Abstract
Cancer-related pain is one of the most common and debilitating symptoms among cancer patients. Undertreated cancer-related pain interferes with daily activities and increases morbidity and mortality. While opioids continue to play an essential role in treating moderate to severe cancer-related pain, they are associated with many adverse effects including misuse. While preclinical and retrospective studies have shown a negative association between opioid use and cancer outcomes, randomized control trials demonstrate that opioid use does not influence cancer recurrence. Additionally, analgesics and adjuvants used for perioperatively or chronic pain control are unlikely to improve oncological outcomes. This article focuses on the pharmacological management of cancer-related pain and offers an overview regarding the use of these medications perioperatively and the cancer outcomes.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. . Update on prevalence of pain in patients with cancer: systematic review and meta-analysis. J. Pain Symptom Manage. 51(6), 1070–1090 e1079 (2016).
- 2. . Why patients are afraid of opioid analgesics: a study on opioid perception in patients with chronic pain. Pol. Arch. Intern. Med. 128(2), 89–97 (2018).
- 3. . Surgical patients' fear of addiction to pain medication: the effect of an educational program for clinicians. Clin. J. Pain 17(2), 157–164 (2001).
- 4. . A comprehensive review of opioid-induced hyperalgesia. Pain Physician 14(2), 145–161 (2011).
- 5. . Perioperative opioid analgesia-when is enough too much? A review of opioid-induced tolerance and hyperalgesia. Lancet 393(10180), 1558–1568 (2019). • This manuscripts highlits important mechanisms of opioid-induced tolerance, opioiod-induced hyperalgesia and summrizes to the concept of multimodal analgesia.
- 6. The impact of pain and opioids use on survival in cancer patients: results from a population-based cohort study and a meta-analysis. Medicine (Baltimore) 99(9), e19306 (2020).
- 7. . Association of opioid requirement and cancer pain with survival in advanced non-small cell lung cancer. Br. J. Anaesth. 113(Suppl. 1), I109–I116 (2014).
- 8. . The immune-suppressive effects of pain. Adv. Exp. Med. Biol. 521, 117–125 (2003).
- 9. . Pain management for patients with advanced cancer in the opioid epidemic era. Am. Soc. Clin. Oncol. Educ. Book 39, 24–35 (2019). • Critically summarizes the literature on opioid indications for patients with advanced cancer and their risk for misuse.
- 10. WHO Guidelines Approved by the Guidelines Review Committee. In: WHO Guidelines for the Pharmacological and Radiotherapeutic Management of Cancer Pain in Adults and Adolescents. World Health Organization, Geneva, Switzlerland (2018).
- 11. . Nociceptin/orphanin FQ receptor ligands and translational challenges: focus on cebranopadol as an innovative analgesic. Br. J. Anaesth. 121(5), 1105–1114 (2018).
- 12. . beta-arrestins: regulatory role and therapeutic potential in opioid and cannabinoid receptor-mediated analgesia. Handb. Exp. Pharmacol. 219, 427–443 (2014).
- 13. . Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology 115(6), 1363–1381 (2011).
- 14. . Opioid receptors. Annu. Rev. Biochem. 73, 953–990 (2004).
- 15. . Expression of opioid receptors in cells of the immune system. Int. J. Mol. Sci. 22(1), (2020).
- 16. . Opioids: modulators of angiogenesis in wound healing and cancer. Oncotarget 8(15), 25783–25796 (2017).
- 17. . Opioids and cancer prognosis: a summary of the clinical evidence. Neurosci. Lett. 746, 135661 (2021).
- 18. . Opioids in cancer development, progression and metastasis: focus on colorectal cancer. Curr. Treat. Options Oncol. 21(1), 6 (2020).
- 19. Renaud AMCaHGaFL. Inhibition by opioids of phagocytosis in peritoneal macrophages. Neuropeptides 18(1), 35–40 (1991).
- 20. . Antinociceptive and immunosuppressive effects of opiate drugs: a structure-related activity study. Br. J. Pharmacol. 121(4), 834–840 (1997).
- 21. . Opioids and cancer: friend or foe? Curr Opin Support Palliat Care. 10(2), 109–118 (2016).
- 22. . Opioids and the immune system – friend or foe. Br. J. Pharmacol. 175(14), 2717–2725 (2018).
