Chemotherapy-Induced Peripheral Neuropathy Treatments

Introduction

Chemotherapy-induced peripheral neuropathy (CIPN) affects between 40% and 70% of individuals undergoing chemotherapy and may significantly affect quality of life by worsening symptomatic clusters, such as psychological distress, fatigue-related pain, and abdominal discomfort.¹˒²

A host of treatment and prevention modalities have been studied for CIPN, but there is still no clear preventive or treatment option.⁴ A majority of current treatment modalities center on pharmaceutical regimens rooted in duloxetine and opioids, which come with their own well-known variety of adverse effects.⁵˒⁶ Although conservative management with multimodal pain control and physical therapy serves a purpose as first-line therapy, a growing body of evidence supports the use of spinal cord stimulation (SCS) and dorsal root ganglion (DRG) stimulation both as an adjuvant treatment to conservative management and as second-line therapy for treatment-resistant CIPN.

Review Methods

A PubMed search of the keywords “chemotherapy induced peripheral neuropathy” and “spinal cord stimulators in CIPN” was investigated. The search was further narrowed by articles published in English and limited to articles published since 2004. These results were further classified into study types: case reports, case series, prospective studies, and RCTs.

A second PubMed search was conducted using the keywords “chemotherapy induced peripheral neuropathy,” “dorsal root ganglion stimulation,” and “dorsal root ganglion stimulation and CIPN.” These studies were filtered to exclude non-English language articles not and articles published before 2005.

The following review highlights both medication and emerging neuromodulation strategies for the treatment of chemotherapy-induced neuropathy.

There are currently no FDA-approved medication for CIPN prevention or treatment; duloxetine is the only pharmacologic that has shown any therapeutic potential.⁶ The limited treatment options surrounding CIPN may be a result of this condition’s multifaceted pathophysiology, unknown pathogenesis, and variable clinical presentation. Several classes of medications discussed below were initially thought to be beneficial, but further investigations have shown limited therapeutic value.

Although CIPN is a neuropathic pain state, anticonvulsants such as gabapentin have not shown efficacy in its treatment. In a randomized, double-blind, placebo-controlled, crossover Phase 3 trial of 115 patients, statistically similar changes were seen in symptom severity between the treatment (2700 mg of gabapentin for 6 weeks) and placebo arms.⁷

Another randomized, double-blind placebo-controlled trial analyzed 131 patients receiving either lamotrigine (target dose of 300 mg/day) or placebo for 10 weeks. Over the course of the study, pain scores dropped in both the treatment and placebo arms with no statistically significant difference observed between the changes in the two groups.⁸ The lack of a significant clinical or statistical difference between these two groups brings the role of anticonvulsants as part of the CIPN treatment regimen into question.

SSRIs and TCAs

Given their already researched efficacy in the management of neuropathy at large (not limited to chemotherapy-induced), selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) have traditionally played a role in the medical management of CIPN. These classes of medications are thought to exert their effects on serotonin and norepinephrine along the descending spinal pain pathways. There are also theories that antidepressants may exert adjunctive benefit through their actions on histamine receptors and sodium channel manipulation.⁹

Of the antidepressants mentioned, duloxetine appears to have the greatest therapeutic potential and as such, is considered a first-line agent for the treatment of CIPN.¹² A study of 231 CIPN patients across 8 NCI-funded cooperative research networks showed significant improvement in average pain scores in the treatment arm (duloxetine 30 mg daily for the first week, then 60 mg for four additional weeks) as compared to the placebo arm (P = 0.003).

A more recent trial of 34 patientsyielded similar results with significant decreases in visual analog scale pain scores in the treatment arm (duloxetine 20 mg/day orally for the first week and 40 mg/day for the next 3 weeks) as compared to vitamin B12 (VB12) 1.5 mg/day orally for 4 weeks.¹³ This study also included a 2- to 4-week washout period, after which treatment was crossed over for another 4 weeks. The first group of duloxetine showed significant differences with respect to numbness (P = 0.03) and pain (P = 0.04) in patients suffering from CIPN caused by oxaliplatin, paclitaxel, vincristine, or bortezomib.

