Preoperative opioid use: a modifiable risk factor for poor postoperative outcomes

Abstract

And far and wide, in a scarlet tide, the poppy's bonfire spreadBayard Taylor (1825–1878) Patients with chronic pain taking long-term opioids and presenting for surgery are more likely to have a turbulent perioperative course than their opioid-naive counterparts. Their postoperative pain can be more challenging to manage,1Macintyre P.E. Roberts L.J. Huxtable C.A. Management of opioid-tolerant patients with acute pain: approaching the challenges.Drugs. 2020; 80: 9-21Crossref PubMed Scopus (9) Google Scholar and they have a higher risk of opioid-induced ventilatory impairment and persistent postoperative opioid use.2Levy N. Quinlan J. El-Boghdadly K. et al.An international multidisciplinary consensus statement on the prevention of opioid-related harm in adult surgical patients.Anaesthesia. 2021; 76: 520-536Crossref PubMed Scopus (46) Google Scholar In addition, there are some less well-known adverse effects of long-term opioid therapy that can impact on short- and long-term postoperative outcomes. These may affect both the patient in terms of complication rates and postoperative recovery trajectories, and the healthcare system in terms of costs, including those related to longer hospital stay. Some of these adverse outcomes may be related to the recognised immunosuppressive effects of opioids and to opioid-related endocrinopathies. There has been a significant increase in the number of patients who have been prescribed opioids over the past 30 yr1Macintyre P.E. Roberts L.J. Huxtable C.A. Management of opioid-tolerant patients with acute pain: approaching the challenges.Drugs. 2020; 80: 9-21Crossref PubMed Scopus (9) Google Scholar particularly for the treatment of chronic non-cancer pain, and many of these patients will be presenting for surgery. Patients awaiting elective surgery (e.g. total joint arthroplasty) may be on a waiting list for some time, prolonged further because of the impact of the COVID-19 pandemic, which presents an opportunity to address existing long-term opioid use and mitigate the risks.3Levy N. Selwyn D.A. Lobo D.N. Turning ‘waiting lists’ for elective surgery into ‘preparation lists’.Br J Anaesth. 2021; 126: 1-5Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Numerous recent publications have shown that long-term preoperative opioid use is associated with a higher risk of both short- and long-term adverse postoperative outcomes after a number of different types of surgery.4Bedard N.A. DeMik D.E. Dowdle S.B. Owens J.M. Liu S.S. Callaghan J.J. Does preoperative opioid use increase the risk of early revision total hip arthroplasty?.J Arthroplas. 2018; 33: S154-S156Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 5Blevins Peratikos M. Weeks H.L. Pisansky A.J.B. Yong R.J. Stringer E.A. Effect of preoperative opioid use on adverse outcomes, medical spending, and persistent opioid use following elective total joint arthroplasty in the United States: a large retrospective cohort study of administrative claims data.Pain Med. 2020; 21: 521-531Crossref PubMed Scopus (40) Google Scholar, 6Jain N. Brock J.L. Malik A.T. Phillips F.M. Khan S.N. Prediction of complications, readmission, and revision surgery based on duration of preoperative opioid use: analysis of major joint replacement and lumbar fusion.J Bone Jt Surg Am. 2019; 101: 384-391Crossref PubMed Scopus (56) Google Scholar, 7Kalakoti P. Volkmar A.J. Bedard N.A. Eisenberg J.M. Hendrickson N.R. Pugely A.J. Preoperative chronic opioid therapy negatively impacts long-term outcomes following cervical fusion surgery.Spine (Phila Pa 1976). 2019; 44: 1279-1286Crossref PubMed Scopus (19) Google Scholar, 8Shadbolt C. Schilling C. Inacio M.C. et al.Opioid use and total joint replacement.Curr Rheumatol Rep. 2020; 22: 58Crossref PubMed Scopus (8) Google Scholar, 9Waljee J.F. Cron D.C. Steiger R.M. Zhong L. Englesbe M.J. Brummett C.M. Effect of preoperative opioid exposure on healthcare utilization and expenditures following elective abdominal surgery.Ann Surg. 2017; 265: 715-721Crossref PubMed Scopus (106) Google Scholar, 10Wilson J.M. Farley K.X. Bradbury T.L. Erens G.A. Guild G.N. Preoperative opioid use is a risk factor for complication and increased healthcare utilization following revision total knee arthroplasty.Knee. 2020; 27: 1121-1127Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 11Wilson J.M. Farley K.X. Erens G.A. Bradbury T.L. Guild 3rd, G.N. Preoperative opioid use is a risk factor for complication following revision total hip arthroplasty.Hip Int. August 6, 2020; https://doi.org/10.1177/1120700020947400Crossref Scopus (6) Google Scholar, 12Wilson J.M. Farley K.X. Gottschalk M.B. Daly C.A. Wagner E.R. Preoperative opioid use is an independent risk factor for complication, revision, and increased health care utilization following primary total shoulder arthroplasty.J Shoulder Elbow Surg. 2021; 30: 1025-1033Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 13Yerneni K. Nichols N. Abecassis Z.A. Karras C.L. Tan L.A. Preoperative opioid use and clinical outcomes in spine surgery: a systematic review.Neurosurgery. 