From Compression to Itch: Exploring the Link Between Nerve Compression and Neuropathic Pruritus

Definition of Neuropathic Itch from Spinal Impingement

Neuropathic itch from spinal impingement is itch without a primary rash caused by spinal impingement, as in brachioradial pruritus (BRP), notalgia paresthetica (NP), and anogenital itch, which are forms of neuropathic itch—defined as the sensation of pruritus that is caused by neural dysfunction at any point along the afferent pathway [1]. This non-dermatological itch is typically chronic in nature and may be accompanied by other abnormal sensory symptoms in a dermatomal distribution, such as paresthesia, hyperesthesia, or hypoesthesia [2]. This sensory combination may lead to feelings more characteristic of pain, such as burning, stinging, or tingling [3]. Another distinguishing feature of neuropathic itch is the potential presence of other forms of neural damage, including motor or autonomic damage [2]. The pruritus may be localized due to compression of a single nerve fiber or generalized due to broader nerve degeneration [3]. Of note, neuropathic pruritus tends to be moderate to severe, with an average itch severity of 6.5–7.8 on a mean numeric rating scale (NRS) [4, 5]. This likely contributes to a host of comorbid features that negatively impact quality of life in patients with chronic pruritus, especially depressed mood, disrupted sleep, and strained social relationships [5, 6].

Epidemiology

Neuropathic itch is a common origin of chronic pruritus, accounting for an estimated 8% of cases in the general population, according to a German database [3, 7]. Epidemiological studies exploring the prevalence and incidence of neuropathic itch are notably lacking in the existing literature. The most common forms of neuropathic itch are BRP, NP, and anogenital itch, albeit there are no detailed epidemiologic data.

Identifying the cause of neuropathic itch can be a convoluted process, and recognizing key epidemiological factors may be a helpful tool in narrowing the potential contributing mechanisms. BRP, for instance, is 2–3 times more commonly seen in white women in the fifth to sixth decades of life [3, 8, 9]. The prevalence of BRP in the general population is unknown, although it is considered to be rare [10]. BRP also appears to be more common in the tropics or subtropics compared with moderate climates or may present with disease flares during the warmer months with remission during cooler periods [11, 12]. The increased prevalence of BRP in regions with high ultraviolet (UV) exposure may relate to sun damage of itch -inhibitory nerve fibers in skin [12–14].

Similar to BRP, NP is 2–3 times more likely to occur in women than men and is commonly seen in middle-aged individuals, although pediatric cases are possible, as reported in association with multiple endocrine neoplasia syndrome type 2A [15–17]. There does not appear to be a racial or temperate predilection [18]. Despite its impact on individuals worldwide, the general prevalence of NP remains to be elucidated [18].

Anogenital pruritus refers to itch localized to the anal, perianal, or genital skin. The prevalence of anogenital itch may differ on the basis of the areas affected. In general, anogenital pruritus impacts 1–5% of the adult population [19]. Unlike in BRP and NP, pruritus ani affects men more frequently than women, with up to a 4:1 ratio and with those effected often being between the ages of 40 and 60 years [20–22]. With respect to genital itch in the female population, the vulva is reportedly affected in 5–10% of cases [23, 24]. In the setting of an ambulatory vulvar specialty clinic, 70% of patients endorsed vulvar itch [25]. The true prevalence of vulvar and anogenital itch is likely gravely underestimated, given patients may be hesitant or embarrassed to report this symptom [26]. This reluctance can lead to underreporting, which contributes to the underestimation of the true prevalence of these conditions. The stigma attached to discussing genital symptoms can also discourage patients from seeking medical advice, resulting in delayed diagnosis and treatment [19, 27]. Additionally, cultural and societal norms may further inhibit individuals from openly discussing these issues, thereby impacting their willingness to report symptoms to healthcare providers [28].

