I. Postherpetic neuralgia and its management
Herpes zoster is a common clinical condition with a high incidence especially in immunocompromised groups and is often accompanied by neuralgia of varying degrees in addition to skin lesions. In some patients, the pain can last for weeks or even months or years after the rash subsides. This persistent pain is known as “postherpetic neuralgia” (PHN). Although researchers have different definitions of PHN, it is generally accepted that the pain associated with herpes zoster can be divided into 3 categories. Acute herpetic pain: pain that occurs with the rash and lasts for about 30 days; subacute herpetic pain: pain that lasts for 30-120 days after the onset of the rash; PHN: pain that lasts for more than 120 days after the onset of the rash.
II. Clinical features of post-herpetic neuralgia
Herpes zoster rash occurs as a result of the multiplication and replication of varicella-zoster virus (VZV) in the infected sensory ganglia and peripheral sensory nerve fibers. vZV can also reach the corresponding dorsal root ganglia and adjacent spinal cords along the nerve pathways and even enter the blood circulation. activation of VZV induces cellular immunity in the body and can also cause inflammation, hemorrhage and structural destruction of neurons. During this period, the patient may experience prodromal pain or discomfort in the skin area corresponding to the affected nerve. These prodromal symptoms usually last for several days. However, the characteristic herpes zoster rash and nerve pain occur when the viral particles reach the dermis and epidermis. In addition to age, the severity of the rash and pain during the acute phase are risk factors for the development of PHN. A controlled clinical trial of acyclovir for the treatment of herpes zoster in older adults (age >50 years) showed that the incidence of pain was 54% in the placebo group at 3 months and 35% at 6 months after the onset of the rash.
Most patients with PHN complain of several different types of pain and sensory abnormalities: drilling pain, stabbing pain, flashing pain, burning pain, electric shock-like pain, abnormal pain, pain that gradually increases in response to repeated stimuli, sensory hypersensitivity, and intolerable itching. Itching after herpes zoster has rarely been mentioned in the literature, but it is the only clinical manifestation in some patients and can occur alone or in combination with PHN, the incidence of which is increased in patients with ocular herpes zoster. Although the incidence of herpes zoster is higher in adults with human immunodeficiency virus (HIV) infection, the incidence of PHN is not increased.
The mechanism of PHN
PHN is the same as the acute pain of herpes zoster, which is neuropathic pain. It is not only the result of peripheral nerve injury, but also related to the change of signal processing in the central nervous system. In the peripheral nervous system, on the one hand, the ectopic impulses generated by virus-induced nerve injury are accompanied by enhanced expression of mRNA for certain voltage-gated sodium channels in primary afferent neurons. The aggregation of sodium channels at the site of ectopic impulses resulted in a decrease in the action potential threshold. On the other hand, the cytokine TNF-α produced by activated macrophages induces ectopic activity in primary afferent injury receptors, causing acute inflammation of the peripheral nerve trunk, resulting in pain and nociceptive hyperalgesia.
In the CNS, VZV activation leads to inflammation of the dorsal root ganglion and important changes in the CNS afferent nerve block in the pathways of injury perception. These changes lead to abnormally high activity of pain signaling neurons in the CNS; degeneration of unmyelinated primary afferent central terminals causes regeneration of synapses within the posterior horn, resulting in misdirected connections between Aβ2 mechanoreceptor fibers and posterior root neurons, thus preventing normal input to injury receptors; hyperfunction of injury receptors sensitizes the center: experiments in animal models show that central C2 fiber terminals release neuropeptides In animal models, neuropeptides such as substance P and excitatory amino acids are released at the end of central C2 fibers, which act on N-methyl-D-aspartate (NMDA) receptors to sensitize the center. When centrally sensitized, the Aβ2 mechanoreceptor has the function of activating central pain signaling neurons.
