Opioid-induced Neurotoxicity Research Articles

Possible unusual presentation of opioid side effect in a child: a case report

Atypical presentations are commonly encountered in the Pediatric intensive care unit (PICU) but having a high index of suspicion is crucial to prevent or treat severe and life-threatening conditions. This case describes the clinical presentation and course of a 14-month-old girl with congenital heart disease who was admitted to the PICU after cardiac repair and remained agitated, irritable, in hysteria and delirium despite adequate sedation. Different measures to relieve her condition were attempted but to no avail. All the common causes of this atypical presentation including pain, ventilator induced agitation, low cardiac output syndrome (LCOS), opioid side effects, toxicity, opioid induced neurotoxicity (OIN) as well as withdrawal syndrome were ruled out. However, the use of naloxone as a last resort after exhausting all the other options has led to immediate and successful reversal of her symptoms.

Routine Monitoring of QTc Interval as a Barrier for Efficient Use of Methadone in Palliative Care

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

Opioid-induced Neurotoxicity in Patients with Cancer Pain.

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.

Identifying risk factors for opioid-induced neurotoxicity in cancer patients receiving oxycodone.

The aim of this study was to determine the frequency of opioid-induced neurotoxicity (OIN) in cancer patients receiving oral controlled-release oxycodone and to define risk factors for OIN. This was a single-center, retrospective study of hospitalized adult cancer patients receiving oral controlled-release oxycodone between April 1, 2013, and April, 30, 2020. The onset of OIN within 30days after oxycodone initiation in the study patients was investigated. OIN was defined as any of the following: delirium, hallucinations (visual or auditory), seizure, myoclonus, hyperesthesia, and excessive somnolence. Multivariate logistic regression analysis was performed to identify risk factors for OIN in patients receiving oxycodone. In total, 520 patients were included in this study. The number of patients with OIN was 65 (12.5%). The median time until onset of OIN after oxycodone initiation was 7.5days. Multivariate logistic regression analysis revealed that age ≥ 65years (OR = 2.74, 95% CI [1.30-5.78], p = 0.008), total bilirubin ≥ 1.3mg/dL (OR = 4.85, 95% CI [2.13-11.0], p < 0.001), and concomitant use of pregabalin or mirogabalin (OR = 3.11, 95% CI [1.47-6.61], p = 0.003) were significant independent risk factors for OIN. Age ≥ 65years, liver dysfunction, and concomitant use of pregabalin or mirogabalin were independent risk factors for OIN in patients receiving oxycodone. Patients with these risk factors who are receiving oxycodone should be monitored for OIN, especially early in the administration of oxycodone.

Ameliorating effects of low-dose ketamine administrations on opioid-induced memory impairments and neurodegeneration in mice

Aim: Opioids have indispensable roles in pain management. There is a strong link between opioid use and memory impairments, mainly with continuous use. This study investigated the effects of two opioid drugs, meperidine and fentanyl, on emotional memory functions and brain morphology and the possible protective effects of low-dose ketamine in mice. Material and Methods: A passive avoidance (PA) test was used to measure emotional memory functions following seven daily drug applications in 48 male Balb/C mice (30-35 g). Meperidine (10 mg/kg), fentanyl (0.3 mg/kg), ketamine (5 mg/kg), and combinations of ketamine with the opioids were intraperitoneally injected daily. No drugs were utilized during the testing days. Brain tissues were obtained after sacrification and put into diluted formalin solution for histopathological analysis. Results: Transfer latencies of the meperidine and fentanyl-treated groups were lower than in the vehicle-treated group (p&lt;0.01, p&lt;0.05, respectively). Ketamine combined with meperidine had higher latencies than in the meperidine-treated group (p&lt;0.05). The protective effects of ketamine were evident against fentanyl and meperidine-induced neurotoxicity; histologic alterations were reduced. Conclusion: Low-dose ketamine may fend against opioid-induced neurotoxicity and emotional memory impairments, especially against meperidine, which can be a practical alternative to fentanyl in clinical settings.

Identification and management of opioid-induced neurotoxicity in older adults.

What are the symptoms of opioid-induced neurotoxicity, and how can I avoid this often unrecognized and serious adverse drug reaction (ADR)? Canada is the second-largest per capita consumer of opioids in the world.[1][1] Canadians who are 65 years or older have a higher likelihood of taking opioid

Disproportionality Analysis of Safety Signals for a Wide Variety of Opioid-Related Adverse Events in Elderly Patients Using the Japanese Adverse Drug Event Report (JADER) Database.

