Effectiveness of opioid switching for dyspnea and its predictors in cancer patients: a single-center retrospective observational study.

BACKGROUND: Morphine is the most used opioid for dyspnea, but other opioids such as oxycodone and fentanyl are increasingly used, and opioid switching to these is sometimes undertaken. No studies have verified the effectiveness of opioid switching for relief of dyspnea. We retrospectively investigated the effectiveness of opioid switching for dyspnea and its predictors. METHODS: All patients with opioid switching for dyspnea during hospitalization at Komaki City Hospital from January 2019 to August 2022 were included. Opioid switching was defined as a change to another opioid, and the assessment period for evaluating the effectiveness and adverse events of opioid switching was set as 1 week. Patients with Numeric Rating Scale or Japanese version of the Support Team Assessment Schedule reduction for dyspnea of at least 1, or with clear improvement based on medical records, were considered valid. Mitigating factors for dyspnea were identified using logistic regression analysis. RESULTS: Of the 976 patients with opioid switching, 57 patients had opioid switching for relief of dyspnea. Of these, opioid switching was effective in 21 patients (36.8%). In a multivariate analysis, older patients (odds ratio: 5.52, 95% CI: 1.50-20.20, P < 0.01), short prognosis for post-opioid switching (odds ratio: 0.20, 95% CI: 0.04-0.87, P = 0.03) and cachexia (odds ratio: 0.12, 95% CI: 0.02-0.64, P < 0.01) were significantly associated with opioid switching effects for dyspnea. There were no serious adverse events after opioid switching. CONCLUSION: This study indicates that opioid switching for dyspnea may have some effect. Furthermore, opioid switching for dyspnea may be more effective in older patients and less effective in terminally ill patients or in those with cachexia.

Opioid-induced Neurotoxicity in Patients with Cancer Pain.

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

A better interpretation of data regarding the opioid switching to methadone.

In a recent study methadone has been reported more effective witha 3-day switch (3DS) was more effective than the stop and go strategy (SAG). Many shorcomings, however, are of concerns. The poor selection fo patients with low level of pain intensity, the incomprehensibile choice of of SAG or 3DS, and considerations reported in a previous controlled study with evident methodological limits, make their conclusion inaccurate. Controlled studies are fundamental in research. However, a pragmatic approach reflecting daily practice should be carefully taken into consideration. A more flexible use of SAG strategy and strict clinical observation to change doses according to the clinical response may provide the optimal treatment in patients receiving high doses of opioids.

Reply to "A better interpretation of data regarding the opioid switching to methadone".

In our article ?Methadone switching for refractory cancer pain' (BMC palliative care, 2022) we explore the efficacy, safety and economics of methadone in treatment of patients with refractory cancer pain in China. Professor Mercadante provided a better interpretation of data regarding the opioid switching to methadone in the Matters Arising. In this article, we answered the questions in Mercadante et al.'s comments one by one.

Conversion ratios for opioid switching: a pragmatic study.

BACKGROUND: The final conversion ratios among opioids used for successful switching are unknown. The aim of this study was to determine the initial and final conversion ratios used for a successful opioid switching in cancer patients, and eventual associated factors. METHODS: Ninety-five patients who were successfully switched were evaluated. The following data were collected: age, gender, Karnofsky performance score, primary cancer, cognitive function, the presence of neuropathic, and incident pain. Opioids, route of administration, and their doses expressed in oral morphine equivalents used before OS were recorded as well as opioids use for starting opioid switching, and at time of stabilization. Physical and psychological symptoms were routinely evaluated by Edmonton Symptom Assessment Scale. RESULTS: No statistical changes were observed between the initial conversion ratios and those achieved at time of stabilization for all the sequences of opioid switching. When considering patients switched to methadone, there was no association between factors taken into considerations. CONCLUSION: Opioid switching is a highly effective and safe technique, improving analgesia and reducing the opioid-related symptom burden. The final conversion ratios were not different from those used for starting opioid switching. Patients receiving higher doses of opioids should be carefully monitored for individual and unexpected responses in an experienced palliative care unit, particularly those switched to methadone. Future studies should provide data regarding the profile of patients with difficult pain to be hospitalized.

[Opioid rotation in cancer related "mixed pain" scenario : How a "chronic pain patient" becomes a "palliative patient"-a case report]. / Opioidrotation bei "mixed pain" in der Tumorschmerztherapie : Wie aus einer "chronischen Schmerzpatientin" eine "Palliativpatientin" wird ­ ein Fallbericht.

