Background: Intravenous lidocaine infusions have been shown to be effective for cancer related pain, but access is restricted to acute care settings. If able to be shown to be safe and effective, the subcutaneous route could expand access to residential hospices or patients' homes.
Objectives: This randomized, double-blind, placebo controlled, 2 × 2 crossover trial evaluated the effectiveness, safety, toxicity, and impact on quality of life of a limited duration subcutaneous lidocaine infusion (SCLI) for chronic cancer pain.
Mthods: Patients with the life expectancy of three months or more, who were experiencing cancer-related pain with a worst severity of at least 4 on a 0–10 scale despite a trial of at least one opioid and appropriate adjuvant analgesic, received two subcutaneous infusions at least a week apart; lidocaine 10 mg/kg over 5.5 hours and saline placebo. The primary outcome was either a reduction in worst pain intensity of two points out of 10 or a reduction in 24 hours opioid dose of at least 30% without worsening of pain scores, in seven days.
Results: The SCLI was only effective for two subjects. One of these subjects experienced a drop in worst pain score and the other experienced a reduction in opioid dose.
Conclusions: A weight-based subcutaneous infusion of lidocaine does not achieve sufficiently predictable blood levels for determining lidocaine responsiveness. This study does not allow any conclusion to be drawn on whether or not lidocaine would have been more effective had it been titrated to higher blood levels.
Background: Optimal pain management in the palliative care setting often requires multiple pharmacological interventions including novel and off-label therapies. Ketamine is an anesthetic agent with increasing evidence supporting its use for pain. Through N-methyl-d-aspartate antagonism and activity at opioid receptors, it is an adjuvant to traditional analgesics with the benefit of being opioid sparing. Ketamine has a wide safety profile with limited reports of overdose. Little is published on supratherpeutic dosing in the pain setting.
Objective: We report a case of a 41-year-old male with refractory nociceptive and neuropathic cancer-related pain. Conventional therapies were ineffective. Ketamine was initiated to reduce opioid burden and attenuate pain with good response. The patient received an iatrogenic overdose (10 times ordered dose) of the drug. Several self-limited physiologic and psychologic reactions were observed during subsequent monitoring.
Design: This is a study and analysis of a patient with refractory nociceptive and neuropathic pain syndrome treated with ketamine who sustained an iatrogenic overdose of ketamine.
Conclusions: Ketamine's use to treat pain is increasing along with its evidence of efficacy. Despite ketamine's wide safety profile, the medication is not without risk, especially in palliative care wherein patients are on multiple drugs with potentially severe interactions. Careful examination of the risks of overdose, especially of the various formulations of the drug, is needed.
Patients with serious illnesses are often asked whether they would prioritize relief of pain and suffering or longevity if these 2 goals were to come into conflict. A significant majority state that they would prioritize relief of pain and suffering. However, it is difficult for clinicians and family caregivers to operationalize such preferences without knowing the limits of these preferences or how much time alive patients would be willing to sacrifice in the service of their palliative goals. We sought to quantify trade-offs between survival time and avoidance of intensive care near the end of life among seriously ill hospitalized patients.
This article will focus on the following objectives specific to end-of-life care for professional case management:
Discuss recent industry topics that influence care processes.
Explore the opioid epidemic's impact on pain management.
Identify terms associated with end-of-life and life-limiting care.
Understand types of advance directives and care defining tools.
Define the purpose of psychiatric advance directives.
Discuss the shifting diagnostic face.
Discuss how inclusion manifests for the lesbian, gay, bisexual, transgender, queer/questioning (LGBTQ) population.
Explore challenges working through adolescent decision making and treatment.
Review regulation and reimbursement shifts across the industry.
Identify the use of artificial intelligence.
Discuss the value of ethics committees in health care organizations.
Define the Four Cs of Care Considerations.
Identify ethical principles for consideration by the workforce.
Context: Despite being associated with dependence and social stigma, methadone is a potential end-of-life option in complex cancer pain.
Objectives: To explore attitudes and opinions about methadone and its potential role and current use in complex end-of-life pain.
Methods: Semi-structured interviews (n = 30) with physicians in specialized palliative care, transcribed and analyzed with conventional qualitative content analysis.
