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

Abstract

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.

Risk Factors for Delirium in the Palliative Care Population: A Systematic Review and Meta-Analysis

“…Symptom management is a key element of palliative care, but many drugs used to control symptoms (e.g., opioids, steroids and anticholinergic drugs) are considered to correlate with delirium (37). Opioids, as the mainstay of cancer pain management, could precipitate delirium by increase dopamine release in the nucleus accumbens through opioid receptors (38,39), which has been confirmed in palliative care population (40)(41)(42). However, the impact of opioid dose on delirium is still controversial.…”

Comparison of the prevalence and associated factors of hyperactive delirium in advanced cancer patients between inpatient palliative care and palliative home care

“…However, Senel et al reported that the use of opioids (used or not used) was one of the risk factors for delirium among cancer patients in PCUs 17 . Lim et al also found that a high daily morphine equivalent dose at the start of palliative care consultation was positively associated with the incidence of opioid‐induced neurotoxicity, which includes delirium 18 . One possible reason for the different results is that we may have underestimated the prevalence of agitated delirium because our assessment was based on point estimation.…”

“…We assessed the presence of agitated delirium on admission and at 3 days before death. To adjust for background factors with a potential influence on the prevalence of agitated delirium at the time of assessment, we collected several other data on the day of enrollment based on previous studies and discussion among researchers, 11,13,[16][17][18][19] including age, gender, Eastern Co-operative Oncology Group Performance Status (ECOG PS), central nervous system metastasis, chemotherapy within a month, use of oxygen therapy, use of any catheter, age-adjusted Charlson Comorbidity Index (ACCI), 20,21 pleural effusion, asities, symptom severity defined by the Integrated Palliative Care Outcome Scale (IPOS), [22][23][24] opioid dosage, usage of antipsychotics, usage of benzodiazepines, data to formulate Prognosis in Palliative Care Study predictor models-A (PiPS-A), 25,26 site of primary cancer, metastatic site, Abbreviated Mental Test judged by the physician, heart rate, anorexia, dysphagia, dyspnea, and weight loss in the previous month. We assessed the symptom severity of pain, shortness of breath, weakness or lack of energy, drowsiness, and sore or dry mouth using IPOS, which was scored as 0 (not at all), 1 (slight), 2 (moderate), 3 (severe), and 4 (overwhelming), and defined the prevalence as any IPOS symptoms specified as 2 (moderate), 3 (severe), or 4 (overwhelming).…”

“…As possible factors affecting the prevalence of agitated delirium on admission, we used the following independent variables based on previous studies and discussion among the authors 11,13,[16][17][18][19] : place of care, age (≥65 years), gender, presence of central nervous system metastasis, chemotherapy within a month, ECOG PS (≥3 on admission), modified PiPS-A (months, weeks, days), ACCI, using oxygen therapy, using any catheter, and opioid dosage on admission (oral morphine equivalent: OME ≥60 mg/day). Similarly, as possible factors affecting the prevalence of agitated delirium 3 days before death, we used the following independent variables based on previous studies and discussion among the authors 11,13,[16][17][18][19] : place of care, age (≥65 years), gender, presence of central nervous system metastasis, chemotherapy within a month, ECOG PS (≥3 on admission), modified PiPS-A (months, weeks, days), ACCI, opioid dosage 1 week before death (oral morphine equivalent ≥60 mg/day), 18 symptoms 3 days before death, fever, and parenteral hydration 1 week before death. We defined the presence of symptoms as any IPOS symptoms specified as moderate, severe, or debilitating based on a previous study.…”

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

“…Opioid-induced AEs include constipation, nausea, respiratory depression, delirium and somnolence. 4) Furthermore, "opioid-induced neurotoxicity (OIN)" is a distressing symptom in palliative care patients receiving opioids. 5) Symptoms of OIN include delirium, drowsiness, hallucinations, myoclonus and seizures.…”