Pruritus Severity and Serum Phosphate in CKD: A Post Hoc Analysis of Difelikefalin Studies.

Key Points: No correlation was observed between pruritus severity and serum phosphate or response to placebo or difelikefalin in patients with CKD-associated pruritus undergoing hemodialysis. Difelikefalin improved itch versus placebo irrespective of baseline serum phosphate.

Background: CKD-associated pruritus (CKD-aP) has historically been associated with elevated serum phosphate (sP).

Difelikefalin in Black/African American Hemodialysis Patients with Moderate-to-Severe Pruritus: Post hoc Analysis of KALM-1 and KALM-2.

Introduction: Black and African American (AA) people are over-represented in the kidney failure population; therefore, the safety and efficacy of difelikefalin in Black/AA patients was evaluated.

Methods: This was a post hoc, pooled exploratory subgroup analysis of the Phase 3 KALM-1 and -2 studies. Patients undergoing hemodialysis (HD) who had moderate-to-severe chronic kidney disease-associated pruritus (CKD-aP) at enrollment were stratified into self-reported Black/AA or White subgroups.

CKD-Associated Pruritus and Clinical Outcomes in Nondialysis CKD.

Rationale & Objective: Itching is a frequent symptom experienced by people with chronic kidney disease (CKD). We investigated the associations of CKD-associated pruritus (CKD-aP) with clinical outcomes.

Study Design: This was a longitudinal cohort study.

Difelikefalin improves itch-related sleep disruption in patients undergoing haemodialysis.

Background: Poor sleep quality is associated with higher mortality and lower quality of life in patients with chronic kidney disease-associated pruritus (CKD-aP). Difelikefalin reduces itch in patients with CKD-aP undergoing haemodialysis (HD). This post hoc analysis of the Phase 3 difelikefalin studies (Study 3105 and the pooled dataset from KALM-1 and KALM-2) evaluated whether itch reduction in individuals with CKD-aP improved sleep quality.

The Burden of Pruritus Associated With CKD: A Mixed Methods Analysis Among Patients Undergoing Dialysis.

Rationale & Objective: Despite its prevalence and distress to patients, chronic kidney disease-associated pruritus (CKD-aP) is poorly characterized, which may contribute to the condition's underdiagnosis and inadequate management. This study aimed to understand the symptom experience of patients with CKD-aP and the extent to which pruritus impacts their lives.

Study Design: Mixed methods study including one-on-one qualitative interviews and completion of the Skindex-10 Questionnaire (measuring itch-related quality of life).

Safety and Effectiveness of Difelikefalin in Patients With Moderate-to-Severe Pruritus Undergoing Hemodialysis: An Open-Label, Multicenter Study.

Rationale & Objective: Individuals with chronic kidney disease frequently suffer from chronic kidney disease-associated pruritus (CKD-aP), impacting sleep quality and quality of life (QoL) and increasing the likelihood of depression. Difelikefalin is a kappa-opioid receptor agonist recently approved in the United States for the treatment of moderate-to-severe CKD-aP in hemodialysis patients. Study 3105 was conducted to further assess the safety of difelikefalin and the effects on pruritus and QoL.

Safety and Tolerability of Difelikefalin for the Treatment of Moderate to Severe Pruritus in Hemodialysis Patients: Pooled Analysis From the Phase 3 Clinical Trial Program.

Rationale & Objective: We report a pooled safety analysis of intravenous difelikefalin in participants with moderate to severe chronic kidney disease-associated pruritus (CKD-aP) treated by hemodialysis in 4 phase 3 clinical studies.

Study Design: KALM-1 and KALM-2 were randomized, double-blind, placebo-controlled, pivotal phase 3 studies; CLIN3101 (52 weeks) and CLIN3105 (12 weeks) were open-label studies.

Setting & Participants: Adults with moderate to severe CKD-aP treated by hemodialysis in North America, Europe, and the Asia-Pacific region.

Efficacy of Difelikefalin for the Treatment of Moderate to Severe Pruritus in Hemodialysis Patients: Pooled Analysis of KALM-1 and KALM-2 Phase 3 Studies.

Rationale & Objective: Chronic kidney disease-associated pruritus (CKD-aP) in patients treated by hemodialysis (HD) impairs quality of life (QoL). Difelikefalin, a selective κ-opioid receptor agonist, decreased the intensity of CKD-aP in patients undergoing HD. This pooled analysis evaluated difelikefalin's efficacy and the itch-related QoL overall and in subgroups defined by demographics or disease characteristics.

Psychometric validation and meaningful change thresholds of the Worst Itching Intensity Numerical Rating Scale for assessing itch in patients with chronic kidney disease-associated pruritus.

