Drug-drug interaction perpetrators of oxycodone in patients with cancer: frequency and clinical relevance.

AIM: Oxycodone is known to have numerous drug-drug interactions (DDIs) that can potentially decrease efficacy or lead to adverse drug reactions (ADRs). However, there is limited research on the frequency of DDIs associated with oxycodone, which is important in optimising pharmacovigilance and the need for additional research on certain DDIs. In this study, the frequency of pharmacologically and clinically relevant DDI perpetrators was studied in patients with cancer. METHODS: This was a cross-sectional study using hospital pharmacy records of patients with cancer who were prescribed oxycodone between September 2021 and September 2022. Medication records of patients prescribed oxycodone during a period of ≥ 5 consecutive days (= oxycodone treatment episodes) were reviewed to identify the concomitant use of pharmacologically relevant perpetrators, based on reference sources (Lexicomp®, Micromedex®, the Dutch Kennisbank and the Dutch Commentaren Medicatiebewaking). The clinical relevance was examined by a clinical pharmacologist and a medical oncologist. Additionally, the frequency of double interactions-concomitant oxycodone use with two CYP3A4 and / or CYP2D6 perpetrators-was studied. RESULTS: Overall, 254 oxycodone treatment episodes were included, of which 227 (89.4%) were found to contain at least one pharmacologically relevant DDI perpetrator. Of these, 210 (82.7%) were considered to be clinically relevant. A total of 80 different pharmacologically relevant perpetrators were identified, with 65 (81.3%) being considered clinically relevant. Double interactions were observed in 21 (8.3%) oxycodone treatment episodes. CONCLUSION: A high frequency of pharmacologically and clinically relevant perpetrators of oxycodone was observed in our cohort. Moreover, a high number of double interactions involving oxycodone was registered. More intense monitoring of DDIs may be needed to improve medication safety of patients with cancer taking oxycodone.

Enzalutamide Reduces Oxycodone Exposure in Men with Prostate Cancer.

BACKGROUND AND OBJECTIVE: Up to 90% of patients with castration-resistant prostate cancer (CRPC) will develop symptomatic bone metastases requiring pain medication, with opioids being the mainstay of therapy in treating moderate and severe pain. Enzalutamide is an androgen receptor antagonist for the treatment of CRPC and a strong inducer of cytochrome P450 (CYP)3A4. Hereby, enzalutamide potentially reduces the exposure of oxycodone, an opioid metabolized by CYP3A4 and CYP2D6. Our objective was to evaluate the potential drug-drug interaction of enzalutamide and oxycodone. METHODS: A prospective, nonrandomized, open-label, two-arm parallel study was performed. All patients received a single dose of 15 mg normal-release oxycodone. Patients in the enzalutamide arm (ENZ-arm) received enzalutamide 160 mg once daily. Plasma concentrations of oxycodone and its metabolites were quantified using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. RESULTS: Twenty-six patients (13 ENZ-arm; 13 control arm) were enrolled in the study. Enzalutamide decreased the mean AUC0-8 h and Cmax of oxycodone with, respectively, 44.7% (p < 0.001) and 35.5% (p = 0.004) compared with the control arm. The AUC0-8 h and Cmax of the active metabolite oxymorphone were 74.2% (p < 0.001) and 56.0% (p = 0.001) lower in the ENZ-arm compared with the control arm. In contrast, AUC0-8 h and Cmax of the inactive metabolites noroxycodone and noroxymorphone were significantly increased by enzalutamide. CONCLUSION: Co-administration of enzalutamide significantly reduced exposure to oxycodone and its active metabolite oxymorphone in men with prostate cancer. This should be taken into account when prescribing enzalutamide combined with oxycodone.

Assessing the binding interaction of polystyrene sulfonate with amitriptyline in healthy volunteers: a cross-over design - The BIND study.

