- Email: [email protected]
Randomized control trial of opioid- versus nonopioid-based analgesia after thyroidectomy
Surgery xxx (2020) 1e5
Contents lists available at ScienceDirect
Surgery journal homepage: www.elsevier.com/locate/surg
Randomized control trial of opioid- versus nonopioid-based analgesia after thyroidectomy Vardan Papoian, MD, MPHa,*, Kevin G. Handy, MDb, Anthony M. Villano, MDa, Rafael A. Tolentino, MDa, Mohamed T. Hassanein, MDa, Lauren S. Nosanov, MDa, Erin A. Felger, MDa a b
Department of Surgery, MedStar Georgetown University/Washington Hospital Center, Washington, DC Department of Anesthesiology, MedStar Washington Hospital Center, Washington, DC
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 21 January 2020 Available online xxx
Background: Opioid-based analgesia is the most common method for pain control in the postoperative period. Limited data exist to compare the adequacy of pain control in the post thyroidectomy period with nonopioid-based analgesia. We aimed to evaluate the efficacy of nonopioid-based, postoperative analgesia. Methods: After institutional review board approval, patients were randomized to 1 of 2 pain control regimens. Sample size was calculated to assess for a pain score difference of 1 based on a visual analog scale. The control group received opioid-based, postoperative analgesia, whereas the study group received nonopioid-based analgesia of acetaminophen and ibuprofen. Pain scores (measured on visual analog scale) and opioid use (converted to morphine equivalent dose) were measured after completion of the operation. Results: The sample sizes for the study and control groups were 49 and 46 patients, respectively. The pain score for the study and control groups 1 hour after the operation (3.3 vs 3.9, P ¼ .35), 6 hours after the operation (2.8 vs 3.0, P ¼ .08), on postoperative day 1 (1.6 vs 2.4, P ¼ .08) and on the first office visit (0.2 vs 0.1, P ¼ .82) did not have a statistically significant difference. Morphine equivalent opioid requirement for pain control in the postoperative period was 0.8 vs 6.9 mg (P < .01), respectively. Conclusion: In a randomized control trial, we showed that patients treated with nonopioid analgesia had similar pain scores to those treated with opioids, with the benefit of having lower opioid exposure in the perioperative period. © 2020 Elsevier Inc. All rights reserved.
Introduction Thyroid surgery is the most common endocrine surgery performed in the United States.1 Postoperative pain control methodology varies greatly between providers in terms of utilization of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioid medications.2-4 The opioid epidemic currently engulfing
All authors have made substantial contributions to the following: (1) the conception and design of the study, acquisition of data, or analysis and interpretation of data; (2) drafting the article or revising it critically for important intellectual content; and (3) final approval of the version to be submitted. Presented at the American College of Surgeons Clinical Congress 2019 in San Francisco, CA. * Reprint requests: Vardan Papoian, MD, MPH, 106 Irving St. NW, Suite 124 South Building, Washington, DC 20010. E-mail address: [email protected] (V. Papoian). https://doi.org/10.1016/j.surg.2020.01.011 0039-6060/© 2020 Elsevier Inc. All rights reserved.
the United States has caused healthcare providers to take a closer look at their utilization of opioid medications.5 One of the contributing factors to this epidemic has been postoperative opioid exposure, which has been shown to be one of the initial triggering factors on the way to opioid dependence and abuse.6 Our aim was to evaluate the efficacy of a nonopioid-based pain control regimen after thyroidectomies, in comparison with conventional use of postoperative opioids, to determine if pain control can be optimized using a multimodal, nonopioid approach. A limited number of studies have shown that adding nonopioid-based analgesics to the postoperative pain regimen can decrease opioid use. Additionally, Tharakan et al evaluated the prescription pattern at their institution and showed that in patients who underwent a thyroidectomy or parathyroidectomy, the majority did not take any opioids after discharge and more than 80% of the opioid pills prescribed were not used.7 These findings support the assumption that pain control after a thyroidectomy does not require opioids at all.
2
V. Papoian et al. / Surgery xxx (2020) 1e5
Our hypothesis was that patients treated with a combination of acetaminophen and NSAIDs alone will have comparable pain scores to those treated with conventional opioid pain medications. Methods Study design A 2-arm, nonblinded randomized trial was conducted at single centers in the United States from August 2018 to September 2019. The authors designed the study, analyzed and held the data, and wrote the manuscript. Institutional review board approval was obtained before the initiation of recruitment for the study. The study was registered at ClinicalTrials.gov (Identifier: NCT03988075). Patient selection Patients were identified from the endocrine surgery clinic at a high-volume, single tertiary referral center. Patients were approached to participate in the study if they were to undergo a thyroidectomy and were over the age of 18 years. Recruitment was performed by the principle investigator. Patients were excluded from the study if they met any of the following criteria: (1) current use of opioid pain medications; (2) having used opioid pain medications within 30 days of enrollment; (3) chronic kidney disease; (4) liver disease; (5) other medical reason for which patients cannot tolerate a NSAID or acetaminophen (eg, allergy, gastrointestinal bleed due to NSAID); and (6) the need for a more extensive operation than a thyroid lobectomy or total thyroidectomy with or without central lymph node dissection (eg, median sternotomy or modified radical neck dissection). After review of the study protocol and consent, patients were enrolled during their preoperative office visit.
