Implantable Neuromodulation for Chronic Pain & Headache

Chronic pain affects approximately 20% of adults in the US,¹ and is associated with enormous personal, social, and economic burdens. Neuromodulation has emerged as an essential component of a multidisciplinary approach to pain management. Neuromodulation refers to the modification of nervous system activity via the precise delivery of electrical stimulation or pharmacologic agents to the brain, spinal cord, or peripheral nerves.

The most common neuromodulation procedures for pain are spinal cord stimulation (SCS), peripheral nerve stimulation (PNS), and intrathecal pump (ITP) implantation. Important features of these devices include reversibility, adjustability, and a nondestructive nature. The most challenging and arguably most important aspect of neuromodulation clinically is patient selection, greatly influencing short- and long-term outcomes.

An important factor to consider during patient selection is the presence of any psychiatric comorbidities. It is standard to have a multidimensional psychologic evaluation before implantation of a neuromodulation device. Individuals with untreated major depressive disorder, psychosis, or history of substance abuse are less likely to have positive functional outcomes, and more likely to have their device removed within 1 year—usually because of a lack of efficacy.^2,3 This highlights the importance of a collaborative approach to patient care and selection with appropriate psychologic counseling

In this article, we highlight the use of neuromodulation for treatment of refractory pain syndromes. We incorporate 3 cases to discuss the use of different neuromodulation modalities with a brief historical perspective and review of the relevant evidence.

SCS

SCS electrodes comprise an array of metal contacts that generate a therapeutic electric field when programmed in combinations of anodes (positive) and cathodes (negative).⁴ Despite decades of clinical use and research, the underlying mechanism is not well understood. The gate control theory of spinal cord pain transmission posits activation of large-diameter fibers inhibits smaller-diameter fibers that carry pain signals.⁵ Although studies show SCS is more complex than simple pain gating explains, discovering modifiable pain pathways created a paradigm shift from ablative surgery to neuromodulation.

SCS has been studied and used to treat many presentations of chronic pain, most commonly in the context of postlaminectomy syndrome, or failed back surgery syndrome, and CRPS. Patients are required to have an external trial first, during which device settings can be adjusted and optimized.

Postlaminectomy syndrome is the development of chronic pain after spine surgery. In appropriately selected individuals, SCS provides superior pain relief and improved quality-of-life outcomes compared with conventional medical management or repeat spinal surgery.^6,7 Similarly, SCS is highly effective for CRPS, a poorly understood pain syndrome in which pain is typically out of proportion to the inciting injury and is associated with sensory, vasomotor, sudomotor, and motor/trophic signs and symptoms. Randomized controlled trials of SCS for CRPS have demonstrated improved pain control and quality of life.^8,9

Traditionally, SCS used tonic stimulation, producing parasthesia—a tingling sensation meant to overlap a person’s somatotopic pain distribution. Low-frequency stimulation at 40 to 100 Hz produces tonic stimulation. In more recent paradigms, minimal to no paresthesias are felt, termed subperception, subthreshold, or paresthesia-free waveforms. These paradigms include high-frequency stimulation (>500 up to 10,000 Hz). The absence of paresthesias suggests that there is no neuronal activation of dorsal column fibers,¹⁰ contradicting the gate control theory. Burst stimulation is another new paradigm, hypothesized to mimic innate neurologic activity.

Tonic SCS was considered more effective for limb than axial pain; however, both high-frequency and burst paradigms alleviate chronic back and leg pain more effectively than tonic SCS.¹¹ More recent advances include dorsal root ganglion stimulation, a more targeted therapy for specific nerve root distributions of pain. In a randomized controlled trial, dorsal root ganglion stimulation was superior to conventional dorsal column SCS for lower extremity pain in CRPS lasting up to 12 months.^12,13

PNS

The first clinical use of PNS was reported by Wall and Sweet, who stimulated their own infraorbital nerves to test the gate control theory of pain.¹⁴ Early PNS was mostly done via open exposure of the involved nerve for direct visualization and electrode placement. Percutaneous PNS was popularized in 1999 with the first report of occipital nerve stimulation.¹⁵

Considering that many neuropathic pain presentations are attributable to peripheral etiology, a PNS electrode theoretically can be implanted anywhere in the body. Traditionally, these devices were an off-label use of SCS electrodes, associated with high rates of migration, lead breakage, and infection. Although craniofacial pain syndromes are still treated with SCS electrodes prone to these complications, there are now dedicated PNS systems specifically approved for the indications of back and extremity pain. These systems are designed to reduce lead migration and infection, and data regarding complication rates are forthcoming.

Craniofacial pain syndromes potentially treated with PNS are diverse and include neuralgia (eg, trigeminal, glossopharyngeal, or occipital), neuropathy (eg, nerve injury or postherpetic), central pain (eg, poststroke or multiple sclerosis), secondary pain (cancer, postoperative, or giant-cell arteritis), and headaches (eg, migraine). The most common use of PNS is occipital nerve stimulation (ONS) for occipital neuralgia; however, only small studies exist with a low overall level of evidence.¹⁶

Chronic migraine is a controversial indication, with efficacy in feasibility studies,¹⁷ but no significant differences in active vs sham stimulation in a large randomized trial, although there was a significant reduction in headache days.¹⁸ Furthermore, an impressive 70% of patients experienced an adverse event at long-term follow-up.¹⁹ Importantly, these studies were performed prior to the Food and Drug Administration (FDA) approval of onabotulinumtoxinA and monoclonal antibodies for preventive treatment of chronic migraine. Overall, ONS may be effective for migraine refractory to medical management,²⁰ but evidence is limited and further research needed to define the appropriate patient selection and indications. Some practitioners may find insurance approval or reimbursement difficult, because ONS for occipital neuralgia or chronic migraine is considered experimental.