Opioids are widely used for the treatment of moderate/severe pain in cancer and noncancer patients. In this study, we searched for safety signals for a wide variety of opioid-related adverse events (AEs) in elderly patients by disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database. Data from the JADER database from April 2004 to May 2018 were obtained from the Pharmaceuticals and Medical Devices Agency website. Safety signal detection of opioid-related AEs in elderly patients was defined using the relative elderly reporting odds ratio (ROR). Among the analyzed AEs, opioid-induced neurotoxicity (OIN) was assessed based on the time to onset using the Weibull shape parameter. The following safety signals were detected in elderly patients: respiratory depression, somnolence, hallucinations, akathisia and OIN. Fentanyl, tramadol, oxycodone and morphine exhibited a large relative elderly ROR for OIN. The median time to onset of OIN of transdermal fentanyl, oral tramadol, oral oxycodone and oral morphine was 13.5, 6, 9, and 6 d, respectively. These opioids were classified as early failure types using the Weibull distribution. Our results showed that elderly patients who are administered opioids should be closely monitored for AEs, such as respiratory depression, OIN and akathisia.

Differential Regulation of Angiogenic Gene Networks in Postmortem Brains of Opioid Use Disorder Subjects

Opioid abuse can cause brain alterations, including neuroinflammation and increased risk for ischemic stroke. Cancer studies show that opioids affect angiogenesis and endothelial cell proliferation. However, human brain studies are scarce, and the molecular mechanisms of opioid-induced neurotoxicity are unclear. This study comprehensively interrogated the transcriptomic and proteomic profiles of the dorsolateral prefrontal cortex (BA9) in subjects with opioid use disorder (OUD), to investigate the molecular effects of opioid abuse in the human brain.

Tolerability and safety of strong opioid analgesics in children and adolescents with incurable oncological diseases

Relevance. One of the basic tasks of palliative medical care is to control pain in an incurable patient. To administer strong opioid analgesics as basic pain management in terminal patients, a treating physician must understand the risk of opioid-related adverse effects. According to the World Health Organization, the occurrence of the pain syndrome and importance of correct analgesic therapy in children and adolescents with incurable oncological diseases are underestimated.Purpose. To improve the quality of palliative medical care provided to children and adolescents with incurable oncological diseases.Materials and methods. A retrospective and prospective study was carried out. 400 patients with incurable oncological diseases aged 0 months to 20 years (median 9 years) were included into the study from June 2014 to December 2017, in particular, 235 boys and 165 girls (189 patients with extracranial solid tumors, 117 patients with CNS tumors and 94 patients with hemoblastoses). The study was approved by the Independent Ethics Committee and the Council of Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology (Protocol No. 5 dated May 21, 2013). Of 284 patients with the pain syndrome, 227 (80%) of children and adolescents aged 0–20 years (median 12 years) used strong opioid analgesics (morphine hydrochloride, morphine sulfate and transdermal therapeutic system with fentanyl) for pain relief. Their dosage was set in accordance with WHO 2012 recommendations related to the management of persisting pain syndrome in children. To estimate the severity of adverse events (AE) when strong opioids were used (nausea, vomiting, constipation, skin itching, urinary retention and respiratory failure), the CTCAE (Common Terminology Criteria for Adverse Events) displays Grades 1 through 5. Opioid-induced hyperalgesia and opioid-induced neurotoxicity were estimated by clinical signs (absence or presence of a symptom).Results. Of 227 patients, 59 (26%) patients had AE associated with the administration of strong opioid analgesics: 11.5% of cases for constipation, 7.5% cases for nausea, 4% of cases for pruritus, 2.2% of cases for urinary retention, 0.44% of cases for opioid-induced hyperalgesia, 0.44% of cases for opioid-induced neurotoxicity. No respiratory failure was noted when strong opioid analgesics were used. In the majority of cases (95%), the registered AE were mild and required no termination of therapy with opioid analgesics. Of 284 patients, 281 (98.9%) underwent analgesic therapy with complete pain management.Conclusion. Strong opioid analgesics are safe and effective in children and adolescents with incurable oncological diseases.

Ketamine Use for Complex Pain in the Palliative Care Population.

