Learning Objectives/Outcomes: After participating in this CME/CNE activity, the provider should be better able to:
1. Define central spinal cord and peripheral nerve stimulation and review proposed mechanisms of action.
2. Examine the criteria for proper patient selection and compare the benefits and risks of each modality.
3. Describe barriers to implementation and the future of neurostimulation in pain management.
When implemented in conjunction with a multidisciplinary approach to pain management, neuromodulation of the nervous system can have significant, sustained effects. Central and peripheral nerve stimulations continue to evolve and increasingly promise long-term management of chronic pain conditions.
Neurostimulation affects the nervous system, mediating pain through therapeutically dosing electrical current in a variety of pulse forms, amplitudes, and frequencies and is most effective when supplemented with behavioral and psychosocial support. Neurostimulation is reversible, adjustable, and typically harmless to the nervous system. These features are largely responsible for nerve stimulation's increase in popularity as an adjunct or alternative to surgery or management with narcotic medications.
The key to the success of nerve stimulation is patient selection with appropriate patient understanding of risks and expectations. Neurostimulation is usually reserved for failed conservative and medical therapy. Typical methods use high-frequency, low-current electrical stimulation delivered by electrodes either to peripheral nerves or centrally to the spinal cord.
There are multiple techniques to deliver electrical current to peripheral nerves. Centrally, methods involve implantation of electrodes in the epidural space to stimulate the dorsal column or spinal nerve roots.
In summary, neurostimulation techniques are selected based on the patient's type and location of pain and can be performed with spinal cord stimulation (SCS) and peripheral nerve stimulation (PNS). Both modalities have varying mechanisms of action, indications, and complications, but they are vital tools that should be considered in management of chronic pain patients.
Spinal Cord Stimulation
Mechanism of Action
SCS has become increasingly popular and successful due to refined patient selection criteria, greater accuracy in electrode placement, and overall improvement in the system. Spinal cord stimulator implantation typically involves percutaneous introduction of electrodes into the epidural space, and the device (consisting of a power supply, programmable impulse generator, and wireless transmitter) is implanted in the patient's back, under the skin. Before implantation, the patient will have responded successfully to a less-invasive trial period with an external device.
Although the exact mechanism of action of SCS is unknown, there are numerous theories. Early theories were based on gate theory, stating that SCS exerts its pain-relieving effects by enhancing pain inhibition through modulation of descending inhibitory pathways. SCS electrodes are typically placed in the thoracic spinal cord epidural area, so that effects are carried out through the release of spinal dynorphin neuropeptides throughout this segment of the cord, thus dampening the nociceptive signal through reduction of substance P release from the dorsal horn.2 However, this does not seem to be the only effect of SCS in pain modulation.
Another theory involves that fact that chronic pain patients experienced overexcitability of neurons in the dorsal horn. A nerve that is transmitting a pain signal does so with increased glutamate release compared with [gamma]-aminobutyric acid (GABA).3 It is proposed that SCS reduces pain intensity by increasing GABA release to alter the neurotransmitter relative proportions.4
A final theory is that there are also elements of supraspinal pain transmission pathways influenced by SCS and leading to its effects.
The SCS device itself has 3 main parts: an electrical pulse generator, a lead wire that transmits the electrical pulses to the spinal cord, and a hand-held remote the user can use to adjust the stimulator settings and turn it on and off. The SCS, through electrical pulses, activates nerves where a patient's pain is felt. This activation changes the way the brain perceives pain. By interrupting the afferent pain signals, the patient ideally will feel only a tingling or paresthesia sensation, or better yet no sensation at all, in place of the previous, often debilitating pain he or she previously felt.
Indications and Contraindications
Before permanent implantation of SCS, patients must undergo a preimplantation screening trial. The trial is minimally invasive due to electrode placement via Tuohy epidural rather than laminectomy and allows for evaluation of the type of effects SCS has on patient's symptoms. The trial period can last from a few days to a few weeks. The ideal pain relief is 50% reduction from baseline, indicating that permanent SCS will be similarly beneficial, and that these benefits will outweigh risks of complication of the invasive procedure.5
The first reported case of an implanted SCS was in 1967 when Shealy et al1 used it for pain relief in a patient with metastatic cancer. Since that time, SCS has improved in both various features but also with ever-expanding indications. The most common indications for SCS include many forms of neuropathic pain and failed back surgery syndrome (FBSS) with radicular symptoms, complex regional pain syndrome (CRPS), critical limb ischemia (CLI) pain, and refractory angina.
