This case-control study examines the association between multimodal analgesia administration and perioperative opioid requirements in patients undergoing head and neck surgery with free flap reconstruction and investigates whether multimodal analgesia alters the duration of stay in the postanesthesia care unit.
Key Points
Question
Is there an association between the administration of oral celecoxib, gabapentin, and/or tramadol hydrochloride before surgery and perioperative opioid requirements in patients undergoing head and neck surgery with free flap reconstruction?
Findings
In this case-control study of 149 patients who received oral celecoxib, gabapentin, and/or tramadol medications before surgery and 208 patients who did not, opioid use and the duration of stay in the postanesthesia care unit were reduced in patients who received the medications.
Meaning
The findings of this case-control study suggest that the use of a multimodal analgesia regimen, such as celecoxib, gabapentin, and/or tramadol, may decrease opioid use during the perioperative period and shorten the duration of stay in the postanesthesia care unit.
Abstract
Importance
The opioid epidemic has reignited interest in opioid-sparing strategies in managing pain. However, few studies have focused on opioid use during perioperative care in patients undergoing head and neck surgery with free flap reconstruction.
Objectives
To examine the association between multimodal analgesia (MMA) administration and perioperative opioid requirements in patients undergoing head and neck surgery with free flap reconstruction and to investigate whether MMA alters the duration of stay in the postanesthesia care unit (PACU).
Design, Setting, and Participants
In this retrospective case-control study, data were collected between April 1, 2016, and December 31, 2017. The study was conducted at a single cancer center in the United States. Participants were 357 patients 18 years or older scheduled for head and neck surgery with free flap reconstruction.
Exposures
Patients in the treatment group received oral celecoxib, gabapentin, and/or tramadol hydrochloride before surgery. Control group patients did not receive any of these medications.
Main Outcomes and Measures
The amount of opioid administered in the operating room and in the PACU was converted to morphine equivalent daily dose (MEDD) for comparison between the 2 groups. The duration of stay in the PACU was based on the start time and end time of PACU care recorded by nurses in the PACU.
Results
In total, 149 patients (mean [SD] age, 60.3 [13.7] years; 104 [69.8%] men) were included in the treatment group, and 208 patients (mean [SD] age, 64.2 [13.6] years; 146 [70.2%] men) were included in the control group. The mean (SD) MEDD of opioid given during surgery was 51.7 (19.8) in the treatment group and 67.9 (24.7) in the control group, for a difference in the means (treatment vs control) of −16.17 (95% CI, −20.81 to −11.52). In the PACU, the mean (SD) MEDD of opioid given was 11.7 (13.3) in the treatment group and 14.9 (15.7) in the control group, for a difference in the means (treatment vs control) of −3.22 (95% CI, −6.40 to −0.03). The MMA treatment remained largely associated with reduced amount of opioid given during surgery, in the PACU, and both combined after controlling for other important factors.
Conclusions and Relevance
This case-control study found that the patients who received MMA before head and neck surgery with free flap reconstruction required less opioid medication. The treatment group also had shorter duration of stay in the PACU compared with the control group.
Introduction
The recent opioid epidemic has reignited interest in opioid-sparing strategies used in managing surgical pain. The administration of analgesic medications with different mechanisms of action and the use of various regional or neuraxial anesthesia techniques have synergistic associations with decreasing perioperative pain scores, thereby reducing opioid requirements.1 In turn, less opioid use has the potential to reduce the incidence of opioid-related adverse effects, such as respiratory depression, postoperative nausea and vomiting, constipation, and oversedation. Individually and in combination, celecoxib, gabapentin, and/or tramadol hydrochloride have been used successfully as part of multimodal analgesia (MMA). These analgesics have shown benefit in orthopedic, breast, abdominal, and gynecological surgical procedures, sometimes as a part of enhanced recovery after surgery (ERAS) pathways.2,3,4,5
Oncologic head and neck surgery involving free flap reconstruction is a type of surgery in which regional blocks and local infiltration cannot routinely be used. Patients who undergo this procedure are also at high risk for respiratory complications because of airway manipulation, edema, and pain associated with their surgical procedures. The use of MMA may reduce additional respiratory complications associated with opioid requirements in this patient population and shorten postsurgical recovery. Recent studies6,7,8,9,10 have found MMA to be beneficial in outpatient and more complex oncologic head and neck surgery. However, to our knowledge, no study has examined the association between administration of a single oral dose of MMA before surgery and intraoperative and postanesthesia care unit (PACU) opioid requirements in patients undergoing head and neck surgery with free flap reconstruction. Therefore, the objectives herein were to examine the association between oral MMA (celecoxib, gabapentin, and/or tramadol) administration and opioid requirements during surgery and in the PACU among this patient population and to investigate whether MMA alters the duration of stay in the PACU.
