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. 

In This Article

Results

The search identified 6,709 citations, with first level screening based on title and abstract yielding 115 studies for full text review, of which 70 new studies fulfilled the inclusion criteria (Figure 1). The majority of the 45 excluded studies did not follow participants for at least 3 months (n = 15), were not placebo controlled (n = 9), were not double-blinded (n = 7), were not relevant to the prevention of chronic postsurgical pain (n = 6), or did not evaluate drugs administered systemically (n = 4). Full details regarding the excluded studies are summarized in Supplemental Digital Content 2 (appendix B, http://links.lww.com/ALN/C629). Our trial database searches yielded 46 ongoing and unpublished studies. Ongoing studies are evaluating ketamine (n = 12), pregabalin (n = 11), IV lidocaine (n = 8), dexamethasone (n = 4), gabapentin (n = 3), dexmedetomidine (n = 2), magnesium (n = 2), acetyl-salicylic acid (n = 1), cannabinoids (n = 1), clonidine (n = 1), duloxetine (n = 1), lamotrigine (n = 1), meloxicam (n = 1), midazolam (n = 1), propranolol (n = 1), sevoflurane (n = 1), and tramadol-paracetamol (n = 1). A summary of the 46 ongoing studies is included in Supplemental Digital Content 3 (appendix C, http://links.lww.com/ALN/C630).

Figure 1.

Study flow diagram.

Characteristics of Included Studies

Characteristics of the 110 included studies (70 new plus 40 from the previous review)[4] are summarized in Table 1 and Supplemental Digital Content 4 (appendix D, http://links.lww.com/ALN/C631). Studies (new and from previous review) involved various surgeries including breast (n = 19), total hip or knee arthroplasty (n = 16), thoracotomy (n = 14), spine (n = 14), abdominal or pelvic (n = 12), heart (n = 8), limb amputation (n = 5), thyroidectomy (n = 5), inguinal herniorrhaphy (n = 4), caesarean section (n = 3), carpal tunnel (n = 2), brain (n = 1), mandibular fracture (n = 1), and a combination of surgeries (n = 6) (Table 1).

Of all the new and previous studies, only 37 studies included patients that were free of pain before surgery. Patients taking various analgesics were excluded from 36 trials. Preoperative pain or analgesic use was unclear in 11 studies. Patients with preexisting pain were included in 26 studies (Table 1).

Studies received financial support from research granting agencies (n = 28), institutional and/or departmental sources (n = 18), pharmaceutical companies (n = 10), and granting agencies and pharmaceutical companies (n = 1); 10 studies stated that no funding was received; and the source of funding was not reported for 43 studies (Supplemental Digital Content 4, appendix D, http://links.lww.com/ALN/C631). Insufficient reporting prohibits further investigation of possible correlations between sources of financial support and study outcomes and it is beyond the scope and preplanned objectives of the current review. Seventy-nine of 110 (71.8%) included studies had at least four of seven items that qualified as low risk of bias (Supplemental Digital Content 5, appendix E, http://links.lww.com/ALN/C632). Most studies were of small sample size having fewer than 50 participants per arm (n = 70 [64%]), greater than or equal to 50 and fewer than 100 per arm (n = 29 [26%]), and greater than or equal to 100 per arm (n = 11 [10%]).

Ketamine

Thirteen new studies (n = 1,283 participants)[14–27] evaluated ketamine or (S)-ketamine (total, 27 studies; n = 2,757).[14–41] Nine of 27 studies reported prevalence of any pain at 3 months,[16,20,22,26,29,37,39–41] 16 studies at 6 months,[14–17,22,24–26,30,33–37,40,41] and five studies at 12 months.[14–16,28,30] Prevalence of any pain at 3 months ranged from 5.6 to 72.2% (mean, 35.0%) in the placebo arm and 5.6 to 83.3% (mean, 31.5%) in the ketamine arm. No treatment effect of ketamine was observed on prevalence of any pain regardless of outcome timing, duration of drug administration, or surgical procedure (Figure 2). Forest plots for studies evaluating ketamine are included in Supplemental Digital Content 6 (appendix F, http://links.lww.com/ALN/C633). In 2013, subgroup analysis based on duration of treatment suggested a significant effect of ketamine compared to placebo (odds ratio, 0.37 [95% CI, 0.14 to 0.98]; two studies; 135 participants) on the prevalence of any pain at 3 months for studies evaluating ketamine treatment for more than 24 h; however, the current review did not demonstrate a similar treatment effect (risk ratio, 0.83 [95% CI, 0.58 to 1.18]; five studies; 331 participants).

