Existing Treatments for Postoperative Pain

Currently, the predominant interventions to provide postoperative pain control are oral and/or intravenous analgesics. Nonopioid analgesics, such as acetaminophen or nonsteroidal antiinflammatory drugs, are commonly used with minimal risk of side-effects, but are often insufficient by themselves for treating acute postoperative pain. Nonopioid analgesics are typically paired with opioid analgesics, which do provide greater pain relief than when used alone. However, opioids carry risks of dependence and debilitating side-effects (e.g., sedation, dizziness, nausea, constipation, urinary retention, sleeping problems, respiratory depression) that can greatly impair QoL and delay recovery ( ). Anticonvulsants (e.g., gabapentin, pregabalin) are also commonly used to reduce the neuropathic component of postoperative pain ( ). However, anticonvulsants also carry risks of side-effects that can delay recovery, reduce QoL, and interfere with activities of daily living (impaired cognition, sedation, dizziness, headache, blurred vision) ( ).

Because these analgesics have significant limitations or adverse side-effects, local anesthetic-based central and peripheral nerve blocks are often added as part of a multimodal analgesic strategy to reduce postoperative pain. Unfortunately, the longest-acting local anesthetic still provides less than 16 h of analgesia when administered through a single injection. Although a continuous local anesthetic infusion via a percutaneous perineural catheter may prolong pain control for multiple weeks, practically speaking these modalities are limited to just a few days’ duration due to induced motor, sensory, and proprioception blockade (possibly increasing the risk of falls and limiting early rehabilitation), relatively high consumption of local anesthetic, hemodynamic effects (e.g., hypotension), infection risk from the percutaneous catheter, and increasing incidence of catheter dislocation. Considering that most surgical procedures result in multiple days or weeks—and sometimes months—of pain, an analgesic technique avoiding these pitfalls would be highly valuable to patients and the surgical community.

Following hospital discharge, patients are given oral analgesics (including opiates) to use for several days to weeks as the primary intervention to relieve their pain. This can be problematic, as approximately one in four patients prescribed opioids for the first time will continue receiving prescriptions in the long term (at least 90 days) ( ), which may increase the risk of opioid dependence and misuse. Single-injection nerve blocks cannot be delivered outside the clinical setting, and continuous infusions generally are not used long term due to the infection risks from indwelling catheters. Furthermore, pumps used to administer continuous nerve blocks are inconvenient to use long term because they are bulky, must be carried by the patient, and are often noisy. Thus patients are often left with unsatisfactory pain control at home following hospital discharge.

History: Treating Postoperative Pain With Electrical Stimulation

The use of electrical current to treat pain was first described by the ancient Romans using live torpedo fish ( ). For nearly two millennia after the Romans first described its use to treat pain, applications for the use of electrical current were exclusively chronic pain states such as gout ( ), sciatica, and lumbosacral neuralgia ( ). Following the publication of Melzack and Wall’s “gate-control theory” in the 1960s ( ), Reynolds noted that rats could undergo surgery with little discernable pain during periventricular brain stimulation ( ).

The decade after the introduction of the gate-control theory and Reynold’s observation of electro-anesthesia in rats, transcutaneous electrical nerve stimulation (TENS) was employed to provide postoperative analgesia in patients ( ). TENS uses surface (patch) electrodes placed on the skin around the regions of pain to generate pain relief locally. It has been used to treat postoperative pain following numerous types of surgeries, but reports on the effectiveness of TENS have been mixed at best. While some studies have found statistically significant reductions in postoperative pain scores and/or analgesic usage ( ), the majority of reports conclude that insufficient analgesia is provided to justify its use following surgery ( ). The success of TENS is highly dependent on the stimulation intensity (i.e., amplitude and/or pulse duration). The analgesic effect of TENS is commonly believed to be due to the activation of subcutaneous afferent nerve fibers rather than superficial cutaneous nerve fibers ( ). Accordingly, TENS delivered with low stimulation intensities may not activate sufficient numbers of the deeper subcutaneous fibers to provide adequate analgesia ( ). Large stimulation intensities can activate the deeper subcutaneous fibers but can irritate the skin and activate cutaneous nerve endings, causing discomfort and/or pain ( ). Consequently, TENS has been limited in practice by its inability to activate deep nerve fibers comfortably and effectively, resulting in low patient compliance.