PURPOSE: Polystyrene sulfonate is used for binding potassium in patients with chronic kidney disease (CKD). Because of its binding properties, it can potentially bind other medications and thereby decrease their bioavailability and effectiveness. Amitriptyline, often used by CKD patients for neuropathic pain, shows significant binding to polystyrene sulfonate in vitro. The purpose of this study was to determine the effect of polystyrene sulfonate on the exposure of amitriptyline in vivo when taken concomitantly in healthy volunteers. METHODS: We performed a prospective cross-over study in nine healthy volunteers. Participants were 18 years of age or older, did not use any medication, and had no known allergy to amitriptyline or polystyrene sulfonate. Participants visited Deventer Teaching Hospital twice. Once they received a single dose of amitriptyline 50 mg and once they received a single dose of both polystyrene sulfonate 15 g and amitriptyline 50 mg taken concomitantly, with a wash out period of at least 1 week. After intake of the medication, six blood samples were collected, at 2, 3, 4, 5, 6, and 8 h. Blood samples were analysed to determine maximum concentration (Cmax) and area under the curve 0-8 h after intake (AUC0-8 h). Difference in Cmax and AUC0-8 h was analysed with a paired T-test or Wilcoxon signed rank test, depending on normality of the data. A p-value < 0.05 was considered statistically significant. RESULTS: Of the nine participants included, eight participants completed both visits to the hospital. Mean maximum concentration (Cmax) of amitriptyline was 35.61 µg l-1 (95% CI 27.90-43.33 µg l-1) when taken alone, compared to 9.25 µg l-1 (95% CI 6.59-11.92 µg l-1) when taken with polystyrene sulfonate (p < 0.001). Mean AUC0-8 h of amitriptyline was 168.20 µg × h l-1 (95% CI 139.95-196.45 µg × h l-1) when taken alone and 45.78 µg × h l-1 (95% CI 30.20-61.36 µg × h l-1) when taken with polystyrene sulfonate (p < 0.0001). CONCLUSION: These results show a significant decrease in exposure of amitriptyline of approximately 75% when taken concomitantly with polystyrene sulfonate, thereby probably compromising therapy efficacy. Patients using both amitriptyline and polystyrene sulfonate should be informed to separate intake of these medications. TRIAL REGISTRATION: NL8539 (17 April 2020).

High prevalence of peripheral neuropathy in multiple myeloma patients and the impact of vitamin D levels, a cross-sectional study.

PURPOSE: Peripheral neuropathy (PN) is common in patients with multiple myeloma (MM). We hypothesized that the relationship between hypovitaminosis D and PN described in diabetes mellitus patients may also be present in MM patients. METHODS: To study this potential association, we assessed the incidence of hypovitaminosis D (vitamin D < 75 nmol/L [= 30 ng/mL]) in smouldering and active MM patients in two Dutch hospitals. Furthermore, a validated questionnaire was used to distinguish different PN grades. RESULTS: Of the 120 patients included between January 2017 and August 2018, 84% had an inadequate vitamin D level (median vitamin D level 49.5 nmol/L [IQR 34-65 nmol/L]; mean age: 68 years [SD ± 7.7]; males: 58%). PN was reported by 69% of patients (n = 83); however, of these 83 patients, PN was not documented in the medical records of 52%. An association was found between lower vitamin D levels and higher incidence of PN in the total population (P = 0.035), and in the active MM patients (P = 0.016). CONCLUSION: This multi-centre cohort study showed that PN and hypovitaminosis D are common in MM patients, and addressing low vitamin D levels in the treatment of MM patients might be beneficial in reducing the risk of PN. More attention for PN is warranted, as PN is underreported by clinicians. Further research is needed to fully understand the implications of vitamin D in the development of PN in patients with MM. CLINICAL TRIAL REGISTRATION: Netherland Trial Register NL5835, date of registration July 28, 2016.

Exploring co-dispensed drug use in patients on sevelamer or polystyrene sulfonate to identify potential novel binding interactions: a cross sectional in silico study : Potential novel binding interactions with resins.

