Advances in pain management are mainly manifested in the re-evaluation of the effects of traditional analgesic drugs and the widespread use of minimally invasive interventions. In recent years, a wealth of information has been accumulated on the molecular and cellular mechanisms of pathological pain caused by peripheral nerve injury, especially at the level of primary sensory neurons (DRG) and spinal cord. The establishment of animal models of peripheral nerve and DRG cell bodies as well as dorsal root nerve injury has provided a powerful tool for understanding the mechanisms of neuropathic pain and for screening therapeutic drugs. The abnormally enhanced excitability of primary sensory neurons, the abnormal distribution of primary afferent nerve endings in the dorsal horn of the spinal cord and the synaptic remodeling between them and dorsal horn neurons, and the changes in the type of chemical transmitters in the DRG and its central afferent endings constitute the basic structural chemical and physiological basis of neuropathic pain. Current research on drugs for chronic pain treatment is focused on analgesics, sodium channel blockers, bradykinin blockers, 5-HT blockers, growth factor inhibitors, glutamate inhibitors, adenosine inhibitors, etc. The following is a brief introduction to the treatment of chronic pain: I. Progress in the study of analgesics for chronic pain 1. The traditional concept is that the long-term use of opioids in patients with chronic pain is not only ineffective but also unsafe. However, many studies in recent years have shown that long-term use of opioid analgesics in a portion of chronic pain patients is not only effective, but also improves function and has very little addictive properties. Fentanyl transdermal patch is a better choice for chronic moderate to severe non-cancer pain, and the preliminary application effect in China has shown that its pain relief rate can reach more than 70%. Methadone has agonistic effects on μ and δ receptors and antagonistic effects on NMDA receptors (similar to ketamine). In addition to its use in cancer pain, it also has a good effect on neuropathic pain, but the results reported so far are inconsistent. 2. Recently, a study reported that a snail toxin (ACV1) extracted from sea snails can significantly reduce various types of chronic pain, and its analgesic strength is 10,000 times that of morphine, and it has no addictive properties and side effects. The mechanism of analgesia is not fully understood, and it is speculated that it may work by blocking nicotinic receptors (N receptors), receptors involved in nociceptive transmission. It is expected to be transferred to clinical trial studies soon. Second, the progress of adjuvant analgesics in the treatment of chronic pain Adjuvant analgesics refer to its main indication is not the treatment of pain, but can assist in the treatment of certain painful diseases, especially chronic neurogenic pain, such as trigeminal neuralgia, postherpetic neuralgia (PHN), complex local pain syndrome (CRPS), etc. Adjuvant analgesics are now used as first-line therapeutic drugs for the treatment of chronic pain. 1, antidepressants Antidepressants, especially tricyclic antidepressants such as amitriptyline and nortriptyline, have a wide range of effects on different kinds of pain, especially neuropathic pain. Antidepressants produce antidepressant effects along with analgesia and can improve the mood of some patients to some extent. Tricyclic antidepressants require smaller doses to produce analgesic effects than those needed to treat depression and produce analgesic effects within one to two weeks of administration, much faster than the time required to produce antidepressant effects. Among the new class of antidepressants, chloperidone and selective 5-hydroxytryptamine reuptake inhibitors (SSRIs), such as cloxetine (Prozac), also have some analgesic effect. Among these drugs, SSRI has the best safety, such as Fluvoxamine (Fluvoxamine), 50 mg daily, taken once at night. SSRI is more tolerable than tricyclic antidepressants and has fewer side effects. 2, anticonvulsants Anticonvulsants are one of the more effective drugs for the treatment of neuropathic pain. In the past, phenytoin sodium and carbamazepine were most commonly used, but their side effects are large and sometimes difficult for patients to tolerate. Gabapentin is a new generation of anticonvulsants that has recently been shown to be very effective in controlling neuropathic pain, including postherpetic neuralgia, and its mechanism of action is not yet clear. It may bind to specific receptors in the brain to inhibit voltage-dependent sodium currents and increase the release or action of GABA. It has fewer side effects than similar drugs, and most patients tolerate gabapentin even while taking high doses of other classes of drugs. Its initial dose is 100 mg/dose, taken three times daily, and then gradually increased. In the treatment of PHN, the therapeutic dose is 1800-3600 mg/d. Other drugs (1) α2 adrenergic agonists: α2 adrenergic agonists are multifunctional analgesics, and colistin is the only drug available for clinical application. Studies have shown that colistin can be administered systemically, locally, and intrathecally, with intrathecal administration being the most effective, indicating that the active site of colistin is mainly in the spinal cord. The combination of epidural and intrathecal colistin with opioids and neostigmine has significantly improved the analgesic effect in cancer pain and refractory chronic low back pain. (2) NMDA receptor antagonists: ketamine is one of them, which can be applied systemically or