2020; 86: E490-E507Crossref PubMed Scopus (12) Google Scholar, 14Aizpuru M. Gallo L.K. Farley K.X. et al.Economic burden and clinical impact of preoperative opioid dependence for patients undergoing lower extremity bypass surgery.J Vasc Surg. 2020; 71: 1613-1619Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar These include increased rates of surgical infection and revision surgery, higher readmission rates, longer lengths of hospital stay, and higher medical costs after surgery (Table 1).4Bedard N.A. DeMik D.E. Dowdle S.B. Owens J.M. Liu S.S. Callaghan J.J. Does preoperative opioid use increase the risk of early revision total hip arthroplasty?.J Arthroplas. 2018; 33: S154-S156Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 5Blevins Peratikos M. Weeks H.L. Pisansky A.J.B. Yong R.J. Stringer E.A. Effect of preoperative opioid use on adverse outcomes, medical spending, and persistent opioid use following elective total joint arthroplasty in the United States: a large retrospective cohort study of administrative claims data.Pain Med. 2020; 21: 521-531Crossref PubMed Scopus (40) Google Scholar, 6Jain N. Brock J.L. Malik A.T. Phillips F.M. Khan S.N. Prediction of complications, readmission, and revision surgery based on duration of preoperative opioid use: analysis of major joint replacement and lumbar fusion.J Bone Jt Surg Am. 2019; 101: 384-391Crossref PubMed Scopus (56) Google Scholar, 7Kalakoti P. Volkmar A.J. Bedard N.A. Eisenberg J.M. Hendrickson N.R. Pugely A.J. Preoperative chronic opioid therapy negatively impacts long-term outcomes following cervical fusion surgery.Spine (Phila Pa 1976). 2019; 44: 1279-1286Crossref PubMed Scopus (19) Google Scholar, 8Shadbolt C. Schilling C. Inacio M.C. et al.Opioid use and total joint replacement.Curr Rheumatol Rep. 2020; 22: 58Crossref PubMed Scopus (8) Google Scholar, 9Waljee J.F. Cron D.C. Steiger R.M. Zhong L. Englesbe M.J. Brummett C.M. Effect of preoperative opioid exposure on healthcare utilization and expenditures following elective abdominal surgery.Ann Surg. 2017; 265: 715-721Crossref PubMed Scopus (106) Google Scholar, 10Wilson J.M. Farley K.X. Bradbury T.L. Erens G.A. Guild G.N. Preoperative opioid use is a risk factor for complication and increased healthcare utilization following revision total knee arthroplasty.Knee. 2020; 27: 1121-1127Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 11Wilson J.M. Farley K.X. Erens G.A. Bradbury T.L. Guild 3rd, G.N. Preoperative opioid use is a risk factor for complication following revision total hip arthroplasty.Hip Int. August 6, 2020; https://doi.org/10.1177/1120700020947400Crossref Scopus (6) Google Scholar, 12Wilson J.M. Farley K.X. Gottschalk M.B. Daly C.A. Wagner E.R. Preoperative opioid use is an independent risk factor for complication, revision, and increased health care utilization following primary total shoulder arthroplasty.J Shoulder Elbow Surg. 2021; 30: 1025-1033Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 13Yerneni K. Nichols N. Abecassis Z.A. Karras C.L. Tan L.A. Preoperative opioid use and clinical outcomes in spine surgery: a systematic review.Neurosurgery. 2020; 86: E490-E507Crossref PubMed Scopus (12) Google Scholar, 14Aizpuru M. Gallo L.K. Farley K.X. et al.Economic burden and clinical impact of preoperative opioid dependence for patients undergoing lower extremity bypass surgery.J Vasc Surg. 2020; 71: 1613-1619Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar The risk of some of these poorer outcomes (e.g. length of hospital stay, surgical infection and revision rates, readmission rates, and medical costs after surgery) has been reported to be proportional to opioid dose,5Blevins Peratikos M. Weeks H.L. Pisansky A.J.B. Yong R.J. Stringer E.A. Effect of preoperative opioid use on adverse outcomes, medical spending, and persistent opioid use following elective total joint arthroplasty in the United States: a large retrospective cohort study of administrative claims data.Pain Med. 2020; 21: 521-531Crossref PubMed Scopus (40) Google Scholar,9Waljee J.F. Cron D.C. Steiger R.M. Zhong L. Englesbe M.J. Brummett C.M. Effect of preoperative opioid exposure on healthcare utilization and expenditures following elective abdominal surgery.Ann Surg. 2017; 265: 715-721Crossref PubMed Scopus (106) Google Scholar,13Yerneni K. Nichols N. Abecassis Z.A. Karras C.L. Tan L.A. Preoperative opioid use and clinical outcomes in spine surgery: a systematic review.Neurosurgery. 2020; 86: E490-E507Crossref PubMed Scopus (12) Google Scholar but many studies do not state dosages.Table 1Adverse effects of long-term opioid therapy on short- and long-term postsurgical outcomes.Operation typeOutcomesHip and knee arthroplasty: primary4Bedard N.A. DeMik D.E. Dowdle S.B. Owens J.M. Liu S.S. Callaghan J.J. Does preoperative opioid use increase the risk of early revision total hip arthroplasty?.J Arthroplas. 