OBJECTIVE: Opioid conversion calculators (OCCs) are used to convert between opioids. The purpose of this study was to describe the variability in OCC results in critically ill children transitioned from fentanyl to hydromorphone infusions.
METHODS: This was a descriptive, retrospective study. Seventeen OCCs were identified and grouped into 6 groups (groups 1-6) based on the equianalgesic conversions. The OCCs were used to calculate the hydromorphone rate in critically ill children (<18 years) converted from fentanyl to hydromorphone. Information from a previous study on children stabilized on hydromorphone (defined as the first 24-hour period with no change in the hydromorphone rates, <3 hydromorphone boluses administered, and 80% of State Behavior Scale scores between 0 and -1) were utilized. The primary objective was to compare the median hydromorphone rates calculated using the 17 OCCs. The secondary objective was to compare the percent variability of the OCC-calculated hydromorphone rates to the stabilization rate.
RESULTS: Seventeen OCCs were applied to data on 28 children with a median age and hydromorphone rate of 2.4 years and 0.08 mg/kg/h, respectively. The median hydromorphone rate calculated using the 17 OCCs ranged from 0.06 to 0.12 mg/kg/h. Group 3 and group 6 OCCs resulted in a calculated hydromorphone rate that was higher than the stabilization rate in 96% and 75% of patients, respectively. Use of group 4 and group 5 OCCs resulted in a calculated hydromorphone rate that was lower than the stabilization rate in 64% and 75% of patients, respectively.
CONCLUSIONS: Given the considerable variability of OCCs, caution should be used when applying OCCs to critically ill children.

BACKGROUND: Methadone is a commonly prescribed opioid amongst cancer patients. It has unique pharmacological properties which can benefit in treating complex pain syndromes and neuropathic pain. However, strict guidelines have been created in a generalized manner for chronic pain and long-term survival patients. These guidelines, such as QT interval monitoring can lead to limitations for methadone use in patients with comfort-associated goals. We present two cases of patients with metastatic cancer who were treated for pain with methadone and had to undergo opioid rotation due to abnormal QT intervals.
METHODS: Case one was a female with open ulcerated wounds due to metastatic breast cancer who presented with uncontrolled pain on her current opioid regimen. She achieved pain relief when rotated to methadone but a repeat electrocardiogram a few months later showed QTc prolongation. She underwent opioid rotation with different medications, but her pain remained poorly controlled. Case two was a female with poorly controlled pain in the setting of bilateral breast cancer. She presented with concerns for opioid-induced neurotoxicity and was rotated to methadone. She achieved optimal pain relief. A few weeks later, her machine read QT interval was prolonged and she was rotated off methadone. The electrocardiogram was manually read which showed a normal QT interval and she was restarted on methadone with pain relief.
CONCLUSIONS: In the palliative care setting, monitoring QTc per chronic pain guidelines may lead to uncontrolled pain and a significant impact on quality of life.

Opioid-induced neurotoxicity (OINT) is a neuropsychiatric syndrome observed with opioid therapy. The mechanism of OINT is thought to be multifactorial, and many risk factors may facilitate its development. If symptoms of OINT are seen, the prescriber should consider hydration, discontinuation of the offending opioid drug, or switching of opioid medication, or the use of some adjuvants. Multiple factors like inter- and intraindividual differences in opioid pharmacology may influence the accuracy of dose calculations for opioid switching. Experience and clinical judgment in a specialistic palliative care setting should be used and individual patient characteristics considered when applying any conversion table.

The objective of this study was to understand the effect buprenorphine rotations have on respiratory risk and other safety outcomes. This was a retrospective observational study evaluating Veterans who underwent an opioid rotation from full-agonist opioids to buprenorphine products or to alternative opioids. The primary endpoint was change in the Risk Index for Overdose or Serious Opioid-induced Respiratory Depression (RIOSORD) score from baseline to six months post-rotation. Median baseline RIOSORD scores were 26.0 and 18.0 in the Buprenorphine Group and the Alternative Opioid Group, respectively. There was no statistically significant difference between groups in baseline RIOSORD score. At six months post-rotation, median RIOSORD scores were 23.5 and 23.0 in the Buprenorphine Group and Alternative Opioid Group, respectively. The difference in change in RIOSORD scores between groups was not statistically significant (p = 0.23). However, based on changes in RIOSORD risk class, an 11% and 0% decrease in respiratory risk was observed in the Buprenorphine and Alternative Opioid groups, respectively. This finding may be considered clinically significant given a change in risk was observed as predicted by RIOSORD score. Further research is needed to clarify the effect that opioid rotations have on respiratory depression risk and other safety outcomes.