Palliative care patients are predisposed to complex pain, including refractory pain, neuropathic pain, opioid-induced hyperalgesia, and opioid-induced neurotoxicity. Palliative care complex pain management can include use of subanesthetic parenteral ketamine. Support for subanesthetic ketamine exists from anecdotal experiences and nonrandomized studies, but there is a lack of statistically significant evidence to support or dismiss its use. Ketamine is sought for illegal, nonmedical purposes, so the lack of evidence coupled with potential for exploitation makes judicious and knowledgeable use critical. Palliative care nurse practitioners, as experts in symptom management, should evaluate and consider all potentially beneficial treatment strategies for complex pain, including novel strategies such as subanesthetic ketamine treatment. Several databases and clinical guideline repositories, along with inspection of germane articles' reference lists, were utilized to collect original research, retrospective studies, literature reviews, and case reports pertinent to the management of palliative care complex pain with parenteral ketamine. In conclusion, the evidence-based clinical decision-making process is engaged to outline a method to weigh the risks versus benefits of subanesthetic ketamine for this population of patients.

Frequency, Outcomes, and Associated Factors for Opioid-Induced Neurotoxicity in Patients with Advanced Cancer Receiving Opioids in Inpatient Palliative Care.

Context: Opioid-induced neurotoxicity (OIN) is an underdiagnosed yet distressing symptom in palliative care patients receiving opioids. However, there have been only a limited number of studies on OIN. Objectives: Our aim was to determine the frequency of and risk factors for OIN in patients receiving opioids during inpatient palliative care. Methods: We randomly selected 390 of 3014 eligible patients who had undergone palliative care consultations from January 2014 to December 2014. Delirium, drowsiness, hallucinations, myoclonus, seizures, and hyperalgesia were defined as OIN and were recorded. The other 10 common symptoms in cancer patients were assessed using the Edmonton Symptom Assessment Scale (ESAS). Patient demographics, morphine equivalent daily dose (MEDD), comorbidities, OIN management, and overall survival (OS) duration were also assessed. The associations between the incidence of OIN and MEDD, the other 10 symptoms, and OS were analyzed. Results: Fifty-seven (15%) patients had OIN. The most common symptom was delirium (n = 27). On multivariate analysis, a high MEDD (p = 0.020), high ESAS pain score (p = 0.043), drowsiness (p = 0.007), and a poor appetite (p = 0.014) were significantly associated with OIN. OIN was not significantly associated with a shorter OS duration (p = 0.80). Conclusions: OIN was seen in 15% of patients receiving opioids as part of inpatient palliative care. Although OIN was not associated with OS, routine monitoring is especially needed in cancer patients.

Successful Opioid De-Escalation With Dexmedetomidine in a 1 year old with Worsening Pain and Opioid-Induced Neurotoxicity

Background: Junctional Epidermolysis Bullosa (JEB) is the most severe form of Epidermolysis Bullosa (EB), a skin blistering disease, which causes widespread pain, infection, and typically death by age 2 or earlier. Opioid use can be very high in these children, putting them at risk for opioid-induced neurotoxicity (OIN). Treatment for OIN …

Successful Opioid De-Escalation With Dexmedetomidine in a 1 year old with Worsening Pain and Opioid-Induced Neurotoxicity

Successful Opioid De-Escalation With Dexmedetomidine in a 1 year old with Worsening Pain and Opioid-Induced Neurotoxicity

Evidence for Morphine or Hydromorphone-Induced Neurotoxicity in Renal Impairment: A Systematic Review (S705)

•Describe opioid-induced neurotoxicity and its risk in renal impairment.•Summarize evidence for morphine or hydromorphone neurotoxicity in hospice and palliative care patients with renal impairment.•Understand current opioid guidelines in renal impairment. Opioids are the mainstay of symptom control for seriously ill patients with pain. The accumulation of active metabolites, particularly with use of morphine and hydromorphone, is thought to increase risk of neurotoxicity in patients with renal impairment exacerbating the high symptom burden of these patients. To identify and assess the quality of evidence for opioid-induced neurotoxicity in patients with renal impairment receiving morphine or hydromorphone. Systematic searches were conducted of the following databases from inception to December 2015: MEDLINE, CINAHL, EMBASE, in addition to hand-searching relevant review articles’ citations. Studies were included if they reported neurotoxic effects of either morphine or hydromorphone for chronic or malignant pain in patients with renal impairment. Review articles and case reports were excluded. Narrative review was undertaken. The Grading of Recommendations, Assessment, Development and Evaluation approach was used to assess study quality. Six original articles, including three prospective and three retrospective studies were identified and assessed. No relevant randomized clinical trials were identified. Though morphine and hydromorphone may be associated with neurotoxic effects in patients with renal impairment, current evidence is limited to very low-quality studies with conflicting findings. Clinicians may consider using either morphine or hydromorphone in mild to moderate renal impairment, while closely monitoring for neurotoxic effects, particularly when used in high doses and for extended duration.

