Norwegian adolescents' use of energy drinks and painkillers and misuse of prescription drugs prior to and during the initial COVID-19 pandemic year: Evidence from the MyLife study.

AIMS: This study aimed to examine and compare the use of energy drinks, over-the-counter (OTC) painkillers and misuse of prescription drugs in two cohorts of Norwegian adolescents entering high school (i.e. grade 11) immediately prior to and during the initial year of the COVID-19 pandemic. METHODS: Accelerated longitudinal design and multi-cohort sampling enabled identification of the two socio-demographically comparable cohorts of grade 11 students: (a) COVID-19 cohort assessed in the autumn of 2020 (n=915) and (b) pre-COVID-19 cohort assessed in the autumn of 2018/19 (n=1621). Unadjusted and adjusted logistic and Poisson models were used to estimate the proportion of (mis)users and use frequencies among (mis)users in two cohorts. RESULTS: Energy drinks use was both more common in the COVID-19 cohort (60.8% vs. 52.5%; adjusted odds ratio=1.40, 95% confidence interval (CI) 1.18-1.66, p<0.001) and more frequent among users from this cohort than among their pre-COVID-19 counterparts (9.58 vs. 7.79 days past month, adjusted incidence risk ratio (aIRR)=1.23, 95% CI 1.14-1.32, p<0.001). No cohort differences were observed in OTC painkillers use. Prescription drugs misuse was equally common in the two cohorts but was more frequent among misusers from the COVID-19 cohort than among their pre-COVID-19 counterparts (18.94 vs. 12.45 times past year, aIRR=1.52, 95% CI 1.10-2.10, p<0.001). CONCLUSIONS: Norwegian adolescents from the COVID-19 cohort were more likely to use energy drinks and, once engaged in these behaviours, to use energy drinks and misuse prescription drugs more frequently than their pre-COVID-19 counterparts.

Screen-Printed Voltammetric Sensors-Tools for Environmental Water Monitoring of Painkillers.

The dynamic production and usage of pharmaceuticals, mainly painkillers, indicates the growing problem of environmental contamination. Therefore, the monitoring of pharmaceutical concentrations in environmental samples, mostly aquatic, is necessary. This article focuses on applying screen-printed voltammetric sensors for the voltammetric determination of painkillers residues, including non-steroidal anti-inflammatory drugs, paracetamol, and tramadol in environmental water samples. The main advantages of these electrodes are simplicity, reliability, portability, small instrumental setups comprising the three electrodes, and modest cost. Moreover, the electroconductivity, catalytic activity, and surface area can be easily improved by modifying the electrode surface with carbon nanomaterials, polymer films, or electrochemical activation.

Novel evidence on the effect of tramadol on self-paced high-intensity cycling.

The use of tramadol is a controversial topic in cycling. In order to provide novel evidence on this issue, we tested 29 participants in a pre-loaded cycling time trial (TT; a 20-min TT preceded by 40-min of constant work-rate at 60% of the VO2max) after ingesting 100 mg of tramadol (vs placebo and paracetamol (1.5 g)). Participants performed the Psychomotor Vigilance Task (PVT) at rest and a Sustained Attention to Response Task (SART) during the 60 min of exercise. Oscillatory electroencephalography (EEG) activity was measured throughout the exercise. The results showed higher mean power output during the 20-min TT in the tramadol vs. paracetamol condition, but no reliable difference was reported between tramadol and placebo (nor paracetamol vs. placebo). Tramadol resulted in faster responses in the PVT and higher heart rate during exercise. The main effect of substance was reliable in the SART during the 40-min constant workload (no during the 20-min TT), with slower reaction time, but better accuracy for tramadol and paracetamol than for placebo. This study supports the increased behavioural and neural efficiency at rest for tramadol but not the proposed ergogenic or cognitive (harmful) effect of tramadol (vs. placebo) during self-paced high-intensity cycling.

Opioid Receptors and Protonation-Coupled Binding of Opioid Drugs.

Opioid receptors are G-protein-coupled receptors (GPCRs) part of cell signaling paths of direct interest to treat pain. Pain may associate with inflamed tissue characterized by acidic pH. The potentially low pH at tissue targeted by opioid drugs in pain management could impact drug binding to the opioid receptor, because opioid drugs typically have a protonated amino group that contributes to receptor binding, and the functioning of GPCRs may involve protonation change. In this review, we discuss the relationship between structure, function, and dynamics of opioid receptors from the perspective of the usefulness of computational studies to evaluate protonation-coupled opioid-receptor interactions.

