Learning Objectives: After participating in this continuing professional development activity, the provider should be better able to:
1. Describe the origin and evolution of peripheral nerve stimulation (PNS) and its mechanism of action.
2. Explain the applications of PNS for acute and chronic pain with neuronal and nonneuronal causes.
3. List absolute and relative contraindications to PNS.
Brief History of Peripheral Nerve Stimulation
The history of peripheral nerve stimulation (PNS) is rich and quite extensive. The first recorded use of electrostimulation to modulate pain dates back to the year 47 in the Common Era, when Scribonius Largus, a Mesopotamian physician, used eels to mitigate patients' pain.1 He attached an eel to the skin of a patient or asked patients to place their limbs inside a water tank full of eels. He found that a single discharge could transmit up to 600 V.
Despite that primitive discovery of the potential for electrical nerve stimulation, the first use of PNS electrodes was not until 1966, when Shelden and colleagues used technology for pain relief in trigeminal neuralgia, published later as a mechanism to be used more specifically for facial pain.2-4 The method of PNS used by Shelden and other physicians at the time consisted of surgically dissecting the tissues to physically see the occipital nerve, and then positioning the PNS directly next to the nerve.2 As this procedure was both complex and could result in severe complications, it was adapted in 1999 by Weiner and his colleagues, who performed a safer and more refined PNS insertion percutaneously for pain relief in patients with occipital neuralgia.5 This percutaneous approach for PNS placement has remained a mainstay technique since then, but as technology continues to evolve, the technique for PNS placement is also undergoing changes.
Mechanism of Action
PNS involves electrical stimulation of a specific nerve trunk via implanted subcutaneous electrodes. The exact mechanism of PNS is unknown. The potential benefits of counterirritation were reported decades before Wall and Sweet's landmark publication.6 Temporary pain relief was observed on withdrawal of many irritating stimuli; irritants used for this study included heat, ice, and vibration.7 Gate control theory of pain proposed by Melzack and Wall in 1965 is one of the most accepted theories regarding the mechanism behind PNS.8 This theory proposed that pain nerve fibers of different sizes act as "gates" for different types of sensory information and suggested that one can decrease the perception of pain by providing competing, nonpainful stimulation through large fiber neurons to close the small-fiber pain "gates." Stimulation of the A[beta] fibers in the same region as the C fibers can result in the closure of the "gate," resulting in blocking the transmission of pain impulses. Thus, nonpainful stimulation of the peripheral nerve territory results in decreased pain signals. Several additional theories have been proposed, many relating to the effects of PNS to changes in various neuromodulators.7,9
A[delta] fibers are 2 to 5 mm in diameter, myelinated, have a fast conduction velocity (5-40 m/s), and carry sharp or prickling localized pain information mainly from the nociceptive-mechanical or mechanothermal-specific nociceptors. Their receptive fields are small. Therefore, they provide precise localization of pain. C fibers are 0.4 to 1.2 mm in diameter, unmyelinated, have a slow conduction velocity (0.5-2.0 m/s), and are activated by a variety of high-intensity mechanical, chemical, and thermal stimulation and carry information from polymodal nociceptors. C fibers comprise about 70% of all the fibers carrying noxious input. The receptive field of these neurons is large and, therefore, less precise for pain localization.10
It has been postulated that PNS is used as a method of orthodromic stimulation of large-diameter low-threshold A[beta] fibers, which are responsible for carrying the nonnociceptive stimuli. Activation of these fibers results in the excitation of respective dorsal horn interneurons that are involved in the processing and transmitting nociceptive information via peripheral A[delta] and C (responsible for carrying the painful stimuli) nerve fibers. Studies have suggested an acute modulation of the local microenvironment with downregulation of neurotransmitters and endorphins in addition to local inflammatory mediators may also be a critical piece on how PNS may be effective in treating chronic pain. Other potential methods of pain modulation could result from reducing ectopic discharges in addition to reducing Wallerian degeneration.4
Centrally, analgesic effects of PNS may involve the serotonergic (5HT2, 5HT3), GABAergic, and glycinergic pathways in the spinal cord. PNS has been shown to improve endogenous pain inhibition by interfering with the interaction of large nociceptive fibers and central pathways at the spinal dorsal level via increased inhibition of dorsal wide dynamic range neurons.3
Clinical Applications and Indications
The utility of PNS to provide analgesia is multifaceted and wide-ranging. PNS is a treatment modality often reserved for patients with chronic pain for whom pain management options such as medications or physical therapy have failed.