the start of the operation. The volume of anesthetic used was determined by the size of the planned incision in which 1 cc of local anesthesia was injected for every 1 cm of planned incision length. At the conclusion of the operation, the patient was taken to the postoperative care unit where the pain control regimen was started based on the group to which the patient was randomized. All pain control orders were placed by the same study personnel to assure adherence to study protocol. The control group was placed on a pain control regimen of 650 mg acetaminophen as needed every 4 hours for pain level 1 to 3, 5 mg oxycodone as needed every 4 hours for pain level 4 to 7, and 10 mg oxycodone as needed every 4 hours for pain level 8 to 10. On discharge, the patient was given a prescription for 5 mg oxycodone with instructions to take 1 or 2 pills every 4 to 6 hours as needed for pain; a total of 30 pills with no refill. The study group was placed on a pain control regimen of 650 mg acetaminophen every 8 hours and ibuprofen 800 mg every 8 hours. The administration of the acetaminophen and ibuprofen were offset by 4 hours to ensure that the patient received 1 of the pain medications every 4 hours. On discharge, the patient was given a prescription for 650 mg acetaminophen (instructions: take 1 pill every 8 hours as needed for pain, space out the time between the acetaminophen and ibuprofen to 4 hours apart; total of 30 pills with no refill) and 800 mg ibuprofen (instructions: take 1 pill every 8 hours as needed for pain, space out the time between the acetaminophen and ibuprofen to 4 hours apart; total of 30 pills with no refill). For all patients, if a patient had significant pain which was not alleviated by the assigned pain control regimen, an in-house physician was allowed to evaluate the patient and make a clinical determination if additional pain medications were necessary. Standard practice at our institution is for thyroid lobectomies to be discharged on the same day of the operation, and total thyroidectomies to be observed overnight with a discharge the morning after the operation.
Sample size Sample size was calculated to detect a 1-point difference in the Visual Analog Scale (VAS) pain score after thyroidectomy (2-sided alpha of 5% and beta of 20%). A total of 41 subjects were required in each study arm. With a dropout or loss to follow-up of 20%, each study arm would require 50 patients. Randomization The patients were randomized to either the opioid-based pain control group (control group) or nonopioid-based pain control group (study group) at the time of enrollment. A pregenerated table with block randomization assignments (block sizes of 2, 4, and 6) was formed by the coinvestigator at the start of the study by use of the service www.randomization.com. Patient assignments were concealed in sequential envelopes by a coinvestigator and were not known by the recruiter until the patient was enrolled into the study and the sequential envelope was unsealed. The 2 groups were treated in parallel fashion. The study was not blinded to the patient or provider, as the pain control methods differed postoperatively for each group and were noted with which group the patient belonged.
Collected information Collected information included demographic information (age, sex, ethnicity), preoperative survey answers, indications for the operation, intraoperative information (extent of operation, start and stop times of operation), postoperative pain scores, and opioid medication use during hospital stay and recovery until the first postoperative office visit. The patient was shown a VAS (0 ¼ no pain; 10 ¼ worst pain) at various intervals postoperatively (intervals: 1 hour post operation, 6 hours post operation, postoperative day 1, on first postoperative clinic visit) to assess pain level. The time the patient arrived at the post anesthesia care unit was considered “time zero” upon which the times for the VAS administration were based. At the time of discharge, patients were provided a pain tracker sheet to document their use of pain medication in the outpatient setting, which they were instructed to bring to their first postoperative office visit. Opioid use was standardized for reporting to morphine equivalent dosing. Measured outcomes
Pain control methods All operations were performed by a single surgeon to minimize variability in surgical technique. All patients received local anesthesia (1:1 of 0.5% bupivacaine: 1% lidocaine with epinephrine) at
Primary outcome measure was the pain scores based on the VAS at the described intervals. Secondary outcome measure was the opioid use during the postoperative care period.
V. Papoian et al. / Surgery xxx (2020) 1e5 Table I Patient demographics Variable
Control
Study
n Age (y) Female sex (%) Indication for surgery Nodule Cancer Graves Goiter Ethnicity White Black Hispanic Asian Other Operation Lobectomy Total thyroidectomy Operative time (min)
46 53 41 (89%)
49 55 34 (69%)
13 7 6 20
18 9 6 16
23 12 4 1 6
22 19 1 1 6
2 44 147
3 46 149
P .38 .02 .70
.51
.70
.83
Statistical analysis Analysis was performed with intention-to-treat analysis. For continuous variable analysis, a 2-tailed Student’s t test was used for pairwise comparisons. Categorical variables were analyzed with Fisher exact test, and percentages between groups were assessed by Pearson c2 statistic. Two-tailed P values of < .05 were considered statistically significant. Given the maldistribution of sex between the study arms, a multilinear regression model was created to adjust for sex in evaluating pain scores at the measured intervals. Statistical analysis was performed using SAS software version 9.4. (SAS Institute Inc, Cary, NC).
