Deprescribing NSAIDs: The Potential Role of Community Pharmacists.

Non-steroidal anti-inflammatory drugs (NSAIDs) are largely used for controlling various pain conditions and are widely available in community pharmacies, with and without prescription. Despite their effectiveness, NSAIDs can pose significant risks due to potential side effects and drug interactions, particularly in polypharmacy and comorbidity contexts and for vulnerable users. This study investigated whether and how NSAIDs deprescribing can be conducted at the community pharmacy level by assessing pharmacists' confidence, attitudes, and potential barriers and facilitators. Additionally, we aimed to identify any deprescribing guidelines that pharmacists could use. A literature search and a cross-sectional digital questionnaire targeting community pharmacists in Norway were conducted. Results showed that study participants (N = 73) feel confident in identifying needs for deprescribing NSAIDs but barriers such as time constraints, lack of financial compensation, and communication challenges were noted. Participants reported positive attitudes toward deprescribing but highlighted a need for better guidelines and training. This study highlights a gap in specific guidelines for deprescribing NSAIDs and a potential for enhancing pharmacists' roles in the deprescribing process, for example, through training and improved financial incentives. Further research is encouraged to develop concrete strategies for an effective implementation where community pharmacists can be involved in the deprescribing of NSAIDs.

Social Media Use and Consumption of Prescription-Free Medications for Anxiety, Sleep, and Pain among Norwegian University Students.

A relationship has been recognized between social media use and health issues. However, no studies have explored the potential link between social media use and consumption of over-the-counter (OTC) medications. We examined social media use, self-reported anxiety, depression, sleep problems, pain, and OTC medications use among Norwegian university students. The goal was to gain insights that would guide preventive health strategies for this target group. A quantitative, cross-sectional study was conducted with an online questionnaire distributed to university student Facebook groups in Norway. A total of 132 completed surveys were analyzed. Among the respondents, 28% experienced anxiety, 35% depression, 64% sleep problems, 71% headaches, and 78% musculoskeletal pain. Moreover, 56% reported using OTC analgesics or sleep aids, mostly purchased from community pharmacies. No statistically significant correlation was found between social media use and headache, musculoskeletal pain, sleep disturbances, or consumption of OTC medications among university students in Norway. The findings, however, demonstrated a positive trend, highlighting the need for further research with larger, more diverse samples, and potentially employing a qualitative or longitudinal design. We propose increased awareness of the potential negative effects of social media among university students, the inclusion of social media and health topics in study curricula, and the more proactive engagement of community pharmacists with young clients concerning the consumption of OTC medications.

The Brain, the Eating Plate, and the Gut Microbiome: Partners in Migraine Pathogenesis.

This review summarizes the relationship between diet, the gut microbiome, and migraine. Key findings reveal that certain dietary factors, such as caffeine and alcohol, can trigger migraine, while nutrients like magnesium and riboflavin may help alleviate migraine symptoms. The gut microbiome, through its influence on neuroinflammation (e.g., vagus nerve and cytokines), gut-brain signaling (e.g., gamma-aminobutyric acid), and metabolic function (e.g., short-chain fatty acids), plays a crucial role in migraine susceptibility. Migraine can also alter eating behaviors, leading to poor nutritional choices and further exacerbating the condition. Individual variability in diet and microbiome composition highlights the need for personalized dietary and prebiotic interventions. Epidemiological and clinical data support the effectiveness of tailored nutritional approaches, such as elimination diets and the inclusion of beneficial nutrients, in managing migraine. More work is needed to confirm the role of prebiotics, probiotics, and potentially fecal microbiome translation in the management of migraine. Future research should focus on large-scale studies to elucidate the underlying mechanisms of bidirectional interaction between diet and migraine and develop evidence-based clinical guidelines. Integrating dietary management, gut health optimization, and lifestyle modifications can potentially offer a holistic approach to reducing migraine frequency and severity, ultimately improving patient outcomes and quality of life.

Exploring the Role of Community Pharmacists in Pain Management: Enablers and Challenges.