The specificity and efficacy of PNS makes it a robust treatment option to manage pain. Moreover, in comparison to other next-step options to manage pain, PNS can be much less invasive. First and foremost, PNS can be used to mitigate pain due to a variety of causes. For example, currently, PNS is used to treat chronic pain, postoperative pain, posttraumatic pain, complex regional pain syndrome, and phantom limb pain.4 There is 60-day peripheral nerve stimulator approved by the FDA for postsurgical acute pain (Figures 1 and 2).
PNS is also greatly beneficial for neuropathic pain, including lumbar or cervical radiculitis, occipital neuralgia, femoral or sciatic or obturator neuropathy, brachial or lumbar plexus neuropathy, median or ulnar or radial neuropathy, and meralgia paresthetica.11 Moreover, research has shown that PNS can effectively reduce migraine pain, headaches, and facial pain.12
Gynecologic and GI Pain
PNS as a way to treat pain has also been a focal point of research in obstetrics and gynecology. The utility of PNS to treat chronic pelvic pain has been articulated in various studies.13 In particular, using PNS to target the pudendal nerve and treat pudendal neuralgia has been demonstrated before.13 Another study by Sudol et al14 also illustrated how PNS can be used to manage interstitial cystitis and bladder pain syndrome, particularly through stimulation of the tibial nerve. Moreover, a study by Yazdany et al15 demonstrated that stimulation of the sacral nerve was an effective means to help treat lower urinary tract disorders.
PNS has been widely studied to treat gastrointestinal pain. A key condition where PNS has been successful is in the treatment of chronic pancreatitis. Chronic pancreatitis has posed a unique challenge to pain management physicians, as it can persist despite a celiac plexus block, yet the implementation of a peripheral nerve stimulator in the thoracic spine has been shown to cause a drastic improvement in chronic pancreatitis pain. In fact, with regard to abdominal pain, certain cases have shown that PNS can treat not only chronic pancreatitis pain, but also pain after a liver transplant and inguinal neuralgia.16
Noncardiac Chest Pain
Chest pain caused by noncardiac causes may also be treated by PNS, as literature has shown how PNS of the thoracic paravertebral plexus was used to treat pain after a mastectomy and multiple rib fractures.17
PNS can be effective not only in the treatment of musculoskeletal pain, but also as a guiding tool in regional anesthesia. Behera et al18 compared ultrasound-guided femoral nerve blocks to PNS-guided femoral nerve blocks after knee arthroscopy procedures, and found both methods to be equally effective with respect to block duration.
Gadsden et al19 considered the value of electrical nerve stimulation on evoked motor responses. They found that, compared with nerve stimulation, ultrasound guidance significantly improved block success and decreased the need for rescue analgesia with less procedural pain and lower rates of vascular puncture. They concluded that nerve stimulation is not only a technique to locate nerves but can be an adjunct to ultrasound by serving as a monitor against needle-nerve contact and avoiding nerves that are in the needle trajectory during specific ultrasound-guided techniques. Nerve stimulation is also a useful adjunct in teaching students who are just beginning to learn how to use ultrasound for regional anesthesia purposes.
Ilfeld et al20 reported a case series following 8 patients after total knee arthroplasty showing significant improvements in the Western Ontario and McMaster Universities arthritis index (WOMAC). The WOMAC is a clinical scale that reports pain, stiffness, and difficulty with activities of daily living. On average, subjects in this study had improvement in the WOMAC by 76% and 86% at 6 and 12 weeks, respectively, in comparison to before surgery.20
Postoperatively in patients who underwent orthopedic surgeries such as anterior cruciate ligament reconstruction or rotator cuff repair, PNS of the femoral nerve and brachial plexus, respectively, led to lower average pain intensity.21 In this study, Ilfeld et al21 used percutaneous PNS as an analgesic technique to study the ability to reduce postoperative pain after in a multicenter study.
