I. Diagnosis of PHN
(A) Definition of PHN
The definition of postherpetic neuralgia is quite controversial in the literature. One definition is a person with persistent pain for more than 1 month after clinical cure of acute herpes zoster, and another definition is a person with persistent pain for more than 3 months after the acute phase (i.e., 4 months after the beginning of rash).Dworkin and Portenoy proposed to divide herpes zoster pain into three periods of definition which are recognized by many scholars, i.e., acute, subacute and chronic phases. Acute phase: acute herpes zoster pain, defined as pain arising within the first 30 days of rash emergence; subacute pain: those with persistent pain not exceeding 3 months after the acute phase; and chronic phase (i.e., PHN): those with persistent pain exceeding 3 months after the acute phase (i.e., 4 months after the start of rash emergence). This staging method tends to be consistent with the International Association for the Classification of Pain in Chronic Pain Syndromes’ division of the time interval between acute and chronic pain, and with the definition of PHN as a chronic pain syndrome [2,3]. International guidelines recommend adding an NRS ≥3 score to this staging method [3].
(ii) Pathophysiological changes of PHN
Patients with PHN have a series of pathophysiological alterations from the peripheral nerve endings to the central nervous system [4].
1. peripheral alterations.
Under optical microscopy, inflammatory reactions, cytopenia, collagen deposition and scar formation are seen in the dorsal root ganglion of PHN patients at the lesion stage. The inflammatory response in peripheral nerves can last for weeks or even months, leading to demyelination, degenerative changes, and even sclerosis.
2., Central changes.
Patients with PHN also have significant degenerative changes in the dorsal horn of the spinal cord. Imaging and autopsy studies have shown that the dorsal horn of the spinal cord is atrophied in patients with PHN, and it is unclear whether this phenomenon is a direct result of the inflammatory response of the spinal cord or a degenerative change due to synaptic connections.
(C) Possible mechanisms of pain onset
The possible mechanisms of postherpetic neuralgia can be divided into peripheral, central, and immune mechanisms.
Peripheral mechanisms.
1, ectopic discharge of injured peripheral afferent fibers. Studies have confirmed that the virus in the acute phase of herpes that damaged primary afferent receptors, damaged nerve integrity was damaged, resulting in changes in the composition, distribution and functional properties of its transmembrane ion channels, which generate abnormal electrical impulses that travel to the spinal cord into spontaneous pain.
2, the neuronal impulse signal cross-mixed transmission that “Cross-Talk” phenomenon. Injured neurons or nerve fibers are weakly insulated by demyelination, and the excitation of neurons or fibers can often spread to adjacent neurons or fibers, forming a loop that repeatedly issues impulses, and the number and frequency of discharging neurons are constantly amplified, thus causing nociceptive hypersensitivity [5].
3, Excitation of injured neurons by sympathetic nerves.
Central mechanisms.
1, sensitization of spinal cord dorsal horn neurons.
2, Decreased function of spinal cord inhibitory neurons.
3. “Budding” of dorsal horn neurons [5].
4. Central sensitization. The decrease in peripheral afferents leads to an increase in the electrical activity of the corresponding central neurons, which is an adaptive mechanism and a functional compensation for the decrease in the number of primary sensory neurons. Once central sensitization is established, even mild non-injurious stimuli can excite low-threshold mechanoreceptive neurons via Aδ and Aβ fiber signaling causing the generation of pain signals in the dorsal horn of the spinal cord.
Immune mechanisms: Studies have shown that peripheral blood CD3 and CD4 are significantly decreased and CD8 levels are increased in patients with PHN. The significant decrease in CD3 and CD4 causes severe autoimmune dysfunction, and the increase in CD8 levels has an intensive immunosuppressive effect. Therefore, it is suggested that the occurrence of PHN is closely related to the reduced function of the T-lymphocyte subpopulation in the patient’s organism [6,7].
(IV) Clinical manifestations of PHN
After the rash heals in the acute phase, the skin of the lesion area often appears red, dark red or brown. After the disappearance of these shades, a grayish-white scar is often left behind. Sometimes, severe pain can occur without scarring. The scarred area generally shows at least hyperalgesia and often loss of sensation, but touch stimuli often cause marked superficial tissue pain (touch-induced pain), and injurious stimuli can cause increased pain (nociceptive hypersensitivity) or increased sensitivity to touch (sensory hypersensitivity).
