Protocol for a pragmatic trial of Cannabidiol (CBD) to improve chronic pain symptoms among United States Veterans.

BACKGROUND: Chronic pain affects over 100 million Americans, with a disproportionately high number being Veterans. Chronic pain is often difficult to treat and responds variably to medications, with many providing minimal relief or having adverse side effects that preclude use. Cannabidiol (CBD) has emerged as a potential treatment for chronic pain, yet research in this area remains limited, with few studies examining CBD's analgesic potential. Because Veterans have a high need for improved pain care, we designed a clinical trial to investigate CBD's effectiveness in managing chronic pain symptoms among Veterans. We aim to determine whether CBD oral solution compared to placebo study medication is associated with greater improvement in the Patient Global Impression of Change (PGIC). METHODS: We designed a randomized, double-blind, placebo-controlled, pragmatic clinical trial with 468 participants. Participants will be randomly assigned in a 1:1 ratio to receive either placebo or a CBD oral solution over a 4-week period. The trial is remote via a smartphone app and by shipping study materials, including study medication, to participants. We will compare the difference in PGIC between the CBD and placebo group after four weeks and impacts on secondary outcomes (e.g., pain severity, pain interference, anxiety, suicide ideation, and sleep disturbance). DISCUSSION: Once complete, this trial will be among the largest to date investigating the efficacy of CBD for chronic pain. Findings from this clinical trial will contribute to a greater knowledge of CBD's analgesic potential and guide further research. Given the relative availability of CBD, our findings will help elucidate the potential of an accessible option for helping to manage chronic pain among Veterans. TRIAL REGISTRATION: This protocol is registered at clinicaltrials.gov under study number NCT06213233.

Linalool: Therapeutic Indication And Their Multifaceted Biomedical Applications.

This comprehensive review endeavors to illuminate the nuanced facets of linalool, a prominent monoterpene found abundantly in essential oils, constituting a massive portion of their composition. The biomedical relevance of linalool is a key focus, highlighting its therapeutic attributes observed through anti-nociceptive effects, anxiolytic properties, and behavioral modulation in individuals affected by dementia. These findings underscore the compound's potential application in biomedical applications. This review further explores contemporary formulations, delineating the adaptability of linalool in nano-emulsions, microemulsions, bio-capsules, and various topical formulations, including topical gels and lotions. This review covers published and granted patents between 2018-2024 and sheds light on the evolving landscape of linalool applications, revealing advancements in dermatological, anti-inflammatory, and antimicrobial domains.

Enhancing Emergency Department Pain Management for Older Adults with the Hip Fracture Fast-Track (HFFT) Protocol in a Middle-Income Country.

Purpose: This study aimed to evaluate the impact of the Hip Fracture Fast-Track (HFFT) protocol, designed specifically for older patients at our hospital, which commenced on January 1, 2022, on the management of emergency department (ED) pain in older adults with hip fractures. Patients and Methods: Retrospective pre- and post-study data from electronic health records (EHR) at our hospital, using the International Classification of Diseases (ICD)-10 codes S72.0, S72.1, S72.8, and S72.9, were utilized. The study included patients aged 65 years or older who presented to the ED with low-energy, non-pathologic isolated hip fractures or proximal femur fractures. The pre-HFFT period included patients from January 1, 2020, to December 31, 2021, and the post-HFFT period included patients from January 1, 2022, to October 31, 2023. Data were compared for the proportion of patients undergoing pain evaluation in the ED, before discharge, time to first analgesia, number of patients receiving pain relief in the ED, and the use of fascia iliaca compartment blocks (FICBs) and pericapsular nerve group blocks (PENGBs). Results: The final analysis involved 258 patients, with 116 in the pre-protocol group and 142 in the post-protocol group. The rate of analgesic use increased significantly in the post-HFFT group (78 [67.24%] vs 111 [78.17%], P = 0.049). The rate of pain score screening at triage increased from 51.72% before the HFFT protocol to 86.62% post-HFFT protocol (p < 0.001). Compared with the pre-HFFT protocol, the post-HFFT protocol exhibited a higher rate of FICB (0% vs 14.08%, p < 0.001) and PENGB (0% vs 5.63%, p = 0.009) administration. Conclusion: The HFFT protocol's implementation was associated with improved ED pain evaluation and analgesic administration in older adults with hip fractures. These findings indicate that tailored protocols, such as the HFFT, hold promise for enhancing emergency care for this vulnerable population.