FBSS refers to a subset of patients who have persistent or new pain after having spinal surgery. It affects more than 1.5 million Americans and is the most common indication for SCS. A study by Taylor et al6 showed that SCS lowers pain and improves quality of life in FBSS patients without significant adverse effects. One randomized control trial (RCT) showed that SCS was superior to reoperation for treatment of FBSS.7 Another study that compared SCS with conventional medical management in patients with FBSS with radicular leg pain showed that patients with SCS had significantly higher levels of pain relief, more than 50% reduction in baseline pain, as compared with the medical management group.8
Type 1 chronic regional pain syndrome (CRPS) was previously known as reflex sympathetic dystrophy, and type II CRPS was known as causalgia. SCS can help manage these pain syndromes, which are frequently chronic, defined as greater than 6 months in duration, and they are often debilitating. These pain conditions usually affect limbs and can occur after a surgery or trauma to a region.
CRPS results from dysfunction in the central and peripheral nervous systems. CRPS leads to a neuropathic pain condition with burning, allodynia, hyperalgesia, and vasomotor changes. Studies show that SCS in CRPS patients not only has beneficial effect on the neuropathic-like pain and vasomotor disturbances but also affects immune function. SCS attenuates T-cell activation, improves peripheral tissue oxygenation, and decreases antiangiogenetic activity, which leads to improved blood flow and immune system.9
One RCT looked at 54 patients with CRPS I and compared the effects of SCS with physical therapy (PT) versus PT alone. Results showed significant improvement at 6 months in the SCS group.10
In another prospective study, quality-of-life assessments were used to evaluate the effect of SCS in the management of CRPS. The results determined that 80% of patients experienced at least 50% pain relief.11 Current recommendations for management of CRPS state that the primary focus should be to improve function using rehabilitation, psychological therapy, and noninvasive medical management. However, if no response to conventional treatments is noted within 12 to 16 weeks, SCS should be considered, as it has been shown to restore function in affected extremities and improve the patient's quality of life.
CLI is a painful peripheral arterial disease leading to ischemic pain, wounds, and gangrene. It is commonly caused by atherosclerosis due to hypertension, diabetes, smoking, or a combination of these. The chronic pain experienced is a mix of nociceptive and neuropathic pain. In patients unable to undergo revascularization of the limb ischemia, SCS could be a viable option for pain control and to prevent amputation, as SCS has been shown to improve microcirculatory blood flow. This effect on blood flow is due to suppression of sympathetic vasoconstriction and activation of vasodilatory molecules, causing endothelial nitric oxide release and stimulating smooth muscle relaxation.12
In 1 randomized, controlled trial, a comparison of SCS versus analgesic treatment in patients with CLI showed that SCS provided long-term pain relief.13
Another study looked at 150 patients with implanted SCS for gangrene in severe lower limb ischemia, and the results showed a pain relief of greater than 75% in 85 patients at 71 months.14 Patients with pain relief of more than 50% and an increase of transcutaneous oxygen tension (TcPO2) of more than 15 mm Hg after an SCS trial stimulation should be considered for full implantation of SCS.
Contraindications to SCS include a wide range of issues starting with the patient's psychosocial status. Doctors should be careful in offering SCS implantation in patients with unclear motives who may be concerned with secondary gain or involved in ongoing litigation seeking compensation. Typically, patients with significant psychiatric illness, cognitive impairment, or active substance abuse issues should not be considered, as they may be unable to appreciate the goals and limitations of SCS.15 Patients on anticoagulation therapy, with pacemakers or implanted defibrillators, who are pregnant, or who have spinal stenosis should be managed conservatively, and consultation with the appropriate medical team should be sought before implantation of SCS. Anticoagulation, for example, increases the risk of epidural hematoma formation.
Adverse Effects
SCS is an invasive procedure and device and thus does have some risk of complications ranging from minor to life-threatening. Overall, the complication rate has been reported to be around 30% to 40%.16 Hardware-related malfunction is the most common at around 38% and included problems with the lead migrating from the original implantation site, failure of the lead connection, and lead breakage. The majority of cases with hardware-related complications required replacement or revision of the system.