Epidemiological Characteristics of Sedative-Hypnotics and Opioid Painkillers at High-Frequency Exposure. / é«˜é¢‘æš´éœ²å‚¬çœ é•‡é™è¯åŠé˜¿ç‰‡ç±»é•‡ç—›è¯çš„æµè¡Œç— å­¦ç‰¹ç‚¹.

Drug poisoning has a high incidence and serious consequences in medical institutions; its epidemiological characteristics also directly affect the changes in national laws and policies and the implementation of local management policies. Chinese statistics on drug-related abnormal death cases generally come from judicial appraisal centers and medical units. However, due to differences in work content and professional restrictions, there are differences in information management forms, which makes it difficult for appraisers to conduct a professional and systematic analysis of drug-related cases. This article focuses on the analysis of epidemiological characteristics of sedative-hypnotics and opioid painkillers and their exposure patterns in cases of poisoning death by analyzing the annual report of the American Association of Poison Control Center, combined with the characteristics of drug exposure in China.

Misuse of prescribed opioids in the United States.

PURPOSE: To assess the prevalence and correlates of self-reported misuse of prescribed-opioid medications in the US general population. METHOD: In 31 068 adult participants of the National Survey on Drug Use and Health (NSDUH) 2015 and 2016 who reported using opioids in the past year, we assessed the prevalence and correlates of self-reported misuse of prescribed opioids, defined as using a larger dose, more frequently, or longer than prescribed. Multivariable logistic-regression models and the machine-learning method of boosted regression were used to identify the correlates of misuse. RESULTS: On the basis of weighted NSDUH estimates, of more than 89 million US adults who used prescription opioids every year, close to 3.9 million (4.4%) reported misused the prescribed medications. Prescribed-opioid misuse was most strongly associated with co-occurring misuse of opioids without a prescription, misuse of benzodiazepines, other drug-use disorders, history of illegal activity, and psychological distress. Misuse of prescribed opioids was also strongly associated with prescription opioid-use disorder, especially among those who misused more potent opioids or started misusing opioids before the current year. CONCLUSIONS: Misuse of prescribed opioids is associated with other high-risk behaviors and adverse health outcomes. The findings call for better monitoring of opioid prescription in clinical practice.

Do painkillers serve as "hillbilly heroin" for rural adults with high levels of psychosocial stress?

Nonmedical use of painkillers has increased in recent years, with some authors suggesting that painkillers serve as "hillbilly heroin": a drug chosen by rural adults to cope with psychosocial stresses in their lives. The present study compared rural and urban adults for their reported use of 5 drugs during the past year (painkillers, marijuana, cocaine, methamphetamine, heroin) and for associations between these 5 drugs and their reported psychosocial stressors. This study conducted secondary analyses of anonymous survey data provided by the 2014 National Survey on Drug Use and Health with responses from 8,699 rural and 18,481 urban adults. The survey included demographics (gender, age, race, education, marital status, family income), reports of whether participants had used each of 5 illicit drugs during the past year, and measures of psychological distress and social functioning problems. Controlling for demographics, rural adults showed no greater prevalence of painkiller use than urban adults, but rural adults were more likely than urban adults to use methamphetamine and less likely to use marijuana, cocaine, and heroin. Controlling for demographics, rural adults showed no associations between psychological or social stressors and the use of painkillers, but such stressors were significantly associated with the use of marijuana, methamphetamine, and heroin. Urban adults showed significant associations of psychological and social stressors with the use of painkillers, as well as with the use of marijuana, cocaine, and heroin. Results suggest that painkillers are unlikely to serve as "hillbilly heroin" for rural adults, but they may serve as "big-city heroin" for urban adults.

Low-dose naltrexone and opioid consumption: a drug utilization cohort study based on data from the Norwegian prescription database.