This case report describes the situation of a 67-year-old chronic pain patient who is confronted with the diagnosis of metastatic small cell lung cancer due to an incidental finding. Previously, she had been struggling with chronic lumboischialgia. As she progressed, treatment-resistant tumor pain became increasingly prominent. The importance of recognizing the change in pain quality is described. The tumor pain with a neuropathic component or "mixed pain" made symptom control difficult in the present case report. A switch from transdermally applied fentanyl to a subcutaneous perfusor system with morphine was made and shortly thereafter, due to lack of pain control, to an oral sustained-release oxycodone preparation. This dual opioid rotation is discussed below. Aspects such as resistance development, incomplete cross-tolerance and genetic polymorphisms are highlighted with the help of scientific literature review.

Opioid switching and variability in response in pain cancer patients.

INTRODUCTION: Opioid switching is a possible strategy for inadequate analgesia or unmanageable side effects. Its effectiveness ranges from 50 to 90% and is still debated. PURPOSE: We analyzed the impact of opioid switching in a cancer pain population treated with strong opioids for pain. METHODS: This is a post hoc analysis from a multicenter, randomized, four-arm, controlled, phase IV clinical trial. Outcome variables included the percentages of switches, the reasons for the switch, the dose changes before and after the switch, depending on the starting opioid, the response in case of inadequate analgesia, and unmanageable toxicity, and the variability of response among and within patients. RESULTS: We analyzed 498 patients. The opioid was switched in 79 patients (15.9%) 87 times, mainly for uncontrolled pain (52.3%), adverse opioid reactions (22.1%), both of these (4.8%), and dysphagia (20.8%). The reasons for switching varied depending on the starting opioid. Pain reduction was good after 51.45% of switches and control of opioid side effects was good after 43.5%. The relief of opioid-induced toxicity varied among adverse events and within each patient. The daily doses were higher after switching oral opioids and lower after transdermal drugs. CONCLUSIONS: Half of the patients who underwent switching experienced improved relief of pain or amelioration of opioid toxicity. The switch can help in the management of some cases but with many limits and uncertainties.

Risk Factors for Poor Pain Control after Opioid Switching from Oxycodone Tablet to Fentanyl Patch.

Pain control becomes poor in some cases after opioid switching from oxycodone tablet (OXC) to fentanyl patch (FP). However, fewer studies on risk factors have been reported. In this study, we surveyed the states of pain control (PC) and opioid administration, patient background, laboratory test values, and concomitant drugs retrospectively in 86 patients switching from OXC to FP between June 2010 and April 2018 in Mazda Hospital and Hiroshima Prefectural Hospital. The subjects were divided into 2 groups based on the median number of days to the initial dose increase after switching to FP. Between the early (<7.5 d) and late (≥7.5 d) increase groups, a significant difference was noted in the presence or absence of liver metastasis (LM), concomitant drugs with a high protein binding rate (CDHPBR), and the state of PC before and after switching to FP (p < 0.05). Binary logistic regression analysis showed the presence of CDHPBR, absence of LM, and poor PC after switching were risk factors for early dose increase (presence of CDHPBR: odds ratios (OR), 3.30, 95% confidence interval (CI), 1.09-9.98; presence of LM: OR, 0.31, 95% CI, 0.10-0.93; good PC: OR, 0.23, 95% CI, 0.07-0.79, respectively). The initial dose increase after switching to FP was earlier in patients with CDHPBR and/or without LM than those without CDHPBR and with LM (p < 0.05, log-rank test). It was suggested that the analgesic effect of FP after switching from OXC is likely to be insufficient in patients treated with CDHPBR and patients without LM.

Efficacy and Safety of Oxycodone Injection for Relieving Cancer Pain: A Study in Japan Consisting of Two Open Trials for Intravenous and Subcutaneous Administration.