Other complications included localized pain or infection in 3% to 5% of cases, cerebrospinal fluid leak, or hematoma in 0.3% of patients.17 Hematoma formation can result in paralysis or even death. However, the incidence of these complications also seems to be decreasing with better techniques and technology leading to more resilient leads and better anchoring techniques.
Peripheral Nerve Stimulation
Mechanism of Action
PNS involves electrodes stimulating nerves using electrical impulses to disrupt the transmission of a pain signal from a peripheral location to the central nervous system, thus reducing perceived pain. Applying high-frequency, low-intensity electrical current to a nerve has been found to cause paresthesia and analgesia.18 PNS can be achieved through transcutaneous electrical nerve stimulation (TENS) techniques19 or by implanting electrode(s) directly next to a nerve or in a peripheral nerve field. Both have similar proposed mechanisms, which have been discussed.
PNS electrodes can be placed using an introducer needle or, less commonly, by cutting down to a nerve directly. Ultrasound is typically used to guide a needle within 0.5 to 3 mm of the targeted nerve. Once the desired depth and position are found, an electrode is secured in place at this location. One monopolar electrode can be placed, or multiple electrodes, depending on whether a single nerve is the target or if targeting sensory cutaneous nerve fibers in peripheral nerve field stimulation (PNfS) is the goal.
PNS can be used alone or in conjunction with SCS. PNS pulse generators can be implanted, making this a long-term pain treatment modality.
The mechanisms of action proposed for PNS are similar to those proposed for SCS, but the signal disruption begins from outside the spinal cord. One of the oldest theories is the gate control mechanism, previously discussed. The signal ascends the target nerve(s) to the spinal cord and outcompetes the pain signal. The most common sensation experienced from PNS is tingling or vibration, which is carried by A[beta] fast adapt fibers. The mechanism involves modulating dorsal root column pathways as the peripheral nerves enter the spinal cord, decreasing C-fiber nociceptive transmission.20
Also, PNS may reduce pain sensation by altering the local inflammatory action of pain-mediating neuropeptides.21
Finally, PNS can have sustained effects even after treatment is stopped, as it seems to disrupt the recurring central pain cycle by allowing an increase in physical activity with reduced pain, which normalizes neural inputs through neuroplasticity.22 PNS reduces pain, increases functionality, and can even reverse the reorganization of neural networks to provide lasting effects even after stimulation is decreased or stopped.
Indications and Contraindications
The indications for PNS continue to increase in number as new applications are found and technology improves. It has been successful in managing acute and chronic pain, limb pain in amputees, back pain, headache and facial pain, shoulder pain, neuropathic pain, CRPS, and postoperative pain.23
PNS is useful on its own or in place of SCS when the central neuroaxis is difficult to access. PNS is indicated when an isolated area, limb, nerve distribution, or nerve injury can be identified and targeted, confirmed by a diagnostic nerve block.24 There is increasing demand for this modality in the setting of the opioid epidemic, and it may be indicated in place of medication treatment.
Although PNS has historically been used to manage chronic pain conditions, it is also useful in managing acute pain and even postoperative pain. PNS does not have abuse potential or any of the side effects of opioids, such as nausea, vomiting, urinary retention, ileus, and respiratory depression, seen in up to 20% of patients and most commonly in patients older than 65 years who are also at risk for opioid-induced delirium.25 Therefore, PNS may increasingly be adopted as an alternative or supplement to typical pain treatment modalities in these patients, especially.
PNS has been used since the 1960s and continues to be used if medications are ineffective or have undesired side effects or when surgery fails to resolve the source of pain. There are few contraindications to PNS because of its minimally invasive profile and reversibility. However, some do exist, including infection of the affected limb or local area of electrode implantation, allergy to PNS materials, and relative contraindications to bleeding disorders and anticoagulation.
As with SCS, patient selection is important and PNS is most successful when avoiding patients with personality disorders and major depression whose perceived pain may be less related to nerve injury and more to psychosocial issues.24
Causes of Pain and PNS Targets
Injuring a nerve during a surgery or procedure is an undesired but known complication. Oftentimes nerves can recover, but when they do not, patients can be left with a "cutting," "burning," or "drilling" pain sensation.
