August 2018 FAQs
August 2018 FAQs Heading link
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What data support the use of andexanet alfa (ANDEXXA) for the reversal of factor Xa inhibitors?
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
Study design and duration
Subjects
Interventions
Results
Conclusions
Siegal 20155
ANNEXA-A, ANNEXA-R
Phase 3, DB, RCTs
Safety outcomes assessed on days 15, 36, and 43 after study drug administration
Healthy volunteers, 50 to 75 years of age
Participant characteristics: mean age 57.9 years, 39% women
101 participants randomly assigned to andexanet; 44 to placebo
ANNEXA-A:
- Apixaban 5 mg PO BID for 3.5 days
- Andexanet 400 mg IV bolus (30 mg/min) or 400 mg IV bolus followed by continuous infusion of 4 mg/min for 120 min (total 480 mg)
ANNEXA-R:
- Rivaroxaban 20 mg PO daily for 4 days
- Andexanet 800 mg IV bolus (30 mg/min) or 800 mg IV bolus followed by continuous infusion of 8 mg/min for 120 min (total 960 mg)
Randomly assigned in 3:1 ratio (ANNEXA-A) or 2:1 ratio (ANNEXA-R) to receive andexanet or placebo
IV bolus:
- Andexanet reduced anti-factor Xa activity to a greater extent than placebo within 2 to 5 min in the apixaban study (94% vs 21% reduction; P<0.001) and the rivaroxaban study (92% vs 18% reduction; P<0.001); reversal of anti-factor Xa activity persisted for 2 hours
IV bolus plus continuous infusion:
- Andexanet reduced anti-factor Xa activity to a greater extent than placebo in the apixaban study (92% vs 33% reduction; P<0.001) and the rivaroxaban study (97% vs 45% reduction; P<0.001); reversal persisted for 1 to 2 hours after infusion completion
No serious adverse or thrombotic events reported
Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban within minutes after administration and for 2 hours after the dose
without evidence of serious adverse effects in healthy volunteers
Connolly 20167,8
ANNEXA-4
Phase 3b/4 ongoing, MC, prospective, OL, single-group study
Follow up to 30 days after andexanet
Interim report describes 67 patients as of June 17, 2016
Eligible patients: ≥18 years, reported to receive apixaban, rivaroxaban, edoxaban, or ≥ 1 mg/kg enoxaparin within the past 18 hours with acute major bleeding
Mean age 77 years, all patients had history of thrombotic events and CV disease
Acute major bleeding: GI (49%), intracranial (42%), other (9%)
Mean time from ED presentation to andexanet IV bolus was 4.8 hours
- Andexanet IV bolus (15 to 30 min) followed by 2-hour infusion
- Andexanet 400 mg IV bolus and 480 mg infusion if patients took apixaban or rivaroxaban > 7 hours before andexanet administration
- Andexanet 800 mg IV bolus and 960 mg infusion if patients took enoxaparin, edoxaban, or rivaroxaban ≤ 7 hours before andexanet administration or at an unknown time
- After IV bolus, median anti-factor Xa activity decreased by 89% (95% CI, 58 to 94) from baseline in rivaroxaban patients and by 93% (95% CI, 87 to 94) in apixaban patients
- 4 hours after andexanet infusion, there was a decrease from baseline in anti-factor Xa activity of 39% in rivaroxaban and 30% in apixaban patients
- 37 of 47 patients in the efficacy population were judged to have excellent or good hemostasis 12 hours after andexanet infusion (79%; 95% CI, 64 to 89)
- Thrombotic events occurred in 12 of 67 patients (18%) during 30-day follow-up
Updated interim results released at ACC 2018 (n=228 patients):
- The rate of excellent or good hemostasis was achieved in 109 of 132 patients (83%) within 12 hours
Effective hemostasis was achieved in 86% of patients with GI bleeding and 81% patients with intracranial bleeding; hemostatic efficacy was similar for patients on apixaban (82%) and rivaroxaban (83%)
Thrombotic event rate was 11% (n=24) for entire population and 12% (n=17) among those with ICH
Mortality rate for all patients was 12% (n=27)
2 of 228 patients experienced an infusion reaction but no patient had antibodies to andexanet
Andexanet IV bolus and subsequent 2-hour infusion substantially reduced anti-factor Xa activity in patients with acute major bleeding associated with factor Xa inhibitors
Abbreviations: ACC=American College of Cardiology, BID=twice daily, CI=confidence interval, CV=cardiovascular, DB=double blind, ED=emergency department, GI=gastrointestinal, ICH=intracranial hemorrhage, IV=intravenous, MC=multicenter, OL=open-label, PC=placebo controlled, PO=by mouth, RCT=randomized controlled trial.
