Abstract
Peripheral nerve stimulation (PNS) has been used to treat pain successfully in many types of patients for over 5 decades. Since the 1960s multiple studies have demonstrated the potential for clinically significant pain relief and improvements in quality of life, including reductions in disability, decreased analgesic usage, increases in daily activities, and improvements in sleep. But despite its potential to provide nonnarcotic pain relief, historically only a fraction of the patients who could benefit from PNS have actually received it. This chapter reviews the evolution of PNS while noting the challenges that have limited its adoption, highlights key movements within the field to address these challenges, and provides an overview of technology developed specifically for PNS that has recently been cleared by the United States Food and Drug Administration. The use of improved techniques, availability of devices developed specifically for PNS, and additional studies have renewed interest in PNS and may open the door to expanded utility of this therapeutic tool.
Keywords
Cleared, Effectiveness, Efficacy, FDA, Lead, Pain, PNS, Relief, Safety
Outline
Introduction 729
Multiple Theories Exist as to the Exact Mechanism/s Through Which PNS Achieves Pain Relief 730
PNS Has a Long History of Success, But Existing Technology and Early Methods of Implantation Previously Required Precise Neurosurgical Placement, Limiting Clinical Use 730
Leads Initially Designed for Spinal Cord Stimulation Have Been Used for PNS, But Studies Indicated That Technology Designed Specifically for PNS Was Needed to Overcome Challenges 730
New Technique Introduced to Overcome Barriers to PNS 731
Peripheral Field Stimulation 732
Ultrasound Guidance Improves Outcomes 732
Recent FDA Clearance of Next-Generation PNS Systems May Enable the Potential of PNS Documented in Research Studies to Be Translated into Routine Clinical Practice 733
StimQ PNS System Has Received FDA Clearance 733
StimRouter TM Neuromodulation System Has Received FDA Clearance 734
SPRINT ® PNS System Has Received FDA Clearance 734
Other Investigational PNS Systems Are in Development 737
Conclusion 737
Disclosures [CR]
References 737
Disclosures
Joseph Boggs, PhD, is an employee of and owns equity in SPR Therapeutics.
John Chae, MD, ME, is a consultant to and owns equity in SPR Therapeutics.
Maria Bennett, MS, is an employee of and owns equity in SPR Therapeutics.
Introduction
It is common for electrical stimulation of named peripheral nerves to produce consistently high success rates in achieving pain relief (60%–80%) in well-selected patients when delivered by skilled clinicians ( ). The potential for peripheral nerve stimulation (PNS) to reduce opioid analgesic usage has also been demonstrated ( ). Conventionally, the goal of PNS has been to place the lead as close as possible to the nerve innervating the region of pain ( ). The primary challenge has been to achieve pain relief without unwanted side-effects ( ).
Multiple Theories Exist as to the Exact Mechanism/s Through Which PNS Achieves Pain Relief
While there are some differences in the theories, review and analysis of theories, approaches, and outcomes across multiple studies suggest that to achieve a successful clinical outcome electrical stimulation should be delivered to the nerve innervating the painful region to provide pain relief and stimulation should be comfortable for the patient, confirming that the unwanted effects of nontarget fiber activation have been avoided ( ). This guidance is consistent with the results of animal studies indicating that PNS can reduce signaling within the central nervous system (CNS) pathways that is often associated with the perception of pain ( ). Other studies in animals ( ) and humans ( ) also suggest that PNS may have the potential to reduce peripheral mediators of pain. In both scenarios of pain suppression through central and peripheral mechanisms, the potential to reduce activity within the pain pathways appeared to be most significant when PNS is delivered to the nerve innervating the peripheral region of pain, which is consistent with the majority of clinical studies ( ).
PNS Has a Long History of Success, But Existing Technology and Early Methods of Implantation Previously Required Precise Neurosurgical Placement, Limiting Clinical Use
Early approaches to PNS were successful, but often time consuming, complex ( ), and requiring a high level of specialized skill, which greatly limited the number of clinicians who could offer PNS as part of their practice ( ). Overall, PNS has been used in various forms on multiple peripheral nerves in multiple anatomical locations to provide highly clinically significant pain relief, and in some cases reduction or elimination of reliance on opioid analgesics ( ). But early successes with PNS, replicated in multiple studies, were mixed with challenges that limited enthusiasm ( ). Clinical adoption beyond major academic centers was significantly limited, largely due to the state of the technology at that time and the invasive surgery and neurosurgical expertise required to place the existing leads correctly ( ). Improvements to both the technology and the approach to placement have begun to move PNS from a treatment of last resort to something that is becoming more accepted and offered more commonly across a range of medical centers as a practical modality for multiple types of pain ( ).