- 23. . Do all opioid drugs share the same immunomodulatory properties? a review from animal and human studies. Front. Immunol. 10, 2914 (2019). • Summarizes preclinical and clinical evidence on the effect of opioids in the immune system. It concludes by saying that it is not correct to generalize immunosuppression as a common side effect of all opioid molecules.
- 24. Evidence that opioids may have Toll-like receptor 4 and MD-2 effects. Brain Behav. Immun. 24(1), 83–95 (2010).
- 25. . Opioids and neovascularization; pro or anti? Br. J. Anaesth. 115(6), 821–824 (2015).
- 26. . Opioid receptors beyond pain control: the role in cancer pathology and the debated importance of their pharmacological modulation. Pharmacol. Res. 159, 104938 (2020).
- 27. Morphine promotes the angiogenesis of postoperative recurrent tumors and metastasis of dormant breast cancer cells. Pharmacology 104(5–6), 276–286 (2019).
- 28. . A mitogen-activated protein kinase pathway is required for mu-opioid receptor desensitization. J. Biol. Chem. 273(20), 12402–12406 (1998).
- 29. Fentanyl stimulates tumor angiogenesis via activating multiple pro-angiogenic signaling pathways. Biochem. Biophys. Res. Commun. 532(2), 225–230 (2020).
- 30. . Opioids inhibit angiogenesis in a chorioallantoic membrane model. Pain Physician 20(2S), SE11–SE21 (2017).
- 31. . Morphine decreases the pro-angiogenic interaction between breast cancer cells and macrophages in vitro. Sci. Rep. 6, 31572 (2016).
- 32. . The kappa opioid receptor may be a potential tumor suppressor by regulating angiogenesis in breast cancer. Med. Hypotheses 150, 110568 (2021).
- 33. The novel role of the mu opioid receptor in lung cancer progression: a laboratory investigation. Anesth. Analg. 112(3), 558–567 (2011).
- 34. Mu-opioid receptor activation promotes in vitro and in vivo tumor growth in head and neck squamous cell carcinoma. Life Sci. 278, 119541 (2021).
- 35. The mu-opioid receptor (MOR) promotes tumor initiation in hepatocellular carcinoma. Cancer Lett. 453, 1–9 (2019).
- 36. . The dual effect of morphine on tumor development. Clin. Transl. Oncol. 21(6), 695–701 (2019).
- 37. . The role of opioids in cancer progression. Int. Anesthesiol. Clin. 58(2), 57–63 (2020). • Pays special attention to mechanisms by which opioids affect inflammation, immunity, angiogenesis and their direct effects cancer cells.
- 38. . Morphine stimulates migration and growth and alleviates the effects of chemo drugs via AMPK-dependent induction of epithelial-mesenchymal transition in esophageal carcinoma cells. Biol. Pharm. Bull. 43(5), 774–781 (2020).
- 39. Morphine promotes cancer stem cell properties, contributing to chemoresistance in breast cancer. Oncotarget 6(6), 3963–3976 (2015).
- 40. Morphine, a potential antagonist of cisplatin cytotoxicity, inhibits cisplatin-induced apoptosis and suppression of tumor growth in nasopharyngeal carcinoma xenografts. Sci. Rep. 6, 18706 (2016).
- 41. . Evaluation of effects of morphine and ionizing radiation in cancer cell lines. J. Cancer Res. Ther. 15(8), 144–152 (2019).
- 42. The role of opioids in cancer response to immunotherapy. J. Transl. Med. 19(1), 119 (2021).
- 43. . Morphine suppresses liver cancer cell tumor properties in vitro and in vivo. Front. Oncol. 11, 666446 (2021).
- 44. . Prevention and delay in progression of human pancreatic cancer by stable overexpression of the opioid growth factor receptor. Int. J. Oncol. 33(2), 317–323 (2008).
- 45. . The opioid growth factor (OGF) and low dose naltrexone (LDN) suppress human ovarian cancer progression in mice. Gynecol. Oncol. 122(2), 382–388 (2011).
- 46. . Opioid growth factor – opioid growth factor receptor axis inhibits proliferation of triple negative breast cancer. Exp. Biol. Med. (Maywood). 238(6), 589–599 (2013).
