BACKGROUND: More than 15,000 children die annually in the United States due to an underlying life-limiting disease and the majority of those children experience distressing symptoms, which are not adequately relieved, such as pain and dyspnea. Multimodal analgesia, that is multiple agents, interventions, rehabilitation, psychological modalities, and integrative (nonpharmacologic) therapies, act synergistically for more effective pediatric pain and symptom control with fewer side effects than a single analgesic or modality. However, opioids, such as morphine, fentanyl, hydromorphone, oxycodone, and methadone (in the United Kingdom: diamorphine) remain the mainstay medication to effectively treat pain and dyspnea in children with serious illness.
METHODS: This article reviews commonly used opioids in Pediatric Palliative Care, which a special emphasis on 2 potentially particularly effective multimechanistic opioids: tramadol and methadone.
RESULTS: Methadone, due to its multimechanistic action profile, is possibly among the most effective and most underutilized opioid analgesics in children with severe unrelieved pain at end of life. However, methadone should not be prescribed by those unfamiliar with its use: Its effects should be closely monitored for several days, particularly when it is first started and after any dose changes.
CONCLUSIONS: Tramadol appears to play a key role in treating episodes of inconsolability in children with progressive neurologic, metabolic, or chromosomally based condition with impairment of the central nervous system. However, the recent 2017 United States Food and Drug Administration (FDA) warning against pediatric use of tramadol does not seem to be based on clinical evidence, and therefore puts children at risk for unrelieved pain or increased respiratory depression.
OBJECTIVES: To summarise the current body of published evidence on the use of low-dose and/or adjuvant methadone in the palliative care setting.
METHODS: The authors searched multiple databases (PubMED, SCORPUS, EMBASE and the Cochrane library) for relevant articles using the terms 'methadone', 'palliative', 'low dose' and 'adjuvant'. The review was restricted to articles published between 2003 and 2018. Paediatric and single-case studies were also excluded. Evidence quality was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) method.
RESULTS: Our search yielded 171 results, of which seven met the inclusion criteria. Four were retrospective chart reviews, one was a retrospective cohort study, one was a case series and one was a double-blind randomised control trial. The overall quality was found to be very low. Of the seven articles, all seven reported some improvement in pain with the addition of low-dose or adjuvant methadone. This improvement was statistically significant in four out of seven articles; statistical significance was not commented on in the remaining three articles.
CONCLUSION: While case series and chart reviews offer promising results about the utility of adjuvant and/or low-dose methadone in the management of complex pain, the very low evidence quality, relative dearth of studies and near absence of randomised controlled trials make it impossible to draw firm conclusions. Thus, while very preliminary evidence suggests methadone is a potentially effective and valuable agent, further research must be performed before such findings can be implemented into clinical practice.
BACKGROUND: Methadone may play a role in the control of refractory cancer pain in opioid switching, although some cases fail to switch to methadone.
OBJECTIVE: To evaluate the differences in the clinical aspects in switching to methadone between successful cases (SCs) and unsuccessful cases (UCs).
DESIGN: This was a retrospective study of the clinical aspects of cancer patients who experienced opioid switching from other opioids to methadone.
SETTING/SUBJECTS: Eighty-seven patients who were prescribed oral methadone in our hospital were analyzed. Methadone was initiated from other opioids due to refractory pain in the stop-and-go switching. Among the 87 cases, 7 cases were excluded from further analysis because methadone administration was stopped due to vomiting or self-cessation within six days from switching.
RESULTS: Among the 80 cases who had methadone for seven days or more, 70 cases (SCs) were successful in switching to methadone, according to the Japanese definition, although 10 cases (UCs) who experienced the rapid progression of illness failed due to oral difficulty in the course of titration. In comparison of the clinical characteristics between SCs and UCs, the number of days alive from the start of the administration of methadone was significantly greater in the SCs than in the UCs (SCs: 87.1, UCs: 19, p < 0.0001), but no significant differences were observed for any other factors.
CONCLUSION: From this comparative retrospective study of opioid switching to methadone for cancer pain control between SCs and UCs, early switching to methadone may be useful for patients with advanced cancer pain.