Results: According to the physicians, patients and relatives expressed unexpectedly few negative attitudes, not affecting methadone’s use as an analgesic. Complex pain in bone-metastatic cancer of the prostate, breast and kidney, as well as pancreatic cancer and sarcomas were recurrent suggestions of appropriate indications.
Most of the informants stated that they applied a mechanism-based treatment and mainly prescribed low-dose methadone as an add-on to an existing opioid therapy to benefit from methadone´s proposed NMDA-receptor inhibiting properties, e.g. in cases with reduced opioid sensitivity. Despite its complex pharmacokinetics with a long half-life, most informants expressed defined strategies to avoid side-effects such as respiratory depression, especially when initiating treatment in the home-care setting.
While many palliative care physicians expressed an overly enthusiastic attitude, others stressed the risks of overconfidence, low precision in use, and overlooked treatment options. Besides the obvious physical pain-relieving effects, they stated that effective pain relief could result in a reduced workload and emotional empowerment, both for physicians and staff.
Conclusion: Methadone, especially in the form of low-dose add-on to other opioids is widely advocated in Swedish specialized palliative care as a practical and safe method with rapid onset in complex pain situations at the end of life.
Background/objectives: Opioids relieve symptoms in terminal care. We studied opioid underuse in long-term care facilities, defined as residents without opioid prescription despite pain and/or dyspnoea, 3 days prior to death.
Design and setting: In a proportionally stratified randomly selected sample of long-term care facilities in six European Union countries, nurses and long-term care facility management completed structured after-death questionnaires within 3 months of residents’ death.
Measurements: Nurses assessed pain/dyspnoea with Comfort Assessment in Dying with Dementia scale and checked opioid prescription by chart review. We estimated opioid underuse per country and per symptom and calculated associations of opioid underuse by multilevel, multivariable analysis.
Results: nurses’ response rate was 81.6%, 95.7% for managers. Of 901 deceased residents with pain/dyspnoea reported in the last week, 10.6% had dyspnoea, 34.4% had pain and 55.0% had both symptoms. Opioid underuse per country was 19.2% (95% confidence interval: 12.9–27.2) in the Netherlands, 25.2% (18.3–33.6) in Belgium, 29.3% (16.9–45.8) in England, 33.7% (26.2–42.2) in Finland, 64.6% (52.0–75.4) in Italy and 79.1% (71.2–85.3) in Poland (p < 0.001). Opioid underuse was 57.2% (33.0–78.4) for dyspnoea, 41.2% (95% confidence interval: 21.9–63.8) for pain and 37.4% (19.4–59.6) for both symptoms (p = 0.013). Odds of opioid underuse were lower (odds ratio: 0.33; 95% confidence interval: 0.20–0.54) when pain was assessed.
Conclusion: Opioid underuse differs between countries. Pain and dyspnoea should be formally assessed at the end-of-life and taken into account in physicians orders.
Objectifs : Une approche clinique globale et analytique, prenant en compte des causes multifactorielles, s’avère nécessaire pour comprendre et traiter les douleurs complexes et réfractaires liées au cancer. Un guide a été élaboré afin d’aider le praticien dans son raisonnement clinique. Il associe quatre approches : sémiologique, physiopathologique, anatomique et fonctionnelle. Ainsi, l’objectif principal de cette étude était d’évaluer la faisabilité d’utilisation de ce guide par des médecins d’unités de soins palliatifs. Les objectifs secondaires étaient de connaître les résultats de ces approches combinées et d’observer les modifications des coanalgésies médicamenteuses et si possible les approches multimodales.
Méthode : Cette étude de faisabilité était interventionnelle, non thérapeutique, et multicentrique sur les cinq unités de soins palliatifs d’Aquitaine. Dans un travail préliminaire, le guide de raisonnement clinique a été élaboré par six médecins puis soumis à la lecture critique de huit autres médecins par entretien et enfin par questionnaire. L’étude s’est déroulée auprès de sept médecins de quatre unités de soins palliatifs, tous expérimentés et diplômés en soins palliatifs. Un questionnaire remis aux médecins portait sur l’évaluation critique de l’utilisation du recueil : son utilité, ses avantages, ses limites, ses conditions d’utilisation.
