Although cancer treatment has made great clinical and social progress in recent years, there are still a large number of patients who do not receive effective relief from cancer pain. In the survey of cancer pain patients, 80% of patients’ greatest fear is not death but pain. Therefore, if the pain cannot be solved effectively, not only the patient’s self-esteem is deprived, but also the continuous pain often causes a series of psychological changes such as despair, restlessness and irritability, which leads to increased sensitivity to pain and deterioration of the patient’s condition. This is an extremely serious but easily overlooked global public health problem. About one-third of cancer patients around the world have insufficient or no treatment for cancer pain, and about 25% of patients have no relief of severe cancer pain before they die. The goals of cancer pain management are: to control pain to a level acceptable to the patient; to assess pain and evaluate the efficacy of treatment in a timely manner; to take into account all factors affecting pain; and to relieve pain at night, at rest, and during activity Provide patients and their healthcare providers with the most up-to-date information on analgesic medications. In the case of metastatic cancer pain in bone, pain relief remains the primary therapeutic goal through a multidisciplinary effort. At present, there are various clinical methods for treating cancer pain, which are applied individually or in combination according to the specific conditions of the patients, in order to increase the chance of cure, obtain satisfactory analgesic effect with minimum adverse effects, and at the same time, eliminate the symptoms related to cancer pain (e.g., anxiety and depression), and enable the patients to maintain a certain state of health. I. Drug treatment Drug analgesia is the most basic and commonly used method to deal with cancer pain. The principle of using pain-relieving drugs should follow the five key points recommended by WHO for the treatment of cancer pain, i.e. oral administration, on time, according to the ladder, individualized administration and focusing on specific details, the core of which is “on time” administration and “according to the ladder” administration. The sensitivity of cancer pain patients to narcotic analgesics varies greatly, so there is no standard dose of opioids, and any dose that can relieve pain is the appropriate dose. Common routes of pain relief include oral, intramuscular, rectal, and cutaneous and mucosal administration. The World Health Organization (WHO) has put forward the principle of three-step medication for cancer pain, and a study of more than 8,000 patients has confirmed the effect of WHO analgesic ladder in the treatment of cancer pain: more than 71% of the patients with cancer pain were relieved of their pain with the appropriate application of WHO analgesic ladder. The first step of the ladder is the use of non-opioid analgesics, mainly non-steroidal anti-inflammatory drugs (NSAIDs), for patients with mild to moderate pain; the second step of the ladder is the use of weak opioids, such as codeine, in small doses for patients with moderate pain; and the third step of the ladder is the use of strong opioid analgesics, such as morphine and fentanyl, in large doses for patients with moderate to severe pain. The satisfactory standard of cancer pain treatment is to relieve pain in the 1st week, minimize the occurrence of explosive pain in the 2nd week, and maintain stable analgesic efficacy in the 3rd week, and pain assessment and targeted treatment should be carried out respectively at different times. 1, non-steroidal anti-inflammatory drugs It has been confirmed that prostaglandin-like (prostanoids) in the modulation of inflammation, tumor angiogenesis and many other cellular responses and pathophysiological processes play an important role. Cyclooxygenase (COX) is the key enzyme that catalyzes the production of prostaglandin E from arachidonic acid, including COX-1/COX-2.The primary mechanism of action of nonsteroidal anti-inflammatory drugs (NSAIDs) is the inhibition of (COX), which inhibits prostaglandin synthesis.COX-1 is expressed in a variety of tissues such as the gastrointestinal tract, platelets, and kidneys, where it exerts cytoprotective effects.COX-2 has been shown to play a role in inflammation, growth factors and tumor stimulants is rapidly activated and is highly expressed on tumor cells and macrophages that aggregate around them. Specific COX-2 inhibitors do not affect the effects of COX-1 and have both anti-inflammatory and anti-tumor effects. For example, celecoxib and rofecoxib have been approved by the US FDA for the treatment of osteoarthritis, rheumatoid arthritis, and acute pain, but similar drugs celebrex failed to exert a good analgesic effect in cancer pain trials. The role of non-steroidal anti-inflammatory drugs in the treatment of cancer pain needs to be further clarified, but in cases of cancer pain with elevated prostaglandins, non-steroidal anti-inflammatory drugs play a key role in analgesia. Side effects can occur in the gastrointestinal tract, hematopoietic system, kidneys, central nervous system and cardiovascular system. Due to the high dose application may increase the incidence of stroke and myocardial infarction, rofecoxib and valdexcoxib, two new non-steroidal anti-inflammatory drugs have been banned in the United States. 