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
Factor Xa Inhibitor
Factor Xa Inhibitor Last Dose
< 8 Hours or Unknown Time Since Last Dose
≥ 8 Hours Since Last Dose
Apixaban
≤ 5 mg
Low Dose
Low Dose
Apixaban
> 5 mg or unknown
High Dose
Rivaroxaban
≤ 10 mg
Low Dose
Rivaroxaban
> 10 mg or unknown
High Dose
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
- 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.
- Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic therapy and prevention of thrombosis, 9th ed: ACCP evidence-based clinical practice guidelines. Chest. 2012;141(2)(Suppl):e419S-e494S.
- Farina N, Miller JT. Pharmacologic reversal of direct oral anticoagulants. Crit Care Nurs Q. 2018;41(2):121-128.
- 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.
- 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.
- Andexxa [package insert]. South San Francisco, CA: Portola Pharmaceuticals; 2018.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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?
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
Medication
Antinociceptive Potency
Duration of Action
Immunosuppressive
Hydrocodone
Moderate
Short
No
Tramadol
Moderate
Short
No
Codeine
Moderate
Short
Yes
Hydromorphone
Strong
Short
No
Oxycodone
Strong
Short
No
Oxycodone (sustained release)
Strong
Long
No
Fentanyl (transdermal)
Strong
Long
Yes
Morphine (immediate release)
Strong
Short
Yes
Morphine (controlled release)
Strong
Long
Yes
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
Article
Subjects
Objective
Results
Conclusions
Dublin S, et al.
Use of opioids or benzodiazepines and risk of pneumonia in older adults: a population-based case-control study6
Nested case-control study
1039 immunocompetent adults with confirmed pneumonia and 2022 matched controls without pneumonia
Primary outcome:
To determine if pneumonia risk would be elevated among people using benzodiazepines and opioids compared to nonusers, and that risk would be highest for long-acting opioids and opioids deemed to be immunosuppressive in prior immunologic studies.
13.9% (144/1039) of cases and 8.0% (161/2022) of controls used prescription opioids
Overall risk of pneumonia was higher with opioid use: aOR 1.38 (95% CI 1.08 to 1.76) vs. nonuse.
Risk was highest for opioids categorized as immunosuppressive: OR 1.88 (95% CI 1.26 to 1.79) vs. nonuse
No difference in risk with non-immunosuppressive opioids: OR 1.23 (95% CI 0.89 to 1.69) vs nonuse
Risk was highest in the first 14 days of use: OR 3.24 (95% CI 1.64 to 6.39) vs. nonuse
Risk increased with long-acting opioids: OR 3.43 (95% CI 1.44 to 8.21) vs. nonuse
No difference in risk with short-acting opioids: OR 1.27 (95% CI 0.98 to 1.64) vs. nonuse.
No increased risk was seen for current benzodiazepine use OR 1.08 (95% CI 0.80 to 1.47) vs. nonuse
Use of opioids, but not benzodiazepines, was associated with increased pneumonia risk.
