Methadone versus other opioids for refractory malignant bone pain: a pilot randomised controlled study

Methadone versus other opioids for refractory malignant bone pain: a pilot randomised controlled study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Methadone versus other opioids for refractory malignant bone pain: a pilot randomised controlled study Merlina Sulistio, alexandra Gorelik, Hoong Jiun Tee, Robert Wojnar, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4380470/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Purpose Refractory cancer-induced bone pain (CIBP) affects a patient’s functional capacity and quality of life, but there is limited evidence to guide opioid choice. We assessed the feasibility, tolerability, and possible efficacy of methadone rotation (MR) compared to other opioid rotations (OOR) in this cohort. Methods Adults with CIBP and worst pain intensity ≥ 4/10 and/or opioid toxicity graded ≥ 2 on the Common Terminology Criteria for Adverse Events were randomised 1:1 to methadone or another opioid rotation. Standardised assessment tools were used at pre-defined study time points up to fourteen days. Results From 51 eligible participants, 38 (74.5%) consented, and 29 (76.3%, MR: 14, OOR: 15) completed the fourteen days follow up post opioid rotation. Both groups displayed significant reduction in average (MR: d= -1.2, p = 0.003, OOR: d= -0.8, p = 0.015) and worst pain (MR: d= -0.9, p = 0.042, OOR: d= -0.6, p = 0.048), and total pain interference score (MR: d=-1.1, p = 0.042, OOR: d=-0.7, p = 0.007). Oral morphine equivalent daily dose reduced significantly in MR compared to OOR group (d= -0.8, p = 0.05). The incidence of opioid related adverse event following MR was unchanged but lower in the OOR group (d = 0.9, 95% CI 0.1,1.7, p = 0.022). There was no within group or between group differences in satisfaction with analgesia at the end of the study. Conclusion This pilot study demonstrated that MR and OOR in patients with refractory CIBP are feasible, safe, and acceptable to patients. Appropriately powered multi-centre randomised controlled studies are needed to confirm the efficacy of MR and OOR in this cohort. Trial registration number ACTRN12621000141842 registered 11 February 2021. Bone pain refractory pain opioid pain control methadone Figures Figure 1 Figure 2 INTRODUCTION Cancer-induced bone pain (CIBP) is a common cancer pain syndrome, with a mixture of inflammatory, nociceptive, and neuropathic pain requiring a multimodal approach to analgesia management [ 1 ]. Current treatments for CIBP include radiotherapy and radioisotopes, opioids, and co-analgesics, pharmaceuticals with antiresorptive properties, and targeted interventional procedures [ 2 , 3 ]. Despite radiotherapy being the gold standard treatment for painful bone metastasis, studies estimated that 40% of patients fail to respond and only 30% experience complete pain relief [ 4 ]. Furthermore, it could take one to fifteen weeks following radiotherapy before pain reduction is observed [ 4 ]. Opioids are the foundation of cancer pain management and should be offered to treat moderate-to-severe cancer pain [ 5 ]. However, opioids remain underutilised in CIBP [ 2 ], with between 25.8–84% of patients with moderate to severe metastatic bone pain not receiving a strong opioid [ 6 – 8 ]. When an opioid is prescribed, the combination of background and breakthrough (spontaneous and incident) pain commonly seen in CIBP presents challenges in balancing analgesia and opioid adverse effects [ 9 ], with the prevalence of breakthrough cancer pain remaining at 59% [ 10 , 11 ]. Animal modelling of CIBP has revealed a degree of opioid resistance and involvement of neuropathic pain mechanisms [ 1 ]. However, no clear clinical benefit has been noted with the routine use of neuropathic agents [ 3 , 12 ]. A multi-centre, double-blind, randomised controlled trial (RCT) of pregabalin versus placebo in 233 patients with CIBP showed no statistically significant difference in average pain or pain interference between both groups [ 13 ]. Hence, there has been limited translation from laboratory knowledge of CIBP into clinical practice to guide the choice of analgesic treatments, including opioid choice [ 12 ]. Refractory cancer pain, whereby standard opioid and/or co-analgesic therapy provides inadequate pain relief and/or patients experience unacceptable analgesic adverse effects is described in 10–20% of cancer patients [ 14 ]. The practice of switching from one opioid molecule to another (opioid rotation) for refractory cancer pain is widely supported in palliative care [ 14 – 15 ]. Rotation to methadone is commonly considered in the management of refractory cancer pain due to methadone’s antagonistic property at the N-methyl-D-aspartate (NMDA) receptor and inhibition of serotonin and noradrenaline reuptake [ 15 – 16 ]. Our preliminary retrospective study of 94 patients rotated to methadone for refractory CIBP demonstrated a reduction in pain intensity from 5.6 to 2.1, with 70% and 53% of patients achieving a ≥ 30% and ≥ 50% reduction in pain, respectively [ 17 ]. Methadone rotation (MR) resulted in a reduction in the mean number of daily breakthrough opioid analgesics, with over 70% of patients requiring an actual lower dose of methadone compared to their calculated daily methadone dose [ 17 ]. In this pilot trial, we aimed to assess the feasibility, acceptability, safety, and possible efficacy of a MR compared to other opioid rotation (OOR) for patients with refractory CIBP. Changes in worst and average pain intensity, effect on pain interference, satisfaction with pain relief and change in opioid requirements will be reported. The trial was registered with the Australia New Zealand Clinical Trial Registry (ACTRN12621000141842) with a detailed study protocol previously published [ 18 ]. METHOD Design and participants This pilot, open-label, randomised, controlled trial with two parallel groups was conducted between March 2021 and March 2023 at an 850-bed metropolitan hospital in Melbourne, Australia. Convenience sampling was used to screen patients attending the palliative care and radiotherapy departments against eligibility criteria. Eligible participants were ≥ 18 years-old with a cancer diagnosis, an estimated prognosis of ≥ eight weeks and met the diagnostic criteria for CIBP as defined by The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks-American Pain Society (ACTTION-APS) [ 19 ]. Participants were additionally defined as having refractory CIBP if they a) were established on a strong baseline opioid [ 20 ]; b) had ongoing worst pain score of ≥ 4/10 at CIBP site(s) [ 21 ]; and/or c) demonstrated opioid toxicity, with severity grade of ≥ 2 on the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 (Supplementary 1) [ 22 ]. Participants with pain additional to CIBP were eligible for the study, but all pain assessments pertained to the sites where refractory CIBP arose. Participants with a corrected QT interval of > 500ms on an electrocardiogram [ 23 ], already on methadone, actively receiving radiotherapy or deemed unsuitable for clinical reasons were excluded. We initially excluded those within a week of completing radiotherapy but removed this exclusion due to recruitment challenges. Six patients were recruited prior to protocol alteration. Study procedure and randomisation Following written consent, participants were randomised in a 1:1 ratio using a computer-generated random number sequence with allocation concealed using sealed envelopes. Participants were enrolled and rotated in the inpatient setting from their existing opioid to racemic methadone or another strong opioid (morphine, oxycodone, or hydromorphone) based on best practice guidelines [ 24 ]. Participants and investigators were not blinded to the interventions to facilitate dose titration and mitigate the risk of toxicity. The statistician involved in data analysis was blinded to allocation during data analysis. Opioid rotation Opioid rotation was implemented based on established opioid conversion ratios (Supplementary 2) [ 25 , 26 ]. For OOR, clinician investigators determined which opioid (morphine, oxycodone, or hydromorphone) to switch to depending on the participant’s opioid history, allergy profile, hepatic/renal function, and clinician preference, allowing for a 25–50% dose reduction to account for incomplete cross-tolerance [ 27 ]. MR was conducted using the rapid conversion Stop-and-Go method [ 23 , 25 ]. A daily dose of oral methadone (DDOM) was calculated (Supplementary 3) [ 28 – 30 ], taking into account potential medication interactions, opioid tolerance and physiological changes affecting volume distribution [ 23 , 25 ]. Racemic methadone was administered in three or four divided doses. Methadone dosing and frequency was adjusted to clinical effect and observed toxicity, with dose adjustment limited to ≤ 5 mg/ day [ 23 ], aiming for twice or thrice daily dosing on discharge. Unlimited dosing of immediate-release (IR) and/or rapid-onset opioids (ROO) to manage breakthrough cancer pain was allowed. Titration of co-analgesic medications was restricted during the study period to ensure that the observed changes in pain intensity were attributable only to the study intervention. Adjustments to laxatives and other drugs used to manage opioid adverse effects were permitted. Participants were followed up for 14 days from the initiation of the study intervention using face-to-face or over-the-telephone assessments. Study Objectives Feasibility was assessed by recruitment and retention rates. Considering a 20–30% attrition rate in palliative care studies, we aimed for > 70% of participants completing the study procedures to day 14 [ 31 ]. Acceptability was assessed by the rate of completed data at each study time point and patient satisfaction with analgesia at baseline, day 7 and day 14 post opioid rotation. Safety and tolerability of MR and OOR were evaluated using the CTCAE v.5, with grade 2 adverse effect considered moderate severity. A change in the CTCAE composite score for opioid side effects was calculated to compare safety and tolerability between the two study arms [ 22 ]. Clinical outcomes assessed were change in worst and average pain intensity on day 14, effect on pain interference, satisfaction with pain relief and overall change in opioid requirements. Data collection and measures Participants’ basic demographic and clinical information pertaining to cancer diagnosis, CIBP characteristics and analgesic use were obtained at baseline (Fig. 1 ). Data were collected at each time point via face-to-face or telephone assessment. The Average and worst pain intensities were assessed as per the study procedure (Fig. 1 ) using a numerical rating score (NRS 0-no pain, 10-most severe pain). The following standardised assessment tools were utilised as per study protocol: Common Terminology Criteria for Adverse Events: measured opioid adverse events, with composite score ranging from 0–38 [ 22 ]. Australia-modified Karnofsky Performance Scale: measured performance status [ 32 ]. Douleur Neuropathique 4 (DN4): assessed the neuropathic element of CIBP with a score of ≥ 4/10 suggesting the presence of neuropathic pain [ 33 ]. Subscales of Brief Pain Inventory (BPI): assessed pain interference with daily activities (0-does not interfere and 10-complete interference) [ 34 ]. Oral morphine equivalent daily dose (OMEDD): calculated to compare opioid requirements from baseline to end of study (Supplementary 2). Hospital Anxiety and Depression Scale (HADS): screened for anxiety and depression [ 35 ] EuroQOL thermometer: rated quality of life (QOL) status from 0-worst to 100-best possible [ 35 ] AKPS, Australia-modified Karnofsky Performance Scale; BPI, Brief Pain inventory; CTCAE, Common Terminology Criteria for Adverse Events; DN4, Douleur Neuropathique 4; ECG, electrocardiogram; EuroQOL, quality of life standardised measure; HADS, hospital anxiety and depression scale; NRS, numerical rating scale; OEI, opioid escalation index; OMEDD, oral morphine equivalent daily dose for long-acting opioid analgesia; PICF, patient information and consent form. Study failure/withdrawal Participants with severe adverse reactions secondary to MR/OOR, complications unrelated to the study intervention and those who required invasive analgesic techniques or radiation therapy during the study were withdrawn. Sample size We aimed to recruit 50 participants based on published MR RCTs in palliative care [ 36 ]. Recruitment was affected by the challenges imposed by the coronavirus-19 outbreaks, thus ceased at thirty-eight participants. Statistical analysis The data analysis was performed using the complete case approach. Participants were included in the analysis if they contributed data for both baseline and day-14 assessment. Baseline differences between included and excluded participants were assessed using either