Opioids have classically played a role in the treatment of cancer-related pain, although their effectiveness alone is limited when targeting CIPN pain. In patients with neuropathic pain either due to postherpetic neuralgia (PHN), posttraumatic neuropathy, or CIPN, it was found that the combination nortriptyline–morphine showed superior efficacy than either medication alone at treating neuropathic pain.¹⁴ A similar phenomenon was exhibited when gabapentin was utilized. While observed in patients with non-CIPN neuropathic pain syndromes, those with diabetic neuropathy or postherpetic neuralgia achieved better analgesia with the combination of gabapentin and morphine in the treatment of their neuropathic pain, suggesting a possible additive effect between the two medications.¹⁵

Within the opioid class itself, morphine has traditionally played a role in the management of cancer-related pain and is recommended as a first-line opioid in the WHO Cancer Pain Relief Guidelines.¹⁶

Methadone has been explored as an alternative opioid given its potential advantage as a relatively potent N-methyl-D-aspartate (NMDA) receptor antagonist, which may play a role in targeting neuropathic pain. Bruera et al concluded that methadone did not demonstrate an advantage over morphine in the treatment of cancer-related pain in terms of its efficacy or tolerability over a 1-month period.¹⁷ However, it is important to highlight that this RCT included a low number of patients with suspected neuropathic pain and did not include neuropathic pain improvement as a primary endpoint. Therefore, additional research is needed to elucidate the effect of methadone in neuropathic pain relief.

Spinal cord stimulation works at the level of the dorsal columns and activates both spinal and supraspinal neurophysiologic mechanisms to inhibit pain. SCS can acutely inhibit wind-up (short-form neuronal sensitization) and long-term potentiation at the level of the dorsal columns and dorsal horns. This mechanism of action suggests that SCS might have preventive effects, as well as a therapeutic benefit, for people living with CIPN.⁷

Technically speaking, SCS is considered one of the most challenging procedures in interventional pain management.⁷ Although still a minimally invasive procedure and performed in the outpatient setting, it requires multiple steps to achieve successful placement. Under fluoroscopy, a lead is first sterilely introduced into the epidural space and then directed to its target location. For instance, lower extremity CIPN SCS leads enter the epidural space at the T12-L1 level, yet the leads are typically placed at the T6-7 level.

SCS in the Literature

While our search turned up no human subject RCTs for the use of SCS and only one animal model study for electroacupunture¹⁸ in the treatment of chemotherapy-induced peripheral neuropathy, we did come across multiple case reports, summarized below.

Abd-Elsayed et al (2016) presented a series of three cases where treatment with SCS led to marked improvement in otherwise treatment-resistant cases of peripheral neuropathy secondary to HIV, diabetes mellitus, and chemotherapy (see Table I).¹⁹ In one patient with CIPN, SCS leads were placed at T10-T11. On follow-up at 3 months and 2 years post-implant, the patient reported continued pain relief, improvement in ADLs, improvements in sleep patterns, and a reduction in breakthrough medication use.

Abd-Elsayed et al (2021) followed a 47-year-old man with bilateral upper extremity CIPN due to eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisolone to combat diffuse B-cell lymphoma.²¹ After eight years of failed conservative therapy for CIPN, he underwent a successful trial followed by permanent implant with lead placement at C4-C5 and sustained pain relief of the upper extremity.

Another 51-year-old woman developed bilateral lower extremity CIPN secondary to fluorouracil, leucovorin, and oxaliplatin therapy during her colorectal cancer treatment.²² Despite medication management with first-line medications (pregabalin, gabapentin, amitriptyline, venlafaxine, duloxetine), second-line medications (subcutaneous botulinum toxin injection, tramadol), and third-line medications (oxycodone and methadone) at maximally tolerated doses, there was no improvement in her CIPN. However, after SCS implantation, her bilateral lower extremity CIPN resolved.

The first patient also reported 90% relief after an SCS trial at the L1 level with maintained relief even up until day 4 after its removal, after which pain levels returned to pre-SCS baseline. One week later, the patient was implanted with a permanent SCS at L1 with ensuing improvement up to the 4-month follow-up and a reduction in his medication requirement.

In a separate case, a 47-year-old man with a history of multiple sclerosis developed bilateral lower extremity CIPN as a result of oxaliplatin therapy for rectal adenocarcinoma, predominantly localized to his feet.²⁴ After failing medication management (gabapentin, amitriptyline, duloxetine, trazodone, vitamin B12, and compounded ketamine topical cream), the patient received a SCS trial at the posterior epidural spaces of left T12-L1 and right L1-L2. The patient reported minimal stimulation and subsequent relief paresthesia in his feet. Instead, the SCS was targeting the proximal lower extremities by sending more stimulation to those regions.