Despite conservative treatment, many patients continue to have significant pain that impacts their quality of life. One common etiology is nerve lesion after hip or knee surgery. Another is damage during a traumatic injection. Finally, nerve graft surgery, performed to restore nerve function after prior damage, can sometimes result in persistent pain.
One study involved 154 patients with these etiologies and found 46 of them to be suitable for PNS. Patients with entrapment neuropathy were also included. To be included, patients had to have failed medications and TENS. They also had to respond to diagnostic nerve block before PNS. In the lower extremities, the investigators targeted sciatic, femoral, posterior tibial, peroneal, and lateral femoral cutaneous nerves, depending on the pain distribution. They also targeted the median, ulnar, radial, and intercostal nerves in the upper extremities and trunk. Patients had control of the PNS and stimulated their targeted nerve for 1 hour every hour, then less frequently as needed. Their visual analog scale, a 0- to 100-point pain rating system, dropped from 69 +/- 12 before PNS implantation to 24 +/- 28 postoperatively (P < 0.001).24
Chronic low back pain (CLBP) is a prevalent, challenging musculoskeletal condition, which reduces quality of life and productivity in the United States. It is challenging to treat both in cases where the pain is from nonspecific causes, or even when surgery can resolve a defined lesion, but does not resolve the pain. This has been theorized to be from central pain-processing hypersensitivity, which develops and persists after an injury has healed, with exaggerated response to stimuli, and no peripheral inhibitory pathway changes seen. Persistent pain in such cases suggests the problem is with central nociceptive processing.26 Additionally, psychosocial factors may play a role.
Taking all of these theories into consideration, studies have found treating the pain in the peripheral nervous system does improve experienced pain in some patients and is worth considering in those unresponsive to other treatment modalities, as the cause of CLBP is frequently unknown.
One trial analyzed PNS for CLBP, which targeted the medial branches of the dorsal rami in the affected lumbar region bilaterally. The examiners used ultrasound guidance and selective activation of the lumbar multifidus to select optimal electrode locations. Of the 9 patients who met inclusion criteria, 67% experienced a statistically and clinically significant reduction in average pain intensity (<0.005, <50% pain reduction, respectively). The authors suggested that the 30 days of percutaneous PNS seemed to disrupt centrally maintained pain and improved activities of daily living (Table 1).27
Another study analyzed PNS in CLBP implanted permanent neurostimulators in the 50% of patients who responded to the trial stimulation and followed-up for 2 years. They found that the permanent implant resulted in a 92% reduction in opioid usage by 24-month follow-up, and that 85% of patients were either satisfied or highly satisfied.28
Postsurgical analgesia in extremity surgery is another role for PNS. Nerve blocks are common in the treatment of rotator cuff repair postoperative pain. A nerve block of the brachial plexus can be performed and is still ideal for immediate pain control, but PNS was effective at reducing pain significantly in 1 to 14 days after ambulatory rotator cuff repair. Opioid requirement was also reduced.29 Another example of PNS applications for postoperative pain control is in total knee arthroplasty (TKA). TKA is increasingly common with an aging population in the United States, and femoral and sciatic nerve stimulation after surgery was shown in a 5-patient case series to provide more than 50% pain reduction in 4 out of 5 patients, suggesting it may be a practical modality to study in larger trials.23
To list a few other causes and targets in brief, CRPS can be treated by PNS, which peripherally targets the dorsal root ganglion (DRG), adjacent to nerve entry, and PNS can be a safer and slightly superior option than SCS to treat this condition.30 DRG stimulation also can be used for post-zoster pain, as it effectively targets a painful dermatome of the trunk or groin.19 PNS has been shown to be effective in hemiplegic shoulder pain in stroke survivors targeting the axial nerve.31 It was shown to be successful as far back as 1999 in treating intractable headaches by targeting greater occipital nerves.32 Additionally, PNS has been used off-label for many other applications including median nerve distribution pain relief, and more.21
Adverse Effects
PNS carries less risk for complications than SCS. While in SCS, hematoma formation is a serious complication, peripheral hematoma formation is much less likely to cause serious or life-threatening complications. Allergic reactions to stimulator or dressing materials do occur. However, PNS systems can easily be removed or dressing materials can be exchanged.