Background Sevelamer and polystyrene sulfonate are used for treating hyperphosphatemia and hyperkalaemia in chronic kidney disease patients. Because of their binding properties, these resins potentially bind other drugs in the gastrointestinal tract, thereby decreasing their bioavailability and clinical effectiveness. Aim The aim of this study was to explore co-dispensed drug use in patients on sevelamer or polystyrene sulfonate to identify potential novel binding interactions. Method In this in silico study, the 100 drugs most frequently co-dispensed with sevelamer/polystyrene sulfonate in the period 2000-2018 were extracted from the University Groningen IADB.nl database. Drugs dispensed to < 5% of patients, drugs not orally administered, drugs administered once daily before bedtime and drugs for which information on binding interactions with sevelamer or polystyrene was already available were excluded. The likelihood of an interaction (yes or no) of the included drugs was assessed based on pKa- and Log P values. For sevelamer, drugs with a pKa (acid) between 1.5 and 7.4 and or a Log P value > 2.0 were identified as potential interacting drug. For polystyrene sulfonate, drugs with a pKa (base) > 1.5 were identified as potential interacting drug. Results Of the top 100 drugs most frequently co-dispensed with sevelamer/polystyrene sulfonate, 22 and 27 potentially clinically relevant new interacting drugs were identified for sevelamer and polystyrene sulfonate respectively. Conclusion Several potentially relevant novel binding interactions for sevelamer and polystyrene sulfonate were identified based on dispensing data and assessment of chemical properties for which further interaction research is warranted.

Identifying patients with metformin associated lactic acidosis in the emergency department.

Background Metformin associated lactic acidosis (MALA) is a serious adverse event with a high mortality rate of 30-50%. Early recognition of MALA and timely starting treatment may reduce its morbidity and mortality. Objective The aim of this study was to explore clinical parameters to identify patients with MALA in patients with suspected sepsis induced lactic acidosis in the emergency department ED. Setting A retrospective single centre study was conducted at the Deventer Teaching Hospital in the Netherlands. Method Patients with lactate concentration > 4.0 mmol/l admitted at the ED between 2010 and 2017 with suspected sepsis or confirmed MALA and referred to the Intensive Care Unit were included. Baseline characteristics (pH, lactate, creatinine and CRP) of MALA patients were compared with patients with suspected sepsis induced lactic acidosis. Creatinine and lactate concentration were selected as potential relevant parameters. Main outcome measure Sensitivity and specificity of the highest tertiles of the creatinine and the lactate concentrations separately, in combination, and both combined with metformin use, were calculated. Results Thirteen MALA and 90 suspected sepsis induced lactic acidosis patients were included. Lactate (14.7 vs 5.9 mmol/l, p < 0.01) and creatinine concentration (642 vs 174 µmol/l, p < 0.01) were significantly higher in the MALA group and arterial pH (7.04 vs 7.38, p < 0.01) and CRP (90 vs 185 mg/l, p < 0.01) were significantly lower. The combined parameters lactate ≥ 8.4 mmol/l, creatinine ≥ 256 µmol/l had a sensitivity of 85% and a specificity of 95% for identifying MALA in suspected sepsis induced lactic acidosis patients in the ED. When combined with metformin use the specificity increased to 99%. Conclusion When managing lactic acidosis in the ED the diagnosis MALA should be considered in patients with a creatinine concentration ≥ 256 µmol/l and lactate concentration ≥ 8.4 mmol/l.

Burden of early, advanced and metastatic breast cancer in The Netherlands.

BACKGROUND: The aim of this study was to estimate the total economic and health related burden of breast cancer in the Netherlands. METHODS: Data on incidence, prevalence, mortality and survival were extracted from the Dutch National Cancer Registry and were used to calculate the economic and health related burden of breast cancer for overall, DCIS (stage 0), early- (stage I), locally advanced- (stage II-III) and metastatic- (stage IV) breast cancer by age groups and by year (if applicable). RESULTS: The overall incidence of breast cancer increased from 103.4 up to 153.2 per 100,000 women between 1990 and 2014. The increase was driven by DCIS and early breast cancer as the incidence of locally advanced and metastatic breast cancer remained stable. Between 1990 and 2014, ten-year overall survival rates increased from 87% to 93% for early breast cancer, 41% to 62% for locally advanced- and from 6% to 9% for metastatic disease. Annually, breast cancer in the Netherlands is responsible for approximately 3100 deaths, 26,000 life years lost, 65,000 Disability Adjusted Life Years (DALYs) and an economic burden of €1.27 billion. CONCLUSIONS: This study provides a comprehensive assessment of the burden of breast cancer and subsequent trends over time in the Netherlands.

Dosing oxaliplatin in a haemodialysis patient with metastatic rectum cancer monitored by free platinum concentrations.

