Chronic itch and available treatments
Chronic intractable pruritus is nonhistaminergic (as opposed to acute, histaminergic itch) and is mediated through neural pathways. Nonhistaminergic pruritogens activate receptors on small, unmyelinated C-fibers with the cell bodies of itch sensing neurons positioned in the dorsal root ganglion (DRG). Many treatments have been directed to manipulation of these receptors or elimination of pruritogens.
Over the last years, significant progress has been made in the identification of the underlying pathways responsible for chronic pruritus and has presented the field with opportunities for drug development and use of existing drugs targeting implicated pathways. Most recently, there has been a focus on the use of drugs targeting the neural system in addition to GABA-ergic drugs, Kappa opioid modulators, Neurokinin1 inhibitors, and TRKA 1 inhibitors1.
These classes of systemic treatments have shown some promising results for control of chronic pruritus. They do, however, present with their own array of adverse effects. In addition, these treatments do leave a small subsect of patients untreated who have exhausted all available options and continue to suffer from chronic intractable pruritus.
Similarities between chronic itch and chronic pain
Chronic itch and chronic pain share many similarities. Both are unpleasant experiences, although they elicit different behavioral responses: scratch and withdrawal, respectively. Both, if uncontrolled, can lead to significant impairment and reduction in quality of life.
Chronic itch and chronic pain are believed to share similar fiber tracts and pathways. In fact, studies have shown that for patients with chronic itch conditions, repetitive painful stimuli may be perceived as itch2,3. This is the opposite of what is seen in healthy subjects, as noxious stimulus or scratching inhibits itch4. This is also seen in atopic dermatitis patients, where the painful act of scratching induces more itch which induces more scratching, and so goes the cycle. Histamine iontophoresis is perceived as painful in chronic pain patients, suggesting a phenotypic alteration from an expected itch sensation with histamine to pain5.
Neuropathic pain and neuropathic itch are also very similar to one another, both arising from a pathology along their respective and partly shared afferent pathways. This is why some painful conditions also present with itch. For example, postherpetic neuralgia is most recognized as a neuropathic pain condition, but itch is also seen in over 40% of these patients6. Another example is seen in brachioradial pruritus (BRP), a phenomenon of chronic pruritus over the neck and arm as a result of compression in the cervical spine. This condition presents mainly with localized pruritus, but may also present with burning, stinging, and tingling sensations7,8. In addition, BRP may result in phenomenon known as BRP-triggered generalized pruritus, in which a localized chronic itch becomes generalized. This expansion of the pruritic area in BRP patients presents similarities to chronic neuropathic pain, which can often start in a localized area and eventually generalize7,9. Perception of itch and pain are mediated through similar areas of the brain, as noted through functional magnetic resonance imaging studies10.
Another conserved theme between chronic pain and chronic itch is the involvement of “On” and “Off” cells of the central nervous system (CNS). Rostroventromedial medullar “On” and “Off” cells are thought to mediate chronic pain transmission and are differentiated based on their response to painful stimuli11. On cells uphold and allow passage of the pain signal, while activation of the Off cells inhibits these signals. These cells’ roles in pruritus were explored in a study, which showed that On cells were activated by injecting intradermal pruritogens and production of physical scratch stimuli11. Off cells were conversely inhibited with these same stimuli, concluding that ascending pruriceptive signals activate rostroventromedial medullar On and inhibit Off cells. Other studies have shown that many spinal neurons of the dorsal horn that respond to intradermal pruritogen injection also respond to algogens, proving it difficult to differentiate between pain and pruritus pathways12. Although there are some itch-specific tract neurons, most dorsal horn neurons have been shown to respond to both pruritogens and algogens2. Furthermore, conserved perception pathways between pain and pruritus incudes the demonstration that MrgprA3-expressing sensory neurons responded to pruritogens and algogens13.