the Student T-test or Wilcoxon rank-sum test for continuous data or Fisher’s exact test for categorical variables. Summary statistics were used to describe study cohort categorical variables and either mean (SD) or median (IQR) for continuous variables. The changes in all outcomes were calculated as a difference between baseline and the end of the study results. One-sample t-test was used to assess within the group change, while between group differences were assessed using either the Student T-test or Wilcoxon rank-sum test for continuous data or Chi2 or Fisher’s exact test for categorical variables subject to data distribution and frequencies. Effect sizes were calculated using Cohen d to provide guidance about the strength of effect given the exploratory nature of this pilot work. Test for proportions was used to examine the between group differences in the proportion of participants with ≥ 30% and ≥ 50% pain reduction at the end of the study. Opioid escalation index (OEI%) [ 37 ], a surrogate marker of opioid responsiveness and/or opioid tolerance, was calculated using the following equation: $$\frac{\frac{\text{T}\text{o}\text{t}\text{a}\text{l} \text{O}\text{M}\text{E}\text{D}\text{D} \text{a}\text{t} \text{d}\text{a}\text{y} 14- \text{T}\text{o}\text{t}\text{a}\text{l} \text{O}\text{M}\text{E}\text{D}\text{D} \text{p}\text{r}\text{e}\_\text{r}\text{o}\text{t}\text{a}\text{t}\text{i}\text{o}\text{n}}{\text{T}\text{o}\text{t}\text{a}\text{l} \text{O}\text{M}\text{E}\text{D}\text{D} \text{p}\text{r}\text{e}\_\text{r}\text{o}\text{t}\text{a}\text{t}\text{i}\text{o}\text{n}}}{14}*100$$ The data analysis was performed using Stata17 (StataCorp LLC, College station, TX, USA) with p < 0.05 considered statistically significant for all tests. All results have been interpreted with respect to both statistical significance and clinical relevance/importance. RESULTS Feasibility: Participant recruitment, characteristics and retention Figure 2 provides details of screening, randomisation, and attrition. Of the 365 patients screened, fifty-one met the eligibility criteria, thirty-eight (74.5%) consented and were randomised. Twenty participants were randomised to MR and 18 to OOR (17 to hydromorphone due to clinician preference), with 14 (70.0%) and 15 (83.3%) participants completing the intervention, respectively (p = 0.454). The most common cause for study withdrawal was clinical deterioration unrelated to the intervention. Table 1 details participants baseline demographic and clinical characteristics. Most were female (52.6%), with a mean age of 68 (SD 11.4) years, with a diagnosis of prostate cancer (26.3%) and required occasional care assistance. The spine was the most common site of CIBP (82.9%), with 65.8% of participants reporting multiple sites of CIBP. The median worse pain intensity was 8 (IQR 6–9). Half of the participants in the MR group and two-thirds in the OOR group also had ≥ 1 opioid adverse effects graded ≥ 2, with a mean composite CTCAE score of 4 (SD 2). Commonly reported adverse effects were constipation (31.5%) and somnolence (10.5%). The median OMEDD was 85mg (IQR 60–120) and the mean analgesic satisfaction was 68.1% (SD 22.6). The study arms were well balanced with the only significant difference noted for a higher anxiety and depression score [MR:3 (IQR 1–6) vs. OOR:6 (IQR 3.3–12) p = 0.028 and MR: 4.5 (IQR 3–7) vs OOR: 9 (IQR 5–12) p = 0.029, respectively]. Supplementary file 4 details baseline comparison between study completers and non-completers. The arms in this cohort too were well balanced other than for the CTCAE composite score [MR: 3.0 (SD 2) vs. OOR: 4.5 (SD 1.9) p = 0.041] and anxiety score [MR:2 (IQR 1–4) vs. OOR:6 (IQR 3–7) p = 0.013]. Table 1 Baseline demographic and clinical characteristics All Patients (N = 38) MR (n = 20) OOR (n = 18) p-value Demographics Age, mean years (SD) 68.3 (11.4) 68.6 (8.3) 68 (14.4) 0.874 Sex, n (%) Female Male 20 (52.6) 18 (47.4) 12 (60.0) 8 (40.0) 8 (44.4) 10 (55.6) 0.338 AKPS, median (IQR) 60 (50–80) 60 (50–80) 70 (50–80) 0.694 Primary diagnosis, n (%) 0.156 Prostate 10 (26.3) 5 (25.0) 5 (27.8) Gastrointestinal 6 (15.8) 0 6 (33.3) Lung 6 (15.8) 4 (20.0) 2 (11.1) Breast 6 (15.8) 4 (20.0) 2 (11.1) Renal 2 (5.3) 0 2 (11.1) Haematology 2 (5.3) 2 (10.0) 0 Other a 6 (15.8) 5 (25.0) 1 (5.6) Site of bone metastases, n (%) b Spine 35 (92.1) 19 (95.0) 16 (88.9) 0.459 Pelvis 32 (84.2) 17 (85.0) 15 (83.3) 0.616 Rib 21 (55.2) 11 (55.0) 10 (55.6) 0.615 Long bone 20 (52.6) 10 (50.0) 10 (55.6) 0.757 Site of CIBP, n (%) b Spine 29 (82.9) 14/19 (73.7) 15/16 (93.8) 0.187 Pelvis 22 (68.8) 14/17 (82.4) 8/15 (53.3) 0.128 Long bone 13 (65.0) 6/10 (60.0) 7/10 (70.0) 1.000 Rib 10 (47.6) 5/11 (45.5) 5/10 (50.0) 1.000 Radiotherapy in the last 4 weeks, n (%) 15 (39.5 10 (50.0) 5 (27.8) 0.198 Pain Characteristics Average pain intensity, median (IQR) 4 (3–6) 5.5 (4–7) 5.5 (4–7) 0.687 Worst pain intensity, median (IQR) 8 (6–9) 8 (7–9) 8 (8–10) 0.209 Neuropathic pain, n (%) 9 (23.7) 5 (25.0) 4 (22.2) 0.604 Total Pain interference score, mean (SD) 32.7 (17.9) 36.7 (16.5) 41.1 (16.9) 0.419 Opioids OMEDD, median (IQR) 85 (60–120) 90 (60–120) 60 (60-116.3) 0.657 Composite opioid adverse effects score, mean (SD) 4.0 (2.0) 3.6 (2.0) 4.4 (1.8) 0.182 Satisfaction with analgesia, mean (SD) 68.1 (22.6) 63 (23.2) 67.8 (20.2) 0.505 Psychological wellbeing HADS, median (IQR) Anxiety Depression 5 (1.5-9) 6 (4-10.5) 3 (1–6) 4.5 (3–7) 6 (3.3–12) 9 (5–12) 0.028 0.029 Quality of Life score, mean (SD) 49.4 (22.7) 41.1 (14.3) 51.7 (22.4) 0.087 AKPS, Australia-modified karnofsky performance status; CIBP, cancer induced bone pain; HADS, hospital anxiety and depression scale; MR, Methadone Rotation; OMEDD, oral morphine equivalent daily dose; OOR, Other Opioid Rotation a 1 primary bone cancer in each group; 1 gynaecological cancer, 1 cancer of unknown primary and 2 melanomas in the MR group b % total to greater than 100% as most patients have more than one site of bone metastases/ CIBP Table 2 Change analysis for all participants who completed 14 days of opioid rotation (n = 14 for MR and n = 15 for OOR) Day 14 measures Mean change (95% CI) Within group effect size (95% CI) Within group P-value * MR-OOR # MR OOR MR OOR MR OOR MR OOR Mean difference (95% CI) Effect Size (95% CI) P-value Pain Characteristics (BPI-SF) Average pain NRS median (IQR) 3 (2–4) 4 (3–5) -2.4 (-3.9, -1.0) -1.7 (-3.1, -0.4) -1.2 (-1.9, -0.4) -0.8 (-1.5, -0.1) 0.003 0.015 -0.7 (-2.6, 1.2) -0.3 (-1.0, 0.5) 0.458 Worst pain NRS median (IQR) 5.5 (3–8) 8 (5–8) -1.8 (-3.5, -0.1) -1.5 (-2.9, -0.01) -0.9 (-1.6, -0.2) -0.6 (-1.3, 0.1) 0.042 0.048 -0.3 (-2.4, 1.8) -0.1 (-0.8, 0.6) 0.761 Total pain Interference mean (SD) 19.4 (16.0) 30.4 (13.1) -12.8 (-25.1, -0.5) -10.9 (-18.3, -3.4) -1.1 (-1.8, -0.3) -0.7 (-1.4, 0.001) 0.042 0.007 -1.9 (-15.4, 11.5) -0.1 (-0.8, 0.6) 0.772 Opioids OMEDD median (IQR) 47 (41.1–70.5) 80 (40–120) -36.1 (-63.1, -9.1) -1.3 (-25.9, 23.3) 0.9 (0.2, 1.7) 0.03 (-0.7, 0.7) 0.013 0.909 -34.8 (-69.5, -0.03) -0.8 (-1.5, -0.001) 0.050 Escalation index median (IQR) -2.9 (-3.8 to -0.1) -1.2 (-2.4 to 7.1) -0.8 (-1.5, -0.001) 0.141 CTCAE composite score mean (SD) 3.4 (2.2) 2.7 (1.8) 0.4 (-0.7, 1.6) -1.9 (-3.5, -0.2) -0.1 (-0.8, 0.6) -1.0 (-1.7, -0.3) 0.426 0.029 2.3 (0.4, 4.2) 0.9 (0.1, 1.7) 0.022 Satisfaction with Analgesia mean (SD) 72.5 (27.1) 69.3 (20.5) 8.2 (-8.6, 25.1) -0.7 (-8.9, 7.6) 0.4 (-0.3, 1.1) -0.1 (-0.8, 0.6) 0.312 0.306 8.9 (-8.6, 26.4) 0.4 (-0.4, 1.1) 0.306 Psychological wellbeing HADS-Anxiety median (IQR) 3.5 (1–7) 5 (1–6) 0.8 (-0.6, 2.2) -1.3 (-2.8, 0.3) -0.03 (-0.7, 0.7) -0.4 (-1.1, 0.3) 0.258 0.095 2.1 (0.1, 4.1) 0.8 (0.02, 1.6) 0.043 HADS-Depression median (IQR) 5.5 (1–9) 6.5 (4–10) 0 (-1.8, 1.8) -0.3 (-2.8, 2.2) 0.1 (-0.6, 0.7) -0.2 (-0.9, 0.5) 1.000 0.808 0.3 (-1.6, 1.3) -0.1 (-0.8, 0.7) 0.842 Quality of Life Mean (SD) 42.3 (23.2) 55 (20.6) 3.4 (-8.9, 15.7) 5 (-6.2, 16.2) -0.1 (-0.8, 0.6) -0.2 (-0.8, 0.5) 0.560 0.356 -1.6 (17.4, 14.2) -0.1 (-0.8, 0.7) 0.835 BTA, average frequency of breakthrough analgesia used in 24 hours; BPI-SF, brief pain inventory – short form; CTCAE, common terminology criteria for adverse events; HADS, hospital anxiety and depression scale; MR, methadone rotation; NRS, numerical rating scale; OMEDD, oral morphine equivalent daily dose; OOR, other opioid rotation. *The p.value is based on one = sample t-test testing if change equal 0; # difference between groups in change from the baseline Acceptability: data completion at each study time points and satisfaction with analgesia Participants completed on average 17 datasets in the MR arm and 16 datasets in the OOR arm across 5 timepoints following baseline data collection (Fig. 2 ). Neither within groups nor between groups differences in satisfaction with analgesia rating reached statistical significance (Table 2 ). Safety and tolerability Table 3 details the number of reported grade ≥ 2 adverse events and the number of affected participants in the study groups. As illustrated, in most participants these adverse events improved or resolved by the end of the study, with only ten participants (6 MR, 4 OOR participants) with grade 2 adverse events (constipation, somnolence, dry mouth and nausea) and no reported grade 3 adverse events at the end of the study. The mean CTCAE composite scores at the end of the study were 3.4 (SD 2.2) for the MR group and 2.7 (SD 1.8) for the OOR group. Within the OOR group, there was a significant reduction in the CTCAE composite score at day 14, with a mean group difference of 2.3 (0.4 to 4.2), d = 0.9, p = 0.022. Of note, one participant in the OOR group was withdrawn from the study at day 10 due to poorly controlled pain and dose-limiting toxicity. Table 3 Total number of grade 2 or greater adverse events as reported by participants at five pre-defined timepoints, excluding baseline. CTCAE variables Grade a MR (N = 14) OOR (N = 15) Constipation 2 8 events, 6 participants (3 b , 2 c ) 10 events, 6 participants (2 bc ) 3 0 1 Somnolence 2 7 events, 6 participants (1 b , 2 c ) 9 events, 7 participants (3 b , 1 c ) 3 0 1 Xerostomia 2 5 events, 4 participants (2 bc ) 7 events, 6 participants (2 b ) nausea 2 3 events, 2 participants (1 bc ) 3 events, 1 participant c Pruritus 2 3 events, 1 participant b 0 Vomiting 2 0 1 Confusion 2 1 0 Hallucinations 2 1 0 CTCAE, Common Terminology Criteria for Adverse Events; MR, methadone rotation; OOR, other opioid rotation. a Grade 2 – moderate severity requiring local or non-invasive intervention, limiting age-appropriate instrumental activity of daily living, Grade 3 – severe or medically significant events requiring hospitalization or prolongation of hospitalization, impacting on self-care but not life-threatening. b no of participants with event present from screening/baseline. c no of participants with event present at the end of study (Day 14). Intervention Outcomes Pain Characteristics Table 2 shows the significant within groups reduction in average [MR: d=-1.2 (95% CI -1.9 to -0.4), p = 0.003 vs OOR: d= -0.8 (95% CI -1.5 to -0.1), p = 0.015] and worst [MR: d=-0.9 (95% CI -1.6 to -0.2), p = 0.042 vs OOR: d=-0.6 (95% CI -1.3 to 0.1), p = 0.048] pain intensities, with no statistical significance between groups [d = -0.3 (95% CI -1.0 to 0.5), p = 0.458 for average pain intensity and d= -0.1 (95% CI -0.8 to 0.6), p = 0.761 for worst pain intensity]. At least 30% reduction in average pain intensity was observed in ten participants on methadone (71.4%; 95% CI 47.7–95.1) vs eight participants in the OOR group (53.3%; 95% CI 28.1–78.5%), a mean group difference of 18.1 (95% CI -16.5 to 52.7, p = 0.32). Similarly, at least 50% reduction in average pain intensity was observed in eight participants on methadone (57.1%; 95% CI 31.2–83.0%) and four participants in the OOR group (26.7%; 95% CI 4.3–64.7%), a mean group difference of 30.4 (95% CI -3.9 to 64.7, p = 0.097). The proportions of responders were less when the worst pain intensity was assessed [MR: 35.7% with at least 30% pain reduction and 28.6% with at least 50% pain reduction vs OOR: 26.7% and 6.7%, p = 0.7 and p = 0.169, respectively). Whilst both groups displayed improvement in average and worst pain intensities by day three, the MR group appeared to benefit from further reduction in pain intensities up to day fourteen (Fig. 3 ). Both MR and OOR participants demonstrated a significant reduction in total pain interference [MR: d=-1.1 (95% CI -1.8 to -0.3), p = 0.0420; OOR: d= -0.7, (95% CI -1.4 to 0.001), p = 0.007] with no significant between group differences (p = 0.772). Opioid requirements OMEDD following MR reduced significantly compared to OOR [d= -0.8 (95% CI -1.5 to -0.001), p = 0.05] but there was no difference in the opioid escalation index between groups (p = 0.141). Anxiety, depression and QOL There were no significant differences between arms in participants’ HADS-Depression (p = 0.842) or quality of life scores (p = 0.835) at the end of the