Risk was highest with a recent initiation of opioid use (within 14 days) or when long-acting opioids were chosen, as well as known immunosuppressive opioids
Wiese AD, et al. Opioid analgesic use and risk for invasive pneumococcal diseases7
Nested case-control study
1,233 case patients with IPD matched to 24,399 at-risk, but without disease, controls matched by diagnosis index date, age, and county of residence.
Primary Outcome:
To determine if prescription opioid use is an independent risk factor for IPD
Multivariable analysis found that current opioid use was associated with a higher risk of IPD compared to nonusers (aOR 1.62, 95% CI, 1.36 to 1.92)
The increased risk between current opioid use and IPD was demonstrated for both pneumonia (aOR 1.54, 95% CI, 1.26 to 1.88) and non-pneumonia IPD (aOR 1.94, 95% CI 1.36 to 2.77)
Compared to nonusers, opioid induced immunosuppressive associations were strongest for opioids that were long acting (aOR 1.87, 95% CI 1.24 to 2.82), of high potency (aOR 1.72, 95% CI 1.32 to 2.25), or were used at high dosages (50 to 90 MME/d: aOR 1.71, 95% CI 1.22 to 2.39; ≥90 MME/d: aOR 1.75, 95% CI, 1.33 to 2.29)
Opioid use is associated with an increased risk for
IPD and represents a novel risk factor for these diseases
The association is found to be the strongest in current opioid users who are on long acting, high potency, or previously described opioids with immunosuppressive properties
Suzuki M, et al. Correlation between the administration of morphine or oxycodone and the development of infections in patients with cancer pain8
Retrospective chart review
134 cancer patients receiving oxycodone (n=74) or morphine (n=60) for pain
Primary outcome:
To determine if there is a correlation between the administration of morphine or oxycodone and the development of infection in patients with cancer pain.
18 (30%) and 10 (13.5%) patients developed infections in the morphine and oxycodone groups, respectively
On multivariable regression analysis, the only significant difference risk factor was the type of opioid used (morphine vs oxycodone, OR 3.595, 95% CI 1.397 to 9.256)
There was increased infection frequency in patients receiving morphine than in the oxycodone group.
Shao YJ, et al. Contribution of opiate analgesics to the development of infections in advanced cancer patients9
Retrospective chart review
303 advanced cancer patients (stage IV) receiving either morphine (n=85), oxycodone (n=41), or fentanyl (n=68) for >14 days
Primary outcome:
To determine if opiate analgesics contribute to the development of infections in advanced cancer patients
Secondary outcome:
To investigate how infection rates differ among various opiates
87 (28.7%) patients developed infections; 20 (23.5%), 10 (24.4%), and 14 (20.6%) patients developed infections in the groups that received only morphine, oxycodone, and fentanyl, respectively (comparison between groups, P>0.05).
Logistic regression identified daily OME as an independent variable influencing development of infection (OR=1.002, P<0.01)
There was no difference in infection risk found for the different types of opiates used, but there was an estimated 2% increased risk for developing infections per 10 mg increase in daily OME.
Cozowicz C, et al Opioid prescription levels and postoperative outcomes in orthopedic surgery10
Retrospective cohort study
Orthopedic surgery patient data from the National Premier Perspective database; N=1,035,578 cases for lower joint arthroplasties and N=220,953 cases for spine fusions were analyzed by the amount of opioids prescribed in the postoperative period.
Primary Outcome:
To determine if there was a dose response relationship between opioid prescriptions and postoperative outcomes.
High (upper quartile) vs. low (bottom quartile) opioid dosing:
High opioid doses significantly increased odds for postoperative infections (OR 1.49, 95% CI 1.24 to 1.78, P<0.001 respectively).
Higher opioid dosing was associated with a significant increase in LOS and cost by 12% and 6%, P<0.001 respectively for both.
Increase in complication risk occurred stepwise, suggesting a dose–response gradient.
Higher opioid doses were associated with an increase in most postoperative complications including postoperative infections, cost, and LOS.
