August 2018 FAQs

What data support the use of andexanet alfa (ANDEXXA) for the reversal of factor Xa inhibitors?

Background

The direct factor Xa inhibitors apixaban, edoxaban, and rivaroxaban are recommended antithrombotic therapy for the prevention and treatment of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE).¹ They are currently preferred to vitamin K antagonists (VKA) for DVT of the leg or PE without cancer. This is a change from the 2012 CHEST guideline recommendations where VKA therapy was preferred to low-molecular-weight heparin (LMWH) and LMWH preferred to dabigatran or rivaroxaban for long-term therapy in patients with DVT of the leg or PE without cancer.² 

The direct oral anticoagulants (DOACs) – dabigatran (Pradaxa), rivaroxaban (Xarelto), apixaban (Eliquis), edoxaban (Savaysa), and betrixaban (Bevyxxa) – are attractive alternative agents to the traditional VKA, warfarin, for several reasons including lack of intense monitoring requirements and less cumbersome drug interactions.³ While some food and drug interactions do exist with the DOACs, they are not as abundant and restrictive to patients as those with warfarin are. However, the risk of bleeding with the DOACs and lack of specific reversal agents have been major concerns.^3,4 Until 2015 when idarucizumab (Praxbind) was approved for dabigatran reversal and 2018 when andexanet alfa (Andexxa) was approved for apixaban and rivaroxaban reversal, no DOAC-specific reversal agent was available.^3,5,6 With the absence of specific reversal agents, inactivated prothrombin complex concentrates (PCCs) were generally considered first-line agents for factor Xa inhibitor-associated major bleeding.^3,4

Andexanet alfa is a recombinant modified human coagulation factor Xa protein that exerts a procoagulant effect by binding and sequestering apixaban and rivaroxaban.⁶ It also inhibits tissue factor pathway inhibitor (TFPI) activity, increasing thrombin generation. Andexanet alfa is indicated for reversal of anticoagulation in patients treated with apixaban or rivaroxaban in cases of life-threatening or uncontrolled bleeding.

Clinical literature summary

Andexanet alfa was approved via the accelerated approval pathway based on its anti-factor Xa activity; however, post-marketing studies demonstrating the drug’s ability to control bleeding in patients are required by the Food and Drug Administration (FDA).⁶ Key clinical trials are summarized in Table 1.

Table 1. Studies evaluating the use of andexanet alfa.^5,7,8

Dosing and administration

The dosing of andexanet alfa is based on the specific factor Xa inhibitor, dose of the factor Xa inhibitor, and time since last dose of factor Xa inhibitor.⁶ See Table 2 for additional dosing information. Low dose andexanet alfa is given as an initial intravenous (IV) bolus of 400 mg (target rate of 30 mg/min) with follow-up IV infusion of 4 mg/min for up to 120 minutes. High dose andexanet alfa is given as initial IV bolus of 800 mg (target rate of 30 mg/min) with follow-up IV infusion of 8 mg/min for up to 120 minutes.

Table 2. Andexanet alfa dose based on apixaban or rivaroxaban dose and timing.⁶

Discussion

The approval of andexanet alfa provides clinicians with a specific antidote for the reversal of anticoagulation in apixaban- or rivaroxaban-treated patients in cases of life-threatening or uncontrolled bleeding.⁶ The FDA initially declined to approve andexanet alfa, requesting the need for more information related to the manufacturing process. The FDA also questioned whether the company could provide adequate supply of andexanet after approval, and requested additional data to support its efficacy in edoxaban- and enoxaparin-treated patients.^9,10

The studies evaluating andexanet alfa do have some limitations. The initial studies, ANNEXA-A and ANNEXA-R, were completed in healthy volunteers and not in patients requiring urgent reversal of factor Xa inhibitors due to bleeding.⁵ Therefore, although the laboratory results appear to be promising, there were no clinical outcomes assessed.