study. Participants in the OOR group demonstrated a non-significant reduction in the HADS-Anxiety score at the end of study, resulting in a significant between group difference (d = 0.8; p = 0.043). DISCUSSION This pilot randomised trial was the first reported opioid rotation study for refractory CIBP. We demonstrated study feasibility and acceptability through the enrolment of 38 participants (75% participation), with 29 participants completing the study (76.3% retention) and only 3 missing data points amongst the 29 study completers. We found that patients with refractory CIBP were willing to participate in a palliative focused study and accepted randomisation. We encountered recruitment challenges where patients screened were lost to follow up with the initial eligibility criteria requiring participants to wait at least a week following completion of radiotherapy before enrolment. Similarly, given radiotherapy is considered the gold standard treatment for CIBP, some eligible patients declined clinical trial with concern of delaying radiotherapy and two participants dropped out from the methadone group to proceed with radiotherapy 10 days post opioid rotation. The unexpected challenges imposed by COVID-19 affected this study recruitment with recruitment closed prior to achieving the targeted 50 participants. This study participants started with a low CTCAE composite score, with no significant increase in score at the end of the study, suggesting that the study interventions were tolerable and safe. The significant reduction in CTCAE composite score in the OOR group further suggests that opioid rotation can be beneficial in reducing toxicities through improved opioid responsiveness and resultant reduction in OMEDD. The low baseline CTCAE composite score in this study implies the practice of ‘early’ opioid rotations before undue escalation of existing opioids to the point of dose-limiting toxicity. Despite this, we noted a significant reduction in the OMEDD post-MR, suggesting improved opioid responsiveness with methadone. In addition to its action on the mu, delta and kappa opioid receptors, incomplete cross-tolerance may result from the methadone antagonistic effect at the NMDA receptor and the inhibition of serotonin and noradrenaline reuptake [ 16 ]. These additional properties of methadone are theoretically beneficial in the modulation of neuropathic pain and prevention of chronic pain, though neuropathic pain studies have demonstrated mixed results [ 38 – 40 ]. In this study, we have noted no difference in the prevalence of assessed neuropathic pain between groups to account for the improved opioid responsiveness seen with MR. We observed early and sustained pain reduction with MR. Methadone’s greater analgesic potency with repeated administration can be explained by its lipophilic property and phased elimination, resulting in a long and variable half-life of 8-120 hours [ 29 ]. A reduction in the average pain intensity was achieved in most participants in both groups, but a significant reduction in worst pain intensity was only observed in about a third of participants on methadone, and a quarter of participants rotated to another opioid. In this study, we chose at least moderate worst pain intensity as an inclusion criterion, as worst pain has been shown to have a higher correlation with most functional interference scores and has been recommended to evaluate response to radiotherapy for bone metastases [ 41 ]. Despite the relatively small proportion of participants with significant worst pain reduction, both treatment groups demonstrated a statistically significant reduction in worst pain intensity and total pain interference. Opioid rotation, whether to methadone or another opioid is beneficial in reducing both average and worst pain intensities, and pain interference. Although not adequately powered, this study suggests that methadone rotation may have the added benefit of further reducing overall opioid requirement, providing earlier and more sustained pain reduction over fourteen days with no significant worsening of opioid toxicity compared to baseline. We suggest that an appropriately powered multi-centre RCT to be a worthwhile pursuit in addressing the opioid management of refractory CIBP. Study limitations This study could not exclude the potential impact of concurrent oncology-specific therapy. The generalisability of this study is limited by the small sample size, single site recruitment, with most participants in the OOR group being rotated to hydromorphone. We are not able to identify any patient variables or pain characteristics to guide selection of opioid (methadone vs other opioids). Furthermore, we are not able to firmly conclude on the observed difference in opioid toxicity reporting between groups nor the impact of pain perception by anxiety as the observed significant differences in CTCAE composite scores and anxiety scores between groups may be accounted by their pre-existing baseline group differences. Given the pilot nature of this study, we chose to conduct a per-protocol analysis to provide a better estimate of the true efficacy of the study interventions and provide guidance on future studies’ sample sizes. Based on the observed small effect size on pain intensities between groups, a future sample of 123 participants in each group will be required for the study to achieve 80% power to detect small effect size (Cohen’s d = 0.2), assuming two-sided α of 0.05. Future studies will need to consider the high attrition rate in this study population, control for anxiety/depression and the impact of radiotherapy or other concurrent oncology-specific therapy. A larger multi-centre study may also explore patient variables and/or pain characteristics that can guide opioid selection in this patient cohort. CONCLUSION This pilot RCT demonstrates that rotation to methadone or other opioids in patients with refractory CIBP is feasible and acceptable with comparable efficacy. Methadone rotation provided the additional benefit of lower opioid requirement. This study supports the conduct of an appropriately powered multi-centre RCT to examine the impact of methadone versus other opioid rotation for the management of refractory CIBP. Declarations Acknowledgements The authors acknowledge Ioana Logan and Gaye Moore who provided administrative research support, Dr Ian Porter who supported the screening of patients for the study and the patients who willingly participated. Author Contribution MS, NM and DK designed the initial study; MS piloted and modified the study design; MS, HJT and NM led recruitment; MS, AG, NM and DK conducted statistical analysis; MS wrote the initial manuscript, and all authors approved the final manuscript. MS is responsible for the overall content as guarantor. Funding This research was funded by the Cabrini Foundation Sambor Research Grant. The funding body was not involved in the study’s design, data collection, analysis interpretation or writing of the manuscript. Competing interests None declared. Consent for publication Written informed consent was obtained from all patients. Ethics approval This study involves human participants and was approved by Monash Health Research Ethics Committee: RES-20-0000-869C). Participants gave written informed consent to participate in the study before taking part. Provenance and peer review Not commissioned; externally peer reviewed. Data availability The datasets generated during the study will be available upon reasonable request. References Kane CM, Hoskin P, Bennett MI (2015) Cancer induced bone pain. BMJ 350:h315. doi: 10.1136/bmj.h315 Colosia A, Njue A, Bajwa Z, Dragon E, Robinson RL, Sheffield KM, Thakkar S, Richiemer SH (2022) The Burden of Metastatic Cancer-Induced Bone Pain: A Narrative Review. J Pain Res 15:3399–3412. doi: 10.2147/JPR.S371337 Middlemiss T, Laird BJ, Fallon MT (2011) Mechanisms of cancer-induced bone pain. 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Support Care Cancer 28 (8):3721–3729. doi: 10.1007/s00520-019-05200-6 LoMartire R, Ang BO, Gerdle B, Vixner L (2020) Psychometric properties of Short Form-36 Health Survey, EuroQol 5-dimensions, and Hospital Anxiety and Depression Scale in patients with chronic pain. Pain 161 (1):83–95. doi: 10.1097/j.pain.0000000000001700 Cubero DI, del Giglio A (2010) Early switching from morphine to methadone is not improved by acetaminophen in the analgesia of oncologic patients: a prospective, randomized, double-blind, placebo-controlled study. Support Care Cancer 18 (2):235–242. doi: 10.1007/s00520-009-0649-8 Mercadante S (1997) Malignant bone pain: pathophysiology and treatment. Pain 69 (1–2):1–18. doi: 10.1016/s0304-3959(96)03267-8 Hanna V, Senderovich H (2021) Methadone in Pain Management: A Systematic Review. The journal of pain: official journal of the American Pain Society 22 (3):233–245. doi: 10.1016/j.jpain.2020.04.004 Rigo FK, Trevisan G, Godoy MC, Rossato MF, Dalmolin GD, Silva MA, Menezes MS, Caumo W, Ferreira J (2017) Management of Neuropathic Chronic Pain with Methadone Combined with Ketamine: A Randomized, Double Blind, Active-Controlled Clinical Trial. Pain Physician 20 (3):207–215 Madden K, Bruera E (2017) Very-Low-Dose Methadone To Treat Refractory Neuropathic Pain in Children with Cancer. J Palliat Med 20 (11):1280–1283. doi: 10.1089/jpm.2017.0098 Harris K, Li K, Flynn C, Chow E (2007) Worst, average or current pain in the Brief Pain Inventory: which should be used to calculate the response to palliative radiotherapy in patients with bone metastases? Clinical oncology (Royal College of Radiologists (Great Britain)) 19 (7):523–527. doi: 10.1016/j.clon.2007.04.007 Additional Declarations No competing interests reported. Supplementary Files Supplementary1COMMONTERMINOLOGYCRITERIAFORADVERSEEVENTS.docx Supplementary2OpioidConversionRatio.docx Supplementary3MorphinetoMethadoneConversionRatioGuideline.docx Supplementary4Baselinecomparisonbetweenstudycompletersandnoncompleters.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 17 Jun, 2024 Reviews received at journal 16 Jun, 2024 Reviews received at journal 13 Jun, 2024 Reviewers agreed at journal 13 Jun, 2024 Reviewers agreed at journal 13 Jun, 2024 Reviewers agreed at journal 11 Jun, 2024 Reviewers agreed at journal 11 Jun, 2024 Reviewers invited by journal 11 Jun, 2024 Editor assigned by journal 08 Jun, 2024 Submission checks completed at journal 13 May, 2024 First submitted to journal 07 May, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4380470","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":301739163,"identity":"45868ca0-4c52-4811-9164-40112fa8426d","order_by":0,"name":"Merlina Sulistio","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+klEQVRIiWNgGAWjYBACg/NnzBh//Plvz8/e/ODwxz91ifMbmB8+5mGQSGzAocXyRo4ZQ2KbBI9kzzHDx5JtEoVtDGzGxnMYbHBqsb/BA9TSIMFjcCNH2Ji3TaKyjYFHTPoPQxpOLWZwLTffsElLQrSwSecwHMatBegXhoQ/QC23c9ikP/6RyCWs5QDQLwlsUC2SH4jQYgDXcvMM+2/eGRLpYC08DP+J0HID6GveHolksPd58NlyIy0NGshpZiDvJ7cxAwOZx+CwMQ4dwKg8fPzjjz8SwKg8/Ez6YxswKtubgVFZcVgOlxYsgBlsFAkaRsEoGAWjYBRgAAAYUmBLZqhT3QAAAABJRU5ErkJggg==","orcid":"","institution":"Cabrini Health","correspondingAuthor":true,"prefix":"","firstName":"Merlina","middleName":"","lastName":"Sulistio","suffix":""},{"id":301739164,"identity":"3feee8b5-5bbb-44a6-89f3-51cc1df69ff3","order_by":1,"name":"alexandra Gorelik","email":"","orcid":"","institution":"Monash University","correspondingAuthor":false,"prefix":"","firstName":"alexandra","middleName":"","lastName":"Gorelik","suffix":""},{"id":301739165,"identity":"f021f9ee-5956-4035-8bf7-bcf319874da2","order_by":2,"name":"Hoong Jiun Tee","email":"","orcid":"","institution":"Cabrini Health","correspondingAuthor":false,"prefix":"","firstName":"Hoong","middleName":"Jiun","lastName":"Tee","suffix":""},{"id":301739166,"identity":"4ae98c82-c4b6-449a-8717-1d46583384e6","order_by":3,"name":"Robert Wojnar","email":"","orcid":"","institution":"Cabrini Health","correspondingAuthor":false,"prefix":"","firstName":"Robert","middleName":"","lastName":"Wojnar","suffix":""},{"id":301739167,"identity":"004cc7a4-e545-4f00-98a3-53de51bf790d","order_by":4,"name":"David Kissane","email":"","orcid":"","institution":"Cabrini Health","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Kissane","suffix":""},{"id":301739168,"identity":"215a90a5-77ce-4c46-9200-dc2a725ad5d3","order_by":5,"name":"Natasha Michael","email":"","orcid":"","institution":"The University of Notre Dame Australia","correspondingAuthor":false,"prefix":"","firstName":"Natasha","middleName":"","lastName":"Michael","suffix":""}],"badges":[],"createdAt":"2024-05-07 05:51:55","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4380470/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4380470/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57292169,"identity":"8d4e9a47-3558-4d7e-ac61-cdbfb9075288","added_by":"auto","created_at":"2024-05-28 18:01:54","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":113490,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStudy Procedure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAKPS, Australia-modified Karnofsky Performance Scale; BPI, Brief Pain inventory; CTCAE, Common Terminology Criteria for Adverse Events; DN4, Douleur Neuropathique 4; ECG, electrocardiogram; EuroQOL, quality of life standardised measure; HADS, hospital anxiety and depression scale; NRS, numerical rating scale; OEI, opioid escalation index; OMEDD, oral morphine equivalent daily dose for long-acting opioid analgesia; PICF, patient information and consent form.