Mora AL, et al. Moderate to high use of opioid analgesics are associated with an increased risk of Clostridium difficle infection11
Retrospective cohort study
32,775 total patients who were hospitalized for ≥48 hours and received broad spectrum antibiotics; of whom 192 had developed CDI.
21,496 patients had no narcotic usage, 6977 had mild narcotic usage, 3233 had moderate narcotic usage and
1069 had high narcotic usage.
* Patients with no or mild narcotic usage were compared with patients with moderate to high usage.
Primary Outcome:
To determine if opioid analgesics increase the risk of developing CDI in hospitalized patients receiving broad-spectrum antibiotics.
Univariate analysis comparing opioid users to non-opioid users:
Mild opioid use – OR 0.68, 95% CI 0.43 to 1.1, P=0.10
Moderate opioid use – OR 2.0, 95% CI 1.3 to 3.0, P=0.0009
High opioid use – OR 8.3, 95% CI 5.7 to 12.1, P<0.0001
Multivariate analysis produced consistent results; CDI risk increased with moderate and high opioid use compared to non-users (HR, 3.3 and HR 16.9, respectively; p<0.0001 for both)
Moderate to high use of opioid analgesics were associated with an increased risk of CDI
Wiese AD, et al. Opioid analgesics and the risk of serious infections among patients with rheumatoid arthritis: a self-controlled case series study12
Self-controlled case series study
1790 patients with RA and at least one serious infection, individual patient comparisons were made within-person comparing periods of opioid use vs. nonuse
* Patients could contribute more than one serious infection during the course of follow-up (if 2nd infection occurs after 30 days).
Primary Outcome:
To compare the risk of serious infection during periods of opioid use vs non-use in patients with RA
The adjusted incidence rate of serious infection was higher during periods of current opioid use compared with non-use IRR 1.39 (95% CI 1.19 to 1.62).
The incidence rate was also higher during periods of long-acting opioid use, immunosuppressive opioid use, and new opioid use compared with non-use (IRR: 2.01 [95% CI 1.52 to 2.66]; IRR: 1.72 [95% CI 1.33 to 2.23]; IRR: 2.38 [95% CI 1.65 to 3.42], respectively).
In within-person comparisons of patients with RA, opioid use was associated with an increased risk of hospitalizations for serious infection.
There was an increased risk of infection when patients received opioids at a dose greater than 15 mg/day, with the largest estimate seen among long-acting opioid use.
Schwacha MG, et al. The contribution of opiate analgesics to the development of infectious complications in burn patients13
Nested case-control study
187 burn patients with confirmed infections (cases) were matched with 187 controls that had not developed an infection.
*Controls were within 1 year of age of cases and had the same percent TBSA (within 5%, burned).
Primary Outcome:
To determine if opiate analgesics contribute to the development of infectious complications in burn patients
Secondary Outcome:
Cumulative opiate analgesic use during the exposure period (time from admission to date of infection complication)
Cases (confirmed infections) had higher median opiate equivalent (OME) values 14.0 vs. 10.0 when compared with controls (P=0.06)
Cases were more likely to be classified into the high OME group relative to controls (OR 1.24, 95% CI, 1.00 to 1.54; P=0.0495)
Among patients who sustained small burns (<13% TBSA burned), cases were 1.73 times (95% CI, 1.20 to 2.49; P=0.0033) more likely to be in the high OME group
Cases had a significantly longer LOS (31.2 vs 17.3 days; P<0.0001) and increased mortality rate (12.7% vs 5.5%; P=0.003).
High opiate intake in patients with mild to moderate injuries increases the risk for infectious complications
In burn patients who developed infectious complications, they were much more likely to have been receiving higher opioid doses than burn patients who did not develop an infection, particularly in patients with small burn areas
Inagi T, et al. Remifentanil-based anesthesia increases the incidence of postoperative surgical site infection14
Prospective observational study
235 patients who underwent elective open colorectal surgery under both epidural and general anesthesia receiving either remifentanil (n=146) or fentanyl (n=89)
Propensity-matched cohorts analyzed (n=61 for each group)
Primary Outcome:
To investigate the influence of remifentanil on the development of SSI
More patients developed SSI with remifentanil-based anesthesia before propensity matching (11.6% [17/146] vs. 3.4% [3/89], remifentanil vs. fentanyl, P=0.03); results were consistent after propensity matching (16.4% [10/61] vs. 3.3% [2/61], remifentanil vs. fentanyl, P=0.029).