The first study conducted in patients with bleeding related to factor Xa inhibitors, ANNEXA-4, is being conducted without a comparator group.⁷ In the ongoing ANNEXA-4 study, interim results indicate a mean 4.8 hour time delay from presentation to the emergency department and receipt of andexanet alfa which may not be similar to real emergency department situations. Key exclusion criteria in this trial were the receipt of blood products including PCCs, whole blood, or plasma, which may limit the generalizability of these studies in an acute, life-threatening bleed since it is unknown how these will affect the efficacy or safety of andexanet alfa. Patients requiring surgery within 12 hours of enrollment were also excluded from ANNEXA-4; thus, data are lacking on outcomes in patients who require emergency surgery.¹⁰

Other ongoing clinical trials include a phase 2 pharmacokinetic/pharmacodynamic, safety, and tolerability study evaluating the use of andexanet alfa after betrixaban use (NCT03330457) and the ongoing ANNEXA-4 phase 3 study assessing the use of andexanet alfa in patients with factor Xa inhibitor-associated acute major bleeding (NCT02329327).^11,12 Interim results for the ANNEXA-4 study continue to be intermittently released; the estimated study completion date is November 2022. A study randomizing patients to andexanet alfa or usual care is expected to be initiated in 2019 (NCT03537521).¹³

Conclusion

Andexanet alfa appears to be effective for reversing factor Xa inhibitor-associated uncontrolled bleeding, but its exact place in therapy is uncertain based on current evidence.

References

1. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315-352.
2. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic therapy and prevention of thrombosis, 9^th ed: ACCP evidence-based clinical practice guidelines. Chest. 2012;141(2)(Suppl):e419S-e494S.
3. Farina N, Miller JT. Pharmacologic reversal of direct oral anticoagulants. Crit Care Nurs Q. 2018;41(2):121-128.
4. Tomaselli GF, Mahaffey KW, Cuker A, et al. 2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017;70(24):3042-3067.
5. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373(25):2413-2424.
6. Andexxa [package insert]. South San Francisco, CA: Portola Pharmaceuticals; 2018.
7. Connolly SJ, Milling TJ, Eikelboom JW, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016;375(12):1131-1141.
8. Portola news release. Portola pharmaceuticals announces new interim results from ongoing ANNEXA-4 study of factor Xa inhibitor reversal agent AndexXa® (Andexanet Alfa) in patients with life-threatening bleeding. Portola Pharmaceuticals website. http://investors.portola.com/phoenix.zhtml?c=198136&p=irol-newsroomArticle&ID=2337591. March 2018. Accessed June 13, 2018.
9. Kaatz S, Bhansali H, Gibbs J, Lavender R, Mahan CE, Paje DG. Reversing factor Xa inhibitors – clinical utility of andexanet alfa. J Blood Med. 2017;8:141-149.
10. Sartori M, Cosmi B. Andexanet alfa to reverse the anticoagulant activity of factor Xa inhibitors: a review of design, development and potential place in therapy. J Thromb Thrombolysis. 2018;45(3):345-352.
11. A healthy volunteer PK/PD, safety and tolerability study of andexanet after betrixaban dosing. ClinicalTrials.gov website. https://www.clinicaltrials.gov/ct2/show/NCT03330457?term=NCT03330457&rank=1. Last updated June 2018. Accessed June 13, 2018.
12. A study in patients with acute major bleeding to evaluate the ability of andexanet alfa to reverse the anticoagulation effect of direct and indirect oral anticoagulants. ClinicalTrials.gov website. https://www.clinicaltrials.gov/ct2/show/NCT02329327?term=NCT02329327&rank=1. Last updated May 2018. Accessed June 13, 2018.
13. Reversal agent use in patients treated with direct oral anticoagulants or vitamin k antagonists (RADOA). Focus on new antidotes. ClinicalTrials.gov website. https://www.clinicaltrials.gov/ct2/show/NCT03537521?term=andexanet&draw=2&rank=12. Last updated May 2018. Accessed June 20, 2018.