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4380470/v1/08f1bcbc7fbf9599572a5baf.png"},{"id":57292658,"identity":"88f7ed26-6a26-4a81-a9ab-29e6dcd22bdd","added_by":"auto","created_at":"2024-05-28 18:09:54","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":126238,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCONSORT (Consolidated Standards of Reporting Trials) participant flow diagram.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMR – methadone rotation, OOR – other opioid rotation, QTc – corrected QT interval\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea \u003c/sup\u003eNine rotated from oxycodone, six from fentanyl, three rotated from morphine, and two from hydromorphone\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb \u003c/sup\u003eEight rotated from fentanyl to hydromorphone, six rotated from morphine to hydromorphone, three rotated from oxycodone to hydromorphone, and one rotated from hydromorphone to oxycodone/naloxone\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ec\u003c/sup\u003e withdrawn from study\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4380470/v1/a96da190c62bc8e6ae5f023e.png"},{"id":57292919,"identity":"7aad016e-5a13-46af-84e2-7ce19f3eec9d","added_by":"auto","created_at":"2024-05-28 18:17:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1070712,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4380470/v1/332a72e1-41a3-4346-81ba-6ab3240432ac.pdf"},{"id":57292167,"identity":"d3d5e414-e9ab-4e89-925a-b87eab4bb94d","added_by":"auto","created_at":"2024-05-28 18:01:54","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":27146,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary1COMMONTERMINOLOGYCRITERIAFORADVERSEEVENTS.docx","url":"https://assets-eu.researchsquare.com/files/rs-4380470/v1/a058f3760da9f7526fc2fbe7.docx"},{"id":57292170,"identity":"cf02058e-0c41-4d76-9cb3-877213b046ca","added_by":"auto","created_at":"2024-05-28 18:01:55","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":15615,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary2OpioidConversionRatio.docx","url":"https://assets-eu.researchsquare.com/files/rs-4380470/v1/68cd573f640ee10050681181.docx"},{"id":57292171,"identity":"454496f6-2743-4fc4-97c8-80f6d5b4fc99","added_by":"auto","created_at":"2024-05-28 18:01:55","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":15432,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary3MorphinetoMethadoneConversionRatioGuideline.docx","url":"https://assets-eu.researchsquare.com/files/rs-4380470/v1/4511291302561c22584a27a2.docx"},{"id":57292659,"identity":"eee496ea-16be-44eb-8b25-41d6a3252710","added_by":"auto","created_at":"2024-05-28 18:09:55","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":19834,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary4Baselinecomparisonbetweenstudycompletersandnoncompleters.docx","url":"https://assets-eu.researchsquare.com/files/rs-4380470/v1/bfdc1c7297321bdfb197e46a.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Methadone versus other opioids for refractory malignant bone pain: a pilot randomised controlled study","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eCancer-induced bone pain (CIBP) is a common cancer pain syndrome, with a mixture of inflammatory, nociceptive, and neuropathic pain requiring a multimodal approach to analgesia management [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Current treatments for CIBP include radiotherapy and radioisotopes, opioids, and co-analgesics, pharmaceuticals with antiresorptive properties, and targeted interventional procedures [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Despite radiotherapy being the gold standard treatment for painful bone metastasis, studies estimated that 40% of patients fail to respond and only 30% experience complete pain relief [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Furthermore, it could take one to fifteen weeks following radiotherapy before pain reduction is observed [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOpioids are the foundation of cancer pain management and should be offered to treat moderate-to-severe cancer pain [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, opioids remain underutilised in CIBP [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], with between 25.8\u0026ndash;84% of patients with moderate to severe metastatic bone pain not receiving a strong opioid [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. When an opioid is prescribed, the combination of background and breakthrough (spontaneous and incident) pain commonly seen in CIBP presents challenges in balancing analgesia and opioid adverse effects [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], with the prevalence of breakthrough cancer pain remaining at 59% [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAnimal modelling of CIBP has revealed a degree of opioid resistance and involvement of neuropathic pain mechanisms [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. However, no clear clinical benefit has been noted with the routine use of neuropathic agents [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. A multi-centre, double-blind, randomised controlled trial (RCT) of pregabalin versus placebo in 233 patients with CIBP showed no statistically significant difference in average pain or pain interference between both groups [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Hence, there has been limited translation from laboratory knowledge of CIBP into clinical practice to guide the choice of analgesic treatments, including opioid choice [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRefractory cancer pain, whereby standard opioid and/or co-analgesic therapy provides inadequate pain relief and/or patients experience unacceptable analgesic adverse effects is described in 10\u0026ndash;20% of cancer patients [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The practice of switching from one opioid molecule to another (opioid rotation) for refractory cancer pain is widely supported in palliative care [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Rotation to methadone is commonly considered in the management of refractory cancer pain due to methadone\u0026rsquo;s antagonistic property at the N-methyl-D-aspartate (NMDA) receptor and inhibition of serotonin and noradrenaline reuptake [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur preliminary retrospective study of 94 patients rotated to methadone for refractory CIBP demonstrated a reduction in pain intensity from 5.6 to 2.1, with 70% and 53% of patients achieving a\u0026thinsp;\u0026ge;\u0026thinsp;30% and \u0026ge;\u0026thinsp;50% reduction in pain, respectively [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Methadone rotation (MR) resulted in a reduction in the mean number of daily breakthrough opioid analgesics, with over 70% of patients requiring an actual lower dose of methadone compared to their calculated daily methadone dose [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In this pilot trial, we aimed to assess the feasibility, acceptability, safety, and possible efficacy of a MR compared to other opioid rotation (OOR) for patients with refractory CIBP. Changes in worst and average pain intensity, effect on pain interference, satisfaction with pain relief and change in opioid requirements will be reported. The trial was registered with the Australia New Zealand Clinical Trial Registry (ACTRN12621000141842) with a detailed study protocol previously published [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e"},{"header":"METHOD","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eDesign and participants\u003c/h2\u003e \u003cp\u003eThis pilot, open-label, randomised, controlled trial with two parallel groups was conducted between March 2021 and March 2023 at an 850-bed metropolitan hospital in Melbourne, Australia. Convenience sampling was used to screen patients attending the palliative care and radiotherapy departments against eligibility criteria. Eligible participants were \u0026ge;\u0026thinsp;18 years-old with a cancer diagnosis, an estimated prognosis of \u0026ge;\u0026thinsp;eight weeks and met the diagnostic criteria for CIBP as defined by The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks-American Pain Society (ACTTION-APS) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Participants were additionally defined as having refractory CIBP if they a) were established on a strong baseline opioid [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]; b) had ongoing \u003cem\u003eworst\u003c/em\u003e pain score of \u0026ge;\u0026thinsp;4/10 at CIBP site(s) [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]; and/or c) demonstrated opioid toxicity, with severity grade of \u0026ge;\u0026thinsp;2 on the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 (Supplementary 1) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Participants with pain additional to CIBP were eligible for the study, but all pain assessments pertained to the sites where refractory CIBP arose.\u003c/p\u003e \u003cp\u003eParticipants with a corrected QT interval of \u0026gt;\u0026thinsp;500ms on an electrocardiogram [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], already on methadone, actively receiving radiotherapy or deemed unsuitable for clinical reasons were excluded. We initially excluded those within a week of completing radiotherapy but removed this exclusion due to recruitment challenges. Six patients were recruited prior to protocol alteration.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy procedure and randomisation\u003c/h2\u003e \u003cp\u003eFollowing written consent, participants were randomised in a 1:1 ratio using a computer-generated random number sequence with allocation concealed using sealed envelopes. Participants were enrolled and rotated in the inpatient setting from their existing opioid to racemic methadone or another strong opioid (morphine, oxycodone, or hydromorphone) based on best practice guidelines [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Participants and investigators were not blinded to the interventions to facilitate dose titration and mitigate the risk of toxicity. The statistician involved in data analysis was blinded to allocation during data analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eOpioid rotation\u003c/h2\u003e \u003cp\u003eOpioid rotation was implemented based on established opioid conversion ratios (Supplementary 2) [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. For OOR, clinician investigators determined which opioid (morphine, oxycodone, or hydromorphone) to switch to depending on the participant\u0026rsquo;s opioid history, allergy profile, hepatic/renal function, and clinician preference, allowing for a 25\u0026ndash;50% dose reduction to account for incomplete cross-tolerance [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMR was conducted using the rapid conversion Stop-and-Go method [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. A daily dose of oral methadone (DDOM) was calculated (Supplementary 3) [\u003cspan additionalcitationids=\"CR29\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], taking into account potential medication interactions, opioid tolerance and physiological changes affecting volume distribution [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Racemic methadone was administered in three or four divided doses. Methadone dosing and frequency was adjusted to clinical effect and observed toxicity, with dose adjustment limited to \u0026le;\u0026thinsp;5 mg/ day [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], aiming for twice or thrice daily dosing on discharge.\u003c/p\u003e \u003cp\u003eUnlimited dosing of immediate-release (IR) and/or rapid-onset opioids (ROO) to manage breakthrough cancer pain was allowed. Titration of co-analgesic medications was restricted during the study period to ensure that the observed changes in pain intensity were attributable only to the study intervention. Adjustments to laxatives and other drugs used to manage opioid adverse effects were permitted. Participants were followed up for 14 days from the initiation of the study intervention using face-to-face or over-the-telephone assessments.