locally. It not only has good effect in neuropathic pain model experiments, but also has been clinically confirmed with double-blind method for its effectiveness of intravenous drip. There are reports of long-term oral ketamine treatment of PHN for up to 4 years, and some people have also used ketamine continuously for PHN with subcutaneous infusion and received certain effects (0.05 mg・kg-1・h-1 with a syringe pump, with the injection rate adjusted to between 0.075, 0.10 or 0.15 mg・kg-1・h-1 depending on the degree of pain and response to ketamine). The main side effects are itching at the injection site, local hardness, and nausea, fatigue and dizziness. Recently, a newly developed NADA receptor antagonist, memantine, was found to significantly reduce nocturnal pain intensity in diabetic neuralgia (n=400) compared to placebo. (3) Sodium channel blockers: Lidocaine intravenous infusion relieves central pain, mainly for widespread agonistic neuronal hyperexcitability in the spinal cord. Some patients with chronic neuropathic pain respond well to its tablets (cardioplegia), and lidocaine patches are also available. (4) Calcitonin: It has significant analgesic effect, and the mechanism of action is not well understood, probably related to the modulation of downstream pain sensory control pathways. Calcitonin has been used for the treatment of osteoporosis, but also for phantom limb pain and even complex regional pain syndrome (CRPS). (5) Specific calcium channel blockers: The selective N-type calcium channel blocker ziconotide is now the first peptide calcium channel blocker to be used in the clinical treatment of neuropathic pain. (6) GABA receptor agonists: baclofen has been effective in the treatment of trigeminal neuralgia. The new drug under development has also entered phase II clinical trials. Nerve block therapy for chronic pain A large number of basic experimental studies on pain and clinical application studies have confirmed that nerve block therapy applied to pain treatment is not “temporary pain relief”, and the connotation of its mechanism of action is far beyond people’s subjective speculation. (a) Diagnostic nerve block 1. peripheral nerve block Nerve block can help the diagnosis and treatment of pain. Peripheral and central nerve blocks help to localize the origin of pain. A temporary nerve block must be done before a permanent nerve block can be performed. In some neuropathic pain syndromes (e.g., nerve injury), it is sometimes unclear whether the pain arises from the peripheral or central nerves (above the spinal cord), and if a peripheral nerve block results in complete pain relief, the pain is indicated to be in the peripheral nervous system. The use of nerve blocks in patients with refractory pain is gaining increasing attention. 2.Sympathetic nerve block If the pain is relieved after sympathetic nerve block, it is called sympathetic dependent pain (SMP). If the pain is not reduced, it is called sympathetic non-dependent pain (SIP). Pain disorders that are combined with SMP include postherpetic neuralgia, metabolic disorder neuralgia, phantom limb pain, and traumatic neuralgia. Sympathetic nerve block therapy has received increasing attention with the gradual recognition of the relationship between the sympathetic nervous system and the sensory nervous system in the pathogenesis of neuropathic pain. Sympathetic local anesthetic block and intravenous regional sympathetic block (IRSB) with α-adrenergic drugs are commonly used as non-destructive blockade methods. Some authors consider sympathetic blockade as the most effective treatment for CRPSI type (reflex sympathetic dystrophy, RSD), and Bonelli suggested that guanethidine and phentolamine IRSB had similar effects to stellate ganglion block. However, due to the lack of long-term efficacy studies on IRSB, it is currently believed that local anesthetic sympathetic block is the most effective. Sympathetic nerve block has been reported to reduce pain in 70% to 80% of patients 3 months after the onset of herpes zoster and has a preventive effect on PHN. However, for patients with PHN of longer duration, the effect of sympathetic blockade is significantly reduced. Recent basic research has found that stellate ganglion block (SGB) can affect the release of neuropeptides and neurotransmitters within the ganglion, and not only sympathetic ganglia and preganglionic and postganglionic fibers, but also sensory nerves terminating in the stellate ganglion can be blocked. It is mainly applied to various diseases of the head and neck, face and upper extremities, and some literature reports that it is suitable for the treatment of about 120 kinds of diseases. It is expected that the range of indications will be expanded even more than now. (2) Therapeutic nerve block 1, temporary nerve block ① epidural space local anesthetics combined with opioids, colistin, ketamine can enhance the analgesic effect and reduce side effects; ② recently it has been reported that lidocaine combined with colistin as peripheral nerve block can improve the clinical effect of the application alone; ③ cancer pain by WHO three step therapy can not be adequate analgesia or systemic opioid analgesics with serious side effects, switch to The use of intralesional continuous analgesia or abdominal plexus block has been recognized in the last century. In the new century, nerve block therapy will show its importance in the field of pain treatment. 