- Email: [email protected]
Comparing Methadone Rotation to Consensus Opinion
Vol.
-
No.
- -
2019
Journal of Pain and Symptom Management
1
Brief Report
Comparing Methadone Rotation to Consensus Opinion Michael A. Smith, PharmD, BCPS, Kyle C. Quirk, PharmD, D’Anna C. Saul, MD, Phillip E. Rodgers, MD, and Maria J. Silveira, MD, MA, MPH Department of Pharmacy Services (M.A.S., K.C.Q.), Michigan Medicine, Ann Arbor, Michigan; University of Michigan College of Pharmacy (M.A.S., K.C.Q.), Ann Arbor, Michigan; Department of Internal Medicine (D.A.C.S., M.J.S.), Michigan Medicine, Ann Arbor, Michigan; Department of Pediatrics (D.A.C.S.), Ann Arbor, Michigan; and Department of Family Medicine (P.E.R.), Michigan Medicine, Ann Arbor, Michigan, USA
Abstract Context. Methadone is a complex but useful medication for pain management in palliative care. Recent expert opinions have been published on the safe and effective use of methadone. Objectives. To determine the success of methadone rotations and evaluate concordance with consensus recommendations by a palliative care consult service. Methods. A retrospective study of methadone rotation practice by a palliative care consult service and outcomes for patients hospitalized between January 1, 2012 and December 31, 2018 at a single academic medical center. A successful rotation was defined as a 30% reduction in pain or as-needed medication use sustained for at least three consecutive days. Patient outcomes were compared with expert consensus recommendations. Results. About 59 patients met the inclusion criteria. The study population was mostly Caucasian men and women of equal proportions who were started on methadone for inadequate pain control. Sixty-eight percent of patients were successfully rotated. Subjects who were rotated using a standardized protocol were six times more likely to have a successful rotation (odds ratio 6.28 [1.25e30.92]; P ¼ 0.0238). Conclusion. The utilization of a standardized protocol was associated with better patient outcomes. J Pain Symptom Manage 2019;-:-e-. Ó 2019 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. Key Words Methadone rotation, guideline adherence, successful opioid rotation
Key Message Standardizing prescribing using a protocol is associated with successful methadone rotations.
Introduction Methadone, a mu-opioid receptor agonist and Nmethyl-D-aspartate antagonist, has a unique role in the management of pain. It is a racemic mixture of R (8e50 times more potent) and S enantiomers.1 Methadone binds to mu, kappa, and delta opioid receptors; inhibits the reuptake of serotonin and
Address correspondence to: Michael A. Smith, PharmD, BCPS, Department of Pharmacy Services, University of Michigan College of Pharmacy, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA. E-mail: [email protected] Ó 2019 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.
norepinephrine; and noncompetitively binds to Nmethyl-D-aspartate receptors.2 Patients with pain refractory to traditional opioids, intolerances to traditional opioids, or complex pain may benefit from conversion to methadone.3 However, unlike other opioids, there is no standard method of rotation to methadone or equianalgesic dose conversion ratio, making rotations to methadone challenging and potentially dangerous.3 Many methods of methadone rotation have been proposed, including rapid conversion or stop-and-go method (i.e., stopping original opioid and starting methadone at full dose),4 crosstapering or three-day switch (i.e., decreasing the original opioid while
Accepted for publication: September 13, 2019.
0885-3924/$ - see front matter https://doi.org/10.1016/j.jpainsymman.2019.09.014
2
Smith et al.
increasing methadone),5,6 and ad libitum (i.e., allowing patients to self-titrate using as-needed methadone),7 but no single method of rotation has been proven to be superior to others. A systematic review of opioid methadone rotation methods among patients with cancer-related pain identified 25 studies but found insufficient evidence to recommend one method over another.3 Successful rotation to methadone (as defined by a statistically or a clinically significant reduction in pain and/or adverse events) occurred among 72%e93% of patients in the studies, depending on the method and outcome definition.3 Notably, there have been no comparative effectiveness studies comparing rotation methods to one another. Given this gap in the literature, clinicians are left with little evidence to guide their methadone rotation practice. A recent white paper (hereafter defined as consensus recommendations) described consensus recommendations from a panel of 15 experts on the appropriate use of methadone in palliative care patients.8 The panel reviewed the limited literature and the American Pain Society’s existing guidelines on methadone use to develop guidance specific to the palliative care and hospice patients. Their recommendations covered appropriate candidates, risk assessment, drug interactions, dosing, and electrocardiogram (ECG) monitoring. In this study, we aimed to describe the impact of implementing internal guidelines (hereafter defined as internal protocol) for methadone rotation, relative to the published consensus recommendations referenced previously, for inpatients being followed by palliative care consultation services at a single academic medical center. We hypothesized that concordance with the consensus recommendations would lead to greater rates of successful rotation to methadone. Furthermore, we hypothesized that successful rotation to methadone would be seen in more patients after the initiation of our internal protocol compared with prior practice.