Pure oxycodone injection became increasingly necessary after oral oxycodone was launched in Japan in 2003. However, trials clarifying the efficacy and safety of injection are rare. Therefore, a multicenter open study on injection was designed and carried out in 2010, resulting in the launch of injection therapy in 2012. As published domestic case reports on efficacy already show widespread prescription, this study aimed to provide useful information for cancer pain relief in Japan and other countries. Our oxycodone injection study consisted of two trials, one of intravenous (S#9131) and the other of subcutaneous (S#9132) administration. The minimum required number of enrolled patients suffering cancer pain was determined to be 70 in S#9131 and 20 in S#9132. These studies had the same dose-titration protocol as the main endpoint, i.e., pain relief rate (PRR) defined as the rate of achieving adequate pain control (APC), as in prior oral oxycodone trials in Japan. In S#9131, PRR was 81.4% (95% confidence interval: 70.3-89.7%), therefore, the null hypothesis of PRR<70% was rejected using the binominal one-sided test (p=0.0217). In S#9132, PRR was 73.7% also surpassing 70%. Safety was also assessed in the same way as in prior trials. The majority of adverse effects were moderate or mild and recovered with no sequelae. As shown above, the injection was considered to be effective and safe in cancer pain treatment. The details of these trials, particularly the dose-titration protocol for achieving APC and route switching information, are expected to enhance injection convenience for prescribers.

A Survey of the Status of Methadone Switching in Japan Using a Hospital-Based Administrative Claims Database.

Methadone is generally used for the management of cancer pain in patients who cannot obtain adequate analgesia from other strong opioids; however, it has a complicated and inconsistent conversion ratio from pre-switching opioid dosage to methadone. This issue may be pronounced in Japan because only oral tablets are commercially available. We aimed to elucidate the status of methadone switching in Japan, focusing on its dosage. Using a Japanese hospital-based administrative claims database, we included patients who switched to methadone between April 2008 and January 2021. The proportion of methadone switching completion that required more than the defined conversion ratio in the Japanese package insert (called "high-dose methadone switching") was evaluated as a primary endpoint. Other endpoints included "the duration from initiation to completion of methadone switching" and "factors affecting high-dose methadone switching by using multivariate logistic regression analysis". Of 1585 patients who received methadone, 370 were enrolled. Among those, 130 (35.1%) received high-dose methadone switching. The median duration of methadone switching completion (12 days) was longer in the high-dose methadone switching group than in other patients. Four variables were identified as factors affecting high-dose methadone switching. Younger age and outpatient status increased the risk of requiring high-dose methadone switching, whereas the concomitant use of nonsteroidal anti-inflammatory drugs and fentanyl as a pre-switching opioid decreased the risk. In conclusion, more than 30% of the patients underwent high-dose methadone switching and required long completion periods, suggesting that methadone switching remains challenging in Japan.

An overview of the current drug treatment strategies for moderate to severe, chronic malignant tumor-related pain.

INTRODUCTION: The pharmacological management of cancer pain is a complex issue that requires knowledge and experience in the use of analgesics. The aim of this expert review is to provide a panorama of the pharmacological strategies in cancer pain management. AREAS COVERED: Opioid dose titration is a delicate process regarding the start of opioid treatment in different clinical conditions. How to improve the opioid response is a fundamental step, which includes different strategies when an initial treatment with opioids fails. The use of adjuvants is another relevant issue that should be considered in some specific circumstances to optimize the management of cancer pain management. Some clinical conditions, such as neuropathic pain and breakthrough pain, deserve a special attention. Relevant literature was selected to provide an overview of cancer pain management strategies. EXPERT OPINION: Opioid therapy still remains the cornerstone of pharmacological management of cancer pain. Opioids should be used according to the level of tolerance, also personalizing the treatment (route, drug, and dosing). Adjuvant drugs may help in specific conditions, although their use should be balanced with the adverse effects. Breakthrough pain requires expertise in tailoring a treatment according to patient's profile and characteristics of episodes.

Switching to Intravenous Methadone in Advanced Cancer Patients: A Retrospective Analysis.

