ADVERTISEMENT
The Ugly Truth: Opioids and the History of the Opioid Epidemic
Throughout my training and experience as a student, resident, and attending, I have observed a pervasive idea that opioids should be the cornerstone of postoperative and acute pain management. There is no standard or protocol for the exact amount or morphine milliequivalents (MME) that should be dispensed after surgery, so it seems many prescribe an arbitrary number that either they learned in training, or “have always done it that way.” Many physicians will prescribe 20–60 doses of oxycodone or hydrocodone 5mg (150–450 MME) after foot or ankle surgery.1 The cornerstone of medicine is practicing in an evidence-based manner, and I believe prescribing more than 100 MME for most foot surgery is harmful and should be frowned upon.
To determine what postoperative analgesic medications should be prescribed for acute postsurgical foot and ankle pain, the efficacy, safety profile, and cost should all be considered. Oftentimes the default prescription for postoperative pain relief is generally an opioid, due to the persistent but flawed thought that opioids are the optimal pain relief drugs.2 The World Health Organization (WHO) has come out with a pain relief ladder that emphasizes that the foundation should be rooted in non-opioid medicines with adjuvants; however, American physicians do not typically follow this.3 Orthopedic surgeons (including podiatrists) are among the highest prescribers of opioids per capita.4 The liberal use of opioid medication by physicians in general is possibly at least in part due to a lack of comprehensive education on postoperative pain management. Also, the addiction, respiratory depression, and other sinister side effects are rarely discussed or mentioned with patients.
The History of Opioid Overconsumption and Marketing
The current epidemic in the United States is taking the lives of over 80,000 people every year.5 While part of the responsibility is on physicians, the history of the current opioid epidemic has its roots in disingenuous marketing tactics and outside pressure from hospitals and patients alike. There has been a history of overprescribing opioids, especially in the late 1990s and early 2000s.5 However, there are various extraneous pressures that have led to overprescribing. Large pharmaceutical companies willingly misled physicians with their “opioids are non-addictive” claims based on falsified data.6 This gave the appearance that opioid drugs were near-perfect for pain control: effective, non-addictive, and few negative side effects. These claims have all been proven time and again to have been misrepresentation of data that was lobbied for by various organizations.
This “data” initially stemmed from a letter to the editor in the New England Journal of Medicine in 1980 by Porter and Jick.6 This letter (which was not a peer-reviewed study) had analyzed hospital inpatients who were suffering from cancer or chronic pain with a tightly controlled opioid dosing regimen and claimed that the development of addiction was incredibly rare in this subset of patients. This study was then misrepresented many times, by influential magazines Scientific American and Time, as well as Purdue Pharma, claiming this was a “landmark” or “extensive” study, despite the fact that this was merely a letter to the editor without passing the rigor of peer review.7,8
The very aggressive marketing of opioids directly to patients and doctors has led to patients expecting opioids when they are in pain, which was further pushed due to the Joint Commission’s “pain is the fifth vital sign” campaign.9 While well intentioned, the campaign tied physician and hospital compensation to the patient's subjective pain scores after leaving the hospital, which may have incentivized overtreatment for pain.10 The Joint Commission has since changed its pain standards after nearly 20 years, with an emphasis on patient safety and multimodal analgesia.11
Physicians also faced pressure from patients expecting opioids who could threaten the physician and hospital with negative reviews and lower Press-Ganey scores, which lowers compensation for both the hospital and the physician in question.10,12,13 This could lead to a downward cycle of increased opioid prescriptions, often inappropriately. There are also patients who inappropriately use prescriptions and turn to other dangerous illicit substances (such as heroin or fentanyl).