Association between awareness and knowledge of medication-overuse headache with medication-taking behavior among adults with migraine.

Frequent use of pain relief medications among patients with migraine can result in disease worsening and medication-overuse headache (MOH), a painful and debilitating condition. We sought to conduct a cross-sectional survey among adult patients diagnosed with migraine to determine: 1) their awareness of MOH, and 2) their knowledge of the condition and its prevention, and 3) the association of these factors with actual use of pain relief medications. We recruited and interviewed 200 English-speaking adults with migraine who had a clinic visit with a neurologist or primary care provider within the past month. Patients were identified via an electronic health record query. Almost 40% of participants had never heard of the term 'medication-overuse headache.' In bivariate analyses, participants who were Black or Hispanic and those with limited health literacy were less likely to have heard of MOH. Participants scored an average of 2.1 (range: 0-3) on a MOH knowledge measure; older participants, those with limited health literacy, lower education, and little or no migraine-related disability demonstrated less knowledge. Almost a third (31.5%) of patients reported overusing pain relief medication and were at risk for MOH. Overuse was not significantly associated with MOH awareness, knowledge, or sociodemographic factors, but was related to greater migraine-related disability. Our findings suggest that patient awareness and knowledge of MOH is suboptimal, particularly among older adults, racial and ethnic minority groups, and those with limited health literacy. Interventions are needed to prevent MOH and better inform patients about risks associated with frequent use of pain relief medications.

Identifying Barriers to Effective Cancer Pain Management in Oman: Implications for Palliative Care.

BACKGROUND: Effective cancer pain management is essential for improving the quality of life of patients. However, the use of analgesics is often suboptimal due to various patient-related barriers. This study aims to explore the perceptions, knowledge, and attitudes toward analgesic use among cancer patients in Oman, which may influence their pain management strategies. METHODS: In a cross-sectional study, we assessed 68 cancer patients undergoing pain management at an inpatient cancer clinic of a tertiary hospital in Oman from a pool of 154 eligible participants. The Barriers Questionnaire (BQ) and the Patient Pain Questionnaire (PPQ), both Arabic versions, were administered to evaluate the patients' barriers to cancer pain management. The study period and the criteria for patient selection are specified. RESULTS: With a participation rate of 44.2% and a female-to-male ratio of 2.28:1, the mean score on the BQ was 2.52 (SD 0.84), indicating a moderate level of perceived barriers. Patients' scores suggested notable barriers, with older patients exhibiting reluctance toward analgesics for fear of masking symptoms and female patients expressing greater concerns about developing drug tolerance. CONCLUSION: The findings highlight significant attitudinal barriers to effective cancer pain management in Oman, notably a prevalent fear of medication tolerance. The study stresses on the need for targeted patient education and the correction of misconceptions. It also points to the influence of cultural and religious beliefs on patient responses, advocating for the implementation of culturally sensitive, evidence-based pain management guidelines, and the support of multidisciplinary palliative care teams.

Pain management in total knee arthroplasty.

Total knee arthroplasty is a frequently performed orthopaedic surgery and the trend indicates an increase in annual procedures. Many patients experience severe postoperative pain. In this review article, a review of the literature reveals evidence supporting a multimodal approach to pain management, which involves basic analgesic treatment in combination with glucocorticoids and local infiltration analgesia. Effective pain control can reduce postoperative pain, lower opioid consumption, and its associated adverse effects, and enhance postoperative rehabilitation and patient satisfaction.

Progress in the validation of nociception monitoring in guiding intraoperative analgesic therapy.