- 47. The role of opioids and their receptors in urological malignancy: a review. J. Urol. 204(6), 1150–1159 (2020).
- 48. Increased mu-opioid receptor expression is associated with reduced disease-free and overall survival in laryngeal squamous cell carcinoma. Br. J. Anaesth. 125(5), 722–729 (2020).
- 49. . Increased mu-opioid receptor expression in metastatic lung cancer. Br. J. Anaesth. 113(Suppl. 1), i103–108 (2014).
- 50. Association of Mu-opioid receptor(MOR) expression and opioids requirement with survival in patients with stage I–III pancreatic ductal adenocarcinoma. Front. Oncol. 11, 686877 (2021).
- 51. Mu opioid receptor 1 (MOR-1) expression in colorectal cancer and oncological long-term outcomes: a five-year retrospective longitudinal cohort study. Cancers (Basel) 12(1), (2020).
- 52. Impact of pain, opioids, and the mu-opioid receptor on progression and survival in patients with newly diagnosed stage IV pancreatic cancer. Am. J. Clin. Oncol. 43(8), 591–597 (2020).
- 53. A retrospective analysis of the effect of intraoperative opioid dose on cancer recurrence after non-small cell lung cancer resection. Cancer Med. 3(4), 900–908 (2014).
- 54. . Epidural analgesia during open radical prostatectomy does not improve long-term cancer-related outcome: a retrospective study in patients with advanced prostate cancer. PLoS ONE 8(8), e72873 (2013).
- 55. Does postoperative morphine consumption for acute surgical pain impact oncologic outcomes after colorectal cancer resection?: a retrospective cohort study. Medicine (Baltimore) 98(18), e15442 (2019).
- 56. Intraoperative opioids use for laryngeal squamous cell carcinoma surgery and recurrence: a retrospective study. J. Clin. Anesth. 27(8), 672–679 (2015).
- 57. Effects of intraoperative opioid use on recurrence-free and overall survival in patients with esophageal adenocarcinoma and squamous cell carcinoma. Anesth. Analg. 127(1), 210–216 (2018).
- 58. Intraoperative opioids are associated with improved recurrence-free survival in triple-negative breast cancer. Br. J. Anaesth. 126(2), 367–376 (2021).
- 59. Recurrence of breast cancer after regional or general anaesthesia: a randomised controlled trial. Lancet 394(10211), 1807–1815 (2019). •• This randomized controlled trial demostrates that the use of regional anesthesia does not impact cancer progression in women with breast cancer requiring mastectomy.
- 60. Opioids and premature biochemical recurrence of prostate cancer: a randomised prospective clinical trial. Br. J. Anaesth. 126(5), 931–939 (2021).
- 61. Long-term survival after combined epidural–general anesthesia or general anesthesia alone: follow-up of a randomized trial. Anesthesiology 135(2), 233–245 (2021).
- 62. . Ketamine: current applications in anesthesia, pain, and critical care. Anesth. Essays Res. 8(3), 283–290 (2014).
- 63. . Ketamine for chronic pain: old drug new trick? Anesthesiology 133(1), 13–15 (2020).
- 64. . Ketamine as an adjuvant to opioids for cancer pain. Cochrane Database Syst. Rev. 6, CD003351 (2017).
- 65. . Ketamine: NMDA receptors and beyond. J. Neurosci. 36(44), 11158–11164 (2016).
- 66. . A review on the recent application of ketamine in management of anesthesia, pain, and health care. J. Family Med. Prim. Care 9(3), 1317–1324 (2020).
- 67. . Ketamine inhibits colorectal cancer cells malignant potential via blockage of NMDA receptor. Exp. Mol. Pathol. 107, 171–178 (2019).
- 68. . Effects of ketamine, s-ketamine, and MK 801 on proliferation, apoptosis, and necrosis in pancreatic cancer cells. BMC Anesthesiol. 15, 111 (2015).
- 69. Ketamine induces apoptosis in lung adenocarcinoma cells by regulating the expression of CD69. Cancer Med. 7(3), 788–795 (2018).
- 70. Intraoperative opioid exposure, tumour genomic alterations, and survival differences in people with lung adenocarcinoma. Br. J. Anaesth. 127(1), 75–84 (2021).