Methods
This single-center retrospective case-control study included patients 18 years or older scheduled for head and neck surgery with immediate free flap reconstruction between April 1, 2016, and December 31, 2017. The study was conducted at The University of Texas MD Anderson Cancer Center. The study was approved by The University of Texas MD Anderson Cancer Center institutional review board. Patient consent for medical record review was waived because deidentified data were used.
Cases and Controls
The practice of administering oral celecoxib, gabapentin, and/or tramadol as part of ERAS to patients undergoing these surgical procedures began in June 2017. Among 357 patients included in the study, 149 (41.7%) received at least 1 of the above medications before surgery (treatment group), whereas 208 (58.3%) did not (control group). The treatment group included patients who were enrolled in our institution’s ERAS pathway. The control group consisted of patients who underwent surgery before ERAS was implemented at our institution. Patients were excluded if they were 17 years or younger or if they were not scheduled for the specified surgical procedures.
Baseline data included patient characteristics, such as age, sex, body mass index, preexisting diagnoses (particularly any history of cardiac, pulmonary, kidney, or hepatic disease and stroke or diabetes), and preadmission opioid and other pain medication use. Preoperative data recorded included the doses of oral celecoxib (400 mg), gabapentin (300 mg), and/or tramadol hydrochloride (300 mg) given before surgery. Intraoperative data included the total doses of any opioid (eg, fentanyl citrate, hydromorphone hydrochloride, and morphine sulfate) given during surgery and the duration of anesthesia. For comparison between the 2 groups, the amount of opioid administered in the operating room and in the PACU was converted to morphine equivalent daily dose (MEDD) based on a reference established by our institutional pain task force.11 The duration of stay in the PACU was based on the start time and end time of PACU care recorded by PACU nurses. Postoperative data collected included opioid requirements, disposition (PACU vs intensive care unit), duration of stay in the PACU (from PACU admission until the ready-for-discharge event entered in the electronic medical record), and the last pain score in the PACU on a numeric pain scale of 0 to 10, with 0 indicating no pain and 10 indicating “the worst pain of your life.”
Outcomes
The primary outcomes of this study were the total doses of any opioid given during surgery, in the PACU, and both combined. The secondary outcomes of this study were the duration of stay in the PACU and the last pain score in the PACU. We chose at least 20% reduction in MEDD from the mean control and 30 minutes or greater reduction in the duration of stay in the PACU as clinically meaningful.12,13,14,15 For ease of interpretation, the primary outcomes were categorized as follows for the multivariable analyses: 55 MEDD (ie, ≤55 vs >55 MEDD) for the total doses of any opioid given during surgery, 12 MEDD (ie, ≤12 vs >12 MEDD) for the total doses of any opioid given in the PACU, and 66 MEDD (ie, ≤66 vs >66 MEDD) for both combined.