PURPOSE: Low-dose naltrexone (LDN) is used in a wide range of conditions, including chronic pain and fibromyalgia. Because of the opioid antagonism of naltrexone, LDN users are probably often warned against concomitant use with opioids. In this study, based on data from the Norwegian prescription database, we examine changes in opioid consumption after starting LDN therapy. METHODS: We included all Norwegian patients (N = 3775) with at least one recorded LDN prescription in 2013 and at least one dispensed opioid prescription during the 365 days preceding the first LDN prescription. We allocated the patients into three subgroups depending on the number of collected LDN prescriptions and recorded the number of defined daily doses (DDDs) on collected prescriptions on opioids, nonsteroidal anti-inflammatory drugs and other analgesics and antipyretics from the same patients. RESULTS: Among the patients collecting ≥4 LDN prescriptions, annual average opioid consumption was reduced by 41 DDDs per person (46%) compared with that of the previous year. The reduction was 12 DDDs per person (15%) among users collecting two to three prescriptions and no change among those collecting only one LDN prescription. We observed no increase in the number of DDDs in nonsteroidal anti-inflammatory drugs or other analgesics and antipyretics corresponding to the decrease in opioid use. CONCLUSIONS: Possibly, LDN users avoided opioids because of warnings on concomitant use or the patients continuing on LDN were less opioid dependent than those terminating LDN. Therapeutic effects of LDN contributing to lower opioid consumption cannot be ruled out. © 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.

Is the New Heroin Epidemic Really New? Racializing Heroin.

Heroin abuse as an outcome of the prior use of painkillers increased rapidly over the past decade. This "new epidemic" is unique because the new heroin users are primarily young White Americans in rural areas of virtually every state. This commentary argues that the painkiller-to-heroin transition could not be the only cause of heroin use on such a scale and that the new and old heroin epidemics are linked. The social marketing that so successfully drove the old heroin epidemic has innovated and expanded due to the use of cell-phones, text messaging and the "dark web" which requires a Tor browser, and software that allows one to communicate with encrypted sites without detection. Central city gentrification has forced traffickers to take advantage of larger and more lucrative markets. A second outcome is that urban black and Latino communities are no longer needed as heroin stages areas for suburban and exurban illicit drug distribution. Drug dealing can be done directly in predominantly white suburbs and rural areas without the accompanying violence associated with the old epidemic. Denial of the link between the new and old heroin epidemics racially segregates heroin users and more proactive prevention and treatment in the new epidemic than in the old. It also cuts off a half-century of knowledge about the supply-side of heroin drug dealing and the inevitable public policy measures that will have to be implemented to effectively slow and stop both the old and new epidemic.

Experience of the use of Ketamine to manage opioid withdrawal in an addicted woman: a case report.

BACKGROUND: Opioids are good painkillers, but many patients treated with opioids as painkillers developed a secondary addiction. These patients need to stop misusing opioids, but the mild-to-severe clinical symptoms associated with opioid withdrawal risk increasing their existing pain. In such cases, ketamine, which is used by anaesthetists and pain physicians to reduce opioid medication, may be an effective agent for managing opioid withdrawal. CASE PRESENTATION: We describe the case of a woman who developed a severe secondary addiction to opioids in the context of lombo-sciatic pain. She presented a severe opioid addiction, and her physicians refused to prescribe such high doses of opioid treatment (oxycontin® extended-release 120 mg daily, oxycodone 60 mg daily, and acetaminophen/codeine 300 mg/25 mg 6 times per day). To assist her with her opioid withdrawal which risked increasing her existing pain, she received 1 mg/kg ketamine oral solution, and two days after ketamine initiation her opioid treatment was gradually reduced. The patient dramatically reduced the dosage of opioid painkillers and ketamine was withdrawn without any withdrawal symptoms. CONCLUSION: Ketamine displays many interesting qualities for dealing with all symptoms relating to opioid withdrawal. Accordingly, it could be used instead of many psychotropic treatments, which interact with each other, to help with opioid withdrawal. However, the literature describes addiction to ketamine. All in all, although potentially addictive, ketamine could be a good candidate for the pharmacological management of opioid withdrawal.

Pharmacovigilance, risks and adverse effects of self-medication.