2018; 33: S154-S156Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 5Blevins Peratikos M. Weeks H.L. Pisansky A.J.B. Yong R.J. Stringer E.A. Effect of preoperative opioid use on adverse outcomes, medical spending, and persistent opioid use following elective total joint arthroplasty in the United States: a large retrospective cohort study of administrative claims data.Pain Med. 2020; 21: 521-531Crossref PubMed Scopus (40) Google Scholar, 6Jain N. Brock J.L. Malik A.T. Phillips F.M. Khan S.N. Prediction of complications, readmission, and revision surgery based on duration of preoperative opioid use: analysis of major joint replacement and lumbar fusion.J Bone Jt Surg Am. 2019; 101: 384-391Crossref PubMed Scopus (56) Google Scholar,8Shadbolt C. Schilling C. Inacio M.C. et al.Opioid use and total joint replacement.Curr Rheumatol Rep. 2020; 22: 58Crossref PubMed Scopus (8) Google ScholarIncreased risk of surgical site and periprosthetic infectionsIncreased rate of early-revision arthroplastyProlonged hospital stayGreater likelihood of non-home dischargeHigher readmission ratesHigher healthcare costs (from before admission to up to 1 yr after discharge)Hip and knee arthroplasty: revision10Wilson J.M. Farley K.X. Bradbury T.L. Erens G.A. Guild G.N. Preoperative opioid use is a risk factor for complication and increased healthcare utilization following revision total knee arthroplasty.Knee. 2020; 27: 1121-1127Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar,11Wilson J.M. Farley K.X. Erens G.A. Bradbury T.L. Guild 3rd, G.N. Preoperative opioid use is a risk factor for complication following revision total hip arthroplasty.Hip Int. August 6, 2020; https://doi.org/10.1177/1120700020947400Crossref Scopus (6) Google ScholarIncreased risk of surgical site and periprosthetic joint infectionProlonged hospital stayGreater likelihood of non-home dischargeHigher readmissions ratesHigher number of post-discharge emergency department visitsIncreased risk of further revision surgeryShoulder arthroplasty12Wilson J.M. Farley K.X. Gottschalk M.B. Daly C.A. Wagner E.R. Preoperative opioid use is an independent risk factor for complication, revision, and increased health care utilization following primary total shoulder arthroplasty.J Shoulder Elbow Surg. 2021; 30: 1025-1033Abstract Full Text Full Text PDF PubMed Scopus (9) Google ScholarIncreases in surgical site and periprosthetic joint infectionsProlonged hospital stayGreater likelihood of non-home dischargeHigher readmission ratesHigher number of post-discharge emergency department visitsHigher healthcare costsSpinal surgery6Jain N. Brock J.L. Malik A.T. Phillips F.M. Khan S.N. Prediction of complications, readmission, and revision surgery based on duration of preoperative opioid use: analysis of major joint replacement and lumbar fusion.J Bone Jt Surg Am. 2019; 101: 384-391Crossref PubMed Scopus (56) Google Scholar,7Kalakoti P. Volkmar A.J. Bedard N.A. Eisenberg J.M. Hendrickson N.R. Pugely A.J. Preoperative chronic opioid therapy negatively impacts long-term outcomes following cervical fusion surgery.Spine (Phila Pa 1976). 2019; 44: 1279-1286Crossref PubMed Scopus (19) Google Scholar,13Yerneni K. Nichols N. Abecassis Z.A. Karras C.L. Tan L.A. Preoperative opioid use and clinical outcomes in spine surgery: a systematic review.Neurosurgery. 2020; 86: E490-E507Crossref PubMed Scopus (12) Google ScholarIncreased risks of wound complications (including surgical site infection)Higher readmission ratesHigher number of post-discharge emergency department visitsHigher lumbar and cervical fusion revision ratesProlonged hospital staysHigher healthcare costsElective abdominal surgery9Waljee J.F. Cron D.C. Steiger R.M. Zhong L. Englesbe M.J. Brummett C.M. Effect of preoperative opioid exposure on healthcare utilization and expenditures following elective abdominal surgery.Ann Surg. 2017; 265: 715-721Crossref PubMed Scopus (106) Google ScholarProlonged hospital staysHigher readmission ratesHigher inpatient and postoperative costsGreater likelihood of non-home dischargeLower extremity bypass surgery14Aizpuru M. Gallo L.K. Farley K.X. et al.Economic burden and clinical impact of preoperative opioid dependence for patients undergoing lower extremity bypass surgery.J Vasc Surg. 2020; 71: 1613-1619Abstract Full Text Full Text PDF PubMed Scopus (9) Google ScholarHigher rates of surgical site infectionProlonged hospital stayHigher hospitals costs Open table in a new tab The effect of opioids on the immune system is attributable to the presence of opioid receptors on the surface of various immune cells, including natural killer cells, macrophages and dendritic cells of the innate immune system, and T and B lymphocytes of the adaptive immune system.15Khosrow-Khavar F. Kurteva S. Cui Y. Filion K.B. Douros A. Opioids and the risk of infection: a critical appraisal of the pharmacologic and clinical evidence.Expert Opin Drug Metab Toxicol. 