Résultats : Sept médecins ont participé à l’étude. Parmi eux, quatre ont dit utiliser un raisonnement clinique auparavant. Six ont jugé le guide utile pour étudier les éléments manquants à l’évaluation et mieux soulager. Cinq ont estimé qu’il pourrait être généralisé dans les unités de soins palliatifs, deux qu’il pourrait être intégré au dossier dès l’admission du patient. Pour deux, le manque de temps pouvaitt être un frein à sa faisabilité. Soixante-huit patients ont été inclus, représentant 84 cas de douleur (59 % nociceptives, 35 % mixtes et 6 % neuropathiques). Parmi les douleurs évaluées, 19 comprenaient une composante neuropathique (DN4 positif). La coanalgésie a été modifiée pour tous les patients dans les 24h suivant l’admission.
Discussion : Pour la plupart des médecins interrogés, le guide est utile et faisable. Le manque de disponibilité, les besoins d’intégration des approches biomédicale et psychorelationnelle, d’appropriation du guide par un apprentissage et un compagnonnage ont été relevés par certains répondants.
Conclusion : L’évaluation de ce guide doit être poursuivie, notamment en médecine générale et en gériatrie. Son impact sur la prise en charge des douleurs liées au cancer est également à étudier.
Background: Uncontrolled cancer pain is a significant problem in palliative medicine. Opioids are often first-line treatment that increase risks of analgesic tolerance and hyperalgesia. Topical ketamine with other adjuvant pain medications is an often-overlooked treatment, yet may be most effective in difficult-to-treat cancer pain.
Objective: We report a case series of hospice patients with uncontrolled cancer pain who were suboptimally treated with opioids and nerve blocks, whose symptoms responded to topical ketamine with other adjuvants. We review the pronociceptive properties of opioids and how topical multimodal treatment of cancer pain can be more effective than standard opioids, other topical adjuvant medications, and nerve blocks. We discuss the shortcomings of the World Health Organization (WHO) stepladder for the treatment of cancer pain and suggest an adjuvant treatment algorithm, directing physicians to appropriate adjuvant pain agents based on pain type and distinct receptor actions.
Design: This is a retrospective case series of patients who responded to topical multimodal pain treatment with implementation of findings into an addendum to the WHO stepladder.
Subjects: Subjects were from a case series of community-based hospice patients with previously uncontrolled cancer pain.
Measurement: Measurement was made by self-report of pain levels using the 10-point numeric pain rating scale.
Results: Patients' pain was controlled with topical adjuvant medications with return to previously lost function and prevention of otherwise escalating opioid dosing.
Conclusions: These patient cases reveal how ketamine-based topical treatment for cancer pain can be more effective than standard opioids, other topical adjuvant medications, and nerve blocks with no noted side effects and observed reduction in opioid consumption.
BACKGROUND: Depressive disorders are common among cancer patients. Ketamine can quickly relieve depression, and its subcutaneous administration appears to be as effective as and probably safer than its standard intravenous administration. Herein, we report a case verifying the antidepressant effect of a subcutaneous esketamine formulation.
CASE PRESENTATION: A 65-year-old male with metastatic abdominal tumor reported sadness, weight loss, fatigue, hopelessness, insomnia, inattention, and reduced motivation. His scores on the visual analogical scale for pain and Montgomery-Asberg depression rating scale were 8/10 and 30/60, respectively.
POSSIBLE COURSES OF ACTION: Monoaminergic antidepressants are effective, but their response is slow for end-of-life care.
FORMULATION OF A PLAN: Esketamine was preferred because it possibly contributes to pain relief. It can repeatedly be infused intravenously, but was subcutaneously administered twice a week for safety reasons.
OUTCOME: The patient showed continuous mood improvement, achieving depression remission on day 7. Pain relief was observed but without stability. His vital signs remained stable, and he remained calm, without major complaints.
LESSONS FROM THE CASE: Repeated subcutaneous esketamine injections are possibly safe and effective in pain and depression relief in palliative care cancer patients.
VIEW ON RESEARCH PROBLEMS, OBJECTIVES, OR QUESTIONS GENERATED BY THE CASE: Placebo-controlled studies with similar cases are needed to establish efficacy and safety.
Purpose: Transcutaneous electrical nerve stimulation (TENS) is a treatment option for cancer pain, but the evidence is inconclusive. We aimed to evaluate the efficacy and safety of TENS.