Remifentanil-based anesthesia increased the incidence of SSI when compared with fentanyl.
Abbreviations: aOR, adjusted odds ratio; CDI, Clostridium difficile infection; CI, confidence interval; HR, hazard ratio; IPD, invasive pneumococcal disease; IRR, incidence rate ratio; LOS, length of stay; MME, morphine milligram equivalents; OME, oral morphine equivalent; OR, odds ratio; RA, rheumatoid arthritis; SSI, surgical site infection; TBSA, total body surface area.
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
- Odunayo A, Dodam JR, Kerl ME, Declue AE. Immunomodulatory effects of opioids. J Vet Emerg Crit Care. 2010;20(4):376-385.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Cozowicz C, Olson A, Poeran J, et al. Opioid prescription levels and postoperative outcomes in orthopedic surgery. Pain. 2017;158(12):2422-2430.
- 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.
- 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.
- 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.
- 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?
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
Drug Name
Equianalgesic Dose
Half-life
Duration of Analgesic Effect
Fentanyl
0.1 mg IV
7 to 12 hours
0.5 to 1 hour*
Hydromorphone
1.5 mg IV
2 to 3 hours
3 to 4 hours
Morphine
10 mg IV
2 to 3 hours
4 to 5 hours
Methadone
10 mg IV
12 to 150 hours
3 to 4 hours*
*Duration of effect increases after repeated use
Abbreviations: IV=intravenous
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
Study Design
Subjects
Interventions
Endpoints
Conclusion
Komen 201820
SC, DB, RCT
N=60 patients undergoing elective same-day discharge ambulatory surgical procedures that required general anesthesia
Methadone 0.1 mg/kg IBW IV once intraoperatively
Methadone 0.15 mg/kg IBW IV once intraoperatively
Conventional practice (intraoperative short-duration opioid such as fentanyl or hydromorphone)
In the PACU, patients received fentanyl or hydromorphone
Additional oral analgesics for postoperative pain were prescribed at the discretion of the surgical team
Patients were followed for 30 days postoperatively
Primary:
Median in-hospital nonmethadone opioid consumption:
Conventional practice: 35.3 mg ME
Methadone 0.1 mg/kg: 7.1 mg ME (p<0.0001 vs. conventional practice)
Methadone 0.15 mg/kg: 3.3 mg ME (p<0.0001 vs. conventional practice)
Secondary:
Median in-hospital opioid consumption:
Conventional practice: 35.3 mg ME
Methadone 0.1 mg/kg: 13.3 mg ME (p<0.0001 vs. conventional practice)
Methadone 0.15 mg/kg: 12.3 mg ME (p<0.0001 vs. conventional practice)
Median non-OR nonmethadone opioid consumption:
Conventional practice: 10 mg ME
Methadone 0.1 mg/kg: 5.4 mg ME (p=0.42 vs. conventional practice)
Methadone 0.15 mg/kg: 3.3 mg ME (p=0.01 vs. conventional practice)
On the operative day, no significant differences were seen between groups in terms of pain score at rest, with coughing, or with activity (numbers not provided; p=0.177); in the 30 days following the procedure, patients who received methadone 0.15 mg/kg had less pain at rest compared to controls (numbers not provided; p=0.02)
Median number of opioid pills used in 30 days post-discharge:
Conventional practice: 10
Methadone 0.1 mg/kg: 7 (p=0.087 vs. conventional practice)
Methadone 0.15 mg/kg: 5 (p<0.001 vs. conventional practice)
Safety:
No significant differences were seen between groups for opioid-related symptoms at discharge
A single intraoperative dose of methadone 0.15 mg/kg IV significantly reduced postoperative and total opioid requirements in patients undergoing ambulatory surgical procedures while maintaining adequate pain control.