CONTEXT: Information about opioid switching to intravenous methadone is lacking. OBJECTIVES: The aim of this study was to assess the outcome of opioid switching to intravenous methadone (IV-ME) in patients admitted to an acute supportive/palliative care unit (ASPCU). The secondary outcome was to assess the conversion ratio from IV-ME to oral methadone at time of hospital discharge. METHODS: We retrieved from the pharmacy registry the list of patients who were prescribed IV-ME during their ASPCU admission for a period of 47 months. Poor analgesia with previous opioids and/or adverse effects were the main indications for opioid switching. IV-ME was titrated until acceptable analgesia was achieved. The effective dose was multiplied by three to establish the intravenous daily dose, given as a continuous infusion. Doses were then changed according to the clinical needs. Once the patient was stabilized, IV-ME dose was converted to oral methadone, by using an initial ratio of 1:1.2. Further dose changes were made according to clinical needs until stabilization, before patients' discharge. Information about patients' characteristics, pain scores on the Edmonton Symptom Assessment Scale (ESAS), Memorial Delirium Assessment Scale (MDAS), Cut-down, Annoyed, Guilty, Eye-opener (CAGE) questionnaire, previous opioids and their doses, expressed as oral morphine equivalents (OME), were recorded. The effective bolus of IV-ME, initial daily infusion rate, and oral methadone doses were assessed, and conversion ratios calculated. RESULTS: Forty-one patients were taken into consideration for the study. The mean effective bolus of IV-ME titrated for achieving acceptable analgesia was 9 mg (range 5-15 mg). The mean daily continuous infusion rate of IV-ME was 27.6 mg/day (SD 21). The mean daily dose of oral methadone at time of discharge was 46.8 mg/day (SD 43). Discharge occurred within a median of seven days (range 6-9) after admission. Previous opioid (OME)/IV-ME, oral-IV-ME, and previous opioid (OME)/oral methadone were 6.25, 1.7, and 3.7, respectively. CONCLUSION: IV-ME dose titration followed by intravenous infusion allowed a rapid pain control in few minutes in patients with severe pain intensity, not responsive to previous opioids. Conversion to oral route was successful and facilitated home discharge. Further studies should be performed to confirm these preliminary results.

Oral Methadone for Patients With Neuropathic Pain Due to Neoplastic Brachial Plexopathy.

Background: The brachial plexus nerves originate from the cervical (C5-C8) and first thoracic (T1) spinal nerves, and innervate muscles and skin of the chest, shoulder, arm and hand. Brachial plexus injuries can occur as a result of shoulder trauma and inflammation. Malignant tumors can also cause neoplastic brachial plexopathy (NBP), and refractory neuropathic pain is the most common symptom of NBP. Methadone is a synthetic opioid with high efficacy as an opioid-receptor agonist, and its inhibitory effects on N-methyl-D-aspartate (NMDA) may play a role in pain relief. However, there is a need to examine if oral methadone exhibits safety and efficacy against neuropathic pain due to NBP. Case Presentations: NBP was diagnosed in 3 cases without brain or cervical spine metastasis. The clinical features of these patients were analyzed retrospectively. None of the cases had an indication for surgery because of advanced cancer and all had received radiation therapy that had an insufficient effect, prior to methadone treatment. All 3 patients had nociceptive and neuropathic pain. Methadone for refractory pain was initiated using the stop-and-go method. NRS pain scores decreased in all cases and there were no severe side effects. Discussion: For the purpose of pain relief, patients with NBP may receive surgery, radiation therapy and nerve block, but these are not always effective. Methadone was recently shown to be superior to fentanyl in treating neuropathic pain in patients with head-and-neck cancer in a RCT, and our findings suggest that methadone may also be effective for patients with NBP. Conclusion: More studies are necessary, but results in 3 cases suggest that oral methadone may be a safe analgesic agent for patients with neuropathic pain due to NBP.

Methadone Switching for Cancer Pain: A New Classification of Initiation Protocols, Based on a Critical Literature Review.

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

Practical management of opioid rotation and equianalgesia.

PURPOSE: To review the recent literature on opioid rotation (ie, switching from one opioid drug to another or changing an opioid's administration route) in cancer patients experiencing severe pain and to develop a novel equianalgesia table for use in routine clinical practice. METHODS: The MEDLINE database was searched with terms "cancer pain," "opioid rotation," "opioid switching," "opioid ratio," "opioid conversion ratio," and "opioid equianalgesia" for the major opioids (morphine, oxycodone, fentanyl, and hydromorphone) and the intravenous, subcutaneous, oral, and transdermal administration routes. Selected articles were assessed for the calculated or cited opioid dose ratio, bidirectionality, and use of the oral morphine equivalent daily dose or a direct drug-to-drug ratio. RESULTS: Twenty publications met our selection criteria and were analyzed in detail. We did not find any large-scale, prospective, double-blind randomized controlled trial with robust design, and most of the studies assessed relatively small numbers of patients. Bidirectionality was investigated in seven studies only. CONCLUSION: The updated equianalgesic table presented here incorporates the latest data and provides information on bidirectionality. Despite the daily use of equianalgesic tables, they are not based on high-level scientific evidence. More clinical research is needed on this topic.

Opioid switching in cancer pain: From the beginning to nowadays.