Background: Chronic kidney disease-associated pruritus (CKD-aP) is characterized by persistent itch that often leads to substantially impaired quality of life. The Worst Itching Intensity Numerical Rating Scale (WI-NRS) is a single-item patient-reported outcome measure in which patients indicate the intensity of the worst itching they experienced over the past 24 h. Here, we evaluated the content validity and psychometric properties of the WI-NRS and confirmed the threshold of meaningful change in hemodialysis patients with moderate-to-severe CKD-aP.

Self-reported Pruritus and Clinical, Dialysis-Related, and Patient-Reported Outcomes in Hemodialysis Patients.

Rationale & Objective: Chronic kidney disease (CKD)-associated pruritus, generalized itching related to CKD, affects many aspects of hemodialysis patients' lives. However, information regarding the relationship between pruritus and several key outcomes in hemodialysis patients remains limited.

Study Design: Prospective cohort.

A Phase 3 Trial of Difelikefalin in Hemodialysis Patients with Pruritus.

Background: Difelikefalin is a peripherally restricted and selective agonist of kappa opioid receptors that are considered to be important in modulating pruritus in conditions such as chronic kidney disease.

Methods: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned patients undergoing hemodialysis who had moderate-to-severe pruritus to receive either intravenous difelikefalin (at a dose of 0.5 μg per kilogram of body weight) or placebo three times per week for 12 weeks.

Evaluation of the Ototoxicity Potential of Once-Daily, Single-Entity Hydrocodone in Patients with Chronic Pain: Results of Two Phase-3 Clinical Studies.

Background: Use/misuse of the opioid combination hydrocodone-acetaminophen has been associated with permanent hearing loss. Although reports have been rare, this potential effect can have significant detrimental effect on patients' overall quality of life. To date, the ototoxic effect of hydrocodone alone has not been systematically investigated.

Long-term effectiveness and safety of once-daily, single-entity, extended-release hydrocodone in patients of ≥75 years of age with moderate to severe nonmalignant and nonneuropathic pain.

In elderly (≥75 years) individuals, age-associated physiologic changes and a higher prevalence of comorbidities, polypharmacy, and increased susceptibility to medication-induced side effects complicate pain management. Hysingla ER (HYD) is a once-daily, single-entity, extended-release hydrocodone formulation approved for the treatment of chronic pain that is insufficiently controlled by alternative treatments. In this post-hoc analysis of a previously reported study, the effectiveness and safety of HYD for the treatment of moderate-to-severe chronic pain among the elderly (≥75 years) for a 52-week duration was investigated.

Efficacy and Safety of Once-Daily Extended-Release (ER) Hydrocodone in Individuals Previously Receiving ER Morphine for Chronic Pain.

Objectives: This post hoc analysis examined the effectiveness and safety of hydrocodone bitartrate (HYD) in patients with moderate-to-severe chronic pain who were previously taking extended-release morphine (morphine ER) for pain management.

Study Design: The primary analysis was an open-label, 12-month study.

Setting: The study was conducted in 88 sites in the United States.

Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations.

There is tremendous interpatient variability in the response to analgesic therapy (even for efficacious treatments), which can be the source of great frustration in clinical practice. This has led to calls for "precision medicine" or personalized pain therapeutics (ie, empirically based algorithms that determine the optimal treatments, or treatment combinations, for individual patients) that would presumably improve both the clinical care of patients with pain and the success rates for putative analgesic drugs in phase 2 and 3 clinical trials. However, before implementing this approach, the characteristics of individual patients or subgroups of patients that increase or decrease the response to a specific treatment need to be identified.

Pharmacokinetic Profile and Sustained 24-hour Analgesia of a Once-daily Hydrocodone Bitartrate Extended-release Tablet with Abuse-deterrent Properties.

Purpose: The purpose of this study was to evaluate the pharmacokinetics (PK) and 24-hour analgesic effectiveness of once-daily, single-entity, extended-release hydrocodone (HYD) with abuse-deterrent properties.

Methods: Four studies were included. Three open-label PK studies had the following designs: single-dose, 5-treatment, 4-period, crossover, dose-proportionality study; HYD 120 mg for 5 days (steady-state study 1); 2-treatment, 2-period, multiple-dose crossover study assessing the relative bioavailability of HYD 30 mg and hydrocodone 7.

Pain intensity and interference with functioning and well-being in subgroups of patients with chronic pain treated with once-daily hydrocodone tablets.

Background: A previous 52-week trial of patients with chronic noncancer, non-neuropathic pain (CNNP) showed clinically meaningful improvement in pain intensity, pain interference, and physical health-related quality of life (HRQL) following daily treatment with an extended-release, once-daily hydrocodone (Hysingla(®) ER; HYD) bitartrate tablet.