SCS Discussion

As shown, the case reports and series from this literature review highlight a successful outcome of SCS for CIPN at long-term follow-up. Additionally, the single animal model RCT studying electroacupuncture showed significant therapeutic benefit in rats, providing a potential molecular mechanism of action for SCS in CIPN.

Notably, there were no negative outcomes reported, such as failure of SCS to improve pain, adverse effects, or unintended complications. Given the nature of these types of studies, there is likely a reporting bias. Additionally, due to the small number of patients in each of these reports and varying variables – such as medication use or degree of neuropathy – more structured research is needed to solidify SCS as a valid treatment option for CIPN.

DRG Stimulation

Dorsal root ganglion stimulation is a more selective form of neuromodulation that targets the dorsal root ganglion. It is currently FDA-approved for the treatment of complex regional pain syndrome (CRPS) but has gained increasing traction in the treatment of neuropathic pain conditions, including CIPN. Compared with SCS, DRG stimulation may offer a more targeted approach to CIPN. CIPN is thought to disproportionately affect neurons at the DRG since the DRG is not protected by the blood-brain barrier.²⁵˒²⁶

• post-synaptic activation of pain-gating circuitry in the dorsal horn and possibly the DRG itself
• augmentation of the low pass filtering of painful signals at the T-junction of nociceptive neurons
• reduction of the intrinsic excitability of DRG neurons

Further research is needed to determine the degree to which each of these theories contribute to the overall analgesic effects of DRG stimulation. Delineation of its method may then guide a provider to recommend DRG stimulation over SCS for certain patients.

An understanding of the anatomy of the DRG is essential to discussing proper placement technique. There are bilateral pairs of dermatomal DRGs at each vertebral level, and these are encased by the meninges. As described by Graham et al, “during the implantation of a DRG [stimulator] system, electrode lead bodies are percutaneously inserted using a Touhy needle, guided through the epidural space of the spinal column using x-ray fluoroscopy, and routed into the intra-foraminal space where the array of electrode contacts are placed along the dorsal side of the DRG. The electrode leads are connected to an implanted pulse generator, which resides in a body cavity usually around the posterior lateral flank.”²⁷ The anatomy of the DRG neurons, particularly their location in the DRG relative to the stimulating electrodes, has a major impact on which cells are being stimulated by the DRG stimulation leads.²⁷

The aforementioned 47-year-old patient with CIPN secondary to oxaliplatin therapy for rectal adenocarcinoma described by Finney et al elected to trial dorsal root ganglion stimulation with bilateral placement at the DRG of S1 and S2, resulting in successful relief of paresthesia in his feet bilaterally.²⁴

Additionally, Grabnar et al reported success after DRG stimulation in a patient with bilateral lower extremity CIPN who had previously failed conservative therapies.²⁸ Similarly, another female patient with thalidomide-induced CIPN reported significant improvement after placement of bilateral S1 DRG leads.²⁸

Table III provides additional relevant data points supporting the use of DRG stimulation in CIPN.

DRG Discussion

Of the four case reports included for DRG stimulation, three described significant relief in otherwise treatment-resistant CIPN. One of these three patients had previously failed a SCS trial, suggesting some utility for DRG stimulation as a potential alternative. Although most of the literature highlights positive outcomes from neuromodulation, it is important to recognize that these techniques are technically challenging procedures with a moderate risk of complications.

Overall, DRG stimulation may present a more targeted neuromodulation approach, and it is hoped that these examples will stimulate further investigation of the technique.

It is worth noting that alternative modalities such as physical or occupational therapy, biofeedback, guided imagery, and acupuncture may be employed for CIPN but often only provide minimal, short-lasting relief.

The literature discussed in this review supports neuromodulation as a long-term treatment option for chemotherapy-induced peripheral neuropathy that is refractory to medication management. Based on the favorable outcomes of the reviewed case reports, there is strong evidence that both SCS and DRG-S may play a beneficial role in the treatment of cancer-related neuropathic pain syndromes.

While spinal cord stimulation presents a promising method to treat chronic neuropathic pain, its technique is not without limitations. It is not uncommon for SCS electrodes to migrate, which may lead to unpredictable results. DRG stimulation may improve these outcomes by targeting focused regions of pain. Limitations notwithstanding, both techniques serve as valuable adjuncts to the current mainstay of CIPN treatment. Further studies with RCT would be required to establish these procedures in the treatment paradigm of CIPN.