Opioid switching is the process of changing from one opioid to another to obtain a satisfactory clinical balance between analgesia and adverse effects. This pharmacological technique has been introduced about 20 years ago to enhance the opioid response in advanced cancer patients with chronic pain. More information is now available. This review will examine many different aspects of opioid switching, including the history and evolution through the last decades, some clinical aspects based on the most recent experience, controversies on the indications, conversion ratios and modalities of switching in some specific circumstances, and evidence based recommendations.

Indication of Adequate Transdermal Fentanyl Dose in Opioid Switching From Oral Oxycodone in Patients With Cancer.

OBJECTIVE: The present study aimed to examine affecting factors for conversion ratio and to predict adequate fentanyl dose for patients with cancer pain in opioid switching from oral oxycodone. METHODS: Patient characteristics, biochemical parameters, daily oxycodone dose, and reasons for opioid switching were retrospectively collected. The effect of variables on the conversion ratio was analyzed by multiple regression analysis. RESULTS: Regression analysis for the data from 122 patients suggested that the typical conversion ratio was 95:1; however, this ratio was significantly reduced in patients taking a daily oral morphine-equivalent dose of <45 mg/d and in patients with poor pain control to 52:1 and 64:1, respectively. CONCLUSION: We should carefully and rapidly control pain in opioid switching based on the adequate dose indicated in this study.

Morphine or oxycodone for cancer-related pain? A randomized, open-label, controlled trial.

CONTEXT: There is wide interindividual variation in response to morphine for cancer-related pain; 30% of patients do not have a good therapeutic outcome. Alternative opioids such as oxycodone are increasingly being used, and opioid switching has become common clinical practice. OBJECTIVES: To compare clinical response to oral morphine vs. oral oxycodone when used as first-line or second-line (after switching) treatment in patients with cancer-related pain. METHODS: In this prospective, open-label, randomized, controlled trial (ISRCTN65155201) with a selected crossover phase, patients with cancer-related pain were randomized to receive either oral morphine or oxycodone as first-line treatment. Dose was individually titrated until the patient reported adequate pain control. Patients who did not respond to the first-line opioid (either because of inadequate analgesia or unacceptable adverse effects) were switched to the alternative opioid. RESULTS: Two hundred patients were recruited. On intention-to-treat analysis (n = 198, morphine 98, oxycodone 100), there was no significant difference between the numbers of patients responding to morphine (61/98 = 62%) or oxycodone (67/100 = 67%) when used as a first-line opioid. Similarly, there was no significant difference in subsequent response when patients were switched to either morphine (8/12 = 67%) or oxycodone (11/21 = 52%). Per-protocol analysis demonstrated a 95% response rate when both opioids were available. There was no difference in adverse reaction scores between morphine and oxycodone either in first-line responders or nonresponders. CONCLUSION: In this population, there was no difference between analgesic response or adverse reactions to oral morphine and oxycodone when used as a first- or second-line opioid. These data provide evidence to support opioid switching to improve outcomes.

Modified glasgow prognostic score predicting high conversion ratio in opioid switching from oral oxycodone to transdermal fentanyl in patients with cancer pain.

The aim of this study was to identify predictive factors for higher conversion ratio in opioid switching from oral oxycodone to transdermal fentanyl (TDF) in patients with cancer pain. The participants of this study were 156 hospitalized cancer patients who underwent opioid switching from oral oxycodone to TDF at the Affiliated Hospital of Binzhou Medical University between January 1st, 2010 and March 31st, 2014. Patient characteristics, modified Glasgow Prognostic Score (mGPS), daily oxycodone dose, and reasons for opioid switching were retrospectively collected. The effect of variables on the conversion ratio was analyzed by multiple regression analysis to identify the predictive factors for higher conversion ratio in opioid switching from oral oxycodone to TDF. The results showed that the mGPS (odds ratio [OR], 2.358; 95% CI 1.379-4.031; P = 0.002), the reason for opioid switching (OR, 0.497; 95% CI, 0.298-0.828; P = 0.007) and equivalent oral morphine dose (OR, 1.700; 95% CI, 1.008-2.867; P = 0.046) were found to be significant predictors requiring higher conversion ratio in opioid switching. This study indicates that higher mGPS, poor pain control before switching and higher equivalent oral morphine dose are significant predictors of a need for higher conversion ratio in opioid switching from oral oxycodone to TDF. These results could contribute to the establishment of evidence-based medicine in cancer pain relief.