Statistical Analysis
Patient demographics, perioperative factors, and intraoperative and PACU variables were summarized using descriptive statistics. Effect size metrics reflect difference in the means for continuous variables and odds ratios (ORs) for categorical variables (with corresponding 95% CIs). For continuous outcomes, Cohen d was used to express the magnitude of the difference between compared groups, with 0.2 indicating a small effect size, 0.5 indicating a medium effect size, and 0.8 indicating a large effect size. Cohen w was used to express the magnitude of the difference between compared groups for the last pain score in the PACU, with 0.10 indicating a small effect size, 0.30 indicating a medium effect size, and 0.50 indicating a large effect size.16 Univariate and multivariable logistic regression models were fit to study the association between study group and outcomes in unadjusted analysis and adjusted analysis, respectively. Variables associated with the outcomes at α = .20 in univariate analyses were included in a model selection process to build multivariable models with the most relevant factors. We applied a backward model selection strategy based on the P value and retained variables with 2-sided P < .10 in the final models. The presence of multicollinearity was assessed by examining parameter estimates and SEs after removing each variable at a time from the models. The Hosmer-Lemeshow goodness-of-fit test was used to assess goodness of fit of the final models. Statistical analyses were conducted in R, version 3.4.2 (R Project for Statistical Computing).
Results
A total of 357 patients 18 years or older scheduled for head and neck surgery with free flap reconstruction were included in the study. In total, 149 patients (mean [SD] age, 60.3 [13.7] years; 104 [69.8%] men) were included in the treatment group, and 208 patients (mean [SD] age, 64.2 [13.6] years; 146 [70.2%] men) were included in the control group. On average, patients were aged 62.6 (13.8) years, and 250 (70.0%) were men. The mean body mass index (calculated as weight in kilograms divided by height in meters squared) of patients was 27.3 (6.5). About half of the patients (187 [52.4%]) had a history of hypertension, and most patients did not have a history of stroke, pulmonary embolism, deep vein thrombosis, cardiac disease, pulmonary disease, kidney disease, or diabetes. About half of the patients had a history of using opioids (188 [52.7%]) or other pain medications (190 [53.2%]), and 106 (29.7%) had taken tramadol. One hundred forty-nine patients (41.7%) used at least one of the following medications before surgery: celecoxib, gabapentin, and/or tramadol. Two hundred eight patients (58.3%) had not used any of these medications before surgery. There were large differences between the treatment vs control groups with respect to the following baseline variables: age (effect size, −3.85; 95% CI, −6.74 to −0.97), stroke (effect size, 0.29; 95% CI, 0.09-0.87), cardiac disease (effect size, 0.49; 95% CI, 0.27-0.88), and history of tramadol use (effect size, 0.16; 95% CI, 0.09-0.28). A summary of patient demographics and clinical characteristics by study group is listed in Table 1.
Table 1. Patient Demographics and Clinical Variables Overall and by Study Groupa.
| Variable | Treatment group (n = 149) | Control group (n = 208) | Effect size (95% CI)b |
|---|---|---|---|
| Age, mean (SD), y | 60.3 (13.7) | 64.2 (13.6) | −3.85 (−6.74 to −0.97) |
| Male sex | 104 (69.8) | 146 (70.2) | 0.98 (0.62 to 1.58) |
| BMI, mean (SD) | 27.9 (7.2) | 26.8 (5.6) | 1.18 (−0.23 to 2.59) |
| ASA classification | |||
| 2 | 10 (6.7) | 15 (7.2) | 1.08 (0.45 to 2.53)c |
| 3 | 138 (92.6) | 188 (90.4) | |
| 4 | 1 (0.7) | 5 (2.4) | |
| Hypertension | 73 (49.0) | 114 (54.8) | 0.79 (0.51 to 1.23) |
| Stroke | 4 (2.7) | 18 (8.7) | 0.29 (0.09 to 0.87) |
| Pulmonary embolism | 1 (0.7) | 4 (1.9) | 0.35 (0.01 to 2.68) |
| Deep vein thrombosis | 8 (5.4) | 3 (1.4) | 3.86 (0.95 to 17.2) |
| Cardiac disease | 20 (13.4) | 50 (24.0) | 0.49 (0.27 to 0.88) |
| Pulmonary disease | 19 (12.8) | 25 (12.0) | 1.07 (0.54 to 2.06) |
| Kidney disease | 4 (2.7) | 6 (2.9) | 0.93 (0.24 to 3.52) |
| Diabetes | 20 (13.4) | 34 (16.3) | 0.79 (0.43 to 1.48) |
| History of opioid use | 86 (57.7) | 102 (49.0) | 1.42 (0.91 to 2.17) |
| History of tramadol use | 16 (10.7) | 90 (43.3) | 0.16 (0.09 to 0.28) |
| History of other pain medication use | 88 (59.1) | 102 (49.0) | 1.50 (0.96 to 2.30) |
Abbreviations: ASA, American Society of Anesthesiologists; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared).
