I. Definition and Classification
The International Association for the Study ofPain (rASP) defined neuropathic pain (NP) in 1994 as “pain initiated or caused by a primary lesion or dysfunction in the nervous system ( In 2008, the IASP Neuropathic Pain Special Interest Group (NeuPSIG) updated this definition to “pain caused by damage or disease of the somatosensory system”. In 2008, the IASP Neuropathic Pain Special Interest Group (NeuPSIG) updated the definition to “pain caused by a lesion or disease of The somatosensory system” (neuropathic pain is defined as pain caused by a lesion or disease of The somatosensory system).
The new definition has undergone the following important changes.
(1) The term “impairment” or “disease” is used instead of “dysfunction”.
(2) The term “somatosensory system” has been replaced by “neurological system”, which makes its position more clear. In order to accurately reflect the above definition and to take into account the Chinese language habits, it is proposed to call it “neuropathic pain”. Neuropathic pain is divided into two types: peripheral and central, and different types of pain have similar or common pathogenesis.
Common types of neuropathic pain.
Peripheral neuropathic pain Central neuropathic pain Postherpetic neuralgia Post-stroke pain Diabetic peripheral neuropathy Spinal cavernous pain.
Trigeminal neuralgia Ischemic myelopathy pain Glossopharyngeal neuralgia Compressive myelopathy (e.g., spinal cord type) Radiculopathy (cervical, thoracic, or lumbosacral) Cervical spondylosis, tumor) pain
Inset neuropathy (e.g., carpal tunnel syndrome) Post-radiation myelopathy pain Post-traumatic neuralgia Spinal cord injury pain Post-operative chronic pain Multiple sclerosis pain
Post-chemotherapy neuropathy Parkinson’s disease pain Post-radiotherapy neuropathy Phantom limb pain Residual limb pain Myelitis pain Tumor compression or infiltration-induced neuropathy Alcoholic polymyalgia
Neuropathy Syphilitic neuropathy HIV neuropathy Dystrophic neuropathy Toxic exposure neuropathy Immune neuropathy
The definition and classification of the diseases in the above table are not uncontroversial. For example, sympathetic-related pain such as complex regional pain syndrome type I (CRPS-I), fibromyalgia (FMS), and visceral pain are not classified as neuropathic pain according to the new definition, but are still treated clinically with reference to neuropathic pain.
II. Epidemiology and disease burden
NeuPSIG believes that the prevalence of neuropathic pain is about 3.3%-8.2%. Another study from Europe shows that the prevalence of neuropathic pain in the general population is as high as 8.0%. Based on this data, there are about 90 million patients with neuropathic pain in China. Although there are no systematic studies on the quality of life of patients with neuropathic pain in China, the impact of neuropathic pain on the quality of life of patients is obvious. Chronic pain not only affects patients’ ability to sleep, work, and live, but also increases the incidence of emotional disorders such as depression and anxiety. Some studies have shown that the quality of life score of patients with postherpetic neuralgia is about 1/2 of the normal population.
III. Etiology
Neuropathic pain can arise for many reasons, ranging from physical and chemical injury to metabolic complex neuropathy. Although patients have similar clinical symptoms, their etiology varies. Trauma, metabolic disorders, infection, toxicity, vascular lesions, nutritional disorders, tumors, nerve compression, immunity and genetics are among the many etiologies that can lead to nerve damage. Common etiologies include: diabetes, herpes zoster, spinal cord injury, stroke, multiple sclerosis, cancer, HIV infection, lumbar or cervical radiculopathy and traumatic or postoperative nerve damage.
IV. Mechanism
The pathogenesis of neuropathic pain is complex, including anatomic structural changes and functional impairment, and is often caused by multiple mechanisms. They include peripheral sensitization, central sensitization, dysfunction of the downstream inhibitory system, activation of spinal glial cells, and alteration of ion channels. The pathological changes that may be involved include: nerve injury, neurogenic inflammation, . Abnormalities in peripheral nerve excitability, abnormalities in the sympathetic nervous system, and changes in neuroplasticity.