BACKGROUND: A third of patients with advanced cancer and bone metastasis suffer from cancer induced bone pain (CIBP), impeding quality of life, psychological distress, depression and anxiety. This study will evaluate the impact of an opioid rotation, comparing methadone rotation with other opioid rotation in patients with refractory CIBP.
METHODS: This open-label randomised controlled trial will recruit cancer patients with CIBP and inadequate pain control despite established baseline opioid and/or intolerable opioid side effects from cancer and palliative care services. Participants will be at least 18 years old, with a predicted prognosis of greater than 8 weeks, meet the core diagnostic criteria for CIBP, have a worst pain score of ≥ 4 of 10 from CIBP and/ or have opioid toxicity (graded ≥ 2 on Common Terminology Criteria for Adverse Events). Participants will have sufficiently proficient English to complete questionnaires and provide informed consent. Participants will be randomised 1:1 to be rotated to methadone to another opioid. The primary objective is to examine the impact of opioid rotation in improving CIBP by comparing analgesic efficacy, safety and tolerability in the two arms. Secondary objectives will assess changes in the intensity, duration and frequency of breakthrough pain, requirement of breakthrough analgesia, overall opioid escalation index, and time taken to observe improvement in pain reduction, pain interference and quality of life.
CONCLUSIONS: Laboratory studies suggest the involvement of neuropathic involvement in the mechanism of CIBP, though there remains no clear evidence of the routine use of neuropathic agents. Methadone as an analgesic agent may have a role to play in this cohort of patients, thus warranting further exploratory studies.
BACKGROUND: Australian New Zealand Clinical Trials Registry No: ACTRN12621000141842. Registered 11 February 2021.

Levorphanol is a potent opioid agonist and NMDA receptor blocker with minimal drug interactions, and there are few reports of its use in cancer patients.
We aimed to determine the frequency of successful opioid rotation (OR) to levorphanol and the median opioid rotation ratio (ORR) from Morphine Equivalent Daily Dose (MEDD).
This is a prospective, single-group, interventional study. Cancer outpatients requiring an OR and receiving a MEDD of 60-300 mg were rotated to levorphanol using a ratio of 10:1 and assessed daily for 10-day. Successful OR was defined as a 2-point improvement in the Edmonton Symptom Assessment System (ESAS) pain score on day 10 or achieving the personalized pain goal between days 3-10 in patients with uncontrolled pain or resolution of opioid side effects (OSE) in those undergoing OR for OSE alone. The ORR to levorphanol was calculated using net-MEDD (MEDD before OR minus the MEDD of the breakthrough opioid used along with levorphanol after OR).
Forty patients underwent OR to levorphanol, and uncontrolled pain 35/40 (87.5%) was the most common indication. The median net-MEDD and levorphanol doses were 95 and 10 mg, respectively, and 33/40 (82.5%) had a successful OR with a median (IQR) ORR of 8.56 (7.5-10). Successful OR was associated with significant improvement in ESAS and OSE scale scores. There was a strong association between MEDD and levorphanol dose.
This study provided preliminary data that cancer patients could be successfully rotated to levorphanol using an ORR of 8.5. Levorphanol was associated with improved pain and symptom control and was well- tolerated.

Background: The opioid rotation ratios (ORRs) and conversion ratios (CRs) used worldwide among palliative care (PC) professionals to perform opioid rotations (ORs) and route conversions may have a wide variation. Methods: We surveyed PC professionals on opioid ratios used through email to the Multinational Association of Supportive Care in Cancer\'s PC study group and Twitter and Facebook posts between September and November 2020. Results: We received 370 responses from respondents from 53 countries: 276 (76%) were physicians, 46 (13%) advanced practice providers, 39 (11%) pharmacists, and 9 respondents did not report their profession. There were statistically significant variations in median CR from intravenous (IV) to oral morphine (2-3), IV to oral hydromorphone (2-4.5), ORR from IV hydromorphone to oral morphine (10-20), and ORR from transdermal fentanyl mcg/hour to oral morphine (2-3.5) across various groups. Conclusion: This survey highlights the wide variation in ORRs and CRs among PC clinicians worldwide and the need for further research to standardize practice.