Leads Initially Designed for Spinal Cord Stimulation Have Been Used for PNS, But Studies Indicated That Technology Designed Specifically for PNS Was Needed to Overcome Challenges
Until recently, all commercially available PNS systems were designed to be placed directly on the nerve or as close as possible to it ( Fig. 57.1 ), and the majority of systems used for PNS were originally designed for spinal cord stimulation (SCS) ( ). The Medtronic manual indicated that to implant a paddle lead for PNS the peripheral nerve should be surgically exposed and carefully dissected free from surrounding tissue, such that a 5–6 cm section of nerve was isolated ( ). The paddle lead is then placed under the isolated section of the nerve and the paddle portion of the lead sutured in multiple locations to the surrounding tissue, sometimes positioning and suturing an additional layer of fascia as needed ( ). This surgical approach and variations of it have been used successfully in many patients who had severe intractable pain and for whom alternative therapies were unsuccessful ( Fig. 57.2 ) ( ). The number of patients documented to have benefited was substantial if quantified in absolute numbers, but could also be considered relatively small if measured as a proportion of those who could have benefited ( ).
PNS became an accepted pain management modality, with growing support from peer-reviewed literature ( ) and reimbursement coding within well-defined patient populations, but clinical adoption remained limited outside academic and leading private centers. The primary barriers to adoption included the invasiveness of the surgical procedure to place the leads, the challenge of screening patients prior to surgery to determine their potential for benefit, and the failure rate of the commercially available devices when used for PNS relative to the failure rate when they were used for SCS, for which they were originally developed ( ). These barriers highlighted the need for improved techniques and technology to be developed specifically for PNS ( ).
New Technique Introduced to Overcome Barriers to PNS
To overcome the previous barriers to PNS, a new technique of percutaneously inserting leads for PNS (i.e., percutaneous PNS) was developed ( ). Once the potential for long-term benefit using a percutaneous approach to PNS had been demonstrated ( ), other studies and publications quickly followed and reported on modifications of the technique and adaptations enabling other nerves to be targeted with a minimally invasive approach, often using leads developed for SCS ( ). Other nerves initially included those in the head, face, and neck ( ). Subsequently new approaches were developed and demonstrated the potential to deliver PNS through leads placed percutaneously adjacent to nerves in both the upper and the lower extremities ( ).
An example that received significant interest in the last decade was PNS of the occipital nerve. While there is variation in the results, case series studies have demonstrated the potential for PNS of the occipital nerve to reduce pain by approximately 40%–90%, decrease the frequency of headache days by up to 50%–80%, and improve quality of life (QOL) by up to 40%–90% in well-selected patients when performed by experienced practitioners ( ).
Given the clinical need for treatment of migraines and the encouraging case series studies, three multicenter randomized controlled trials (RCTs) were conducted to evaluate occipital nerve stimulation for the treatment of migraine ( ). Although the RCTs were encouraging, they did not meet their primary endpoints ( ). Review of the data from one of the RCTs indicates that a significant difference in the proportion of subjects who attained clinically significant (at least 30%) improvement in pain was achieved, but the study was not considered a success because this was not the predefined primary endpoint.
It is well accepted that advancement in the commercially available PNS technology could further improve outcomes and reduce complications ( ). Many of the existing approaches to PNS use leads originally intended for SCS and designed specifically for placement in the epidural space ( ). When used for PNS the leads are subjected to a different set of mechanical stresses that are unique to the periphery outside the epidural space ( ). Placing leads in highly mobile areas such as the neck, torso, and limbs, or across joints, and tunneling them significant distances can expose them to significant stress and repeated bending and flexing ( ).
A detailed review of a recent RCT indicates there were 222 adverse effects (AEs) in 157 patients who received permanent implants ( ). Approximately 71% of the patients reported an AE, and 76% (167 of 221) of the AEs were device or procedure related. Of the 167 device- or procedure-related AEs, 41% were related to the hardware (most commonly lead migration), 42% to biological events (e.g., hematoma, pain, etc.), and 14% to unwanted effects of stimulation ( ). Overall, the community remains enthusiastic regarding the potential benefit of PNS for occipital neuralgia, with the understanding that the recent RCTs support the need for refinement in future study designs, patient selection criteria, and PNS devices ( ). Publications reviewing AEs for PNS have concluded that “development of customized PNS equipment is likely to decrease device- and procedure-related complications and to improve treatment efficacy as well as patient satisfaction” ( ) and “the reduction in complication rate is expected to occur when the hardware used in PNS procedures is appropriately adapted for PNS applications” ( ).