Unless otherwise indicated, data are given as No. (%).
Difference in the means for continuous variables and odds ratios (with exact 95% CIs) for categorical variables (treatment vs control).
ASA classification 3 + 4 vs 2.
Of the 357 patients included in the study, 35 (8 in the treatment group and 27 in the control group) did not go from the operating room to the PACU but instead went to the intensive care unit. Therefore, PACU outcomes were not obtained for these patients. No large differences were observed between patients with missing vs present PACU outcomes with respect to baseline characteristics in the treatment group or in the control group.
Summary statistics for the primary outcomes of the study by study group are listed in Table 2. The mean (SD) MEDD of opioid given during surgery was 51.7 (19.8) in the treatment group and 67.9 (24.7) in the control group, for a difference in the means (treatment vs control) of −16.17 (95% CI, −20.81 to −11.52). In the PACU, the mean (SD) MEDD of opioid given during surgery was 11.7 (13.3) in the treatment group and 14.9 (15.7) in the control group, for a difference in the means (treatment vs control) of −3.22 (95% CI, −6.40 to −0.03). Overall, the mean (SD) MEDD of opioid administered during surgery and in the PACU was 64.0 (23.6) in the treatment group and 82.2 (30.1) in the control group, for a difference in the means (treatment vs control) of −18.21 (95% CI, −24.10 to −12.32). There was a moderate treatment effect (ie, attributed to receiving medication before surgery) on the amount of opioid given during surgery (Cohen d = −0.71; 95% CI, −0.93 to −0.49) or during surgery and in the PACU (Cohen d = −0.66; 95% CI, −0.89 to −0.44). However, the treatment effect on the amount of opioid given in the PACU only was small (Cohen d = −0.22; 95% CI, −0.44 to 0.00).
Table 2. Primary Outcomes.
| Variable | Study group | Mean (SD) | Median (range) | No.a | Effect size (95% CI)b | ≥20% Reduction in MEDD from the mean control, No. (%) |
|---|---|---|---|---|---|---|
| Operating room opioids, MEDD | Treatment | 51.7 (19.8) | 50 (15 to 114) | 149 | NA | 90 (60.4) |
| Control | 67.9 (24.7) | 64 (5 to 200) | 208 | −16.17 (−20.81 to −11.52) | 63 (30.3) | |
| PACU opioids, MEDD | Treatment | 11.7 (13.3) | 10 (0 to 80) | 141 | NA | 88 (62.4) |
| Control | 14.9 (15.7) | 10 (0 to 106) | 181 | −3.22 (−6.40 to −0.03) | 100 (55.2) | |
| Operating room + PACU opioids, MEDD | Treatment | 64.0 (23.6) | 60 (20 to 160) | 141 | NA | 92 (65.2) |
| Control | 82.2 (30.1) | 80 (5 to 231) | 181 | −18.21 (−24.10 to −12.32) | 54 (29.8) |
Abbreviations: MEDD, morphine equivalent daily dose; NA, not applicable; PACU, postanesthesia care unit.
Eight patients in the treatment group and 27 patients in the control group went to the intensive care unit after surgery.
Difference in the means (treatment vs control).
The percentages of patients within each study group who achieved a clinically meaningful reduction in MEDD across the 2 settings (operating room and PACU) are listed in Table 2. In the operating room, 90 of 149 patients (60.4%) in the treatment group compared with 63 of 208 patients (30.3%) in the control group achieved a clinically meaningful reduction in MEDD, for a difference between the groups of 30.0% (95% CI, 19.8%-39.6%). In the PACU, 88 of 141 patients (62.4%) in the treatment group compared with 100 of 181 patients (55.2%) in the control group achieved a clinically meaningful reduction in MEDD, for a difference between the groups of 7.2% (95% CI, −3.7% to 17.7%). For both combined, 92 of 141 patients (65.2%) in the treatment group and 54 of 181 patients (29.8%) in the control group achieved a clinically meaningful reduction in MEDD, for a difference between the groups of 35.4% (95% CI, 24.6%-45.0%).
