For millions living with osteoarthritis, pain and stiffness can transform routine activities into daunting challenges. While conventional approaches—such as over-the-counter analgesics and corticosteroid injections—may offer temporary relief, they do not halt the progressive deterioration of joint structures.
Emerging research from Yale University points toward a novel strategy. Published in Bioactive Materials, the study demonstrates that lacosamide—an existing epilepsy medication—may address osteoarthritis through a dual mechanism: alleviating pain while actively reversing cartilage degradation. These benefits proved most pronounced when the drug was administered directly into the joint via a specialized hydrogel delivery system.
The Biological Basis of Cartilage Destruction
Osteoarthritis is frequently characterized as simple “wear and tear,” yet this characterization overlooks the complex biological processes driving the disease.
Healthy joints rely on chondrocytes—specialized cells that maintain cartilage by continuously balancing tissue synthesis with degradation. In osteoarthritis, this equilibrium collapses; cartilage deteriorates faster than the body can rebuild it, ultimately permitting bone-on-bone contact. As the condition progresses, patients may face invasive interventions including total knee arthroplasty.
“There remains a critical unmet need in osteoarthritis treatment,” explains the study’s principal investigator, Chuan-Ju Liu, PhD, Charles W. Ohse Professor of Orthopaedics & Rehabilitation. “We require therapies that do more than mask symptoms—they must fundamentally alter disease progression.”
Currently, no FDA-approved medication simultaneously targets osteoarthritis pain and prevents structural cartilage breakdown. Liu’s research suggests that a single therapeutic approach may eventually address both challenges.
The research team repurposed an existing pharmaceutical agent and combined it with an advanced gel formulated to retain the drug within the joint. This strategy could preserve joint tissue while providing sustained analgesia without the risks associated with opioid dependence.
A Molecular Link Between Pain and Cartilage Degradation
The investigation centers on Nav1.7, a protein that functions as a voltage-gated sodium channel. These molecular gates regulate electrical signaling across cell membranes and play crucial roles in physiological processes.
Nav1.7 has traditionally been associated with nociceptive neurons responsible for transmitting pain signals to the brain. However, recent findings from Liu and colleagues demonstrate that this protein is also highly expressed in chondrocytes—the very cells tasked with cartilage maintenance.
In healthy joints, Nav1.7 activity remains minimal. During osteoarthritis, however, expression escalates dramatically. The researchers discovered that this upregulation amplifies pain signaling while simultaneously driving chondrocytes to degrade the cartilage they normally preserve.
This dual functionality makes Nav1.7 an unconventional therapeutic target, as it appears to govern both the perception of pain and the physical degradation of articular tissue.
“When Nav1.7 becomes dysregulated, it drives both joint degeneration and pain perception,” Liu explains. “Our data indicate that Nav1.7 functions as a dual-acting target. By inhibiting this single protein, we may simultaneously suppress pain signaling and reprogram cartilage cells to halt degradation and initiate repair.”
An Established Epilepsy Medication Promotes Cartilage Restoration
Rather than developing an entirely novel compound, Liu’s team evaluated existing sodium channel inhibitors. Among these candidates, lacosamide demonstrated potent biological activity at significantly lower concentrations while exhibiting a more favorable safety profile compared with older agents in the same class.
Although lacosamide is currently indicated for epilepsy, the researchers found that its effects on cartilage were highly dose-dependent.
Higher doses did not yield superior outcomes. At an optimal low concentration, lacosamide stimulated chondrocytes to synthesize cartilage-building proteins while inhibiting catabolic processes. Deviations from this narrow therapeutic window—either too high or too low—diminished these beneficial effects.
“This indicates a finely tuned biological system,” Liu observes. “There exists an optimal concentration range where the drug restores equilibrium without overcorrection. What proved remarkable was not merely its efficacy, but the minimal dose required to achieve it.”
Further analysis revealed that lacosamide also modulates cellular communication, stimulating the secretion of two beneficial signaling proteins: HSP70 and midkine.
HSP70 assists cellular stress responses and supports tissue repair mechanisms, while midkine regulates inflammation and shields joint tissue from degradation. Together, these proteins appear to establish a microenvironment conducive to cartilage preservation.
“These proteins establish a supportive milieu for cartilage maintenance,” Liu explains. “They enable the drug’s effects to transcend individual cells, influencing tissue-level behavior.”
Engineered Hydrogel Retains Drug Within the Joint
While oral lacosamide proved effective in preclinical models, systemically administered drugs circulate throughout the body, increasing the risk of off-target effects.
Consequently, the researchers explored intra-articular injection, enabling direct delivery into the affected joint.
A significant challenge remained. “The knee—osteoarthritis’s most common site—behaves like a leaky bucket,” Liu notes. “The body’s lymphatic drainage can clear injected liquids from the knee within hours.”
To prolong intra-articular retention, the team developed a specialized Collagen II hydrogel. This thermoresponsive material remains liquid within a cool syringe but transitions to a firm, gel-like state upon reaching body temperature.
Once deployed within the joint, the hydrogel serves as a localized reservoir for lacosamide, maintaining drug concentration at the target site while enabling gradual release over several weeks.
“The hydrogel functions as a local depot,” Liu states. “It retains the drug at the site of pathology and releases it slowly over time, effectively transforming a daily oral regimen into a sustained, localized therapy active for a month or longer.”
In the same preclinical studies, a single injection of the lacosamide-loaded gel administered every four weeks prevented cartilage loss more effectively than daily oral dosing.
Approved Status May Accelerate Clinical Translation
A key advantage of lacosamide is its established safety profile in humans. This existing approval could facilitate faster progression to clinical trials in osteoarthritis patients compared with de novo drug development.
Lacosamide has also been evaluated in humans with Nav1.7-related neuropathic pain conditions. These clinical data bolster the researchers’ confidence that laboratory findings may translate into meaningful analgesia for patients.
This work reflects a broader trend in medicine: combining pharmacologic agents with advanced biomaterials to precisely control where and how treatments are delivered. Should this approach prove successful in humans, it could reduce procedural burdens, minimize adverse effects, and provide prolonged protection against structural joint deterioration.
“We are not merely developing a treatment,” Liu concludes, “but an integrated system that enables medicine to function more effectively precisely where needed. Our objective extends beyond symptom management toward genuine disease modification. This endeavor brings us measurably closer to that goal.”