Murphy 20178
SC, DB, DD, PC, RCT
N=115 adult patients undergoing elective posterior lumbar, thoracic, or lumbothoracic spinal fusion surgery
Methadone 0.2 mg/kg ABW IV once at induction (n=62)
Hydromorphone 2 mg IV once at the end of surgery (n=53)
Saline placebos were given in both groups to maintain blinding
In the PACU, patients received hydromorphone IV as needed for pain management
Postoperative pain was managed with hydromorphone PCA on POD 1-3 and hydrocodone/acetaminophen 10/325 mg when PO intake was tolerated
Patients were followed for 3 days postoperatively
Primary:
Median amount of hydromorphone used in the first 24 hours after surgery: 4.56 mg with intraoperative methadone vs. 9.9 mg with hydromorphone (difference, -4.80 mg; 95% CI, -6.40 to -3.10; p<0.0001)
Secondary:
Median total hydromorphone consumption in the postoperative period was lower in the methadone group (5.85 mg vs. 14.60 mg; difference, -8.20 mg; 99% CI, -12.10 to -4.50; p<0.0001)
Median total number of oral pain tablets consumed was lower in the methadone group (7.5 vs. 12; difference, -4; 99% CI, -8 to -1; p=0.001)
Pain scores at rest were significantly lower in the methadone group at all time points, except in the afternoon for POD 1, 2, and 3
Safety:
No differences were seen in the incidences of nausea, vomiting, itching, hypoventilation, or hypoxemic events
A single intraoperative dose of IV methadone significantly reduced postoperative opioid requirements and improved pain scores in patients undergoing posterior spinal fusion surgery.
Murphy 201512
SC, DB, RCT
N=156 patients undergoing elective cardiac surgery with cardiopulmonary bypass and extubation anticipated within 12 hours of surgery
Methadone 0.3 mg/kg (maximum 30 mg) IV (n=77)
Fentanyl 12 mcg/kg (maximum 1200 mcg) IV (n=79)
For each study drug, half of the total dose was given over 5 minutes at induction, and the remaining half was given over the next 2 hours
Pain was monitored every 2 hours in the ICU and every 4-6 hours on the surgical ward
IV morphine and oral hydrocodone/acetaminophen were used for pain that was more than mild in severity
Patients were followed for 72 hours postoperatively
Primary:
Median amount of morphine given in the first 24 hours after surgery: 6 mg in the methadone group vs. 10 mg in the fentanyl group (difference, -4; 99% CI, -8 to -2; p<0.001)
Median pain score with coughing at 12 hours after extubation: 4 in the methadone group vs. 6 in the fentanyl group (difference, -2; 99% CI, -3 to -1; p<0.001)
Secondary:
Total amount of morphine used in the first 72 hours after surgery was lower in the methadone group (8 mg vs. 14 mg; p<0.001)
Pain scores at rest and with coughing were lower in the methadone group throughout the first 72 hours
Safety:
Opioid-related adverse effects (nausea, vomiting, itching, hypoventilation, hypoxemia, sedation) were similar between groups
Administering IV methadone at induction of anesthesia reduced postoperative analgesic requirements and improved pain scores in cardiac surgical patients.