Vol.
-
No.
- -
2019
without the involvement of the PCCS or if they had a history of an opiate use disorder or prior exposure to methadone. Patients with incomplete medication administration data also were excluded. Data were abstracted from the electronic medical record by individual chart review of subjects identified as meeting inclusion criteria.9 We abstracted clinical information (primary diagnosis, history of opiate use disorder, comorbidities, and pain levels), demographic data, and medication administration records. Our primary outcome of interest was successful rotation defined as at least 30% reduction in either baseline pain score or as-needed (per re nata [PRN]) medication use sustained for at least three consecutive days.10 In addition, we evaluated adherence to five specific consensus recommendations: 1) selected dose matched the initial recommended ratio, 2) titrations no sooner than five to seven days after last dose change, 3) escalations of no more than 5 mg per day in opioid-naive patients or opioid-tolerant patients on less than 40 mg of methadone, 4) starting dose of methadone for opioid-tolerant patients did not exceed 40 mg per day, and 5) dose increases were no more than 10 mg per day in those receiving more than 40 mg per day of methadone. When an initial dose exceeded the recommended dose of consensus recommendations, we examined whether there was a subsequent dose reduction. Patients were described using means and ranges for continuous variables and frequencies for categorical variables. Characteristics of patients with successful rotation were compared with those with unsuccessful rotation using t-tests for continuous variables and Chi-squared analysis for bivariate variables. The sample size was not sufficient to allow multivariable modeling. The study was exempted from institutional review board based on Exemption 4 (ii) at 45 Code of Federal Regulations 46.104(d).
Results Methods This is a descriptive study of methadone rotation practice and outcomes for patients hospitalized at a single academic medical center during a six-year period, including time before and after the adoption of an internal protocol. The internal protocol was adopted on June 1, 2017. Patients included in the study were at least 18 years of age, hospitalized between January 1, 2012 and December 31, 2018, followed by the inpatient palliative care consult service (PCCS), and recommended by the PCCS to be treated with methadone for pain management during their hospitalization. Subjects were excluded if they were rotated to methadone
During the study period, 1166 patients received methadone as inpatients. Of these, 246 patients were seen by the PCCS. Seventy-six percent were excluded from the study: 170 were prescribed methadone before being seen by PCCS, 10 had substance use disorders, and seven had incomplete data. The remaining 59 were included in the study. The study population consisted of mostly Caucasian men and women in equal proportions, of middle age who were started on methadone for inadequate pain control (98.3%) (Table 1). Most subjects hospitalized had a primary diagnosis of cancer (83.1%). Baseline pain scores for all patients was 6.2 (scale 0e10).
Vol.
-
No.
- -
2019
Comparing Methadone Rotation to Consensus Opinion
3
Table 1 Sociodemographic and Clinical Characteristics of Patients Rotated to Methadone (N ¼ 59) Characteristics Gender Female Male Mean age (range) Race Caucasian African American Other Hospitalized after protocol implementation Primary diagnosis Cancer Calciphylaxis End-stage renal disease Other Average pain score at baseline
Entire Population
Successful
Unsuccessful
N ¼ 59
n ¼ 40 (67.8%)
n ¼ 19 (32.2%)
31 (52.5) 28 (47.5) 51 (23e91)
21 (52.5) 19 (47.5) 50 (24e81)
7 (36.8) 12 (63.2) 52 (23e91)
51 (86.4) 7 (11.9) 1 (1.7) 19 (32.2)
33 (82.5) 6 (15) 1 (2.5) 17 (42.5)
18 (94.7) 1 (5.3) 0 (0) 2 (10.5)
32 (80) 4 (10) 2 (5) 2 (5) 6.3
17 (89.5) 0 (0) 0 (0) 2 (10.5) 6.2
Pa NS
49 4 2 4
(83.1) (6.8) (3.4) (6.8) 6.2
NS NS
0.0174 NS
NS
NS ¼ not significant. a Categorical data were analyzed using Fisher’s exact tests, whereas continuous data were analyzed using t-test comparison of means.