Pain is a common complaint, and the consumption of analgesics is prevalent. Community pharmacists, as primary contact points for patients, can play a crucial role in guiding patients toward rational pharmacotherapy or alternative pain management strategies. However, there are no specific educational curricula or standard guidelines to support this role, and the perception of this potential role is not well known. We conducted an anonymous online questionnaire among community pharmacists in Norway to assess their knowledge, perspectives, and willingness to engage in pain care. The survey also explored potential facilitators and barriers, and the use of any current guidelines. Seventy-one community pharmacists participated from various regions in Norway. Findings revealed that community pharmacists felt knowledgeable and willing to engage in pain management but anticipated barriers such as time constraints and a lack of standard guidelines. Participants also highlighted the need for better collaboration with other healthcare professionals and continuous professional development to enhance their role. To optimize the role of community pharmacists in pain management, therefore, integrating them into multidisciplinary healthcare teams, minimizing barriers, and providing continuous education and standard guidelines seem essential. This approach can empower community pharmacists and improve pain management outcomes.

A Preservative-Free Approach - Effects on Dry Eye Signs and Symptoms After Cataract Surgery.

Purpose: To compare the effect of treatment with preservative-free dexamethasone, NSAIDs and trehalose/hyaluronic acid eye drops with the preservative benzalkonium chloride containing dexamethasone and NSAIDs after cataract surgery in dry versus non-dry eyes. Patients and Methods: In this prospective randomized intervention study, dry eye tests were performed before and 6 weeks after cataract surgery. Patients were considered as having dry eye, SDE (sign of dry eye), if at least one of the following dry eye tests were abnormal; corneal fluorescein staining (CFS), non-invasive keratograph breakup time (NIKBUT) or tear osmolarity. Patients with SDE were randomly assigned to one of two groups. Group 1 patients were treated with dexamethasone and bromfenac eye drops with the preservative benzalkonium chloride (BAC). Group 2 patients were treated with preservative-free dexamethasone and preservative-free diclofenac, as well as a preservative-free lubricant with trehalose and hyaluronic acid both before and after surgery. Patients with normal tear film status acted as the control group (group 3) and received same treatment as group 1. Results: A total of 215 patients were enrolled six weeks after surgery, the number of patients with SDE decreased significantly in groups 1 and 2 (p <0.001). Subjective symptoms and objective measures including osmolarity, NIKBUT, CFS, and tear film thickness (TFT) improved after surgery, tear production remained unchanged, while corneal sensitivity and meibomian gland dysfunction (MGD) parameters worsened. In the control group with normal tear-film status, SDE increased significantly after the surgery (p <0.001). There were no statistically significant differences in tear film parameters between the three groups after surgery. Conclusion: After cataract surgery, patients with mild to moderate dry eyes may experience improved tear film status and reduced symptoms. However, we found no additional beneficial effect on dry eye parameters with treatment with preservative-free dexamethasone, NSAIDs, and lubricants compared to preservative-containing eye drops.

Social Prescribing Competence among Community Pharmacists and Pharmacy Students in Norway.

Background and aim: Social prescribing, which links patients to non-clinical services and involves general physicians, has been gaining traction. Community pharmacists, who are integral to primary healthcare, have untapped potential in social prescribing. This study explores social prescribing competence among Norwegian community pharmacists and pharmacy students. Method: A cross-sectional study utilizing an anonymous online questionnaire to collect quantitative data was conducted. Inspired by the limited relevant literature, the questionnaire was constructed, pilot-tested, and distributed in a one-week window within a Facebook group for Norwegian pharmacists. The questionnaire comprised 23 questions categorized into demographic details and competence assessment, covering general knowledge, attitude, and barriers/facilitators related to social prescribing. Statistical analyses were employed to determine the competence of the participants. Results: The online questionnaire collected data from 96 participants, primarily females (79.2%), aged 25-34 (40.6%), who were identified as community pharmacists (49.0%). Most (91.7%) worked in community pharmacies, with 31.3% having over 10 years of experience. Despite positive client relationships (93.8%), statistical analysis revealed no significant associations between competence and variables such as work experience, education, or gender. The custom scoring system yielded an average competence score of 1.98 on a 5-point scale, with attitudes and perceptions of participants scoring 3.82. Overall competence was calculated at 3.4, indicating a moderate level. Conclusions: The findings of this study reveal that the participants had limited knowledge regarding social prescribing, emphasizing the need for education. However, the participants showed strong enthusiasm for competence development. This groundwork paves the way for future investigations centered on pilot-testing strategies to boost social prescribing knowledge and engagement among Norwegian community pharmacists and pharmacy students.

Diet and migraine: what is proven?