Udelsmann 201113
DB, RCT
N=55 patients undergoing cardiac surgery with extracorporeal circulation and extubation within 24 hours of surgery
Methadone 20 mg IV once (n=18)
Morphine 20 mg IV once (n=19)
Saline placebo IV once (n=18)
Assigned study drug administered soon after induction of anesthesia
Postoperative pain was managed with morphine 0.03 mg/kg IV as needed
Patients were followed for 24 hours postoperatively
Number of patients requiring analgesic doses:
Methadone: 10
Morphine: 14
Placebo: 17
(p=0.025 for methadone vs. unspecified comparator)
Mean number of analgesic doses:
Methadone: 0.89
Morphine: 1.32
Placebo: 2.39 (p<0.001 for placebo vs. active groups)
Mean VAS scores:
Methadone: 0.5
Morphine: 1.84
Placebo: 2.83
(p<0.01 for methadone vs. unspecified comparator)
Number of patients with nausea and/or vomiting:
Methadone: 1
Morphine: 6
Placebo: 9
(p=0.013 for methadone vs. other groups)
Intraoperative methadone significantly improved postoperative VAS scores in the first 24 hours; however, it did not decrease the number of postoperative analgesic doses given compared to morphine (possibly due to small sample size).
Gottschalk 201114
SB, RCT
N=29 adult patients undergoing multilevel thoracolumbar spine surgery with instrumentation and fusion
Methadone 0.2 mg/kg IV once after intubation (n=13)
Sufentanil 0.75 mcg/kg IV once just prior to incision, followed by a 0.25 mcg/kg/h continuous infusion (n=16)
Postoperative pain was managed via fentanyl, morphine, or hydromorphone PCA
Patients were followed for 72 hours postoperatively
VAS scores were significantly lower in the methadone group at 48 hours post-extubation, but the difference was not significant at 24 or 72 hours post-extubation (values not provided)
Opioid requirements were significantly lower in the methadone group at 48 hours post-extubation (median 25 mg ME vs. 63 mg ME; p=0.023) and 72 hours post-extubation (median 15 mg ME vs. 34 mg ME; p=0.024)
Rates of hypotension, respiratory depression, hypoxemia, arrhythmia, nausea, and vomiting were similar between groups
A single intraoperative dose of IV methadone improved pain control and reduced opioid requirements in spinal surgery patients.
Laur 199515
DB, RCT
N=30 orthopedic surgery patients with duration of anesthesia between 3 and 6 hours
Methadone 0.3 mg/kg IV (n=15)
Morphine 0.3 mg/kg IV (n=15)
Patients received 25% of the total opioid dose after proper positioning in the OR, 50% at induction of anesthesia, and the remaining 25% prior to incision
Patients were followed 24 hours postoperatively
Mean total amount of narcotic administered in the first 24 hours after surgery: 54.7 ± 55.3 mg in the methadone group vs. 45.3 ± 32.9 mg in the morphine group (no p-value reported)
Pain scores up to 120 minutes after extubation were not different between the treatment groups
In patients undergoing orthopedic surgery, intraoperative IV methadone did not provide prolonged postoperative analgesia compared to morphine.
Chui 199216
DB, RCT
N=30 patients undergoing elective abdominal hysterectomy
Methadone 0.25 mg/kg IV once at induction of anesthesia (n=15)
Morphine 0.25 mg/kg IV once at induction of anesthesia (n=15)
In the recovery room, study drug was given IV every 15 minutes until the patient remained pain-free for 30 minutes
For postoperative pain management, patients received morphine 7.5 mg IM every 2 hours as needed
Patients were followed for 48 hours postoperatively
In the 48 hours after surgery, patients in the methadone group required fewer doses of morphine than patients in the morphine group (numbers not provided; p<0.001)
In the methadone group, 67% of patients did not require any supplemental morphine doses in the 48 hours following surgery, while all patients in the morphine group required at least 2 doses of morphine in the same time period
Patients in the morphine group had a higher total pain score in the first 48 hours after surgery (numbers not provided; p<0.001), and pain scores were significantly lower in the methadone group at all time points except 12 hours post-surgery
More patients in the methadone group had nausea and vomiting in the recovery room (11 vs. 3), but the incidences of other adverse events in the recovery room and on the surgical floor were similar between groups
In patients undergoing hysterectomy, a single dose of IV methadone at induction provided prolonged analgesia in the postoperative period.