Of the 59 patients who were started on methadone while hospitalized, 40 (68%) were successfully rotated. Of those, 27 (67.5%) reduced their use of their asneeded medications and seven (17.5%) experienced less pain; six (15%) did both. There were no statistically significant differences between the successful and unsuccessful population with regard to sociodemographic or clinical characteristics. Subjects with successful rotation to methadone were six times more likely to have been hospitalized after the adoption of the internal protocol (odds ratio 6.28 [1.25e30.92]; P ¼ 0.0238). They also were more likely to receive a follow-up ECG, have a lower QTc postrotation, and continue on methadone 30 days after discharge (Table 2). Patients with successful rotations had longer lengths of stay, longer time to start the rotation, and longer time to receive palliative care consultation; however, none of these were statistically significant. More patients in the successful rotation group were rotated to methadone from multiple opioids (60% vs. 32%; P ¼ 0.0539). Baseline oral morphine equivalents were 454.9 vs. 490.9 in the successful and unsuccessful groups, respectively (P ¼ 0.7966). Initial total daily dose and final total daily dose of methadone between the groups was not statistically significant (19.85 vs. 15.2; P ¼ 0.0738; and 29.225 vs. 18.2; P ¼ 0.0882) although they trended toward significance. The proportion of patients having a baseline ECG, their baseline average QTc, and the proportion of those with a baseline QTc >450 milliseconds did not differ between the groups. There was a statistically significant difference between groups in terms of proportion of patients receiving a follow-up ECG during rotation (82.9% vs. 50%; P ¼ 0.0310). In addition, patients in the unsuccessful group were more likely to have a higher average postmethadone
QTc than those in the successful rotation group (481 vs. 450.4; P ¼ 0.0280). More successful rotation patients were on methadone 30 days after discharge (70 vs. 42.1; P ¼ 0.0504); however, there was no difference in mortality 30 days after discharge (27.5 vs. 42.1; P ¼ 0.3717). Patients who were successfully rotated to methadone were more likely to have their doses titrated slowly (40% vs. 25%) and at smaller increments (56% vs. 0%), although these differences were not
Table 2 Factors Associated With Successful Rotation vs. Not
Characteristics LOS, average (days) Time to rotation start (days) Time to PC consult (days) Converting from more than one opioid (%) OME, average TDD methadone initial, average TDD methadone final, average Baseline ECG (%) QTc, average Follow-up ECG during (%) Highest post-start QTc, average On methadone 30 days postdischarge (%) Deceased 30 days postdischarge (%)
Successful (n ¼ 40)
Not Successful (n ¼ 19)
22.5 10.9
12.5 7.4
NS NS
7 60
3.7 31.6
NS NS
490.9 15.2
NS NS
18.2
NS
454.9 19.85 29.225
Pa
87.5 437.2 82.9 450.4
73.7 451.4 50 481
NS NS 0.0310 0.0280
70
42.1
NS
27.5
42.1
NS
LOS ¼ lengths of stay; NS ¼ not significant; PC ¼ palliative care; OME ¼ oral morphine equivalent; TDD ¼ total daily dose; ECG ¼ electrocardiogram. a Nominal data were analyzed using Fisher’s exact tests, whereas continuous data were analyzed using a t-test.
4
Smith et al.
statistically significant (Table 3). Other consensus recommendations were followed less often in successful cases than unsuccessful ones. Twenty-one patients were started on methadone doses that exceeded consensus recommendations (14 in the successful rotation group and seven in the unsuccessful rotation group). Dose reductions were necessary in 21% of those who were successfully rotated and 43% of those who were not (P ¼ 0.3544). Dose reductions were recommended at the discretion of the palliative care provider and were in response to mild sedation that did not require interventions (other than dose reduction). Higherthan-recommended doses were observed before and after the protocol (14 before the protocol: seven successful and seven unsuccessful; seven after the protocoldall successful) and not associated with any patient-specific characteristics.
Discussion Many guidelines exist for prescribing opioids in various populations; however, they often omit methadone. It has been shown that patients under the care of physicians with low knowledge of guidelines have worse pain control.11 The 2019 consensus recommendations by McPherson et al.8 provide expert recommendations on the safe and appropriate use of methadone in hospice and palliative care. We report here findings of the first study to evaluate the impact of implementing a standardized internal protocol for methadone rotation relative to consensus recommendations for patients seen by an inpatient palliative care service in a single academic medical center. Our study determined our overall success rate of rotation to methadone to be 67.8%, which is within the reported range in the literature, although our definition of success was stricter than reported in most prior studies.12 When our group implemented an internal protocol for our providers to use, the success rate of rotations improved from 57.5% to 89.5%. In our study, there were no differences between the successful and unsuccessful groups in terms of matching the dosing recommendations in the consensus recommendations. The increase in successful rotations postimplementation of the internal protocol was likely because of standardizing prescribing patterns. An internal survey of providers before this study showed that there were various methods of rotation used (five different methods were previously used by our provider group). However, there was a difference in the intensity of care (e.g., monitoring) provided, which was likely driven by the implementation of the internal protocol. The internal protocol has 10 recommended steps, one of which was a follow-up ECG. Only 45% of patients before the internal protocol
Vol.
-
No.