Prepared by:

Nicole Coglianese, PharmD

PGY1 Pharmacy Resident

University of Illinois at Chicago

August 2018

The information presented is current as of June 8, 2018. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What new data are available linking an increased infection risk with chronic opioid therapy?

Background

Numerous immune factors and responses are significantly suppressed following opioid exposure in human subjects and animal models.¹ These hindered immune functions include suppressed cytokine/chemokine production, cytokine/chemokine expression, antibody production, lymphocyte proliferation, neutrophil function, and macrophage phagocytic activity. Opioids alter immune response through 2 different pathways: by acting on opioid receptors in the central nervous system (CNS) and acting peripherally through interaction with receptors on immune cells. Specifically, both changes are mediated by 3 different G-protein coupled opioid receptors, termed mu (MOR), delta (DOR), and kappa (KOR), which are present in the CNS and on immune cells. Centrally, opioids interact primarily with MOR to produce the central immunomodulatory effects that lead to changes in neuroendocrine and autonomic function. Centrally mediated suppression is responsible for reducing natural killer (NK) cell activity, lymphocyte proliferation and interferon (IFN)-gamma activity. Peripherally, direct stimulation of the DOR and MOR receptors on immune cells is primarily responsible for the peripheral immunosuppression effects.

Evidence regarding the immunosuppressive effects of opioids were derived mainly from studies evaluating morphine.^2,3 However, this effect has not been universally noted in all opioids. Sacerode et al determined that the molecule structure is predicative of the immunosuppressive properties, independent from their antinociceptive activity.⁴ Opioids that contain a hydroxyl group at C3 and C6 (eg, morphine) possess the most immunosuppressive properties. Changes in these groups can remove their immunosuppressive activity. For example, when a carbonylic group is substituted at C6, as with hydromorphone and oxycodone, the modification preserves the analgesic effects while removing the immunosuppressive activity found in the respective parent morphine and codeine.  

Similar to morphine, fentanyl has been shown to be immunosuppressive in vitro while there have been conflicting results in vivo.⁵  In experimental animals, fentanyl induces a clear dose-related immunosuppression and also negatively impacts the development of experimental tumor metastasis.² In contrast with other opiates, tramadol does not have immunosuppressive properties, but has immunostimulating activity in various models. Tramadol is a centrally acting opiate with an immunoenhancing effect on NK activity, lymphoproliferation, and cytokine production. In animal and human studies tramadol has also shown to preserve NK activity even in surgical-induced immune suppression.^2,5 A summary of these as well as other common opioids and their known immunosuppressive properties can be found in Table 1.

Table 1. Summary of opiates and their properties.^2,6,7

Literature Review

This literature review did not include studies that evaluated an increase in infection susceptibility and rates in patients with HIV/AIDS, hepatitis C, or illicit drug users. A summary of the clinical trials evaluating the non-illicit use of opioids in immunocompetent patients and their findings can be found below in Table 2. These studies were selected as they provide greater insight on whether opioids increase the propensity for developing infections, even for patients who may not be considered at high-risk for developing an infection.

Recently, studies have looked at various disease states and found that there is significant opioid-induced immunosuppression and increased risk for infection among different opiates. When comparing morphine and oxycodone use in cancer patients, Suzuki et al found that there was an increased infection frequency in patients receiving morphine compared to oxycodone, an opioid without established immunosuppressive properties.⁸ Shao et al found no significant differences in the infection rate of between several different opioids (morphine, oxycodone, or fentanyl) in advanced cancer patients.⁹ However, they did observe a 2% increased risk for developing infections per 10 mg increase in daily oral morphine equivalent. Cozowicz et al, Mora et al, and Wiese et al, all found a dose dependent relationship between opiate intake and increased risk for infection in other patient populations as well.^10-12  

In burn patients, Schwacha et al found that opiate analgesic use has a synergistic effect and can lead to a significant risk for infection.¹³ This was most evident in mild/moderate burn patients or in those with smaller burn areas, but it was not seen in severely burned patients or in those with larger burn areas. Among patients with smaller burn areas, there was an increased susceptibility to infection when an opioid was used. It was hypothesized that patients with a large burn area have reached maximum immunosuppression due to their injuries and increased opiate intake does not further effect this. 