PURPOSE OF REVIEW: The purpose of this review is to present the latest research findings about diet and migraine, what can be used in the clinic now, and what needs further investigation. RECENT FINDINGS: Recent findings highlight that dietary triggers exist for migraine, for example, coffee and alcohol, according to a new systematic review. Elimination diets must be personalized to delineate a balanced diet with acceptable quality and pattern. A piece of average-quality evidence shows that the ketogenic diet (KD) and the Dietary Approaches to Stop Hypertension (DASH) are effective in reducing the frequency, duration, and severity of migraine headaches in adult patients. The gut microbiome is altered in patients with migraine, and further research will identify the benefits of pre and probiotic use for migraine. Advanced digital technology in continuous monitoring can provide educational content based on patients' needs, help patients adhere to dietary plans, and strengthen personalized care. The complex interaction of lifestyle factors, the influence of age and sex, and patients' needs in various life phases are essential in formulating dietary plans. SUMMARY: The diet-migraine interaction is a dynamic bidirectional phenomenon that requires careful monitoring, review, and justification of dietary choices to yield the optimal outcome while minimizing potential risks.

Is Burning Mouth Syndrome Associated with Extraoral Dryness? A Systematic Review.

Burning mouth syndrome (BMS) is characterized by a persistent intraoral burning sensation, often experienced by postmenopausal women. The etiology of BMS remains partially understood, and consequently, treatments remain suboptimal. Extraoral manifestations of BMS, such as extraoral dryness, are less studied. However, it has been suggested that the identification of the frequency and patterns of extraoral dryness and potential underlying mechanisms are essential to optimize treatment strategies and reduce the burden of disease. Therefore, we conducted this systematic review to provide existing evidence about extraoral dryness in BMS. The guidelines for the conduction and reporting of systematic reviews were followed. An electronic search was conducted in four major databases-PubMed, Web of Science, COCHRANE Library, and EBSCOhost-and the grey literature was assessed through Google Scholar. From each included article, information on extraoral dryness in BMS was extracted, and odds ratios were calculated for extraoral dryness among BMS patients compared with non-BMS controls. The findings demonstrated higher odds of the prevalence of extraoral dryness in BMS, which was found to a high degree in the lips, eyes, skin, and genitalia. The pattern of spread and locations of extraoral dryness propose a potential central mechanism. Based on our findings, we encourage the standardization of the assessment, recording, and reporting of the extraoral characteristics of BMS, including extraoral dryness, which can lead to better management strategies and enhance the quality of life of the affected patients.

Intelligent Digital Twins for Personalized Migraine Care.

Intelligent digital twins closely resemble their real-life counterparts. In health and medical care, they enable the real-time monitoring of patients, whereby large amounts of data can be collected to produce actionable information. These powerful tools are constructed with the aid of artificial intelligence, machine learning, and deep learning; the Internet of Things; and cloud computing to collect a diverse range of digital data (e.g., from digital patient journals, wearable sensors, and digitized monitoring equipment or processes), which can provide information on the health conditions and therapeutic responses of their physical twins. Intelligent digital twins can enable data-driven clinical decision making and advance the realization of personalized care. Migraines are a highly prevalent and complex neurological disorder affecting people of all ages, genders, and geographical locations. It is ranked among the top disabling diseases, with substantial negative personal and societal impacts, but the current treatment strategies are suboptimal. Personalized care for migraines has been suggested to optimize their treatment. The implementation of intelligent digital twins for migraine care can theoretically be beneficial in supporting patient-centric care management. It is also expected that the implementation of intelligent digital twins will reduce costs in the long run and enhance treatment effectiveness. This study briefly reviews the concept of digital twins and the available literature on digital twins for health disorders such as neurological diseases. Based on these, the potential construction and utility of digital twins for migraines will then be presented. The potential and challenges when implementing intelligent digital twins for the future management of migraines are also discussed.

Presence of Small-Conductance Calcium-Activated Potassium (SK) Channels in the Central and Peripheral Nervous Systems and Their Role in Health and Disease.

Potassium (K+) channels establish and maintain the resting potential of most living cells. Their activity is predominantly regulated by the membrane voltage or the K+ gradient across the cell membrane. However, many cells also express small-conductance calcium-activated potassium (SK) channels, which have the unique ability to translate changes in the level of the intracellular second messenger, Ca2+ to changes in the membrane K+ conductance and, therefore, the resting membrane potential. This article reviews the structure, presence, distribution, and function of SK channels, their pharmacological modulation, and their role in health and disease, emphasizing nociception and pain.

Prevalence of Dry Eye Disease Among Individuals Scheduled for Cataract Surgery in a Norwegian Cataract Clinic.

