unclear	6	1,200 mg	None	None	1,200 mg	Sen et al., ⁸⁵ 2009 (2013 review)
Gabapentin	Cesarean	132	No	3	600 mg	None	None	600 mg	Short et al., ⁷⁷ 2012 (new)
Gabapentin	Cesarean	132	No	3	300 mg	None	None	300 mg	Short et al., ⁷⁷ 2012 (new)
Gabapentin	Cardiac	40	Taking analgesics excluded	6	1,200 mg	None	1,200 mg for 2 days	3,600 mg	Ucak et al., ⁸⁶ 2011 (2013 review)
IV lidocaine	Colectomy	95	No	6	60 mg	60 mg/h for 48 h		43.2 mg/kg†	Beaussier et al., ⁹⁰ 2018 (new)
IV lidocaine	Thyroidectomy	90	No	3	2 mg/kg	3 mg · kg^–1 · h^–1	None	9.4 mg/kg†	Choi et al., ⁹¹ 2017 (new)
IV lidocaine	Breast	36	No	3	1.5 mg/kg	1.5 mg · kg^–1 · h^–1	1.5 mg/kg for 1 h	4.5 mg/kg†	Grigoras et al., ⁹⁷ 2012 (2013 review)
IV lidocaine	Spine	44	Chronic opioid use excluded	3	2 mg/kg	3 mg · kg^–1 · h^–1	None	7.4 mg/kg†	Ibrahim et al., ⁹² 2018 (new)
IV lidocaine	Nephrectomy	63	No	3	1.5 mg/kg	1 mg · kg^–1 · h^–1	1 mg/kg for 24 h	27.8 mg/kg†	Jendoubi et al., ¹⁸ 2017 (new)
IV lidocaine	Breast	150	No	6	1.5 mg/kg	2 mg · kg^–1 · h^–1	None	8.1 mg/kg†	Kendall et al., ⁹³ 2018 (new)
IV lidocaine	Breast	100	No	3	1.5 mg/kg	2 mg · kg^–1 · h^–1	None	5.1 mg/kg†	Khan et al., ⁵¹ 2019 (new)
IV lidocaine	Breast	126	No	3	2 mg/kg	2 mg · kg^–1 · h^–1	None	6.3 mg/kg†	Kim et al., ⁹⁴ 2017 (new)
IV lidocaine	Total hip arthroplasty	60	Taking corticosteroids or opioids excluded	3	1.5 mg/kg	1.5 mg · kg^–1 · h^–1	1.5 mg/kg for 1h	6.8 mg/kg†	Martin et al., ⁹⁵ 2008 (new)
IV lidocaine	Breast	80	No	6	1.5 mg/kg	2 mg · kg^–1 · h^–1	2 mg/kg for 2 h	11.1 mg/kg†	Terkawi et al., ⁹⁶ 2015 (new)
Parecoxib	Thoracotomy	86	No	12	40 mg	None	80 mg for 2.5 days	240 mg	Ling et al., ¹⁰³ 2016 (new)
Parecoxib	Breast augmentation	219	Chronic analgesic use excluded	12	40 mg	None	None	40 mg	Romundstad et al., ¹⁰⁷ 2006 (2013 review)
Ibuprofen	Total hip arthroplasty	902	Taking NSAIDs within 48 h excluded	6–12	None	None	1,200 mg for 14 days	16,800 mg	Fransen et al., ¹⁰⁵ 2006 (2013 review)
Ibuprofen	Breast	30	Chronic use of aspirin or NSAIDs excluded	6	400 mg	None	1,600 mg for 2 days	2,000 mg	Lakdja et al., ¹⁰⁶ 1997 (2013 review)
Celecoxib	Total knee arthroplasty	107	Taking narcotics daily excluded	12	None	None	400 mg for 42 days	16,800 mg	Schroer et al., ¹⁰⁰ 2011 (new)
Dexketoprofen	Thoracotomy	60	Unclear	6	50 mg	None	50 mg	100 mg	Comez et al., ¹⁰¹ 2015 (new)
Flurbiprofen axetil	Breast	60	No	12	50 mg	None	50 mg	100 mg	Sun et al., ¹⁰² 2013 (new)
Parecoxib	Breast	138	No	12	40 mg	None	40 mg	80 mg	van Helmond et al., ¹⁰⁴ 2016 (new)
Celecoxib					None	None	200 mg for 5 days	1,000 mg
Dexamethasone	Total hip arthroplasty	50	Yes	12	40 mg	None	None	40 mg	Bergeron et al., ¹¹² 2009 (2013 review)
Dexamethasone	Spine	160	Taking steroids or strong opioids excluded	12	16 mg	None	None	16 mg	Nielsen et al., ^109,110 2015; 2016 (new)
Dexamethasone	Spine	112	Yes	24	0.2 mg/kg	None	4 doses of 0.06 mg/kg	0.44 mg/kg	Jeyamohan et al., ¹⁰⁸ 2015 (new)
Hydrocortisone	Cardiac	36	Unclear	6	100 mg	240 mg for 1 day, 120 mg for 1 day, 60 mg for 1 day, 30 mg for 1 day		550 mg	Weis et al., ¹¹³ 2006 (2013 review)
Methylprednisolone	Breast augmentation	219	Chronic analgesic use excluded	12	125 mg	None	None	125 mg	Romundstad et al., ¹⁰⁷ 2006 (2013 review)
Methylprednisolone	Cardiac	1,043	Yes	6	500 mg	None	None	500 mg	Turan et al., ¹¹¹ 2015 (new)