2019; 15: 565-575Crossref PubMed Scopus (15) Google Scholar,16Plein L.M. Rittner H.L. Opioids and the immune system—friend or foe.Br J Pharmacol. 2018; 175: 2717-2725Crossref PubMed Scopus (202) Google Scholar In addition, opioids affect both the hypothalamic–pituitary–adrenal axis and the sympathetic nervous system, both of which modulate immune responses,15Khosrow-Khavar F. Kurteva S. Cui Y. Filion K.B. Douros A. Opioids and the risk of infection: a critical appraisal of the pharmacologic and clinical evidence.Expert Opin Drug Metab Toxicol. 2019; 15: 565-575Crossref PubMed Scopus (15) Google Scholar which may lead to a downregulation of the immune system with resultant immunosuppression. Most in vivo studies looking at the immunosuppressive effects of opioids have been carried out in animals, or human studies with different short-term opioids after surgery, rather than patients taking long-term opioids.17Franchi S. Moschetti G. Amodeo G. Sacerdote P. Do all opioid drugs share the same immunomodulatory properties? A review from animal and human studies.Front Immunol. 2019; 10: 2914Crossref PubMed Scopus (55) Google Scholar Morphine is the most studied opioid and has repeatedly been shown to lead to immune suppression.15Khosrow-Khavar F. Kurteva S. Cui Y. Filion K.B. Douros A. Opioids and the risk of infection: a critical appraisal of the pharmacologic and clinical evidence.Expert Opin Drug Metab Toxicol. 2019; 15: 565-575Crossref PubMed Scopus (15) Google Scholar 'The immunological effects of opioids are many and varied, with some studies showing conflicting results and the degree of immunosuppression differing between opioids; laboratory studies suggest that morphine, dihydrocodeine, fentanyl, methadone, and codeine are the most immunosuppressant, whilst buprenorphine, hydromorphone, oxycodone, tramadol,15Khosrow-Khavar F. Kurteva S. Cui Y. Filion K.B. Douros A. Opioids and the risk of infection: a critical appraisal of the pharmacologic and clinical evidence.Expert Opin Drug Metab Toxicol. 2019; 15: 565-575Crossref PubMed Scopus (15) Google Scholar and possibly tapentadol17Franchi S. Moschetti G. Amodeo G. Sacerdote P. Do all opioid drugs share the same immunomodulatory properties? A review from animal and human studies.Front Immunol. 2019; 10: 2914Crossref PubMed Scopus (55) Google Scholar display the least immunosuppressant effects. Tramadol and tapentadol may have less immunosuppressant effect, as a large proportion of their analgesic effect is exerted via non-opioid receptors.17Franchi S. Moschetti G. Amodeo G. Sacerdote P. Do all opioid drugs share the same immunomodulatory properties? A review from animal and human studies.Front Immunol. 2019; 10: 2914Crossref PubMed Scopus (55) Google Scholar Researchers, whilst confirming the impact of opioids on the immune system, highlight the complexity of interpreting data, with dose and duration effects currently unclear, and the translation of preclinical studies to patient populations.15Khosrow-Khavar F. Kurteva S. Cui Y. Filion K.B. Douros A. Opioids and the risk of infection: a critical appraisal of the pharmacologic and clinical evidence.Expert Opin Drug Metab Toxicol. 2019; 15: 565-575Crossref PubMed Scopus (15) Google Scholar Therefore, it is not currently possible to base the clinical choice of opioid on immunomodulatory effects. Future clinical studies may help elucidate the significance and strength of these heterogeneous effects on patient outcomes. The effects of opioids on the CNS may also contribute to impaired host defence mechanisms that can lead to increased risks of infection. For example, the depressant effects of opioids on the midbrain respiratory centre can lead to impaired coughing, and effects on opioid receptors in the hypothalamic hypocretin/orexin arousal system can cause sedation, all of which can contribute to a higher risk of lower respiratory tract infections.15Khosrow-Khavar F. Kurteva S. Cui Y. Filion K.B. Douros A. Opioids and the risk of infection: a critical appraisal of the pharmacologic and clinical evidence.Expert Opin Drug Metab Toxicol. 2019; 15: 565-575Crossref PubMed Scopus (15) Google Scholar Importantly, for perioperative stakeholders, there is now evidence that chronic opioid use is associated with increased risks of superficial and deep surgical site infections, including periprosthetic joint infection (Table 1).4Bedard N.A. DeMik D.E. Dowdle S.B. Owens J.M. Liu S.S. Callaghan J.J. Does preoperative opioid use increase the risk of early revision total hip arthroplasty?.J Arthroplas. 