- 71. . The immunomodulatory effect of ketamine in colorectal cancer surgery: a randomized-controlled trial. Can. J. Anesth. 68(5), 683–692 (2021).
- 72. . Intravenous lidocaine for acute pain: a systematic review. Pharmacotherapy 38(12), 1250–1259 (2018).
- 73. . Perioperative use of intravenous lidocaine. Anesthesiology 126(4), 729–737 (2017).
- 74. . Lidocaine for cancer pain in adults: a systematic review and meta-analysis. J. Palliat. Med. 22(3), 326–334 (2019).
- 75. Lidocaine stimulates the function of natural killer cells in different experimental settings. Anticancer Res. 37(9), 4727–4732 (2017).
- 76. Intraoperative intravenous lidocaine exerts a protective effect on cell-mediated immunity in patients undergoing radical hysterectomy. Mol. Med. Report. 12(5), 7039–7044 (2015).
- 77. . Modulation of dendritic cell activation and subsequent Th1 cell polarization by lidocaine. PLoS ONE 10(10), e0139845 (2015).
- 78. Neutrophil extracellular trapping and angiogenesis biomarkers after intravenous or inhalation anaesthesia with or without intravenous lidocaine for breast cancer surgery: a prospective, randomised trial. Br. J. Anaesth. 125(5), 712–721 (2020). •• In this manuscript, iv. perioperative lidocaine decreased postoperative expression of NETosis and MMP3, regardless of general anaesthetic technique. This supports the hypothesis that iv. lidocaine during cancer surgery of curative intent might reduce recurrence.
- 79. Regulation of podosome formation in macrophages by a splice variant of the sodium channel SCN8A. J. Biol. Chem. 284(12), 8114–8126 (2009).
- 80. Lidocaine inhibits the proliferation of lung cancer by regulating the expression of GOLT1A. Cell Prolif. 50(5), (2017).
- 81. . Lidocaine inhibits growth, migration and invasion of gastric carcinoma cells by up-regulation of miR-145. BMC Cancer 19(1), 233 (2019).
- 82. . Nav1.5-E3 antibody inhibits cancer progression. Transl Cancer Res. 8(1), 44–50 (2019).
- 83. Lidocaine induces apoptosis and suppresses tumor growth in human hepatocellular carcinoma cells in vitro and in a xenograft model in vivo. Anesthesiology 126(5), 868–881 (2017).
- 84. . Lidocaine suppresses glioma cell proliferation by inhibiting TRPM7 channels. Int. J. Physiol. Pathophysiol. Pharmacol. 9(2), 8–15 (2017).
- 85. . Lidocaine inhibits glioma cell proliferation, migration and invasion by modulating the circEZH2/miR-181b-5p pathway. Neuroreport 32(1), 52–60 (2021).
- 86. Lidocaine inhibits cytoskeletal remodelling and human breast cancer cell migration. Br. J. Anaesth. 121(4), 962–968 (2018).
- 87. . Clinically relevant concentrations of lidocaine inhibit tumor angiogenesis through suppressing VEGF/VEGFR2 signaling. Cancer Chemother. Pharmacol. 83(6), 1007–1015 (2019).
- 88. . Lidocaine suppresses cell proliferation and aerobic glycolysis by regulating circHOMER1/miR-138-5p/HEY1 axis in colorectal cancer. Cancer Manag. Res. 12, 5009–5022 (2020).
- 89. Lidocaine enhances the effects of chemotherapeutic drugs against bladder cancer. Sci. Rep. 8(1), 598 (2018).
- 90. . Lidocine potentiates the cytotoxicity of 5-fluorouracil to choriocarcinoma cells by downregulating ABC transport proteins expression. J. Cell. Biochem. 120(10), 16533–16542 (2019).
- 91. . Lidocaine inhibits cervical cancer cell proliferation and induces cell apoptosis by modulating the lncRNA-MEG3/miR-421/BTG1 pathway. Am. J. Transl. Res. 11(9), 5404–5416 (2019).
- 92. . The effect of clinically therapeutic plasma concentrations of lidocaine on natural killer cell cytotoxicity. Reg. Anesth. Pain Med. 40(1), 43–48 (2015).
- 93. Neutrophil extracellular trapping and angiogenesis biomarkers after intravenous or inhalation anaesthesia with or without intravenous lidocaine for breast cancer surgery: a prospective, randomised trial. Br. J. Anaesth. 125(5), 712–721 (2020).