Brachioradial Pruritus

BRP is largely believed to result from radiculopathies involving the cervical dorsal root, as in spinal stenosis, or compression of spinal nerves that leads to the localized sensation of pruritus in a dermatomal distribution [34]. Rarely, degenerative changes of the spine may lead to nerve compression. Alternatively, some authors have also postulated that sun-induced cutaneous injury to peripheral nerves plays a role in the pathogenesis, given that BRP may worsen with exposure to ultraviolet (UV) light and warmth [14, 35, 36].

In the periphery, BRP is associated with reduced epidermal and dermal nerve fibers, which normalize with the cessation of symptoms [12]. Nerve fiber density in pruritic skin is decreased by 23–43% compared with controls [12]. Another recent study found that patients with BRP exhibited a reduced density of intraepidermal nerve fibers (IENFD) along with distinct branching patterns in the epidermis contrasting with abundant lower epidermal branching in chronic nodular prurigo (CNPG) [37]. The study revealed reduced linear nerve fibers in the lower epidermis and branching in the upper epidermis levels of BRP patients [37]. These findings indicate altered neuroanatomy, disease-specific innervation profiles, and a potential involvement of nerve fiber plasticity in the pathophysiology of BRP [37]. Interestingly, these histological changes mimic those seen in the skin following phototherapy, supporting the hypothesis that exposure to sunlight may be an eliciting factor for BRP [38]. The solar radiation may cause spontaneous firing of damaged peripheral nerve fibers, leading to the exacerbation of pruritus. Mirzoyev and Davis found that bilateral symptoms and prolonged sun exposure correlated with BRP in 111 patients, further supporting the ultraviolet radiation (UVR) theory [39]. UV light exposure releasing β-endorphin in the skin could be an area of interest linking UVR and cervical spine theories [40]. Notably, cutaneous regeneration genes are not upregulated in BRP as they are in some inflammatory pruritic conditions (atopic dermatitis and prurigo nodularis), lending support to a true underlying neuropathic origin of BRP [37].

The central mechanisms underlying BRP predominantly stem from the processes leading to nerve impingement in the spine. Cervical spine disease has been identified as a potential predisposing factor to BRP. Etiologies may include osteoarthritic changes, spondylosis, spinal or foraminal stenosis, or disc protrusions [10]. In a study of 16 patients with BRP, 6 suffered from neck pain, and 5 had confirmed spinal pathology on imaging at the C5–C7 level [12]. Similarly, in a retrospective, single-center study of 22 patients with BRP, 11 patients had cervical spinal radiographs, of which all displayed abnormalities [41]. In another magnetic resonance tomography study of 41 patients with BRP, all patients had detectable changes. The location of nerve compression was significantly associated with the dermatomal location of pruritus in 80.5% of patients [34], supporting cervical spine pathology’s role in BRP.

In some cases of BRP, underlying tumors such as ependymomas may be discovered, which can contribute to the symptoms [42, 43]. These tumors can cause compression of the spinal cord or nerve roots, leading to neuropathic itch as a symptom. Identifying such tumors is crucial, as their removal or treatment can potentially alleviate the pruritus associated with BRP [42].

Notalgia Paresthetica

The exact pathophysiology underlying NP is not clear, and many theories regarding both peripheral and central mechanisms have been proposed with supporting evidence. However, it is broadly accepted that damage to the cutaneous branches of the dorsal primary rami of thoracic spinal nerves contributes to sensory neuropathy in NP [44]. The nerves originating from the T2–T6 region of the spine are the most commonly affected. In this area, it has been hypothesized that the dorsal rami may be at increased risk for trauma and entrapment due to their angular 90-degree course through the muscles [45]. Another theory that has been suggested as a peripheral mechanism contributing to NP is an injury to the long thoracic nerve, which originates from cervical spinal nerves C5–C7, leading to dysfunction of the serratus anterior muscle [46]. Subsequent loss of scapular protraction may in turn generate compression of the cutaneous branches of the thoracic dorsal primary rami of the spinal nerves as they travel through the muscle toward the skin [46–48].