Self-medication means resorting to one or more drugs in order to treat oneself without the help of a doctor. This phenomenon is developing fast. In this review, we will discuss the main definitions of self-medication; we will then present a few important characteristics of this therapeutic practice: prevalence, reasons, populations involved and drugs used. Whilst the theoretical risks of self-medication have been abundantly discussed in the literature (adverse effects, interactions, product, dosage or treatment duration errors, difficulty in self-diagnosis, risk of addiction or abuse…), there is in fact very little detailed pharmacovigilance data concerning the characteristics and the consequences of this usage in real life. This study therefore describes the all too rare data that is available: patients, clinical characteristics, "seriousness" and drugs involved in the adverse effects of self-medication. It also discusses leads to be followed in order to minimize medication risks, which are obviously not well known and clearly not sufficiently notified.

Psychosocial characteristics of the general population who habitually use hypnotics: Results from a national survey on drug use among the Japanese.

Aim: The aim of this study was to examine the characteristics of habitual hypnotic users in Japan. Methods: This nationwide, cross-sectional survey used self-administered questionnaires. Data were collected from four national surveys conducted every 2 years between 2015 and 2021. The participants were Japanese individuals who had taken prescription hypnotics in the past year or had never taken them. We divided 13,396 participants into three groups to compare the social background and status of taking medication and controlled drugs, drinking, and smoking among the three groups: people who use hypnotics habitually daily (habitual hypnotic users [HUs]), people who use them only occasionally (occasional hypnotic users [OUs]), and people who do not use them (hypnotic non-users [NUs]). We compared the perception of using hypnotics between the HU and OU groups. Results: HUs were more likely to be older, unemployed, and to habitually use anxiolytics and analgesics than NUs. The main reasons for taking anxiolytics in HUs were alleviating insomnia and reducing anxiety, whereas the main reason for taking analgesics was improving joint pain. Additionally, the HU group had a higher proportion of habitual smokers than the OU group. There was no difference in drinking status or taking of controlled drugs among the three groups. HUs were more likely to use hypnotics and to have concerns about their side-effects than OUs. Conclusion: HUs were more likely to be unemployed, habitually use anxiolytics and analgesics, smoke heavily, and take hypnotic drugs with concerns regarding side-effects. These results may help encourage the appropriate use of hypnotics.

Assessment of Preferences in Taking Painkillers among Students of Medicine, Dentistry, and Pharmacy: A Pilot Study.

Students of pharmacy, medicine, and dentistry are important for shaping drug policy. The aim of this study is to assess and compare students preferences in taking painkillers. The study group consists of 382 students of pharmacy (28.8%), medicine (40.0%), and dentistry (30.1%). An anonymous questionnaire consisting of 17 questions was prepared using the Google Forms platform and distributed through social media. Ibuprofen was the most frequently preferred, regardless of the study major (57.8%). Pharmacy students expressed the least concern about the possible side effects of analgesics (17.5%). The fast onset of painkillers was more important for dental students (59.1%) and pharmacy students (44.7%), compared to medical students (39.22%). Medicine and pharmacy students indicated their studies to be their main source of information about painkillers compared to dentistry students (p = 0.001). There are no differences in pain severity regarding which analgesics are used among student groups (p = 0.547). Dental students experienced odontogenic pain less frequently (57.3%) than medical (79.7%) and pharmacy students (79.8%), (p = 0.000). Ketoprofen was the most frequently chosen prescription painkiller for odontogenic pain in all groups (49.4%). Gastrointestinal complaints were the most often reported side effects, regardless of the study major (87.1%). Choice of studies, gender, and year of study were the most important determinants of the choice of painkillers.

Comparative effectiveness of endoscopic plantar fasciotomy, needle knife therapy, and conventional painkillers in the treatment of plantar fasciitis: a real-world evidence study.

Plantar fascia (PF) is the commonest causes of foot pain in the adult population. Several surgical treatments are available to treat PF. This study was aimed to investigate the clinical efficacy of three different treatments for plantar fasciitis. It was conducted among 60 patients, divided equally into three treatment groups named Needle Knife Therapy, Endoscopic Plantar Fasciotomy, and Conventional Painkillers. Descriptive and analytical analysis were done by using SPSS 25 software. VAS and AOFAS scores were analyzed. The maximum (n = 31) participants were in 41-60 year age range group with normal BMI. These differences of mean VAS and AOFAS pain scores between different treatment groups were statistically significant (One-way ANOVA, p < 0.01). Both scores found lower in the Endoscopic Plantar Fasciotomy group. This study opens a new window of knowledge to achieve sustained pain relief and functional improvement. Moreover, the superiority of Endoscopic Plantar Fasciotomy in treating plantar fasciitis compared to Needle Knife Therapy and Conventional Painkillers was explored.