Another parallel between chronic pain and chronic itch is the neuroplastic sensitization phenomenon—both central and peripheral. This refers to the hypersensitivity or inappropriately increased responsiveness of nociceptive and pruriceptive neurons. Peripheral sensitization refers to that affecting the primary afferent neurons, while central sensitization affects nociceptors in the CNS. In chronic itch, these sensitizations are manifested as dysesthesias including alloknesis (similar to allodynia in pain) and hyperknesis (similar to hyperalgesia in pain)14. Interestingly, this sensitization phenomenon is only recognized in chronic, nonhistaminergic itch and not observed in acute, histaminergic itch15. In chronic neuropathic pain and lower back pain, localized, and widespread hyperalgesia is widely recognized16. The pain associated with a neuropathic condition often extends into regions beyond those innervated by the involved nerve17. In chronic lower back pain, many studies have shown hyperalgesia18,19.
Neuromodulation techniques for the treatment of chronic pain
Given the significant overlap between chronic itch and pain states, consideration should be given to the utility of treatments and interventions intended for chronic pain patients for use in chronic itch patients.
Neurostimulation is an established treatment option for patients with chronic, refractory pain conditions. It is generally reserved for patients who have exhausted more common noninvasive treatment options, as it is an invasive procedure that comes with its own set of risks and adverse effects.
The method by which neurostimulation acts on chronic pain is through modulation of nerve fiber transmission. Activation or ablation of spinal glycinergic interneurons suppressed or facilitated itch perception, respectively20. GABA agonists, like baclofen, have been shown to suppress itch behavior21,22. Therefore, these inhibitory neurotransmitters are implicated in the suppression of spinal itch processing. This leads to the targeting of such inhibitory neurons using neuromodulatory techniques and inhibiting ascending pain signals.
Spinal cord stimulation (SCS) is commonly used for the treatment of chronic, intractable pain after conventional therapies have failed. It has been shown to be an effective treatment of neuropathic pain conditions including intractable leg and back pain (usually following failed surgical intervention), neuropathy and complex regional pain syndrome (CRPS). A known difficulty that arises with SCS is the ability to target specific anatomic locations, which is thought to be less specific to address specific dermatomal level with this modality. Since its inception, there have been numerous advances in the delivery of the SC stimulation including changes in electrode geometry, programming, etc.
Role of the DRG in chronic pain and chronic itch
The DRG is in the lateral epidural space within the spinal foramen and houses the cell bodies of the primary sensory afferent neurons which have their pruritogen and pain receptors in the skin. From the DRG, the cell body sends out a pseudounipolar axon, which then splits and extends toward peripherally toward the innervated dermatome and centrally toward the spinal cord23. These primary somatosensory neurons in the DRG transmit itch, pain, and touch sensation. Through RNA sequencing efforts, these neurons have been categorized based on their unique gene expression profiles. Through this, 3 subtypes of itch neurons (NP1, NP2, and NP3) have been identified with their cell bodies housed in the DRG23. NP1 neurons are Mrgpr+, while NP2 and NP3 both express histamine and IL-33 receptors. Uniquely, NP2 neurons express MrgprA3 and MrgprC11, while NP3 neurons express serotonin and IL-31 receptors23.
This makes the DRG a prime target for neuropathic pain and itch as it transmits signals from the peripheral nervous system to the CNS. Interestingly, the DRG does not only serve as a transmission relay station. Rather, it is now recognized as a dynamic structure that is involved in the processing of sensory inputs. This is further explored in the Gate Control Theory of pain transmission, a theory implicating the role of the DRG in the processing of pain signals24. Newer theories regarding the role of the DRG in sensory signal transmission suggests that the DRG acts as a summation point from peripheral signals until an activation threshold is achieved, allowing further propagation of the signal past the DRG to the CNS25. In addition, its anatomic location in the epidural space makes it easily accessible with minimally invasive procedures.
Treatment at the DRG may reduce responses to neuropathic painful stimuli through a number of proposed mechanisms. These mechanisms further support the idea that localized inflammation at the DRG is essential to the development of neuropathic pain25, potentially through modulation of processing at the T-cell junction, similar to what was described by Melzack and Wall as the Gate Control Theory.