PURPOSE OF REVIEW: This article summarizes the current level of validation for several nociception monitors using a categorized validation process to facilitate the comparison of performance. RECENT FINDINGS: Nociception monitors improve the detection of a shift in the nociception and antinociception balance during anesthesia, guiding perioperative analgesic therapy. A clear overview and comparison of the validation process for these monitors is missing. RESULTS: Within a 2-year time-frame, we identified validation studies for four monitors [analgesia nociception index (ANI), nociception level monitor (NOL), surgical pleth index (SPI), and pupillometry]. We categorized these studies in one out of six mandatory validation steps: developmental studies, clinical validation studies, pharmacological validation studies, clinical utility studies, outcome improvement studies and economical evaluation studies. The current level of validation for most monitors is mainly focused on the first three categories, whereas ANI, NOL, and SPI advanced most in the availability of clinical utility studies and provide confirmation of a clinical outcome improvement. Analysis of economical value for public health effects is not yet publicly available for the studied monitors. SUMMARY: This review proposes a stepwise structure for validation of new monitoring technology, which facilitates comparison between the level of validation of different devices and identifies the need for future research questions.

Galacturonic acid-capsaicin prodrug for prolonged nociceptive-selective nerve blockade.

There is an urgent clinical need to develop nerve-blocking agents capable of inducing long duration sensory block without muscle weakness or paralysis to treat post-operative and chronic pain conditions. Here, we report a galacturonic acid-capsaicin (GalA-CAP) prodrug as an effective nociceptive-selective axon blocking agent. Capsaicin selectively acts on nociceptive signaling without motor nerve blockade or disruption of proprioception and touch sensation, and the galacturonic acid moiety enhance prodrug permeability across the restrictive peripheral nerve barriers (PNBs) via carrier-mediated transport by the facilitative glucose transporters (GLUTs). In addition, following prodrug transport across PNBs, the inactive prodrug is converted to active capsaicin through linker hydrolysis, leading to sustained drug release. A single injection of GalA-CAP prodrug at the sciatic nerves of rats led to nociceptive-selective nerve blockade lasting for 234 ± 37 h, which is a sufficient duration to address the most intense period of postsurgical pain. Furthermore, the prodrug markedly mitigated capsaicin-associated side effects, leading to a notable decrease in systemic toxicity, benign local tissue reactions, and diminished burning and irritant effects.

Generalized music therapy to reduce neuroactive drug needs in critically ill patients. Study protocol for a randomized trial.

BACKGROUND: Critically ill patients are exposed to several physical and emotional stressors, needing analgesic and sedative drugs to tolerate invasive procedures and the harsh intensive care unit (ICU) environment. However, this pharmacological therapy presents several side effects: guidelines suggest using a light sedation target, keeping critically ill patients calm, conscious, and cooperative. Personalized music therapy (MT) can reduce stress and anxiety, decreasing the need for drugs. The aim of the current investigation is to compare different approaches for MT in the ICU: a personalized approach, with music selected by patients/families and listened through headphones, or a generalized approach, with ambient music chosen by a music therapist and transmitted through speakers. PRIMARY OUTCOME: number of days "free from neuroactive drugs" in the first 28 days after ICU admission. SECONDARY OUTCOMES: total amount of neuroactive drugs (midazolam, propofol, morphine, fentanyl, haloperidol), stress during ICU stay (sleep at night, anxiety and agitation, use of physical restraints, stressors evaluated at discharge), the feasibility of generalized MT (interruptions requested by staff members and patients/families). METHODS: Randomized, controlled trial with three groups of critically ill adults: a control group, without MT; a personalized MT group, with music for at least 2 h per day; a generalized MT group, with music for 12.5 h/day, subdivided into fifteen 50-min periods. DISCUSSION: One hundred fifty-three patients are expected to be enrolled. This publication presents the rationale and the study methods, particularly the strategies used to build the generalized MT playlist. From a preliminary analysis, generalized MT seems feasible in the ICU and is positively received by staff members, critically ill patients, and families. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03280329. September 12, 2017.

Magnesium sulfate for postoperative pain in orthopedic surgery: A narrative review.