Baseline variables, including age, American Society of Anesthesiologists classification, hypertension, stroke, cardiac disease, and history of opioid, tramadol, or other pain medication use, were statistically significantly associated with the amount of opioid given during surgery and/or in the PACU. Table 3 summarizes the association of study group with the primary outcomes of interest in multivariable analyses. The MMA treatment remained largely associated with reduced amount of opioid given during surgery, in the PACU, and both combined after controlling for variables found to be statistically significant in univariate analyses. In the operating room, patients in the treatment group were 68% less likely to receive more than 55 MEDD of opioid compared with patients in the control group (OR, 0.32; 95% CI, 0.20-0.52), controlling for age and history of tramadol use. In the PACU, patients in the treatment group were 45% less likely to receive more than 12 MEDD of fentanyl, hydromorphone, or morphine compared with patients in the control group (OR, 0.55; 95% CI, 0.33-0.90), controlling for age, American Society of Anesthesiologists classification, pulmonary disease, and history of narcotic use. In both combined, patients in the treatment group were 79% less likely to receive more than 66 MEDD of opioid compared with patients in the control group (OR, 0.21; 95% CI, 0.12-0.36), controlling for age and history of tramadol use.
Table 3. Multivariable Linear Regression Models of the Primary Outcomes.
| Variable | OR (95% CI) |
|---|---|
| Operating room opioids >55 MEDD | |
| Treatment group vs control group | 0.32 (0.20-0.52) |
| Age | 0.98 (0.96-0.99) |
| History of tramadol use | 2.35 (1.35-4.09) |
| PACU opioids >12 MEDD | |
| Treatment group vs control group | 0.55 (0.33-0.90) |
| Age | 0.96 (0.94-0.98) |
| ASA classification 3 + 4 vs 2 | 0.36 (0.14-0.95) |
| Pulmonary disease | 2.55 (1.24-5.26) |
| History of narcotic use | 1.89 (1.15-3.11) |
| Operating room + PACU opioids >66 MEDD | |
| Treatment group vs control group | 0.21 (0.12-0.36) |
| Age | 0.95 (0.93-0.97) |
| History of tramadol use | 3.20 (1.68-6.10) |
Abbreviations: ASA, American Society of Anesthesiologists; MEDD, morphine equivalent daily dose; OR, odds ratio; PACU, postanesthesia care unit.
The mean duration of stay in the PACU was shorter (a 22-minute reduction) for patients who received at least one MMA medication before surgery, for a difference in the means (treatment vs control) of −0.36 (95% CI, −0.63 to −0.09) (Table 4). In total, 51.1% (72 of 141) of the patients in the treatment group were in the PACU for 2.97 hours or less, and 36.5% (66 of 181) of the patients in the control group were in the PACU for 2.97 hours or less (ie, at least a 30-minute reduction in the duration of stay in the PACU). There was a small treatment effect on the duration of stay in the PACU (Cohen d = −0.30; 95% CI, −0.52 to −0.08).
Table 4. Secondary Outcomes.
| Variable | Treatment group (n = 141) | Control group (n = 181) | Effect size (95% CI)a |
|---|---|---|---|
| Duration of stay in the PACU, mean (SD), h | 3.11 (1.25) | 3.47 (1.17) | −0.36 (−0.63 to −0.09) |
| Last pain score in the PACU, No. (%) | |||
| 0 | 52 (37.4) | 51 (29.0) | 1 [Reference] |
| 1-3 | 45 (32.4) | 64 (36.4) | 0.69 (0.40 to 1.19) |
| 4-6 | 38 (27.3) | 48 (27.3) | 0.78 (0.44 to 1.38) |
| ≥7 | 4 (2.9) | 13 (7.4) | 0.30 (0.09 to 0.99) |
Abbreviation: PACU, postanesthesia care unit.