This pattern of overconsumption is clearly demonstrated by this startling fact: Americans, despite only being 4.6% of the world's population, consume 99% of the world’s hydrocodone and 80% of the oxycodone.14 American patients do not experience pain any more or less than other populations. However, opioids have leeched their way into our medical system and I find many patients now expect them for their acute or chronic pain (surgical or not), causing further and greater use. An interesting study done in the Netherlands compared Dutch and American patients after bimalleolar ankle fracture surgery, finding American patients took significantly more opioids and pain medicine in every metric recorded. The authors concluded that this implies a large psychological component is involved and managing expectations preoperatively can likely reduce postoperative pain.15,16
Weighing Opioid Benefits Against Risks
The commonly known negative side effects of opioids—like nausea, constipation, respiratory depression, and confusion—are often largely downplayed by physicians due to the thought that opioids’ benefits of significant pain reduction outweigh the potential risks. However, when comparing opioids to other pain-relieving medicines, opioids have been shown to be inferior to nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen in the postoperative setting, which have a much safer side effect profile.17,18
Helmerhorst demonstrated in a randomized controlled trial (RCT) that after an extremity fracture, there was no difference in relief between acetaminophen versus acetaminophen plus an opioid.19 Saini and colleagues found that in a RCT, there was no difference in pain relief of acetaminophen vs. acetaminophen with tramadol for breakthrough pain after orthopedic surgery.20 A study in Prescrire International found that tramadol and acetaminophen was no more effective at pain control than ibuprofen and similarly, Edwards and colleagues reviewed five RCTs and found that for postoperative pain, tramadol with acetaminophen was similar to 400mg of ibuprofen.21,22 Brattwall and colleagues demonstrated that etoricoxib was more effective at postoperative analgesia after hallux valgus surgery than tramadol.23 Treating acute, perioperative, or chronic pain for many foot and ankle pathologies does not need to be anchored with copious amounts of opioids.
On top of this, a number of studies have also demonstrated overprescription of opioid pain relievers after surgical intervention. Finney and colleagues showed that almost 13% of hallux valgus surgery patients did not fill their opioid prescription at all.24 Kvarda and colleagues showed that patients routinely took 50% or fewer than the opioids prescribed to them.25 Merrill and colleagues demonstrated rampant overprescription specifically in foot and ankle surgery (as well as oral, general, and urological surgery specialties), though the authors did not offer a protocol to help curb this.1 Zhu and colleagues studied lower extremity trauma (fracture and dislocations) and 60% of the patients used less than their prescription and 10% didn’t fill it at all.26 Finney and colleagues showed around 6.2% of patients who were given opioid prescriptions after hallux valgus surgery were persistent users 1 year later.24 This suggests a significant need to address appropriate non-opioid pain management in hallux valgus surgery. Saini, Basilico and their respective colleagues revealed similar trends in the literature—surgeons are giving their patients too many opioids and there can be dire consequences from this.20,27 Another reason this is concerning is that this leaves a large reservoir of unused pills, and 80% of modern heroin users reported nonmedical use of legal prescription opioid use prior to heroin initiation.28-31 Similarly shocking, 66% of opioids used for nonmedical purposes are obtained from a friend or relative.29,30
Opioids also have many lesser-appreciated negative effects on the outcomes of surgery. There have been associations with decreases in bone and wound healing. Buchheit and colleagues recently found a significant increase in nonunion risk in patients who use opioids, with the highest risk in patients who are chronic opioid users.32 Patients who are chronic opioid users also have decreased bone mass density compared to non-opioid using controls.33 Opioids effect may be related to their central nervous system side effects, their endocrine effects, or direct action on bone cells. Opioid pain medicine leads to weaker bone callus as well as impeding callus maturation when compared to controls.33,34 There have also been animal models showing a negative effect on bone remodeling and healing after use of fentanyl.35 Something that lends credence to this idea is that opioid antagonists are being utilized for treatment of osteoporosis and this accelerates bone healing in those patients.35