A common complication with PNS is lead dislodgement or migration of electrodes away from the original insertion location. There is frequently even lead fracture. Innovative PNS electrodes are being developed that mitigate these problems, but technical issues will likely continue to be a problem. Outcomes are improving with time and will continue to do so, but some patients may not have the desired effect because of one or more of these issues. Suturing electrodes to the nerves and using anchors under the skin, with an adhesive sterile dressing, can help prevent the common problem of lead dislodgement.
Patient safety is always a concern with adoption of novel systems. In a prospective, multicenter, randomized, double-blinded, partial-crossover study of PNS in patients with chronic pain of peripheral nerve origin, 94 patients met inclusion criteria and chose to participate. They were followed up for 320 days. Although 55 patients experienced adverse events, these typically occurred within the first 3 months, were self-limited, and included issues such as skin rash, redness, and soreness. Additionally, no serious adverse events occurred, exemplifying an overall reassuring safety profile.33
There are minimal side effects of PNS, but one can be discomfort, which in theory is preferable to pain, but which is indeed a potential side effect. Part of the setup procedure involves adjusting the location of the leads and the programing of the system. If the electrode is deep enough and the intensity is just enough to achieve the desired effect, discomfort or bothersome paresthesia can be minimized.
Barriers to Implementation of Neurostimulation
Neurostimulation has been an effective pain management practice since the 1960s but is still continuing to emerge in many ways. Its growth has been prohibited by cost, lack of study data in some applications, availability, and slow adoption rate with other modalities-such as opioids-that had previously been favored. Also, in some applications there has yet to be standardization of optimal lead location, insertion techniques, and stimulation protocols.29
There is a high cost associated with SCS and PNS systems, and their implantation and insurance coverage can be difficult to obtain in many cases. However, the case could be made that neurostimulation can lead to better use of health care resources and savings for insurers if used correctly: Patients with decreased pain may visit hospitals less frequently, spend less time hospitalized, and if used in conjunction with or shortly following a surgery, may be able to go home instead of a rehabilitation facility in certain situations, saving money overall.
Another barrier of implementation is the number of available devices. In 2012, the FDA approved a handful of devices for peripheral nerve or peripheral nerve field stimulation, and some for migraine and overactive bladder, but the options are still limited. There is only a handful of manufacturers for SCS devices and even fewer approved PNS systems.
Future of Neurostimulation
The market for neurostimulation devices is growing, despite the shortage of approved devices available. This barrier will improve with time, research and development, and larger studies demonstrating efficacy on a large scale.
Although SCS and PNS are relatively safe, complications do occur. In the future, the complication rate will decrease with improved systems and standardized proven techniques, and clinicians-and patients-will increasingly recognize that the complications from pain control modalities such as chronic opioid use typically outweigh the risks of neuromodulatory modalities.
In the future, large, prospective randomized controlled studies are needed to determine the optimal management of chronic, acute, and postoperative pain using neuromodulation. Additionally, many studies are sponsored by device-development companies. Although this does not discount the validity of their study findings, additional large-scale studies performed by investigators with no conflicts of interest would benefit the data pool and guide decision-making of pain management clinicians in the future.
PNS for postoperative pain control can apply to any nerve that would be targeted with a nerve block and has the benefit of requiring only a small, wearable stimulator power source, which is more portable than a continuous local anesthetic infusion pump, does not need to be refilled, and does not experience fluid leakage complications. Additionally, nerve stimulation of the femoral nerve does not carry the same risks of falling associated with continuous femoral nerve blocks.34
Conclusion
It is essential for all pain physicians and practitioners to be aware of the benefits and risks of neurostimulation as a modality of pain management, especially because in the setting of the ongoing opioid epidemic, SCS and PNS for chronic pain will continue to grow in popularity and usage.
Patient selection for these modalities is critical to success. Large, prospective randomized controlled studies are still needed to determine the optimal management of chronic, acute, and postoperative pain using neuromodulation.
Although neurostimulation is relatively safe, complications do occur, yet the risk may be outweighed by the benefit to pain control and quality of life. The risks may be lower overall than those of opioid therapy, especially for patients with persistent, chronic pain.
As prices decrease for the devices, additional stimulation systems compete for market share, and the devices continue to improve, patients will increasingly benefit from these devices and systems.
References