WHAT IS KNOWN AND OBJECTIVE: Oxaliplatin in combination with fluorouracil and folinic acid is one of the preferred chemotherapeutic options in the treatment of metastatic rectum cancer. However, oxaliplatin is contraindicated in patients with a creatinine clearance <30 mL/min and dosing guidelines in patients on haemodialysis have not been established. CASE SUMMARY: A 77-year-old haemodialysis patient with metastatic rectum cancer was treated with FOLFOX and bevacizumab (oxaliplatin 70 mg/m2 , folinic acid 200 mg/m2 , 5-FU 340 mg/m2 bolus and 2040 mg/m2 continuous infusion during 44 hours and bevacizumab 5 mg/kg) every three weeks. Haemodialysis started immediately after infusion of oxaliplatin. The oxaliplatin dose was monitored by measuring free platinum ultrafiltrate concentrations. The AUC0-50 of free platinum plasma ultrafiltrate after cycles 1-3, respectively, was 24.3, 24.7 and 25.8 µg*h/mL. The Cmax was, respectively, 1.3, 1.3 and 2.2 µg/mL. There was no accumulation of free platinum detectable. The patient experienced no toxicity, and after 3 cycles, the CT scan showed a decrease in the liver metastases after which hemihepatectomy and metastasectomy were performed without any complications. A CT scan 6 months after the surgery showed no new liver metastases. However, lymphatic metastasis was diagnosed for which palliative treatment was started. WHAT IS NEW AND CONCLUSION: Dosing oxaliplatin in a haemodialysis patient monitored by free platinum concentrations was effective, safe and feasible in clinical practice. Further research is needed to determine the best pharmacokinetic parameter or combination of parameters and corresponding target values to further optimize the oxaliplatin dose for the individual haemodialysis patient.

[Treating poisoning; how do you choose the best type of gastrointestinal decontamination?] / De behandeling van vergiftigingen.

- A new guideline: 'Intoxication: initial approach in the hospital' will be published this year. This guideline sets out the latest insights on gastrointestinal decontamination in intoxication; the advice is summarized in a flowchart.- The advice is to generally administer activated charcoal, unless there are indications that the toxin will not bind to activated charcoal or that the amount of toxin that the patient has ingested is too great; in these cases gastric lavage can be considered.- Activated charcoal can be administered up to 2 hours after the ingestion of a toxic substance, unless there are contra-indications. Multiple-dose activated charcoal in combination with a laxative can be administered in cases of overdose with toxins that use the enterohepatic circulation (such as theophylline, carbamazepine, quinine, dapsone and phenobarbital).- Gastric lavage should be limited to extremely serious intoxication, when the substance has been ingested less than 1-2 hours previously.- Whole-bowel irrigation should not be performed routinely but should be limited to ingestion of toxins with sustained release or enteric coating, or for toxins that do not bind to activated charcoal.

Predictors for total hospital and cardiology cost claims among patients with atrial fibrillation initiating dabigatran or acenocoumarol in The Netherlands.

AIMS: The prevalence of atrial fibrillation (AF) has increased over the past years due to aging of the population, and healthcare costs associated with AF reflect a significant financial burden. The aim of this study was to explore predictors for the real-world AF-related in-hospital costs in patients that recently initiated anticoagulation with acenocoumarol or dabigatran. METHODS: Predictors for claimed total hospital care costs and cardiology costs in AF patients were explored by using hospital financial claims data from propensity score matched patient groups in a large Dutch community hospital. This study analyzed the total dataset (n = 766) and carried out a secondary analysis for all matched pairs of anticoagulation naïve AF patients (n = 590) by ordinal regression. RESULTS: Dabigatran was a predictor for significantly lower cardiology and total hospital care costs (Odds Ratio [OR] = 0.43, 95% confidence interval (CI) = 0.33-0.57; and OR = 0.60, 95% CI = 0.46-0.79, respectively). Female gender was a predictor for lower total hospital care costs. Predictors for an increase in total hospital care costs were the occurrence of stroke or systemic embolism, major bleeding, and minor bleeding. The costs predictors were comparable when limiting the analysis to patients that were anticoagulation naïve. Age and CHA2DS2-VASc were not predictors for either cardiology or total hospital care costs in both analyses. CONCLUSION: Dabigatran treatment was as a predictor for lower cardiology costs and lower total hospital care costs in AF patients that initiated oral anticoagulation.

[5-HT3-antagonists as a substitute for metoclopramide and domperidone: a literature review]. / 5-HT3-receptorantagonisten als vervangers van metoclopramide en domperidon.