Results Enrollment of 100 patients was completed between August 2018 to September 2019. Five patients were excluded from the final analysis. Three patients from the control group canceled the operation, 1 patient from the study group canceled the operation, and 1 patient from the control group was excluded as he underwent modified radical neck dissection owing to metastatic lymph nodes, which were discovered after enrollment into the study. The final cohort comprised of 49 patients in the study group and 46 patients in the control group. Two of the patients in the control group were placed on the nonopioid-based analgesia protocol owing to miscommunication between study coordinator and treating physicians. Patient demographics are presented in Table I. It is notable that there is a misdistribution of sex between the 2 groups, but no differences are noted between the groups in terms
3
of age, ethnicity, or indications for operation. Table II presents the patient encounter and preferences about opioid use in the perioperative period. It is notable that there is a high percentage of patients who show concern for opioid use during the operation and the desire to undergo nonopioid-based control in the postoperative period. The pain score for the study and control groups 1 hour after the operation (3.3 ± 2.8 vs 3.9 ± 2.8, P ¼ .35), 6 hours after the operation (2.8 ± 2.1 vs 3.0 ± 3.0, P ¼ .08), on postoperative day 1 (1.6 ± 2.2 vs 2.4 ± 2.5, P ¼ .08), and on first office visit (0.2 ± 0.8 vs 0.1 ± 0.6, P ¼ .82) did not show a difference between the groups. The relationship of the pain scales is represented in Fig 1. In the multivariate analysis in which the pain scores were compared while controlling for sex, there was no significant difference between the VAS scores at hour 1 (P ¼ .41), hour 6 (P ¼ .13), on postoperative day 1 (P ¼ .22), or during the first office visit (P ¼ .69). Morphine equivalent opioid requirement for pain control in the postoperative period was 0.8 vs 6.9 mg (P < .01). Three of the patients in the study group and 18 patients in the control group were given opioid medications. Only 22 patients completed the outpatient medication tracker (17 from the study group and 5 from the control group) showing morphine equivalent opioid use of 0 mg vs 3 mg (P ¼ .01). Discussion A thyroidectomy is one of the most common procedures performed in the United States with an estimated 100,000 operations performed annually.1 There is no standard postoperative pain control modality, as they are based on the patient's preferences, surgeon’s preferences, and access to medications. A limited number of studies evaluate the need for opioids after a thyroidectomy. Nguyen et al compared pain scores in patients who received ibuprofen with patients who received hydrocodone for otolaryngology procedures (including thyroidectomies) and noted that pain levels were similar in both groups, with less opioids administered to those taking ibuprofen as a first line analgesic.8 Thuener et al showed that the number of opioid prescriptions decreased when discharge medications were based on protocol-based methodology, thus showing the provider bias that played a role in the opioid prescriptions.9 Additionally, it has been reported that the majority of patients who undergo thyroidectomy do not take any opioids after discharge, and over 80% of the opioid pills that are prescribed are not used.7 At the present time, there is an epidemic of narcotic use with more than 500 opioid-related deaths every week.5 Studies have shown that many patients’ first encounter with opioid medications is in the perioperative period. As many as 10% of those patients continue to use opioids long term.5,6 There have been limited studies to show if there is any advantage in the use of opioid-based
Table II Preoperative survey results Question
Total responded (n)
Answer “Yes” (n)
Answered “Yes” (%)
1. Have you had any surgery before this surgery? If you answered “yes” to question 1, please answer questions 2e6: 2. Were you given opioid medications during or after the surgery while in the hospital? 3. Did you find opioid medications necessary to control your pain in the hospital? 4. Were you prescribed opioid medications when you were discharged? 5. If you were prescribed opioids, did you fill the prescription and take the medication? 6. Did you find opioid medications necessary to control your pain after discharge? 7. Have you taken opioid pain medications for any reason (other than mentioned above)? 8. Do you have concerns about taking opioid medications for this surgery? 9. If given the choice to have current surgery without opioids, would you choose that option? 10. Do you have concerns for possible addiction or dependence after using opioids for surgery?