- -
2019
Table 3 Process Measures
Characteristics Selected dose matched the recommended initial ratio (%) Titration occurred no sooner than five to seven days (%) Dose increases were no more than 5 mg per day for opioid-naive patients or opioid-tolerant patients on <40 mg of methadone per day (%) Starting dose for opioid-tolerant patients did not exceed 40 mg per day (%) Dose increases were no more than 10 mg per day for patients on more than 40 mg per day of methadone (%)
Successful (n ¼ 40)
Not Successful (n ¼ 19)
P
12/40 (30.0)
9/19 (47.4)
0.2483
10/25 (40.0)
2/8 (25)
0.6776
15/25 (60.0)
6/8 (75)
0.3741
33/37 (89.2)
15/16 (93.8)
1.0
0/1 (0)
1.0
5/9 (55.6)
received a follow-up ECG during their stay, whereas 94.7% of patients after the internal protocol was implemented had a follow-up ECG completed. The consensus recommendations provide three levels of vigilance for monitoring. The internal protocol does not make that distinction during an inpatient admission, so all patients were monitored equally in terms of having at least one follow-up ECG. Repeat ECGs thereafter outside the internal protocol were at the discretion of each provider. Many studies have published on methods and outcomes of methadone rotation in palliative care patients; however, they have lacked detail to describe factors associated with success. One recent study showed that days alive after methadone rotation were different between groups, whereas no other factor was associated with success.13 Our study found no statistically significant difference between 30-day mortality rates between the groups, although a smaller proportion of patients in the successful group were deceased (27.5% vs. 42.1%). A separate study reported on doses ordered vs. recommended doses but did not report success rates or associated factors with success.14 Our study evaluated whether ordered doses
Vol.
-
No.
- -
2019
Comparing Methadone Rotation to Consensus Opinion
matched recommended doses and failed to find an association with a successful rotation. This study was limited by its retrospective observational design, small sample size, and single-study site; however, it does provide important information relating to adherence with recommendations. Although we did not find any differences in successful rotations between the patients before and after the internal protocol was in place, it is important to note that the internal protocol seemed to drive better outcomes in patients despite the small number. The consensus recommendations advise the use of a protocol for monitoring, which our data also support. It may be that a standardized protocol in the face of multiple providers using a complex medication is the best guidance to date. In our study, there was no association between compliance with the consensus recommendations and a successful rotation; however, implementation of a standardized internal protocol appeared to drive the improved monitoring of patients. It is clear that more research is needed to drive the optimal prescribing of methadone for palliative care patients. Our study identified that standardizing practice across a group of providers improves pain control and monitoring of patients rotated to methadone. Future studies should look to build on these data and provide detailed patient outcome data further testing the consensus recommendations.
Disclosures and Acknowledgments This research received no specific funding/grant from any funding agency in the public, commercial, or not-for-profit sectors. The authors declare no conflicts of interest.
5
2. Manfredi PL, Houde RW. Prescribing methadone, a unique analgesic. J Support Oncol 2003;1:216e220. 3. McLean S, Twomey F. Methods of rotation from another strong opioid to methadone for the management of cancer pain: a systematic review of the available evidence. J Pain Symptom Manage 2015;50:248e259. 4. Mercadante S, Ferrara P, Villari P, et al. Switching from oxycodone to methadone in advanced cancer. Support Care Cancer 2012;20:191e194. 5. Nixon AJ. Methadone for cancer pain: a case report. Am J Hosp Palliat Care 2005;22:337. 6. Moksnes K, Dale O, Rosland JH, et al. How to switch from morphine or oxycodone to methadone in cancer patients? A randomised clinical phase II trial. Eur J Cancer 2011;47:2463e2470. 7. Morley JS, Makin MK. The use of methadone in cancer poorly responsive to other opioids. Pain Rev 1998;5:51e58. 8. McPherson ML, Walker KA, Davis MP, et al. Safe and appropriate use of methadone in hospice and palliative care: expert consensus white paper. J Pain Symptom Manage 2019;57:635e645. 9. Hanauer D, Mei Q, Law J, et al. Supporting information retrieval from electronic health records: a report of University of Michigan’s nine-year experience in developing and using the Electronic Medical Record Search Engine (EMERSE). J Biomed Inform 2015;55:290e300. 10. Mercadante S, Ferrera P, Villari P, Casuccio A. Rapid switching between transdermal fentanyl and methadone in cancer patients. J Clin Oncol 2005;23:5229e5234. 11. Kim DY, Ahn JS, Lee KH, et al. A nationwide survey of knowledge of and compliance with cancer pain management guidelines by Korean physicians. Cancer Res Treat 2014;46:131e140. 12. Weschules DJ, Bain KT. A systematic review of opioid conversion ratios used with methadone for the treatment of pain. Pain Med 2008;9:595e612.
References
13. Okayama S, Matsuda Y, Yoshikawa Y. A comparative study of opioid switching to methadone for cancer pain control in successful and unsuccessful cases. J Palliat Med 2019;22: 844e847.
1. Kristensen K, Christensen CB, Christrup LL. The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine. Life Sci 1995;56: PL45ePL50.
14. Karimian P, Atayee RS, Ajayi TA, Edmons KP. Methadone dose selection for treatment of pain compared with consensus recommendations. J Palliat Med 2017;20: 1385e1388.
