Abstract
Background:
Despite the risk of drug-induced delirium, it is difficult to avoid the use of opioids in palliative care. However, no previous study has carefully investigated how the development of delirium varies among patients injected with different opioids for the first time.
Objectives:
To reveal the difference in the incidence of delirium between different opioids.
Design:
The incidence of delirium was compared among 114 patients who had started morphine, oxycodone, or fentanyl injection at Shizuoka Cancer Center between June 2012 and September 2014.
Results:
The incidence of delirium was 28.9% in the morphine group (n = 38), 19.5% in the oxycodone group (n = 41), and 8.6% in the fentanyl group (n = 35). There was a significant difference between the morphine and fentanyl groups (Fisher’s exact test, P = 0.04) but not between the morphine and oxycodone groups (P = 0.43) nor between the oxycodone and fentanyl groups (P = 0.21).
Conclusions:
The incidence of delirium after the commencement of fentanyl injection was significantly lower, suggesting that fentanyl is a useful opioid injection drug from the perspective of delirium risk.
Background
Delirium is a significant problem in the field of palliative medicine, making its proper management and prevention extremely important. Among the pharmaceuticals used in the field of palliative medicine, those associated with delirium are opioids, benzodiazepines, steroids, H2 receptor antagonists, anticonvulsants, antihistaminergics, and anticholinergics 1 (Table 1). In addition, over-the-counter medications that have the same effects as the above-mentioned drugs and herbs such as cannabinoids also induce delirium. 2 In particular, opioids among many other drugs induce delirium, but it is difficult to avoid the use of opioids in palliative care. The mechanism underlying the induction of delirium by opioids is currently unclear. However, previous studies have shown the involvement of opioids in the release of dopamine and the inhibition of sodium–potassium adenosine triphosphatase in neurons, suggesting potential pathways of delirium. 3,4 Morphine was reported to exacerbate delirium in a dose-dependent manner. 5 Opioid switching 6 -8 and the administration of antipsychotic drugs 9,10 are recommended for patients who have developed delirium after the administration of opioids, but previous studies had limited data on the risk of delirium induced by different opioids after the first administration. In this study, we therefore compared the incidence of delirium after the commencement of morphine, oxycodone, or fentanyl injection.
Drugs Associated With Delirium.a
aModified from Tuma and DeAngelis.1
Objectives and Methods
Participants were 114 opioid-naive patients who had undergone continuous intravenous infusion of morphine hydrochloride, oxycodone hydrochloride, or fentanyl citrate for the first time in their life at Shizuoka Cancer Center between June 2012 and September 2014. Patients with a history of oral or intravenous opioid use prior to this study were excluded.
The study period was 1 week from the injection of opioids in individual patients, and information from patient medical records such as the type of opioid, dose, incidence of delirium, and number of days in delirium were evaluated retrospectively by the first author (RT). Delirium was evaluated using the Intensive Care Delirium Screening Checklist. 11 The incidence rates of delirium were compared between groups using Fisher exact test with significance set at 5% (P < .05).
The following patient background factors were investigated in each group: age, sex, disease stage, general condition, central nervous system tumor/metastasis, central nervous system disease, dementia, history of alcohol consumption, history of epidural anesthesia, renal failure, and hepatic failure. Age was analyzed using Student t test, and other patient background factors were compared between the groups using Fisher exact test, with significance set at 5% (P < .05). According to the Common Terminology Criteria for Adverse Events (version 4.0), a grade 1 or higher elevation in serum creatinine level (≥1.04 and ≥0.79 mg/dL in men and women, respectively) was defined as renal dysfunction, and a grade 1 or higher elevation in serum aspartate aminotransferase/alanine transaminase level (≥40 U/L for both) was defined as hepatic dysfunction. In all cases, no chemotherapy, radiotherapy, or other cancer treatment had been started between 1 week before and 1 week after the commencement of opioid injection.
Furthermore, concurrent use of drugs that affect the incidence of delirium was investigated in each group in the period between 1 week before and 1 week after the commencement of opioid injection, specifically, the concurrent use of benzodiazepines (etizolam, brotizolam, flunitrazepam, alprazolam, lorazepam, or diazepam), steroids (prednisolone, hydrocortisone, dexamethasone, or betamethasone), H2 receptor antagonists (famotidine, ranitidine, or lafutidine), antihistaminergics (chlorpheniramine, promethazine, or hydroxyzine), anticholinergics (atropine or scopolamine), and antidopaminergics (prochlorperazine or metoclopramide). Fisher exact test was used to compare data between the groups with significance set at 5% (P < .05). In all cases, no anticonvulsants, over-the-counter medications, or herbal products were administered between 1 week before and 1 week after the commencement of opioid injection. This study was approved by the Institutional Review Board of the Shizuoka Cancer Center.