Most of the current literature was retrospective in nature, which presents limitations of the available data as other confounding factors could introduce bias into the studies. However, the majority of studies have shown an overall trend supporting that certain opioids increase the susceptibility of infection in several different populations. Overall, the articles recommend choosing an opiate that is known to not cause opioid-induced immunosuppression (ie, avoiding morphine, fentanyl, and codeine).

Table 2. Studies evaluating opiate analgesics and the risk for infections.^6-14

Conclusion

Opioid use is associated with an increased risk of infection due to opioid-induced immunosuppression. Various studies have shown that this association is increased when patients are given an opioid with longer duration of action, higher potency, or if immunosuppressive properties have been previously shown.^6,7,11,12 Increased risk of infection has also been shown to be dose dependent.^4,9-12As demonstrated in animal and human models, immune function is suppressed upon opioid exposure by suppressing cytokine/chemokine production, cytokine/chemokine expression, antibody production, lymphocyte proliferation, neutrophil function, and macrophage phagocytic activity.¹ Not all opioids exhibit immunosuppressive activity such as tramadol, oxycodone, and hydromorphone.^2,5 The current literature is limited in patient size and looks at different endpoints in various disease states. Different opiates are also studied across the literature and are only described as opiate morphine equivalents or having high/low opiate intake. As a general recommendation and when possible, it is best to use an opioid that that is shown to not have immunosuppressive properties. If an opioid with immunosuppressive properties must be used, a lower morphine equivalent dose as well as a shorter duration of action is a better choice to decrease risk of infection.

References

1. Odunayo A, Dodam JR, Kerl ME, Declue AE. Immunomodulatory effects of opioids. J Vet Emerg Crit Care. 2010;20(4):376-385.
2. Sacerdote P, Franchi S, Panerai AE. Non-analgesic effects of opioids: mechanisms and potential clinical relevance of opioid-induced immunodepression.  Curr Pharm Des. 2012;18(37):6034-6042.
3. Roy S, Ninkovic J, Banerjee S, et al. Opioid drug abuse and modulation of immune function: consequences in the susceptibility to opportunistic infections. J Neuroimmune Pharmacol. 2011;6(4):442-465.
4. Sacerdote P, Manfredi B, Mantegazza P, Panerai AE. Antinociceptive and immunosuppressive effects of opiate drugs: a structure-related activity study. Br J Pharmacol, 1997;121(4):834-840.
5. Liu Z, Gao F, Tian Y. Effects of morphine, fentanyl and tramadol on human immune response. J Huazhong Univ Sci Technolog Med Sci. 2006;26(4):478-481.
6. Dublin S, Walker RL, Jackson ML, et al. Use of opioids or benzodiazepines and risk of pneumonia in older adults: a population-based case-control study. J Am Geriatr Soc. 2011;59(10):1899-1907.
7. Wiese AD, Griffin MR, Schaffner W, et al. Opioid analgesic use and risk for invasive pneumococcal diseases. Ann Intern Med. 2018;168(6):396-404.
8. Suzuki M, Sakurada T, Gotoh K, et al. Correlation between the administration of morphine or oxycodone and the development of infections in patients with cancer pain. Am J Hosp Palliat Care. 2012;30(7):712–716.
9. Shao Y, Liu W, Guan B, et al. Contribution of opiate analgesics to the development of infections in advanced cancer patients. Clin J Pain. 2017;33(4):295-299.
10. Cozowicz C, Olson A, Poeran J, et al. Opioid prescription levels and postoperative outcomes in orthopedic surgery. Pain. 2017;158(12):2422-2430. 
11. Mora AL, Salazar M, Pablo-Caeiro J, et al. Moderate to high use of opioid analgesics are associated with an increased risk of Clostridium difficile infection. Am J Med Sci. 2012;343(4):277-280.
12. Wiese AD, Griffin MR, Stein CM, Mitchel EF, Grijalva CG. Opioid analgesics and the risk of serious infections among patients with rheumatoid arthritis: a self-controlled case series study. Arthritis Rheumat. 2016;68(2):323-331.
13. Schwacha MG, Mcgwin G, Hutchinson CB, Cross JM, Maclennan PA, Rue LW. The contribution of opiate analgesics to the development of infectious complications in burn patients. Am J Surg. 2006;192(1):82-86.
14. Inagi T, Suzuki M, Osumi M, Bito H. Remifentanil-based anaesthesia increases the incidence of postoperative surgical site infection. J Hosp Infect. 2015;89(1):61-68.