Figure 2.

Summary of ketamine meta-analyses. Data are presented as the pooled results for each outcome. Drug ≤ 24 h indicates drugs were administered for 24 h or less; drug > 24 h indicates drugs were administered for longer than 24 h.

Two studies reported prevalence of moderate to severe pain at 3 months (placebo: range, 14.7 to 16.7%; mean, 15.7; ketamine: range, 9.1 to 32.3%; mean 20.7),[16,22] six studies at 6 months (placebo: range, 0.0 to 39.1%; mean, 17.9; ketamine: range, 3.2 to 26.7%; mean, 12.2),[14,16,22,33,35,37] and two studies at 12 months (placebo: range, 7.1 to 26.1%; mean, 16.6; ketamine: range, 0.0 to 12.5%; mean, 6.3).[14,16] No treatment effect of ketamine was observed on prevalence of moderate to severe pain regardless of outcome timing, duration of drug administration, or surgical procedure (Figure 2). Only two of the 27 ketamine studies provided data regarding dropouts due to treatment-related adverse effects. Of those, 4 of 70 (5.7%) received ketamine and 4 of 70 (5.7%) received placebo. Adverse events included hallucinations, delayed emergence, dizziness, diplopia, and confusion.[19,25]

Ketamine has been evaluated in three recent reviews for orthopedic surgery,[42,43] and thoracotomy.[44] Consistent with the current review, the majority (two of three) indicated results to be inconclusive.[43,44] In disagreement, one narrative systematic review evaluating various interventions for adults receiving primary total knee arthroplasty concluded a treatment effect of ketamine claiming "good-quality evidence for a small benefit";[42] however, their conclusion was based on one small randomized controlled trial.[14]

Pregabalin

Twenty-one new studies (n = 3,184)[21,45–61] evaluated pregabalin (total, 26 studies; n = 3,693).[21,45–67] Nineteen of 26 studies reported prevalence of any pain at 3 months,[21,45,47–51,53,57,58,61–63,65–67] six studies at 6 months,[45,48,54,58,63] and two studies at 12 months.[54,65] Prevalence of any pain at 3 months ranged from 3.1 to 80.0% (mean, 39.5%) in the placebo arm and 3.7 to 88.0% (mean, 31.9%) in the pregabalin arm. Subgroup analyses resulted in a statistically significant treatment effect of pregabalin 3 months after cardiac surgery (three trials; risk ratio, 0.25 [95% CI, 0.13 to 0.50]), and 3 months after total knee arthroplasty (three trials; risk ratio, 0.75 [95% CI, 0.58 to 0.97]). No treatment effects were observed for any pain evaluated at 3, 6, or 12 months when drug administration was for 24 h or less or more than 24 h or for other types of surgical procedures (Figure 3). Forest plots for studies evaluating pregabalin are included in Supplemental Digital Content 7 (appendix G, http://links.lww.com/ALN/C634). In 2013, only one study evaluated the prevalence of any pain at 6 months therefore no subgroup analyses were performed; in the current review, six studies were included in meta-analysis and did not demonstrate a treatment effect of pregabalin when drugs were administered for more than 24 h (risk ratio, 0.78 [95% CI, 0.47 to 1.28]).

Figure 3.

Summary of gabapentinoid meta-analyses. Data are presented as the pooled results for each outcome. Drug ≤ 24 h indicates drugs were administered for 24 h or less; drug > 24 h indicates drugs were administered for longer than 24 h.