P202 Switching Back to Opioids Previously Associated with Opioid-induced Neurotoxicity

P202 Switching Back to Opioids Previously Associated with Opioid-induced Neurotoxicity

Growth hormone is protective against acute methadone-induced toxicity by modulating the NMDA receptor complex

Human growth hormone (GH) displays promising protective effects in the central nervous system after damage caused by various insults. Current evidence suggests that these effects may involve N-methyl-d-aspartate (NMDA) receptor function, a receptor that also is believed to play a role in opioid-induced neurotoxicity. The aims of the present study were to examine the acute toxic effects of methadone, an opioid receptor agonist and NMDA receptor antagonist, as well as to evaluate the protective properties of recombinant human GH (rhGH) on methadone-induced toxicity. Primary cortical cell cultures from embryonic day 17 rats were grown for 7days in vitro. Cells were treated with methadone for 24h and the 50% lethal dose was calculated and later used for protection studies with rhGH. Cellular toxicity was determined by measuring mitochondrial activity, lactate dehydrogenase release, and caspase activation. Furthermore, the mRNA expression levels of NMDA receptor subunits were investigated following methadone and rhGH treatment using quantitative PCR (qPCR) analysis. A significant protective effect was observed with rhGH treatment on methadone-induced mitochondrial dysfunction and in methadone-induced LDH release. Furthermore, methadone significantly increased caspase-3 and -7 activation but rhGH was unable to inhibit this effect. The mRNA expression of the NMDA receptor subunit GluN1, GluN2a, and GluN2b increased following methadone treatment, as assessed by qPCR, and rhGH treatment effectively normalized this expression to control levels. We have demonstrated that rhGH can rescue cells from methadone-induced toxicity by maintaining mitochondrial function, cellular integrity, and NMDA receptor complex expression.

The Opioid Rotation Ratio From Transdermal Fentanyl to “Strong” Opioids in Patients With Cancer Pain

ContextOne-third of cancer patients require opioid rotation (OR) to treat uncontrolled pain or opioid-induced neurotoxicity. Although fentanyl is the most frequently rotated opioid in cancer patients, the accurate opioid rotation ratio (ORR) from transdermal fentanyl (TDF) to other so-called “strong” opioids is unknown. ObjectivesWe aimed to determine the ORR of TDF to strong opioids, as measured by morphine equivalent daily dose (MEDD). MethodsWe reviewed 2471 consecutive patient visits (938 patients) to our supportive care center for an OR from TDF to strong opioids. Information regarding demographics, symptoms, and MEDD was collected in patients who followed up within six weeks. Linear regression analysis was used to estimate the ORR between TDF dose and net MEDD (MEDD after OR minus MEDD of the breakthrough opioid used along with TDF before OR). ResultsAmong 47 eligible patients, the median age was 54 years, 53% were male, and 77% had advanced cancer. The median time to follow-up was 14 days. Uncontrolled pain (83%) was the most common reason for OR. In patients with OR and no worsening of pain at follow-up (n = 41), the median ORR (range) from TDF mg/day to net MEDD mg/day was 100 (12.5–217) and from TDF mcg/hour to net MEDD was 2.4 (0.3–5.2); the correlation of TDF dose to net MEDD was 0.60 (P < 0.0001). ConclusionThe median ORR from TDF mg/day to MEDD is 100 and from TDF mcg/hour to MEDD is 2.4, suggesting that TDF 100 mcg/hour is equivalent to an MEDD of 240 mg.

Impact of a Palliative Care Checklist on Clinical Documentation.

Checklists are used in many different settings for the purpose of standardization and reduction of preventable errors in practice. Our group sought to determine whether a palliative care checklist (PCC) would improve the clinical documentation of key patient information. An initial review of 110 randomly selected medical records dictated by 10 physicians was performed. The authors identified portions of the dictated medical records that were included regularly, as well as those that were frequently missed. A PCC was drafted after final approval was obtained from the 13 faculty members. Dictations from 13 clinical faculties in the supportive care center were reviewed. A χ(2) test or Fisher's exact test was applied to assess the difference in overall checked rates before and after checklist use. A paired t test was used to examine the difference in the average complete rate and checked rates before and after checklist use. There were improvements in the documentation before and after the checklist for scores on the Cut-down, Annoyed, Guilty, Eye-opener questionnaire for alcoholism (79% v 94%; P ≤ .0001), psychosocial history (69% v 95%; P ≤ .0001), Eastern Cooperative Oncology Group performance status (38% v 81%; P ≤ .0001), advance care planning (28% v 41%; P = .0008), and overall (78% v 95%; P ≤ .0001). There was no significant improvement in the documentation for opioid-induced neurotoxicity (37% v 37%; P = .9492) or the Edmonton Symptom Assessment Scale (98% v 99%; P = .4511). Our study showed that the use of a PCC improved the quality of the documentation of a patient visit in an outpatient clinical setting.