Unlike in the BRP studies mentioned above, there appears to be a weaker correlation between the thoracic spinal damage on imaging and the cutaneous location of sensory symptoms endorsed by patients with NP [48].

Anogenital Pruritus

The etiologies capable of causing pruritus in the anal and genital areas are plentiful. However, when an obvious trigger is unable to be identified and no primary rash exists, an underlying neuropathic process should be highly considered.

Damage to nerves in the lower spine is the most common cause of neuropathic anogenital pruritus. Furthermore, it may be underrecognized by providers due to unknown spinal pathologies in patients. In a study of 20 patients with anogenital pruritus of unknown origin, 80% were found to have evidence of degenerative changes to the lower spine on radiographs and lumbosacral radiculopathy on nerve conduction studies [49]. Consistent with other forms of localized neuropathic itch, anogenital itch can present as a manifestation of compression of a nerve or nerve root due to spinal injury or lumbosacral arthritis [50]. The spinal levels affecting genital sensation range between L4 and S2 [49]. Figure 1 shows the various mechanisms by which nerve impingement or damage induces neuropathic itch.

Small-fiber polyneuropathy affecting the unmyelinated C-fibers and thinly myelinated A-δ fibers is one peripheral mechanism that may contribute to neuropathic itch localized to the genitals, especially in chronic diabetic patients [3, 51, 52].

Another cause of neuropathic genital pruritus is postherpetic neuralgia [51]. Reactivation of the varicella-zoster virus can lead to irritation or injury in a nerve that has already been damaged, leading to localized itch [53]. Of note, repeated injury to the same nerves may lead to long-lasting damage, causing persistent itch and/or pain [50].

Brachioradial Pruritus

BRP is a localized neuropathic pruritus characterized by abnormal sensations in the dorsolateral areas of the upper extremities, with some cases involving the shoulders and neck [14, 40]. This sensory abnormality is characterized by enduring sensations of itching, that can in some cases involve burning and stinging. It can manifest unilaterally or bilaterally, often favoring a bilateral distribution along the C5–C6 dermatomes [35]. Alloknesis and hyperknesis are important sensory phenomena observed in patients with BRP, reflecting heightened neural sensitivity. Alloknesis refers to the perception of itch in response to normally non-itchy stimuli [60], while hyperknesis indicates an exaggerated itch response to pruritogenic stimuli [61]. Recent studies on BRP patients have highlighted these phenomena, showing that chronic nerve compression and alterations in intraepidermal nerve fiber density contribute to these heightened responses [62]. The reduction in nerve fiber density, as seen in BRP, may lead to changes in neural signaling pathways, resulting in increased sensitivity to stimuli that would not typically provoke an itch response [37, 62, 63].

While there are no primary skin lesions linked to BRP, scratching can lead to secondary skin lesions such as excoriations, prurigo nodules, and lichenification on the affected skin [40]. In fact, BRP can expand and become generalized similar to chronic neuropathic pain [9]. BRP individuals are commonly outdoor lovers, including bikers, hikers, tennis and golf players, and tanners, with a significant history of sunburn. Despite the prevalence of cervical spine abnormalities observed on imaging among BRP patients, retrospective studies indicate that very few of these patients report cervical spine narrowing, neck pain, or neck trauma [58].

The correlation between brachioradial pruritus (BRP) and cervical spine changes, particularly from C3 to C7 and notably at C5–C6, is well-documented. Imaging studies, including X-rays and MRIs, often reveal joint degeneration, neural foraminal stenosis, disc protrusion, central canal stenosis, nerve compression, and spondylosis at these levels, which correspond with BRP’s dermatomal distribution [42, 58, 64–66]. Electromyography studies further support this by showing denervation and fewer motor units along C5/C6 or C6 nerve roots [10]. Case studies have also shown resolution of pruritus following spinal decompression surgery, reinforcing the link between cervical spine disease and BRP [65], and another finding an intramedullary ependymoma in a BRP patient’s spinal cord with nerve compression [42].

