Neuropathic pain in COVID-19 and future therapeutic approaches for the treatment of neuropathic pain.

Neuropathic pain is characterized by abnormal hypersensitivity to stimuli (hyperalgesia) and nociceptive responses to non-noxious stimuli (allodynia). The conditions and the pathophysiological states that determine the onset of neuropathic pain are heterogeneous, such as metabolic disorders, neuropathy caused by viral infections, and autoimmune diseases affecting the central nervous system (CNS). Neuropathic pain in the general population is estimated to have a prevalence ranging between 3% and 17%. Most of the available treatments for neuropathic pain have moderate efficacy and present side effects that limit their use; therefore, other therapeutic approaches are needed for patients.

Neuropathic pain is defined as a painful condition caused by neurological lesions or diseases. Sometimes, neurological disorders may also be associated with neuropathic pain, which can be challenging to manage. For example, multiple sclerosis (MS) may cause chronic centralized painful symptoms due to nerve damage. Other chronic neuropathic pain syndromes may occur in the form of post-stroke pain, spinal cord injury pain, and other central pain syndromes. Chronic neuropathic pain is associated with dysfunction, disability, depression, disturbed sleep, and reduced quality of life. Early diagnosis may help improve outcomes, and pain control can be an important factor in restoring function. There are more than 100 different types of peripheral neuropathy and those involving sensory neurons can provoke painful symptoms. Accurate diagnosis of peripheral neuropathy is essential for pain control. Neuropathic pain has been linked to CoronaVirus Disease (COVID) infection both during acute infection and as a post-viral syndrome known as long COVID. In this last case, neuropathic pain relates to the host’s response to the virus. However, neuropathic pain may occur after any critical illness and has been observed as part of a syndrome following intensive care unit hospitalization.

There is general agreement among the numerous guidelines for pharmacologic treatment of neuropathic pain, all of which advise a stepwise approach from the first-line to other treatments. The first-line approach includes tricyclic antidepressants (TCAs) and gabapentinoids. For localized neuropathic pain, some suggest lidocaine patch as the first-line treatment, but it should be noted that anticonvulsants and antidepressants are supported by evidence-based guidelines, whereas the lidocaine patches are supported by data from randomized controlled trials. Pharmacological therapy that affects peripheral sensitization would include capsaicin, local anesthetics, and TCAs. Pharmacological therapy for pain associated with central sensitization would include α2δ ligands (gabapentinoids), TCAs, opioids, and tramadol. In some cases, it is effective to target descending pain modulation using SNRIs, TCAs, opioids, or tramadol. More recently, botulinum toxin has been used to treat certain cases of neuropathic pain; it acts by inhibiting pro-inflammatory mediators and peripheral neurotransmitters from the sensory nerves. A treatment algorithm has been published that shows the stepwise progression of various approaches; combination therapy is often appropriate for treating neuropathic pain.

The prescribing choices for the first-line therapy must be carefully considered and customized for each patient. For example, gabapentinoids are recommended as a possible first-line drug class; there are two main drugs with the same mechanism of action to consider: gabapentin and pregabalin. While both are similarly efficacious, pregabalin has a better pharmacokinetic profile, but gabapentin is less expensive. Selective serotonin-norepinephrine reuptake inhibitors (SSNRIs) as well as TCAs are also first-line treatments. In general, TCAs are more effective than SSNRIs, but SSNRIs have a better safety profile. Combination treatments, in which two or more agents with complementary mechanisms of action are used, are familiar analgesic regimens. The advantages to combination therapy are several: compared to monotherapy, combination treatment may offer superior analgesia, better tolerability, and minimal common side effects, such as anxiety, depression, and disordered sleep. The first step in managing chronic neuropathic pain is to initiate the treatment with one or more of the first-line agents (gabapentinoids, SNRIs, and TCAs) and monitor the patient’s response. If the patient has adequate pain relief and tolerates the medication, then that regimen may continue and the clinical team should monitor the patient to be sure effects are durable. If pain relief is partial, then another first-line medication should be added to see if there is any further improvement.

Novel agents in the pipeline for the treatment of neuropathic pain are few. They include subtype-selective sodium-blockers (NaV1.7 antagonists), a novel angiotensin-II antagonist (EMA 401), transient receptor potential vanilloid (TRPV) subtype 1 (TRPV-1) antagonists, and nerve growth factor (NGF) antagonists.

The symptoms of COVID are many and diverse. Certain prominent symptoms, such as fatigue, anosmia, dysgeusia, headache, vertigo, and myalgia, suggest a direct invasion of the nervous system. Long-haul or long COVID is a recently reported postviral syndrome associated with a constellation of symptoms not necessarily the same as the symptoms the patient experienced with acute COVID. In addition to neuropathic symptoms that may occur during acute or postviral COVID, the treatments to which patients are subjected may further contribute to certain neuropathic pain syndromes. The circulating SARS-CoV-2 virus may increase pro-inflammatory cytokine production (sometimes resulting in “cytokine storm”) and directly invade the olfactory epithelium. Anosmia and ageusia occur with other viral infections but appear to be particularly prevalent among those with acute COVID infections. COVID infection has resulted in an increased rate of neuropathic pain, which in itself is a predictor of neurological complications.

As with many viral infections, the tissue tropism of COVID requires accessible viral receptors and entry cofactors on the host cells. Neuropilin-1 (NRP1), a transmembrane receptor, appears to enhance the infectivity of the SARS-CoV-2 virus [102]. Thus, NRP1 can be viewed as a host factor for COVID and a potential therapeutic target. There is some preclinical evidence that NRP1 may facilitate the entry of the virus into the brain via the olfactory epithelium. Endothelial dysregulation appears to play a role in severe COVID infection and has been associated with vasoconstriction, vascular leaks, thrombosis, excessive inflammation, and disruption of the body’s natural antiviral immune defenses.

Much more research is needed to better understand the neurological ramifications of COVID. The healthcare system must anticipate that many COVID survivors will develop de novo neuropathic pain symptoms in the weeks or months following acute infection. COVID survivors who had pre-existing neuropathic painful conditions may experience a deterioration of their condition and exacerbation of their neuropathic pain. The presence of neuropathic pain in a COVID survivor is an indicator of potential neurological damage. Overall, the healthcare system will likely see an increase in neuropathic pain in the coming years. The duration of neurological manifestations of COVID remains unknown

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