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStudy Objectives\u003c/h2\u003e \u003cp\u003eFeasibility was assessed by recruitment and retention rates. Considering a 20\u0026ndash;30% attrition rate in palliative care studies, we aimed for \u0026gt;\u0026thinsp;70% of participants completing the study procedures to day 14 [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Acceptability was assessed by the rate of completed data at each study time point and patient satisfaction with analgesia at baseline, day 7 and day 14 post opioid rotation.\u003c/p\u003e \u003cp\u003eSafety and tolerability of MR and OOR were evaluated using the CTCAE v.5, with grade 2 adverse effect considered moderate severity. A change in the CTCAE composite score for opioid side effects was calculated to compare safety and tolerability between the two study arms [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eClinical outcomes assessed were change in worst and average pain intensity on day 14, effect on pain interference, satisfaction with pain relief and overall change in opioid requirements.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eData collection and measures\u003c/h2\u003e \u003cp\u003eParticipants\u0026rsquo; basic demographic and clinical information pertaining to cancer diagnosis, CIBP characteristics and analgesic use were obtained at baseline (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Data were collected at each time point via face-to-face or telephone assessment. The Average and worst pain intensities were assessed as per the study procedure (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) using a numerical rating score (NRS 0-no pain, 10-most severe pain).\u003c/p\u003e \u003cp\u003eThe following standardised assessment tools were utilised as per study protocol:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eCommon Terminology Criteria for Adverse Events: measured opioid adverse events, with composite score ranging from 0\u0026ndash;38 [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eAustralia-modified Karnofsky Performance Scale: measured performance status [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eDouleur Neuropathique 4 (DN4): assessed the neuropathic element of CIBP with a score of \u0026ge;\u0026thinsp;4/10 suggesting the presence of neuropathic pain [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSubscales of Brief Pain Inventory (BPI): assessed pain interference with daily activities (0-does not interfere and 10-complete interference) [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eOral morphine equivalent daily dose (OMEDD): calculated to compare opioid requirements from baseline to end of study (Supplementary 2).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eHospital Anxiety and Depression Scale (HADS): screened for anxiety and depression [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eEuroQOL thermometer: rated quality of life (QOL) status from 0-worst to 100-best possible [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAKPS, Australia-modified Karnofsky Performance Scale; BPI, Brief Pain inventory; CTCAE, Common Terminology Criteria for Adverse Events; DN4, Douleur Neuropathique 4; ECG, electrocardiogram; EuroQOL, quality of life standardised measure; HADS, hospital anxiety and depression scale; NRS, numerical rating scale; OEI, opioid escalation index; OMEDD, oral morphine equivalent daily dose for long-acting opioid analgesia; PICF, patient information and consent form.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStudy failure/withdrawal\u003c/h2\u003e \u003cp\u003eParticipants with severe adverse reactions secondary to MR/OOR, complications unrelated to the study intervention and those who required invasive analgesic techniques or radiation therapy during the study were withdrawn.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eSample size\u003c/h2\u003e \u003cp\u003eWe aimed to recruit 50 participants based on published MR RCTs in palliative care [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Recruitment was affected by the challenges imposed by the coronavirus-19 outbreaks, thus ceased at thirty-eight participants.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe data analysis was performed using the complete case approach. Participants were included in the analysis if they contributed data for both baseline and day-14 assessment. Baseline differences between included and excluded participants were assessed using either the Student T-test or Wilcoxon rank-sum test for continuous data or Fisher\u0026rsquo;s exact test for categorical variables.\u003c/p\u003e \u003cp\u003eSummary statistics were used to describe study cohort categorical variables and either mean (SD) or median (IQR) for continuous variables. The changes in all outcomes were calculated as a difference between baseline and the end of the study results. One-sample t-test was used to assess within the group change, while between group differences were assessed using either the Student T-test or Wilcoxon rank-sum test for continuous data or Chi2 or Fisher\u0026rsquo;s exact test for categorical variables subject to data distribution and frequencies. Effect sizes were calculated using Cohen d to provide guidance about the strength of effect given the exploratory nature of this pilot work. Test for proportions was used to examine the between group differences in the proportion of participants with \u0026ge;\u0026thinsp;30% and \u0026ge;\u0026thinsp;50% pain reduction at the end of the study.\u003c/p\u003e \u003cp\u003eOpioid escalation index (OEI%) [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], a surrogate marker of opioid responsiveness and/or opioid tolerance, was calculated using the following equation:\u003cdiv id=\"Equa\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equa\" name=\"EquationSource\"\u003e\n$$\\frac{\\frac{\\text{T}\\text{o}\\text{t}\\text{a}\\text{l} \\text{O}\\text{M}\\text{E}\\text{D}\\text{D} \\text{a}\\text{t} \\text{d}\\text{a}\\text{y} 14- \\text{T}\\text{o}\\text{t}\\text{a}\\text{l} \\text{O}\\text{M}\\text{E}\\text{D}\\text{D} \\text{p}\\text{r}\\text{e}\\_\\text{r}\\text{o}\\text{t}\\text{a}\\text{t}\\text{i}\\text{o}\\text{n}}{\\text{T}\\text{o}\\text{t}\\text{a}\\text{l} \\text{O}\\text{M}\\text{E}\\text{D}\\text{D} \\text{p}\\text{r}\\text{e}\\_\\text{r}\\text{o}\\text{t}\\text{a}\\text{t}\\text{i}\\text{o}\\text{n}}}{14}*100$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eThe data analysis was performed using Stata17 (StataCorp LLC, College station, TX, USA) with \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 considered statistically significant for all tests. All results have been interpreted with respect to both statistical significance and clinical relevance/importance.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eFeasibility: Participant recruitment, characteristics and retention\u003c/h2\u003e\n \u003cp\u003eFigure \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e provides details of screening, randomisation, and attrition. Of the 365 patients screened, fifty-one met the eligibility criteria, thirty-eight (74.5%) consented and were randomised. Twenty participants were randomised to MR and 18 to OOR (17 to hydromorphone due to clinician preference), with 14 (70.0%) and 15 (83.3%) participants completing the intervention, respectively (p\u0026thinsp;=\u0026thinsp;0.454). The most common cause for study withdrawal was clinical deterioration unrelated to the intervention.\u003c/p\u003e\n \u003cp\u003eTable \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e details participants baseline demographic and clinical characteristics. Most were female (52.6%), with a mean age of 68 (SD 11.4) years, with a diagnosis of prostate cancer (26.3%) and required occasional care assistance. The spine was the most common site of CIBP (82.9%), with 65.8% of participants reporting multiple sites of CIBP. The median\u0026nbsp;\u003cem\u003eworse\u003c/em\u003e pain intensity was 8 (IQR 6\u0026ndash;9). Half of the participants in the MR group and two-thirds in the OOR group also had\u0026thinsp;\u0026ge;\u0026thinsp;1 opioid adverse effects graded\u0026thinsp;\u0026ge;\u0026thinsp;2, with a mean composite CTCAE score of 4 (SD 2). Commonly reported adverse effects were constipation (31.5%) and somnolence (10.5%). The median OMEDD was 85mg (IQR 60\u0026ndash;120) and the mean analgesic satisfaction was 68.1% (SD 22.6). The study arms were well balanced with the only significant difference noted for a higher anxiety and depression score [MR:3 (IQR 1\u0026ndash;6) vs. OOR:6 (IQR 3.3\u0026ndash;12) p\u0026thinsp;=\u0026thinsp;0.028 and MR: 4.5 (IQR 3\u0026ndash;7) vs OOR: 9 (IQR 5\u0026ndash;12) p\u0026thinsp;=\u0026thinsp;0.029, respectively]. Supplementary file 4 details baseline comparison between study completers and non-completers. The arms in this cohort too were well balanced other than for the CTCAE composite score [MR: 3.0 (SD 2) vs. OOR: 4.5 (SD 1.9) p\u0026thinsp;=\u0026thinsp;0.041] and anxiety score [MR:2 (IQR 1\u0026ndash;4) vs. OOR:6 (IQR 3\u0026ndash;7) p\u0026thinsp;=\u0026thinsp;0.013].\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBaseline demographic and clinical characteristics\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAll Patients (N\u0026thinsp;=\u0026thinsp;38)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMR (n\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOOR (n\u0026thinsp;=\u0026thinsp;18)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003e\u003cem\u003eDemographics\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge, mean years (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68.3 (11.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68.6 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68 (14.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.874\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSex, n (%)\u003c/p\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 (52.6)\u003c/p\u003e\n \u003cp\u003e18 (47.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (60.0)\u003c/p\u003e\n \u003cp\u003e8 (40.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (44.4)\u003c/p\u003e\n \u003cp\u003e10 (55.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.338\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAKPS, median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60 (50\u0026ndash;80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60 (50\u0026ndash;80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70 (50\u0026ndash;80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.694\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrimary diagnosis, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.156\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProstate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (26.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (27.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGastrointestinal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (15.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLung\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (15.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBreast\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (15.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHaematology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOther \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (15.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (5.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSite of bone metastases, n (%) \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSpine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35 (92.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (95.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (88.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.459\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePelvis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32 (84.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 (85.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (83.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.616\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21 (55.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (55.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (55.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.615\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLong bone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 (52.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (55.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.757\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSite of CIBP, n (%) \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSpine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29 (82.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14/19 (73.