2. Tramadol Tramadol’s affinity for μ-opioid receptors is 1/6000 that of morphine, and has an effect on amine receptors (α2 adrenergic receptors and 5-HT). It also acts on amine receptors (α2 adrenergic receptors and 5-HT), and the two mechanisms synergize to produce a strong analgesic effect for moderate to severe pain. At therapeutic doses, Tramadol has no significant respiratory or cardiovascular side effects; the main side effects are nausea and vomiting, dizziness and headache. Excessive doses can produce convulsions and 5-HT syndrome. Tramadol can be administered orally, rectally, intravenously or intramuscularly. In the treatment of severe cancer pain and postoperative pain can be used up to 600mg daily dose. 3, bisphosphonate (bisphosphonate) bisphosphonates have developed more than a dozen products, according to its molecular structure can be divided into three generations: the first generation of the molecular structure of the side chain of straight hydrocarbons, such as chlorophosphonic acid (clodronate), etidronate (etidronate); the second generation of the introduction of the amino acid in the side chain, also known as the amine bisphosphonate, such as alendronate (alendronate), Pamidronate, Pamidronate, and other bisphosphonates, which are also called amine bisphosphonates. The second generation introduces amino group in the side chain, also known as aminobisphosphonates, such as alendronate, pamidronate, ibandronate and olpadronate; the third generation has a cyclic side chain in its structure, such as risedronate, tiludronate, incadronate and zoledronate; the third generation has a cyclic side chain in its structure, such as risedronate, incadronate and zoledronate. The most commonly used drugs for the treatment of metastatic bone disease are risedronate, tiludronate, incadronate and zoledronate. The bisphosphonates most commonly used in the treatment of metastatic bone pain are: clodronate, pamidronate, zoledronate and ibandronate. Recent studies have shown that bisphosphonates have direct anticancer properties while achieving some analgesia. Their mechanism of action is through the promotion of apoptosis in tumor cells. It can also affect tumor cell invasion, adhesion, migration, degeneration, etc. in vitro, and thus the application of this class of drugs to assist in the treatment of bone metastases is under clinical study. In vitro studies have shown that disodium aminohydroxydiphosphate (pamidronate) and zoledronic acid (zoledronic acid) have inhibitory effects on multiple myeloma, breast cancer and prostate cancer cells. Among them, zoledronic acid has the widest anti-tumor scope and the strongest efficacy, and it promotes apoptosis in human breast cancer and prostate cancer cells. Bisphosphonates were initially used to treat bone tumor-induced hypercalcemia, and are also an effective analgesic, with 50% of patients experiencing pain relief. Bisphosphonates induce apoptosis in breast cancer and myeloma cells, inhibit osteoclast activity, proliferation of osteoclasts and tumor cells, and the production of cytokines IL-6 and MMP-1 (Matrix-metallo-proteinase-1), and concentrate their effects at the skeletal site because of their strong affinity for calcium ions. The effectiveness of the second-generation bisphosphonate compound pamidronate disodium in bone metastatic cancer pain has been well established. Tibia cancer pain rat model application of the third generation of bisphosphonates, namely, zoledronic acid 30 mg/kg subcutaneous injection significantly inhibited tumor cell proliferation and bone destruction, the number of osteoclasts is reduced in large quantities, the pain behavior is reduced, and the content and density of bone mineral are maintained at the normal level. 4.Narcotic analgesics More than 80% of cancer patients need opioids to control pain. Codeine and morphine are important analgesics, but can appear its analgesic effect of tolerance and excitement, drowsiness, constipation, nausea, vomiting and respiratory depression and other side effects. It is estimated that opioids lack efficacy in one-fifth of cancer patients. (1) Morphine: Opioids (especially morphine) remain the gold standard in the treatment of patients with cancer pain against other drugs. Morphine is the most commonly used analgesic for advanced cancer pain, and its metabolite morphine-6-glucuronide (M6G) also produces analgesic effects. It is readily absorbed orally, with a bioavailability of about 25%. Morphine plasma half-life of 3 hours, healthy people M6G plasma half-life of more than 3 hours, but in renal insufficiency patients will be significantly prolonged. The duration of action of oral morphine controlled-release tablets can be up to 12 hours, after the patient’s pain is controlled, its morphine dosage stabilizes within 48 hours, at which time it can be converted to an extended-release morphine dosage form. Morphine sulfate 24 hours controlled release capsules (Morphine sulfate extended release capsules) is mainly characterized by the effect lasts 24 hours, and can be given once a day. (2) Fentanyl: Transdermal fentanyl patch (TTS-Fentanyl) is an important drug in the treatment of advanced cancer pain. Fentanyl is also a strong opioid, µ agonist, and its analgesic strength is 70-100 times of morphine. Because of its small molecular weight, high fat solubility, low skin irritation, it is suitable to be made into a slow-release transdermal patch, so it is suitable for patients who can not be taken orally. The transdermal fentanyl patch has a skin absorption utilization of 92-94%, with peak plasma concentrations reached in 6-12 hours for the initial dose and steady-state plasma concentrations reached in 12-24 hours. Stable blood concentrations are maintained by changing the patch every 72 hours. The amount of fentanyl released is proportional to the drug content of the