Difference in the means for the duration of stay in the PACU and odds ratios (with asymptotic 95% CIs [ie, the 95% CI is calculated based on a large sample approximation to the sampling distribution of the log odds ratio]) for the last pain score in the PACU (treatment vs control).
Table 4 summarizes the association between the use of preoperative medication and the last pain score in the PACU. Effect sizes were 0.69 (95% CI, 0.40-1.19) for a pain score of 1 to 3, 0.78 (95% CI, 0.44-1.38) for a pain score of 4 to 6, and 0.30 (95% CI, 0.09-0.99) for pain score of at least 7. The treatment effect on the last pain score in the PACU was small (Cohen w = 0.12; 95% CI, 0.06-0.24).
Discussion
In this retrospective case-control study of 357 patients, we found that patients who took at least 1 of certain medications (celecoxib, gabapentin, and/or tramadol) before head and neck surgery with free flap reconstruction required a lower opioid dose during surgery and/or in the PACU than control patients. In addition, compared with control patients, these patients had a shorter duration of stay in the PACU.
There are numerous possible reasons for the observed association between the use of these medications and perioperative opioid requirements. One is because, individually, these medications have been shown to be effective for treating various types of pain. Celecoxib, a nonsteroidal anti-inflammatory drug, is efficacious for postoperative pain relief after various surgical procedures and has no adverse effects on free flap survival or wound healing.17 Gabapentin is an anticonvulsant drug that also has neuropathic analgesia effects.18 Gabapentinoids provide analgesia possibly via reducing the sensitivity of presynaptic neurons by blocking the α2/∆ subunit of voltage-sensitive calcium channels.19 Although preoperative gabapentin use seems to have variable analgesic effectiveness based on the type of surgery studied, it has been shown to be efficacious for patients undergoing head and neck reconstruction with a thigh flap.20 In addition, a systematic review21 of the perioperative use of gabapentin concluded that it was generally beneficial in reducing pain and opioid consumption. Finally, tramadol is a weak opioid agonist and a weak noradrenaline and serotonin reuptake inhibitor. Because of this unique dual mechanism of action, tramadol exerts analgesic benefits, with an improved tolerability profile compared with other opioids.22 It has no clinically relevant associations with cardiovascular and respiratory parameters and has a low potential for abuse and dependence.22,23
Evidence has shown that implementing MMA therapy statistically significantly reduced opioid use in various types of surgery, such as colorectal, gynecological, and orthopedic.2,3,4,5 Until recently, few studies6,7,8,9,10,20 had focused on multimodal pain therapy in head and neck surgery. To our knowledge, this study is the first to examine the association of a single dose of MMA before head and neck surgery and immediate free flap reconstruction with opioid administration during surgery and in the PACU. The findings reported herein suggest that the benefits of these medications (celecoxib, gabapentin, and/or tramadol) are immediate and that patients can reduce their opioid requirements even by receiving them only 1 time.
Our results regarding gabapentin and tramadol in reducing opioid use are consistent with the findings of other studies.13,19,23 Eggerstedt et al9 found that patients who received combined celecoxib and gabapentin required less opioid use in the first 72 hours after head and neck free flap surgery. Chiu et al20 demonstrated that patients who were administered single preoperative doses of gabapentin had substantial reductions in postoperative pain in the first 24 hours after tongue reconstruction.
With respect to the duration of stay in the PACU, we observed a 22-minute reduction for patients who received at least 1 MMA medication before surgery; based on the data, the reduction in the duration of stay ranged from 5.4 to 37.8 minutes. The lack of precision in the point estimate indicates that a 30-minute reduction or less in the duration of stay in the PACU for a patient who takes these medications before surgery needs to be verified in future research. The reduction may have been associated with decreased nausea or possibly less sedation because of reduced opioid use. In contrast, the treatment effect on the last pain score in the PACU (one of our secondary outcomes) was small. This finding is consistent with work by Du et al,8 who found that MMA did not alter patients’ pain scores. However, Eggerstedt et al9 reported that patients who received repeated MMA had lower postoperative pain scores during the first 72 hours after head and neck free flap reconstruction compared with a control group.