Methods: A blinded, randomized, sham-controlled pilot cross-over trial (NCT02655289) was conducted on an inpatient specialist palliative care ward. We included adult inpatients with cancer pain = 3 on an 11-point numerical rating scale (NRS). Intensity-modulated high TENS (IMT) was compared with placebo TENS (PBT). Patients used both modes according to their preferred application scheme during 24 h with a 24-h washout phase. The primary outcome was change in average pain intensity on the NRS during the preceding 24 h. Responders were patients with at least a “slight improvement.”
Results: Of 632 patients screened, 25 were randomized (sequence IMT-PBT = 13 and PBT-IMT = 12). Finally, 11 patients in IMT-PBT and 9 in PBT-IMT completed the study (N = 20). The primary outcome did not differ between groups (IMT minus PBT: - 0.2, 95% confidence interval - 0.9 to 0.6). However, responder rates were higher in IMT (17/20 [85%] vs. 10/20 [50%], p = 0.0428). Two patients experienced an uncomfortable feeling caused by the current, one after IMT and one after PBT. Seven patients (35%) desired a TENS prescription. Women and patients with incident pain were most likely to benefit from TENS.
Conclusion: TENS was safe, but IMT was unlikely to offer more analgesic effects than PBT. Even though many patients desired a TENS prescription, 50% still reported at least “slight pain relief” from PBT. Differences for gender and incident pain aspects demand future trials.
AIM AND OBJECTIVES: To explore the experiences and views of nurses who provide non-pharmacological therapies for chronic pain management in palliative care.
BACKGROUND: Nursing expertise in palliative care is essential in providing pain relief to patients with chronic diseases. Examinations of the use of non-pharmacological therapies for chronic pain management in palliative care have revealed what non-pharmacological therapies have been used, but there is insufficient knowledge regarding nurses' attitudes, views, and experiences regarding pain therapies in this context.
DESIGN: A qualitative descriptive design was chosen.
METHODS: Data were collected through individual interviews in a purposive sample with 15 nurses to ensure maximum variation. The data were analyzed using qualitative content analysis. This study aligns with the Consolidated Criteria for Reporting Qualitative Research (COREQ) checklist.
RESULTS: The analysis yielded four categories, as follows: "Building and sustaining favorable therapeutic relationships" involved the creation of trust and a solid relationship; in "recognizing the diversity of patients' needs," person-centered care is expressed as being vital for individualized non-pharmacological pain management; "incorporating significant others" describes how nurses can help to ease the patient's pain by identifying positive encounters with family members or friends; and in "recognizing the existence of barriers," nurses highlight vulnerable groups such as children, for whom nurses require special education to enable optimal non-pharmacologic pain management.
CONCLUSION: The unique knowledge that nurses gain about the patient through the nurse-patient relationship is central and crucial for successful non-pharmacological pain management.
RELEVANCE TO CLINICAL PRACTICE: This study emphasizes the need for nurses to get to know their patient and to be open and sensitive to patients' descriptions of their unique life situations, as this provides the necessary knowledge for optimal care and pain management. Nurses should be encouraged and given the opportunity to attend specialized training in palliative care and pain management.
Background: The prevalence of undertreated cancer pain remains high. Suboptimal pain control affects quality of life and results in psychological and emotional distress. Barriers to adequate pain control include fear of opioid dependence and its side effects.
Aim: To investigate the attitudes and perceptions of morphine use in cancer pain in advanced cancer patients and their caregivers and to examine the influence of caregivers’ attitudes and perceptions on patients’ acceptance of morphine.
Design: Qualitative study involving semi-structured individual interviews transcribed verbatim and analyzed thematically.
Setting/Participants: A total of 18 adult opioid-naïve patients with advanced cancer and 13 caregivers (n = 31) were recruited at a private tertiary hospital via convenience sampling.
Results: Attitudes and perceptions of morphine were influenced by previous experiences. Prevalent themes were similar in both groups, including perceptions that morphine was a strong analgesic that reduced suffering, but associated with end-stage illness and dependence. Most participants were open to future morphine use for comfort and effective pain control. Trust in doctors’ recommendations was also an important factor. However, many preferred morphine as a last resort because of concerns about side effects and dependence, and the perception that morphine was only used at the terminal stage. Caregivers’ attitudes toward morphine did not affect patients’ acceptance of morphine use.