Results
Of 114 patients, 38 were injected with morphine, 41 with oxycodone, and 35 with fentanyl. In all patients, the starting dose was 6.0 to 9.0 mg/day based on the conversion rates for morphine injection drugs in previous studies. 12 -14 The conversion between morphine–oxycodone–fentanyl was performed using a ratio of 1:1:0.01.
Patient background factors in the oxycodone and fentanyl groups were compared to those in the morphine group in Table 2. No significant difference was observed in age, sex, disease stage, general condition, central nervous system tumor or metastasis, central nervous system disease, dementia, history of alcohol consumption, renal failure, or hepatic failure between the morphine and oxycodone, morphine and fentanyl, or oxycodone and fentanyl groups.
Patient Background.
aStudent t test.
bFisher exact test.
The concurrent use of drugs in the oxycodone and fentanyl groups was compared to that in the morphine group in Table 3. No significant difference was observed in the use of benzodiazepines, steroids, H2 receptor antagonists, antihistaminergics, anticholinergics, or antidopaminergics between the morphine and oxycodone, morphine and fentanyl, or oxycodone and fentanyl groups.
Concurrent Drug Use.
aFisher exact test.
The incidence of delirium was 28.9% in the morphine group (n = 38), 19.5% in the oxycodone group (n = 41), and 8.6% in the fentanyl group (n = 35), as shown in Figure 1. There was a significant difference between the morphine and the fentanyl groups (Fisher exact test, P = .04) but not between the morphine and oxycodone groups (P = .43) nor between the oxycodone and fentanyl groups (P = .21).
The incidence of delirium induced by different opioids.
Discussion
In this study, the incidence of delirium was significantly lower in the fentanyl group than in the morphine group, suggesting the utility of fentanyl in palliative care. In addition, fentanyl showed the lowest incidence of delirium among the drugs investigated, followed by oxycodone and morphine.
All 3 drugs used in this study had a high incidence of delirium compared to the previous clinical studies conducted in Japan (morphine injection, 5.0% 15 ; oxycodone injection, 8.9% 16 ; and fentanyl injection, incidence unknown 17 ). Patients who receive opioid injections are often in the advanced stages of disease or have a poor general condition, and this might have affected the study results. In this study, while the daily dose of fentanyl did not differ significantly from that of morphine or oxycodone, the incidence of delirium and the number of days with delirium were overall lower in the fentanyl group. This may be attributable to the pharmaceutical property of fentanyl, that is, high specificity for the µ-opioid receptors. Although fentanyl is highly lipophilic and thought to be transported into the brain readily, 18 the present findings suggest that fentanyl plays a relatively minor role in the induction of delirium. On the other hand, the high incidence of delirium in the morphine group may reflect the involvement of its metabolites, morphine-3-glucuronide and morphine-6-glucuronide, in delirium. 19 However, it is currently unknown whether these metabolites were involved in delirium because we did not measure the serum levels of morphine, oxycodone, fentanyl, or their metabolites. We also observed a significant difference between fentanyl and morphine but not between fentanyl and oxycodone or between oxycodone and morphine. This is presumably because our study was a retrospective study with a relatively limited number of patients.
With regard to Table 2, it seems like there were more patients with poor Performance Status and stage IV disease in the morphine group. Although no significant intergroup difference was observed, the outcome of this study might have been influenced by multiple confounding factors.
The serum concentrations of electrolytes (Na+, K+, and Ca2+); hypoxemia; dehydration; and concurrent pathology such as paraneoplastic syndrome, hematological disorder, transient cerebral ischemia, stroke, malnutrition, and endocrinopathies had not been assessed or screened in some patients at the commencement of opioid injection. Because this was a retrospective study, we were unable to compare their serum concentrations or concurrent pathologies as patient background factors in this study, which might have affected the study outcome. It is also possible that postoperative and terminal-stage delirium affected the incidence of delirium. The incidence of delirium in each group might have also been affected differently by drug types and dosages.
The concurrent use of antidopaminergics and benzodiazepines tended to be higher in the morphine and fentanyl group, respectively. Although no significant intergroup difference was observed, the outcome of this study might have been influenced by the administration of multiple drugs in some patients. Because fentanyl causes drowsiness less frequently, benzodiazepines were prescribed more often as sleep aid in the fentanyl group during admission. On the other hand, antidopaminergics, such as prochlorperazine and metoclopramide, were administered more frequently in the morphine group to treat nausea, a major side effect of morphine. However, we did not use antidopaminergics as a preventive medication for delirium, like haloperidol in this study.
In summary, it is difficult to exclude the influence of confounding factors entirely because this was a retrospective study, but the present findings suggest that fentanyl is an effective opioid injection drug with a lower risk of delirium.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.