Methadone has several unique characteristics that make it an attractive option for pain relief in serious illness, but the safety of methadone has been called into question after reports of a disproportionate increase in opioid-induced deaths in recent years. The American Pain Society (APS), College on Problems of Drug Dependence, and the Heart Rhythm Society collaborated to issue guidelines on best practices to maximize methadone safety and efficacy, but guidelines for the end-of-life scenario have not yet been developed. A panel of 15 interprofessional hospice and palliative care experts from the US and Canada convened in February 2015 to evaluate the APS methadone recommendations for applicability in the hospice and palliative care setting. The goal was to develop guidelines for safe and effective management of methadone therapy in hospice and palliative care. This article represents the consensus opinion of the hospice and palliative care experts for methadone use at end of life, including guidance on appropriate candidates for methadone, detail in dosing, titration, and monitoring of patients' response to methadone therapy.
CONTEXT: Methadone is a long-acting opioid known for its unique pharmacokinetic and pharmacodynamic properties. Most research on methadone in children is limited to its effect on the prolongation of the corrected QT (QTc) interval.
OBJECTIVES: To better understand the attitudes, beliefs, and practices of pediatric palliative care physicians regarding the use of methadone in children with advanced cancer.
METHODS: A survey was sent to The American Academy of Pediatrics Section of Hospice and Palliative Medicine LISTSERV®. Information on demographics, dosing of methadone, and the use of electrocardiograms (ECGs) was collected.
RESULTS: One-hundred and five respondents (91%) provide palliative care to children = 50% of the time, and a majority (81, 77%) prescribe methadone.
Most (62, 77%) physicians were board-certified in Hospice and Palliative Medicine and most (39, 63%) certified via the direct pathway (“grandfathering”).
Most physicians (57, 70%) do not use loading doses of methadone. Board-certified physicians trended towards decreasing methadone dose more (40% ± 19%) than non-board-certified physicians (28%, ±20%) when changing from the oral to intravenous route (p = 0.07).
Respondents defined a QTc interval as “prolonged” (mean ± SD) at 444 milliseconds (±68 milliseconds). The percentage of patients receiving a baseline ECG was 65% (±33%). The most common reason for not performing a baseline ECG was that the patient was on hospice (13, 36%).
CONCLUSIONS: There are consistent practices, attitudes, and beliefs of pediatric palliative care providers with regards to methadone. More education is needed on the accurate value of a prolonged QTc interval.
A patient receiving maintenance treatment with methadone (MTM) was treated with parenteral methadone for intense pain crises in cancer of the tongue with severe mucositis and dysphagia. Authors like Manfredi et al describe good results in the use of methadone as an analgesic in patients with MTM. The difficulties which arise with parenteral use derive from the drug itself and from those to whom the treatment is administered: serious side effects like malignant arrhythmias and respiratory depression and the complex nature of these patients, addicted to opiates with a terminal illness and pain which is difficult to treat. It should be administered by experts in palliative care in a healthcare unit where it can be successfully monitored.
BACKGROUND: Palliative care physicians often assist with pain management in children with cancer, but little is known about how they use long-acting opioids for chronic pain with these patients.
OBJECTIVE: To determine the practices, attitudes, and beliefs of palliative care physicians toward the use of long-acting opioids in children with advanced cancer.
DESIGN: An electronic survey was sent to all members of The American Academy of Pediatrics (AAP) Section of Hospice and Palliative Medicine (SOHPM) and those identified as physicians who provide palliative care to children on the AAP SOHPM LISTSERV®.
RESULTS: The response rate to the survey was 62% (116/188). A majority (66% [77/116]) of physicians are board certified in both pediatrics and hospice and palliative medicine. This represents 28% of all board-certified pediatric palliative care physicians. Most palliative care physicians report comfort in using long-acting opioids in children (84â€“94%), with the exception of long-acting hydromorphone (37%). Physicians perceived methadone as least costly (3%) but associated it with a higher perceived family resistance (51%). As compared with pediatric palliative care fellowship-trained physicians, nonpediatric fellowship-trained physicians perceived titration of oxycodone ER and morphine ER to be easier (p = 0.06, p = 0.07) and less likely to agree that the main reason for starting methadone is that the existing formulations of other long-acting opioids are unsuitable for children (p = 0.05).