-
No.
- -
2019
Journal of Pain and Symptom Management
1
Brief Report
Comparing Methadone Rotation to Consensus Opinion Michael A. Smith, PharmD, BCPS, Kyle C. Quirk, PharmD, D’Anna C. Saul, MD, Phillip E. Rodgers, MD, and Maria J. Silveira, MD, MA, MPH Department of Pharmacy Services (M.A.S., K.C.Q.), Michigan Medicine, Ann Arbor, Michigan; University of Michigan College of Pharmacy (M.A.S., K.C.Q.), Ann Arbor, Michigan; Department of Internal Medicine (D.A.C.S., M.J.S.), Michigan Medicine, Ann Arbor, Michigan; Department of Pediatrics (D.A.C.S.), Ann Arbor, Michigan; and Department of Family Medicine (P.E.R.), Michigan Medicine, Ann Arbor, Michigan, USA
Abstract Context. Methadone is a complex but useful medication for pain management in palliative care. Recent expert opinions have been published on the safe and effective use of methadone. Objectives. To determine the success of methadone rotations and evaluate concordance with consensus recommendations by a palliative care consult service. Methods. A retrospective study of methadone rotation practice by a palliative care consult service and outcomes for patients hospitalized between January 1, 2012 and December 31, 2018 at a single academic medical center. A successful rotation was defined as a 30% reduction in pain or as-needed medication use sustained for at least three consecutive days. Patient outcomes were compared with expert consensus recommendations. Results. About 59 patients met the inclusion criteria. The study population was mostly Caucasian men and women of equal proportions who were started on methadone for inadequate pain control. Sixty-eight percent of patients were successfully rotated. Subjects who were rotated using a standardized protocol were six times more likely to have a successful rotation (odds ratio 6.28 [1.25e30.92]; P ¼ 0.0238). Conclusion. The utilization of a standardized protocol was associated with better patient outcomes. J Pain Symptom Manage 2019;-:-e-. Ó 2019 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. Key Words Methadone rotation, guideline adherence, successful opioid rotation
Key Message Standardizing prescribing using a protocol is associated with successful methadone rotations.
Introduction Methadone, a mu-opioid receptor agonist and Nmethyl-D-aspartate antagonist, has a unique role in the management of pain. It is a racemic mixture of R (8e50 times more potent) and S enantiomers.1 Methadone binds to mu, kappa, and delta opioid receptors; inhibits the reuptake of serotonin and
Address correspondence to: Michael A. Smith, PharmD, BCPS, Department of Pharmacy Services, University of Michigan College of Pharmacy, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA. E-mail: [email protected] Ó 2019 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.
norepinephrine; and noncompetitively binds to Nmethyl-D-aspartate receptors.2 Patients with pain refractory to traditional opioids, intolerances to traditional opioids, or complex pain may benefit from conversion to methadone.3 However, unlike other opioids, there is no standard method of rotation to methadone or equianalgesic dose conversion ratio, making rotations to methadone challenging and potentially dangerous.3 Many methods of methadone rotation have been proposed, including rapid conversion or stop-and-go method (i.e., stopping original opioid and starting methadone at full dose),4 crosstapering or three-day switch (i.e., decreasing the original opioid while
Accepted for publication: September 13, 2019.
0885-3924/$ - see front matter https://doi.org/10.1016/j.jpainsymman.2019.09.014
2
Smith et al.
increasing methadone),5,6 and ad libitum (i.e., allowing patients to self-titrate using as-needed methadone),7 but no single method of rotation has been proven to be superior to others. A systematic review of opioid methadone rotation methods among patients with cancer-related pain identified 25 studies but found insufficient evidence to recommend one method over another.3 Successful rotation to methadone (as defined by a statistically or a clinically significant reduction in pain and/or adverse events) occurred among 72%e93% of patients in the studies, depending on the method and outcome definition.3 Notably, there have been no comparative effectiveness studies comparing rotation methods to one another. Given this gap in the literature, clinicians are left with little evidence to guide their methadone rotation practice. A recent white paper (hereafter defined as consensus recommendations) described consensus recommendations from a panel of 15 experts on the appropriate use of methadone in palliative care patients.8 The panel reviewed the limited literature and the American Pain Society’s existing guidelines on methadone use to develop guidance specific to the palliative care and hospice patients. Their recommendations covered appropriate candidates, risk assessment, drug interactions, dosing, and electrocardiogram (ECG) monitoring. In this study, we aimed to describe the impact of implementing internal guidelines (hereafter defined as internal protocol) for methadone rotation, relative to the published consensus recommendations referenced previously, for inpatients being followed by palliative care consultation services at a single academic medical center. We hypothesized that concordance with the consensus recommendations would lead to greater rates of successful rotation to methadone. Furthermore, we hypothesized that successful rotation to methadone would be seen in more patients after the initiation of our internal protocol compared with prior practice.