Their technique involved the percutaneous implantation of a lead, followed by the delivery of electric current by an external pulse generator. Although the technique had been used for chronic pain, these researchers planned to study the effects more pointedly in acute postoperative pain and to determine any effect on opioid consumption. Today, PNS involves microleads that are smaller than the diameter of a quarter (Figures 3 and 4).
Preoperatively, an electrical lead was percutaneously implanted to target the appropriate nerve: sciatic nerve for major foot and ankle procedures, the femoral nerve for anterior cruciate ligament reconstruction, and the brachial plexus for rotator cuff repair. A single injection of a long-acting local anesthetic along the same nerve/plexus was administered. After surgery, patients were randomized to 14 days of either electrical stimulation (n = 32) or sham stimulation (n = 34) using an external pulse generator.
Outcome measures were:
1. cumulative opioid consumption (in oral morphine equivalents); and
2. mean values of the "average" daily pain scores measured on the 0- to 10-point Numeric Rating Scale within the first 7 postoperative days.
The authors found that, during the first 7 postoperative days, opioid consumption in participants receiving active stimulation was a median (interquartile range) of 5 mg (0-30) versus 48 mg (25-90) in patients given sham treatment (ratio of geometric means, 0.20; 97.5% confidence interval [CI], 0.07 to 0.57; P < 0.001). The average pain intensity in treated patients was a mean +/- standard deviation of 1.1 +/- 1.1 versus 3.1 +/- 1.7 in those given sham (difference, 1.8; 97.5% CI, 2.6 to 0.9; P < 0.001).
The conclusions drawn were that percutaneous PNS reduced pain scores and opioid requirements free of systemic side effects during at least the initial week after ambulatory orthopedic surgery.
A similar finding was reported in an observational study looking at patients with brachial plexus avulsion, in which PNS was instrumental in leading to reduced pain levels.22 Furthermore, even for chronic back, shoulder, or knee pain, PNS has been used and shown to be effective.7
PNS can also play a role in the treatment of pain caused by autoimmune diseases. For example, PNS of the occipital nerve has not only been shown to treat migraine and trigeminal neuralgia pain, but can also treat pain caused by fibromyalgia.23
In a literature review of animal, human, and imaging studies, Lin et al24 concluded the peripheral and central analgesic mechanisms of PNS allow modulation of the inflammatory pathways, the autonomic nervous system, and the endogenous pain inhibition pathways, with involvement of the cortical and subcortical areas. Further understanding of the mechanism of PNS can help guide stimulation approaches and parameters to optimize the use of PNS.
Moreover, PNS of the vagal nerve can not only mitigate migraine pain but can also reduce pain associated with rheumatoid arthritis and Crohn's disease.24
PNS is advantageous not only in reducing pain levels, but also in minimizing opioid usage for pain relief. For example, several studies have demonstrated that PNS significantly decreases opioid consumption for analgesia.25,26
The efficacy of PNS as an analgesic has even been shown to have a positive socioeconomic impact. One study demonstrated that 42% of the patients studied were able to work after PNS implantation, thus experiencing a major socioeconomic benefit as a result of the pain relief from PNS.27
Following on in this study, Xu et al27 did a literature search including randomized trials, observational studies, and case reports of PNS in acute or chronic pain. In all, 227 studies met inclusion criteria and were included in qualitative synthesis. They found that evidence synthesis based on randomized controlled trials (RCTs) and observational studies showed level I and II evidence of PNS in chronic migraine headache; level II evidence in cluster headache, postamputation pain, chronic pelvic pain, chronic low back, and lower extremity pain; and level IV evidence in peripheral neuropathic pain, and postsurgical pain. Peripheral field stimulation has level II evidence in chronic low back pain, and level IV evidence in cranial pain.