Survival among cancer patients undergoing opioid rotation to methadone as compared to other opioids.

183 Background: Recent studies have reported that methadone has antineoplastic activity. Other studies have associated methadone with lower overall survival in patients with chronic pain. Methadone is the most frequent opioid chosen for purpose of opioid rotation (OR) in cancer patients experiencing refractory pain or opioid induced neurotoxicity. There is no data available on the association of methadone with overall survival in cancer patients. Our aim was to compare the characteristics and overall survival in cancer patients in methadone group with other strong opioid group. Methods: In this ad hoc analysis, we reviewed 2471 consecutive patient visits to the supportive care center of a tertiary cancer center in 2008 for ORs from strong opioids to methadone or other strong opioids with a follow-up visit within 6 weeks. Information regarding demographics, Edmonton Symptom Assessment Scale (ESAS), and morphine equivalent daily dose (MEDD) were collected. Successful pain response was defined as 2-point or 30% reduction in pain score. Kaplan-Meier curves were used to evaluate survival. Results: Of the 102 eligible patients, 54 underwent OR to methadone and 48 to other strong opioids. The median age was 56 years, 56% were male, and 81% had advanced cancer. There were no significant differences between the methadone group and the other opioid group in patient characteristics, performance status, MEDD, and ESAS scores. Although both the groups showed significant pain response, methadone group (72%) had a significantly higher pain response as compared to the other opioid group (65%; P = 0.04). The Kaplan-Meier curves revealed no significant difference in overall survival (OS) between the methadone group and the other opioid group [median OS: 5.2 months (95% CI 3.64-7.41) vs. 5.9 months (95% CI 2.6-9.2); P = 0.89]. Conclusions: We observed no significant difference in overall survival in cancer patients in methadone group as compared to other opioids. Further validation studies in a larger sample are warranted.

The Opioid Rotation Ratio (ORR) to transdermal fentanyl (TDF) in cancer patients.

181 Background: Cancer patients frequently undergo opioid rotation (OR) for uncontrolled pain or opioid induced neurotoxicity. TDF is one of the most common opioids prescribed to cancer patients. However, the accurate ORR from other opioids to TDF is unknown and various currently used methods result in a wide variation of ORRs. Our aim was to determine the ORR of morphine equivalent daily dose (MEDD) to TDF when correcting for MEDD of breakthrough opioids (net MEDD) in cancer outpatients. Methods: We reviewed records of 22,532 consecutive patient visits at our Supportive Care Center in 2010-13 for OR from to TDF by a palliative medicine specialist. Data regarding Edmonton Symptom Assessment Scale (ESAS) and MEDD were collected in patients who returned for follow up within 5 weeks. Linear regression analysis was used to estimate the ORR between TDF dose and net MEDD (MEDD prior to OR minus MEDD of breakthrough opioid used along with TDF after OR). Successful OR was defined as 2-point or 30% reduction in pain score and continuation of the new opioid at follow up. Results: 129 patients underwent OR to TDF from other opioids. The mean age was 56 years, 59% male, and 88% had advanced cancer. The median time between OR and follow up was 14 days. Uncontrolled pain (80%) was the most frequent reason for OR and 59% had a successful OR with significant improvement in ESAS pain, constipation, and symptom distress scores. In 101 patients with OR and no worsening of pain at follow up, the median ORR (range) from net MEDD to TDF mg/day was .01 (-0.02-0.04) and correlation of TDF dose to net MEDD was .77 (P &lt; .0001). The ORR was not significantly impacted by variables such as mucositis, serum albumin, and body mass index (BMI). The ORR of .01 suggests that MEDD of 100mg is equivalent to 1mg TDF/day or 40mcg/hour TDF patch (1000mcg/24hours). Conclusions: The median ORR from MEDD to TDF mg/day is .01 and the ORR from MEDD to TDF mcg/hour patch is 0.4. Further validation studies are needed. [Table: see text]