In chronic pain states, the DRG shows pathologic changes. The proposed mechanisms by which the DRG is involved in the development and maintenance of chronic pain include changes in the membrane properties of the neuron, expression of membrane proteins, hyperexcitability, etch26–28.
Importantly, neuropathic pain has been suggested to be commonly driven by ectopic discharges originating in injured peripheral nerves. Studies in the spinal nerve ligation model showed that the cell bodies of the DRG contribute significantly more to the ectopic discharges (ectopia) than the actual site of nerve injury29–31. In an animal model of peripheral nerve injury, dorsal horn neurons continue to fire following the resection of spinal nerve neuroma and such activity was only silenced by transection of the DRG30. Selective pharmacologic targeting and inhibition of these DRG ectopic discharges relieved allodynia with preservation of normal sensory and motor function31. These findings suggest that the spike electrogenesis in the DRG is a primary driver of neuropathic pain and sensitization and possibly neuropathic itch and its sensitization, presenting a clinical target in the DRG.
Dorsal root ganglion stimulation (DRGS)
Although traditional low-frequency SCS has been shown to be largely successful in the treatment of neuropathic pain conditions, its efficacy has been challenged in focal pain conditions like CRPS, phantom limb pain, and peripheral nerve injury or disease25.
DRGS was approved for clinical use in the United States in 201632. A major advantage that DRGS over SCS is the ability to selectively target stimulation of anatomically challenging areas. With DRGS, regional pain relief could be achieved. This was first shown by Liem et al33 in 2011, as they demonstrated the efficacy of DRGS for focal nerve-related pain syndromes or mononeuropathies. DRGS for chronic pain has benefit in limited group of the patients with focal neuropathic pain syndromes and is especially valuable to areas that are difficult to target with SCS or maintain long-term with SCS34.
Despite the overall success of SCS in treating many neuropathic pain conditions, focal pain conditions such as CRPS, phantom limb pain, and injury or disease of the peripheral nervous system have created challenges to SCS efficacy. Focal areas of pain such as the trunk, groin, knee, foot, hand, and sacral areas have not always been captured reliably, resulting in unwanted paresthesias or failure to provide relief32.
GABA has been proposed to have a major role in nociceptive and non-nociceptive processing according to the Gate Control Theory24. The Gate Control theory explains that T cell (central transmission cell of the dorsal horn) activity which ultimately transmits signal to the brain may differ from the total input converging from the periphery as the substantia gelatinosa cells of the dorsal horn act as gates, summating peripheral input.
SCS can theoretically only modulate Aβ fiber signaling, while DRGS may also modulate Aδ and C-type fiber signaling35. One would then predict that since Aβ fibers are activated with DRGS that DRGS would also activate cellular release of GABA in the dorsal horn. There is recent evidence, however, suggesting that the mechanisms by which SCS and DRGS work for chronic pain states are unique. GABA is a key neurotransmitter in in the processing and modulation of the nociceptive signaling in the spinal cord and is important to nociceptive processing in the Gate Control Theory.
SCS was shown to increase extracellular GABA levels in the dorsal horns of allodynic rats, attributing the development of allodynia to decreased spinal release of GABA36. Baclofen, a GABA agonist, improved response rates to SCS in chronic pain patients37. Elevated extracellular spinal GABA has been shown in SCS induced analgesia. SCS responders showed decreased intracellular GABA levels in the spinal dorsal horn cells38.
There is evidence that DRGS does not induce GABA release from the cells of the spinal dorsal horn39. Koetsier and colleagues concluded that DRGS does not act via stimulation-induced GABA-mediated mechanisms in the dorsal horn specifically. They suggest that DRG stimulation may still be a GABA-mediated process, but at the DRG, not at dorsal horn39,40. This is in contrast or addition to dorsal column SCS effect of increased GABA release from the spinal dorsal horn cells38.
The key components of GABA-ergic transmission are present in the DRG41. Moreover, depolarizing stimuli induce GABA release in the DRG, thereby reducing DRG neuronal excitability. Same study showed that GABA infusion into the DRG alleviated neuropathic pain41. Therefore, there is an endogenous GABA-ergic control in the DRG and DRGS acts at least in part via modulation of a GABA at the DRG level.