Magnesium Sulfate (MgSO4) is a widely used adjuvant in anesthesia. Often administered with local anesthetics, it is known to reduce analgesic and opioid consumption while extending the duration of analgesia. MgSO4 applications extend to orthopedic surgeries, cardiovascular and urogenital procedures, offering extended postoperative pain relief. While commonly administered through various routes, there is a research gap concerning the comparative efficacy of intrathecal (IT) and intravenous (IV) MgSO4 administration. This narrative review aims to provide a comparison between IT and IV administration of MgSO4 particularly following orthopedic procedures, where pain management is paramount. A comprehensive literature search was conducted across several electronic databases, trial registries, and gray literature from inception to 2023. Inclusion criteria encompassed studies investigating the effects of perioperative IT administration of magnesium compared to perioperative IV administration of MgSO4 in patients undergoing surgery, with no language restrictions. Our search identified 4326 articles, of which 9 randomized controlled trials met our inclusion criteria. We summarized these selected articles. Four studies discussed IT magnesium sulfate (MgSO4) administration, 2 focused on IT administration in orthopedic surgeries, and 3 explored both IV and IT administration of MgSO4 in orthopedic surgery. IT MgSO4 shows promise in postoperative pain management, delaying block onset and extending duration. Personalized administration choice, considering patient factors and surgery type, is crucial. Further research is needed to refine strategies for better patient outcomes, particularly following orthopedic surgeries.

Pregabalin-induced rhabdomyolysis: a case series and literature analysis.

Pregabalin is a prescription medicine that has recently been approved for individuals who suffer from fibromyalgia, neuropathic pain, anxiety disorder, or epilepsy. Pregabalin has the side effects of dizziness, sleepiness, and angioedema. Pregabalin-induced rhabdomyolysis has been rarely reported, with only four reports to date. We report two cases of rhabdomyolysis after pregabalin treatment. A man aged older than 90 years presented with exhaustion, muscle aches, and a high serum creatine kinase concentration after taking 75 mg of pregabalin on the first day of treatment. A woman in her 90s with long-term use of pregabalin presented with considerably elevated serum creatine kinase concentrations. Both patients had a long history of taking statins. Pregabalin therapy was stopped, high-volume intravenous fluids were administered, and serum electrolytes were frequently checked. Alkalinisation was performed with excellent outcomes. The Naranjo Adverse Drug Reaction scale and previous research suggest an association between pregabalin and rhabdomyolysis. Clinicians should be alert to the possibility of rhabdomyolysis occurring with the use of pregabalin, especially when taking statins.

Design and synthesis of oxytocin glycosides for the treatment of pain and substance use disorder.

Peptide drugs are a promising alternative to classical small molecule therapeutics with diverse applications, ranging from antibiotic resistant infection to prostate cancer. Oxytocin (OT) is a highly evolutionarily conserved peptide neurohormone and has been of interest for pharmaceutical use since 1909. Despite their increased safety profile relative to most small molecule drugs, peptides are poor candidates based on the pharmacokinetic (PK) properties from their peptide nature. Broad application of OT as a drug has been limited by these same PK issues. Several strategies have been proposed to overcome these limitations, among them glycosylation, which was used in combination with other sequence modifications to produce robust antinociception in mouse models, increased selectivity and potency at the OT receptor, and improved stability in rats.

Pharmacological treatment of pain in Swedish nursing homes: Prevalence and associations with cognitive impairment and depressive mood.

OBJECTIVES: Chronic pain is highly prevalent in nursing home residents and often occurs with depression as well as cognitive impairment, which can severely influence and limit the expression of pain. METHODS: The present cross-sectional study aimed to estimate the prevalence of pain, depressive mood, and cognitive impairment in association with pharmacological treatment against pain and depressive symptoms among Swedish nursing home residents. RESULTS: We found an overall pain prevalence of 52.8%, a prevalence of 63.1% for being in a depressive mood, and a prevalence of cognitive impairment of 68.3%. Among individuals assessed to have depressive mood, 60.5% were also assessed to have pain. The prevalence of pharmacological treatment for pain was 77.5 and 54.1% for antidepressants. Prescription of pharmacological treatment against pain was associated with reports of currently having pain, and paracetamol was the most prescribed drug. A higher cognitive function was associated with more filled prescriptions of drugs for neuropathic pain, paracetamol, and nonsteroidal anti-inflammatory drugs (NSAIDs), which could indicate an undertreatment of pain in those cognitively impaired. CONCLUSION: It is important to further explore the relationship between pain, depressive mood, and cognitive impairment in regard to pain management in nursing home residents.

