A mechanism-based proof of concept study on the effects of duloxetine in patients with painful knee osteoarthritis

Abstract

Background The global burden of osteoarthritis (OA) is steadily increasing due to demographic and lifestyle changes. The nervous system can undergo peripheral and central neuroplastic changes (sensitization) in patients with OA impacting the options to manage the pain adequately. As a result of sensitization, patients with OA show lower pressure pain thresholds (PPTs), facilitated temporal summation of pain (TSP), and impaired conditioned pain modulation (CPM). As traditional analgesics (acetaminophen and non-steroidal anti-inflammatory drugs) are not recommended for long-term use in OA, more fundamental knowledge related to other possible management regimes are needed. Duloxetine is a serotonin-noradrenalin reuptake inhibitor, and analgesic effects are documented in patients with OA although the underlying fundamental mechanisms remain unclear. The descending pain inhibitory control system is believed to be dependent on serotonin and noradrenalin. We hypothesized that the analgesic effect of duloxetine could act through these pathways and consequently indirectly reduce pain and sensitization. The aim of this mechanistic study is to investigate if PPTs, TSP, CPM, and clinical pain parameters are modulated by duloxetine. Methods This proof of concept study is a randomized, placebo-controlled, double-blinded, crossover trial, which compares PPTs, TSP, and CPM before and after 18 weeks of duloxetine and placebo in forty patients with knee OA. The intervention periods include a titration period (2 weeks), treatment period (60 mg daily for 14 weeks), and a discontinuation period (2 weeks). Intervention periods are separated by 2 weeks. Discussion Duloxetine is recommended for the treatment of chronic pain, but the underlying mechanisms of the analgesic effects are currently unknown. This study will investigate if duloxetine can modify central pain mechanisms and thereby provide insights into the underlying mechanisms of the analgesic effect. Trial registration ClinicalTrials.govNCT04224584. Registered on January 6, 2020. EudraCT 2019-003437-42. Registered on October 22, 2019. The North Denmark Region Committee on Health Research Ethics N-20190055. Registered on October 31, 2019.

The effect of duloxetine on mechanistic pain profiles, cognitive factors and clinical pain in patients with painful knee osteoarthritis—A randomized, double‐blind, placebo‐controlled, crossover study

“…The study was approved by The Danish Medicines Agency (case number: 2019082317), The North Denmark Region Committee on Health Research Ethics (case number: N‐20190050), registered at http://clinicaltrial.gov (http://clinicaltrials.gov identifier: NCT04224584), and in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT number: 2019–003437‐42). The study protocol is published (Ammitzbøll et al, 2021). The trial was continuously monitored by the Good Clinical Practice (GCP) Unit of Aalborg University Hospital, externally audited by the Danish Medicines Agency, and was conducted in accordance with The Helsinki Declaration, GCP, and all applicable Danish regulatory requirements.…”

Biological Targets of Multimolecular Therapies in Middle-Age Osteoarthritis

“…On the other hand, psychotropic drugs, such as duloxetine, which is a serotonin-noradrenalin re-uptake inhibitor, is recommended for chronic pain from hyperalgesia and central sensitization 44. At present, the effects of duloxetine on hyperalgesia and central sensitization in knee OA are under investigation 45–47. These examples reflect current trends in OA research and stress the importance of patient stratification according to their predominant pain mechanism.…”

“…44 At present, the effects of duloxetine on hyperalgesia and central sensitization in knee OA are under investigation. [45][46][47] These examples reflect current trends in OA research and stress the importance of patient stratification according to their predominant pain mechanism. However, such research approach has not been taken in PRP research.…”