Nine studies reported prevalence of moderate to severe pain at 3 months (placebo: range, 4.2 to 34.0%; mean, 20.2; pregabalin: range, 0.0 to 20.0%; mean, 8.7),[45,47,48,51,53,57,59,61,63] and three studies at 6 months (placebo: range, 11.3 to 28.0%; mean, 17.9; pregabalin: range, 2.7 to 8.8%; mean, 5.8).[45,48,63] When pregabalin was administered for more than 24 h the overall effectiveness risk ratio showed a statistically significant treatment effect of pregabalin compared to placebo at 3 months (nine trials; risk ratio, 0.47 [95% CI, 0.33 to 0.68]), and 6 months (three trials; risk ratio, 0.29 [95% CI, 0.14 to 0.58]) for varying surgical procedures, and 3 months after total knee arthroplasty (two trials; risk ratio, 0.42 [95% CI, 0.22 to 0.81]) (Figure 3). Only eleven of the 26 pregabalin studies provided data regarding dropouts due to treatment-related adverse effects. Of those, 56 of 1,295 (4.3%) received pregabalin and 27 of 819 (3.3%) received placebo. Adverse events included dizziness, nausea, vomiting, sedation, diplopia, somnolence, visual disturbances, fainting, fatigue, constipation, and allergic reaction.[45,47,49,56–58,62–64]

Pregabalin has been evaluated in four recent reviews for orthopedic surgery,[42] thoracotomy,[68] breast cancer surgery,[69] and various surgeries.[70] Consistent with the current review, half (two of four) of these reviews did not have sufficient evidence to make a clear recommendation.[69,70] Two reviews concluded a treatment effect of pregabalin. One narrative systematic review evaluating various interventions for total knee arthroplasty[42] was limited to one randomized controlled trial from 2010[63] and the other review included nine studies for thoracotomy, seven of which were excluded from the present review due to lack of blinding, not placebo controlled, and lack of long term pain assessment.[68] Furthermore, two of the nine studies that were included in our review did not find a reduction in the prevalence of postsurgical chronic pain.[47,53] Despite the high proportion of studies lacking data on adverse events, consistent with our review adverse events included sedation,[42,70] dizziness,[68,70] drowsiness,[68,69] and visual disturbances.[70]

Gabapentin

Eight new studies (n = 1,367)[52,71–77] evaluated gabapentin (total, 18 studies; n = 2,166).[38,52,71–86] Six of 18 studies reported prevalence of any pain at 3 months,[72,81–84,86] four studies at 6 months,[72,73,80,84] and one study at 12 months.[73] Prevalence of any pain at 3 months ranged from 20.0 to 66.7% (mean, 49.9%) in the placebo arm and 12.5 to 70.2% (mean, 47.8%) in the gabapentin arm. No treatment effects were observed for any pain evaluated at 3 or 6 months (Figure 3). Forest plots for studies evaluating gabapentin are included in Supplemental Digital Content 8 (appendix H, http://links.lww.com/ALN/C635). Consistent with the 2013 review, meta-analyses of studies evaluating gabapentin failed to demonstrate statistical significance upon comparison to placebo at three or six months.

Two studies reported prevalence of moderate to severe pain at 3 and 6 months,[72,76] however results were not pooled given heterogeneity of timing and duration of administration. When drug administration was for 24 h or less, the prevalence of moderate to severe pain at 3 months was 21.1% in the placebo group and 22.2% in the gabapentin group and 10.5% and 16.7% at 6 months, respectively.[76] When drug administration was for more than 24 h, the prevalence of moderate to severe pain at 3 months was 13.5% in the placebo group and 12.8% in the gabapentin group and 8.1% and 16.7% at 6 months, respectively.[72] Only five of the 18 gabapentin studies provided data regarding dropouts due to treatment-related adverse effects. Of those, 32 of 506 (6.3%) received gabapentin and 18 of 401 (4.5%) received placebo. Adverse events included severe sedation, dizziness, nausea, syncope, paresthesia of the legs, and elevated serum creatinine.[72–74,83,84]