Objective: To examine treatment response within patient subgroups and to assess between-subgroup differences in effectiveness and side effect profile.

Methods: Data were from an open-label 52-week trial of treatment with HYD tablets (20-120 mg, once-daily) for patients with moderate-to-severe CNNP.

12-Month safety and effectiveness of once-daily hydrocodone tablets formulated with abuse-deterrent properties in patients with moderate to severe chronic pain.

Objective: To characterize the long-term safety and effectiveness of Hysingla™ ER, single-entity, once-daily, extended-release hydrocodone bitartrate tablets formulated with abuse-deterrent properties (HYD), offering a new treatment option for appropriate patients with chronic pain.

Design: An open-label study with a dose-titration period (up to 45 days) and a maintenance period (12 months).

Patients, Participants: A total of 922 patients with chronic nonmalignant and non-neuropathic moderate to severe pain received open-label HYD tablets 20-120 mg; 728 of these achieved a stabilized dose of HYD at the end of dose-titration and entered the maintenance period.

A multicenter, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of single-entity, once-daily hydrocodone tablets in patients with uncontrolled moderate to severe chronic low back pain.

Objectives: This multicenter, randomized, double-blind, placebo-controlled study with an enriched enrollment, randomized withdrawal design was conducted to evaluate the analgesic efficacy and safety of single-entity, once-daily hydrocodone 20 to 120 mg tablets (HYD) in opioid-naive and opioid-experienced patients with uncontrolled moderate to severe chronic low back pain (CLBP).

Research Design And Methods: The primary endpoint was week 12 pain intensity scores (11-point scale, 0 = no pain) using a mixed effect model with repeated measures incorporating a pattern mixture model framework. Responder analysis was a secondary endpoint.

A Subgroup Analysis Found no Diminished Response to Buprenorphine Transdermal System Treatment for Chronic Low Back Pain Patients Classified with Depression.

Background: Chronic pain (CP) patients with depression typically exhibit worse post-treatment outcomes than nondepressed CP patients. The cause is often assumed to reflect a differential response to treatment, neglecting other potential explanations, such as the continuation of differences in pretreatment outcomes. This post hoc analysis examines whether worse post-treatment outcomes for depressed patients with chronic low back pain (CLBP) are driven by reduced treatment efficacy.

Buprenorphine Transdermal System Improves Sleep Quality and Reduces Sleep Disturbance in Patients with Moderate-to-Severe Chronic Low Back Pain: Results from Two Randomized Controlled Trials.

Objective: To evaluate the impact of buprenorphine (Butrans®) transdermal System (BTDS) treatment on sleep outcomes for patients with moderate-to-severe chronic low back pain (CLBP).

Methods: Two enriched-enrollment, randomized-withdrawal, double-blind, controlled trials examined BTDS treatment for patients with moderate-to-severe CLBP. Trial I evaluated BTDS 10 and 20 mcg/hour against a placebo control among opioid-naïve patients.

Buprenorphine transdermal system compared with placebo reduces interference in functioning for chronic low back pain.

Objective: This study examines the efficacy of the buprenorphine transdermal system (BTDS) for reducing the interference of pain on physical and emotional functioning associated with chronic low back pain (CLBP).

Methods: A post-hoc analysis used data from a randomized, placebo-controlled, double-blind trial of patients with moderate-to-severe CLBP. The Brief Pain Inventory (BPI) measured pain interference at screening, following a run-in period, and during the 12-week double-blind treatment phase.

Efficacy and safety of once-daily, extended-release hydrocodone in individuals previously receiving hydrocodone/acetaminophen combination therapy for chronic pain.

Background: Hydrocodone/acetaminophen combination analgesics are frequently prescribed for chronic pain management; however, acetaminophen presents potential hepatotoxicity to patients and thus dose limitations. These opioid medications are also widely abused. Once-daily, single-entity hydrocodone (Hysingla™ ER tablets [HYD]) is a novel formulation with abuse-deterrent properties for the management of chronic pain and represents a suitable option for those patients receiving analgesics containing the same opioid analgesic, hydrocodone.

The impact of buprenorphine transdermal delivery system on activities of daily living among patients with chronic low back pain: an application of the international classification of functioning, disability and health.

Objectives: The buprenorphine transdermal delivery system (BTDS) is indicated for reduction of pain in moderate to severe chronic low back pain (CLBP), which can affect patients' ability to perform routine activities of daily living (ADLs). This post hoc analysis of clinical trial data examines the impact of BTDS treatment on CLBP patients' ability to perform ADLs that relate to functioning with low back pain.

Methods: Data are drawn from a multicenter, enriched enrollment, randomized, placebo-controlled, double-blind 12-week trial of BTDS for pain control among opioid-naive patients with moderate to severe CLBP.