CONCLUSIONS: Most physicians who provide palliative care to children are comfortable using opioids but there is significant variation in the level of comfort with different opioids. This information will be helpful in developing targeted education for palliative care providers.
BACKGROUND: Methadone is an attractive medication for treating children with advanced cancer with pain as it is the only long-acting opioid available as a liquid. However, it is not frequently used due to concerns about potential toxicities and side effects.
OBJECTIVE: Evaluate the efficacy and safety of methadone as the first long-acting opioid in children with advanced cancer.
DESIGN: Retrospective chart review of 52 consecutive patients referred to Pediatric Supportive Care for pain management started on methadone as their first long-acting opioid. Data collected at baseline, follow-up visits #1 (F1) and #2 (F2) included child and parent-reported outcomes for various physical and psychological symptoms, opioid side effects and other clinical data. Symptoms were rated on a 0 (not at all) to 4 (a lot) scale.
RESULTS: Pain (mean ± standard deviation [SD]) scored by the child was 3.6 (±0.6)/4 at baseline and 1.8 (±1.1)/4 at F1 (p < 0.0001). Compared to baseline, pain scored by the child at F2 was 1.2 (±1.3)/4 (p < 0.0001). Pain scored by the parent was 3.5 (±0.7)/4 at baseline and 1.4 (±1.3)/4 at F1 (p < 0.0001). Compared to baseline, pain scored by the parent at F2 was 1.0 (±1.2)/4 (p < 0.0001). Thirty-three (70%) patients at F1 and 23 (79%) patients at F2 did not need a change in dose of methadone. No cardiac arrhythmias or opioid neurotoxicity was observed.
CONCLUSIONS: Initiation of methadone was effective and safe as the first long-acting opioid in children with pain.
Palliative care providers across India lobbied to gain access to methadone for pain relief and this has finally been achieved. Palliative care activists will count on the numerous strengths for introducing methadone in India, including the various national and state government initiatives that have been introduced recognizing the importance of palliative care as a specialty in addition to improving opioid accessibility and training. Adding to the support are the Non-Governmental Organizations (NGOs), the medical fraternity and the international interactive and innovative programs such as the Project Extension for Community Health Outcome. As compelling as the need for methadone is, many challenges await. This article outlines the challenges of procuring methadone and also discusses the challenges specific to methadone. Balancing the availability and diversion in a setting of opioid phobia, implementing the amended laws to improve availability and accessibility in a country with diverse health-care practices are the major challenges in implementing methadone for relief of pain. The unique pharmacology of the drug requires meticulous patient selection, vigilant monitoring, and excellent communication and collaboration with a multidisciplinary team and caregivers. The psychological acceptance of the patient, the professional training of the team and the place where care is provided are also challenges which need to be overcome. These challenges could well be the catalyst for a more diligent and vigilant approach to opioid prescribing practices. Start low, go slow could well be the way forward with caregiver education to prescribe methadone safely in the Indian palliative care setting.
Since the 2014 Amendment to the NDPS Act methadone has been released in India for pain management. The methadone is supplied as racemic mixture with R & S methadone with benefit in pain management and associated adverse effects. Physicians need to be aware of adverse effects so that methadone can be administered safely. Similarly, patients and families need to store and use methadone carefully and experience the benefits and not increase the risk of further morbidity. Considerable amount of literature on methadone is available and sometimes conflicting, hence the article is attempting to guide a physician to use methadone safely to acquire experience and expertise over time.
BACKGROUND: Methadone has been shown to be effective for cancer pain. Most published switching methods are complete in less than three days, requiring very close supervision, usually in an inpatient setting. This need for hospitalization is a barrier to access. We present a large retrospective study of slow outpatient methadone starts and describe our starting method.
METHODS: Charts were reviewed of patients referred to the Pain and Symptom Management/Palliative Care clinics at the six BC Cancer Agency's regional centers that underwent initiation of methadone for analgesia over a 14-year period. Patient characteristics, method of start, and outcomes of methadone treatment were recorded.