One of their most potent effects is a decrease in testosterone production, which is absolutely critical for anabolic pathways, including bone and wound healing. Bawor and colleagues completed a systematic review and demonstrated that up to 50% of endogenous testosterone is lost in opioid-using patients.36 A similar result was found by Colluzi and colleagues, who found that in non–cancer patients, testosterone production dropped significantly as well.37 Fimmel, Demling and their respective colleagues have demonstrated that testosterone is absolutely critical in order to have patients recover properly in the postoperative period.38,39 On top of the decrease in testosterone, opioids modulate and weaken the immune system due to specialized mu receptors, and the immune system is necessary to respond to inflammation, which is a vital step in the process to heal bone and soft tissue. These effects on surgical wound healing in orthopedic procedures have not been fully elucidated, but it is not an unreasonable hypothesis that opioids are potentially delaying healing and recovery in surgical patients, possibly synergizing with patient comorbidities that already modulate the immune response.40-43 Opioid tolerance and induced hyperalgesia are also large drawbacks that aren’t commonly discussed.44 Sleep is also interrupted as opioids are sedatives, not sleep-enhancing agents. Opioids create a worse sleep quality and less-restful sleep, which can lead to an increased perception of pain, an increase in sleep-disordered breathing, as well as a significant decrease in quality of life.45-49
There are problems with specific opioids as well. For example, hydromorphone, which is sometimes given for large reconstructive surgery, was found to be indistinguishable from diacetylmorphine (heroin) in a blinded trial in active heroin users.50,51 Tramadol is an incredibly toxic drug that is made even more dangerous by the common misnomer that “it’s not a real opioid.”21,52 Tramadol has many drug-drug interactions, induces the CYP2D6, lowers the seizure threshold, its effects are all not fully reversed by naloxone, tramadol use can lead to hypoglycemia, and tramadol been shown to increase the risk of serotonin syndrome.53,54,55
In Conclusion
Further research into decreasing opioid prescribing by an even greater amount will require collaboration with the preoperative staff, anesthesia, the surgeon, and post-anesthesia care unit (PACU) staff. There is promising data to suggest that a preoperative cocktail of acetaminophen, celecoxib, and gabapentin can significantly reduce opioid consumption.56 During the procedure, there is data to suggest that ketorolac, dexamethasone, ketamine, magnesium, or dexmedetomidine can decrease pain and opioid consumption as well.57-65 Future data may bring to light an optimal opioid-sparing protocol following foot and ankle surgery.
Dr. Ehlers is in private practice in Arvada, CO, and is an attending at the Highlands-Presbyterian/St. Luke’s Podiatric Residency Program. He finds interest in debunking medical myths and dogma.
References
1. Merrill HM, Dean DM, Mottla JL, et al. Opioid consumption following foot and ankle surgery. Foot Ankle Int. 2018 Jun;39(6):649-656. doi: 10.1177/1071100718757527. Epub 2018 Mar 5. PMID: 29506395.
2. Gupta A, Kumar K, Roberts MM, et al. Pain management after outpatient foot and ankle surgery. Foot Ankle Int. 2018 Feb;39(2):149-154. doi: 10.1177/1071100717738495. Epub 2017 Oct 27. PMID: 29078056.
3. Anekar AA, Cascella M. WHO Analgesic Ladder. [Updated 2022 May 15]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554435/
4. Volkow ND, McLellan TA, Cotto JH, et al. Characteristics of opioid prescriptions in 2009. JAMA. 2011;305(13):1299-1301. doi:10.1001/jama.2011.401
5. Practice Guidelines for Acute Pain Management in the Perioperative Setting: An Updated Report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2012; 116:248–273 doi: https://doi.org/10.1097/ALN.0b013e31823c1030
6. Porter J, Jick H. Addiction rare in patients treated with narcotics. N Engl J Med. 1980 Jan 10;302(2):123. doi: 10.1056/nejm198001103020221. PMID: 7350425.
7. Boston SA. Less pain, more gain. Time. Published June 24, 2001.
8. Melzack R. The tragedy of needless pain. Scientific American. Published Feb. 1, 1990.
9. Scher C, Meador L, Van Cleave JH, et al. Moving beyond pain as the fifth vital sign and patient satisfaction scores to improve pain care in the 21st century. Pain Manag Nurs. 2018;19(2):125-129. doi:10.1016/j.pmn.2017.10.010
10. Adams J, Bledsoe GH, Armstrong JH. Are pain management questions in patient satisfaction surveys driving the opioid epidemic? Am J Public Health. 2016 Jun;106(6):985-6. doi: 10.2105/AJPH.2016.303228. PMID: 27153016; PMCID: PMC4880256.