Conclusion: Most participants were open to future morphine use despite negative perceptions as they prioritized optimal pain control and reduction of suffering. Focused education programs addressing morphine misperceptions might increase patient and caregiver acceptance of opioid analgesics and improve cancer pain control.
Pain in people with advanced cancer is prevalent. When a stable dose of opioids is established, people still experience episodic breakthrough pain for which dosing of an immediate release opioid is usually a proportion of the total daily dose. This multi-site, double blind, randomised trial tested three dose proportions (1/6, 1/8, 1/12 of total daily dose) in two blocks, each block with three dose proportions in random order (6 numbered bottles in total). When participants required opioid breakthrough doses and it was their first breakthrough dose for that study day, they took the next numbered bottle rather than their usual breakthrough dose. (Subsequent doses on that day reverted to their usual dose.) Eighty five people were randomised in this study of whom 81 took at least one dose and 73 (90%) took at least block one (one of each dose proportion). No dose was found to be optimal at 30 min with approximately one third of participants showing maximal reduction with each dose proportion. Median time to pain relief was 120 min. There were no differences in harms: drowsiness, confusion, nausea or vomiting at 30, 60 or 120 min. This adequately powered study did not show any difference with three dose proportions for reduction in pain intensity, time to pain relief, pain control on the subsequent day nor any difference in harms. From first principles, this suggests 1/12 the 24 hourly dose should be used as the lowest dose that delivers benefit. Future studies should include a placebo arm.
Objectives: To investigate racial differences in implementation of 11 evidence-based cancer pain management strategies in a matched sample of patients in hospice.
Sample & Setting: 32 African American and 32 Caucasian American older adults (aged 65 years or older) with cancer pain receiving hospice care in the midwestern United States.
Methods & Variables: Matched cohort secondary data analysis of postintervention data in a cluster randomized controlled trial was used. Main outcomes are the summative and individual Cancer Pain Practice Index scores.
Results: There were few statistically significant or clinically meaningful differences in implementation of individual best practices for pain management by race. Assessment of primary pain characteristics and management of opioid-induced constipation with a bowel regimen was significantly lower in African Americans than in Caucasian Americans.
Implications for Nursing: African American older adults receiving hospice care at the end of life received pain management that was, overall, comparable to matched Caucasian American older adults. Hospice and oncology nurses play a critical role in effective pain management and should continue to implement evidence-based guidelines for pain management into daily practice. Diffusing the hospice model and principles of pain and symptom management into other settings and specialty care areas may reduce widespread pain disparities.
BACKGROUND: When religious and spiritual (R/S) care needs of patients with advanced disease are met, their quality of life (QoL) improves. We studied the association between R/S support and cancer patients' QoL at end-of-life in Soweto, South Africa.
OBJECTIVES: To identify R/S needs among advanced cancer patients receiving palliative care services and to assess associations of receipt of R/S care with patient QoL and place of death.
METHOD: A prospective cohort study conducted from May 1, 2016 to April 30, 2018 at a tertiary hospital in Soweto, South Africa. Nurses enrolled advanced cancer patients and referred them to the palliative care multidisciplinary team. Spiritual counsellors assessed and provided spiritual care to patients. We compared socio-demographic, clinical, and R/S factors and QoL of R/S care recipients and others.
RESULTS: Of 233 deceased participants, 92 (39.5%) had received R/S care. Patients who received R/S care reported less pain (2.82±1.23 versus 1.93±1.69), used less morphine and were more likely to die at home than patients who did not (57.5% compared to 33.7%). On multivariable logistic regression analysis, adjusting for significant confounding influences and baseline African Palliative Care Association Palliative Outcome Scale (APCA POS) scores, receipt of spiritual care was associated with reduced pain and family worry (OR, 0.33, 95% CI, 0.11-0.95); (OR, 3.43, 95% CI, 1.10-10.70).
CONCLUSION: Cancer patients have R/S needs. R/S care among our patients appreared to improve their end-of-life experience. More research is needed to determine the mechanisms by which R/S care may have improved the observed patient outcomes.
Pain is a common symptom associated with advanced cancer. An estimated 66.4% of people with advanced cancer experience pain from their disease or treatment. Pain management is an essential component of palliative care. Opioids and adjuvant therapies are the mainstay of cancer pain management. Nevertheless, a proportion of patients may experience complex pain that is not responsive to conventional analgesia. Interventional analgesia procedures may be appropriate and necessary to manage complex, cancer-related pain. This narrative review uses a theoretical case to highlight core principles of palliative care and interventional anesthesia, and the importance of collaborative, interdisciplinary care. An overview and discussion of pragmatic considerations of peripheral nervous system interventional analgesic procedures and neuraxial analgesia infusions are provided.