1.Peripheral sensitization and central sensitization
Peripheral sensitization refers to the increased sensitivity of injurious sensory neurons to afferent signals. After peripheral nerve injury, damaged cells and inflammatory cells (e.g., mast cells, lymphocytes) release chemicals such as norepinephrine, bradykinin, histamine, prostaglandins, potassium ions, cytokines, 5 a hydroxytryptamine, and neuropeptides. These cellular mediators sensitize injury receptors and amplify their afferent neural signals.
Central sensitization refers to abnormally elevated excitability or enhanced synaptic transmission of nociceptive-related neurons in the spinal cord and above, including pathological changes such as increased spontaneous firing activity of neurons, enlarged receptive fields, lowered thresholds to external stimuli, and enhanced responses to suprathreshold stimuli, thereby amplifying the transmission of pain signals. The corresponding clinical manifestations include spontaneous pain (spontaneous pain), nociceptive hypersensitivity (hyperalgesia), and nociceptive hypersensitivity (allodynia, or translated as touch-evoked pain). Central sensitization is an important pathogenesis of neuropathic pain, and the maintenance of neuropathic pain mainly lies in central sensitization.
2. Abnormal alterations of ion channels
Abnormalities of various ion channels are involved in the occurrence of neuropathic pain, including calcium channels, sodium channels, chloride channels, potassium channels, etc. Current studies on calcium channels show that after nerve injury, the α2-delta subunits on calcium channels in the posterior horn of the spinal cord (mainly the presynaptic membrane) are highly expressed, calcium channels open abnormally, and calcium inward flow increases, leading to increased excitatory neurotransmitter release and neuronal hyperexcitability, resulting in nociceptive hypersensitivity and nociceptive hypersensitivity.
V. Clinical manifestations
The clinical manifestations of neuropathic pain are complex and diverse, with their own unique nature and characteristics, including both self-conscious and evoked symptoms. The main manifestation is the long duration of the disease, most of which exceeds 3 months. The site of pain is usually consistent with the damaged area. Most of the original pain-causing causes have been eliminated or controlled but the pain remains, seriously affecting the patient’s work and life, and often accompanied by emotional disturbances. The characteristics of pain are as follows.
1. Spontaneous pain: pain can appear locally or regionally without any trauma or injurious stimulation.
2.The painful area can be induced by slight touch, such as contact with clothes or bed sheets, or a small change in temperature, for pain caused by non-injurious stimulation.
3.Nociceptive hypersensitivity: refers to the enhanced pain response to normal pain-causing stimuli.
4.Nature of pain: The nature of pain is not the same, but it is more common to have tugging-like pain, electric shock-like pain, pins and needles-like pain, tearing-like pain, burning-like pain, heavy pressure pain, swelling-like pain and numbness-like pain.
5.Sensory abnormalities: there may be abnormal sensations (paraesthesias), dull sensations (dysesthesias), itching sensations or some other uncomfortable sensations.
VI. Diagnosis
The diagnosis of neuropathic pain is based on a detailed history (including the cause, location and nature of pain, and triggering and relieving factors), a thorough physical examination, especially the examination of the sensory system, and necessary ancillary tests, and sometimes on the patient’s response to treatment.
The IASP 2008 recommended criteria for the diagnosis of neuropathic pain are: (1) the pain is located in a clear neuroanatomical area. (ii) A history suggesting associated damage or disease of the peripheral or central sensory system. ③At least 1 ancillary test confirms that the pain is within the neuroanatomical range. ④At least 1 ancillary examination confirms the presence of relevant damage or disease.
Definite neuropathic pain: meeting criteria 1 to 4 above; likely neuropathic pain: meeting criteria l, 2, 3 or 4 above; possible neuropathic pain: meeting criteria 1 and 2 above, but lacking evidence of ancillary examinations.