11. The Joint Commission. R3 Report I: Requirement, Rationale, Reference. Published Aug. 29, 2017.
12. Chee TT, Ryan AM, Wasfy JH, et al. Current state of value-based purchasing programs. Circulation. 2016 May 31;133(22):2197-205. doi: 10.1161/CIRCULATIONAHA.115.010268. PMID: 27245648; PMCID: PMC5378385.
13. Baker DW. History of the Joint Commission's pain standards: lessons for today's prescription opioid epidemic. JAMA. 2017 Mar 21;317(11):1117-1118. doi: 10.1001/jama.2017.0935. PMID: 28241189.
14. Manchikanti L, Singh A. Therapeutic opioids: a ten-year perspective on the complexities and complications of the escalating use, abuse, and nonmedical use of opioids. Pain Physician. 2008 Mar;11(2 Suppl):S63-88. PMID: 18443641.
15. Lindenhovius AL, Helmerhorst GT, Schnellen AC, et al. Differences in prescription of narcotic pain medication after operative treatment of hip and ankle fractures in the United States and The Netherlands. J Trauma. 2009 Jul;67(1):160-4. doi: 10.1097/TA.0b013e31818c12ee. Erratum in: J Trauma. 2010 Mar;68(3):744.
16. Helmerhorst GT, Lindenhovius AL, Vrahas M, et al. Satisfaction with pain relief after operative treatment of an ankle fracture. Injury. 2012 Nov;43(11):1958-61. doi: 10.1016/j.injury.2012.08.018. Epub 2012 Aug 16. PMID: 22901424.
17. Joseph V. Pergolizzi, Peter Magnusson, Jo Ann LeQuang, et al. Can NSAIDs and acetaminophen effectively replace opioid treatment options for acute pain? Expert Opinion Pharmacother. 2021; 22(9):1119-1126, DOI: 10.1080/14656566.2021.1901885
18. Chang AK, Bijur PE, Esses D, et al. Effect of a single dose of oral opioid and nonopioid analgesics on acute extremity pain in the emergency department: a randomized clinical trial. JAMA. 2017 Nov 7;318(17):1661-1667. doi: 10.1001/jama.2017.16190. PMID: 29114833; PMCID: PMC5818795.
19. Helmerhorst GTT, Zwiers R, Ring D, et al. Pain relief after operative treatment of an extremity fracture: a noninferiority randomized controlled trial. J Bone Joint Surg Am. 2017 Nov 15;99(22):1908-15.
20. Saini S, McDonald EL, Shakked R, et al. Prospective evaluation of utilization patterns and prescribing guidelines of opioid consumption following orthopedic foot and ankle surgery. Foot Ankle Int. 2018 Nov;39(11):1257-1265. doi: 10.1177/1071100718790243. Epub 2018 Aug 19. PMID: 30124084.
21. No authors listed. “Weak" opioid analgesics. Codeine, dihydrocodeine and tramadol: no less risky than morphine. Prescrire Int. 2016 Feb;25(168):45-50. PMID: 27042732.
22. Edwards JE, McQuay HJ, Moore RA. Combination analgesic efficacy: individual patient data meta-analysis of single-dose oral tramadol plus acetaminophen in acute postoperative pain. J Pain Symptom Manage. 2002 Feb;23(2):121-30. doi: 10.1016/s0885-3924(01)00404-3. PMID: 11844632.
23. Brattwall M, Turan I, Jakobsson J. Pain management after elective hallux valgus surgery: a prospective randomized double-blind study comparing etoricoxib and tramadol. Anesth Analg. 2010 Aug;111(2):544-9. doi: 10.1213/ANE.0b013e3181e3d87c. Epub 2010 Jun 28. PMID: 20584877.