BRP is also exacerbated by ultraviolet radiation (UVR) exposure, with patients reporting increased itching when exposed to sunlight [58]. Previously called solar pruritus, BRP was recognized as more common in patients living in warmer climates such as Florida. Wallengren and Dahlbäck reported an increase in BRP symptoms during late summer and a decrease during winter, suggesting a link to sun exposure [67]. Other studies show that using sun protection reduces BRP symptoms, especially for those with seasonal variations [66, 68].

Notalgia Paresthetica

NP is characterized by chronic itching and dysesthesia localized to the upper back, specifically the lower scapular region. The pruritus is often persistent and can be accompanied by pain, burning, or tingling sensations [55]. This condition primarily affects middle-aged individuals and is usually unilateral, though bilateral cases can occur. The skin in the affected area may appear hyperpigmented due to chronic scratching, leading to secondary changes such as lichenification, excoriations, and rarely prurigo nodules [55, 69]. Despite the noticeable itching and post-inflammatory pigmentary changes, primary skin lesions are absent, distinguishing NP from other dermatologic conditions [57]. The underlying cause is thought to be related to nerve entrapment or irritation, leading to sensory changes in the affected dermatome [69–71].

The etiology of NP is primarily linked to nerve impingement or damage to the nerves innervating the skin overlying the upper back [44, 71, 72]. This condition often arises from degenerative changes or trauma to the spine, such as osteoarthritis, scoliosis, motor vehicle accidents, or spinal stenosis [69]. Factors contributing to nerve compression include age-related or occupational-related spinal degeneration, poor posture, and repetitive mechanical stress on the spine [69, 73]. Although less common, NP has been suggested to be associated with diabetic peripheral neuropathy [74]. Additionally, some cases have been linked to herpes zoster and other viral infections that affect the nerves [53]. Interestingly, however, in NP there are no reports of generalization of itch.

A recent large comparative analysis of clinical characteristics in BRP and NP patients revealed that BRP patients experience longer daily itch durations and more generalized itching than NP patients [75]. Although itch intensity was similar for both conditions, scratching was more pleasurable and provided more relief for NP patients [75]. BRP patients, however, showed a higher prevalence of scratch lesions, itching worsened by scratching, and scratching without itch [75]. Additionally, BRP had a more significant impact on sleep overall, with more severe impacts stratified by severity [75]. These findings elucidate distinct clinical profiles for BRP and NP and suggest that BRP can be a more challenging condition to manage.

Another comparative retrospective study by Pereira et al. showed that BRP patients more frequently report multiple paraesthetic symptoms and exhibit decreased intraepidermal nerve fiber density in lesional skin, which is not observed in NP patients [76]. Furthermore, BRP patients tend to have a higher prevalence of scratch lesions and report more significant impacts on sleep and quality of life compared with NP patients [76], corroborating the results of Lipman et al. [75].

Anogenital Neuropathic Pruritus

Anogenital pruritus is characterized by persistent itching in the anal and genital areas [77]. Patients often delay consulting a physician for anogenital itch, leading to later presentations with atypical symptoms or skin changes such as depigmentation, erythema, lichenification, and secondary skin infections due to persistent scratching [77]. Symptoms can be exacerbated by factors such as moisture, sweating, and friction. In some cases, patients might also report a burning or stinging sensation. Given the sensitive nature of the affected region, anogenital pruritus can significantly impact quality of life and result in psychological distress [78, 79], necessitating a thorough evaluation to identify underlying causes and appropriate treatments.