95
76
80%
74 73 74 71 73 94 93 92 94
58 34 63 44 30 16 31 81 38
78% 47% 85% 62% 41% 17% 33% 88% 40%
4
V. Papoian et al. / Surgery xxx (2020) 1e5
Fig 1. Pain scores with 95% confidence intervals.
analgesia in the postoperative period for pain control despite the known risks of opioid exposure. The use of opioid-based pain medications became more widespread owing to aggressive marketing by manufacturers, physician overprescribing, and the assumed “superior” pain-control effects.10 We challenged this assumption to show that opioids do not perform any better than commonly used over-the-counter analgesics in a randomized control study. In our results, it is clear that the postoperative pain scores were not statistically different between the 2 groups. In our preoperative survey, less than half the patients who had a previous operation felt the need for opioids postoperatively in the hospital or at home. Additionally, 1 in 3 had a concern about development of opioid dependence and 88% preferred to avoid opioids if an alternative was available. These are real concerns that patients have, which the primary surgeon needs to take seriously and plan on setting expectations in the preoperative setting on how pain control will be managed postoperatively. As expected, patients who were prescribed opioids had a higher opioidexposure rate without significant difference in pain levels when compared with the study group. It is important to note that less than half of the patients in the control group ended up using opioids at all, and for those who did use opioids, a relatively small dose of opioid exposure took place. These facts support the findings that opioids are not required, and patients tend to avoid them even when they are available. Additionally, discharging patients without an opioid prescription decreases the number of opioid pills that may leak into the community. With just 49 patients in the study group, we prescribed 1,470 fewer opioid pills over a one-year period. There are limitations to our study. The main limitation is the fact that we could only compare 2 specific methods of pain control. There are endless possibilities of pain medication regimens, but we chose 2 methods, which we believe are common regimens used by surgeons. We tried to standardize other pain modifying agents, such as local anesthetics, to minimize variability between our groups. We understand that there are other agents available, such as longer lasting local anesthetics or intravenous forms of acetaminophen and NSAIDs. We intentionally did not include these in order to specifically compare oral opioids with oral acetaminophen and NSAIDs. A second limitation is that nonopioid pain control is not a regimen that is feasible for every patient, as was noted in our
guidelines for exclusions. But given the fact that the majority of thyroidectomies are performed on a generally healthy, middle-aged population, it is reasonable to assume that it would be safe for the vast majority of patients. Third, our low number of postoperative pain tracker completions limits our evaluation for the use of opioids after the patient had been discharged. Finally, the fact that there was a maldistribution of sex in the 2 groups may be a sign that the randomization process was not effective, but we believe that this had minimal effect on our results as the other patient parameters between the 2 groups were distributed evenly, and the multivariate analysis yielded the same results. Despite these limitations, we were able to complete a randomized study that is generalizable to a large proportion of patients who undergo thyroidectomies in the United States. In conclusion, we were able to evaluate the postoperative pain values between patients who underwent pain control with nonopioid-based medications in comparison with patients with opioid-based pain medications and showed that there was no significant difference in pain levels between the 2 groups. Based on our findings, we strongly recommend that nonopioid-based pain control for thyroidectomy should be the baseline pain control modality, with use of opioids on a selective basis where the surgeon truly believes there is a benefit to its use. Funding/Support This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflict of interest/Disclosure The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. References 1. Sun G, DeMonner S, Davis MM. Epidemiological and economic trends in inpatient and outpatient thyroidectomy in the United States, 1996-2006. Thyroid. 2013;23:727e733. 2. Dang S, Duffy A, Li JC, et al. Postoperative opioid-prescribing practices in otolaryngology: A multiphasic study. Laryngoscope. 2019. https://doi.org/ 10.1002/lary.28101.
V. Papoian et al. / Surgery xxx (2020) 1e5 3. Chen Y, Nwaogu I, Chomsky-Higgins K, et al. Postoperative pain and opioid use after thyroid and parathyroid surgery-A pilot, prospective SMS-based survey. J Surg Res. 2019;240:236e240. 4. Abdulla S, Eckhardt R, Netter U, Abdulla W. Efficacy of three IV non-opioidanalgesics on opioid consumption for postoperative pain relief after total thyroidectomy: a randomised, double-blind trial. Middle East J Anaesthesiol. 2012;21:543e552. 5. Scholl L, Seth P, Kariisa M, Wilson N, Baldwin G. Drug and opioid-involved overdose deaths - United States, 2013-2017. MMWR Morb Mortal Wkly Rep. 2018;67:1419e1427. 6. Brummett CM, Waljee JF, Goesling J, et al. New persistent opioid use after minor and major surgical procedures in US adults. JAMA Surg. 2017;152:e170504.
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7. Tharakan T, Jiang S, Fastenberg J, et al. Postoperative pain control and opioid usage patterns among patients undergoing thyroidectomy and parathyroidectomy. Otolaryngol Head Neck Surg. 2019;160:394e401. 8. Nguyen KK, Liu YF, Chang C, et al. A randomized single-blinded trial of ibuprofen- versus opioid-based primary analgesic therapy in outpatient otolaryngology surgery. Otolaryngol Head Neck Surg. 2019;160: 839e846. 9. Thuener JE, Clancy K, Scher M, et al. Impact of perioperative pain management protocol on opioid prescribing patterns. Laryngoscope. 2019. https://doi.org/ 10.1002/lary.28133. 10. Van Zee A. The promotion and marketing of OxyContin: Commercial triumph, public health tragedy. Am J Public Health. 2009;99:221e227.