Purpose: To determine the prevalence of dry eye disease (DED) in patients scheduled for cataract surgery in a Norwegian eye clinic. Patients and Methods: 218 patients scheduled for cataract surgery were examined for DED in one randomly selected eye and questioned regarding symptoms and risk factors. Patients were diagnosed with DED if they fulfilled the DEWS II criteria with symptom score >12/100 with Ocular Surface Disease Index (OSDI) questionnaire, and the presence of any of the three signs: tear osmolarity >307 mOsm/L in either eye or a difference in osmolarity between the two eyes of >8 mOsm/L, corneal fluorescein staining (CSF) ≥ grade 2 and non-invasive tear film breakup time (NIKBUT) of <10 seconds. Additional tests were the Standard Patient Evaluation of Eye Dryness (SPEED) questionnaire, tear meniscus height (TMH), Schirmer 1, tear film thickness (TFT), corneal sensitivity and meibography (meiboscore). Dry eye test outcomes were correlated with risk factors for DED. Results: The prevalence of DED was 55.5% according to the DEWS II criteria. The abnormal osmolarity percentage was 66.5, while 29.8% had shortened NIKBUT and 19.7% exhibited CFS ≥2. 57% had Schirmer 1 ≤ 10 mm/5 min, and 81.1% had a meiboscore of ≥1. 71.2% of subjects scored positive for DED symptoms using the OSDI questionnaire and 69.3% using SPEED. Logistic regression analysis showed that higher age correlated with a lower OSDI symptom score, reduced corneal sensitivity and increased meibomian gland atrophy. Female sex was associated with higher odds of having DED, abnormal NIKBUT and abnormal CFS. Ocular tests for DED did not correlate with OSDI symptom scores when assessed with Spearman`s rank analysis. Conclusion: The prevalence of DED in an elderly Norwegian population scheduled for cataract surgery is high and associated with female sex. There was a lack of correlation between signs and symptoms of DED.

Human Brain Organoids in Migraine Research: Pathogenesis and Drug Development.

Human organoids are small, self-organized, three-dimensional (3D) tissue cultures that have started to revolutionize medical science in terms of understanding disease, testing pharmacologically active compounds, and offering novel ways to treat disease. Organoids of the liver, kidney, intestine, lung, and brain have been developed in recent years. Human brain organoids are used for understanding pathogenesis and investigating therapeutic options for neurodevelopmental, neuropsychiatric, neurodegenerative, and neurological disorders. Theoretically, several brain disorders can be modeled with the aid of human brain organoids, and hence the potential exists for understanding migraine pathogenesis and its treatment with the aid of brain organoids. Migraine is considered a brain disorder with neurological and non-neurological abnormalities and symptoms. Both genetic and environmental factors play essential roles in migraine pathogenesis and its clinical manifestations. Several types of migraines are classified, for example, migraines with and without aura, and human brain organoids can be developed from patients with these types of migraines to study genetic factors (e.g., channelopathy in calcium channels) and environmental stressors (e.g., chemical and mechanical). In these models, drug candidates for therapeutic purposes can also be tested. Here, the potential and limitations of human brain organoids for studying migraine pathogenesis and its treatment are communicated to generate motivation and stimulate curiosity for further research. This must, however, be considered alongside the complexity of the concept of brain organoids and the neuroethical aspects of the topic. Interested researchers are invited to join the network for protocol development and testing the hypothesis presented here.

Competence in Sports Pharmacy among Pharmacy Students in Norway.

Pharmacists are competent to promote the proper use of medicines. According to the International Pharmaceutical Federation, pharmacists must develop competence in sports pharmacy and the contents of the World Anti-Doping Agency code. This explorative study aimed to identify the status of sports pharmacy in pharmacy education in Norway and competence in sports pharmacy among Norwegian pharmacy students. The study curricula of pharmacy education were examined for the content of sports pharmacy. An online questionnaire was also developed and distributed among pharmacy students. The anonymous survey collected demographic information and data on competence in sports pharmacy. Data from 122 participants were analyzed. Only 22.5% of pharmacy students had acquired a form of training in sports pharmacy and 91.7% wished to gain higher competence. In total, 40.2% of respondents were uncomfortable in advising athletes and trainers on medication use in sports. Study year was found to correlate with competence level with a significant difference between the 3rd year (bachelor) and 5th year (master) students. Age, institution, and number of years engaged in sports were not associated with competence level. The inclusion of sports pharmacy in pharmacy programs holds practical relevance for enhancing competency levels. This implementation can be realized through the integration of sports pharmacy modules and/or the incorporation of research-based activities.