Gabapentin has been evaluated in two recent reviews for breast cancer surgery.[69,87] One review concluded low- to very-low–quality evidence that preoperative use of gabapentin does not reduce the rate of chronic postsurgical pain.[69] One review concluded that "preoperative use of gabapentin was able to reduce acute and chronic postoperative pain."[87] However, seven of nine studies were excluded from the current review; six due to follow-up for less than 3 months (range, 12 h to 1 month), and one was a clinical trial with one arm that combined topical analgesia and gabapentin. It is unclear why two of five studies were included in their meta-analysis evaluating chronic pain given their short timeline for follow-up (i.e., 24 h and 7 days).[88,89] Furthermore, it is unclear why two studies included in the meta-analysis by Jiang et al.[87] show a treatment effect of gabapentin: Amr et al.[78] did not report dichotomous results for the incidence of chronic pain and concluded "gabapentin had no effect on chronic pain," and Fassoulaki et al.[81] reported no difference in the proportion of chronic pain between gabapentin 12 of 22 (54.5%) and pregabalin 14 of 24 (58.3%).

IV Lidocaine

Nine new studies (n = 808)[18,51,90–96] evaluated IV lidocaine (total, 10 studies; n = 844).[18,51,90–97] Six of 10 studies reported prevalence of any pain at 3 months,[51,90,91,93,94,97] three studies at 6 months,[90,93,96] and no studies at 12 months. Prevalence of any pain at 3 months ranged from 17.4 to 79.2% (mean, 41.6%) in the placebo arm and 11.8 to 92.3% (mean, 32.7%) in the IV lidocaine arm. One study could not be pooled in meta-analysis due to duration of drug administration for more than 24 h during colectomy.[90] Subgroup analyses of prevalence of any pain at 6 months based on duration of treatment being 24 h or less showed a statistically significant treatment effect of IV lidocaine after breast surgery (two trials; risk ratio, 0.43 [95% CI, 0.23 to 0.80]). No treatment effect of IV lidocaine was observed at 3 months after breast surgery or when the drug was administered for 24 h or less (Figure 4). Forest plots for studies evaluating IV lidocaine are included in Supplemental Digital Content 9 (appendix I, http://links.lww.com/ALN/C636).

Figure 4.

Summary of intravenous lidocaine meta-analyses. Data are presented as the pooled results for each outcome. Drug ≤ 24 h indicates drugs were administered for 24 h or less; drug > 24 h indicates drugs were administered for longer than 24 h.

Two studies reported prevalence of moderate to severe pain at 3 months (placebo: range, 10.0 to 20.8%; mean, 15.4; IV lidocaine: range, 4.7 to 7.7%; mean, 6.2),[51,93] and two studies at 6 months (placebo: range, 3.4 to 22.2%; mean, 12.8; IV lidocaine: range, 3.2 to 8.8%; mean, 6.0).[93,96] No treatment effect of IV lidocaine was observed for this outcome regardless of timing of outcome measurement or surgical procedure (Figure 4). Only 1 of the 10 IV lidocaine studies provided data regarding dropouts due to treatment-related adverse effects. Of those, 1 of 22 (4.5%) received IV lidocaine and 0 of 22 (0.0%) received placebo. One patient in the IV lidocaine group developed convulsions during injection of the loading dose.[92]

Intravenous lidocaine has been evaluated in two recent reviews for breast cancer surgery,[98] and various surgeries.[99] Both reviews were cautiously optimistic in support of IV lidocaine for preventing chronic postsurgical pain. However, higher quality evidence from large, definitive, multicenter clinical trials was called for before a widespread change in practice could be justified.[99]