Spinal cord stimulation (SCS) and conventional (i.e., fully implanted) peripheral nerve stimulation (PNS) can activate nerve fibers from both superficial and deep tissues of the regions of pain by stimulating spinal/peripheral nerves with implanted electrodes, avoiding the cutaneous discomfort of TENS ( ). SCS and conventional PNS may be effective for treating persistent/chronic postoperative pain, where the long duration may justify the invasiveness and cost of the permanent implantable system. For example, SCS produced highly clinically significant reductions in chronic postoperative pain of more than 50% following total knee replacement in two patients refractory to other analgesic methods ( ). Another case report described the use of SCS to provide complete relief of chronic postoperative pain that had lasted 3 years following thoracotomy ( ). In addition, SCS is frequently used to treat failed back surgery syndrome ( ), although the etiology of this pain is not always clear (e.g., pain from the surgical procedure vs. misdiagnosis of original cause of low back pain). However, these stimulation modalities require invasive surgery to implant costly and permanent stimulation systems (i.e., electrodes and stimulator). As a result, they are highly unsuitable as a temporary therapy for acute postoperative pain, which usually requires only a few weeks of stimulation.

Percutaneous Peripheral Nerve Stimulation for Postoperative Pain

Percutaneous PNS is a therapy cleared by the United States Food and Drug Administration (FDA) for various pain indications, including postoperative pain ( ). Percutaneous PNS employs a wire lead that is placed percutaneously and left indwelling for the duration of therapy. An external pulse generator ( Fig. 60.1 ) is used to deliver stimulation for up to 24 h/day, and the lead is removed after the therapy is completed. While multiple lead designs have been reported enabling percutaneous placement ( ), many are fully implanted leads requiring surgical extraction after the end of therapy and are not cleared or approved by the FDA for the treatment of postoperative pain. Only one electrical lead and stimulation system has been cleared by the FDA for PNS to treat postoperative pain ( ), and we therefore specifically address this system in the remainder of this chapter.

Percutaneous peripheral nerve stimulation targeting the femoral nerve using a body-worn external pulse generator.

Figure used with permission from SPR Therapeutics, Cleveland, OH.

Percutaneous PNS has several features that may make it well suited for the treatment of postoperative pain.

• 1.
  

  Minimally invasive lead insertion: no surgical incision to expose the target nerve is required since the lead is introduced via a percutaneous needle.

  
  
• 2.
  

  Lack of induced deficits: no reports of motor ( ), sensory, or proprioception deficits after insertion ( ).

  
  
• 3.
  

  Adjustability: current levels may be titrated to changing analgesic requirements.

  
  
• 4.
  

  Extended duration: percutaneous PNS has repeatedly been used in clinical studies for the treatment of pain for extended durations (e.g., 4–8 weeks), demonstrating its potential to provide multiple weeks of analgesia until resolution of postoperative pain.

  
  
• 5.
  

  Wearable: external pulse generators are now small enough to be affixed to the patient, so no large/bulky/heavy equipment is required for administration ( Fig. 60.1 ).

  
  
• 6.
  

  Safety profile: adverse events have been mild in most cases, anticipated, nonserious, and required little to no intervention to resolve (see below).

  
  
• 7.
  

  Noninvasive lead removal: no surgical incision is required, since removal of the lead requires only gentle traction ( ).

Ultrasound Guidance for Percutaneous Lead Insertion

Using ultrasound imaging, percutaneous lead insertion for peripheral PNS requires a similar procedure and skill set as ultrasound-guided peripheral nerve block administration, without the need for sedation or general anesthesia ( ). The lead is preloaded inside a needle, which is then inserted 5–30 mm away from the intended target nerve under direct ultrasound visualization. The introducer needle is subsequently withdrawn, and the lead remains in place because the distal tip anchors within the adjacent tissue (e.g., muscle, adipose).