How Does Botulinum Toxin Inhibit Itch?

Two decades after reports of the anti-pruritic effects of botulinum neurotoxins (BoNTs), there is still no approved product for the anti-itch indication of BoNTs, and most clinical case reports still focus on the off-label use of BoNTs for various itchy conditions. Few randomized clinical trials have been conducted with controversial results, and the beneficial effects of BoNTs against itch are mainly based on case studies and case series. These studies are valuable in presenting the potential application of BoNTs in chronic pruritic conditions, but due to the nature of these studies, they are categorized as providing lower levels of evidence or lower grades of recommendation. To obtain approval for the anti-pruritic indication of BoNTs, higher levels of evidence are required, which can be achieved through conducting large-scale and well-designed studies with proper control groups and established careful and reliable primary and secondary outcomes. In addition to clinical evidence, presenting the mechanism-based antipruritic action of BoNTs can potentially strengthen, accelerate, and facilitate the current efforts towards further investments in accelerating the field towards the potential approval of BoNTs for itchy conditions. This review, therefore, aimed to provide the state-of-the-art mechanisms underlying the anti-itch effect of BoNTs from basic studies that resemble various clinical conditions with itch as a hallmark. Evidence of the neuronal, glial, and immune modulatory actions of BoNTs in reducing the transmission of itch are presented, and future potential directions are outlined.

Short-Term Functional and Morphological Changes in the Primary Cultures of Trigeminal Ganglion Cells.

Several studies have proved that glial cells, as well as neurons, play a role in pain pathophysiology. Most of these studies have focused on the contribution of central glial cells (e.g., microglia and astrocytes) to neuropathic pain. Likewise, some works have suggested that peripheral glial cells, particularly satellite glial cells (SGCs), and the crosstalk between these cells and the sensory neurons located in the peripheral ganglia, play a role in the phenomenon that leads to pain. Nonetheless, the study of SGCs may be challenging, as the validity of studying those cells in vitro is still controversial. In this study, a research protocol was developed to examine the potential use of primary mixed neuronal-glia cell cultures obtained from the trigeminal ganglion cells (TGCs) of neonate mice (P10-P12). Primary cultures were established and analyzed at 4 h, 24 h, and 48 h. To this purpose, phase contrast microscopy, immunocytochemistry with antibodies against anti-ßIII-tubulin and Sk3, scanning electron microscopy, and time-lapse photography were used. The results indicated the presence of morphological changes in the cultured SGCs obtained from the TGCs. The SGCs exhibited a close relationship with neurons. They presented a round shape in the first 4 h, and a more fusiform shape at 24 h and 48 h of culture. On the other hand, neurons changed from a round shape to a more ramified shape from 4 h to 48 h. Intriguingly, the expression of SK3, a marker of the SGCs, was high in all samples at 4 h, with some cells double-staining for SK3 and ßIII-tubulin. The expression of SK3 decreased at 24 h and increased again at 48 h in vitro. These results confirm the high plasticity that the SGCs may acquire in vitro. In this scenario, the authors hypothesize that, at 4 h, a group of the analyzed cells remained undifferentiated and, therefore, were double-stained for SK3 and ßIII-tubulin. After 24 h, these cells started to differentiate into SCGs, which was clearer at 48 h in the culture. Mixed neuronal-glial TGC cultures might be implemented as a platform to study the plasticity and crosstalk between primary sensory neurons and SGCs, as well as its implications in the development of chronic orofacial pain.

The role of multimodal MRI in mild cognitive impairment and Alzheimer's disease.