There are two types of pain in the scar area: a steady burning-like or aching pain and a paroxysmal electric shock-like pain [8]. Both types of pain can occur spontaneously and are often aggravated by irritation with the lesioned skin, such as extremely light clothing friction or even wind. Applying heavy pressure to the skin can instead reduce the patient’s pain. Some patients describe an unbearable itching, ankylosis, or numbness. In addition to clothing contact irritation, these symptoms can be exacerbated by physical activity, temperature changes, and mood changes. Often, the long-term chronic pain is treated repeatedly and unsatisfactorily, and the patient’s quality of life is significantly reduced.
(E) Diagnostic basis of PHN
PHN mainly relies on medical history and pain characteristics to establish the clinical diagnosis. The diagnosis of PHN can be established with a clear history of herpes zoster, with significant chronic neuropathic pain remaining in the area of the lesion after the herpes has healed, and with a disease duration of more than 3 months [2,3]. The diagnosis of postherpetic neuralgia in occult herpes zoster should be made with great caution and requires meticulous examination to exclude other possible causes of pain.
II. Treatment of PHN
(I) Therapeutic goals of PHN
Since there is a lack of specific drugs and specific treatment methods for PHN, the efficacy of any treatment method or comprehensive treatment plan for PHN is limited and it is impractical to completely eliminate pain. Therefore, the clinical treatment goals for PHN are to control daytime pain to improve functional activities and to relieve nighttime pain to improve sleep [2].
(II) Pharmacological treatment of PHN
The treatment of postherpetic neuralgia includes pharmacological and non-pharmacological treatments. Pharmacological treatment options have matured, and the 2010 edition of the European Joint Society for Neuroscience Collaborative Group [9] guidelines recommend: tricyclic antidepressants, antiepileptics and topical lidocaine preparations as first-line drugs; strong opioid analgesics and tramadol as second-line drugs; and topical capsaicin and oral sodium valproate as third-line drugs.
1, tricyclic antidepressants can block norepinephrine and 5-hydroxytryptamine reuptake to inhibit spinal cord neurons to achieve the utility of pain relief. Commonly used drugs are amitriptyline, nortriptyline, venlafaxine, desipramine and maprotiline. Amitriptyline and nortriptyline are clinically effective in analgesia. The main adverse effects are anticholinergic adverse reactions, such as drowsiness, dry mouth, constipation, increased appetite, occasional blurred vision, urinary retention, glaucoma and mood changes.
2, The efficacy of antiepileptic drugs is related to neuronal membrane stability, which can reduce pain by reducing abnormal neuronal firing [5]. Such drugs include carbamazepine, lamotrigine, topiramate, gabapentin, and pregabalin. Gabapentin and pregabalin are commonly used and more effective, while carbamazepine is less effective only in patients complaining of severe tear-like pain. The main adverse effects are dizziness, nausea, vomiting, drowsiness and drowsiness.
3, topical lidocaine preparations are patches and ointments, due to the higher cost, the clinical commonly used in pain abnormal sensitive small pieces of skin.
4, commonly used strong opioid analgesics are morphine extended-release tablets, oxycodone extended-release tablets and fentanyl transdermal patches, which can exert analgesic effects by agonizing the opioid receptors of the central nervous system. The efficacy of these drugs for PHN is significantly weaker than that for injurious pain. Long-term use of drugs should pay close attention to its constipation, urinary difficulties and other adverse reactions, timely symptomatic treatment
5, tramadol is a weak opioid receptor agonist, common adverse reactions include dizziness, nausea, drowsiness, etc.
Topical capsaicin preparations include ointments and patches, which can play an analgesic role by activating the capsaicin receptors of peripheral nerve C and A fibers, triggering the release of substance P and blocking its synthesis, and finally depleting substance P and other neurotransmitters in nerve endings, reducing or eliminating the transmission of pain stimuli from peripheral nerves to central nerves. Common adverse reactions are local burning sensation with the drug.
7. The mechanism of action of sodium valproate has not been fully elucidated. Animal experimental studies show that it can increase the synthesis of GABA and reduce the degradation of GABA, thus increasing the concentration of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and reducing the excitability of neurons. Common adverse effects manifest as diarrhea, dyspepsia, nausea, vomiting, gastrointestinal cramps, and menstrual cycle changes [10-12]. Combination regimens are recommended for tricyclic antidepressants + gabapentin, and gabapentin + opioids [9].