RESULTS: Of the 652 identified patients, we were able to determine outcomes of methadone initiation in 564 (86.5%). Among these, 422 (74.8%) were deemed successful initiations, as determined by whether or not the patient remained on methadone at follow-up with subjective improvement in pain control, on a stable dose of methadone. Of the unsuccessful trials, 97/142 were primarily due to adverse events, 16 of which were considered serious enough to require hospitalization, including two due to sudden cessation of opioid therapy leading to withdrawal. Some of the included adverse events were not necessarily causal from the initiation of methadone, for example, development of bowel obstruction or delirium. Only one death occurred from a deliberate overdose of multiple medications, including methadone.
CONCLUSIONS: Initiation of methadone for analgesia in ambulatory cancer patients can be done safely in an outpatient setting using a start-low go-slow method, and can be expected to be helpful in ~75% of patients. Discontinuation is more likely to be for side effects than for inadequate analgesia. Access to methadone therapy can safely be widened by slow initiation, avoiding more dangerous rapid switching protocols and reducing the need for hospitalization.
BACKGROUND: Cancer pain is often not well controlled and there is a need for improved treatment strategies. Methadone exhibits unique properties among opioids and recent reports show promising results from adding a low dose of methadone to regular opioid therapy.
OBJECTIVE: To examine the effects of oral low-dose methadone added to regular scheduled opioids in terminally ill patients with complex cancer-related pain.
DESIGN: This was a retrospective chart review.
SETTING/SUBJECTS: All patients with advanced cancer treated in a specialized palliative care unit who had received oral methadone in addition to another regular opioid were identified.
MEASUREMENTS: Intensity of pain, opioid doses, and occurrence of sedation, delirium, and respiratory depression were obtained from the patients' medical records for a period of one week after initiation of methadone.
RESULTS: Eighty patients were included. The median daily methadone dose was 10 mg during the treatment period. Eighty percent of the patients had improved pain control (p < 0.001). There was an increased risk for sedation and delirium, most pronounced in patients living 14 days or less after the start of methadone. No patient experienced respiratory depression.
CONCLUSION: Addition of low-dose oral methadone to regular high-dose opioid treatment in cancer patients with complex pain close to death improves pain control, but also increases the risk for sedation and delirium.
Background: Methadone (ME) is commonly used in pain and palliative care (PPC) patients with refractory pain or intolerable opioid adverse effects (AEs). A unique ME AE is its corrected QT (QTc) interval prolongation risk, but most evidence exists in methadone maintenance therapy patients.
Objective: their goal was to identify QTc interval prolongation risk factors in PPC patients receiving ME and other medications known to prolong the QTc interval and develop a risk stratification tool.
Design: they performed a case–control study of adult inpatients receiving ME for pain management.
Settings/Subjects: Adult inpatients receiving ME with a QTc >470 msec (males) and >480 msec (females) were matched 1:2 according to age, history of QTc prolongation, and gender with ME patients who did not have a prolonged QTc interval. QTc prolongation risk factors were collected for both groups. Covariates were analyzed using conditional logistic regression. Classification and regression tree analysis was used to identify the ME dose associated with QTc prolongation.
Results: Predictors of QTc prolongation included congestive heart failure (CHF) (OR: 11.9; 95% CI: 3.7–38.2; p < 0.00), peptic ulcer disease (PUD) (odds ratio [OR]: 8.3; 95% confidence interval [95% CI]: 2.4–28.9; p < 0.00), hypokalemia (OR: 6.5; 95% CI: 1.5–28.2; p < 0.01), rheumatologic diseases (OR: 4.7; 95% CI: 1.6–13.9; p < 0.00), taking medications with a known torsades de pointes (TdP) risk (OR: 4.4; 95% CI: 1.8–10.7; p < 0.01), malignancy (OR: 3.3; 95% CI: 1.2–9.3; p < 0.03), hypocalcemia (OR: 2.1; 95% CI: 0.9–4.8; p < 0.07), and ME doses >45 mg per day (OR: 1.9; 95% CI: 0.8–4.8; p < 0.16). Mild liver disease was protective against QTc prolongation (OR: 0.05; 95% CI: 0.0–0.46; p < 0.01).