Contents lists available at ScienceDirect
Surgery journal homepage: www.elsevier.com/locate/surg
Randomized control trial of opioid- versus nonopioid-based analgesia after thyroidectomy Vardan Papoian, MD, MPHa,*, Kevin G. Handy, MDb, Anthony M. Villano, MDa, Rafael A. Tolentino, MDa, Mohamed T. Hassanein, MDa, Lauren S. Nosanov, MDa, Erin A. Felger, MDa a b
Department of Surgery, MedStar Georgetown University/Washington Hospital Center, Washington, DC Department of Anesthesiology, MedStar Washington Hospital Center, Washington, DC
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 21 January 2020 Available online xxx
Background: Opioid-based analgesia is the most common method for pain control in the postoperative period. Limited data exist to compare the adequacy of pain control in the post thyroidectomy period with nonopioid-based analgesia. We aimed to evaluate the efficacy of nonopioid-based, postoperative analgesia. Methods: After institutional review board approval, patients were randomized to 1 of 2 pain control regimens. Sample size was calculated to assess for a pain score difference of 1 based on a visual analog scale. The control group received opioid-based, postoperative analgesia, whereas the study group received nonopioid-based analgesia of acetaminophen and ibuprofen. Pain scores (measured on visual analog scale) and opioid use (converted to morphine equivalent dose) were measured after completion of the operation. Results: The sample sizes for the study and control groups were 49 and 46 patients, respectively. The pain score for the study and control groups 1 hour after the operation (3.3 vs 3.9, P ¼ .35), 6 hours after the operation (2.8 vs 3.0, P ¼ .08), on postoperative day 1 (1.6 vs 2.4, P ¼ .08) and on the first office visit (0.2 vs 0.1, P ¼ .82) did not have a statistically significant difference. Morphine equivalent opioid requirement for pain control in the postoperative period was 0.8 vs 6.9 mg (P < .01), respectively. Conclusion: In a randomized control trial, we showed that patients treated with nonopioid analgesia had similar pain scores to those treated with opioids, with the benefit of having lower opioid exposure in the perioperative period. © 2020 Elsevier Inc. All rights reserved.
Introduction Thyroid surgery is the most common endocrine surgery performed in the United States.1 Postoperative pain control methodology varies greatly between providers in terms of utilization of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioid medications.2-4 The opioid epidemic currently engulfing
All authors have made substantial contributions to the following: (1) the conception and design of the study, acquisition of data, or analysis and interpretation of data; (2) drafting the article or revising it critically for important intellectual content; and (3) final approval of the version to be submitted. Presented at the American College of Surgeons Clinical Congress 2019 in San Francisco, CA. * Reprint requests: Vardan Papoian, MD, MPH, 106 Irving St. NW, Suite 124 South Building, Washington, DC 20010. E-mail address: [email protected] (V. Papoian). https://doi.org/10.1016/j.surg.2020.01.011 0039-6060/© 2020 Elsevier Inc. All rights reserved.
the United States has caused healthcare providers to take a closer look at their utilization of opioid medications.5 One of the contributing factors to this epidemic has been postoperative opioid exposure, which has been shown to be one of the initial triggering factors on the way to opioid dependence and abuse.6 Our aim was to evaluate the efficacy of a nonopioid-based pain control regimen after thyroidectomies, in comparison with conventional use of postoperative opioids, to determine if pain control can be optimized using a multimodal, nonopioid approach. A limited number of studies have shown that adding nonopioid-based analgesics to the postoperative pain regimen can decrease opioid use. Additionally, Tharakan et al evaluated the prescription pattern at their institution and showed that in patients who underwent a thyroidectomy or parathyroidectomy, the majority did not take any opioids after discharge and more than 80% of the opioid pills prescribed were not used.7 These findings support the assumption that pain control after a thyroidectomy does not require opioids at all.
2
V. Papoian et al. / Surgery xxx (2020) 1e5
Our hypothesis was that patients treated with a combination of acetaminophen and NSAIDs alone will have comparable pain scores to those treated with conventional opioid pain medications. Methods Study design A 2-arm, nonblinded randomized trial was conducted at single centers in the United States from August 2018 to September 2019. The authors designed the study, analyzed and held the data, and wrote the manuscript. Institutional review board approval was obtained before the initiation of recruitment for the study. The study was registered at ClinicalTrials.gov (Identifier: NCT03988075). Patient selection Patients were identified from the endocrine surgery clinic at a high-volume, single tertiary referral center. Patients were approached to participate in the study if they were to undergo a thyroidectomy and were over the age of 18 years. Recruitment was performed by the principle investigator. Patients were excluded from the study if they met any of the following criteria: (1) current use of opioid pain medications; (2) having used opioid pain medications within 30 days of enrollment; (3) chronic kidney disease; (4) liver disease; (5) other medical reason for which patients cannot tolerate a NSAID or acetaminophen (eg, allergy, gastrointestinal bleed due to NSAID); and (6) the need for a more extensive operation than a thyroid lobectomy or total thyroidectomy with or without central lymph node dissection (eg, median sternotomy or modified radical neck dissection). After review of the study protocol and consent, patients were enrolled during their preoperative office visit.