Vol.
-
No.
- -
2019
without the involvement of the PCCS or if they had a history of an opiate use disorder or prior exposure to methadone. Patients with incomplete medication administration data also were excluded. Data were abstracted from the electronic medical record by individual chart review of subjects identified as meeting inclusion criteria.9 We abstracted clinical information (primary diagnosis, history of opiate use disorder, comorbidities, and pain levels), demographic data, and medication administration records. Our primary outcome of interest was successful rotation defined as at least 30% reduction in either baseline pain score or as-needed (per re nata [PRN]) medication use sustained for at least three consecutive days.10 In addition, we evaluated adherence to five specific consensus recommendations: 1) selected dose matched the initial recommended ratio, 2) titrations no sooner than five to seven days after last dose change, 3) escalations of no more than 5 mg per day in opioid-naive patients or opioid-tolerant patients on less than 40 mg of methadone, 4) starting dose of methadone for opioid-tolerant patients did not exceed 40 mg per day, and 5) dose increases were no more than 10 mg per day in those receiving more than 40 mg per day of methadone. When an initial dose exceeded the recommended dose of consensus recommendations, we examined whether there was a subsequent dose reduction. Patients were described using means and ranges for continuous variables and frequencies for categorical variables. Characteristics of patients with successful rotation were compared with those with unsuccessful rotation using t-tests for continuous variables and Chi-squared analysis for bivariate variables. The sample size was not sufficient to allow multivariable modeling. The study was exempted from institutional review board based on Exemption 4 (ii) at 45 Code of Federal Regulations 46.104(d).
Results Methods This is a descriptive study of methadone rotation practice and outcomes for patients hospitalized at a single academic medical center during a six-year period, including time before and after the adoption of an internal protocol. The internal protocol was adopted on June 1, 2017. Patients included in the study were at least 18 years of age, hospitalized between January 1, 2012 and December 31, 2018, followed by the inpatient palliative care consult service (PCCS), and recommended by the PCCS to be treated with methadone for pain management during their hospitalization. Subjects were excluded if they were rotated to methadone
During the study period, 1166 patients received methadone as inpatients. Of these, 246 patients were seen by the PCCS. Seventy-six percent were excluded from the study: 170 were prescribed methadone before being seen by PCCS, 10 had substance use disorders, and seven had incomplete data. The remaining 59 were included in the study. The study population consisted of mostly Caucasian men and women in equal proportions, of middle age who were started on methadone for inadequate pain control (98.3%) (Table 1). Most subjects hospitalized had a primary diagnosis of cancer (83.1%). Baseline pain scores for all patients was 6.2 (scale 0e10).
Vol.
-
No.
- -
2019
Comparing Methadone Rotation to Consensus Opinion
3
Table 1 Sociodemographic and Clinical Characteristics of Patients Rotated to Methadone (N ¼ 59) Characteristics Gender Female Male Mean age (range) Race Caucasian African American Other Hospitalized after protocol implementation Primary diagnosis Cancer Calciphylaxis End-stage renal disease Other Average pain score at baseline
Entire Population
Successful
Unsuccessful
N ¼ 59
n ¼ 40 (67.8%)
n ¼ 19 (32.2%)
31 (52.5) 28 (47.5) 51 (23e91)
21 (52.5) 19 (47.5) 50 (24e81)
7 (36.8) 12 (63.2) 52 (23e91)
51 (86.4) 7 (11.9) 1 (1.7) 19 (32.2)
33 (82.5) 6 (15) 1 (2.5) 17 (42.5)
18 (94.7) 1 (5.3) 0 (0) 2 (10.5)
32 (80) 4 (10) 2 (5) 2 (5) 6.3
17 (89.5) 0 (0) 0 (0) 2 (10.5) 6.2
Pa NS
49 4 2 4
(83.1) (6.8) (3.4) (6.8) 6.2
NS NS
0.0174 NS
NS
NS ¼ not significant. a Categorical data were analyzed using Fisher’s exact tests, whereas continuous data were analyzed using t-test comparison of means.