24. Finney FT, Gossett TD, Hu HM, et al. New persistent opioid use following common forefoot procedures for the treatment of hallux valgus. J Bone Joint Surg Am. 2019 Apr 17;101(8):722-729. doi: 10.2106/JBJS.18.00793. PMID: 30994590.
25. Kvarda P, Hagemeijer NC, Waryasz G, et al. Opioid consumption rate following foot and ankle surgery. Foot Ankle Int. 2019 Aug;40(8):905-913. doi: 10.1177/1071100719848354. Epub 2019 May 21. PMID: 31113306.
26. Zhu H, Gao Y, Zhang C, Zheng X. A prospective evaluation of patient-reported opioid utilization after nonoperative treatment of fractures and dislocations. J Bone Joint Surg Am. 2018 Jul 18;100(14):1177-83
27. Basilico M, Bhashyam AR, Harris MB, et al. Prescription opioid type and the likelihood of prolonged opioid use after orthopaedic surgery. J Am Acad Orthop Surg. 2019 May 1;27(9):e423-e429. doi: 10.5435/JAAOS-D-17-00663. PMID: 30289795; PMCID: PMC6590520.
28. Kharasch ED, Brunt LM. Perioperative opioids and public health. Anesthesiology. 2016 Apr;124(4):960-5. doi: 10.1097/ALN.0000000000001012. PMID: 26808634.
29. Jones CM. Heroin use and heroin use risk behaviors among nonmedical users of prescription opioid pain relievers - United States, 2002-2004 and 2008-2010. Drug Alcohol Depend. 2013 Sep 1;132(1-2):95-100. doi: 10.1016/j.drugalcdep.2013.01.007. Epub 2013 Feb 12. PMID: 23410617.
30. Lipari RN, Hughes A. How people obtain the prescription pain relievers they misuse. 2017 Jan 12. In: The CBHSQ Report. Rockville (MD): Substance Abuse and Mental Health Services Administration (US); 2013–. PMID: 28252901.
31. Hyland SJ, Brockhaus KK, Vincent WR, et al. Perioperative pain management and opioid stewardship: a practical guide. Healthcare (Basel). 2021;9(3):333. Published 2021 Mar 16. doi:10.3390/healthcare9030333
32. Buchheit T, Zura R, Wang Z, et al. Opioid exposure is associated with nonunion risk in a traumatically injured population: An inception cohort study. Injury. 2018 Jul;49(7):1266-1271. doi: 10.1016/j.injury.2018.05.004. Epub 2018 May 21. PubMed PMID: 29801700.
33. George MD, Baker JF, Leonard CE, et al. Risk of nonunion with nonselective NSAIDs, COX-2 inhibitors, and Opioids. J Bone Joint Surg Am. 2020 Jul 15;102(14):1230-1238. doi: 10.2106/JBJS.19.01415. PMID: 32675672; PMCID: PMC7508275.
34. Kim H, Kim DH, Kim DM, et al. Do nonsteroidal anti-inflammatory or COX-2 inhibitor drugs increase the nonunion or delayed union rates after fracture surgery? A propensity-score-matched study. J Bone Joint Surg Am. 2021 Aug 4;103(15):1402-1410. doi: 10.2106/JBJS.20.01663. PubMed PMID: 34101675.
35. Coluzzi F, Scerpa MS, Centanni M. The effect of opiates on bone formation and bone healing. Curr Osteoporos Rep. 2020 Jun;18(3):325-335. doi: 10.1007/s11914-020-00585-4. PMID: 32249381.
36. Bawor M, Bami H, Dennis BB, et al. Testosterone suppression in opioid users: a systematic review and meta-analysis. Drug Alcohol Depend. 2015 Apr 1;149:1-9. doi: 10.1016/j.drugalcdep.2015.01.038. Epub 2015 Feb 8. PMID: 25702934.
37. Coluzzi F, Billeci D, Maggi M, et al. Testosterone deficiency in non-cancer opioid-treated patients. J Endocrinol Invest. 2018 Dec;41(12):1377-1388. doi: 10.1007/s40618-018-0964-3. Epub 2018 Oct 20. PMID: 30343356; PMCID: PMC6244554.
