Successful treatment of chronic pruritus requires recognizing that its origins might not be as clear-cut as formerly thought, an expert says.
Denver - Successful treatment of chronic pruritus requires recognizing that its origins might not be as clear-cut as formerly thought, an expert says.
“One of the most important factors in managing patients with itch is targeting the right itch. And I’ve changed my theory on this a bit in terms of understanding the anatomic itch classifications,” says Sarina Elmariah, M.D., Ph.D., instructor in dermatology at Massachusetts General Hospital, Boston.
Historically, she says, different forms of itch - pruritoceptive, neuropathic, neurogenic and psychogenic - were believed to arise from discrete sources. For example, Dr. Elmariah says, neuropathic and neurogenic itch arise in the context of damaged neural structures; psychogenic itch originates primarily in the setting of psychiatric illness.
But recently, “I’ve changed my perspective regarding how these types of itch can affect my patients,” says Dr. Elmariah, who spoke in Denver at the annual meeting of the American Academy of Dermatology.
Based on her research and clinical experience, she says, “There’s a blurring of these lines.”
For example, Dr. Elmariah says pruritoceptive itch - which stems primarily from inflammation in the skin that’s relayed to the brain - also has a neural component. “So even these patients might benefit from being on neuromodulatory agents. When we talk about neurocentric strategies, we’re talking about drugs that target the pathways that underlie the relay of itch or the communication between the nerves and the skin.”
In this regard, she says, the peripheral nervous system transmits itch from the skin to the spinal cord; the signal then travels up the spinothalamic tract to the thalamus, then to the brain.
“And when we talk about pruritoceptive processing, various types of receptors - opioid receptors, serotonin receptors, N-methyl-D-aspartate (NMDA) receptors and voltage-gated calcium blockers - are found at every level of neural processing. There’s a heavy component in the spinal cord and brain, in addition to the skin, so many of these drugs may target multiple sites.”
Anticonvulsants stabilize the nerves, Dr. Elmariah says. “They increase the activity of gamma-aminobutyric acid (GABA) in the CNS, and they decrease the activity of excitatory neurotransmitters such as glutamate, norepinephrine and various neuropeptides. They act by blocking voltage-gated calcium channels on nerves in the brain, spinal cord and peripheral nervous system,” she says.
As such, Dr. Elmariah says, gabapentin has been used extensively off-label for neuropathic pain and itch.
“And there’s been efficacy reported for the treatment of neuropathic, brachioradialis, post-burn, uremic, cholestatic and postherpetic itch,” she says.
Reported side effects of gabapentin include somnolence, dizziness, peripheral edema and nausea.
“In children under 12,” Dr. Elmariah says, “gabapentin can precipitate mood swings, hyperactivity and difficulty concentrating. In 2009, the Food and Drug Administration issued a warning regarding increased depression and suicidal ideation for gabapentin and other neuromodulators.”
Regarding dosing, “I start with 100 mg daily at bedtime, which is much lower than most neurologists prescribe,” she says. “Then I increase to BID, then TID dosing over a few weeks. Most patients with itch, whether it's inflammatory or neuropathic, will require at least 2,400 mg daily.”
Another voltage-gated calcium channel blocker, pregabalin, has shown utility in treating uremic, iatrogenic, idiopathic and drug-induced itch, Dr. Elmariah says. In a 71-patient, open-label study, pregabalin provided relief for 81 percent of patients with uremic itch refractory to gabapentin (Rayner H, Baharani J, Smith S, et al. Nephron Clin Pract. 2012;122(3-4):75-79).
Gabepentin and pregabalin tend to work equally well, though gabapentin can take six to eight weeks to produce symptomatic improvement, versus one to two weeks for pregabalin, she says.
“I usually start pregabalin after patients have failed gabapentin - at 50 to 70 mg pregabalin twice daily for a week or two, increasing to 150 to 300 mg twice daily as needed,” she says. Additionally, when patients who had been taking more than 600 to 1,200 mg daily of gabapentin or pregabalin discontinue treatment, “Always taper down. Otherwise it can precipitate withdrawal symptoms.”