Background: The initiation of methadone, a known effective analgesic for cancer pain, is complex. The existing protocols are often inadequately described; therefore, a classification of literature is needed. We reviewed and classified the recent literature on methadone initiation protocols in cancer patients experiencing severe pain. Objective: To provide a new classification of initiation protocols, based on a critical literature review. Data Sources: The MEDLINE database was searched for articles published until March 25, 2021, using the terms \"cancer pain,\" \"methadone,\" \"methadone introduction,\" or \"methadone initiation.\" The search was limited to human studies, randomized controlled trials (RCTs), other clinical trials, meta-analyses, and case reports. Selected articles were assessed for initiation details (rapid or progressive), administered dose (fixed rescue dose or ad libitum), and dose calculation (fixed or progressive ratios using morphine equivalent daily dose [MEDD] for daily or unitary dose). Results: Twenty-four publications that met our inclusion criteria were analyzed. No large-scale prospective double-blind RCTs with robust design were identified. Most studies assessed relatively small numbers of patients. Eight initiation types were identified, of which three involved seven \"high quality\" studies: \"rapid switch-fixed doses and rescue dose-progressive daily ratio,\" \"progressive switch-fixed dose and rescue dose-progressive daily ratio,\" and \"rapid switch-ad libitum-fixed ratio for unitary dose\" protocols. This classification provides the latest information on methadone initiation protocols. The total daily dose of methadone varied largely across protocols. Conclusion: We recommend a maximal daily methadone dose of 100 mg (3 doses of 30 mg or 5 doses of 20 mg) for MEDD <500 mg, when the two \"ad libitum\" protocols are used. Further clinical research on this topic is warranted.

Opioid rotations from fentanyl to hydromorphone may reduce opioid/sedative exposure in critically ill children.
The primary objective was to determine the conversion percentage from fentanyl to hydromorphone infusions using equianalgesic conversions (0.1 mg fentanyl = 1.5 mg hydromorphone). Secondary objectives included identification of the median time and hydromorphone rate at stabilization (defined as the first 24-hour period no hydromorphone rates changed, 80% of State Behavioral Scale [SBS] scores between 0 and -1, and <3 hydromorphone boluses administered). Additional outcomes included a comparison of opioid/sedative requirements on the day of conversion versus the three 24-hour periods prior to conversion.
This retrospective study included children <18 years old converted from fentanyl to hydromorphone infusions over 6.3 years. Linear mixed models were used to determine if the mean cumulative opioid/sedative dosing differed from the day of conversion versus three 24-hour periods prior to conversion.
A total of 36 children were converted to hydromorphone. The median conversion percentage of hydromorphone was 86% of their fentanyl dose (interquartile range [IQR] = 67-100). The median hydromorphone rate at stabilization was 0.08 mg/kg/h (IQR = 0.05-0.1). Eight (22%) were stabilized on their initial hydromorphone rate; 8 (22%) never achieved stabilization. Patients had a significant decrease in opioid dosing on the day of conversion versus the 24-hour period prior to conversion but no changes in sedative dosing following conversion.
A median 14% fentanyl dose reduction was noted when transitioning to hydromorphone. Further exploration is needed to determine if opioid rotations with hydromorphone can reduce opioid/sedative exposure.

Methadone has been an unique, versatile, cost effective, synthetic opioid utilized in nociceptive as well as neuropathic pain. Pain and palliative care physicians started accepting methadone in treatment of complex pain associated with advanced cancer and neuropathic pain syndromes in which conventional opioids were no longer effective. The challenge is in accepting methadone as a main stream first line opioid, from being considered as a second line replacement/substitution drug all these years. Methadone has a significant role as opioid rotation in refractory cancer pain, especially when started early leading to successful conversion. Advantages of methadone in paediatric patients with advanced cancer were its safety and efficacy as a first-choice opioid, availability as a liquid formulation and its infrequent dose requirements. Methadone is neither recommended nor justified to be used as an anti-cancer drug and its role as an anti-cancer agent is a misconception. Many guidelines were proposed after 2008 to address methadone safety. Most of them emphasized on prevention of cardiac arrhythmia and association of methadone with QTc prolongation rather than address the real issue. Methadone has been established to be safe when used in opioid naïve patients with careful titration instituted in an ambulatory setting and has equal success in opioid rotation in outpatient setup. Methadone prescription should be carried out by experienced pain and palliative care providers with careful dose titration and clinical monitoring.