Prepared by:

Hasmik Jasmine Sotelo

PharmD candidate 2020

College of Pharmacy

University of Illinois at Chicago

Reviewed by:

Samantha Spencer, PharmD, BCPS

Clinical Assistant Professor

College of Pharmacy

University of Illinois at Chicago

August 2018

The information presented is current as June 11, 2018. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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Can intraoperative methadone reduce postoperative opioid requirements?

Introduction

Postoperative pain is common among patients who undergo surgical procedures.  According to the US Institute of Medicine, 80% of surgical patients experience postoperative pain; of those patients, 88% experience pain that is moderate to extreme.¹ When postoperative pain is inadequately managed, it can lead to increased morbidity, chronic pain, impaired function and recovery, decreased quality of life, increased medical costs, and prolonged opioid use.

Conventional opioids are typically used to manage postoperative pain; however, while opioids can produce effective pain relief, there are several reasons to limit their use when possible.^1,2 Opioids can cause undesirable side effects, particularly at high doses; these adverse effects may include sedation, respiratory depression, nausea, vomiting, postoperative ileus, and urinary retention.^1-3  Patients undergoing surgical procedures are also at an increased risk for chronic opioid use; therefore, in the context of the ongoing opioid crisis, it is desirable to limit a patient’s postoperative opioid exposure if possible.^4,5  In order to reduce the requirement for opioids while maintaining adequate pain control, multimodal pain management strategies that include local/regional anesthesia and non-opioid analgesics are often used.¹ Another strategy that has been explored for improving postoperative pain control while reducing postoperative opioid requirements is the intraoperative use of intravenous (IV) methadone.

Properties of Methadone

Methadone is an opioid drug; however, it has several properties that make it unique among opioids.⁶  Unlike other opioids, methadone has a long, variable half-life (Table 1).  It also exerts effects on additional receptors (ie, receptors other than mu opioid receptors).  Methadone exists as 2 different isomers; the available methadone products consist of 1:1 racemic mixtures.  The 1-isomer is responsible for methadone’s mu agonist/opioid analgesic activity, while the d-isomer acts as an N-methyl-D-aspartate (NMDA) receptor antagonist.  This NMDA receptor antagonism is thought to reduce or prevent the development of opioid-induced tolerance and hyperalgesia.^7,8  Methadone’s unique traits have generated interest in its use for postoperative pain; the long half-life may allow for a prolonged duration of action at higher doses, so giving a large dose intraoperatively may allow for adequate postoperative analgesia with fewer supplemental opioid doses in the postoperative period.^9,10