Studies have looked into the role of neuropeptide Y (NPY) in the modulation of pain. NPY is expressed in the spinal interneurons of the dorsal horn, receiving inputs from AB and C fibers. Direct injection of NPY into the DRG following spinal nerve ligation injury exacerbated pain-related behavior and resulted in hyperalgesia. Following co-injection of the DRG with NPY and specific Y1 and Y2 receptor antagonists abolished the aforementioned actions of NPY, further isolating the role of NPY. The activation of such receptors activates astrocytes within the dorsal horn, along with satellite cells in the DRG proximal to painful stimuli. These findings showed one of likely many ways NPY plays a role in chronic pain and sensitization through the DRG42.
NPY has also been recognized to play a role in itch perception. Ablation of NPY-expressing spinal interneurons were shown to enhance mechanical itch and alloknesis43. Activating the NPY receptor system in mice through intrathecal injection of a Y1 agonist lessened the itch behavior provoked by both mechanical and chemical (histaminergic) itch stimuli. This effect was reversible with the addition of a Y1 antagonist, strengthening the notion that the NPY system’s role is critical in itch perception and behavior44. Rowan et al45 showed that all NPY-immunoreactive neurons on the dorsal horn in a rat model were also shown to be GABA-immunoreactive. This suggests that NPY, together with GABA, produce presynaptic inhibition of nociceptive primary afferents.
In humans, neuromodulation of DRG is usually accomplished using quadripolar electrodes which are implanted under fluoroscopic guidance as shown in Figures 1 and 2. Once in position near fluoroscopic landmarks for DRG location, the lead is connected to an external stimulator to ensure paresthesias to affected areas before the final lead position is determined.
Before implantation of leads, one must determine the level of DRG to be targeted so to endure coverage of the area of pain. One can rely on a dermatomal map to select the correct target. However, in many chronic pain conditions, there are maladaptive changes in the CNS including deafferentation and central sensitization such that the classic dermatomal distributions do not apply46–48. There has been suggestion that practitioners should preoperatively apply percutaneous stimulation to create a sensory map prior to making decisions on DRG targets49. This issue of determining the appropriate target was studied and found that greater pain reduction was realized with increased number of targeted DRGs and lead placements as described by Hunter et al in 201746. Greater success was also seen when the targeted area of pain was smaller.
The DRGS system is composed of percutaneous leads designed to stimulate the DRG and a pulse generator (external trial or implantable permanent)32. During the initial trial phase, the leads are implanted, and an external pulse generator is connected. Patients are assessed for treatment efficacy and adverse effect profile. Efficacy may be felt almost instantaneously after the pulse generator is activated as are the possible accompanying paresthesias. Paresthesias felt at the targeted dermatomal level suggests proper placement of the leads. Pain relief onset can vary from instantaneously to 24 hours postoperatively. Anecdotally, the paresthesias described by patients are usually pleasant, sometimes likened to a massage or a gentle breeze over the skin.
Based on the results of the trial phase, a patient can decide to have a permanent implantation. Postoperative programming to optimize therapy can be done by manipulating parameters such as firing frequency (Hz), pulse width (microseconds), and amplitude (microAmperes)32. Once permanently implanted, epidural electrodes can stay implanted for a very long period of time, sometimes over 20 years. Leads placed for DRGS are relatively new to the market, but we can assume a similar longevity.
Outcomes on DRG stimulation for chronic, intractable neuropathic pain in the trunk and/or limbs were first reported by Deer et al50. Authors suggested reduction in pain scores of 70% between their initial visit and final visit 4 weeks after DRG stimulation50. Importantly, anatomically adequate pain relief was achieved in the target areas including the lower back, leg, and foot. Liem et al34 evaluated the efficacy of DRGS in the treatment of intractable neuropathic pain of the trunk, sacrum, and/or lower limbs with noted significant improvement in pain perception and quality of life scores.