Of the 59 patients who were started on methadone while hospitalized, 40 (68%) were successfully rotated. Of those, 27 (67.5%) reduced their use of their asneeded medications and seven (17.5%) experienced less pain; six (15%) did both. There were no statistically significant differences between the successful and unsuccessful population with regard to sociodemographic or clinical characteristics. Subjects with successful rotation to methadone were six times more likely to have been hospitalized after the adoption of the internal protocol (odds ratio 6.28 [1.25e30.92]; P ¼ 0.0238). They also were more likely to receive a follow-up ECG, have a lower QTc postrotation, and continue on methadone 30 days after discharge (Table 2). Patients with successful rotations had longer lengths of stay, longer time to start the rotation, and longer time to receive palliative care consultation; however, none of these were statistically significant. More patients in the successful rotation group were rotated to methadone from multiple opioids (60% vs. 32%; P ¼ 0.0539). Baseline oral morphine equivalents were 454.9 vs. 490.9 in the successful and unsuccessful groups, respectively (P ¼ 0.7966). Initial total daily dose and final total daily dose of methadone between the groups was not statistically significant (19.85 vs. 15.2; P ¼ 0.0738; and 29.225 vs. 18.2; P ¼ 0.0882) although they trended toward significance. The proportion of patients having a baseline ECG, their baseline average QTc, and the proportion of those with a baseline QTc >450 milliseconds did not differ between the groups. There was a statistically significant difference between groups in terms of proportion of patients receiving a follow-up ECG during rotation (82.9% vs. 50%; P ¼ 0.0310). In addition, patients in the unsuccessful group were more likely to have a higher average postmethadone
QTc than those in the successful rotation group (481 vs. 450.4; P ¼ 0.0280). More successful rotation patients were on methadone 30 days after discharge (70 vs. 42.1; P ¼ 0.0504); however, there was no difference in mortality 30 days after discharge (27.5 vs. 42.1; P ¼ 0.3717). Patients who were successfully rotated to methadone were more likely to have their doses titrated slowly (40% vs. 25%) and at smaller increments (56% vs. 0%), although these differences were not
Table 2 Factors Associated With Successful Rotation vs. Not
Characteristics LOS, average (days) Time to rotation start (days) Time to PC consult (days) Converting from more than one opioid (%) OME, average TDD methadone initial, average TDD methadone final, average Baseline ECG (%) QTc, average Follow-up ECG during (%) Highest post-start QTc, average On methadone 30 days postdischarge (%) Deceased 30 days postdischarge (%)
Successful (n ¼ 40)
Not Successful (n ¼ 19)
22.5 10.9
12.5 7.4
NS NS
7 60
3.7 31.6
NS NS
490.9 15.2
NS NS
18.2
NS
454.9 19.85 29.225
Pa
87.5 437.2 82.9 450.4
73.7 451.4 50 481
NS NS 0.0310 0.0280
70
42.1
NS
27.5
42.1
NS
LOS ¼ lengths of stay; NS ¼ not significant; PC ¼ palliative care; OME ¼ oral morphine equivalent; TDD ¼ total daily dose; ECG ¼ electrocardiogram. a Nominal data were analyzed using Fisher’s exact tests, whereas continuous data were analyzed using a t-test.
4
Smith et al.
statistically significant (Table 3). Other consensus recommendations were followed less often in successful cases than unsuccessful ones. Twenty-one patients were started on methadone doses that exceeded consensus recommendations (14 in the successful rotation group and seven in the unsuccessful rotation group). Dose reductions were necessary in 21% of those who were successfully rotated and 43% of those who were not (P ¼ 0.3544). Dose reductions were recommended at the discretion of the palliative care provider and were in response to mild sedation that did not require interventions (other than dose reduction). Higherthan-recommended doses were observed before and after the protocol (14 before the protocol: seven successful and seven unsuccessful; seven after the protocoldall successful) and not associated with any patient-specific characteristics.
Discussion Many guidelines exist for prescribing opioids in various populations; however, they often omit methadone. It has been shown that patients under the care of physicians with low knowledge of guidelines have worse pain control.11 The 2019 consensus recommendations by McPherson et al.8 provide expert recommendations on the safe and appropriate use of methadone in hospice and palliative care. We report here findings of the first study to evaluate the impact of implementing a standardized internal protocol for methadone rotation relative to consensus recommendations for patients seen by an inpatient palliative care service in a single academic medical center. Our study determined our overall success rate of rotation to methadone to be 67.8%, which is within the reported range in the literature, although our definition of success was stricter than reported in most prior studies.12 When our group implemented an internal protocol for our providers to use, the success rate of rotations improved from 57.5% to 89.5%. In our study, there were no differences between the successful and unsuccessful groups in terms of matching the dosing recommendations in the consensus recommendations. The increase in successful rotations postimplementation of the internal protocol was likely because of standardizing prescribing patterns. An internal survey of providers before this study showed that there were various methods of rotation used (five different methods were previously used by our provider group). However, there was a difference in the intensity of care (e.g., monitoring) provided, which was likely driven by the implementation of the internal protocol. The internal protocol has 10 recommended steps, one of which was a follow-up ECG. Only 45% of patients before the internal protocol
Vol.
-
No.