The area of pain and abnormal sensation in neuropathic pain should be consistent with the anatomical distribution of the somatosensory nerves and with the identified lesion site. In suspected neuropathic pain, the neurological examination should include a detailed examination of sensory, motor, and autonomic function, with the assessment of sensory nerve function being important and a quantitative analysis being recommended as preferable. Screening for neuropathic pain is recommended using the ID Pain Patient Self-Rated Diagnostic Scale, and the DN4 and LANSS scales are used to differentiate neuropathic pain from injury perception pain.
Since neuropathic pain is often associated with depression, anxiety, and impairment of sleep, social functioning, and quality of life, appropriate scales such as the SF-36, the Nottingham Health Profile (NHP), or the Quality of Life (QOL) Index should be selected. etc. Visual analogue scales (VAS) and numerical rating scales (NRS) are recommended to measure the intensity of pain. Tools such as the McGill Pain Questionnaire (MPQ) and the Short Form McGill Pain Questionnaire (SF-MPQ) can also be applied to help evaluate the intensity of pain.
Relevant laboratory tests should be targeted to clarify the etiology, such as blood, urine, fecal routine, cerebrospinal fluid routine and biochemical, glucose, liver and kidney function tests, as well as microbiological and immunological tests, and possible toxicological tests. A variety of tests should be performed, such as neurophysiological examination, neuroimaging examination, fMRI examination, etc., as well as skin nerve biopsy. Among them, neurophysiological examination is particularly important for the diagnosis of neuropathic pain.
Routine electrophysiological examinations such as nerve conduction velocity and somatosensory evoked potentials are useful in confirming, localizing, and quantifying central and peripheral sensory conduction impairment. For example, electrical stimulation of the trigeminal reflexes (transient reflex and occlusal inhibition reflex) is helpful in differentiating primary trigeminal neuralgia from secondary trigeminal neuralgia (e.g., secondary to pontocerebellar horn tumors and multiple sclerosis).
and multiple sclerosis). When laser-evoked potential (LEP) examinations, especially delayed LEP, are used to more reliably assess injury to the sensory system in peripheral neuropathies, primary and secondary trigeminal neuralgia, spinal cord cavitation, multiple sclerosis, Wallenberg syndrome, and cerebral infarction. Positron emission tomography (PET) and functional magnetic resonance (fMRI) may be of interest in providing insight into the mechanisms of neuropathic pain.
VII. Treatment
Neuropathic pain is an ongoing process, and the condition may recur, requiring long-term treatment. The current status of treatment for this disease is unsatisfactory, and about half of the patients with neuropathic pain fail to achieve adequate pain relief, which may be related to our insufficient understanding of the mechanism of neuropathic pain. The treatment of neuropathic pain should be based on the principles of safety, effectiveness, and economy, and pharmacological analgesic treatment is generally preferred, with minimally invasive treatment or neuromodulation therapy when appropriate. The principles of treatment for neuropathic pain are.
① Early intervention and active causal treatment.
②Effective relief of pain and concomitant symptoms and promotion of nerve repair.
③Cooperate with rehabilitation, psychological, physical and other comprehensive treatments as appropriate.
④Restore the function of the body, reduce the recurrence rate and improve the quality of life.
(I) Pharmacological treatment
Early pharmacological intervention to ensure patients’ sleep and rest can promote the body’s self-repair and may achieve the purpose of stopping disease progression, which is the main treatment means at present. Drug treatment should be based on ensuring sleep and stable emotion, and carefully assessing the nature of pain, signs and symptoms before and after treatment and treatment response. The aim of medication is not only to relieve pain, but also to treat co-morbidities such as depression, anxiety, and sleep disorders. Discontinuation of medication should be based on effective, stable treatment effects and a gradual taper approach.
The latest edition of the 2010 IASP and European Federation of Neurological Societies (EFNS) guidelines recommend first-line medications for the treatment of neuropathic pain, including calcium channel modulators (e.g., pregabalin, gabapentin), tricyclic antidepressants, and 5.hydroxytryptamine, norepinephrine Serotonin, Norepinephrine Reuptake Inhibitor (SNRI).