Table 1. Properties of selected intravenous opioid analgesics.^6,11

Efficacy

Several randomized controlled trials have examined the efficacy of intraoperative methadone for postoperative pain (Table 2).^8,12-19  Most of these trials were relatively small, including less than 50 patients total; the largest trials were conducted in patients undergoing spinal and cardiac procedures.  Methadone was typically dosed at 0.2 to 0.3 mg/kg, or given as a non-weight-based dose of 20 mg.  In some trials, methadone was given as a single bolus dose at induction of anesthesia; in others, the total methadone dose was divided and given at several different time points throughout the procedure.  The timing of methadone administration varied by study, as did the active comparator group (although morphine was most common).  Intraoperative methadone was found to reduce postoperative opioid requirements and improve pain control in patients undergoing spinal, cardiac, and hysterectomy procedures.^{8,12,14,16,18}  Only 1 small study, conducted in 30 orthopedic surgery patients, did not find any differences between methadone and morphine in terms of postoperative pain scores or postoperative opioid requirements.¹⁵  Most studies were performed in adult inpatient surgical populations; however, 1 study in pediatric patients aged 3 to 7 years found that intraoperative methadone 0.2 mg/kg IV resulted in better pain control than intraoperative morphine.¹⁷  A pilot study in patients undergoing ambulatory surgical procedures also found that intraoperative methadone 0.15 mg/kg IV reduced intraoperative and postoperative opioid requirements without increasing side effects or compromising postoperative analgesia.²⁰

Table 2. Summary of evidence for intraoperative methadone.^8,12-20

Safety

Methadone is traditionally associated with significant safety concerns.  Its long, variable half-life may increase the risk of unintentional overdose and significant adverse events, including sedation and respiratory depression.^6,7  In addition to causing adverse effects traditionally associated with opioids, methadone may also prolong the QTc interval; this increases the risk of torsades de pointes, a potentially life-threatening arrhythmia.⁶  In light of these potential concerns, it is important to consider the safety of intraoperative methadone as well as its efficacy.

In general, clinical trials in the intraoperative setting have not found significant safety differences between methadone and comparator opioids.^8,12-19  However, this may be due in part to the small number of patients included in these trials.  A retrospective study of 1,478 patients undergoing elective spinal fusion specifically examined the safety of intraoperative methadone.⁷  Patients in this study received a mean dose of 0.14 mg/kg methadone intraoperatively after induction of anesthesia.  Postoperative respiratory depression occurred in 36.8% of patients, and 79.8% of patients experienced some degree of hypoxemia: however, only 2.3% of patients required naloxone administration, and 1.5% required reintubation.  Postoperative QTc prolongation was observed in 58.8% of patients, with a mean QTc of 469 ms for men and 484 ms for women.  Although 30.1% of patients experienced arrhythmias, most of these arrhythmias were classified as sinus tachycardia; no instances of polymorphic ventricular tachycardia were observed.  Postoperative nausea and vomiting occurred in 44.4% of patients.  The authors of the study concluded that although adverse events do occur with intraoperative methadone, the risk of serious adverse events is low.  However, since no comparator group was included in this study, it is uncertain how these adverse event rates compare to adverse event rates with other intraoperative opioids.

Conclusion

In patients undergoing inpatient spinal, cardiac, or hysterectomy procedures, administering methadone intraoperatively may decrease postoperative opioid requirements and result in better overall pain control.  Although adverse events can occur with intraoperative methadone, serious events related to sedation and respiratory depression appear to be rare.  Therefore, using intraoperative methadone is a reasonable strategy to provide postoperative pain control, as long as adequate monitoring can be performed.  However, it is also important to be aware of limitations in the currently available literature.  Data in pediatric patients are still very limited, and current studies are primarily limited to inpatient surgical settings.  More studies are needed before intraoperative methadone can be recommended for use in settings outside of adult inpatient surgery.

References

1.         Gan TJ. Poorly controlled postoperative pain: prevalence, consequences, and prevention. J Pain Res. 2017;10:2287-2298.

2.         Luo J, Min S. Postoperative pain management in the postanesthesia care unit: an update. J Pain Res. 2017;10:2687-2698.

3.         de Boer HD, Detriche O, Forget P. Opioid-related side effects: Postoperative ileus, urinary retention, nausea and vomiting, and shivering. A review of the literature. Best Pract Res Clin Anaesthesiol. 2017;31(4):499-504.