Peripheral Field Stimulation
The field also expanded to target pain in other regions of the body beyond the head and neck. One approach has been called subcutaneous peripheral field stimulation (PFS), previously known as peripheral nerve field stimulation, in which multicontact leads are typically placed subcutaneously in the region of pain to generate comfortable sensations that overlay the region and provide relief ( ). Although there are some similarities between traditional PNS and PFS where electrical stimulation is delivered to nerve fibers with a goal of relieving pain, there are some important distinctions. Most notably, in PFS a lead is not placed to target activation of a single named nerve; instead, one or more leads are typically placed superficially to target nonspecific sensory nerve endings in the region of pain ( ). Thus PFS has been used when pain is confined to a relatively small region that does not follow a single nerve distribution, while PNS is most commonly used to relieve pain within the distribution of one or more named nerves ( ).
Ultrasound Guidance Improves Outcomes
An important development of the field in the past 10 years was the expansion of percutaneous PNS from the head and neck to named nerves in the arms and legs using ultrasound-imaging guidance ( ). The use of ultrasound for percutaneous PNS holds significant potential to make PNS available to a larger group of pain practitioners and their patients while incrementally decreasing risk to the patient by decreasing the invasiveness of the procedure and the potential for nerve injury, and at the same time avoiding the small, but not insignificant, risk of radiation associated with fluoroscopy ( ).
The early cases of ultrasound-guided percutaneous PNS demonstrated the relatively high levels of efficacy associated with previous studies of PNS, as well as the technical complications inherent in using SCS technology originally designed for the epidural space in mobile parts of the periphery ( ). In a case series of eight patients, six (75%) responded and proceeded to receive a permanent implant. Of the six responders, five (83%) achieved highly clinically significant (at least 50%) pain relief, and five (83%) also reduced analgesic medication usage ( ). Similar results were reported by other groups investigating percutaneous PNS around the same time ( ). A case report documented complete (100%) pain relief and cessation of all analgesic medication long term (20 months) following percutaneous PNS with two eight-contact leads placed precisely in close contact with the femoral nerve ( ).
Many publications have called for improvements in PNS technology to overcome its remaining limitations, which have been described as “mainly related to electrode technology, lead fracture or displacement, and infection” when using technology originally designed for the epidural space ( ). As an example, a case series of percutaneous PNS of the extremities with epidural leads had a revision rate of 1.3 per patient ( ). While part of a revision rate can often be attributed to the learning curve associated with pioneering any new technique ( ), it should be noted that revisions have historically been common and often reported in the range of 27%–89% per patient, with some studies reporting higher and lower rates ( ). The most common causes of revisions have been unwanted electrode movement (sometimes called lead displacement or migration) relative to the original precise placement adjacent to the nerve, and lead fracture that results in an interruption in therapy or a loss of efficacy. It has been suggested that these failures are related to using devices originally designed for the epidural space in the periphery, and devices designed specifically for PNS may enable a lower rate of revisions and complications to be achieved when combined with improved techniques ( ).
The need for a minimally invasive neurostimulation system designed specifically for PNS has long been requested by many PNS pioneers, and the commercial availability of a minimally invasive percutaneous PNS system can create the potential to translate the benefits of neuromodulation from a treatment of last resort to an earlier-stage intervention offered alongside other interventions provided by the pain specialist ( ). In addition, it gives the opportunity to bring the benefits of a nonnarcotic pain management modality to patients with postsurgical and acute pain ( ).
Recent FDA Clearance of Next-Generation PNS Systems May Enable the Potential of PNS Documented in Research Studies to Be Translated into Routine Clinical Practice
Recently three new PNS systems have received United States Food and Drug Administration (FDA) clearance for commercial use: the StimQ PNS System (StimWave, Fort Lauderdale, FL), the StimRouter TM (Bioness, Valencia, CA), and the SPRINT ® PNS System (SPR Therapeutics, Cleveland, OH) ( ). Additional details on each of these PNS systems are given in this section. It should be noted that none of them is intended to treat pain in the craniofacial region ( ).