2018; 33: S154-S156Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 5Blevins Peratikos M. Weeks H.L. Pisansky A.J.B. Yong R.J. Stringer E.A. Effect of preoperative opioid use on adverse outcomes, medical spending, and persistent opioid use following elective total joint arthroplasty in the United States: a large retrospective cohort study of administrative claims data.Pain Med. 2020; 21: 521-531Crossref PubMed Scopus (40) Google Scholar, 6Jain N. Brock J.L. Malik A.T. Phillips F.M. Khan S.N. Prediction of complications, readmission, and revision surgery based on duration of preoperative opioid use: analysis of major joint replacement and lumbar fusion.J Bone Jt Surg Am. 2019; 101: 384-391Crossref PubMed Scopus (56) Google Scholar, 7Kalakoti P. Volkmar A.J. Bedard N.A. Eisenberg J.M. Hendrickson N.R. Pugely A.J. Preoperative chronic opioid therapy negatively impacts long-term outcomes following cervical fusion surgery.Spine (Phila Pa 1976). 2019; 44: 1279-1286Crossref PubMed Scopus (19) Google Scholar, 8Shadbolt C. Schilling C. Inacio M.C. et al.Opioid use and total joint replacement.Curr Rheumatol Rep. 2020; 22: 58Crossref PubMed Scopus (8) Google Scholar, 9Waljee J.F. Cron D.C. Steiger R.M. Zhong L. Englesbe M.J. Brummett C.M. Effect of preoperative opioid exposure on healthcare utilization and expenditures following elective abdominal surgery.Ann Surg. 2017; 265: 715-721Crossref PubMed Scopus (106) Google Scholar, 10Wilson J.M. Farley K.X. Bradbury T.L. Erens G.A. Guild G.N. Preoperative opioid use is a risk factor for complication and increased healthcare utilization following revision total knee arthroplasty.Knee. 2020; 27: 1121-1127Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 11Wilson J.M. Farley K.X. Erens G.A. Bradbury T.L. Guild 3rd, G.N. Preoperative opioid use is a risk factor for complication following revision total hip arthroplasty.Hip Int. August 6, 2020; https://doi.org/10.1177/1120700020947400Crossref Scopus (6) Google Scholar, 12Wilson J.M. Farley K.X. Gottschalk M.B. Daly C.A. Wagner E.R. Preoperative opioid use is an independent risk factor for complication, revision, and increased health care utilization following primary total shoulder arthroplasty.J Shoulder Elbow Surg. 2021; 30: 1025-1033Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 13Yerneni K. Nichols N. Abecassis Z.A. Karras C.L. Tan L.A. Preoperative opioid use and clinical outcomes in spine surgery: a systematic review.Neurosurgery. 2020; 86: E490-E507Crossref PubMed Scopus (12) Google Scholar, 14Aizpuru M. Gallo L.K. Farley K.X. et al.Economic burden and clinical impact of preoperative opioid dependence for patients undergoing lower extremity bypass surgery.J Vasc Surg. 2020; 71: 1613-1619Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar In addition to protecting against infection, the innate and adaptive immune systems protect against cancer, with effective immunosurveillance required to reduce the risk of recurrence or metastasis. There is extensive laboratory research into the potential mechanisms in which opioid use can affect the proliferation of cancer, but this has not translated to clear clinical risk for patients.18Szczepaniak A. Fichna J. Zielinska M. Opioids in cancer development, progression and metastasis: focus on colorectal cancer.Curr Treat Opt Oncol. 2020; 21: 6Crossref PubMed Scopus (14) Google Scholar Large population studies are warranted to examine this association, although current evidence suggests that the fear of cancer occurrence or recurrence is not an indication to withhold opioid therapy.18Szczepaniak A. Fichna J. Zielinska M. Opioids in cancer development, progression and metastasis: focus on colorectal cancer.Curr Treat Opt Oncol. 2020; 21: 6Crossref PubMed Scopus (14) Google Scholar Opioids have an array of effects on the neuroendocrine system and metabolism. Many endocrinopathies related to long-term and, to a lesser extent, short-term opioid use have been identified (Table 2).19Seyfried O. Hester J. Opioids and endocrine dysfunction.Br J Pain. 2012; 6: 17-24Crossref PubMed Google Scholar,20Fountas A. Van Uum S. Karavitaki N. Opioid-induced endocrinopathies.Lancet Diabetes Endocrinol. 2020; 8: 68-80Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar These are often under-recognised and can lead to adverse events. Most importantly, opioid-induced secondary hypoadrenalism can lead to a decreased stress response in patients undergoing all types of surgery, whilst osteopaenia attributable to long-term opioid therapy may impact on outcomes after orthopaedic surgery (Table 2).Table 2Major endocrine and metabolic effects of opioids. Data summarised from Seyfried and Hester19Seyfried O. Hester J. Opioids and endocrine dysfunction.Br J Pain. 2012; 6: 17-24Crossref PubMed Google Scholar and Fountas and colleagues.20Fountas A. Van Uum S. Karavitaki N. Opioid-induced endocrinopathies.Lancet Diabetes Endocrinol. 