Neurology of Itching and its Treatment

Treatment of Neuropathic Itch

Non-pharmacological Therapies


Management of neuropathic itch begins with non-pharmacological measures used for itch in general, followed by other therapies tried in a stepwise approach. Non-pharmacological treatments are the mainstay of initial management and should continue even if drug therapies are required. They include behavioural interventions (e.g., educating the patient about itch effects, nail-cutting and wearing protective garments) , use of moisturizers, wearing loose clothing, and avoidance of warm temperatures (Class IV evidence) . Phototherapy with narrow-band ultraviolet B has been shown to help in five cases of notalgia paraesthetica, but its use has not been explored in other neuropathic itch conditions (Class IV evidence) .

Pharmacological Therapies

As neuropathic itch is often induced without the involvement of histamine, it is not surprising that antihistamines are generally unhelpful in treatment. Any benefit appears related more to the somnolent side effects of H1-antihistamines than to a more specific antipruritic effect .

There are several medications reported for use in neuropathic itch. Capsaicin cream and topical anaesthetics such as a lidocaine patch are commonly used initially (Class IV evidence). The mechanism of capsaicin is TRVP1 activation that leads to receptor desensitization and depletion of substance P from sensory nerve terminals in the skin . In a meta-analysis of six randomized controlled studies testing capsaicin for diverse itch conditions, there was no convincing evidence in favour of the treatment. Methodological and statistical problems limited the validity of these controlled studies. Specifically, it is difficult to design experiments because the burning sensation induced by capsaicin cannot be masked, making it challenging to find a suitable placebo to maintain the blinding of patients and investigators . Other topical agents that have been used with anecdotal claims of benefit include lidocaine 5% gel , cortisone and tacrolimus . The latter activates C-fibres with TRPV1 receptors through an increase of intracellular calcium ions.

As understanding has increased about the aetiologies and pathophysiology of itch, new therapeutic strategies have emerged, including anti-seizure medications and antidepressants. Among the anti-seizure medications, gabapentin—widely used for neuropathic pain—is best studied. As indicated previously, scratching excites inhibitory interneurons to release glycine and gamma-aminobutyric acid and thereby inhibit itch-responsive neurons . Gabapentin is a structural analogue of gamma-aminobutyric acid that is thought to block the alpha2delta subunit of voltage-dependent calcium channels in dorsal horn postsynaptic cells. In a randomized control trial of 60 patients with itch following burns, gabapentin was more effective and faster in action than the antihistamine cetirizine. There was no difference between gabapentin alone and the combination of gabapentin and cetirizine. All patients receiving gabapentin had become itch-free by 28 days, whereas only 3 of 20 patients receiving cetirizine alone became itch-free. Furthermore, gabapentin had no reported side effects, whereas cetirizine caused sedation (Class II evidence) . Other anecdotal reports describe the efficacy of gabapentin—either alone or in conjunction with topical agents such as capsaicin or tacrolimus—in treating single or a few patients with itch syndromes such as trigeminal trophic syndrome and brachioradial pruritus (Class IV evidence). Other anti-seizure and antidepressant agents were tried for itch by analogy with their use for treating neuropathic pain. There are anecdotal reports of antipruritic benefit with pregabalin , carbamazepine, doxepin, amitriptyline, nortriptyline and paroxetine (Class IV evidence). These medications merit more rigorous trials to determine their efficacy.

In refractory cases, thalidomide or injectable treatments may be used, depending on the underlying disorder. Thalidomide is an effective treatment for prurigo nodularis, perhaps due to its suppression of tumour necrosis factor-alpha, which is elevated in many skin disorders with itch (Class IV evidence). The limiting factors are teratogenicity and thalidomide-induced peripheral neuropathy. Injectable treatments include intracutaneous botulinum A toxin , epidural injections of clonidine and bupivacaine , and stellate ganglion blocks (Class IV evidence). In one study, botulinum A toxin was injected into pruritic skin patches at small intervals (1.5 cm apart) in a dose range of 0.8–1.4 units per point. . It showed moderate and mostly transient improvement in patients with localized itch, including notalgia paraesthetica. The proposed mechanism is modulation of TRPV1 receptors in a similar fashion to capsaicin to reduce the release of C-fibre neuropeptides .

Neurostimulation Treatment

Additional treatments for refractory itch include peripheral and central surface stimulators. Cutaneous field stimulation electrically stimulates thin afferent fibres. When applied to the affected regions in patients with localized itch, including brachioradial pruritus and notalgia paraesthetica, there was a 49% reduction of itch compared to baseline and 40% reduction in itch-related epidermal nerve fibres (as determined by immunoreactivity) on skin biopsies (Class IV evidence) ( Transcranial direct current stimulation involves a non-invasive neuromodulator applied to the scalp to influence neuroplasticity. In a case report, it was found to improve one patient's recalcitrant itch, but not pain, for 3 months (Class IV evidence).Further study of stimulation techniques to relieve intractable itch seem warranted.

Surgical Treatment

Except for a case report of microsurgical decompression in notalgia paraesthetica (Class IV evidence) , little has been published on neurosurgical interventions in the management of chronic itch syndromes, and the role of such interventions is unclear at this time.

Other Therapies

Certain other therapies, which have been used to treat non-neuropathic itch, may also be tried in patients with otherwise refractory neuropathic syndromes , although no evidence of efficacy in neuropathic itch has been published. Mu-opioid receptor antagonists and kappa-opioid receptor agonists may alleviate pruritus occurring in the context of systemic or skin diseases. Naloxone has antipruritic effects due to modulation of mu-opioid sensitive interneurons
or wide dynamic range neurons in the spinal cord . It is an effective treatment for opioid-induced itch, cholestatic itch, chronic urticaria and atopic dermatitis . Nalfurafine and butorphanol activate cutaneous kappa-opioid receptors without central side effects, and decrease itch especially in patients with uraemia .