Medication use during end-of-life care in a palliative care centre

Background In end-of-life care, symptoms of discomfort are mainly managed by drug therapy, the guidelines for which are mainly based on expert opinions. A few papers have inventoried drug prescriptions in palliative care settings, but none has reported the frequency of use in combination with doses and route of administration. Objective To describe doses and routes of administration of the most frequently used drugs at admission and at day of death. Setting Palliative care centre in the Netherlands. Method In this retrospective cohort study, prescription data of deceased patients were extracted from the electronic medical records. Main outcome measure Doses, frequency and route of administration of prescribed drugs Results All regular medication prescriptions of 208 patients, 89 % of whom had advanced cancer, were reviewed. The three most prescribed drugs were morphine, midazolam and haloperidol, to 21, 11 and 23 % of patients at admission, respectively. At the day of death these percentages had increased to 87, 58 and 50 %, respectively. Doses of these three drugs at the day of death were statistically significantly higher than at admission. The oral route of administration was used in 89 % of patients at admission versus subcutaneous in 94 % at the day of death. Conclusions Nearing the end of life, patients in this palliative care centre receive discomfort-relieving drugs mainly via the subcutaneous route. However, most of these drugs are unlicensed for this specific application and guidelines are based on low level of evidence. Thus, there is every reason for more clinical research on drug use in palliative care

The Rotterdam Elderly Pain Observation Scale (REPOS) is reliable and valid for non-communicative end-of-life patients

__Background:__ In palliative care, administration of opioids is often indispensable for pain treatment. Pain assessment may help recognize pain and guide treatment in non-communicative patients. In the Netherlands the Rotterdam Elderly Pain Observation Scale (REPOS) is recommended to this aim, but not yet validated. Therefore the objective of this study was to validate the REPOS in non-communicative or unconscious end-of-life patients. __Methods:__ In this observational study, the primary researcher applied the REPOS, while both the researcher and a nurse applied the Numeric Rating Scale (NRS). If possible, the patient in question applied the NRS as well. The NRS scores were compared with the REPOS scores to determine concurrent validity. REPOS scores obtained before and after a pain-reducing intervention were analysed to establish the scale's sensitivity to change. __Results:__ A total of 183 REPOS observations in 100 patients were analysed. Almost 90% of patients had an advanced malignancy; observations were done a median of 3 days (IQR 1 to 13) before death. Internal consistency of the REPOS was 0.73. The Pearson product moment correlation coefficient ranged from 0.64 to 0.80 between REPOS and NRS scores. REPOS scores declined with median 2 points (IQR 1 to 4) after a pain-reducing intervention (p < 0.001). Optimal sensitivity (0.81) and specificity (0.62) were found at cut-off score 3. __Conclusions:__ This study demonstrates that the REPOS has promising psychometric properties for pain assessment in non-communicative end-of-life patients. Its application may be of additional value to relieve suffering, including pain, in palliative care

Pharmacokinetics of Morphine, Morphine-3-Glucuronide and Morphine-6-Glucuronide in Terminally Ill Adult Patients

Background and Objective: Morphine dosing can be challenging in terminally ill adult patients due to the heterogeneous nature of the population and the difficulty of accurately assessing pain during sedation. To determine the pharmacokinetics of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in this population, and to find clinically relevant parameters for dose individualisation, we performed a population pharmacokinetic analysis. Methods: Blood samples were randomly collected from 47 terminally ill patients in both the pre-terminal and terminal phases. Nonlinear mixed-effects modelling (NONMEM) was used to develop a population pharmacokinetic model and perform covariate analysis. Results: The data were accurately described by a two-compartment model for morphine with two one-compartment models for both its metabolites. Typical morphine clearance was 48 L/h and fell exponentially by more than 10 L/h in the last week before death. Decreased albumin levels and a decreased estimated glomerular filtration rate (eGFR) resulted in lower metabolite clearance. Between-subject variability in clearance was 52 % (morphine), 75 % (M3G) and 79 % (M6G), and changed to 53, 29 and 34 %, respectively, after inclusion of the covariates. Conclusions: Our results show that morphine clearance decreased up to the time of death, falling by more than 10 L/h (26 %) in the last week before death, and that M3G and M6G accumulated due to decreased renal function. Further studies are warranted to determine whether dose adjustment of morphine is required in terminally ill patients

Hypoalbuminaemia and decreased midazolam clearance in terminally ill adult patients, an inflammatory effect?

Aims: Midazolam is the drug of choice for palliative sedation and is titrated to achieve the desired level of sedation. Because of large inter-individual variability (IIV), however, the time it takes to achieve adequate sedation varies widely. It would therefore greatly improve clinical care if an individualized dose could be determined beforehand. To find clinically relevant parameters for dose individualization, we performed a pharmacokinetic study on midazolam, 1OH-midazolam (1-OH-M) and 1OH-midazolam-glucuronide (1-OH-MG) in terminally ill patients. Methods: Using nonlinear mixed effects modelling (NONMEM 7.2), a population pharmacokinetic analysis was conducted with 192 samples from 45 terminally ill patients who received midazolam either orally or subcutaneously. The covariates analysed were patient characteristics, co-medication and blood chemistry levels. Results: The data were accurately described by a one compartment model for midazolam, 1-OH-M and 1-OH-MG. The population mean estimates for midazolam, 1-OH-M and 1-OH-MG clearance were 8.4 l h−1 (RSE 9%, IIV 49%), 45.4 l h−1 (RSE 12%, IIV 60.5%) and 5.1 l h−1 (RSE 11%, IIV 49.9%), respectively. 1-OH-MG clearance was correlated with the estimated glomular filtration rate (eGFR) explaining 28.4% of the IIV in 1-OH-MG clearance. In addition, low albumin levels were associated with decreased midazolam clearance, explaining 18.2% of the IIV. Conclusion: Our study indicates albumin levels and eGFR as relevant clinical parameters to optimize midazolam dosing in terminally ill patients. The correlation between low albumin levels and decreased midazolam clearance is probably a result of inflammatory response as high CRP levels were correlated in a similar way

Population pharmacokinetics of haloperidol in terminally ill adult patients

Purpose: Over 80% of the terminally ill patients experience delirium in their final days. In the treatment of delirium, haloperidol is the drug of choice. Very little is known about the pharmacokinetics of haloperidol in this patient population. We therefore designed a population pharmacokinetic study to gain more insight into the pharmacokinetics of haloperidol in terminally ill patients and to find clinically relevant covariates that may be used in developing an individualised dosing regimen. Methods: Using non-linear mixed effects modelling (NONMEM 7.2), a population pharmacokinetic analysis was conducted with 87 samples from 28 terminally ill patients who received haloperidol either orally or subcutaneously. The covariates analysed were patient and disease characteristics as well as co-medication. Results: The data were accurately described by a one-compartment model. The population mean estimates for oral bioavailability, clearance and volume of distribution for an average patient were 0.86 (IIV 55%), 29.3 L/h (IIV 43%) and 1260 L (IIV 70%), respectively. This resulted in an average terminal half-life of haloperidol of around 30 h. Conclusion: Our study showed that the pharmacokinetics of haloperidol could be adequately described by a one-compartment model. The pharmacokinetics in terminally ill patients was comparable to other patients. We were not able to explain the wide variability using covariates