The need for nonopiate and minimally invasive pain management methods coupled with the broad availability of ultrasound machines and the prevalence of anesthesiologists skilled in ultrasound-guided procedures may result in high rates of adoption for percutaneous PNS. In addition, unlike local-anesthetic-based nerve blocks in which the needle must be inserted immediately adjacent to the target nerve within the same fascial plane (generally ≤2 mm), percutaneous PNS is theoretically more effective when the lead is placed farther away (e.g., 5–30 mm away; see below) than when placed closer to the nerve, possibly reducing the risk of nerve injury. Although the distance from the nerve may be greater with an electrical lead compared to a perineural catheter, ultrasound guidance remains necessary in most cases to ensure accurate placement adjacent to the nerve without inadvertently contacting it with the needle and/or lead.

Open-Coil Lead: Design and Safety Profile

Percutaneous PNS has a long history of use across multiple chronic pain indications ( ). A PNS lead was specifically designed for extended percutaneous use in the periphery; it consists of an insulated helical coil wound from seven-strand stainless steel wire, and a terminal noninsulated portion of the electrode bent to anchor in the tissue ( Fig. 60.2 ) ( ). The lead is designed to reduce the risk of infection by limiting pistoning (small movements of the leads in and out of the exit site) as well as the size of the exit site. The open-coil design is intended to reduce pistoning by allowing the lead to stretch and compress, minimizing movements in or out of the skin ( Fig. 60.2 ). This design also encourages tissue ingrowth between the coils, which is intended to secure the lead along its entire length. This encapsulation is intended to provide a barrier to pathogens near the skin surface ( ). The diameter of the open-coil lead (0.2 mm) is smaller than the diameters of noncoiled percutaneous leads used to trial implantable stimulation systems (approx. 1.0–1.3 mm) and perineural catheters used in continuous nerve blocks (0.64–1.1 mm, or 19–23 gauge). Consequently, the open-coil lead is designed to produce a smaller exit site, and thus a smaller entry point for pathogens.

Open-coil lead with flexible anchor at the tip used for percutaneous PNS. Inset shows the small diameter and the coiled, flexible structure of the lead, which are intended to reduce the risk of infection and migration.

Figure used with permission from SPR Therapeutics, Cleveland, OH.

The effectiveness of the open-coil design is reflected in the low infection rates observed throughout its 30+ year history, in which leads have been routinely left indwelling for an average duration of >1 year (with at least one case of a lead being left indwelling for >8 years) ( ). In >1000 leads left indwelling for up to 60 days, the infection rate was 0.07% ( ). This rate is substantially lower than the published infection rate for continuous nerve block catheters by over an order of magnitude (1.45%; 175 infections in 12,078 catheters) ( ). Other temporary percutaneous leads left indwelling for more than 2 days such as SCS leads (i.e., percutaneous trial), continuous epidural block catheters, and intrathecal treatments have been reported to carry a higher risk of infection (mean of 1.0%–1.6%) during indwelling times of up to 60 days ( ).

Over 300 open-coil percutaneous leads have been placed in over 175 subjects in 12 published and unpublished clinical trials for the treatment of pain (i.e., chronic pain and postoperative pain) ( ). The average duration of the therapy was 29 days for all subjects who completed therapy across each of the 12 clinical studies, which also include therapy durations of up to 8 weeks. Across all studies, the safety profile of the lead was consistent throughout the period of therapy, and the most common adverse events were minor skin conditions (e.g., irritation, erythema, blister, mild skin tear) that were often due to the use of bandages, tapes, or the surface return electrode. No serious device-related adverse events have occurred across all studies, and adverse events have required little to no intervention to treat. During lead removal at the end of therapy, small lead fragments usually <0.8 mg in weight and <0.1 mm ³ in volume (less than a 10th of the volume of a common skin staple) may be retained within the tissue. Patients with retained fragments may still undergo magnetic resonance imaging scanning as lead fragments have “MR Conditional” labeling when using common scanning conditions at 1.5 T. Although suspected lead fracture upon removal has been reported in 7.5% of leads used for the treatment of pain (20 of 267 leads) ( ), there have been no reports of any negative sequelae from retained fragments remaining in situ.