- 94. Association between intraoperative intravenous lidocaine infusion and survival in patients undergoing pancreatectomy for pancreatic cancer: a retrospective study. Br. J. Anaesth. 125(2), 141–148 (2020).
- 95. . COX-2 inhibitors: pharmacological data and adverse effects. Minerva Anesthesiol. 71(7–8), 461–470 (2005).
- 96. Expression of cyclooxygenase-1 and -2 in human breast cancer. Surg. Today 33(11), 805–811 (2003).
- 97. . Cyclooxygenase 2 rescues LNCaP prostate cancer cells from sanguinarine-induced apoptosis by a mechanism involving inhibition of nitric oxide synthase activity. Cancer Res. 66(7), 3726–3736 (2006).
- 98. . Mechanisms of phytonutrient modulation of cyclooxygenase-2 (COX-2) and inflammation related to cancer. Nutr. Cancer 70(3), 350–375 (2018).
- 99. Cyclooxygenase-2 is overexpressed in human cervical cancer. Clin. Cancer Res. 7(2), 429–434 (2001).
- 100. COX-2 is expressed in human pulmonary, colonic, and mammary tumors. Cancer 89(12), 2637–2645 (2000).
- 101. . Increased cyclooxygenase-2 expression in human pancreatic carcinomas and cell lines: growth inhibition by nonsteroidal anti-inflammatory drugs. Cancer Res. 59(17), 4356–4362 (1999).
- 102. . A novel plausible mechanism of NSAIDs-induced apoptosis in cancer cells: the implication of proline oxidase and peroxisome proliferator-activated receptor. Pharmacol. Rep. 72(5), 1152–1160 (2020).
- 103. . Inflammation: a driving force speeds cancer metastasis. Cell Cycle 8(20), 3267–3273 (2009).
- 104. . Cyclooxygenase-2 promotes tumor growth and suppresses tumor immunity. Cancer Cell Int. 15, 106 (2015).
- 105. Aspirin and nonsteroidal anti-inflammatory drugs after but not before diagnosis are associated with improved breast cancer survival: a meta-analysis. Cancer Causes Control 26(4), 589–600 (2015).
- 106. . Influence of NSAID use among colorectal cancer survivors on cancer outcomes. Am. J. Clin. Oncol. 40(4), 370–374 (2017).
- 107. Association of nonsteroidal anti-inflammatory drug use with survival in patients with squamous cell carcinoma of the head and neck treated with chemoradiation therapy. JAMA Netw Open. 3(6), e207199 (2020).
- 108. Perioperative neutrophil:lymphocyte ratio and postoperative NSAID use as predictors of survival after lung cancer surgery: a retrospective study. Cancer Med. 4(6), 825–833 (2015).
- 109. Do intraoperative analgesics influence oncological outcomes after radical prostatectomy for prostate cancer? Eur. J. Anaesthesiol. 28(12), 830–835 (2011).
- 110. . NSAIDs use and reduced metastasis in cancer patients: results from a meta-analysis. Sci. Rep. 7(1), 1875 (2017).
- 111. . Nonsteroidal anti-inflammatory drugs and pain in cancer patients: a systematic review and reappraisal of the evidence. Br. J. Anaesth. 123(2), e412–e423 (2019).
- 112. . Non-steroidal anti-inflammatory drugs in the oncological surgical population: beneficial or harmful? A systematic review of the literature. Br. J. Anaesth. 119(4), 750–764 (2017).
- 113. . Intraoperative use of ketorolac or diclofenac is associated with improved disease-free survival and overall survival in conservative breast cancer surgery. Br. J. Anaesth. 113(Suppl. 1), i82–87 (2014).
- 114. Neutrophil:lymphocyte ratio and intraoperative use of ketorolac or diclofenac are prognostic factors in different cohorts of patients undergoing breast, lung, and kidney cancer surgery. Ann. Surg. Oncol. 20, 650–660 (2013).
- 115. . Postoperative non-steroidal anti-inflammatory drug use and oncological outcomes of rectal cancer. BJS Open 5(1), (2021).
- 116. Do intraoperative analgesics influence breast cancer recurrence after mastectomy? A retrospective analysis. Anesth. Analg. 110(6), 1630–1635 (2010).
