August 6, 2024 | One of the most intriguing aspects of neuromodulation is the observed carry-over effects in certain applications, where the therapeutic benefits persist beyond the duration of stimulation. Recently, there have been a number of articles exploring the carry-over effect in peripheral nerve stimulation for the treatment of pain. Interestingly, this phenomenon has been well documented in peripheral nerve stimulation for overactive bladder for nearly 20 years.
Early Applications and Overactive Bladder
One of the early neuromodulation applications integrating the carry-over effect into a product design and treatment protocol was with percutaneous tibial nerve stimulation. Uroplasty (now part of Laborie Medical Technologies) pioneered a tibial nerve stimulator, called the Urgent PC Modulation System, for the treatment of urinary urgency, urinary frequency, and urge incontinence, receiving FDA clearance back in 2005.
With PTNS, the treatment protocol typically involves once-weekly sessions for 12 weeks, followed by monthly maintenance sessions. Interestingly, while sacral nerve stimulation for OAB has demonstrated significant therapeutic benefits, the “carry-over” effect of SNS has not been extensively explored. In fact, a recent overview article (last updated April 2024) by Michael Feloney, chair, department of urology at Creighton University, goes further to state, “Unlike anticholinergics or sacral neuromodulation, PTNS provides a carryover effect of continued symptom improvement even when the nerve is not actively stimulated. PTNS over the last 20 years has gained little traction in part due to the burden on patients to frequent clinics, as well as the relatively low reimbursement by payors for PTNS treatment. More recently, initiatives underway bringing to market implantable systems at the tibial nerve (Bioventus, Valencia Technologies, and others) which solve the patient commitment challenges.
Chronic Pain and Peripheral Nerve Stimulation
The carry-over effect in the treatment of pain has recently received increased attention with the introduction of temporary/percutaneous peripheral nerve stimulation for chronic pain, whereby there may be a long (up to 12 month) carry-over effect in peripheral nerve stimulation for the treatment of various pain conditions.
Recently, a notable prospective study by Tyler West et al., titled “Pain Intensity and Opioid Consumption After Temporary and Permanent Peripheral Nerve Stimulation: A 2-Year Multicenter Analysis,” compared retrospective data on 60-day temporary stimulation with daily stimulation using permanent devices, assessing outcomes at 12 and 24 months. Conducted across multiple centers, the study included 126 patients who received either temporary or permanent PNS implants between January 2014 and February 2022. The analysis focused on changes in pain intensity and opioid consumption as primary outcomes, utilizing mixed-effects regression models to handle missing data and patient dropouts.
The study observed a significant reduction in pain intensity in both temporary and permanent PNS groups at 12 months post-implantation, with pain scores decreasing by a mean difference of -3.0 on an 11-point Numerical Rating Scale. This reduction persisted at three, six, and 24 months, indicating sustained pain relief benefits. Interestingly, no significant difference was found between temporary and permanent PNS cohorts, suggesting that temporary PNS might offer long-lasting pain relief even after lead removal.
Despite the significant reduction in pain intensity, the study found no significant change in daily opioid consumption at 6- and 12-months post-implantation in either cohort.
The article contrasts the proposed mechanism of action of PNS versus SCS, recognizing that the precise MOA of neuromodulation is unknown, and suggests the “gate control theory” for SCS with possible inhibition of central neuroplasticity as a MOA explaining the carry-over effect in temporary stimulation of peripheral nerves. The article notes that in the case of temporary PNS, “decreased neuronal excitability may reset the cycle of central sensitization, partially explaining long-term relief after implant removal.” Limitations of the retrospective study are noted, specifically, potential reporting biases and the lack of standardization of a randomized controlled trial.
In an interview with NBR, Ryan D’Souza from the Mayo Clinic’s department of anesthesiology and perioperative medicine, a coauthor of the paper, explained its relevance for pain neuromodulation clinicians and vendors. He said that PNS tends to have a longer carryover effect than SCS.
“Patients who receive SCS tend to have more diffuse pain or at least pain overlapping several nerve distributions whereas patients who receive PNS tend to have pain that is worse in one or two nerve distributions. Therefore, rationally, it would be more likely that those with SCS devices have a higher pain burden versus those with PNS devices,” he said. He also pointed out that PNS has the added benefit of stimulating motor fibers, even though clinicians tend not to have the amplitude that high as motor contractions can be painful. D’Souza wonders whether motor activation peripherally may assist with restrengthening and conditioning those muscles, something that dorsal column SCS can’t do since it only stimulates sensory fibers.
Other Studies on Carry-Over Effect in Pain Reduction
Other studies have also explored the carry-over effect in pain reduction. A publication titled “A Review of Prospective Studies Regarding Percutaneous Peripheral Nerve Stimulation Treatment in the Management of Chronic Pain” authored by investigators affiliated with SPR Therapeutics, reviewed six studies providing original data from prospective research on percutaneous PNS treatment for various pain conditions (shoulder pain, neuropathic pain, and low back pain). The conclusion was that percutaneous PNS treatment for up to 60 days could reduce pain and improve daily life interference.
Conversely, studies focusing on the carry-over effect for spinal cord stimulation have not demonstrated long-duration carry-over effects. For instance, a January 2024 article titled “Examining the Duration of Carryover Effect in Patients With Chronic Pain Treated With Spinal Cord Stimulation (EChO Study): An Open, Interventional, Investigator-Initiated, International Multicenter Study” found that the median carry-over time for all patients was five hours once stimulation ceased.
Carry-Over Effect in TMS for Epilepsy and Depression
In addition to carry-over effects noted in the treatment of pain and OAB, there appears to be a similar phenomenon in transcranial magnetic stimulation of brain tissue for epilepsy and depression. In a 2024 article titled, “Cellular mechanisms underlying carry-over effects after magnetic stimulation,” the authors note, “effects of magnetic stimulation can still last after the termination of the magnetic stimulation.” The article focuses on providing a mechanism of action at the cellular level, and noting other MOAs which may have some relevance to PNS stimulation for the treatment of pain.
Future Implications
Further investigation into studying the carry-over effect within neuromodulation is needed, specifically conflict-free, prospective, placebo-controlled trials comparing short-term stimulation carry-over effect with long-term stimulation, before making any definitive conclusions. If additional studies on PNS for pain and other applications support these early prospective findings, the implications for companies could be significant. This could impact product design areas such as cyclic stimulation for permanent systems, the development of new products designed for short-term stimulation, and the time to market for new products (with 60-day percutaneous stimulation following the 510(k) pathway and active implantable systems following the PMA pathway), as well as profound effects on patient treatment protocols. Furthermore, a better understanding of the mechanisms underlying this carry-over effect is needed which could also guide optimization of PNS protocols and improve patient outcomes.