2.Persistent nerve block The chemical or physical destruction of a nerve is used to produce a long-term or permanent nerve conduction block. Chemical methods usually use alcohol, phenol glycerin, etc. The most commonly used physical methods are cold (cryotherapy) and heat (radiofrequency or laser). (1) Nerve cryotherapy: A cryoprobe is used to produce a very low temperature to block peripheral nerves, or to destroy nerve endings with very low temperatures to achieve pain relief. Advantages: produces reversible lesions, rarely neuritis, and less costly equipment than radiofrequency neurodesis. Disadvantages: produces temporary nerve block and requires repeated cold injury; cold probe is larger and the percutaneous procedure can be uncomfortable; success of the block is largely dependent on the closeness of the ice ball to the nerve. (2) Radiofrequency thermal coagulation destruction: Radiofrequency thermal coagulation therapy is a physical nerve block therapy that uses controlled temperature to act on the ganglion, trunk, root and other parts of the nerve to coagulate and denature the proteins and block the conduction of nerve impulses. Compared with chemical nerve destruction therapy, it has the following characteristics: ① the size of the injury foci can be precisely controlled; ② the injury temperature can be precisely monitored; ③ the puncture needle can be accurately placed with the help of electrical stimulation test and impedance monitoring; ④ most of the operations can be done under light sedation or local anesthesia; ⑤ most of the thermocoagulated injury foci recover quickly with fewer residual symptoms; ⑥ the incidence of complications and side effects is low with proper operation; especially In recent years, the application of pulsed radiofrequency instrument, the temperature can be reduced to 38 ~ 42 ℃, greater safety. (3) Sympathetic ganglion radiofrequency therapy: In recent years, radiofrequency thermocoagulation of thoracic and lumbar sympathetic ganglia has also made some progress in experimental and clinical research. Auxiliary application in refractory PHN, lumbar and leg pain has achieved preliminary good clinical results. Long-term effects have yet to be confirmed by further clinical and experimental observations. Neuromodulation Through the placement of epidural gap electrodes, electrical stimulation is provided to the posterior roots of the spinal cord called spinal cord stimulation (spinal cordstimulationSCS). Although the mechanism of pain relief by SCS is not well understood, it is reported that it can relieve severe pain in some patients with neuropathic pain according to clinical application. For example: ① radicular pain caused by failed spinal cord surgery; ② pain caused by peripheral nerve injury (except PHN); ③ phantom limb pain; ④ complex regional pain syndrome. V. Other methods 1. Rehabilitation and physiotherapy Rehabilitation and physiotherapy are inseparable parts of the chronic pain treatment plan, aiming to increase functional recovery, avoid disuse atrophy and develop alternative functions. It is important to shorten the course of the disease, reduce the patient’s pain, limit and reduce the occurrence of disability, and reduce the burden of family and society. 2.Psychotherapy Patients with chronic pain all have different degrees of psychological disorders, such as anxiety, tension, depression, abnormal personality characteristics and even suicidal tendencies. Therefore, clinicians must be familiar with, master and pay attention to psychotherapy, pay attention to the emotional changes of patients, and implement corresponding psychotherapy according to different situations. This is a biological pain treatment method. Adrenal medullary chromophores can secrete catecholamine (CA), enkephalin (ENK), neurohypophysein, neuropeptide Y, growth inhibitor and other neuroactive substances at the same time. Studies have shown that after transplantation of adrenal medullary chromophores into the subarachnoid space of the recipient’s spinal cord, the catecholamines and opioids secreted by them can combine with spinal α2 adrenergic receptors and opioid receptors respectively to produce significant central analgesic effects; at the same time, there are synergistic effects between them. It was found that subanalgesic doses of drugs acting on these two receptors not only produced significant analgesic effects, but also prevented the onset of tolerance. The low side effects and long duration of analgesia make it a potentially effective pain treatment. Recent studies have found that cells capable of synthesizing and releasing neurotrophic factors, GABA, glycopeptide, IL-2 and IL-10, etc., transplanted into the central nervous system also have analgesic effects, and synergistic effects between the different active substances released have been found. Throughout these findings, it is expected to provide a promising future for cell transplantation for analgesia and gene therapy for chronic pain. In summary, the treatment of chronic pain, especially neuropathic pain, is very different from acute pain and often requires simultaneous multidisciplinary and comprehensive therapeutic measures including drugs, nerve blocks, neuromodulation, biology, physics, rehabilitation, and psychology in order to provide better pain relief to patients. We are involved in the stage of recognizing the plasticity and controllability of pain, and the study of its mechanisms will provide the possibility of new therapeutic approaches. With a better understanding of the pathological mechanisms of pain and the development of new drugs and technologies, most patients with chronic pain will be able to live and work pain-free with the concerted efforts of multiple disciplines. We hope that all pain workers will work hard to realize the call that “pain relief is the basic right of patients and the sacred duty of doctors”.