Prescription Patterns of Analgesic Drugs in the Management of Pain Among Palliative Care Patients at a Tertiary Hospital in Oman: A Retrospective Observational Study.

Objectives Analgesic drugs are commonly used to alleviate the pain experienced by palliative care (PC) patients. Thus, we sought to determine the prescription patterns of analgesic drugs in the management of pain among haematology and oncology palliative care patients at Sultan Qaboos University Hospital (SQUH) and then see if they were following the World Health Organization (WHO) guidelines. Methods A retrospective observational cross-sectional study was conducted, and adult PC patients prescribed analgesics for pain relief between January 2018 and January 2021 at SQUH constituted the sample. Data were collected from patients' electronic medical records using the SQUH TrakCare system. The data was then presented descriptively using graphs and tables. Results Data from 200 PC patients were analyzed. Breast cancer was the most common malignancy, with 73 (36.5%) patients diagnosed with it. Severe pain was the most reported degree of pain, with exactly 100 (50.0%) patients experiencing it. More patients experienced mild pain than moderate pain. Opioids were the most prescribed analgesics, followed by analgesics and antipyretics, anticonvulsants, and finally non-steroidal anti-inflammatory drugs (NSAIDs). Paracetamol was the most prescribed analgesic for pain overall, with 127 (63.5%) patients utilizing it. For severe pain, morphine was the most prescribed analgesic, with 65.0% of patients using it. Fentanyl and pregabalin, the strongest two analgesics, increased in prescription for severe pain compared to mild and moderate pain, with both being prescribed to 23.0% of patients suffering from severe pain. The oral route of administration was the most prescribed, with 128 (64.0%) utilizing it. Conclusion This study showed the prescription patterns of analgesic drugs for palliative care patients at SQUH. The findings were similar to those of other studies, though there were some differences. The prescription patterns of analgesic drugs prescribed for the various pain levels among PC patients were found to be in accordance with the WHO guidelines.

A comprehensive painkillers screening by assessing zebrafish behaviors after caudal fin amputation.

Recently, the usage of zebrafish for pain studies has increased in the past years, especially due to its robust pain-stimulated behaviors. Fin amputation has been demonstrated to induce a noxious response in zebrafish. However, based on the prior study, although lidocaine, the most used painkiller in zebrafish, has been shown to ameliorate amputated zebrafish behaviors, it still causes some prolonged effects. Therefore, alternative painkillers are always needed to improve the treatment quality of fin-amputated zebrafish. Here, the effects of several analgesics in recovering zebrafish behaviors post-fin amputation were evaluated. From the results, five painkillers were found to have potentially beneficial effects on amputated fish behaviors. Overall, these results aligned with their binding energy level to target proteins of COX-1 and COX-2. Later, based on their sub-chronic effects on zebrafish survivability, indomethacin, and diclofenac were further studied. This combination showed a prominent effect in recovering zebrafish behaviors when administered orally or through waterborne exposure, even with lower concentrations. Next, based on the ELISA in zebrafish brain tissue, although some changes were found in the treated group, no statistical differences were observed in most of the tested biomarkers. However, since heatmap clustering showed a similar pattern between biochemical and behavior endpoints, the minor changes in each biomarker may be sufficient in changing the fish behaviors.

Utilization of Over-the-Counter Painkillers Among Medical Students During Academic Examinations.

The utilization of over-the-counter (OTC) painkillers among medical students during academic exams has raised concerns about health risks and potential implications, including substance abuse and academic performance. This cross-sectional study aimed to estimate the prevalence of OTC painkiller utilization among medical students at Alfaisal University during academic exams. Additionally, the study explored and identified the factors that influenced the patterns of OTC painkiller utilization among these students. The study was conducted from January to May 2023, following approval from the Institutional Review Board. The research involved surveying medical students of different genders, nationalities, and academic years during examination periods. Out of 1,500 medical students, 194 participated, resulting in a response rate of approximately 13%. The study results revealed that 50.5% of medical students used OTC painkillers during exams. While there were no significant variations based on gender or nationality, the prevalence of OTC painkiller utilization varied significantly across academic years. During exam periods, the primary reason reported for using OTC painkillers was pain management. Additionally, some students mentioned using OTC painkillers to seek relaxation, improve sleep, enhance concentration, and stay alert. These insights shed light on the coping strategies practiced by students during high-stress academic periods. Most participants demonstrated familiarity with the guidelines for safe OTC painkiller utilization. Although the majority used painkillers infrequently or as needed, a subgroup reported increased utilization during exams. This finding highlights the importance of continuous monitoring and health education initiatives to prevent or address potential OTC painkiller abuse among medical students during exam periods. Ensuring the well-being of medical students is a priority, and appropriate measures should be employed to address any emerging concerns related to substance abuse. By addressing these issues proactively, educational institutions can promote a healthier academic environment during exam periods.