Acetaminophen	Hysterectomy	140	No	3	None	None	4,000 mg for 3 days	12,000 mg	Koyuncu et al., ¹¹⁴ 2018 (new)
Acetaminophen	Cardiac	150	No	3	None	None	4,000 mg for 1 day	4,000 mg	Turan et al., ¹¹⁵ 2017 (new)
Amantadine	Breast	22	No	6	200 mg	None	200 mg for 13 days	2,800 mg	Eisenberg et al., ¹¹⁶ 2007 (2013 review)
Amantadine	Mandibular fracture	60	Opioid use or dependency excluded	6	100 mg	None	None	100 mg	Yazdani et al., ¹¹⁷ 2016 (new)
Dexmedetomidine	Hysterectomy	80	No	12	0.5 μg · kg^–1 · h^–1		N/A	0.70 μg/kg	Han et al., ¹¹⁸ 2019 (new)
Dextromethorphan	Hysterectomy	50	No	3	750 mg	None	None	750 mg	Ilkjaer et al., ¹¹⁹ 2000 (2013 review)
Duloxetine	Spine	101	Yes	3	30 mg for 5 days, 60 mg for 9 days	None	60 mg for 81 days	5,550 mg	Hyer et al., ¹²⁰ 2015 (new)
Duloxetine	Total knee arthroplasty	106	Chronic use of gabapentin, pregabalin, or opioids excluded	3	60 mg	None	60 mg for 14 days	900 mg	YaDeau et al., ¹²¹ 2016 (new)
Etanercept	Inguinal herniorrhaphy	77	Yes	12	50 mg	None	None	50 mg	Cohen et al., ¹²² 2013 (new)
Fentanyl	Amputation	65	Yes	6	58.3 μg/h	54.5 μg/h for 2 days		Variable	Karanikolas et al., ¹²³ 2011 (2013 review)
Magnesium	Breast	126	No	3	20 mg/kg + 20 mg · kg^–1 · h^–1		63.2 mg/kg	Intraoperative	Kim et al., ⁹⁴ 2017 (new)
Memantine	Amputation	19	Yes	12	None	None	10 mg for 7 days, 20 mg for 7 days, 30 mg for 14 days	630 mg	Schley et al., ¹²⁴ 2007 (2013 review)
Mexiletine	Breast	100	Taking analgesics, sedatives, or antidepressants excluded	3	200 mg	None	400 mg for 6 days	2,600 mg	Fassoulaki et al., ¹²⁵ 2001 (2013 review)
Mexiletine	Breast	75	Taking analgesics, sedatives, hypnotics, or antidepressants excluded	3	200 mg	None	600 mg for 10 days	6,200 mg	Fassoulaki et al., ⁸¹ 2002 (2013 review)
Minocycline	Carpal Tunnel	131	Yes	12	200 mg	None	200 mg for 5 days	1,200 mg	Curtin et al., ¹²⁷ 2017 (new)
Minocycline	Spine	100	Yes	3	200 mg	None	200 mg for 8 days	1,800 mg	Martinez et al., ¹²⁶ 2013 (new)
Nefopam	Total knee arthroplasty	75	Yes	12	0.2 mg/kg	120 μg · kg^–1 · h^–1	60 μg · kg^–1 · h^–1 for 2 days	3,128 μg/kg	Aveline et al., ¹⁴ 2014 (new)
Nefopam	Thyroidectomy	58	Chronic use of opioids or any analgesic drugs >2 weeks excluded	3	0.2 mg/kg + 120 μg · kg^–1 · h^–1		None	520 μg/kg	Kim et al., ¹³⁰ 2018 (new)
Nefopam	Breast	94	Taking any kind of analgesic excluded	3	20 mg	None	None	20 mg	Na et al., ¹²⁸ 2016 (new)
Nitrous oxide	Numerous	2,050	Unclear	54	Intraoperative 70%		None	Intraoperative	Chan et al., ¹³² 2011 (2013 review)
Nitrous oxide	Numerous	3,325	Yes	12	Intraoperative 70%		None	Intraoperative	Chan et al., ¹³¹ 2016 (new)
Valproic acid	Amputation	128	Yes	3	250 mg	None	750 mg for 3.7 days	2,775 mg	Buchheit et al., ¹³³ 2019 (new)
Venlafaxine	Breast surgery	150	Taking antidepressants, anticonvulsants, NSAIDs, opioids excluded	6	37.5 mg	None	37.5 mg for 9 days	375 mg	Amr et al., ⁷⁸ 2010 (2013 review)
Vitamin C	Spinal fusion	123	Yes	12	None	Not reported	Not reported for 45 days	Not reported	Lee et al., ¹³⁴ 2017 (new)

*Cumulative doses have been estimated for comparative purposes only. †Calculation based on reported anesthesia duration. ‡1.5 mg of ketamine per each patient-controlled analgesia opioid bolus. §Calculation based on ketamine consumption and timing of administration. ||Duration of hospital stay postsurgery estimated at 2 days.
IV, intravenous; NSAID, nonsteroidal anti-inflammatory drug.