- 117. Norepinephrine up-regulates the expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9 in nasopharyngeal carcinoma tumor cells. Cancer Res. 66(21), 10357–10364 (2006).
- 118. Platelet-to-lymphocyte ratio and use of NSAIDs during the perioperative period as prognostic indicators in patients with NSCLC undergoing surgery. Cancer Control 23(3), 284–294 (2016).
- 119. . Impact of non-steroidal anti-inflammatory drugs on recurrence and survival after melanoma surgery: a cohort study. Cancer Invest. 38(7), 415–423 (2020).
- 120. . Perioperative analgesia with parecoxib sodium improves postoperative pain and immune function in patients undergoing hepatectomy for hepatocellular carcinoma. J. Eval. Clin. Pract. 26(3), 992–1000 (2019).
- 121. Intraoperative ketorolac in high-risk breast cancer patients. A prospective, randomized, placebo-controlled clinical trial. PLoS ONE 14(12), e0225748 (2019).
- 122. Effect of celecoxib vs placebo added to standard adjuvant therapy on disease-free survival among patients with stage III colon cancer. JAMA 325(13), (2021).
- 123. . Mechanisms of the gabapentinoids and alpha 2 delta-1 calcium channel subunit in neuropathic pain. Pharmacol. Res. Perspect. 4(2), e00205 (2016).
- 124. Gabapentin-induced mitogenic activity in rat pancreatic acinar cells. Toxicol. Sci. 55(1), 52–59 (2000).
- 125. . Gabapentin, an analgesic used against cancer-associated neuropathic pain: effects on prostate cancer progression in an in vivo rat model. Basic Clin. Pharmacol. Toxicol. 118(3), 200–207 (2016).
- 126. . Comparative studies of intracellular Ca2+ in strongly and weakly metastatic rat prostate cancer cell lines. Int. J. Biochem. Cell Biol. 38(3), 366–375 (2006).
- 127. Risk of cancer in patients exposed to gabapentin in two electronic medical record systems. Pharmacoepidemiol. Drug Saf. 21(2), 214–225 (2012).
- 128. . Mechanisms of dexmedetomidine in neuropathic pain. Front. Neurosci. 14, 330 (2020).
- 129. . Multimodal general anesthesia: theory and practice. Anesth. Analg. 127(5), 1246–1258 (2018).
- 130. Dexmedetomidine promotes metastasis in rodent models of breast, lung, and colon cancers. Br. J. Anaesth. 120(1), 188–196 (2018).
- 131. Midazolam and dexmedetomidine affect neuroglioma and lung carcinoma cell biology in vitro and in vivo. Anesthesiology 129(5), 1000–1014 (2018).
- 132. . Alpha2-adrenoceptor agonists trigger prolactin signaling in breast cancer cells. Cell. Signal. 34, 76–85 (2017).
- 133. Dexmedetomidine promotes the progression of hepatocellular carcinoma through hepatic stellate cell activation. Exp. Mol. Med. 52(7), 1062–1074 (2020).
- 134. . Dexmedetomidine upregulates microRNA-185 to suppress ovarian cancer growth via inhibiting the SOX9/Wnt/beta-catenin signaling pathway. Cell Cycle 20(8), 765–780 (2021).
- 135. . Dexmedetomidine suppresses the progression of esophageal cancer via miR-143-3p/epidermal growth factor receptor pathway substrate 8 axis. Anticancer Drugs 31(7), 693–701 (2020).
- 136. The effect of dexmedetomidine on expressions of inflammatory factors in patients with radical resection of gastric cancer. Eur. Rev. Med. Pharmacol. Sci. 21(15), 3510–3515 (2017).
- 137. . Effects of dexmedetomidine on patients undergoing radical gastrectomy. J. Surg. Res. 194(1), 147–153 (2015).
- 138. Effects of serum from breast cancer surgery patients receiving perioperative dexmedetomidine on breast cancer cell malignancy: a prospective randomized controlled trial. Cancer Med. 8(18), 7603–7612 (2019).
- 139. Intraoperative use of dexmedetomidine is associated with decreased overall survival after lung cancer surgery. J. Anaesthesiol. Clin. Pharmacol. 33(3), 317–323 (2017).