In fact, the NMDA receptor antagonist ketamine alleviates PHN pain and abnormal pain, supporting this theory.Oaklander [9] suggested that PHN may be a phantom skin pain, and he measured the concentration of residual neuropil in the skin of subjects who had had herpes zoster 3 months earlier by a release method, and found that the number of neuropil in subjects with PHN was mostly below 670 neuropil/m2 skin, whereas in subjects without PHN subjects with PHN had this number higher than 670/m2 skin, and all axons within the epidermis were injury receptors. Therefore, PHN may be a phantom-skin pain. The number of axons within the patient’s skin must be below a density of 650 axons/m2 of skin area to cause PHN. in-depth studies have also been conducted to explore the mechanism of PHN at the ionic level: murine dorsal root ganglia were infected with herpes zoster virus, and intracellular nerve cells were measured and found to be more sensitive to norepinephrine with increasing basal concentrations, and Ca+ response to norepinephrine was also higher. In conclusion, the mechanism of postherpetic neuralgia is complex, and the pathogenesis may be different for each individual.
IV. Treatment of PHN
The pharmacological approach to the treatment of PHN is threefold: first, local drugs that act on the affected skin; second, drugs that affect the excitability and conductivity of sensory axonal nerves; and third, drugs that act on the synaptic changes associated with nerve injury. the criteria for effective pharmacological treatment of PHN are that the patient feels > 30% pain relief, the side effects are tolerable, and the patient’s vitality and function are enhanced accordingly. Tricyclic antidepressants (TCAs) are most effective for persistent deep pain, and anticonvulsants are most effective for severe tearing pain.
Topical therapy: Topical therapy is more appropriate for elderly patients with PHN who have underlying systemic disease and cannot tolerate systemic therapy. Currently, drugs used for local treatment are divided into three categories: local anesthetics, non-steroidal anti-inflammatory drugs and capsaicin preparations.
1.Local anesthetics
Since the report that procaine supraorbital nerve injection is effective in controlling pain in ocular PHN, local anesthetic subcutaneous infiltration, epidural, intravenous injection and peripheral nerve and intercostal nerve block have been used to control pain and PHN in the acute phase of herpes zoster. 50% to 90% pain relief can be obtained with a single anesthetic subcutaneous infiltration, and the relief lasts for several hours to several weeks.
2. Non-steroidal anti-inflammatory drugs (NSAIDs)
In the active phase of herpes zoster and early post-herpetic period, pain is associated with tissue damage, inflammation, and increased prostaglandin levels. It has been hypothesized that local prostaglandin synthesis inhibitors can reduce pain, so a variety of topical NSAIDs are used for pain control in patients with PHN.
3. Capsaicin preparations
Capsaicin is extracted from the stimulating red pepper and is used as a topical treatment for pain, itching, and inflammation. Its action is mediated by selective excitation and then desensitization of the C-fibers of the peripheral nerves that feel the injury, which leads to the release and depletion of P substances, which are considered to be the main transmitters in the C-fibers associated with painful stimuli. Capsaicin also decreases its key transmitters in fine primary afferent nerve fibers. Capsaicin also decreases the levels of other peptides in primary afferent nerve fibers, such as calcitonin gene-related peptide (CGRP), growth hormone release inhibitory hormone, and vasoactive intestinal polypeptide (VIP).
4.NMDA (N-methyl-D-aspartate) antagonist
NMDA receptors are involved in the pain production of PHN. Ketamine is a non-competitive NMDA receptor antagonist, which is effective for spontaneous pain and abnormal pain by subcutaneous injection. However, injection site pain, painful sclerosis, and psychotomimetic side effects limit the clinical application.Wong [15] et al. treated one case of PHN with a mixture of ketamine 10 mg, morphine 1 mg, and 011% bupivacaine 6 mL epidurally, presumably with a synergistic effect. Another NMDA antagonist, dextromethorphan, was not effective in the treatment of PHN, but its average pain relief in diabetic neuropathic pain was 24%.
5.Intrathecal injection of methylprednisolone
This method was first used by Japanese scholar Kikuchi, in which 60mg of methylprednisolone and 3ml of 3% lidocaine were injected into the subarachnoid space once a week for a maximum of four times, and the patients’ pain was significantly reduced and the dosage of analgesic drugs was also significantly decreased. This method has attracted the attention of many scholars and raised the question that subarachnoid injection of methylprednisolone may cause a series of complications such as meningitis, horse for syndrome, radiculitis, intractable headache, and urinary retention. In any case, this method is still a useful experiment.