Ces recommandations de la Haute Autorité de Santé ont pour objectifs de mieux définir les modalités d'utilisation des traitements médicamenteux, en particulier hors AMM, en situation palliative et phase terminale chez l'adulte :
- pour l'antalgie des douleurs rebelles ou la prévention des douleurs rebelles provoquées ;
- pour la sédation, qu'elle soit proportionnée ou profonde et continue maintenue jusqu'au décès ;
- y compris, le cas échéant, les modalités spécifiques au domicile.
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BACKGROUND: Pain of a moderate or severe intensity affects over half of patients with advanced cancer and remains undertreated in at least one-third of these patients.
AIM: The aim of this study was to provide a pragmatic overview of the evidence supporting the use of interventions in pain management in advanced cancer and to identify where encouraging preliminary results are demonstrated but further research is required.
DESIGN: A scoping review approach was used to examine the evidence supporting the use of guideline-recommended interventions in pain management practice.
DATA SOURCES: National or international guidelines were selected if they described pain management in adult cancer patients and were written within the last 5 years in English. The Cochrane Database of Systematic Reviews (January 2014 to January 2019) was searched for 'cancer' AND 'pain' in the title, abstract or keywords. A MEDLINE search was also made.
RESULTS: A strong opioid remains the drug of choice for treating moderate or severe pain. Bisphosphonates and radiotherapy are also effective for cancer-related bone pain. Optimal management requires a tailored approach, support for self-management and review of treatment outcomes. There is likely a role for non-pharmacological approaches. Paracetamol should not be used in patients taking a strong opioid to treat pain. Cannabis-based medicines are not recommended. Weak opioids, ketamine and lidocaine are indicated in specific situations only.
CONCLUSION: Interventions commonly recommended by guidelines are not always supported by a robust evidence base. Research is required to evaluate the efficacy of non-steroidal anti-inflammatory drugs, anti-convulsants, anti-depressants, corticosteroids, some invasive anaesthetic techniques, complementary therapies and transcutaneous electrical nerve stimulation.
Palliative care is seeing cancer patients earlier in the disease trajectory with a multitude of chronic issues. Chronic non-malignant pain (CNMP) in cancer patients is under-studied. In this prospective study, we examined the prevalence and management of CNMP in cancer patients seen at our supportive care clinic for consultation. We systematically characterized each pain type with the Brief Pain Inventory (BPI) and documented current treatments. The attending physician made the pain diagnoses according to the International Association for the Study of Pain (IASP) task force classification. Among 200 patients (mean age 60 years, 69% metastatic disease, 1-year survival of 77%), the median number of pain diagnosis was 2 (IQR 1-2); 67 (34%, 95% CI 28-41%) had a diagnosis of CNMP; 133 (67%) had cancer-related pain; and 52 (26%) had treatment-related pain. In total, 12/31 (39%) patients with only CNMP and 21/36 (58%) patients with CNMP and other pain diagnoses were on opioids. There was a total of 94 CNMP diagnoses among 67 patients, including 37 (39%) osteoarthritis and 20 (21%) lower back pain; 30 (32%) were treated with opioids. In summary, CNMP was common in the timely palliative care setting and many patients were on opioids. Our findings highlight the need to develop clinical guidelines for CNMP in cancer patients to standardize its management.
The purpose of this article is to describe current evidence-based strategies to manage severe pain in patients living with terminal illnesses. A comprehensive pain assessment is a critical step in the initial development of a pain management plan and for ongoing evaluation of patients' pain. Although we have many effective clinical tools available for pain assessment, they are not always used consistently, which can negatively affect the pain management plan. Home care and hospice nurses need to be consistent in using the tools and documenting the patient's pain level and response to the pain management plan. Patients and caregivers have concerns and fears surrounding medication use, particularly with narcotic analgesics. It is vital that nurses provide thorough patient-centered teaching about medications to help address these concerns. Research has found that nurses who also provided validation to patients and families regarding their concerns, followed by education, were the most effective.