4.         Hah JM, Bateman BT, Ratliff J, Curtin C, Sun E. Chronic opioid use after surgery: implications for perioperative management in the face of the opioid epidemic. Anesth Analg. 2017;125(5):1733-1740.

5.         Sun EC, Darnall BD, Baker LC, Mackey S. Incidence of and risk factors for chronic opioid use among opioid-naive patients in the postoperative period. JAMA Intern Med. 2016;176(9):1286-1293.

6.         Portenoy R, Mehta Z, Ahmed E. Cancer pain management with opioids: optimizing analgesia. UpToDate website. https://www.uptodate.com/. Updated March 7, 2018. Accessed July 18, 2018.

7.         Dunn LK, Yerra S, Fang S, et al. Safety profile of intraoperative methadone for analgesia after major spine surgery: An observational study of 1,478 patients. J Opioid Manag. 2018;14(2):83-87.

8.         Murphy GS, Szokol JW, Avram MJ, et al. Clinical effectiveness and safety of intraoperative methadone in patients undergoing posterior spinal fusion surgery: a randomized, double-blinded, controlled trial. Anesthesiology. 2017;126(5):822-833.

9.         Kharasch ED. Intraoperative methadone: rediscovery, reappraisal, and reinvigoration? Anesth Analg. 2011;112(1):13-16.

10.       Gourlay GK, Wilson PR, Glynn CJ. Pharmacodynamics and pharmacokinetics of methadone during the perioperative period. Anesthesiology. 1982;57(6):458-467.

11.       Mariano E. Management of acute perioperative pain. UpToDate website. https://www.uptodate.com/. Updated April 11, 2018. Accessed July 18, 2018.

12.       Murphy GS, Szokol JW, Avram MJ, et al. Intraoperative methadone for the prevention of postoperative pain: a randomized, double-blinded clinical trial in cardiac surgical patients. Anesthesiology. 2015;122(5):1112-1122.

13.       Udelsmann A, Maciel FG, Servian DC, Reis E, de Azevedo TM, Melo Mde S. Methadone and morphine during anesthesia induction for cardiac surgery. Repercussion in postoperative analgesia and prevalence of nausea and vomiting. Rev Bras Anestesiol. 2011;61(6):695-701.

14.       Gottschalk A, Durieux ME, Nemergut EC. Intraoperative methadone improves postoperative pain control in patients undergoing complex spine surgery. Anesth Analg. 2011;112(1):218-223.

15.       Laur DF, Sinkovich J, Betley K. A comparison of intraoperative morphine sulfate and methadone hydrochloride on postoperative visual analogue scale pain scores and narcotic requirements. CRNA. 1995;6(1):21-25.

16.       Chui PT, Gin T. A double-blind randomised trial comparing postoperative analgesia after perioperative loading doses of methadone or morphine. Anaesth Intensive Care. 1992;20(1):46-51.

17.       Berde CB, Beyer JE, Bournaki MC, Levin CR, Sethna NF. Comparison of morphine and methadone for prevention of postoperative pain in 3- to 7-year-old children. J Pediatr. 1991;119(1 Pt 1):136-141.

18.       Richlin DM, Reuben SS. Postoperative pain control with methadone following lower abdominal surgery. J Clin Anesth. 1991;3(2):112-116.

19.       Gourlay GK, Willis RJ, Lamberty J. A double-blind comparison of the efficacy of methadone and morphine in postoperative pain control. Anesthesiology. 1986;64(3):322-327.

20.       Komen H, Brunt LM, Deych E, Blood J, Kharasch ED. Intraoperative methadone in same-day ambulatory surgery: a randomized, double-blinded, dose-finding pilot study [published online ahead of print May 25, 2018]. Anesth Analg. doi: 10.1213/ane.0000000000003464.

August 2018

The information presented is current as of July 2, 2018. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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