Understand in one article | The more you scratch, the more itchy it becomes. How to correctly deal with uremic pruritus?

Itch is a common and painful symptom in patients with uremia. Many patients with uremia think that it is just itching, which has little impact and will not be fatal. Even many clinicians, including nephrologists and dermatologists, do not pay attention to uremic pruritus (UP). Studies have shown that nearly 70% of doctors underestimate the occurrence of UP and do not pay enough attention to the treatment of UP.

In fact, UP has a significant clinical impact and is closely related to poor quality of life, impaired sleep, depression, and increased mortality in patients with uremia. The risk of depression in UP patients is 2 to 3 times higher than that of the general population, and about 60% of patients have sleep disorders. The DOPPS study showed that compared with patients who were not troubled by pruritus, patients with moderate to severe pruritus had a 24% increased risk of all-cause mortality, a 29% increased risk of cardiovascular mortality, and a 44% increased risk of death from infection. As the disease worsens, the higher the intensity of the pruritus, the worse the patient's quality of life and the lower the survival rate.

The itching symptoms of patients with uremia may be very mild at first, and some patients think that they can just scratch it casually. Indeed, sometimes scratching will stop the itching. This is because scratching the skin can produce pain when scratching the itchy area. The pain is transmitted to the brain through nerves, interfering with the itching signal and temporarily suppressing the itching sensation. In this case, the itching can indeed be relieved. However, the root cause of the itching has not been solved, and it will "come back" in the near future and become more and more serious.

Sometimes the more you scratch, the more itchy it becomes. Why is that? In fact, when you scratch to "induce pain and relieve itching", the body releases serotonin to control the pain. While suppressing pain, serotonin also activates GRPR neurons through 5HT1A receptors, prompting the transmission of information from itch neurons and making the itching more intense. The strong itching will trigger a new round of scratching and pain, causing people to enter a cycle of "the more you scratch, the more itchy, the more itchy, the more you scratch", until the skin breaks and bleeds. In addition, excessive scratching will form scratches and wounds on the surface of the skin, which can easily cause local infection and can also lead to secondary eczema, further exacerbating the itching. For some stubborn UP patients, even if they scratch their skin, the itching is difficult to relieve, and they often have scratches all over, adding new wounds before the old ones are gone.

Scratching can make you happy, but scratching too much can hurt you. Scratching may seem to make you feel better for a while, but it may bring more serious and complicated consequences.

Therefore, for UP patients, the more they scratch, the more itchy they will feel. Only correct responses can relieve the itching. In actual work, if clinicians encounter this situation, they should first advise patients to maintain a good attitude. When itching occurs, they can pat the skin instead of scratching. They can also use ice towels, ice water, etc. for ice compresses to relieve itching. Secondly, remind patients to cut their nails frequently and polish the edges to prevent scratching the skin unconsciously while sleeping at night. In addition, moderate exercise can be performed to promote the excretion of toxins and relieve itching. For UP patients with mild itching caused by dry skin, moisturizers such as glycerin, vaseline, and vitamin E can be applied to keep the skin moist and relieve itching symptoms.

Patients whose pruritus cannot be improved by these simple measures may have more complicated conditions, and clinicians need to take appropriate treatment measures for the patients:

(1) Improving dialysis adequacy: Uremic toxins accumulate in the body, blood calcium and phosphorus levels increase, and high parathyroid hormone levels in the blood lead to UP. For this condition, improved dialysis treatment (such as increasing the amount of dialysate, using a high-flux dialyzer), and calcium and phosphorus management can be considered.

(2) Systemic medication for pruritus mediators: When UP patients have excessive production of pruritus mediators (histamine, substance P, cytokines, etc.), anti-epileptic, antihistamine or anti-allergic drugs such as gabapentin, tacrolimus, and aprepitant can be used. However, there are problems such as unclear antipruritic effects and intolerance to adverse reactions.

If the above measures do not effectively improve the condition, opioid receptor agonists/antagonists should be considered to act on the central and peripheral nerves to suppress itching.

The μ-opioid receptor and κ-opioid receptor interact with each other and jointly regulate the occurrence of pruritus. The activation of the former promotes pruritus, while the activation of the latter inhibits pruritus. The increase in the serum β-endorphin/dynorphin ratio in patients with uremia indicates endogenous opioid disorder.

Therefore, opioid receptor agonists and antagonists, such as nalfuraphine hydrochloride and naltrexone, can be used for refractory uremic pruritus. Among them, naltrexone is only effective for some UP patients and has more adverse events. Nalfuraphine hydrochloride is a highly selective κ receptor agonist that can significantly reduce the degree of itching and the range of scratching in UP patients, and improve sleep disorders. It is a precise treatment of UP based on the mechanism to relieve itching symptoms.

The European Guidelines for the Treatment of Pruritus in Chronic Kidney Disease and the 2020 Japanese Guidelines for the Diagnosis and Treatment of Pruritus both recommend nalfuraphine hydrochloride for the treatment of UP. After nalfuraphine hydrochloride was launched in Japan, the pruritus of hemodialysis patients was significantly improved. Especially for refractory pruritus, the effective relief rate of nalfuraphine hydrochloride can reach 84.9%, and the efficacy is long-lasting. In addition, nalfuraphine hydrochloride can improve patients' sleep disorders, is safe and tolerable, and has no risk of addiction with long-term use. It is reported that nalfuraphine hydrochloride has now completed the Phase III clinical trial stage and will soon be launched in China. We hope that it can bring new hope to UP patients. Summary

At present, UP is often ignored by doctors in clinical practice, and its harm is also underestimated. In fact, UP is very harmful. However, there is no standard treatment for UP in China, and most of the existing drugs are off-label treatments, lacking radical cure measures. It is expected that the emergence of nalfuraphine hydrochloride will bring new breakthroughs in the standardized treatment of UP!