[Analgesics, chronic pain and musculoskeletal rehabilitation]. / Médicaments antalgiques, douleur chronique et réadaptation de l'appareil locomoteur.

The majority of patients following musculoskeletal rehabilitation are taking painkillers. However, apart from one recent observational study, there is a lack of data. The use of analgesics, particularly opioids, is associated with higher scores for pain, anxiety, depression, catastrophizing and disability, as well as poorer results in functional tests. Prescribing analgesic treatment with precise objectives (improving pain and function) should also include identifying psychosocial factors associated with a poor prognosis. Regular reassessment of the treatment should make it possible to limit side-effects and the risk of misuse and help patients to engage in an active rehabilitation programme and resume regular physical activity.

La majorité des patients effectuant une réadaptation musculosquelettique consomme des antalgiques. Cependant, en dehors d'une étude observationnelle récente, les données manquent. La prise d'antalgiques, en particulier les opioïdes, est associée à des scores de douleur, d'anxiété, de dépression, de catastrophisme et de handicap élevés, ainsi qu'à des résultats plus faibles aux tests fonctionnels. La prescription d'un traitement antalgique avec des objectifs précis (amélioration de la douleur et de la fonction) doit également comporter une détection des facteurs psychosociaux de mauvais pronostic. Une réévaluation régulière de la prescription devrait permettre de limiter les effets secondaires, les risques de mésusage et aider les patients à s'engager dans un programme de réadaptation actif et à reprendre une activité physique régulière.

The Use of Compounds Derived from Cannabis sativa in the Treatment of Epilepsy, Painful Conditions, and Neuropsychiatric and Neurodegenerative Disorders.

Neurological disorders present a wide range of symptoms and challenges in diagnosis and treatment. Cannabis sativa, with its diverse chemical composition, offers potential therapeutic benefits due to its anticonvulsive, analgesic, anti-inflammatory, and neuroprotective properties. Beyond cannabinoids, cannabis contains terpenes and polyphenols, which synergistically enhance its pharmacological effects. Various administration routes, including vaporization, oral ingestion, sublingual, and rectal, provide flexibility in treatment delivery. This review shows the therapeutic efficacy of cannabis in managing neurological disorders such as epilepsy, neurodegenerative diseases, neurodevelopmental disorders, psychiatric disorders, and painful pathologies. Drawing from surveys, patient studies, and clinical trials, it highlights the potential of cannabis in alleviating symptoms, slowing disease progression, and improving overall quality of life for patients. Understanding the diverse therapeutic mechanisms of cannabis can open up possibilities for using this plant for individual patient needs.

Pregabalin and amitriptyline as first-line drugs among patients with painful peripheraldiabetic neuropathy: a systematic review and meta-analysis.

OBJECTIVE: Painful peripheral diabetic neuropathy (PRDN) is a common disabling condition. Pregabalin and amitriptyline are commonly prescribed as the first-line for PPDN despite the contradicting recommendations. There is a need to inform the scientific community regarding first-line pain control among patients with PPDN. This meta-analysis assessed pregabalin and amitriptyline effects on PPDN. PATIENTS AND METHODS: We searched PubMed, MEDLINE, Cochrane Library, EBSCO, and Google Scholar; the terms used were amitriptyline, pregabalin, painful diabetic neuropathy, antidepressant, gabapentinoids, quality of life, and adverse events. Boolean operators like AND, and OR were used. Six hundred and thirty-one studies were retrieved, and 37 full texts were screened. However, only six randomized controlled trials fulfilled the inclusion and exclusion criteria. RESULTS: No significant statistical differences between amitriptyline and pregabalin regarding pain score and significant pain reduction (odd ratio, -0.82, 95% CI, -2.21-0.58, and odd ratio, 1.16, 95% CI, 0.76-1.76 respectively). Quality of life, total adverse events, and drug discontinuation were not different between the two drugs (odd ratio, 0.89, 95% CI, -2.11-3.89, odd ratio, 0.98, 95% CI, 0.52-1.85, and odd ratio, 0.51, 95% CI, 0.08-3.15, respectively). CONCLUSIONS: No significant statistical differences between amitriptyline and pregabalin regarding their effects on pain and quality of life. The drugs showed similar total adverse events and drug withdrawal. Further larger real-world studies are needed.