In addition, topical lidocaine can be used as first-line treatment for postherpetic neuralgia (PHN), and carbamazepine can be used as first-line treatment for trigeminal neuralgia. Second-line medications include opioid analgesics and tramadol. Other drugs include other antiepileptic drugs (e.g., lamotrigine, topiramate), NMDA receptor antagonists, and topical capsaicin.
The selection of drugs for neuropathic pain treatment should take into account drug efficacy, safety, and the clinical situation of the patient (e.g., complications, contraindications, and combined medications). Drug selection should be individualized. For refractory neuropathic pain, combination of drugs can be considered, and the combination of drugs should consider: (i) different drug mechanisms; (ii) additive or synergistic drug efficacy; and (iii) non-additive drug side effects. This consensus makes the following recommendations based on the clinical evidence of different drugs.
1. First-line therapeutic drugs.
(1) calcium channel modulators (gabapentin and pregabalin): calcium channel modulators, including gabapentin and pregabalin, are the first-line drugs for neuropathic pain. The mechanism of action of both is to modulate the Ⅸ2 6 subunit of voltage-gated calcium channels, reducing the release of glutamate, norepinephrine and substance P. In addition to potentially reducing pain, they may also improve sleep and mood in patients. Drug absorption is minimally affected by food, does not bind to plasma proteins, is largely unmetabolized by the liver, and has no clinically important drug interactions.
Side effects are mainly dose-dependent drowsiness and dizziness, and should be reduced in patients with renal insufficiency. The usual starting dose of gabapentin is 300 mg three times a day. Pregabalin is a new generation drug based on gabapentin with linear pharmacokinetics. To avoid dizziness and drowsiness, the following principles should be followed: start at night, use in small amounts, gradually increase the dose and slowly decrease the dose.
(2) Antidepressants.
① Tricyclic antidepressants (TCAs) are most commonly used as amitriptyline. It can act on multiple links of the pain transmission pathway: blocking multiple ion channels, inhibiting the reuptake of 5. hydroxytryptamine and norepinephrine, mainly in the downstream pathway of the pain transmission pathway. It is currently the first-line drug for the treatment of neuropathic pain. The first dose of amitriptyline should be taken at bedtime at 12.5-25 mg, and the dose may be increased gradually to a maximum of 150 mg daily depending on the patient’s response. cardiotoxicity, sinus tachycardia, upright hypotension, increased ectopic ventricular beats, myocardial ischemia, and even sudden cardiac death should be noted when using amitriptyline. TCAs should be avoided in patients at risk of ischemic heart disease or sudden cardiac death. in addition, the drug may cause or aggravate cognitive impairment and gait abnormalities.
②5-hydroxytryptamine, norepinephrine reuptake inhibitors (SNRIs) commonly used drugs include venlafaxine and duloxetine. These drugs selectively inhibit 5. serotonin and norepinephrine reuptake, increase the concentration of both in the synaptic gap, and act in the downstream pathway of the pain transmission pathway. The effective dose of venfaraxine is 150 to 225 mg once daily per eye. The starting dose of duloxetine is 30 mg per day, adjusted to 60 mg per day after one week, and can be taken once or in two divided doses. Common adverse reactions include nausea, dry mouth, sweating, malaise, anxiety, and tremor.
(3) Topical lidocaine: It is often used as the first-line drug for herpes zoster-related neuralgia. Commonly used dosage forms include lidocaine gels and patches. Side effects include skin erythema or rash.
(4) Carbamazepine and oxcarbazepine: Carbamazepine and oxcarbazepine are sodium channel blockers and can be used as first-line agents for trigeminal neuralgia. The initial dose of carbamazepine: 200-400 mg daily, and the effective dose is 200-1200 mg per eye. side effects are more common and include sedation, dizziness, gait abnormalities, increased liver enzymes, hyponatremia, and bone marrow suppression. There is a risk of exfoliative dermatitis and, in severe cases, life-threatening Stens-Johnson syndrome and infectious shock. The effective dose of oxcarbazepine is 600 to 1800 mg per eye, and the dose should be increased according to the clinical response of the patient. Oxcarbazepine can produce hepatic enzyme induction, skin allergic reaction is less common than carbamazepine, and carbamazepine has about 25%-30% cross allergy, also can lead to hyponatremia.