StimQ PNS System Has Received FDA Clearance
The StimQ PNS System is indicated for pain management in adults with severe intractable chronic pain of peripheral nerve origin, as the sole mitigating agent or an adjunct to other modes of therapy used in a multidisciplinary approach ( ). Its receiver is built into the body of the stimulator, which is integrated with the lead and is fully programmable ( ). At the time of writing there are no peer-reviewed publications regarding this system to evaluate its efficacy and safety; the following information is thus taken from the manufacturer’s instructions for use and associated FDA documentation. This system uses a style of epidural lead that was originally cleared for SCS ( ). The system is designed to use an external transmitter to power a receiver, which is integrated into a lead that contains flexible circuitry ( ). The instructions for use indicate that the lead can be inserted through a 14-gauge needle. The system shares many similarities to the radiofrequency (RF) devices manufactured by Medtronic and Advanced Neuromodulation Systems (presently Abbott) intended for epidural SCS and also used for PNS ( ). It uses the same electrode material (platinum–iridium 90:10) and stimulator body material (polyurethane), with a comparable lead diameter (1.35 mm), number of electrodes (four or eight), and other characteristics similar to existing leads used for both SCS and PNS ( ).
StimRouter TM Neuromodulation System Has Received FDA Clearance
The StimRouter Neuromodulation System is indicated for pain management in adults who have severe intractable chronic pain of peripheral nerve origin, as an adjunct to other modes of therapy (e.g., medications) ( ). At the time of writing there are two peer-reviewed publications regarding this system. The distal end of the StimRouter lead has three electrode contacts and a silicone anchor ( ); the proximal end contains a receiver which is designed to be placed subcutaneously and is powered by an external pulse transmitter ( ). The lead is approximately 15 cm long, with an outer diameter of 1.2 mm ( ). It has platinum–iridium wires that are coiled and enclosed within silicone tubing, and transmits the electrical current from the receiver to the platinum–iridium contacts to stimulate the peripheral nerve ( ).
Two studies have been conducted with the StimRouter system in which stimulation is delivered in sessions of approximately 6 h/day ( ). One study delivered trial stimulation for 6 h/day for 5 days and noted an average reduction in pain at the end of the daily 6-h session of 44%, with pain tending to return approximately to baseline after treatment ( ). Two of eight patients reported clinically significant pain relief throughout the full 5-day treatment period ( ). The other study ( ) was conducted as a prospective multicenter randomized double-blinded partial cross-over study and successfully met its primary endpoint, in which the treatment (stimulation) group reported a higher proportion of patients (38% of n = 45 patients) relative to the control group (10% of n = 49 patients) achieving clinically significant pain relief. This study demonstrated an average pain reduction of 27% in the treatment group relative to 2% in the control group ( ).
The initial StimRouter study indicated that 50% of procedures were associated with mild tenderness, redness, and swelling following tunneling of the StimRouter leads, and there were three AEs in eight patients not related to the device ( ). In the larger study there were 146 AEs across 94 patients implanted, of whom 75 had received stimulation ( ). Of the patients who received the device, seven had it explanted: five explants were associated with lack of satisfaction with pain relief, one was associated with chronic dermatitis/sensitivity to the electrode patch, and one was associated with a dehiscence near the implant site following the patient picking at the incision site ( ). One of the seven patients retained part of the lead following attempted removal due to tissue encapsulation of the lead ( ). None (0%) of the device-related AEs was considered serious, approximately 80% were considered mild, and the majority were located near the site of surgical lead placement or stimulation ( ).
SPRINT ® PNS System Has Received FDA Clearance
The Sprint PNS System has received FDA clearance and is indicated for up to 60 days in the back and/or extremities for symptomatic relief of chronic intractable pain, postsurgical and posttraumatic acute pain, posttraumatic pain, and postoperative pain ( Fig. 57.3 ) ( ). At the time of writing there are 17 peer-reviewed publications regarding this system. The Sprint PNS System uses the fine-wire MicroLead TM designed to be inserted through a 20-gauge introducer for up to 0.5–3 cm remote to a named peripheral nerve to activate, preferentially, only the target (pain-relieving) fibers while avoiding activation of the nontarget fibers that have traditionally limited the therapeutic window for PNS ( Fig. 57.4 ) ( ). Unlike other SCS and PNS leads used to treat pain, the Sprint PNS System MicroLead has an open-coil, helical (spring-like) construction that is designed to encourage healthy tissue ingrowth between the coils to reduce the risk of infection, stabilize the lead along its length, and allow it to bend and flex repeatedly as needed during movements in the periphery while minimizing the risk of lead migration and fracture during therapy ( ). The lead is 0.2 mm in diameter (approximately five to six times smaller than other PNS leads), and the distal electrode contact is formed into the shape of an anchor to reduce the potential for unwanted movement of the lead relative to the nerve ( ).
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