Limitations
This study has some limitations, including its observational nature, which precludes judgment of causation. Because the study was not blinded, bias may have been introduced into the perioperative pain management strategies of clinicians with regard to opioid administration. Another limitation is the failure to categorize the overall severity of comorbidity for each patient. The burden of comorbidity is likely to have relevance for multiple end points in this study. Listing the number of patients who have a limited number of comorbid illnesses (Table 1) does not describe the overall burden of 1 or more comorbidities within each of the individuals.
Conclusions
The use of MMA may reduce opioid requirements in the operating room and in the PACU among patients undergoing head and neck surgery with free flap reconstruction. In turn, this strategy may enable patients to have a shorter duration of stay in the PACU. Prospective randomized clinical trials are needed to verify these findings. Despite these observed benefits, questions remain, such as which MMA regimens are best and what their long-term effectiveness, safety, and cost will be, and require further investigation.
References
- 1.Wick EC, Grant MC, Wu CL. Postoperative multimodal analgesia pain management with nonopioid analgesics and techniques: a review. JAMA Surg. 2017;152(7):691-697. doi: 10.1001/jamasurg.2017.0898 [DOI] [PubMed] [Google Scholar]
- 2.Parvizi J, Bloomfield MR. Multimodal pain management in orthopedics: implications for joint arthroplasty surgery. Orthopedics. 2013;36(2)(suppl):7-14. doi: 10.3928/01477447-20130122-51 [DOI] [PubMed] [Google Scholar]
- 3.Fassoulaki A, Triga A, Melemeni A, Sarantopoulos C. Multimodal analgesia with gabapentin and local anesthetics prevents acute and chronic pain after breast surgery for cancer. Anesth Analg. 2005;101(5):1427-1432. doi: 10.1213/01.ANE.0000180200.11626.8E [DOI] [PubMed] [Google Scholar]
- 4.Steinberg AC, Schimpf MO, White AB, et al. Preemptive analgesia for postoperative hysterectomy pain control: systematic review and clinical practice guidelines. Am J Obstet Gynecol. 2017;217(3):303-313.e6. doi: 10.1016/j.ajog.2017.03.013 [DOI] [PubMed] [Google Scholar]
- 5.Meyer LA, Lasala J, Iniesta MD, et al. Effect of an enhanced recovery after surgery program on opioid use and patient-reported outcomes. Obstet Gynecol. 2018;132(2):281-290. doi: 10.1097/AOG.0000000000002735 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Oltman J, Militsakh O, D’Agostino M, et al. Multimodal analgesia in outpatient head and neck surgery: a feasibility and safety study. JAMA Otolaryngol Head Neck Surg. 2017;143(12):1207-1212. doi: 10.1001/jamaoto.2017.1773 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Jandali DB, Vaughan D, Eggerstedt M, et al. Enhanced recovery after surgery in head and neck surgery: reduced opioid use and length of stay. Laryngoscope. 2020;130(5):1227-1232. doi: 10.1002/lary.28191 [DOI] [PubMed] [Google Scholar]
- 8.Du E, Farzal Z, Stephenson E, et al. Multimodal analgesia protocol after head and neck surgery: effect on opioid use and pain control. Otolaryngol Head Neck Surg. 2019;161(3):424-430. doi: 10.1177/0194599819841885 [DOI] [PubMed] [Google Scholar]
- 9.Eggerstedt M, Stenson KM, Ramirez EA, et al. Association of perioperative opioid-sparing multimodal analgesia with narcotic use and pain control after head and neck free flap reconstruction. JAMA Facial Plast Surg. 2019;21(5):446-451. doi: 10.1001/jamafacial.2019.0612 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Dort JC, Farwell DG, Findlay M, et al. Optimal perioperative care in major head and neck cancer surgery with free flap reconstruction: a consensus review and recommendations from the Enhanced Recovery After Surgery Society. JAMA Otolaryngol Head Neck Surg. 2017;143(3):292-303. doi: 10.1001/jamaoto.2016.2981 [DOI] [PubMed] [Google Scholar]