Systemic therapies are as follows.
1.TCAs :
TCAs are one of the first choices for the treatment of PHN, Woodforde first used amitriptyline to treat PHN, small dose of amitriptyline (25mg/ d) in the early stage of herpes zoster reduced the pain by more than 50%, Watson treated 90 PHN patients with amitriptyline at an average daily dose of 70mg for 3 months, 61% were satisfied with pain relief, among which 13 cases (14%) had complete pain relief. The other 33 cases of PHN were treated with nortriptyline 50mg/ d for 2 months, 67% of them were satisfied with pain relief, and 2 cases were completely relieved.
2.Anticonvulsants
The antiepileptic drugs carbamazepine, phenytoin sodium and sodium valproate for PHN have inaccurate efficacy. The new anticonvulsant gabapentin is effective in the treatment of neuropathic pain and PHN, and has no significant side effects. The mechanism of action of gabapentin, which is an analogue of γ2 aminotyrosine but has no affinity for γ2 aminotyrosine receptors and does not react with any known neurotransmitter receptors, is unknown. 229 patients with PHN showed that the average daily pain score in the gabapentin group decreased from 613 to 412, which was better than that of the placebo control group (615 to 610), with statistical significance (P < 0.001). 0.001), and can also treat PHN-related sleep disorders, improve mood and quality of life.
3.Opioids
Opioids were previously considered ineffective in the treatment of neuropathic pain, but this view has now changed. Tramadol is a synthetic centrally acting analgesic with opioid-like and non-opioid analgesic effects. The non-opioid effect is related to the inhibition of norepinephrine reabsorption at the spinal level and the elimination of the stimulation of 52-hydroxytryptamine release. The maximum dosage of tramadol for PHN patients is 600 mg/d. Rowbotham has shown that intravenous morphine and lidocaine are equally effective, with morphine rapidly reducing the agonizing pain in most PHN patients. In a group of 11 patients with PHN, epidural morphine was given in only 2 cases with a 50% pain relief effect and a high level of side effects. In a group of 11 patients with PHN, epidural injection of morphine was effective in relieving 50% of pain in only 2 cases, and the side effects were high.
In 38 cases of PHN, the treatment was effective for both paroxysmal autonomic pain and abnormal pain. In addition, cholinesterase (CCK) is an endogenous inhibitor of opioid-mediated analgesia, and the antagonistic effect of CCK receptors not only enhances morphine analgesia, but also prevents opioid tolerance.
V. Prevention of PHN
For PHN prevention, the current consensus is that early detection, consultation and treatment are important prerequisites for the active prevention of PHN. In the acute phase of herpes zoster, some therapies may help reduce the risk of PHN and should be administered early after the onset of the rash. meta-analysis shows that antivirals can shorten the duration of herpes zoster pain. Antivirals, such as acyclovir, famciclovir, and valacyclovir, are now advocated to reduce the duration of herpes zoster pain and the risk of PHN. Older patients (over 50 years of age) who do not receive antivirals have more severe and longer-lasting symptoms of PHN. The efficacy of vaxilovir appears to be better than that of acyclovir.
Patients with herpes zoster often receive a short course of oral, intravenous, or topical corticosteroids to prevent PHN, with oral prednisone often recommended for 3 consecutive weeks, with a dose of 60 mg/d for the first week and 30 mg/d and 15 mg/d for the next 2 weeks. Some studies seem to indicate that corticosteroids can reduce the early pain symptoms of PHN, but not the chronic neuralgia. Other studies have shown no difference in the duration and intensity of PHN in the treatment group treated with prednisone compared to the control group. A recent large, randomized, controlled trial showed that the combination of prednisone and acyclovir significantly reduced the duration of acute neuritis and the duration of pain medication, but was not effective for pain lasting more than 6 months after a herpes zoster episode. The use of high-dose corticosteroids in elderly patients should be weighed against the possible benefits and potential risks.