2020; 8: 68-80Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Effects on growth hormone, prolactin, antidiuretic hormone, oxytocin, and thyroid hormones are variable or less pronounced, and there is no good evidence linking them to adverse post-surgical outcomes. Therefore, they have not been included in the table.Hormone/hormone complexEffectsDuration of treatmentClinical effectsCommentsHypothalamic–pituitary–adrenal axisInhibition of corticotrophin-releasing hormone secretion, resulting in decreased adrenocorticotropic hormone releasePossible direct inhibitory effect on adrenal functionInhibitory effects seen with both short-term and long-term useEffect size may be dose relatedLow basal blood cortisol levelsClinical significance of these findings not clearInstances of Addisonian crisis have been reportedGlucocorticoid therapy may be necessaryImpaired stress response may lead to intraoperative and postoperative hypotensionHypothalamic–pituitary–gonadal axisInhibition of gonadotropin-releasing hormone secretion from the hypothalamus and subsequently the secretion of gonadotropins (luteinising hormone and follicle-stimulating hormone) from the pituitary glandSuppressive effect begins as soon as the drugs are administered and cessation results in axis recovery; also seen with long-term useBone loss, decreased libido, infertility, and depression in both sexesErectile dysfunction, impotence, and decreased muscle mass in men Oligomenorrhoea and amenorrhoea in womenAndrogen deficiency more likely with long-acting opioids than short-acting ones (may be related to duration of effect)Typical opioids tapentadol and buprenorphine may result in milder or no suppressive effectsBone metabolismReduction in bone mineral density indirectly, by causing hypogonadism, and directly, by inhibiting osteoblast activity osteocalcin synthesis and so affecting bone turnoverLong-term useOsteopaeniaOsteoporosisFracturesOther risk factors for decreased bone mineral density and osteoporosis include poor nutritional status, hypogonadism, inhibition of osteoblasts, decreased osteocalcin synthesis, abnormal calcium and parathyroid hormone, and increased bone resorptionThere is an increased risk of bone fracture in patients on opioids, which may also be related to falls and reduced mobilityBody weight and insulinChronic opioid use is associated with weight gain, hyperglycaemia, and worsening diabetes mellitusLong-term useRole in regulating food intake and food choice, reward associated with tasteWeight gainInsulin resistanceDiabetes mellitusMay be a central action via the sympathetic nervous system and impaired insulin secretionHypogonadism is also associated with increased insulin resistance Open table in a new tab Specific attribution of clear causation for many of these adverse effects on short- and long-term postoperative outcomes is not possible from the observational studies published thus far, and the extent to which chronic use of opioids before surgery directly impacts individual outcomes remains unknown. Many of the studies incorporating large cohorts of patients comprise interrogation of hospital, insurance, or other administrative databases, hence may be limited by their retrospective cohort design and reliance on correct coding and data input. Even where studies controlled for some key variables, including patient demographic data and pre-existing comorbidities, other variables, such as patient socio-economic status or hospital- or surgeon-related factors, all of which could impact on patient outcomes, have not been considered.8Shadbolt C. Schilling C. Inacio M.C. et al.Opioid use and total joint replacement.Curr Rheumatol Rep. 2020; 22: 58Crossref PubMed Scopus (8) Google Scholar In addition, definitions and timescales of some of the adverse outcomes vary significantly. For example, the definition of preoperative opioid use may include intermittent or regular use over variable periods (e.g. 3 or 12 months) before surgery, and there is also no consistent definition for the interval between the initial surgery and the time when revision surgery may be considered ‘early’. Furthermore, risk factors may be inter-related. For example, it is known that the prevalence of anxiety and depression is higher in patients taking long-term opioids,1Macintyre P.E. Roberts L.J. Huxtable C.A. Management of opioid-tolerant patients with acute pain: approaching the challenges.Drugs. 2020; 80: 9-21Crossref PubMed Scopus (9) Google Scholar including before surgery,5Blevins Peratikos M. Weeks H.L. Pisansky A.J.B. Yong R.J. Stringer E.A. Effect of preoperative opioid use on adverse outcomes, medical spending, and persistent opioid use following elective total joint arthroplasty in the United States: a large retrospective cohort study of administrative claims data.Pain Med. 2020; 21: 521-531Crossref PubMed Scopus (40) Google Scholar,10Wilson J.M. Farley K.X. Bradbury T.L. Erens G.A. Guild G.N. Preoperative opioid use is a risk factor for complication and increased healthcare utilization following revision total knee arthroplasty.Knee. 2020; 27: 1121-1127Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar,11Wilson J.M. Farley K.X. Erens G.A. Bradbury T.L. Guild 3rd, G.N. Preoperative opioid use is a risk factor for complication following revision total hip arthroplasty.Hip Int. August 6, 2020; https://doi.org/10.1177/1120700020947400Crossref Scopus (6) Google Scholar and that anxiety, depression, and preoperative opioid use are all independent predictors of early-revision hip arthroplasty4Bedard N.A. DeMik D.E. Dowdle S.B. Owens J.M. Liu S.S. Callaghan J.J. Does preoperative opioid use increase the risk of early revision total hip arthroplasty?.J Arthroplas. 