2.Second-line treatment drugs
(1) Tramadol Tramadol has a dual mechanism of action, acting simultaneously on μ-opioid receptors and norepinephrine/5-hydroxytryptamine receptors to achieve analgesic effects. Side effects are dose-related and common side effects include nausea, vomiting, dizziness, etc. The principle of starting with a low dose and increasing it slowly and gradually should be followed. The starting dose is 25-50 mg once or twice a day, with a maximum of 400 mg per day. care should be taken not to use it together with 5-hydroxytryptaminergic drugs (including SNRIs) to avoid the risk of 5-hydroxytryptamine syndrome. The drug has a low abuse rate, but physical dependence can occur and needs to be phased out.
(2) Opioid analgesics Often used as second-line drugs can be used alone or in combination with first-line drugs, commonly used drugs are morphine, oxycodone and fentanyl. The immediate-release form is used for explosive pain, and the extended-release form is used for the long-term treatment of chronic pain. The starting amount for patients who have not used opioids should be quantified on an individual basis, starting with a small dose. Side effects of opioids include nausea, vomiting, excessive sedation, respiratory depression, etc. Tolerance may occur within 1 to 2 weeks after administration, but constipation is intolerant for life and needs to be prevented, and long-term use may lead to dependence. Once the cause of neuropathic pain is removed or modulation therapy effectively relieves pain, the dosage should be slowly reduced to withdrawal of medication.
3.Other drugs
In addition to the above drugs, some drugs have been widely used in clinical practice, including skin inflammation extracts from rabbits vaccinated with cowpox, oxymorphone, topical capsaicin, intravenous lidocaine, meperidine, mexilate, and certain antiepileptic drugs (lamotrigine, sodium valproate, tolvaptan, etc.).
(ii) Neuromodulation techniques
Neuromodulation techniques mainly include electrical (magnetic) stimulation techniques and intrathecal drug infusion techniques, which are recommended treatment techniques for neuropathic pain.
1, nerve electrical stimulation techniques: the paths of action and therapeutic purposes of nerve electrical stimulation techniques vary. HANS stimulates the release of opioid peptides and other neurotransmitters in the brain and spinal cord through the electrical stimulation of acupuncture points, and exerts analgesic effects. The effect produced by different frequency stimulation is different, such as low frequency (2 Hz) electrical stimulation can cause the release of enkephalin and endorphin, 100 Hz (100 Hz) electrical stimulation can cause the release of prednisolone, and the sparse and dense wave (D-D frequency) alternating between 2 Hz and 100 Hz can cause the release of three opioid peptides, enkephalin, endorphin and prednisolone, at the same time to achieve the maximum analgesic effect and full therapeutic effect.
In addition, low-frequency (2 Hz) electrical stimulation induces long-time duration inhibition (L1D) in the dorsal horn of the spinal cord, preventing the uploading of injury information, while high-frequency stimulation causes long-time duration enhancement (LTP) to occur in dorsal horn neurons. Transcutaneous electrical nerve stimulation (TENS) is used to relieve pain by targeting different nerves related to the conduction of pain information and reducing the conduction and reception of pain information. the possible mechanism of action of TENS is that weaker high frequency electrical stimulation excites the thick fibers of sensory nerves, activates the pain gate control system, closes the gate, and prevents pain transmission to the center.