The authors noted, however, that there was generally a lack of high-quality RCTs and meta-analysis was not possible due to wide variations in experimental design, research protocol, and heterogeneity of the study population.
Nevertheless, the conclusions drawn were that PNS is most likely effective in managing chronic headaches, postamputation pain, chronic pelvic pain, and chronic low back and lower extremity pain, with variable levels of evidence in favor of this technique.
It is also important to recognize that although PNS is a mainstay treatment for chronic pain, it can be used for acute postoperative pain, where it has been shown to decrease opioid dependence and increase recovery time.7
Contraindications to PNS
Absolute contraindications to peripheral nerve stimulators include patient refusal and allergy to any part of the stimulator. Relative contraindications include coagulopathy, local infection at the site of stimulator placement, pacemakers or automatic implantable cardioverter defibrillators, severe psychological conditions, pregnancy, and the need for repeat MRI studies.28
Allergies to any part of the stimulator that cannot be treated with premedication should inform the physician to seek an alternative treatment.11
With regard to coagulopathy, risks and benefits should be applied to any patient with an inherent coagulopathy or any patient being treated with an anticoagulant.28 Consulting the physician prescribing the specific medications is advised. In addition, the patient's coagulation status must be within the normal range for PNS placement.
Local infection at the site of stimulator placement can lead to spread of infection to not only nearby structures, but also systemically.29
For pacemakers and automated implantable cardioverter defibrillators, it is advised to consult a cardiologist for prior approval before placement of the peripheral nerve stimulator.11
For severe psychological conditions, psychological screening is recommended before placement of the implant.11 Lastly, it is imperative to assess whether the stimulator is MRI-compatible, as this can impact patients who frequently undergo MRIs for a variety of medical conditions.11
Future of PNS Therapy
PNS exhibits its neuromodulatory effect both peripherally and centrally. Further understanding of the mechanism of PNS can help guide stimulation approaches and parameters to optimize the use of PNS.
On a more investigational front, PNS can also have a great impact on patients who have suffered from nerve transection. In an RCT of patients who had median nerve transection, ultrasound-guided electrical nerve stimulation was able to lead to vast improvement in patients' sensory and motor function.29 Peripheral nerve injuries often result in limited functional recovery even after surgery, causing permanent motor and sensory deficits.
There are few successful results to date to enhance peripheral nerve regeneration. One strategy is the use of low-frequency electrical stimulation perioperatively to an injured nerve at the time of surgical repair. Perhaps by increasing intraneuronal cyclic adenosine monophosphate (AMP), perioperative electrical stimulation accelerates axon outgrowth, remyelination of regenerating axons, and reinnervation of end organs.
Recent, prospective, randomized clinical trials have affirmed electrical stimulation as a clinically translatable technique to enhance functional recovery in patients with peripheral nerve injuries.
Level I evidence from recent, prospective, randomized clinical trials of electrical stimulation, and ongoing and future directions of research into electrical stimulation as a clinically feasible adjunct to surgical intervention in the treatment of patients with peripheral nerve injuries provide promising results.23
This area continues to be an exciting frontier in research with regard to PNS, as investigators aim to elucidate the mechanisms by which PNS can be effective at nerve regeneration.
For example, PNS can play a large role in the future of acute and chronic pain management. PNS technology has had major advancements since the first implantable PNS back in 1999.5
Progressions include externalization of the implantable pulse generator, minimizing generator size, and creating specific leads more applicable for PNS.30 Smaller devices create opportunities to use PNS for smaller nerves that the modern stimulators are able to effectively stimulate. This widens the array of possible chronic pain syndromes for which PNS can provide relief of symptoms that are otherwise not well managed by traditional medical and physical therapies.19
For already established indications as noted before, PNS may be optimized through surgical techniques, modification of waveform parameters, precise placement of stimulation leads, and electrical dose delivery to the target nerve.30,31
Acknowledgment
The authors extend special thanks to our faculty Haijun Zhang, MD, Akwasi Amponsah, MD, and Andrew Kaufman, MD, and to Vishal Dhruva, MS4.
References