BACKGROUND AND PURPOSE: Mild cognitive impairment (MCI) is a prodromal stage of Alzheimer's disease (AD), where neurodegeneration is not as considerable, thereby potentially increasing the effect of treatments. Therefore, highly sensitive and specific classification of subjects with MCI is necessary, where various MRI modalities have displayed promise. METHODS: Structural, diffusion, and resting-state (RS) functional MRI analyses were performed on the AD (n = 26), MCI (n = 5), and healthy control (HC) (n = 14) group. Structural analysis was performed via voxel-based morphometry (VBM) and volumetric subcortical segmentation analysis. Fractional anisotropy and mean diffusivity were estimated during the diffusion analysis. RS analysis investigated seed-based functional connectivity. Classification via support vector machine was performed to evaluate which MRI modality most accurately differentiated the groups. Multiple linear regression was conducted to evaluate the MRI modalities correlation with clinical assessment scores. RESULTS: Classification of MCI and HC displayed highest accuracy based on diffusion MRI, which besides demonstrated high correlation with clinical scores. Classification was equally accurate in AD, when using VBM or diffusion tensor imaging measures. Yet, more variance was explained by VBM measures in the clinical assessment scores of the AD group. CONCLUSIONS: This study highlights the potential of diffusion MRI in differentiating MCI from HC and AD. However, the results need to be interpreted with caution as sample size and artifacts in the MRI data probably influenced the results.

A link between migraine and prolactin: the way forward.

Migraine is an incapacitating neurological disorder that predominantly affects women. Sex and other hormones (e.g., oxytocin, and prolactin) may play a role in sexual dimorphic features of migraine. Initially, prolactin was recognized for its modulatory action in milk production and secretion; later, its roles in the regulation of the endocrine, immune and nervous systems were discovered. Higher prolactin levels in individuals with migraine were found in earlier studies, with a female sex-dominant trend. Studies that are more recent have identified that the expression of prolactin receptor in response to neuronal excitability and stress depends on sex with a dominant role in females. These findings have opened up potentials for explanation of sex-related pathophysiology of migraine, but have left some unanswered questions. This focused review examines the past and present of the link between prolactin and migraine, and presents open questions and directions for future experimental and clinical efforts.

Nightmares in Migraine: A Focused Review.

Nightmares usually occur during the sleep phase of rapid eye movement (REM) and are associated with some physical symptoms, including sweating, shortness of breath, and lower limb movements. Emotions of fear, anger, shame, and sadness may also accompany nightmares. These symptoms can occur during dreaming, upon awakening, or later when the dream experience is recollected. Nightmares may sporadically occur for everyone, but nightmare disorders are associated with features of impaired mental and physical health and require professional medical treatment. The occurrence of nightmares with several disorders has been reported in the literature, but in migraines it has only been investigated in a small number of studies. Considering the existing relationship between sleep disorders and migraine, the occurrence of nightmares in migraine can negatively affect this association and elevate the risk of depression and anxiety. This, in turn, further reduces the quality of life of affected individuals. Hence, expanding the knowledge on the link between nightmares and migraine, promoting an acceptable quantity and quality of sleep through pharmacological and nonpharmacological interventions in the management of nightmares in migraine, and further scientific investigation of the biopsychosocial mechanisms underlying the link, will be highly valuable for optimal care. This focused review, therefore, gives a brief overview of the current understanding of nightmares in migraine to highlight the open questions and value of further research. The ultimate goal is to contribute to timely recognition and sufficient action to offer beneficial outcomes for affected patients.

Complexity of Drug Substitutions Caused by Drug Tenders: A Mixed-Methods Study in Denmark.

Objective: The objective of this study was to investigate factors influencing the complexity of drug substitutions caused by drug tenders in a Danish hospital setting. Methods: A sequential explanatory mixed-methods approach was employed. In the first phase, a custom-made, self-administered questionnaire was distributed to 58 pharmacists and pharmaconomists employed at the Hospital Pharmacy in the North Denmark Region. The questionnaire consisted of 13 questions, which helped to obtain quantitative information on factors complicating drug substitutions. The results were used to inform the construction of an interview guide for a focus group interview held in the following qualitative second phase of the study. The focus group included 11 pharmacists and pharmaconomists from the Hospital Pharmacy in the North Denmark Region working with drug substitutions. The focus group interview was conducted to facilitate validation of results from the questionnaire survey and to add further perspectives on identified factors influencing the complexity of drug substitutions. Results: Findings from both phases of the study revealed that implementation of drug substitutions is more complex when drug strength or pharmaceutical form of a drug changes, compared with changes of drug trade name or package size. Furthermore, it was established that Anatomical Therapeutic Chemical classification codes could be used to identify drug substitutions that are typically complex, for example, L01 and N05. Several external factors were also found to influence implementation of drug substitutions, for example, related to drug usage, number of end users, and hospital wards. Conclusions: From a hospital pharmacy point of view, multiple factors were identified that could influence and complicate the implementation of drug substitutions with different impact size. Those factors included both changed characteristics of drugs, Anatomical Therapeutic Chemical classification codes involved in substitution, and external factors.