Search

(R,S)-Ketamine (ketamine) is a dissociative anesthetic that also possesses analgesic and antidepressant activity. Undesirable dissociative side effects and misuse potential limit expanded use of ketamine in several mental health disorders despite promising clinical activity and intensifying medical need. (2R,6R)-Hydroxynorketamine (RR-HNK) is a metabolite of ketamine that lacks anesthetic and dissociative activity but maintains antidepressant and analgesic activity in multiple preclinical models. To enable future assessments in selected human indications, we report the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of RR-HNK in a Phase 1 study in healthy volunteers (NCT04711005). A six-level single-ascending dose (SAD) (0.1-4 mg/kg) and a two-level multiple ascending dose (MAD) (1 and 2 mg/kg) study was performed using a 40-minute IV administration emulating the common practice for ketamine administration for depression. Safety assessments showed RR-HNK possessed a minimal adverse event profile and no serious adverse events at all doses examined. Evaluations of dissociation and sedation demonstrated that RR-HNK did not possess anesthetic or dissociative characteristics in the doses examined. RR-HNK PK parameters were measured in both the SAD and MAD studies and exhibited dose-proportional increases in exposure. Quantitative electroencephalography (EEG) measurements collected as a PD parameter based on preclinical findings and ketamine's established effect on gamma-power oscillations demonstrated increases of gamma power in some participants at the lower/mid-range doses examined. Cerebrospinal fluid examination confirmed RR-HNK exposure within the central nervous system (CNS). Collectively, these data demonstrate RR-HNK is well tolerated with an acceptable PK profile and promising PD outcomes to support the progression into Phase 2., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Objective: To describe characteristics of older adults who received opioids for chronic non-cancer pain (CP), ascertain types of opioid treatments received, and examine associations between patient characteristics and treatment outcomes., Design: Retrospective cohort study., Setting: Primary care practice in New York City., Patients: Eligible patients were >or=65 and newly started on an opioid for CP., Outcome Measures: Patient characteristics and provider treatments, as well as duration of opioid therapy, proportion discontinuing therapy, and evidence of pain reduction and continued use of opioid for more than 1 year. Other outcomes included the presence and type(s) of side effects, abuse/misuse behaviors, and adverse events., Results: Participants (N = 133) had a mean age of 82 (range = 65-105), were mostly female (84%), and white (74%). Common indications for opioid treatment included back pain (37%) and osteoarthritis (35%). Mean duration of opioid use was 388 days (range = 0-1,880). Short-acting analgesics were most commonly prescribed. Physicians recorded side effects in 40% of cases. Opioids were discontinued in 48% of cases, mostly due to side effects/lack of efficacy. Pain reduction was documented in 66% of patient records, while 32% reported less pain and continued treatment for >or=1 year. Three percent displayed abuse/misuse behaviors, and 5% were hospitalized due to opioid-related adverse events., Conclusions: Over 50% of older patients with CP tolerated treatment. Treatment was discontinued in 48% of cases, mostly due to side effects and lack of analgesic efficacy. Efforts are needed to establish the long-term safety and efficacy of opioid treatment for CP in diverse older patient populations.

This systematic review summarizes existing evidence regarding the efficacy, safety, and abuse and misuse potential of opioids as treatment for chronic noncancer pain in older adults. Multiple databases were searched to identify relevant studies published in English (1/1/80-7/1/09) with a mean study population age of 60 and older. Forty-three articles were identified and retained for review (40 reported safety and efficacy data, the remaining 3 reported misuse or abuse outcome data). The weighted mean subject age was 64.1 (mean age range 60-73). Studies enrolled patients with osteoarthritis (70%), neuropathic pain (13%), and other pain-producing disorders (17%). The mean duration of treatment studies was 4 weeks (range 1.5-156 weeks), and only five (12%) lasted longer than 12 weeks. In meta-analyses, effect sizes were -0.557 (P<.001) for pain reduction, -0.432 (P<.001) for physical disability reduction, and 0.859 (P=.31) for improved sleep. The effect size for the Medical Outcomes Study 36-item Health Survey was 0.191 (P=.17) for the physical component score and -0.220 (P=.04) for the mental component score. Adults aged 65 and older were as likely as those younger than 65 to benefit from treatment. Common adverse events included constipation (median frequency of occurrence 30%), nausea (28%), and dizziness (22%) and prompted opioid discontinuation in 25% of cases. Abuse and misuse behaviors were negatively associated with older age. In older adults with chronic pain and no significant comorbidity, short-term use of opioids is associated with reduction in pain intensity and better physical functioning but poorer mental health functioning. The long-term safety, efficacy, and abuse potential of this treatment practice in diverse populations of older persons remain to be determined.

Objective: Prior to testing the feasibility/potential efficacy of a newly developed self-management pain program for seniors with back pain, this study sought to: 1) determine prospective consumers' prior exposure to self-management pain programs, 2) determine their willingness to participate in the new program, and 3) ascertain perceived barriers/facilitators to program participation., Design: Cross-sectional survey., Setting: Six senior centers located in New York City., Participants: We enrolled a race/ethnicity stratified (African American, Hispanic, or non-Hispanic White) sample of 90 subjects who were ages 60 years or older and had chronic back pain., Results: While 60% of non-Hispanic Whites reported prior participation in a self-management pain program, fewer Hispanic (23%) and African Americans (20%) participants reported prior participation. Most participants (80%) were strongly willing to participate in the new program. Multivariate analyses revealed that only pain intensity had a trend toward significance (P = 0.07), with higher pain scores associated with greater willingness to participate. Few barriers to participation were identified, however, respondents felt that tailoring the course to best meet the needs of those with physical disabilities, providing flexibility in class timing, and informing individuals about program benefits prior to enrollment could help maximize program reach. No race/ethnicity differences were identified with respect to willingness to participate or program participation barriers., Conclusions: These data support efforts to disseminate self-management pain programs in older populations, particularly minority communities. The recommendations made by participants can help to guide implementation efforts of the newly developed pain program and may help to enhance both their reach and success.