the start of the operation. The volume of anesthetic used was determined by the size of the planned incision in which 1 cc of local anesthesia was injected for every 1 cm of planned incision length. At the conclusion of the operation, the patient was taken to the postoperative care unit where the pain control regimen was started based on the group to which the patient was randomized. All pain control orders were placed by the same study personnel to assure adherence to study protocol. The control group was placed on a pain control regimen of 650 mg acetaminophen as needed every 4 hours for pain level 1 to 3, 5 mg oxycodone as needed every 4 hours for pain level 4 to 7, and 10 mg oxycodone as needed every 4 hours for pain level 8 to 10. On discharge, the patient was given a prescription for 5 mg oxycodone with instructions to take 1 or 2 pills every 4 to 6 hours as needed for pain; a total of 30 pills with no refill. The study group was placed on a pain control regimen of 650 mg acetaminophen every 8 hours and ibuprofen 800 mg every 8 hours. The administration of the acetaminophen and ibuprofen were offset by 4 hours to ensure that the patient received 1 of the pain medications every 4 hours. On discharge, the patient was given a prescription for 650 mg acetaminophen (instructions: take 1 pill every 8 hours as needed for pain, space out the time between the acetaminophen and ibuprofen to 4 hours apart; total of 30 pills with no refill) and 800 mg ibuprofen (instructions: take 1 pill every 8 hours as needed for pain, space out the time between the acetaminophen and ibuprofen to 4 hours apart; total of 30 pills with no refill). For all patients, if a patient had significant pain which was not alleviated by the assigned pain control regimen, an in-house physician was allowed to evaluate the patient and make a clinical determination if additional pain medications were necessary. Standard practice at our institution is for thyroid lobectomies to be discharged on the same day of the operation, and total thyroidectomies to be observed overnight with a discharge the morning after the operation.
Sample size Sample size was calculated to detect a 1-point difference in the Visual Analog Scale (VAS) pain score after thyroidectomy (2-sided alpha of 5% and beta of 20%). A total of 41 subjects were required in each study arm. With a dropout or loss to follow-up of 20%, each study arm would require 50 patients. Randomization The patients were randomized to either the opioid-based pain control group (control group) or nonopioid-based pain control group (study group) at the time of enrollment. A pregenerated table with block randomization assignments (block sizes of 2, 4, and 6) was formed by the coinvestigator at the start of the study by use of the service www.randomization.com. Patient assignments were concealed in sequential envelopes by a coinvestigator and were not known by the recruiter until the patient was enrolled into the study and the sequential envelope was unsealed. The 2 groups were treated in parallel fashion. The study was not blinded to the patient or provider, as the pain control methods differed postoperatively for each group and were noted with which group the patient belonged.
Collected information Collected information included demographic information (age, sex, ethnicity), preoperative survey answers, indications for the operation, intraoperative information (extent of operation, start and stop times of operation), postoperative pain scores, and opioid medication use during hospital stay and recovery until the first postoperative office visit. The patient was shown a VAS (0 ¼ no pain; 10 ¼ worst pain) at various intervals postoperatively (intervals: 1 hour post operation, 6 hours post operation, postoperative day 1, on first postoperative clinic visit) to assess pain level. The time the patient arrived at the post anesthesia care unit was considered “time zero” upon which the times for the VAS administration were based. At the time of discharge, patients were provided a pain tracker sheet to document their use of pain medication in the outpatient setting, which they were instructed to bring to their first postoperative office visit. Opioid use was standardized for reporting to morphine equivalent dosing. Measured outcomes
Pain control methods All operations were performed by a single surgeon to minimize variability in surgical technique. All patients received local anesthesia (1:1 of 0.5% bupivacaine: 1% lidocaine with epinephrine) at
Primary outcome measure was the pain scores based on the VAS at the described intervals. Secondary outcome measure was the opioid use during the postoperative care period.
V. Papoian et al. / Surgery xxx (2020) 1e5 Table I Patient demographics Variable
Control
Study
n Age (y) Female sex (%) Indication for surgery Nodule Cancer Graves Goiter Ethnicity White Black Hispanic Asian Other Operation Lobectomy Total thyroidectomy Operative time (min)
46 53 41 (89%)
49 55 34 (69%)
13 7 6 20
18 9 6 16
23 12 4 1 6
22 19 1 1 6
2 44 147
3 46 149
P .38 .02 .70
.51
.70
.83
Statistical analysis Analysis was performed with intention-to-treat analysis. For continuous variable analysis, a 2-tailed Student’s t test was used for pairwise comparisons. Categorical variables were analyzed with Fisher exact test, and percentages between groups were assessed by Pearson c2 statistic. Two-tailed P values of < .05 were considered statistically significant. Given the maldistribution of sex between the study arms, a multilinear regression model was created to adjust for sex in evaluating pain scores at the measured intervals. Statistical analysis was performed using SAS software version 9.4. (SAS Institute Inc, Cary, NC).