OBJECTIVE: To investigate whether the anti-emetics metoclopramide and domperidone can be replaced by 5-HT3-antagonists, as side effects restrict use of these dopamine antagonists. DESIGN: Systematic review. METHOD: We searched the Embase and PubMed databases for articles published in the period 1995-October 2015, in which the efficacy or side effects of metoclopramide or domperidone were compared with at least one of the 5-HT3-antagonists ondansetron, granisetron, tropisetron or palonosetron. These had to be randomised controlled clinical studies into the known indications for metoclopramide and domperidone for prevention and treatment of nausea and vomiting. Two reviewers independently selected articles based on the title and abstract, then assessed for eligibility based on the full texts. RESULTS: In total, 56 articles were included in this review. The conclusion in 51 studies was that the efficacy of 5-HT3-antagonists in nausea and vomiting is comparable or even superior to that of metoclopramide. Metoclopramide more often caused extrapyramidal side effects; 5-HT3-antagonists were more likely to cause headaches and constipation. The majority of the studies compared metoclopramide with ondansetron. None of the articles studied palonosetron, and only one study compared domperidone with a 5-HT3-antagonist. CONCLUSION: We found enough evidence to presume that metoclopramide can be replaced by 5-HT3-antagonists for preventing delayed chemotherapy-induced nausea and vomiting and for prophylaxis or treatment of postoperative nausea and vomiting. More research is needed into the other indications and into the substitutability of domperidone.

Drug-drug interactions in patients treated for cancer: a prospective study on clinical interventions.

BACKGROUND: Drug-drug interactions (DDIs) are of major concern in oncology, since cancer patients typically take many concomitant medications. Retrospective studies have been conducted to determine the prevalence of DDIs. However, prospective studies on DDIs needing interventions in cancer patients have not yet been carried out. Therefore, a prospective study was designed to identify DDIs leading to interventions among ambulatory cancer patients receiving anticancer treatment. PATIENTS AND METHODS: Patients starting with a new treatment regimen with i.v. or oral anticancer medication were asked to participate. The patients' medication was checked for DDIs by using drug interaction software. An expert team of clinical pharmacologists evaluated the relevance of these identified DDIs. If a DDI was qualified as potentially clinically relevant, an intervention was proposed to the treating (hemato)oncologist. Several variables were studied as determinants for performing an intervention. Descriptive statistics and uni- and multivariate logistic regression analyses were carried out. RESULTS: In this study, 302 patients were included. A total of 603 DDIs were identified by the drug interaction software and judged by the expert team. Of all 603 DDIs, 120 DDIs were considered potentially clinically relevant. These 120 DDIs, present in a total of 81 patients, resulted in a clinical intervention already executed by the (hemato)oncologist in 39 patients (13%), while an additional intervention was proposed by a clinical pharmacologist in 42 patients (14%). The number of comorbidities and the number of 'over-the-counter' drugs were identified as determinants. CONCLUSIONS: Clinical interventions on DDIs are frequently required among patients starting with anticancer therapy. Structured screening for these potentially clinically relevant DDIs, by (hemato)oncologists in close collaborations with clinical pharmacologists, should take place before the start and during anticancer treatment. CLINICAL TRIALS NUMBER: This study was registered at the Dutch Trial Registry under number NTR3760.

Increase of baclofen intoxications: risks involved and management.

Baclofen has been increasingly used in the treatment of alcohol withdrawal syndrome (AWS). We present a patient with AWS and psychiatric comorbidity who ingested 700 mg of baclofen. ICU admission was necessary for ventilatory support and symptomatic treatment. The patient was dismissed without sequelae.

Prevalence of potential drug-drug interactions in cancer patients treated with oral anticancer drugs.