Furthermore, dermatologic conditions such as psoriasis, lichen simplex chronicus, and lichen sclerosus should be ruled out before attributing the itch to lumbar spinal radiculopathy [49, 80]. In a study involving 20 patients with anogenital pruritus, lumbosacral radiculopathy was detected in 16 patients (80%), highlighting the role of lumbosacral compression in pruritus generation [80]. The primary cause of neuropathic itch in the genital area often stems from compression of the lumbar and sacral spinal cord dorsal rami, involving nerve roots L1–L5 and S1–S5 [59].

Topical Treatments

First-line options for the treatment of neuropathic itch include the usage of topical medication including transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8) agonists such as menthol, TRPV1 agonists such as capsaicin, local anesthetics such as pramoxine, lidocaine targeting voltage-gated sodium channel (VGSC) inhibitors, and compounded medications.

Cooling therapies have traditionally been utilized in the realm of pain and itch relief, but the exact physiological pathway has not been agreed upon. TRPM8 is a cold-gated ion channel receptor located on peripheral nerves, and studies have demonstrated that TRPM8 inhibition through application of menthol can decrease itch through reduction of nerve excitability [81]. TRPV1, similarly, is a nonselective cation channel in the peripheral nerve system that reduces itch sensation when targeted with medications such as capsaicin [82, 83]. Capsaicin, in particular, is available as a cream (0.025–1%) and a high-dose 8% patch [35]. While the cream formulation can provide relief for some patients, the high-dose patch is often necessary to achieve a significant anti-pruritic effect, especially in cases of severe itch [84, 85]. The patch works by depleting substance P and other neuropeptides from sensory nerve endings, offering longer-lasting relief compared with lower concentrations [9, 86–88].

Applied studies in humans on a VGSC inhibitor containing pramoxine have also exhibited itch reduction [89, 90]. Blockade of N-methyl-D-aspartate receptor and sodium channels through administration of a compounded ketamine–amitriptyline–lidocaine (KAL) topical has shown efficacy in decreasing itch for patients [91]. Additionally, topical formulations containing strontium, a calcimimetic, have shown anti-pruritic effects for NP [92].

Systematic Treatments

As with neuropathic pain, treatment for neuropathic itch has utilized medication classes such as anticonvulsants, neuromodulators, and antidepressants. Although gabapentin and pregabalin have been shown to improve neuropathic itch in the post-recovery period of burn patients, the pathway is unclear but hypothesized to be due to the structural resemblance of gabapentin and pregabalin to that of the neurotransmitter GABA; binding to voltage gated calcium channels limits the excitability that can upregulate itch [93]. Indeed, GABAergic drugs seem to be the most effective drug class for nerve-impingement-induced itch, especially for BRP [94] and NP [95]. In our recent paper investigating treatments for reducing itch in BRP patients, pregabalin both alone and in combination with compounded ketamine 10%, amitriptyline 5%, and lidocaine 5% cream were effective in producing significant reductions in itch scores [94]. Tricyclic antidepressants also have antinociceptive properties, which have been shown to decrease pruritus in patients with chronic, treatment-resistant itch [96]. Medications that act as mu opioid receptor antagonists or kappa opioid agonists, such as butorphanol, naltrexone, and naloxone, have been investigated for the treatment of neuropathic itch as well, though they are usually utilized as third-line treatment options [5, 97–99]. A recent phase 2 study demonstrated that difelikefalin, a peripheral kappa opioid receptor agonist, was effective in significantly reducing itch intensity in NP patients over 8 weeks compared with placebo [100]. Both groups had a mean baseline Worst Itch Numeric Rating Scale (WI-NRS) score of 7.6, indicating severe itch. At week 8, the difelikefalin group saw a clinically and statistically meaningful reduction of 4.0 points, versus the placebo group of 2.4 points [100]. However, a phase 3 study failed to achieve the primary end point and did not demonstrate any clinical benefit at any dose compared with placebo [101]. Some therapeutic benefits have also been reported with botulinum toxin type A injections for NP [35] and BRP[102], suggesting its potent effects on the afferent sensory nervous system by inhibiting the release of neuropeptides such as substance P from sensory nerves and potential for relief of non-histaminergic, localized itch [103]. Moreover, intravenous ketamine, an NMDA receptor antagonist, has been shown to reduce neuropathic itch from nerve impingement [35, 92]. Its neuromodulatory effects for chronic, treatment-refractory neuropathic pruritus were recently confirmed in a case series study by Kwatra et al. [104].