Nonsteroidal Anti-inflammatory Drugs

Five new studies (n = 451) evaluated nonsteroidal anti-inflammatory drugs (NSAID) including one celecoxib,[100] one dexketoprofen,[101] one flurbiprofen axetil,[102] one parecoxib,[103] and one IV parecoxib in combination with oral celecoxib[104] (total, eight studies; n = 1,602).[100–107] Two of eight studies reported prevalence of any pain at 3 months,[103,104] three studies at 6 months,[102,104,106] and four studies at 12 months.[102–104,107] Prevalence of any pain at 3 months ranged from 48.8 to 59.1% (mean, 53.9%) in the placebo arm and 22.5 to 54.3% (mean, 38.4%) in the NSAID arm. Subgroup analysis did not show an effect of NSAIDs compared to placebo for studies evaluating treatment for more than 24 h at 3, 6, and 12 months; however, a statistically significant treatment effect was observed at 12 months when drugs were administered for 24 h or less (Figure 5). Forest plots for studies evaluating NSAIDS are included in Supplemental Digital Content 10 (appendix J, http://links.lww.com/ALN/C637).

Figure 5.

Summary of other drugs meta-analyses. Data are presented as the pooled results for each outcome. Drug ≤ 24 h indicates drugs were administered for 24 h or less; drug > 24 h indicates drugs were administered for longer than 24 h.

One study reported prevalence of moderate to severe pain at 3 and 6 months and concluded no treatment effect of COX-2 inhibitors on persistent pain.[104] Two studies reported prevalence of moderate to severe pain at 12 months; however, results were not pooled due to heterogeneity of timing and duration of NSAID administration. When drug administration was for 24 h or less,[107] the prevalence of moderate to severe pain at 12 months was 3.2% in the placebo group and 0.0% in the NSAID group versus 2.4% versus 0.0%, respectively, when drug administration was for more than 24 h.[104] Only one of the eight NSAID studies provided data regarding dropouts due to treatment-related adverse effects. Of those, 51 of 440 (11.6%) received ibuprofen and 37 of 435 (8.5%) received placebo.[105]

Corticosteroids

Three new studies (n = 1,315) evaluated corticosteroids: two dexamethasone[108–110] and one methylprednisolone[111] (total, six studies; n = 1,620).[107–113] One of six studies reported prevalence of any pain at 3 months,[110] one at 6 months,[111] and one at 12 months.[107] Results were not pooled due to heterogeneity of the timing of outcome measurement.

Two of six studies reported the prevalence of moderate to severe pain at 12 months (placebo: range, 3.2 to 50.0%; mean, 26.6; corticosteroid: range, 5.4 to 72.7%; mean, 39.0).[107,109] Subgroup analysis at 12 months based on duration of treatment for 24 h or less resulted in a statistically significant treatment effect of placebo (two trials; risk ratio, 1.47 [95% CI, 1.05 to 2.06]) (Figure 5). Forest plots for studies evaluating corticosteroids are included in Supplemental Digital Content 11 (appendix K, http://links.lww.com/ALN/C638). No studies evaluating corticosteroids provided data regarding dropouts due to treatment-related adverse effects.

Other Drugs

Fewer studies evaluated acetaminophen (two new; n = 290),[114,115] amantadine (two studies, one new; n = 82),[116,117] dexmedetomidine (one new; n = 80),[118] dextromethorphan (one study, not new; n = 50),[119] duloxetine (two new; n = 207),[120,121] etanercept (one new; n = 77),[122] fentanyl (one study, not new; n = 65),[123] magnesium (one new; n = 126),[94] memantine (one study, not new; n = 19),[124] mexiletine (two studies, not new; n = 175),[81,125] minocycline (two new; n = 231),[126,127] nefopam (four new; n = 307),[14,128–130] nitrous oxide (two studies, one new; n = 5,375),[131,132] valproic acid (one new; n = 128),[133] venlafaxine (one study, not new; n = 150),[78] and vitamin C (one new; n = 123).[134] Primary and secondary outcomes for drugs evaluated in fewer than five studies were inconclusive and shown in Supplemental Digital Content 12 (appendix L, http://links.lww.com/ALN/C639).

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