BACKGROUND: Potential drug-drug interactions (PDDIs) in patients with cancer are common, but have not previously been quantified for oral anticancer treatment. We assessed the prevalence and seriousness of potential PDDIs among ambulatory cancer patients on oral anticancer treatment. METHODS: A search was conducted in a computer-based medication prescription system for dispensing oral anticancer drugs to outpatients in three Dutch centres. Potential drug-drug interactions were identified using electronic (Drug Interaction Fact software) and manual screening methods (peer-reviewed reports). RESULTS: In the 898 patients included in the study, 1359 PDDIs were identified in 426 patients (46%, 95% confidence interval (CI)=42-50%). In 143 patients (16%), a major PDDI was identified. The drug classes most frequently involved in a major PDDI were coumarins and opioids. The majority of cases concerned central nervous system interactions, PDDIs that can cause gastrointestinal toxicity and prolongation of QT intervals. In multivariate analysis, concomitant use of more drugs (odds ratio (OR)=1.66, 95% CI=1.54-1.78, P<0001) and genito-urinary cancer (OR=0.25, 95% CI=0.12-0.52, P<0001) were risk factors. CONCLUSION: Potential drug-drug interactions are very common among cancer patients on oral cancer therapy. Physicians and pharmacists should be more aware of these potential interactions.

A randomised trial of honey barrier cream versus zinc oxide ointment.

In this single-blind multicentre, intervention study, 31 patients with symmetrical intertrigo in large skin folds were included to study the clinical effect of two topical treatments, i.e. standard therapy with zinc oxide ointment versus honey barrier cream. Patients were treated twice daily for 21 days, and the severity of intertrigo was scored in an observation period of 21 days. Patients were used as their own controls by treating symmetrical skin folds, on the left and right side. There was no significant difference in treatment effect between intervention groups. For the majority of patients, both treatments were effective. However, the use of honey barrier cream showed lower pruritus complaints (12.9% versus 29.0%). Honey barrier cream is a suitable alternative in the treatment of intertrigo, and promotes patient comfort.

Acute intoxication patients presenting to an emergency department in The Netherlands: admit or not? Prospective testing of two algorithms.

STUDY OBJECTIVE: After acute intoxication, most patients presenting to the emergency department (ED)--76% of them in The Netherlands--are admitted to hospital. Many will not need medical treatment on the ward. The authors tested two algorithms in the ED, based on vital parameters, ECG findings, and ingested substances, to identify patients who will receive treatment in hospital. METHODS: This prospective inception study enrolled patients aged 14 years and older presenting with acute intoxication between January 2006 and April 2008 to a Dutch university hospital. An algorithm was developed based on a previous retrospective study and the medical literature. In a second algorithm the clinical course during the stay in the ED was also taken into account. RESULTS: Of 313 patients presenting with acute intoxication to the ED, 134 (42.8%) were admitted to a ward for somatic care, but only 74 (23.6%) were treated on the ward. Algorithm 1 had 91.9% sensitivity (95% CI 82.6% to 96.7%) and 53.6% specificity (95% CI 47.0% to 60.0%). Algorithm 2 had 90.5% sensitivity (95% CI 80.9% to 95.8%) and 65.3% specificity (95% CI 58.8% to 71.2%). In line with hospital policy, several patients received N-acetylcysteine treatment for subtoxic paracetamol ingestion because they presented outside of office hours, when no measurements of blood paracetamol concentration are performed by the laboratory. When these patients are considered as untreated, both algorithms had 98.5% sensitivity (95% CI 90.6% to 99.9%). CONCLUSION: The algorithms had good sensitivity and better specificity than current clinical practice in most hospitals. It is too early to advocate their implementation, but results indicate that it is possible to use clinical parameters objectively to reduce unnecessary admissions to the ward.

[A patient who refused treatment after self-poisoning with paracetamol]. / Een patiënt die na een auto-intoxicatie met paracetamol behandeling weigert.

Two patients, a 20-year-old man and a 33-year-old woman, were admitted with paracetamol poisoning. Both patients refused treatment initially but eventually complied. The man had a paracetamol concentration of 47.5 mg/l 2.5-5.0 h after ingestion, so antidote treatment was not considered necessary. The woman had a paracetamol concentration of 1.37 mg/l 32 h after ingestion and elevated liver enzymes and was treated with N-acetylcysteine intravenously. Both patients recovered. When a patient refuses treatment, the physician must judge whether the patient is capable of making that decision by himself or herself. In the acute setting of attempted suicide, the patient is either incapable of deciding or there is not enough time to make a proper judgement. This means that consent for treatment should be sought from a legal representative of the patient. If this is impossible and treatment is necessary to prevent serious harm, the physician must judge whether the advantages of treatment outweigh the disadvantages of enforced treatment. If this is the case, as in serious paracetamol poisoning, the patient must be treated against their will, even if it requires sedation.