38. Fimmel S, Zouboulis CC. Influence of physiological androgen levels on wound healing and immune status in men. Aging Male. 2005 Sep-Dec;8(3-4):166-74. doi: 10.1080/13685530500233847. PMID: 16390741.
39. Demling RH. The role of anabolic hormones for wound healing in catabolic states. J Burns Wounds. 2005 Jan 17;4:e2. PMID: 16921407; PMCID: PMC1501119.
40. Liang X, Liu R, Chen C, et al. Opioid system modulates the immune function: a review. Transl Perioper Pain Med. 2016;1(1):5-13. PMID: 26985446; PMCID: PMC4790459.
41. McCarthy L, Wetzel M, Sliker JK, et al. Opioids, opioid receptors, and the immune response. Drug Alcohol Depend. 2001 Apr 1;62(2):111-23. doi: 10.1016/s0376-8716(00)00181-2. PMID: 11245967.
42. Sacerdote P. Opioids and the immune system. Palliat Med. 2006;20 Suppl 1:s9-15. PMID: 16764216.
43. Plein LM, Rittner HL. Opioids and the immune system - friend or foe. Br J Pharmacol. 2018 Jul;175(14):2717-2725. doi: 10.1111/bph.13750. Epub 2017 Mar 23. PMID: 28213891; PMCID: PMC6016673.
44. Colvin LA, Bull F, Hales TG. Perioperative opioid analgesia-when is enough too much? A review of opioid-induced tolerance and hyperalgesia. Lancet. 2019;393(10180):1558‐1568. doi:10.1016/S0140-6736(19)30430-1
45. Mammoto T, Fujie K, Taguchi N, et al. Short-term effects of early postoperative celecoxib administration for pain, sleep quality, and range of motion after total knee arthroplasty: a randomized controlled trial. J Arthroplasty. 2021 Feb;36(2):526-531. doi: 10.1016/j.arth.2020.08.018. Epub 2020 Aug 18. PubMed PMID: 32900564.
46. Cronin A, Keifer JC, Baghdoyan HA, et al. Opioid inhibition of rapid eye movement sleep by a specific mu receptor agonist. Br J Anaesth. 1995 Feb;74(2):188-92. doi: 10.1093/bja/74.2.188. PubMed PMID: 7696070.
47. Dimsdale JE, Norman D, DeJardin D, et al. The effect of opioids on sleep architecture. J Clin Sleep Med. 2007 Feb 15;3(1):33-6. PubMed PMID: 17557450.
48. Wei H, Zhao W, Wang YX, et al. Pain-related behavior following REM sleep deprivation in the rat: influence of peripheral nerve injury, spinal glutamatergic receptors and nitric oxide. Brain Res. 2007 May 7;1148:105-12. doi: 10.1016/j.brainres.2007.02.040. Epub 2007 Feb 24. PubMed PMID: 17368427.
49. Krause AJ, Prather AA, Wager TD, et al. The pain of sleep loss: a brain characterization in humans. J Neurosci. 2019 Mar 20;39(12):2291-2300. doi: 10.1523/JNEUROSCI.2408-18.2018. Epub 2019 Jan 28. PubMed PMID: 30692228; PubMed Central PMCID: PMC6433768
50. Brands, B, Marsh, D, Busto, U, et al. Comparison of heroin and hydromorphone in opioid users. Clin Pharmacol Therapeutics. 2004; 75: P3-P3. https://doi.org/10.1016/j.clpt.2003.11.008
51. Oviedo-Joekes E, Guh D, Brissette S, et al. Hydromorphone compared with diacetylmorphine for long-term opioid dependence: a randomized clinical trial. JAMA Psychiatry. 2016 May 1;73(5):447-55. doi: 10.1001/jamapsychiatry.2016.0109. PMID: 27049826.