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15/16 (93.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.187\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePelvis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22 (68.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14/17 (82.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8/15 (53.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.128\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLong bone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (65.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6/10 (60.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7/10 (70.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (47.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5/11 (45.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5/10 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRadiotherapy in the last 4 weeks, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (39.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (27.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.198\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003e\u003cem\u003ePain Characteristics\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAverage pain intensity, median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (3\u0026ndash;6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.5 (4\u0026ndash;7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.5 (4\u0026ndash;7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.687\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWorst pain intensity, median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (6\u0026ndash;9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (7\u0026ndash;9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (8\u0026ndash;10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.209\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNeuropathic pain, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (23.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.604\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal Pain interference score, mean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32.7 (17.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36.7 (16.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e41.1 (16.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.419\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003e\u003cem\u003eOpioids\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOMEDD, median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e85 (60\u0026ndash;120)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e90 (60\u0026ndash;120)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60 (60-116.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.657\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eComposite opioid adverse effects score, mean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.0 (2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.6 (2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.4 (1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.182\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSatisfaction with analgesia, mean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68.1 (22.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63 (23.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67.8 (20.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.505\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003e\u003cem\u003ePsychological wellbeing\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHADS, median (IQR)\u003c/p\u003e\n \u003cp\u003eAnxiety\u003c/p\u003e\n \u003cp\u003eDepression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (1.5-9)\u003c/p\u003e\n \u003cp\u003e6 (4-10.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (1\u0026ndash;6)\u003c/p\u003e\n \u003cp\u003e4.5 (3\u0026ndash;7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (3.3\u0026ndash;12)\u003c/p\u003e\n \u003cp\u003e9 (5\u0026ndash;12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.028\u003c/p\u003e\n \u003cp\u003e0.029\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQuality of Life score, mean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e49.4 (22.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e41.1 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e51.7 (22.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.087\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eAKPS, Australia-modified karnofsky performance status; CIBP, cancer induced bone pain; HADS, hospital anxiety and depression scale; MR, Methadone Rotation; OMEDD, oral morphine equivalent daily dose; OOR, Other Opioid Rotation\u003c/p\u003e\n \u003cp\u003e\u003csup\u003ea\u003c/sup\u003e 1 primary bone cancer in each group; 1 gynaecological cancer, 1 cancer of unknown primary and 2 melanomas in the MR group\u003c/p\u003e\n \u003cp\u003e\u003csup\u003eb\u003c/sup\u003e % total to greater than 100% as most patients have more than one site of bone metastases/ CIBP\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eChange analysis for all participants who completed 14 days of opioid rotation (n\u0026thinsp;=\u0026thinsp;14 for MR and n\u0026thinsp;=\u0026thinsp;15 for OOR)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"12\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eDay 14 measures\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eMean change\u003c/p\u003e\n \u003cp\u003e(95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eWithin group effect size\u003c/p\u003e\n \u003cp\u003e(95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eWithin group\u003c/p\u003e\n \u003cp\u003eP-value *\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eMR-OOR\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOOR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOOR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOOR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOOR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMean difference (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEffect Size\u003c/p\u003e\n \u003cp\u003e(95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"12\"\u003e\n \u003cp\u003e\u003cem\u003ePain Characteristics (BPI-SF)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAverage pain NRS\u003c/p\u003e\n \u003cp\u003emedian (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e(2\u0026ndash;4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e(3\u0026ndash;5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.4\u003c/p\u003e\n \u003cp\u003e(-3.9, -1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.7\u003c/p\u003e\n \u003cp\u003e(-3.1, -0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.2\u003c/p\u003e\n \u003cp\u003e(-1.9, -0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.8\u003c/p\u003e\n \u003cp\u003e(-1.5, -0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.7\u003c/p\u003e\n \u003cp\u003e(-2.6, 1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.3\u003c/p\u003e\n \u003cp\u003e(-1.0, 0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.458\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWorst pain NRS\u003c/p\u003e\n \u003cp\u003emedian (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.5\u003c/p\u003e\n \u003cp\u003e(3\u0026ndash;8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e(5\u0026ndash;8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.8\u003c/p\u003e\n \u003cp\u003e(-3.5, -0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.5\u003c/p\u003e\n \u003cp\u003e(-2.9, -0.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.9\u003c/p\u003e\n \u003cp\u003e(-1.6, -0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.6\u003c/p\u003e\n \u003cp\u003e(-1.3, 0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.042\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.048\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.3\u003c/p\u003e\n \u003cp\u003e(-2.4, 1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.1\u003c/p\u003e\n \u003cp\u003e(-0.8, 0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.761\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal pain Interference\u003c/p\u003e\n \u003cp\u003emean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19.4 (16.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30.4 (13.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-12.8\u003c/p\u003e\n \u003cp\u003e(-25.1, -0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-10.9\u003c/p\u003e\n \u003cp\u003e(-18.3, -3.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.1\u003c/p\u003e\n \u003cp\u003e(-1.8, -0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.7\u003c/p\u003e\n \u003cp\u003e(-1.4, 0.001)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.042\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.9\u003c/p\u003e\n \u003cp\u003e(-15.4, 11.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.1\u003c/p\u003e\n \u003cp\u003e(-0.8, 0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.772\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"12\"\u003e\n \u003cp\u003e\u003cem\u003eOpioids\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOMEDD\u003c/p\u003e\n \u003cp\u003emedian (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e47\u003c/p\u003e\n \u003cp\u003e(41.1\u0026ndash;70.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003cp\u003e(40\u0026ndash;120)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-36.1\u003c/p\u003e\n \u003cp\u003e(-63.1, -9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.3\u003c/p\u003e\n \u003cp\u003e(-25.9, 23.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.9\u003c/p\u003e\n \u003cp\u003e(0.2, 1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003cp\u003e(-0.7, 0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.909\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-34.8\u003c/p\u003e\n \u003cp\u003e(-69.5, -0.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.8\u003c/p\u003e\n \u003cp\u003e(-1.5, -0.001)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.050\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEscalation index\u003c/p\u003e\n \u003cp\u003emedian (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.9\u003c/p\u003e\n \u003cp\u003e(-3.8 to -0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.2\u003c/p\u003e\n \u003cp\u003e(-2.4 to 7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.8\u003c/p\u003e\n \u003cp\u003e(-1.5, -0.001)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.141\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCTCAE composite score\u003c/p\u003e\n \u003cp\u003emean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.4 (2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.7 (1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.4\u003c/p\u003e\n \u003cp\u003e(-0.7, 1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.9\u003c/p\u003e\n \u003cp\u003e(-3.5, -0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.1\u003c/p\u003e\n \u003cp\u003e(-0.8, 0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.0\u003c/p\u003e\n \u003cp\u003e(-1.7, -0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.426\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.029\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.3\u003c/p\u003e\n \u003cp\u003e(0.4, 4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.9\u003c/p\u003e\n \u003cp\u003e(0.1, 1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.022\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSatisfaction with Analgesia\u003c/p\u003e\n \u003cp\u003emean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e72.5 (27.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e69.3 (20.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.2\u003c/p\u003e\n \u003cp\u003e(-8.6, 25.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.7\u003c/p\u003e\n \u003cp\u003e(-8.9, 7.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.4\u003c/p\u003e\n \u003cp\u003e(-0.3, 1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.1\u003c/p\u003e\n \u003cp\u003e(-0.8, 0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.312\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.306\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.9\u003c/p\u003e\n \u003cp\u003e(-8.6, 26.