Aprepitant is a neurokinin-1 (NK1) receptor antagonist that has been explored as a treatment option for neuropathic itch. The drug works by blocking the action of substance P, a neuropeptide involved in transmitting itch and pain signals in the central nervous system [105]. Although not commonly used, aprepitant has been shown in case reports to be effective in reducing chronic itch that is resistant to other treatments, offering relief by targeting the neural pathways involved in itch perception [106–109].

Emerging Therapies

Detomidine gel, also known as CLE-400, is a new α₂-adrenergic receptor agonist that has demonstrated benefits in preclinical pruritus models and is currently being explored in a phase 2 trial for notalgia paresthetica. Activation of the α₂-adrenergic receptor reduces sympathetic activity and may help alleviate neuropathic itch by dampening receptor excitability [110].

Non-pharmacological Interventions

Holistic treatment options have been studied as adjuncts to pharmacological interventions in itch management. Acupuncture, in particular, has been found to alleviate itch sensations in various conditions. This effect is hypothesized to result from the stimulation of peripheral nerves and high-density nerve endings at the acupuncture points [111]. Stress reduction tactics through mindfulness techniques, yoga, and cognitive behavioral therapy (CBT) have been well established methods of itch alleviation due to the impact that psychological stress has on modulating the nervous system [112, 113]. The effect of exercise on relieving neuropathic symptoms, including neuropathic itch, has shown limited success in case series reports. The principle is that alleviating nerve impingement or compression through physical activity and stretching directly impacts the etiology of the itch. Physiotherapy can help alleviate symptoms by addressing the underlying musculoskeletal issues that contribute to nerve compression. Techniques such as strengthening exercises and posture correction can reduce pressure on affected nerves, potentially decreasing neuropathic symptoms such as itch [114]. Additionally, physiotherapy may improve overall spinal health, which is crucial in conditions where spinal nerve impingement is a contributing factor [115]. By incorporating physiotherapy into the treatment plan, patients may experience reduced symptom severity and improved quality of life [55, 115, 116]. However, higher-quality studies with randomized groups and placebo arms are needed to confirm these findings [114]. Figure 2 summarizes first-line and subsequent treatment options for neuropathic itch.

Funding

None.

Conflicts of Interest

None to declare for Kayla Mashoudy. None to declare for Sarah Brooks. None to declare for Luis Andrade. None to declare for Jaxon Wagner. Conflicts of interest for Dr. Gil Yosipovitch include: Consultant and Board Member for Sanofi, Regeneron, Pfizer, Galderma, Novartis, Eli Lilly, Abbvie, Clexio, Kiniksa, Trevi, Pierre Fabre, LEO, and Escient; Celldex and Bellus; and research support from Pfizer, Sanofi Regeneron, LEO, Eli Lilly, Kiniksa, Novartis, Escient, Bellus, Galderma, and Celldex; and Clexio. Gil Yosipovitch is an Editorial Board member of the American Journal of Clinical Dermatology. Gil Yosipovitch was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions.

Ethical Approval

Not applicable.

Data availability statement

Not applicable.

Author contribution

Kayla Mashoudy: conceptualization, methodology, and writing—original and final draft preparation. Sarah Brooks: material preparation and writing—original draft preparation. Luis Andrade: material preparation and writing—original draft preparation. Jaxon Wagner: material preparation and writing—original draft preparation. Gil Yosipovitch: supervision, writing, and manuscript review. All authors read and approved the final manuscript.

Patient Consent to Participate/Publish

Not applicable.

Code Availability

Not applicable.