52. Miotto K, Cho AK, Khalil MA, et al. Trends in tramadol: pharmacology, metabolism, and misuse. Anesth Analg. 2017 Jan;124(1):44-51. doi: 10.1213/ANE.0000000000001683. PMID: 27861439.
53. Smith HS. The metabolism of opioid agents and the clinical impact of their active metabolites. Clin J Pain. 2011 Nov-Dec;27(9):824-38. doi: 10.1097/AJP.0b013e31821d8ac1. PMID: 21677572.
54. Eizadi-Mood N, Ozcan D, Sabzghabaee AM, et al. Does naloxone prevent seizure in tramadol intoxicated patients? Int J Prev Med. 2014;5(3):302-307.
55. Ehlers TM, Kruse DL. Tramadol: the "safe" opioid? Podiatry Today. Published June 2022.
56. Ohnuma T, Raghunathan K, Ellis AR, et al. Effects of acetaminophen, NSAIDs, gabapentinoids, and their combinations on postoperative pulmonary complications after total hip or knee arthroplasty. Pain Med. 2020 Oct 1;21(10):2385-2393. doi: 10.1093/pm/pnaa017. PMID: 32101316.
57. Ge DJ, Qi B, Tang G, et al. Intraoperative dexmedetomidine promotes postoperative analgesia and recovery in patients after abdominal hysterectomy: a double-blind, randomized clinical Trial. Sci Rep. 2016 Feb 23;6:21514. doi: 10.1038/srep21514. PMID: 26903197; PMCID: PMC4763240.
58. Jessen Lundorf L, Korvenius Nedergaard H, Møller AM. Perioperative dexmedetomidine for acute pain after abdominal surgery in adults. Cochrane Database Syst Rev. 2016 Feb 18;2:CD010358. doi: 10.1002/14651858.CD010358.pub2. PMID: 26889627.
59. Wieruszewski PM, Wittwer ED. It's all in the details: dexmedetomidine and acute kidney injury after cardiac surgery. J Cardiothorac Vasc Anesth. 2020 Sep;34(9):2549. doi: 10.1053/j.jvca.2020.04.018. Epub 2020 Apr 28. PMID: 32448634.
60. Zhu A, Benzon HA, Anderson TA. Evidence for the efficacy of systemic opioid-sparing analgesics in pediatric surgical populations: a systematic review. Anesth Analg. 2017 Nov;125(5):1569-1587. doi: 10.1213/ANE.0000000000002434. PMID: 29049110.
61. Pockett S. Spinal cord synaptic plasticity and chronic pain. Anesth Analg. 1995 Jan;80(1):173-9. doi: 10.1097/00000539-199501000-00026. PMID: 7802274.
62. Shin HJ, Kim EY, Na HS, et al. Magnesium sulphate attenuates acute postoperative pain and increased pain intensity after surgical injury in staged bilateral total knee arthroplasty: a randomized, double-blinded, placebo-controlled trial. Br J Anaesth. 2016 Oct;117(4):497-503. doi: 10.1093/bja/aew227. Epub 2016 Oct 17. PMID: 28077538.
63. Oh TK, Chung SH, Park J, et al. Effects of perioperative magnesium sulfate administration on postoperative chronic knee pain in patients undergoing total knee arthroplasty: a retrospective evaluation. J Clin Med. 2019 Dec 17;8(12):2231. doi: 10.3390/jcm8122231. PMID: 31861187; PMCID: PMC6947579.
64. Brown EN, Pavone KJ, Naranjo M. Multimodal general anesthesia: theory and practice. Anesth Analg. 2018;127(5):1246‐1258. doi:10.1213/ANE.0000000000003668
65. Li JW, Ma YS, Xiao LK. Postoperative pain management in total knee arthroplasty. Orthop Surg. 2019;11(5):755-761. doi:10.1111/os.12535
Disclaimer: The views and opinions expressed are those of the author(s) and do not necessarily reflect the official policy or position of Podiatry Today or HMP Global, their employees and affiliates. Any content provided by our bloggers or authors are of their opinion and are not intended to malign any religion, ethnic group, club, association, organization, company, individual, anyone or anything.