The study that led to FDA approval of DRG stimulation for intractable chronic pain, the ACCURATE study, compared the efficacy of SCS to DRGS. The ACCURATE study demonstrated that for mononeuropathy with peripheral nerve injury and CRPS patients, DRGS was an effective and safe treatment modality, and was superior to SCS32. There were 81.2% of subjects receiving DRGS who received at least 50% pain relief, while 55.7% (P<0.001) had same result in SCS group. Additional evidence that DRGS is an effective minimally invasive treatment for focal neuropathic pain of other etiologies (non-CRPS) was documented in Shu et al study51.
For the larger areas of involvement, it is clear that SCS is more effective than DRGS, as stimulation of the DRG for greater coverage would require many more electrodes34. In this case series, DRGS was shown to be less effective for failed back surgery syndrome (FBSS) than other conditions that were studied34.
DRGS presents its own set of safety concerns and adverse effects. Lead migration is not uncommon. Typical risks are assumed as with any surgical or implant procedure49–51.
The most frequently occurring procedure related adverse effects were pain at the incision site and postprocedure back pain. The most frequently occurring device related adverse events were lead migration/loss of stimulation, neurostimulator pocket pain, and lead breakage32. The most frequently occurring stimulation-related adverse event was over-stimulation. During the ACCURATE study, no study subjects experienced a stimulation-induced neurological deficit. The ACCURATE study showed a linear relationship between the risk of procedure-related adverse events and the number of leads implanted per subject32.
DRGS for chronic intractable itch
It should be noted that this proposed modality of DRGS targets the DRG in a 1:1 manner; a single lead targets a single DRG. Pain medicine specialists can use up to 4 leads per patient. On average, pain medicine specialists use about 2–3 leads per patient, commonly bilaterally at the single level for bilateral lower back pain. By targeting a single DRG for stimulation, a single nerve root is stimulated. There may be other neurons that travel the dorsal column-medial lemniscus system cephalically by 1 or 2 spinal levels with their cell bodies in the DRG and will therefore also be stimulated and thereby inhibited by this modality. This results in a fairly limited “target area” per implanted lead. For example, an implant targeting the right-sided L2 DRG would inhibit pain signals coming from the right L2 dermatome with possible coverage of right L3 and L4 signals, depending on variation in patient anatomy.
One potential limitation is the decreased safety and increased risk of nerve injury with DRG stimulation in the cervical and thoracic spine. It should be noted that DRG stimulation currently is only approved by the FDA at the spinal levels below T10.
This treatment modality, therefore, may be very beneficial for patients who have chronic intractable itch limited to the certain areas/dermatomes that provide us with obvious targets. Potential indications include neuropathic itch that relates to impingement of nerves from compression syndromes of the lumbosacral spine causing severe scrotal and perianal itch, postherpetic itch and neuropathic itch in the lower legs related to peripheral neuropathy. DRGS would allow us to target lumbosacral DRGs and pruritus arising in those dermatomal regions. Figure 1 shows a fluoroscopic image of quadripolar leads positioned within the left L3 and L5 foramina for DRGS in a CRPS or complex regional pain syndrome patient, while Figure 2 shows a fluoroscopic image of quadripolar leads positioned near the S2 and S3 DRGs bilaterally in a patient with pudendal neuropathy.
In conclusion, DRGS has proven to be effective for chronic neuropathic pain and may have utility in patients with chronic intractable neuropathic itch. As DRGS is focused on treatment of localized pain and neuropathic pain, the use of this modality would be only proposed for localized intractable neuropathic itch in lumbar and sacral dermatomes. If advances in technology and safety will enable to use for cervical and thoracic areas, this modality would help treating conditions like notalgia parasthetica caused by nerve compression in the thoracic spine and BRP caused by nerve compression in the cervical spine.
Sources of funding
No financial support was provided.
Conflict of interest disclosures
L.K.: paid consultant for Abbott. The remaining authors declare that they have no financial conflict of interest with regard to the content of this report.
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