- -
2019
Table 3 Process Measures
Characteristics Selected dose matched the recommended initial ratio (%) Titration occurred no sooner than five to seven days (%) Dose increases were no more than 5 mg per day for opioid-naive patients or opioid-tolerant patients on <40 mg of methadone per day (%) Starting dose for opioid-tolerant patients did not exceed 40 mg per day (%) Dose increases were no more than 10 mg per day for patients on more than 40 mg per day of methadone (%)
Successful (n ¼ 40)
Not Successful (n ¼ 19)
P
12/40 (30.0)
9/19 (47.4)
0.2483
10/25 (40.0)
2/8 (25)
0.6776
15/25 (60.0)
6/8 (75)
0.3741
33/37 (89.2)
15/16 (93.8)
1.0
0/1 (0)
1.0
5/9 (55.6)
received a follow-up ECG during their stay, whereas 94.7% of patients after the internal protocol was implemented had a follow-up ECG completed. The consensus recommendations provide three levels of vigilance for monitoring. The internal protocol does not make that distinction during an inpatient admission, so all patients were monitored equally in terms of having at least one follow-up ECG. Repeat ECGs thereafter outside the internal protocol were at the discretion of each provider. Many studies have published on methods and outcomes of methadone rotation in palliative care patients; however, they have lacked detail to describe factors associated with success. One recent study showed that days alive after methadone rotation were different between groups, whereas no other factor was associated with success.13 Our study found no statistically significant difference between 30-day mortality rates between the groups, although a smaller proportion of patients in the successful group were deceased (27.5% vs. 42.1%). A separate study reported on doses ordered vs. recommended doses but did not report success rates or associated factors with success.14 Our study evaluated whether ordered doses
Vol.
-
No.
- -
2019
Comparing Methadone Rotation to Consensus Opinion
matched recommended doses and failed to find an association with a successful rotation. This study was limited by its retrospective observational design, small sample size, and single-study site; however, it does provide important information relating to adherence with recommendations. Although we did not find any differences in successful rotations between the patients before and after the internal protocol was in place, it is important to note that the internal protocol seemed to drive better outcomes in patients despite the small number. The consensus recommendations advise the use of a protocol for monitoring, which our data also support. It may be that a standardized protocol in the face of multiple providers using a complex medication is the best guidance to date. In our study, there was no association between compliance with the consensus recommendations and a successful rotation; however, implementation of a standardized internal protocol appeared to drive the improved monitoring of patients. It is clear that more research is needed to drive the optimal prescribing of methadone for palliative care patients. Our study identified that standardizing practice across a group of providers improves pain control and monitoring of patients rotated to methadone. Future studies should look to build on these data and provide detailed patient outcome data further testing the consensus recommendations.
Disclosures and Acknowledgments This research received no specific funding/grant from any funding agency in the public, commercial, or not-for-profit sectors. The authors declare no conflicts of interest.
5
2. Manfredi PL, Houde RW. Prescribing methadone, a unique analgesic. J Support Oncol 2003;1:216e220. 3. McLean S, Twomey F. Methods of rotation from another strong opioid to methadone for the management of cancer pain: a systematic review of the available evidence. J Pain Symptom Manage 2015;50:248e259. 4. Mercadante S, Ferrara P, Villari P, et al. Switching from oxycodone to methadone in advanced cancer. Support Care Cancer 2012;20:191e194. 5. Nixon AJ. Methadone for cancer pain: a case report. Am J Hosp Palliat Care 2005;22:337. 6. Moksnes K, Dale O, Rosland JH, et al. How to switch from morphine or oxycodone to methadone in cancer patients? A randomised clinical phase II trial. Eur J Cancer 2011;47:2463e2470. 7. Morley JS, Makin MK. The use of methadone in cancer poorly responsive to other opioids. Pain Rev 1998;5:51e58. 8. McPherson ML, Walker KA, Davis MP, et al. Safe and appropriate use of methadone in hospice and palliative care: expert consensus white paper. J Pain Symptom Manage 2019;57:635e645. 9. Hanauer D, Mei Q, Law J, et al. Supporting information retrieval from electronic health records: a report of University of Michigan’s nine-year experience in developing and using the Electronic Medical Record Search Engine (EMERSE). J Biomed Inform 2015;55:290e300. 10. Mercadante S, Ferrera P, Villari P, Casuccio A. Rapid switching between transdermal fentanyl and methadone in cancer patients. J Clin Oncol 2005;23:5229e5234. 11. Kim DY, Ahn JS, Lee KH, et al. A nationwide survey of knowledge of and compliance with cancer pain management guidelines by Korean physicians. Cancer Res Treat 2014;46:131e140. 12. Weschules DJ, Bain KT. A systematic review of opioid conversion ratios used with methadone for the treatment of pain. Pain Med 2008;9:595e612.
References
13. Okayama S, Matsuda Y, Yoshikawa Y. A comparative study of opioid switching to methadone for cancer pain control in successful and unsuccessful cases. J Palliat Med 2019;22: 844e847.
1. Kristensen K, Christensen CB, Christrup LL. The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine. Life Sci 1995;56: PL45ePL50.
14. Karimian P, Atayee RS, Ajayi TA, Edmons KP. Methadone dose selection for treatment of pain compared with consensus recommendations. J Palliat Med 2017;20: 1385e1388.