Stimulation Paradigm

The open-coil lead delivers monopolar current and enables a stimulation paradigm that is intended to provide analgesia while minimizing unwanted stimulation-induced muscle contractions and discomfort. Theories on the mechanisms of action of PNS for pain relief describe how activation of large myelinated fibers can inhibit transmission of pain signals from the spinal cord to higher centers in the central nervous system to decrease pain perception (e.g., gate-control theory) ( ). In practice, the ability to maximize pain relief is limited by unwanted activation of smaller-diameter fibers (alpha motoneurons, or types III & IV) ( ), which trigger unwanted muscle contraction and/or discomfort. Higher stimulation amplitudes are required to activate small-diameter fibers when compared to amplitudes that stimulate large-diameter fibers ( ). The range of amplitudes between the thresholds required to activate the large-diameter versus small-diameter fibers is the “therapeutic window”: theoretically, amplitudes within this window comfortably produce pain relief while amplitudes outside this window produce discomfort/muscle contractions (greater than the therapeutic window) or no sensation (less than the therapeutic window).

The successful strategy for percutaneous PNS is to place leads remotely away from the nerve (5–30 mm) and minimize pulse durations to provide a wide therapeutic window ( Fig. 60.2 ). The difference in thresholds between large- and small-diameter nerve fibers increases as pulse duration decreases, and as a result the therapeutic window theoretically increases ( ). The therapeutic window theoretically increases further by placing the lead farther from the nerve ( ). The combination of a remotely placed lead and a large therapeutic window theoretically reduces the sensitivity to lead movements (e.g., from shifts in body position) and migration, and theoretically increases the duration of provided pain relief.

Other notable characteristics of this percutaneous PNS approach include the use of monopolar stimulation with the electrode at the distal tip of the lead serving as the cathode and a surface electrode serving as the anode; biphasic, asymmetric rectangular pulses; and stimulation frequency of 100 Hz, which is intended to provide comfortable stimulation more consistently than other frequencies. The ability to activate target fibers selectively to reduce pain and avoid discomfort and muscle contractions has been demonstrated in previous and ongoing clinical studies ( ).

Clinical Studies of Percutaneous PNS for Postoperative Pain

Prospective, case series, and proof-of-concept studies have been conducted to determine the analgesic efficacy of percutaneous PNS to relieve postoperative pain following total knee arthroplasty (TKA), a surgery with one of the highest rates of severe postoperative pain of prolonged duration. Institutional Review Board approval and FDA investigational device exemption were obtained, as needed. Ten subjects experiencing postoperative pain following TKA enrolled: six subjects were tested 6–14 days following surgery, and four subjects were tested 40–100 days following surgery ( ).

Leads were placed percutaneously using ultrasound guidance to target the femoral and/or sciatic nerves, depending on the location of pain (e.g., front or back of the knee). The strategies and locations for needle insertion were similar to those used for regional anesthetic nerve blocks of these nerves: the femoral nerve was targeted by inserting the needle distal to the femoral crease and lateral to the femoral nerve, while the sciatic nerve was targeted using a transgluteal or popliteal approach. The leads were placed with the distal tips located superficial to the targeted nerves, approximately 5–15 mm away from the femoral nerve and 5–30 mm away from the sciatic nerve. The leads were connected to an externally worn pulse generator (SPR Therapeutics, Cleveland, OH), and the return electrode was placed on the abdomen or ipsilateral leg ( Fig. 60.3 ). Stimulation was delivered at 100 Hz, and the amplitude and pulse duration were adjusted based on subject feedback to provide the most comfortable sensations. Following assessment of outcomes, all leads were removed comfortably without complication (e.g., no damage to surrounding tissue) using gentle traction in a brief outpatient procedure (i.e., subjects did not take the stimulation system home).

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