Results Enrollment of 100 patients was completed between August 2018 to September 2019. Five patients were excluded from the final analysis. Three patients from the control group canceled the operation, 1 patient from the study group canceled the operation, and 1 patient from the control group was excluded as he underwent modified radical neck dissection owing to metastatic lymph nodes, which were discovered after enrollment into the study. The final cohort comprised of 49 patients in the study group and 46 patients in the control group. Two of the patients in the control group were placed on the nonopioid-based analgesia protocol owing to miscommunication between study coordinator and treating physicians. Patient demographics are presented in Table I. It is notable that there is a misdistribution of sex between the 2 groups, but no differences are noted between the groups in terms
3
of age, ethnicity, or indications for operation. Table II presents the patient encounter and preferences about opioid use in the perioperative period. It is notable that there is a high percentage of patients who show concern for opioid use during the operation and the desire to undergo nonopioid-based control in the postoperative period. The pain score for the study and control groups 1 hour after the operation (3.3 ± 2.8 vs 3.9 ± 2.8, P ¼ .35), 6 hours after the operation (2.8 ± 2.1 vs 3.0 ± 3.0, P ¼ .08), on postoperative day 1 (1.6 ± 2.2 vs 2.4 ± 2.5, P ¼ .08), and on first office visit (0.2 ± 0.8 vs 0.1 ± 0.6, P ¼ .82) did not show a difference between the groups. The relationship of the pain scales is represented in Fig 1. In the multivariate analysis in which the pain scores were compared while controlling for sex, there was no significant difference between the VAS scores at hour 1 (P ¼ .41), hour 6 (P ¼ .13), on postoperative day 1 (P ¼ .22), or during the first office visit (P ¼ .69). Morphine equivalent opioid requirement for pain control in the postoperative period was 0.8 vs 6.9 mg (P < .01). Three of the patients in the study group and 18 patients in the control group were given opioid medications. Only 22 patients completed the outpatient medication tracker (17 from the study group and 5 from the control group) showing morphine equivalent opioid use of 0 mg vs 3 mg (P ¼ .01). Discussion A thyroidectomy is one of the most common procedures performed in the United States with an estimated 100,000 operations performed annually.1 There is no standard postoperative pain control modality, as they are based on the patient's preferences, surgeon’s preferences, and access to medications. A limited number of studies evaluate the need for opioids after a thyroidectomy. Nguyen et al compared pain scores in patients who received ibuprofen with patients who received hydrocodone for otolaryngology procedures (including thyroidectomies) and noted that pain levels were similar in both groups, with less opioids administered to those taking ibuprofen as a first line analgesic.8 Thuener et al showed that the number of opioid prescriptions decreased when discharge medications were based on protocol-based methodology, thus showing the provider bias that played a role in the opioid prescriptions.9 Additionally, it has been reported that the majority of patients who undergo thyroidectomy do not take any opioids after discharge, and over 80% of the opioid pills that are prescribed are not used.7 At the present time, there is an epidemic of narcotic use with more than 500 opioid-related deaths every week.5 Studies have shown that many patients’ first encounter with opioid medications is in the perioperative period. As many as 10% of those patients continue to use opioids long term.5,6 There have been limited studies to show if there is any advantage in the use of opioid-based
Table II Preoperative survey results Question
Total responded (n)
Answer “Yes” (n)
Answered “Yes” (%)
1. Have you had any surgery before this surgery? If you answered “yes” to question 1, please answer questions 2e6: 2. Were you given opioid medications during or after the surgery while in the hospital? 3. Did you find opioid medications necessary to control your pain in the hospital? 4. Were you prescribed opioid medications when you were discharged? 5. If you were prescribed opioids, did you fill the prescription and take the medication? 6. Did you find opioid medications necessary to control your pain after discharge? 7. Have you taken opioid pain medications for any reason (other than mentioned above)? 8. Do you have concerns about taking opioid medications for this surgery? 9. If given the choice to have current surgery without opioids, would you choose that option? 10. Do you have concerns for possible addiction or dependence after using opioids for surgery?