2018; 33: S154-S156Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar and length of hospital stay.21Vashishta R. Kendale S.M. Relationship between preoperative antidepressant and antianxiety medications and postoperative hospital length of stay.Anesth Analg. 2019; 128: 248-255Crossref PubMed Scopus (12) Google Scholar Nevertheless, some of the currently available evidence suggests that at least some of the risks associated with preoperative opioid use could be mitigated. For example, although much of the evidence to date about the differences between opioids and their effect on immune function comes from in vitro, animal, or preclinical studies, it may be that changing a patient to a less immunosuppressive opioid some months before surgery may be appropriate,5Blevins Peratikos M. Weeks H.L. Pisansky A.J.B. Yong R.J. Stringer E.A. Effect of preoperative opioid use on adverse outcomes, medical spending, and persistent opioid use following elective total joint arthroplasty in the United States: a large retrospective cohort study of administrative claims data.Pain Med. 2020; 21: 521-531Crossref PubMed Scopus (40) Google Scholar,8Shadbolt C. Schilling C. Inacio M.C. et al.Opioid use and total joint replacement.Curr Rheumatol Rep. 2020; 22: 58Crossref PubMed Scopus (8) Google Scholar although clinical evidence is still lacking. There is some early clinical evidence that reducing or ceasing opioids before surgery may be associated with improved outcomes. It is clear that patients taking opioids before surgery have a higher risk of surgical site and periprosthetic joint infection, prolonged hospital stays, readmission rates, and further revision surgery after redo total hip11Wilson J.M. Farley K.X. Erens G.A. Bradbury T.L. Guild 3rd, G.N. Preoperative opioid use is a risk factor for complication following revision total hip arthroplasty.Hip Int. August 6, 2020; https://doi.org/10.1177/1120700020947400Crossref Scopus (6) Google Scholar and knee arthroplasty,10Wilson J.M. Farley K.X. Bradbury T.L. Erens G.A. Guild G.N. Preoperative opioid use is a risk factor for complication and increased healthcare utilization following revision total knee arthroplasty.Knee. 2020; 27: 1121-1127Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar but these risks were reduced if opioids were ceased 6 months before surgery.10Wilson J.M. Farley K.X. Bradbury T.L. Erens G.A. Guild G.N. Preoperative opioid use is a risk factor for complication and increased healthcare utilization following revision total knee arthroplasty.Knee. 2020; 27: 1121-1127Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar,11Wilson J.M. Farley K.X. Erens G.A. Bradbury T.L. Guild 3rd, G.N. Preoperative opioid use is a risk factor for complication following revision total hip arthroplasty.Hip Int. August 6, 2020; https://doi.org/10.1177/1120700020947400Crossref Scopus (6) Google Scholar Similarly, the rates of surgical site infection, prolonged hospital stays, readmissions, emergency room visits, and revision surgery were higher in patients taking opioids for more than 6 months before surgery, but decreased to levels similar to opioid-naive patients if opioids were ceased 3 months before total hip and knee arthroplasty and lumbar fusion.6Jain N. Brock J.L. Malik A.T. Phillips F.M. Khan S.N. Prediction of complications, readmission, and revision surgery based on duration of preoperative opioid use: analysis of major joint replacement and lumbar fusion.J Bone Jt Surg Am. 2019; 101: 384-391Crossref PubMed Scopus (56) Google Scholar It is important to note that these results are observational and retrospective, indicating a patient's willingness to reduce opioids, rather than randomised enforced opioid reduction or cessation. Nevertheless, preoperative opioid use should be considered a modifiable risk factor for poor outcomes after surgery, along the same lines as diabetes mellitus, morbid obesity, smoking, preoperative anaemia, and psychological comorbidities, at least for major joint replacement surgery.3Levy N. Selwyn D.A. Lobo D.N. Turning ‘waiting lists’ for elective surgery into ‘preparation lists’.Br J Anaesth. 2021; 126: 1-5Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Preoperative optimisation of these risk factors, including weaning of opioid doses, may result in better patient outcomes and reduced costs after surgery. It is now clear that long-term opioids are neither safe nor effective for chronic pain, with side-effects and complications that are worsening, not improving, quality of life.22Dowell D. Haegerich T.M. Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016.JAMA. 2016; 315: 1624-1645Crossref PubMed Scopus (2218) Google Scholar Many patients presenting for surgery will have been inappropriately started on opioids previously and, irrespective of surgery, should have their opioids tapered and stopped to reduce everyday risk and improve functional outcomes. Indeed, there is evidence that tapering of opioid doses in patients with chronic pain reduces pain or maintains the same level of pain rather than leading to increased pain in the vast majority.23Dowell D. Haegerich T. Chou R. No shortcuts to safer opioid prescribing.N Engl J Med. 2019; 380: 2285-2287Crossref PubMed Scopus (207) Google Scholar Opioid tapering is not a simple intervention, with a recent softening of advice coming from the US Centers for Disease Control and Prevention23Dowell D. Haegerich T. Chou R. No shortcuts to safer opioid prescribing.N Engl J Med. 2019; 380: 2285-2287Crossref PubMed Scopus (207) Google Scholar after concern that their 2016 guideline,22Dowell D. Haegerich T.M. Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016.JAMA. 2016; 315: 1624-1645Crossref PubMed Scopus (2218) Google Scholar which proposed maximum opioid doses for chronic pain, led to abrupt tapering and cessation of opioids.23Dowell D. Haegerich T. Chou R. No shortcuts to safer opioid prescribing.N Engl J Med. 2019; 380: 2285-2287Crossref PubMed Scopus (207) Google Scholar Many patients established on long-term high-dose opioids have complex dependence, with opioids providing a ‘chemical crutch’ for significant psychological comorbidities, both predating opioid initiation and as a result of long-term opioid changes in affective processing.24Quinlan J. Willson H. Grange K. Hopes and fears before opioid tapering: a quantitative and qualitative study of patients with chronic pain and long-term opioids.Br J Pain. 2021; 15: 120-128Crossref PubMed Scopus (2) Google Scholar Enforced or rapid tapering exposes these patients to risk, precipitating mental health crises in vulnerable patients, and the danger of illicit drug seeking and suicide.8Shadbolt C. Schilling C. Inacio M.C. et al.Opioid use and total joint replacement.Curr Rheumatol Rep. 2020; 22: 58Crossref PubMed Scopus (8) Google Scholar Opioid tapers should be slow, achievable, and patient centred, focusing on non-opioid pain management strategies together with psychological support for the co-factors of pain.25McAnally H. Rationale for and approach to preoperative opioid weaning: a preoperative optimization protocol.Perioper Med (Lond). 2017; 6: 19Crossref PubMed Google Scholar This raises the issue of who should lead a preoperative opioid taper and what constitutes a reasonable timescale; general practitioners may not feel confident to do so,26White R. Hayes C. Boyes A.W. Chiu S. Paul C.L. General practitioners and management of chronic noncancer pain: a cross-sectional survey of influences on opioid deprescribing.J Pain Res. 2019; 12: 467-475Crossref PubMed Scopus (9) Google Scholar whilst pain services may not have sufficient capacity. Identifying these patients at pre-assessment is unlikely to provide sufficient time to achieve a worthwhile dose reduction. The discussion at the initial surgical consultation should include opioid reduction as a prehabilitation goal for elective surgery,3Levy N. Selwyn D.A. Lobo D.N. Turning ‘waiting lists’ for elective surgery into ‘preparation lists’.Br J Anaesth. 2021; 126: 1-5Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar with an acceptance that some patients will not be able to achieve this. The adverse effects of long-term preoperative use on surgical outcomes should be discussed as part of the shared decision-making and consent process. In addition to international guidance,2Levy N. Quinlan J. El-Boghdadly K. et al.An international multidisciplinary consensus statement on the prevention of opioid-related harm in adult surgical patients.Anaesthesia. 2021; 76: 520-536Crossref PubMed Scopus (46) Google Scholar the Faculty of Pain Medicine and the Royal College of Anaesthetists have recently published multidisciplinary evidence-based consensus guidelines on the perioperative use of opioids to assist in the management of these complex patients.27Srivastava D. Hill S. Carty S. et al.Surgery and opioids: evidence-based expert consensus guidelines on the perioperative use of opioids in the United Kingdom.Br J Anaesth. 2021; 126: 1208-1216Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar The impact of preoperative opioids on surgical outcomes extends beyond complex postoperative pain management. An increased risk of wound and periprosthetic infections, higher arthroplasty and spinal fusion revision rates, and longer lengths of hospital stay with higher healthcare costs may be related to the impact of long-term opioid use on immune function and endocrine systems. Weaning of opioids before surgery provides an opportunity to mitigate these risks and improve patient outcomes, but needs to be done collaboratively with the patient, primary care, and pain services, and with enough time to allow gradual and manageable dose reduction.