Conclusions: Predictors of QTc prolongation in their multivariate conditional logistic regression model included CHF, PUD, hypokalemia, rheumatologic disorders, use of medications with a known TdP risk, malignancy, hypocalcemia, and ME doses >45 mg per day.
BACKGROUND: Compared with nociceptive pain, neuropathic pain is a challenging diagnosis to make and successfully treat in children with cancer.
OBJECTIVE: The objective of this case report was to see whether very-low-dose methadone (VLDM) (defined as <50% of accepted starting analgesic dose of methadone for children) would be an effective strategy to treat refractory neuropathic pain due to vincristine in two children with acute lymphoblastic leukemia. METHODS: This case report is based on the clinical experience and parent-reported outcomes of two children with refractory neuropathic pain who received VLDM.
RESULTS: Based on parent/caregiver-reported outcome scores over a one-year period, both children's refractory neuropathic pain syndrome was successfully treated with the addition of VLDM to their pre-existing regimen of gabapentin. Neither child suffered any adverse effects from methadone.
CONCLUSIONS: VLDM shows promise as an effective, safe, and inexpensive way to treat refractory neuropathic pain in children with cancer.
BACKGROUND: Many factors make methadone an appealing option for treatment of pain in patients seen by palliative care; however, complex drug-related properties and variable patient response complicate appropriate conversion ratios from other opioids to methadone. Currently, there is no consensus regarding one accepted conversion method.
OBJECTIVE: Current patterns of prescribing for clinicians at a three-hospital academic health system on initial rotation to methadone for the management of pain were compared with a series of consensus recommendations for methadone dose calculation. DESIGN: Retrospective chart review of 98 hospital patients. Settings/Participants: Adult subjects hospitalized in an academic medical center between January 1, 2013, and January 1, 2015, who were initiated on oral methadone for pain during the same admission. MEASUREMENTS: Final target daily dose of methadone was calculated using End of Life/Palliative Education Resource Center (EPERC) and Friedman conversion methods based on opioids provided in the prior 24 hours. This was then compared with actual dosing as ordered by clinicians and received by the patient.
RESULTS: Average range of final daily methadone dose for new starts was 18.1 +/- 16.7 mg. Final methadone dose as received by two-thirds of patients was below the dosing target calculated by EPERC and Friedman guidelines by an average of 35 mg. In addition, more than 80% of patients' final methadone doses fell below the range recommended by these two methods. No patients received opioid reversal agents during their index hospitalization.
CONCLUSIONS: These findings may question the best approach to clinical application of EPERC and Friedman methods and call for more research to determine the safest, lowest, and most effective methadone target dosing selection. Final methadone dosing as received by patients compared favorably with a conservative methadone dosing method that recommends starting doses no higher than 30-40 mg per day.
La méthadone est utilisée dans de nombreux pays comme traitement antalgique des douleurs liées au cancer. Nous rapportons le cas d'un patient ayant bien répondu à la méthode d'analgésie autocontrôlée préconisée comme méthode d'équilibration par le protocole de l'Afssaps 2010.
Origine : BDSP. Notice produite par APHPDOC HADIR0xm. Diffusion soumise à autorisation
Ce chapitre est consacrée à la douleur et son traitement. En premier lieu, les auteurs traitent la physiopathologie de la douleur. En deuxième lieu, ils abordent les échelles d'évaluation. En troisième lieu, les auteurs décrivent le traitement antalgique de la douleur puis les techniques antalgiques en quatrième lieu. Viennent ensuite les pratiques alternatives telles que l'hypnose, l'auriculothérapie et l'acupuncture en fin de vie en cinquième, sixième et septième lieux respectivement.
Deux spécialistes québécois des soins palliatifs tentent ici de démontrer que la prescription et l'utilisation normale des opiacés dans ce cadre, même lors d’une sédation, ne provoquent pas la mort et permettent de soulager la douleur du patient en fin de vie.