New Generation Gepants: Migraine Acute and Preventive Medications.

Migraine is a debilitating disease whose clinical and social impact is out of debate. Tolerability issues, interactions, contraindications, and inefficacy of the available medications make new options necessary. The calcitonin-gene-related peptide (CGRP) pathway has shown its importance in migraine pathophysiology and specific medications targeting this have become available. The first-generation CGRP receptor antagonists or gepants, have undergone clinical trials but their development was stopped because of hepatotoxicity. The new generation of gepants, however, are efficacious, safe, and well tolerated as per recent clinical trials. This led to the FDA-approval of rimegepant, ubrogepant, and atogepant. The clinical trials of the available gepants and some of the newer CGRP-antagonists are reviewed in this article.

Burden of opioid use for pain management among adult herpes zoster patients in the US and the potential impact of vaccination.

PLAIN LANGUAGE SUMMARYWhat is the context? Herpes zoster or shingles and its complications such as postherpetic neuralgia - a painful condition that affects the nerve fibers and skin - may lead to complex pain that can be addressed using opioids in some patients.The recombinant zoster vaccine (RZV) vaccine prevents shingles and, therefore, may reduce the use of opioids and the negative health outcomes and costs associated with it.What is new? In this retrospective medical claims study, including patients between 2012 and 2017, we evaluated the receipt of pain medication including opioids in herpes zoster patients, and assessed factors associated with opioid prescription.estimated health care resource utilization and costs associated with opioid use among patients with herpes zoster.assessed the impact of vaccination on opioid prescriptions.Among subjects receiving opioids, 78.5% started with a weak opioid dose. Dose escalation was uncommon.Postherpetic neuralgia, immunocompromised status, and comorbidities are the main risk factors associated with opioid prescription.Health care costs are almost double in patients with herpes zoster receiving opioids compared with patients without an opioid prescription.In a population of 1 million adults aged 50 years or older, vaccination with the recombinant zoster vaccine could prevent over 19,000 patients from receiving opioids.What is the impact? Prevention of herpes zoster through vaccination may be a highly effective strategy to reduce opioid prescriptions and costs related to pain management in a susceptible population.Increasing RZV vaccination coverage in adults aged ≥50 years may further reduce potential opioid prescriptions through a decrease in shingles incidence.

Molecular monitoring of patient response to painkiller drugs.

INTRODUCTION: Non-steroidal anti-inflammatory drugs and opioids are widely prescribed for the treatment of mild to severe pain. Wide interindividual variability regarding the analgesic efficacy and adverse reactions to these drugs (ADRs) exist although the mechanisms responsible for these ADRs are not well understood. AREAS COVERED: We provide an overview of the clinical impact of variants in genes related to the pharmacokinetics and pharmacodynamics of painkillers, as well as those associated with the susceptibility to ADRs. In addition, we discuss the current pharmacogenetic-guided treatment recommendations for the therapeutic use of non-steroidal anti-inflammatory drugs and opioids. EXPERT OPINION: In the light of the data analyzed, common variants in genes involved in pharmacokinetic and pharmacodynamic processes may partially explain the lack of response to painkiller treatment and the occurrence of adverse drug reactions. The implementation of high-throughput sequencing technologies may help to unveil the role of rare variants as considerable contributors to explaining the interindividual variability in drug response. Furthermore, a consensus between the diverse pharmacogenetic guidelines is necessary to extend the implementation of pharmacogenetic-guided prescription in daily clinical practice. Additionally, the physiologically based pharmacokinetic and pharmacodynamic modeling techniques may contribute to the improvement of these guidelines and facilitate clinician drug dose adjustment.