The effect of nevirapine once-daily dosing on the pharmacokinetics of methadone and its main metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine, was evaluated in ten HIV positive patients on stable methadone therapy. Nevirapine 200 mg once daily was administered orally from day 1 to day 14. On day 15, nevirapine dose was increased to 400 mg once daily for the following 7 days of study and thereafter. On days 0, 8, and 22, concentration-time profiles of methadone and its metabolite were collected after methadone intake. Noncompartmental pharmacokinetic analysis was performed. Pharmacokinetic parameters obtained on days 8 and 22 were compared with those obtained before nevirapine administration. After starting nevirapine treatment, nine out of ten patients experienced symptoms of abstinence syndrome, and methadone dose had to be increased by 20% on average during the course of the study. After 7 days with nevirapine 200 mg, methadone area under the plasma concentration time curve (AUC) and maximum concentration (C(max)) values were reduced by 63.3% and 55.2%, respectively. Switching to high dose nevirapine (400 mg once daily) did not result in a greater decrease in the methadone AUC and C(max) compared with 200 mg nevirapine. None of the noncompartmental pharmacokinetic parameters of methadone metabolite evidenced statistically significant differences across the three study periods. The decrease in methadone AUC and C(max) administrated once daily was similar to that seen in other studies with nevirapine administrated twice daily, suggesting that the degree of induction of methadone metabolism by nevirapine is similar for both dosing regimens.

Background and Objectives: Descriptions of end-of-life in COVID-19 are limited to small cross-sectional studies. We aimed to assess end-of-life care in inpatients with COVID-19 at Alicante General University Hospital (ALC) and compare differences according to palliative and non-palliative sedation. Material and Methods: This was a retrospective cohort study in inpatients included in the ALC COVID-19 Registry (PCR-RT or antigen-confirmed cases) who died during conventional admission from 1 March to 15 December 2020. We evaluated differences among deceased cases according to administration of palliative sedation. Results: Of 747 patients evaluated, 101 died (13.5%). Sixty-eight (67.3%) died in acute medical wards, and 30 (44.1%) received palliative sedation. The median age of patients with palliative sedation was 85 years; 44% were women, and 30% of cases were nosocomial. Patients with nosocomial acquisition received more palliative sedation than those infected in the community (81.8% [9/11] vs 36.8% [21/57], p = 0.006), and patients admitted with an altered mental state received it less (20% [6/23] vs. 53.3% [24/45], p = 0.032). The median time from admission to starting palliative sedation was 8.5 days (interquartile range [IQR] 3.0–14.5). The main symptoms leading to palliative sedation were dyspnea at rest (90%), pain (60%), and delirium/agitation (36.7%). The median time from palliative sedation to death was 21.8 h (IQR 10.4–41.1). Morphine was used in all palliative sedation perfusions: the main regimen was morphine + hyoscine butyl bromide + midazolam (43.3%). Conclusions: End-of-life palliative sedation in patients with COVID-19 was initiated quite late. Clinicians should anticipate the need for palliative sedation in these patients and recognize the breathlessness, pain, and agitation/delirium that foreshadow death.

The proposed protocol has been widely accepted and it is quite certain that it is to be introduced in at a general hospital level.

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