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.4\u003c/p\u003e\n \u003cp\u003e(-0.4, 1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.306\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"12\"\u003e\n \u003cp\u003e\u003cem\u003ePsychological wellbeing\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHADS-Anxiety\u003c/p\u003e\n \u003cp\u003emedian (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.5\u003c/p\u003e\n \u003cp\u003e(1\u0026ndash;7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e(1\u0026ndash;6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.8\u003c/p\u003e\n \u003cp\u003e(-0.6, 2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.3\u003c/p\u003e\n \u003cp\u003e(-2.8, 0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.03\u003c/p\u003e\n \u003cp\u003e(-0.7, 0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.4\u003c/p\u003e\n \u003cp\u003e(-1.1, 0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.258\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.095\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.1\u003c/p\u003e\n \u003cp\u003e(0.1, 4.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.8\u003c/p\u003e\n \u003cp\u003e(0.02, 1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.043\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHADS-Depression\u003c/p\u003e\n \u003cp\u003emedian (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.5\u003c/p\u003e\n \u003cp\u003e(1\u0026ndash;9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.5\u003c/p\u003e\n \u003cp\u003e(4\u0026ndash;10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e(-1.8, 1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.3\u003c/p\u003e\n \u003cp\u003e(-2.8, 2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003cp\u003e(-0.6, 0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.2\u003c/p\u003e\n \u003cp\u003e(-0.9, 0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.808\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003cp\u003e(-1.6, 1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.1\u003c/p\u003e\n \u003cp\u003e(-0.8, 0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.842\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQuality of Life\u003c/p\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e42.3\u003c/p\u003e\n \u003cp\u003e(23.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003cp\u003e(20.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.4\u003c/p\u003e\n \u003cp\u003e(-8.9, 15.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e(-6.2, 16.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.1\u003c/p\u003e\n \u003cp\u003e(-0.8, 0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.2\u003c/p\u003e\n \u003cp\u003e(-0.8, 0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.560\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.356\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.6\u003c/p\u003e\n \u003cp\u003e(17.4, 14.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.1\u003c/p\u003e\n \u003cp\u003e(-0.8, 0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.835\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eBTA, average frequency of breakthrough analgesia used in 24 hours; BPI-SF, brief pain inventory \u0026ndash; short form; CTCAE, common terminology criteria for adverse events; HADS, hospital anxiety and depression scale; MR, methadone rotation; NRS, numerical rating scale; OMEDD, oral morphine equivalent daily dose; OOR, other opioid rotation.\u003c/p\u003e\n \u003cp\u003e*The p.value is based on one\u0026thinsp;=\u0026thinsp;sample t-test testing if change equal 0; \u003csup\u003e#\u003c/sup\u003edifference between groups in change from the baseline\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003eAcceptability: data completion at each study time points and satisfaction with analgesia\u003c/h2\u003e\n \u003cp\u003eParticipants completed on average 17 datasets in the MR arm and 16 datasets in the OOR arm across 5 timepoints following baseline data collection (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Neither within groups nor between groups differences in satisfaction with analgesia rating reached statistical significance (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003eSafety and tolerability\u003c/h2\u003e\n \u003cp\u003eTable \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e details the number of reported grade\u0026thinsp;\u0026ge;\u0026thinsp;2 adverse events and the number of affected participants in the study groups. As illustrated, in most participants these adverse events improved or resolved by the end of the study, with only ten participants (6 MR, 4 OOR participants) with grade 2 adverse events (constipation, somnolence, dry mouth and nausea) and no reported grade 3 adverse events at the end of the study. The mean CTCAE composite scores at the end of the study were 3.4 (SD 2.2) for the MR group and 2.7 (SD 1.8) for the OOR group. Within the OOR group, there was a significant reduction in the CTCAE composite score at day 14, with a mean group difference of 2.3 (0.4 to 4.2), d\u0026thinsp;=\u0026thinsp;0.9, p\u0026thinsp;=\u0026thinsp;0.022. Of note, one participant in the OOR group was withdrawn from the study at day 10 due to poorly controlled pain and dose-limiting toxicity.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eTotal number of grade 2 or greater adverse events as reported by participants at five pre-defined timepoints, excluding baseline.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCTCAE variables\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGrade\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMR (N\u0026thinsp;=\u0026thinsp;14)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOOR (N\u0026thinsp;=\u0026thinsp;15)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eConstipation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 events, 6 participants\u003c/p\u003e\n \u003cp\u003e(3\u003csup\u003eb\u003c/sup\u003e, 2\u003csup\u003ec\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 events, 6 participants\u003c/p\u003e\n \u003cp\u003e(2\u003csup\u003ebc\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eSomnolence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 events, 6 participants\u003c/p\u003e\n \u003cp\u003e(1\u003csup\u003eb\u003c/sup\u003e, 2\u003csup\u003ec\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 events, 7 participants\u003c/p\u003e\n \u003cp\u003e(3\u003csup\u003eb\u003c/sup\u003e, 1\u003csup\u003ec\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eXerostomia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 events, 4 participants\u003c/p\u003e\n \u003cp\u003e(2\u003csup\u003ebc\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 events, 6 participants\u003c/p\u003e\n \u003cp\u003e(2\u003csup\u003eb\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003enausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 events, 2 participants\u003c/p\u003e\n \u003cp\u003e(1\u003csup\u003ebc\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 events, 1 participant\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePruritus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 events, 1 participant\u003csup\u003e\u003cstrong\u003eb\u003c/strong\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConfusion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHallucinations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eCTCAE, Common Terminology Criteria for Adverse Events; MR, methadone rotation; OOR, other opioid rotation.\u003c/p\u003e\n \u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Grade 2 \u0026ndash; moderate severity requiring local or non-invasive intervention, limiting age-appropriate instrumental activity of daily living, Grade 3 \u0026ndash; severe or medically significant events requiring hospitalization or prolongation of hospitalization, impacting on self-care but not life-threatening.\u003c/p\u003e\n \u003cp\u003e\u003csup\u003eb\u003c/sup\u003e no of participants with event present from screening/baseline.\u003c/p\u003e\n \u003cp\u003e\u003csup\u003ec\u003c/sup\u003e no of participants with event present at the end of study (Day 14).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003eIntervention Outcomes\u003c/h2\u003e\n \u003cdiv id=\"Sec16\" class=\"Section3\"\u003e\n \u003ch2\u003ePain Characteristics\u003c/h2\u003e\n \u003cp\u003eTable \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e shows the significant within groups reduction in average [MR: d=-1.2 (95% CI -1.9 to -0.4), p\u0026thinsp;=\u0026thinsp;0.003 vs OOR: d= -0.8 (95% CI -1.5 to -0.1), p\u0026thinsp;=\u0026thinsp;0.015] and worst [MR: d=-0.9 (95% CI -1.6 to -0.2), p\u0026thinsp;=\u0026thinsp;0.042 vs OOR: d=-0.6 (95% CI -1.3 to 0.1), p\u0026thinsp;=\u0026thinsp;0.048] pain intensities, with no statistical significance between groups [d = -0.3 (95% CI -1.0 to 0.5), p\u0026thinsp;=\u0026thinsp;0.458 for average pain intensity and d= -0.1 (95% CI -0.8 to 0.6), p\u0026thinsp;=\u0026thinsp;0.761 for worst pain intensity]. At least 30% reduction in average pain intensity was observed in ten participants on methadone (71.4%; 95% CI 47.7\u0026ndash;95.1) vs eight participants in the OOR group (53.3%; 95% CI 28.1\u0026ndash;78.5%), a mean group difference of 18.1 (95% CI -16.5 to 52.7, p\u0026thinsp;=\u0026thinsp;0.32). Similarly, at least 50% reduction in average pain intensity was observed in eight participants on methadone (57.1%; 95% CI 31.2\u0026ndash;83.0%) and four participants in the OOR group (26.7%; 95% CI 4.3\u0026ndash;64.7%), a mean group difference of 30.4 (95% CI -3.9 to 64.7, p\u0026thinsp;=\u0026thinsp;0.097). The proportions of responders were less when the worst pain intensity was assessed [MR: 35.7% with at least 30% pain reduction and 28.6% with at least 50% pain reduction vs OOR: 26.7% and 6.7%, p\u0026thinsp;=\u0026thinsp;0.7 and p\u0026thinsp;=\u0026thinsp;0.169, respectively). Whilst both groups displayed improvement in average and worst pain intensities by day three, the MR group appeared to benefit from further reduction in pain intensities up to day fourteen (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Both MR and OOR participants demonstrated a significant reduction in total pain interference [MR: d=-1.1 (95% CI -1.8 to -0.3), p\u0026thinsp;=\u0026thinsp;0.0420; OOR: d= -0.7, (95% CI -1.4 to 0.001), p\u0026thinsp;=\u0026thinsp;0.007] with no significant between group differences (p\u0026thinsp;=\u0026thinsp;0.772).\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\n \u003ch2\u003eOpioid requirements\u003c/h2\u003e\n \u003cp\u003eOMEDD following MR reduced significantly compared to OOR [d= -0.8 (95% CI -1.5 to -0.001), p\u0026thinsp;=\u0026thinsp;0.05] but there was no difference in the opioid escalation index between groups (p\u0026thinsp;=\u0026thinsp;0.141).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\n \u003ch2\u003eAnxiety, depression and QOL\u003c/h2\u003e\n \u003cp\u003eThere were no significant differences between arms in participants\u0026rsquo; HADS-Depression (p\u0026thinsp;=\u0026thinsp;0.842) or quality of life scores (p\u0026thinsp;=\u0026thinsp;0.835) at the end of the study. Participants in the OOR group demonstrated a non-significant reduction in the HADS-Anxiety score at the end of study, resulting in a significant between group difference (d\u0026thinsp;=\u0026thinsp;0.8; p\u0026thinsp;=\u0026thinsp;0.043).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis pilot randomised trial was the first reported opioid rotation study for refractory CIBP. We demonstrated study feasibility and acceptability through the enrolment of 38 participants (75% participation), with 29 participants completing the study (76.3% retention) and only 3 missing data points amongst the 29 study completers. We found that patients with refractory CIBP were willing to participate in a palliative focused study and accepted randomisation. We encountered recruitment challenges where patients screened were lost to follow up with the initial eligibility criteria requiring participants to wait at least a week following completion of radiotherapy before enrolment. Similarly, given radiotherapy is considered the gold standard treatment for CIBP, some eligible patients declined clinical trial with concern of delaying radiotherapy and two participants dropped out from the methadone group to proceed with radiotherapy 10 days post opioid rotation. The unexpected challenges imposed by COVID-19 affected this study recruitment with recruitment closed prior to achieving the targeted 50 participants.\u003c/p\u003e \u003cp\u003eThis study participants started with a low CTCAE composite score, with no significant increase in score at the end of the study, suggesting that the study interventions were tolerable and safe. The significant reduction in CTCAE composite score in the OOR group further suggests that opioid rotation can be beneficial in reducing toxicities through improved opioid responsiveness and resultant reduction in OMEDD.