Depending on the distribution of facial pain, potential targets include the supraorbital, infraorbital, supratrochlear, mental, and auriculotemporal nerves. The optimal positioning is within the subcutaneous space because placement that is too superficial results in a painful pinching sensation, whereas placement that is too deep results in painful muscle contractions. Like SCS, patients first undergo an external trial before proceeding with a permanent implant.

Evidence for PNS treatment of craniofacial pain is limited, consisting mostly of case reports and series. Studies that are available report people treated with PNS experience high overall rates of satisfaction, pain improvements, and quality-of-life improvements.^21,22 In particular, those with trigeminal neuropathic pain—who are often failed by medical therapy—do not have many other treatment avenues. This pain syndrome is characterized by constant facial pain secondary to injury of the trigeminal nerve or ganglion and can be caused by failed treatment for trigeminal neuralgia, dental or sinus surgery, or trauma. Unlike trigeminal neuralgia, there are few effective treatments; thus, despite limited evidence, PNS can make a substantial difference in these individuals’ lives.

PNS shows promising outcomes for a subset of persons with refractory craniofacial pain. Device improvement is needed to decrease the rate of complications, and advances are being made in miniaturization and incorporation of wireless technology. Some dedicated PNS devices have recently been FDA-cleared for clinical use with published studies supporting their use already and additional data regarding efficacy forthcoming. Ongoing studies include the use of PNS in the treatment of knee pain,^a low back pain,^b and postsurgical pain,^c among others.

ITP

ITP drug delivery is an effective treatment for chronic pain, first studied for refractory cancer pain.^23,24 Subsequent clinical study and use has expanded to include treatment of nonmalignant pain etiologies. Morphine (a µ-opioid receptor agonist) and ziconotide (a nonopioid calcium channel antagonist) are the 2 ITP medications approved by the FDA for the indication of chronic pain. Evidence-based guidelines have been developed and are maintained by the Polyanalgesic Consensus Conference.²⁵

ITP morphine and ziconotide are considered first-line agents for chronic malignant or nonmalignant pain refractory to conservative treatment, which can include systemic nonopioid and opioid analgesics. These recommendations are supported by a variety of retrospective and prospective studies, as well as randomized controlled trials.^26-30 The use of both medications typically requires a trial period for noncancer pain, and should be performed by an experienced pain practitioner or team.

ITP morphine is thought to have fewer systemic side effects compared with oral morphine because of the targeted nature of delivery.³¹ Respiratory depression, however, remains the most serious complication common to both routes of administration. Sudden interruption can lead to withdrawal symptoms, and both titration and weaning of therapy must be done slowly. Unique to opioids is the potential of developing a catheter tip granuloma, an inflammatory mass of cells that can alter drug delivery or cause local compression and neurologic deficits. Ziconotide is not associated with respiratory depression or withdrawal symptoms with sudden interruption. Rather, ziconotide has a narrower therapeutic window and can be challenging to dose and titrate.³¹ The most common adverse effects are confusion and memory difficulties. Ziconotide is contraindicated with a pre-existing psychosis.

Use of other agents as monotherapy or in combination with other medications is common, although not approved by the FDA and considered off-label use. Typical agents include alternative opioids (eg, hydromorphone, fentanyl, or sufentanil) and local anesthetics (eg, bupivacaine). It is important to note that the FDA does not regulate compounding of medications, and quality assurance is the responsibility of the pharmacy.³¹ Furthermore, there has been some evidence suggesting a higher rate of ITP stalling with off-label medications compared with approved agents. When choosing an ITP agent, it is essential to consider a patient’s medical history and previous opioid use.

Of note, ITP baclofen (a GABA-B agonist) is FDA-approved for the treatment of spasticity, but not pain, although it is sometimes used in admixtures with an opioid. Spasticity can be secondary to a cranial or spinal etiology, most commonly attributable to stroke, traumatic brain injury, spinal cord injury, or multiple sclerosis. As in ITP pain therapy, patient selection is essential, and depends on the affected limbs, degree of involvement, and response to other modalities. Nonpharmacologic methods such as bracing, physical therapy, and surgery can be considered, but do not directly address spasticity.³² Although botulinumtoxin injections are approved for treating spasticity and effective for many, oral muscle relaxants, including baclofen are also commonly used. Potential adverse effects of baclofen (eg, sedation and difficulties with dosing) make ITP delivery an attractive alternative. A standard adult trial consists of a 50 mcg ITP bolus, followed by a comprehensive physical evaluation. It is then important to discuss starting dose and drug concentration, as well as the size of the pump and catheter placement.³³ Patients and caregivers must be well-versed in the signs and symptoms of baclofen withdrawal or overdose, which can be a dangerous emergency.

Conclusion

The goal of neuromodulation is to reduce pain and improve function. Most patients will continue to experience some residual pain following a successful procedure. It is important to define expectations with patients before implantation and provide regular follow-up care to assess progress and provide programming updates and troubleshooting, as needed.