Berde 199117
DB, RCT
N=35 patients aged 3 to 7 years undergoing major surgery of the back, thorax, abdomen, pelvis, or extremities
Methadone 0.2 mg/kg IV once before incision (n=18)
Morphine 0.2 mg/kg IV once before incision (n=17)
In the recovery room, patients received additional 0.05 mg/kg IV doses of study drug every 10 minutes until comfortable
For postoperative pain management, patients received morphine 0.1 mg/kg IM every 3 hours as needed. When oral intake was tolerated, patients received acetaminophen every 3 hours, with codeine given every 3 hours as needed
Patients were followed for 3 days postoperatively
Mean number of opioid doses required on the operative day: 0.72 in the methadone group vs. 1.35 in the morphine group (p=0.049)
Mean number of opioid doses required on the first POD: 3.28 in the methadone group vs. 4.47 in the morphine group (p=0.059)
Number of “severe” pain scores: 28/152 (18.4%) in the methadone group vs. 52/147 (35.4%) in the morphine group (p=0.0009)
In children undergoing major surgery, a perioperative loading dose of IV methadone resulted in better pain control with fewer supplemental opioid injections on the operative day.
Richlin 199118
SB, SC, RCT
N=40 women undergoing elective abdominal hysterectomy or myomectomy
Methadone 20 mg IV once after induction of anesthesia (n=20)
Morphine 20 mg IV once after induction of anesthesia (n=20)
For postoperative pain management, patients in the methadone group received methadone 5 mg IM every 4 hours as needed, while patients in the morphine group received morphine 0.1 mg/kg IM every 3 hours as needed
Patients were followed for 72 hours postoperatively
Mean pain score over 72 hours postoperatively: 1.9 in the methadone group vs. 3.4 in the morphine group (p<0.01)
Mean total dose of opioid required postoperatively: 26.5 mg in the methadone group vs. 66.8 mg in the morphine group (p<0.01)
Number of patients requiring no opioid doses after leaving the recovery room: 7 (35%) in the methadone group vs. 0 (0%) in the morphine group (p-value not provided)
Patients in the morphine group received higher amounts of opioid in the recovery room (mean 4.4 mg vs. 2.0 mg in the methadone group; p<0.01)
No significant adverse events occurred in either group
Women who received methadone for perioperative pain management required lower opioid doses and achieved better pain control than women who received morphine for perioperative pain management.
Gourlay 198619
DB, RCT
N=20 patients undergoing procedures that involve upper abdominal incision
Methadone 20 mg IV once after induction of anesthesia (n=10)
Morphine 20 mg IV once after induction of anesthesia (n=10)
For postoperative pain management, patients received 5 mg IV of their assigned opioid as needed
Patients were followed for 60 hours postoperatively
Mean total dose of opioid received on the surgical ward: 11.5 mg in the methadone group vs. 41 mg in the morphine group (p<0.001)
Mean total dose of opioid received in the perioperative period: 39.5 mg in the methadone group vs. 70 mg in the morphine group (p<0.001)
Mean pain score on POD 1: 1.14 cm in the methadone group vs. 2.03 cm in the morphine group (p-value NS)
Mean pain score on POD 2: 1.06 cm in the methadone group vs. 2.03 cm in the morphine group (p-value NS)
Vomiting and pulmonary infections did not differ between groups
Patients receiving methadone for perioperative pain management required less opioid to maintain pain control than patients receiving morphine for perioperative pain management.
Abbreviations: ABW=actual body weight; CI=confidence interval; DB=double blind; DD=double dummy; IBW=ideal body weight; ICU=intensive care unit; IM=intramuscular; IV=intravenous; ME=morphine equivalents; NS=not significant; OR=operating room; PACU=postanesthesia care unit; PC=placebo controlled; PCA=patient-controlled analgesia; PO=oral; POD=postoperative day; RCT=randomized controlled trial; SB=single blind; SC=single center; VAS=visual analog scale.
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.