\u003c/p\u003e \u003cp\u003eThe low baseline CTCAE composite score in this study implies the practice of \u0026lsquo;early\u0026rsquo; opioid rotations before undue escalation of existing opioids to the point of dose-limiting toxicity. Despite this, we noted a significant reduction in the OMEDD post-MR, suggesting improved opioid responsiveness with methadone. In addition to its action on the mu, delta and kappa opioid receptors, incomplete cross-tolerance may result from the methadone antagonistic effect at the NMDA receptor and the inhibition of serotonin and noradrenaline reuptake [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. These additional properties of methadone are theoretically beneficial in the modulation of neuropathic pain and prevention of chronic pain, though neuropathic pain studies have demonstrated mixed results [\u003cspan additionalcitationids=\"CR39\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. In this study, we have noted no difference in the prevalence of assessed neuropathic pain between groups to account for the improved opioid responsiveness seen with MR.\u003c/p\u003e \u003cp\u003eWe observed early and sustained pain reduction with MR. Methadone\u0026rsquo;s greater analgesic potency with repeated administration can be explained by its lipophilic property and phased elimination, resulting in a long and variable half-life of 8-120 hours [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. A reduction in the average pain intensity was achieved in most participants in both groups, but a significant reduction in worst pain intensity was only observed in about a third of participants on methadone, and a quarter of participants rotated to another opioid. In this study, we chose at least moderate worst pain intensity as an inclusion criterion, as worst pain has been shown to have a higher correlation with most functional interference scores and has been recommended to evaluate response to radiotherapy for bone metastases [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Despite the relatively small proportion of participants with significant \u003cem\u003eworst\u003c/em\u003e pain reduction, both treatment groups demonstrated a statistically significant reduction in worst pain intensity and total pain interference.\u003c/p\u003e \u003cp\u003eOpioid rotation, whether to methadone or another opioid is beneficial in reducing both average and worst pain intensities, and pain interference. Although not adequately powered, this study suggests that methadone rotation may have the added benefit of further reducing overall opioid requirement, providing earlier and more sustained pain reduction over fourteen days with no significant worsening of opioid toxicity compared to baseline. We suggest that an appropriately powered multi-centre RCT to be a worthwhile pursuit in addressing the opioid management of refractory CIBP.\u003c/p\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eStudy limitations\u003c/h2\u003e \u003cp\u003eThis study could not exclude the potential impact of concurrent oncology-specific therapy. The generalisability of this study is limited by the small sample size, single site recruitment, with most participants in the OOR group being rotated to hydromorphone. We are not able to identify any patient variables or pain characteristics to guide selection of opioid (methadone vs other opioids). Furthermore, we are not able to firmly conclude on the observed difference in opioid toxicity reporting between groups nor the impact of pain perception by anxiety as the observed significant differences in CTCAE composite scores and anxiety scores between groups may be accounted by their pre-existing baseline group differences.\u003c/p\u003e \u003cp\u003eGiven the pilot nature of this study, we chose to conduct a per-protocol analysis to provide a better estimate of the true efficacy of the study interventions and provide guidance on future studies\u0026rsquo; sample sizes. Based on the observed small effect size on pain intensities between groups, a future sample of 123 participants in each group will be required for the study to achieve 80% power to detect small effect size (Cohen\u0026rsquo;s d\u0026thinsp;=\u0026thinsp;0.2), assuming two-sided α of 0.05. Future studies will need to consider the high attrition rate in this study population, control for anxiety/depression and the impact of radiotherapy or other concurrent oncology-specific therapy. A larger multi-centre study may also explore patient variables and/or pain characteristics that can guide opioid selection in this patient cohort.\u003c/p\u003e \u003c/div\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThis pilot RCT demonstrates that rotation to methadone or other opioids in patients with refractory CIBP is feasible and acceptable with comparable efficacy. Methadone rotation provided the additional benefit of lower opioid requirement. This study supports the conduct of an appropriately powered multi-centre RCT to examine the impact of methadone versus other opioid rotation for the management of refractory CIBP.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e The authors acknowledge Ioana Logan and Gaye Moore who provided administrative research support, Dr Ian Porter who supported the screening of patients for the study and the patients who willingly participated.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u0026nbsp;\u003c/strong\u003eMS, NM and DK designed the initial study; MS piloted and modified the study design; MS, HJT and NM led recruitment; MS, AG, NM and DK conducted statistical analysis; MS wrote the initial manuscript, and all authors approved the final manuscript. MS is responsible for the overall content as guarantor.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003eThis research was funded by the Cabrini Foundation Sambor Research Grant. The funding body was not involved in the study\u0026rsquo;s design, data collection, analysis interpretation or writing of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003eNone declared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003eWritten informed consent was obtained from all patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u0026nbsp;\u003c/strong\u003eThis study involves human participants and was approved by Monash Health Research Ethics Committee: RES-20-0000-869C). Participants gave written informed consent to participate in the study before taking part.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProvenance and peer review\u0026nbsp;\u003c/strong\u003eNot commissioned; externally peer reviewed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003eThe datasets generated during the study will be available upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKane CM, Hoskin P, Bennett MI (2015) Cancer induced bone pain. BMJ 350:h315. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/bmj.h315\u003c/span\u003e\u003cspan address=\"10.1136/bmj.h315\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eColosia A, Njue A, Bajwa Z, Dragon E, Robinson RL, Sheffield KM, Thakkar S, Richiemer SH (2022) The Burden of Metastatic Cancer-Induced Bone Pain: A Narrative Review. J Pain Res 15:3399\u0026ndash;3412. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2147/JPR.S371337\u003c/span\u003e\u003cspan address=\"10.2147/JPR.S371337\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiddlemiss T, Laird BJ, Fallon MT (2011) Mechanisms of cancer-induced bone pain. 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The journal of pain: official journal of the American Pain Society 22 (3):233\u0026ndash;245. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jpain.2020.04.004\u003c/span\u003e\u003cspan address=\"10.1016/j.jpain.2020.04.004\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRigo FK, Trevisan G, Godoy MC, Rossato MF, Dalmolin GD, Silva MA, Menezes MS, Caumo W, Ferreira J (2017) Management of Neuropathic Chronic Pain with Methadone Combined with Ketamine: A Randomized, Double Blind, Active-Controlled Clinical Trial. Pain Physician 20 (3):207\u0026ndash;215\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMadden K, Bruera E (2017) Very-Low-Dose Methadone To Treat Refractory Neuropathic Pain in Children with Cancer. 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Clinical oncology (Royal College of Radiologists (Great Britain)) 19 (7):523\u0026ndash;527. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.clon.2007.04.007\u003c/span\u003e\u003cspan address=\"10.1016/j.clon.2007.04.007\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"supportive-care-in-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jscc","sideBox":"Learn more about [Supportive Care in Cancer](https://www.springer.com/journal/520)","snPcode":"520","submissionUrl":"https://submission.nature.com/new-submission/520/3","title":"Supportive Care in Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Bone pain, refractory pain, opioid, pain control, methadone","lastPublishedDoi":"10.21203/rs.3.rs-4380470/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4380470/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eRefractory cancer-induced bone pain (CIBP) affects a patient\u0026rsquo;s functional capacity and quality of life, but there is limited evidence to guide opioid choice. We assessed the feasibility, tolerability, and possible efficacy of methadone rotation (MR) compared to other opioid rotations (OOR) in this cohort.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eAdults with CIBP and worst pain intensity\u0026thinsp;\u0026ge;\u0026thinsp;4/10 and/or opioid toxicity graded\u0026thinsp;\u0026ge;\u0026thinsp;2 on the Common Terminology Criteria for Adverse Events were randomised 1:1 to methadone or another opioid rotation. Standardised assessment tools were used at pre-defined study time points up to fourteen days.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eFrom 51 eligible participants, 38 (74.5%) consented, and 29 (76.3%, MR: 14, OOR: 15) completed the fourteen days follow up post opioid rotation. Both groups displayed significant reduction in average (MR: d= -1.2, p\u0026thinsp;=\u0026thinsp;0.003, OOR: d= -0.8, p\u0026thinsp;=\u0026thinsp;0.015) and worst pain (MR: d= -0.9, p\u0026thinsp;=\u0026thinsp;0.042, OOR: d= -0.6, p\u0026thinsp;=\u0026thinsp;0.048), and total pain interference score (MR: d=-1.1, p\u0026thinsp;=\u0026thinsp;0.042, OOR: d=-0.7, p\u0026thinsp;=\u0026thinsp;0.007). Oral morphine equivalent daily dose reduced significantly in MR compared to OOR group (d= -0.8, p\u0026thinsp;=\u0026thinsp;0.05). The incidence of opioid related adverse event following MR was unchanged but lower in the OOR group (d\u0026thinsp;=\u0026thinsp;0.9, 95% CI 0.1,1.7, p\u0026thinsp;=\u0026thinsp;0.022). There was no within group or between group differences in satisfaction with analgesia at the end of the study.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis pilot study demonstrated that MR and OOR in patients with refractory CIBP are feasible, safe, and acceptable to patients. Appropriately powered multi-centre randomised controlled studies are needed to confirm the efficacy of MR and OOR in this cohort.\u003c/p\u003e\u003ch2\u003eTrial registration number\u003c/h2\u003e \u003cp\u003eACTRN12621000141842 registered 11 February 2021.\u003c/p\u003e","manuscriptTitle":"Methadone versus other opioids for refractory malignant bone pain: a pilot randomised controlled study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-28 18:01:50","doi":"10.21203/rs.3.rs-4380470/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-06-17T09:24:42+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-17T01:22:22+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-13T16:11:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"280814600848671245089068198943627010214","date":"2024-06-13T15:36:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"51560173464244888257378191796021139723","date":"2024-06-13T11:47:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"208319963438883331371711804130151125391","date":"2024-06-11T16:56:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"306926124868382596586337289214806752386","date":"2024-06-11T16:26:29+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-11T11:33:33+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-08T14:36:23+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-13T06:56:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"Supportive Care in Cancer","date":"2024-05-07T05:49:04+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"supportive-care-in-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jscc","sideBox":"Learn more about [Supportive Care in Cancer](https://www.springer.com/journal/520)","snPcode":"520","submissionUrl":"https://submission.nature.com/new-submission/520/3","title":"Supportive Care in Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"e3b19b82-ffc8-40ee-9fc4-f955720b1958","owner":[],"postedDate":"May 28th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-07-01T12:36:23+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-28 18:01:50","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4380470","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4380470","identity":"rs-4380470","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}