Improving door-to-analgesia timing in musculoskeletal injuries in an academic emergency department in India: a quality improvement project.

INTRODUCTION: Pain, more frequently due to musculoskeletal injuries, is a prevalent concern in emergency departments (EDs). Timely analgesic administration is paramount in the acute setting of ED. Despite its importance, many EDs face challenges in pain management and present opportunities for improvement. This initiative aimed to expedite the administration of the first analgesic in patients with musculoskeletal pain in the ED. LOCAL PROBLEM: Observations within our ED revealed that patients with musculoskeletal injuries triaged to yellow or green areas experienced prolonged waiting times, leading to delayed analgesic administration, thereby adversely affecting clinical care and patient satisfaction. SPECIFIC AIM: The aim of our quality improvement (QI) project was to reduce the time to administration of first analgesia by 30% from baseline, in patients with musculoskeletal injuries presenting to our academic ED, in a period of 8 weeks after the baseline phase. METHODS: A multidisciplinary QI team systematically applied Point-of-Care Quality Improvement and Plan-Do-Study-Act (PDSA) cycle methodologies. Process mapping and fishbone analyses identified the challenges in analgesia administration. Targeted interventions were iteratively refined through PDSA cycles. INTERVENTIONS: Interventions such as pain score documentation at triage, fast-tracking of patients with moderate-to-severe pain, resident awareness sessions, a pain management protocol and prescription audits were executed during the PDSA cycles. Successful elements were reinforced and adjustments were made to address the identified challenges. RESULTS: The median door-to-analgesia timing during the baseline phase was 55.5 min (IQR, 25.75-108 min). During the postintervention phase, the median was significantly reduced to 15 min (IQR, 5-37 min), exceeding the anticipated outcomes and indicating a substantial 73% reduction (p value <0.001) from baseline. CONCLUSION: Implementing simple change ideas resulted in a substantial improvement in door-to-analgesia timing within the ED. These findings significantly contribute to ongoing discussions on the optimisation of pain management in emergency care.

Use of electronic health record data to examine administrations of pro re nata analgesics during hip fracture post-acute care.

PURPOSE: Medications prescribed to older adults in US skilled nursing facilities (SNF) and administrations of pro re nata (PRN) "as needed" medications are unobservable in Medicare insurance claims. There is an ongoing deficit in our understanding of medication use during post-acute care. Using SNF electronic health record (EHR) datasets, including medication orders and barcode medication administration records, we described patterns of PRN analgesic prescribing and administrations among SNF residents with hip fracture. METHODS: Eligible participants resided in SNFs owned by 11 chains, had a diagnosis of hip fracture between January 1, 2018 to August 2, 2021, and received at least one administration of an analgesic medication in the 100 days after the hip fracture. We described the scheduling of analgesics, the proportion of available PRN doses administered, and the proportion of days with at least one PRN analgesic administration. RESULTS: Among 24 038 residents, 57.3% had orders for PRN acetaminophen, 67.4% PRN opioids, 4.2% PRN non-steroidal anti-inflammatory drugs, and 18.6% PRN combination products. The median proportion of available PRN doses administered per drug was 3%-50% and the median proportion of days where one or more doses of an ordered PRN analgesic was administered was 25%-75%. Results differed by analgesic class and the number of administrations ordered per day. CONCLUSIONS: EHRs can be leveraged to ascertain precise analgesic exposures during SNF stays. Future pharmacoepidemiology studies should consider linking SNF EHRs to insurance claims to construct a longitudinal history of medication use and healthcare utilization prior to and during episodes of SNF care.