95
76
80%
74 73 74 71 73 94 93 92 94
58 34 63 44 30 16 31 81 38
78% 47% 85% 62% 41% 17% 33% 88% 40%
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V. Papoian et al. / Surgery xxx (2020) 1e5
Fig 1. Pain scores with 95% confidence intervals.
analgesia in the postoperative period for pain control despite the known risks of opioid exposure. The use of opioid-based pain medications became more widespread owing to aggressive marketing by manufacturers, physician overprescribing, and the assumed “superior” pain-control effects.10 We challenged this assumption to show that opioids do not perform any better than commonly used over-the-counter analgesics in a randomized control study. In our results, it is clear that the postoperative pain scores were not statistically different between the 2 groups. In our preoperative survey, less than half the patients who had a previous operation felt the need for opioids postoperatively in the hospital or at home. Additionally, 1 in 3 had a concern about development of opioid dependence and 88% preferred to avoid opioids if an alternative was available. These are real concerns that patients have, which the primary surgeon needs to take seriously and plan on setting expectations in the preoperative setting on how pain control will be managed postoperatively. As expected, patients who were prescribed opioids had a higher opioidexposure rate without significant difference in pain levels when compared with the study group. It is important to note that less than half of the patients in the control group ended up using opioids at all, and for those who did use opioids, a relatively small dose of opioid exposure took place. These facts support the findings that opioids are not required, and patients tend to avoid them even when they are available. Additionally, discharging patients without an opioid prescription decreases the number of opioid pills that may leak into the community. With just 49 patients in the study group, we prescribed 1,470 fewer opioid pills over a one-year period. There are limitations to our study. The main limitation is the fact that we could only compare 2 specific methods of pain control. There are endless possibilities of pain medication regimens, but we chose 2 methods, which we believe are common regimens used by surgeons. We tried to standardize other pain modifying agents, such as local anesthetics, to minimize variability between our groups. We understand that there are other agents available, such as longer lasting local anesthetics or intravenous forms of acetaminophen and NSAIDs. We intentionally did not include these in order to specifically compare oral opioids with oral acetaminophen and NSAIDs. A second limitation is that nonopioid pain control is not a regimen that is feasible for every patient, as was noted in our
guidelines for exclusions. But given the fact that the majority of thyroidectomies are performed on a generally healthy, middle-aged population, it is reasonable to assume that it would be safe for the vast majority of patients. Third, our low number of postoperative pain tracker completions limits our evaluation for the use of opioids after the patient had been discharged. Finally, the fact that there was a maldistribution of sex in the 2 groups may be a sign that the randomization process was not effective, but we believe that this had minimal effect on our results as the other patient parameters between the 2 groups were distributed evenly, and the multivariate analysis yielded the same results. Despite these limitations, we were able to complete a randomized study that is generalizable to a large proportion of patients who undergo thyroidectomies in the United States. In conclusion, we were able to evaluate the postoperative pain values between patients who underwent pain control with nonopioid-based medications in comparison with patients with opioid-based pain medications and showed that there was no significant difference in pain levels between the 2 groups. Based on our findings, we strongly recommend that nonopioid-based pain control for thyroidectomy should be the baseline pain control modality, with use of opioids on a selective basis where the surgeon truly believes there is a benefit to its use. Funding/Support This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflict of interest/Disclosure The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. References 1. Sun G, DeMonner S, Davis MM. Epidemiological and economic trends in inpatient and outpatient thyroidectomy in the United States, 1996-2006. Thyroid. 2013;23:727e733. 2. Dang S, Duffy A, Li JC, et al. Postoperative opioid-prescribing practices in otolaryngology: A multiphasic study. Laryngoscope. 2019. https://doi.org/ 10.1002/lary.28101.
V. Papoian et al. / Surgery xxx (2020) 1e5 3. Chen Y, Nwaogu I, Chomsky-Higgins K, et al. Postoperative pain and opioid use after thyroid and parathyroid surgery-A pilot, prospective SMS-based survey. J Surg Res. 2019;240:236e240. 4. Abdulla S, Eckhardt R, Netter U, Abdulla W. Efficacy of three IV non-opioidanalgesics on opioid consumption for postoperative pain relief after total thyroidectomy: a randomised, double-blind trial. Middle East J Anaesthesiol. 2012;21:543e552. 5. Scholl L, Seth P, Kariisa M, Wilson N, Baldwin G. Drug and opioid-involved overdose deaths - United States, 2013-2017. MMWR Morb Mortal Wkly Rep. 2018;67:1419e1427. 6. Brummett CM, Waljee JF, Goesling J, et al. New persistent opioid use after minor and major surgical procedures in US adults. JAMA Surg. 2017;152:e170504.
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7. Tharakan T, Jiang S, Fastenberg J, et al. Postoperative pain control and opioid usage patterns among patients undergoing thyroidectomy and parathyroidectomy. Otolaryngol Head Neck Surg. 2019;160:394e401. 8. Nguyen KK, Liu YF, Chang C, et al. A randomized single-blinded trial of ibuprofen- versus opioid-based primary analgesic therapy in outpatient otolaryngology surgery. Otolaryngol Head Neck Surg. 2019;160: 839e846. 9. Thuener JE, Clancy K, Scher M, et al. Impact of perioperative pain management protocol on opioid prescribing patterns. Laryngoscope. 2019. https://doi.org/ 10.1002/lary.28133. 10. Van Zee A. The promotion and marketing of OxyContin: Commercial triumph, public health tragedy. Am J Public Health. 2009;99:221e227.