It is mostly used clinically as an adjunct to the treatment of neuropathic pain after peripheral nerve injury. Deep nerve stimulation techniques can be divided into motor cortex electrical stimulation, deep brain electrical stimulation, and spinal cord electrical stimulation. Spinal cord electrical stimulation is the most widely used in the field of neuroelectrical stimulation. Spinal cord electrical stimulation is mainly applied to failed back surgery syndrome, complex regional pain syndrome, adhesive arachnoiditis, peripheral neuropathic pain, residual limb pain, and angina pectoris that cannot be operated immediately when standardized drug therapy is ineffective or drug side effects cannot be tolerated.
2.Intrathecal drug infusion therapy: Intrathecal drug infusion therapy is a drug infusion pump buried in the patient’s body, which infuses the drug inside the pump into the patient’s subarachnoid space and acts on the corresponding sites in the spinal cord or the center, blocking the transmission of pain signals to the center so that the pain signals cannot reach the cerebral cortex, thus achieving the purpose of pain control.
Commonly dispensed intrathecal pumps in China include opioids, local anesthetics, calcium channel blockers, α-2 agonists and NMOA receptor antagonists, among which morphine is the most widely used clinically and is also regarded as the first-line drug. Pre-testing (dose titration) of morphine dose commonly used for continuous injection, generally the initial dose starts from 1% of the parenteral dose and is gradually adjusted according to the analgesic effect and the general condition of the patient to achieve the best analgesic effect and the least adverse effects.
(C) Minimally invasive treatment
The main purpose of minimally invasive treatment is to remove the cause of sensory nerve injury, increase nerve blood flow and promote nerve recovery. The main techniques include nerve block, radiofrequency therapy and nerve destruction. Minimally invasive treatment is also a new trauma to the patient, so it needs to be weighed against its advantages and disadvantages to the patient. The principle of minimally invasive treatment in modern medicine is to first clarify the cause of neuropathic pain sensory nerve damage and to target minimally invasive treatment. Efforts are made to promote the recovery process of sensory nerves and to avoid nerve destruction treatment as much as possible.
1, nerve block: nerve block is a common treatment method for neuropathic pain, the selection of drugs for nerve block must consider the following aspects.
①The mechanism of action of the drug and the purpose of treatment;
②Adverse effects;
③The advantages and disadvantages of combined drugs.
At present, the widely recognized drugs for nerve block treatment mainly include local anesthetics, glucocorticoids, opioids, and nerve-destroying drugs. The nerve block should be done with adequate assessment of the patient’s condition, grasp of the indications for nerve block, familiar with the anatomical structure of the block site, the mechanism of action of the block drugs, standardized puncture and operation techniques, accurate evaluation of the effect of nerve block, and understanding of its possible complications and prevention.
2.Radiofrequency treatment: Radiofrequency treatment includes radiofrequency thermocoagulation and pulsed radiofrequency, the most important feature of which is the ability to get close to the nerve to identify the nature of the nerve such as motor nerve or sensory nerve, and to evaluate the distance between the needle tip and the nerve. Initially, it was thought that the temperature generated during radiofrequency contributed to the denaturation of nerve fibers, thus blocking the transmission of pain. However, the corresponding skin sensation is only briefly absent after radiofrequency treatment, and pain relief is often significantly longer lasting than it should be. Therefore, temperature may not be the only mechanism that alters pain transmission.
Radiofrequency can be used to identify the desired area of destruction by stimulation and impedance monitoring, and the extent and degree of destruction can be adjusted by adjusting the radiofrequency parameters (temperature and time) to avoid side effects such as charring and adhesion. Pulsed radiofrequency is a neuromodulation treatment, the mechanism of which is that pulsed radiofrequency stimulates plasticity changes in pain signal afferent pathways, producing pain inhibition. The use of 2 Hz, 20 ms pulsed radiofrequency current, which produces a temperature lower than 42°C, has no destructive effect on the anatomical structure of nerve fibers, but has a certain effect on the relief of neuropathic pain.
3.Nerve destruction: Destructive treatment includes chemical destruction, physical (radiofrequency, freezing, radiation) destruction and surgical destruction, which are irreversible treatments and may produce complications such as sensory numbness and even muscle strength loss in the area they innervate.