- 11.The University of Texas MD Anderson Cancer Center. Cancer pain—adult. Accessed May 13, 2020. https://www.mdanderson.org/content/dam/mdanderson/documents/for-physicians/algorithms/clinical-management/clin-management-cancer-pain-web-algorithm.pdf
- 12.Nobrega R, Sheehy KA, Lippold C, Rice AL, Finkel JC, Quezado ZMN. Patient characteristics affect the response to ketamine and opioids during the treatment of vaso-occlusive episode-related pain in sickle cell disease. Pediatr Res. 2018;83(2):445-454. doi: 10.1038/pr.2017.197 [DOI] [PubMed] [Google Scholar]
- 13.Khobrani MA, Camamo JM, Patanwala AE. Effect of intravenous acetaminophen on post-anesthesia care unit length of stay, opioid consumption, pain, and analgesic drug costs after ambulatory surgery. P T. 2017;42(2):125-139. [PMC free article] [PubMed] [Google Scholar]
- 14.Altıparmak B, Korkmaz Toker M, Uysal Aİ, Turan M, Gümüş Demirbilek S. Comparison of the effects of modified pectoral nerve block and erector spinae plane block on postoperative opioid consumption and pain scores of patients after radical mastectomy surgery: a prospective, randomized, controlled trial. J Clin Anesth. 2019;54:61-65. doi: 10.1016/j.jclinane.2018.10.040 [DOI] [PubMed] [Google Scholar]
- 15.Turan A, Babazade R, Kurz A, et al. Clonidine does not reduce pain or opioid consumption after noncardiac surgery. Anesth Analg. 2016;123(3):749-757. doi: 10.1213/ANE.0000000000001356 [DOI] [PubMed] [Google Scholar]
- 16.Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed Routledge; 1988. [Google Scholar]
- 17.Wax MK, Reh DD, Levack MM. Effect of celecoxib on fasciocutaneous flap survival and revascularization. Arch Facial Plast Surg. 2007;9(2):120-124. doi: 10.1001/archfaci.9.2.120 [DOI] [PubMed] [Google Scholar]
- 18.Farzi F, Naderi Nabi B, Mirmansouri A, et al. Postoperative pain after abdominal hysterectomy: a randomized, double-blind, controlled trial comparing the effects of tramadol and gabapentin as premedication. Anesth Pain Med. 2016;6(1):e32360. doi: 10.5812/aapm.32360 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Nimmo SM, Foo ITH, Paterson HM. Enhanced recovery after surgery: pain management. J Surg Oncol. 2017;116(5):583-591. doi: 10.1002/jso.24814 [DOI] [PubMed] [Google Scholar]
- 20.Chiu TW, Leung CCH, Lau EYK, Burd A. Analgesic effects of preoperative gabapentin after tongue reconstruction with the anterolateral thigh flap. Hong Kong Med J. 2012;18(1):30-34. [PubMed] [Google Scholar]
- 21.Tiippana EM, Hamunen K, Kontinen VK, Kalso E. Do surgical patients benefit from perioperative gabapentin/pregabalin? a systematic review of efficacy and safety. Anesth Analg. 2007;104(6):1545-1556. doi: 10.1213/01.ane.0000261517.27532.80 [DOI] [PubMed] [Google Scholar]
- 22.McClellan K, Scott LJ. Tramadol/paracetamol. Drugs. 2003;63(11):1079-1086. Published correction appears in Drugs. 2003;63(16):1636. doi: 10.2165/00003495-200363110-00007 [DOI] [PubMed] [Google Scholar]
- 23.Solmaz FA, Kovalak E. Comparison of tramadol/acetaminophen fixed-dose combination, tramadol, and acetaminophen in patients undergoing ambulatory arthroscopic meniscectomy. Acta Orthop Traumatol Turc. 2018;52(3):222-225. doi: 10.1016/j.aott.2018.02.011 [DOI] [PMC free article] [PubMed] [Google Scholar]