Drugs in this category, such as fluoxetine, paroxetine, sertraline and fluvoxamine, inhibit serotonin transport into the presynaptic cell, thereby increasing the amount that’s left in the synaptic cleft.
“Everyone thought that’s how they worked,” Dr. Elmariah says. “But one of the downstream effects is that antidepressants lead to a decrease in some of the postsynaptic, as well as presynaptic, serotonin receptors.”
Although antidepressants’ mechanism of action in itch remains unknown, she says, they’ve shown efficacy in small reports regarding paraneoplastic, aquagenic, cholestatic and psychogenic itch. “I use them pretty frequently in atopic dermatitis (AD) as well.”
In an open-label study involving 72 patients with diverse itch etiologies, researchers found that paroxetine (20 mg to 40 mg daily) or fluvoxamine (50 mg to 150 mg daily) decreased itch in 68 percent of patients overall at approximately five weeks (Ständer S, Böckenholt B, Schürmeyer-Horst F, et al. Acta Derm Venereol. 2009;89(1):45-51). Dr. Elmariah adds that with either drug, “Almost one-third of patients responded with 71 percent to 100 percent reduction in their itch.
“I believe that paroxetine is the best of the SSRIs,” she says.
Again, Dr. Elmariah suggests starting at conservative doses, and then titrating up as needed to manage symptoms.
“I start at 10 mg daily and increase over a week or two to a maximum daily dose of 40 mg.” For patients with renal compromise and those who fail paroxetine, she uses sertraline, starting at 25 mg to 50 mg daily for about two weeks, then increasing to 100 mg daily.
“Patients can see improvement, especially with paroxetine, within a week. But I don’t judge results until they’ve been on it a month or two,” she says. As with anticonvulsants, she adds, patients discontinuing treatment with SSRIs must taper slowly over about six weeks.
“Mu opioid receptors are expressed in the brain, the peripheral nervous system and the skin. When mu is active, particularly in the CNS, it relieves pain but also stimulates itch,” Dr. Elmariah says. Blocking mu tends to reduce itch. Conversely, kappa opioid receptors reduce itch without inducing pain.
An antagonist of both mu and kappa opioid receptors, “Naltrexone is approved for opiate or alcohol dependence, but it’s been used extensively off-label for multiple sclerosis, fibromyalgia and addictions. It also has an antipruritic effect that has been demonstrated for uremic, cholestatic and aquagenic pruritus, as well as the itch of systemic sclerosis. It’s available in PO or topical form.”
A case study involving five patients with chronic refractory vulvar pruritus showed that naltrexone 50 mg daily for three weeks reduced all patients’ itch (Böttcher B, Wildt L. Eur J Obstet Gynecol Reprod Biol. 2014;174:115-116). Three months after stopping naltrexone, “All patients were symptom-free,” Dr. Elmariah says. “This suggests that if you break that itch-scratch cycle, patients may get a chance to heal and start feeling better,” but not necessarily in all cases.
“I believe patients tolerate naltrexone very well. If patients are going to get side effects, they usually happen at around one month. Side effects can include nausea, abdominal cramping, fatigue, blurred vision and, very rarely, hepatitis,” she says. Opioids also can precipitate withdrawal symptoms in opioid-dependent patients.
Dr. Elmariah says her inspiration to prescribe synthetic cannabinoids stems from the case of a 15-year-old boy with intractable AD who confessed - after his mother left the exam room - to smoking marijuana to improve his skin.
“He had gotten much better, and I didn’t know why, because he’d always been refractory to everything I’d ever prescribed,” she says. Other adolescents with AD reported similar experience. As such, over the past year and a half, “I have prescribed cannabinoids and dronabinol in almost 30 patients with AD, vulvar pruritus, idiopathic itch and even drug reactions.”
Synthetic cannabinoids are available in oral and topical formulations.
“There are very limited data in human patients with itch. But there is increasing evidence of efficacy in animal studies, implicating the cannabinoid receptor type1 and type 2 (CB1 and CB2),” she says. In properly selected cases, “Cannabinoids work very well. I’ve become quite a fan.”
Disclosures: Dr. Elmariah reports no relevant financial interests.