patch and the surface area of the patch. Adverse effects are similar to morphine, such as nausea and vomiting and constipation, but occur less frequently than with morphine. Fentanyl mucosal patch (Oral transmucosal fentanyl citrate, OTFC) is administered via the oral mucosa with an onset of action of 5-15 minutes and a duration of action of approximately 2 hours. This is a new approach to treating explosive pain. However, it is expensive. (3) Pethidine: Pethidine is not suitable for the treatment of chronic pain and cancer pain, because of its metabolism in the body to produce demethyl pethidine, the metabolite half-life is 2-3 times that of pethidine, long-term use can lead to accumulation in the body, resulting in a series of central nervous system adverse reactions, such as tremor, myoclonus and even epileptic seizures, and naloxone can’t antagonize the adverse reactions caused by demethyl pethidine, Even there is a tendency to aggravate. (4) Methadone (methadone): the application of methadone in cancer pain is gradually being emphasized, it is a synthetic opioid, can simultaneously act on NMDA, 5-hydroxytryptamine and catecholamine receptors other than opioid receptors. Central NMDA receptors play an important role in morphine tolerance, methadone can act on NMDA receptors and flip the tolerance to morphine, and methadone agonizes both µ and δ-receptors with better analgesic effects without metabolite aggregation. (5) Hydromorphone and oxycodone: The extended-release dosage forms of hydromorphone and oxycodone are similar to morphine. The efficacy and tolerability of hydromorphone and morphine are similar. The active ingredient of hydromorphone 24-hour controlled-release tablets, hydromorphone, is a semi-synthetic strong opioid analgesic, with an analgesic strength 5-715 times that of morphine. Oxycodone is an effective alternative treatment to morphine, with side effects and analgesic efficacy similar to morphine. The bioavailability of oxycodone is higher (60%~90%) and its equivalent dose is 1/2 to 2/3 of the oral morphine dose. (6) BuprenorphineTransdermal patch of buprenorphine is permitted to be used in the treatment of moderate to severe cancer pain. Randomized, double-blind controlled studies have confirmed the effectiveness of buprenorphine transdermal patches. However, the superiority of the effect over oral morphine is not known. (7) New perspectives on the use of narcotic analgesics for analgesia in bone cancer pain: Reducing the dose of opioids, expanding their safety range, slowing the onset of tolerance and dependence, and synergistically applying small doses of opioid antagonists to improve analgesia are the directions for the development of opioid analgesia in the treatment of cancer pain. Replacement of opioid medications Individual differences to different opioid medications have been reported to be related to differences in pain sensitivity and responsiveness to opioid medication due to differences in candidate genes, and therefore medications should be replaced in a timely manner according to treatment response. Some studies have shown that most patients with cancer pain need to change 2-3 opioid analgesics to achieve more satisfactory analgesia. In general, the ratio of the strength of action between morphine and fentanyl is 1:70~1:100; the ratio of the analgesic strength of different routes of administration of morphine is oral: intravenous: epidural: subarachnoid = 1:10:100:300, which can be adjusted according to the interrelationship of the strengths of action of different drugs and different routes of administration of the drugs. Opioid-Induced Abnormal Pain Sensitivity and Opioid Tolerance Opioid-Induced Abnormal Pain Sensitivity (OIAPS) may occur in animals and humans after long-term administration of opioids, and this pain sensitivity is similar to the characteristics of neuropathic pain caused by nerve injury or disease, and its mechanism is related to NMDA receptors and the presence of interactions between neuropathic pain and neuronal mechanisms. This phenomenon should be considered to occur when a patient fails to achieve effective analgesia or experiences opioid toxicity despite incremental increases in opioid dose, at which point increasing the dose will only exacerbate the pain. Since the use of opioids in patients with advanced cancer is primarily for analgesic purposes, drug tolerance and somatic dependence can occur, but unlike the psychological dependence of drug addicts, these two physiological phenomena have nothing to do with addiction, and are psychological in nature, with addiction occurring very rarely (except for pethidine), and there is no need to limit the dosage of opioids in patients with advanced cancer in consideration of the possibility of addiction. Tolerance and physical dependence should not be barriers to the use of opioids for the adequate relief of cancer pain, and a 2003 survey in the United States found that patients with advanced bone cancer pain had inadequate analgesia due to severe opioid insufficiency in the last year before death (<60%). Route of administration Oral administration is the preferred route of administration for patients with advanced cancer pain, and sublingual or transrectal administration is also possible. Fentanyl transdermal patch is an effective non-invasive method of drug delivery. For pain that cannot be controlled by transgastrointestinal administration, transvenous administration may be considered. After oral, intravenous, or transdermal routes have failed or produced unmanageable side effects, intrathecal administration or complex local nerve block therapy may be used instead. Dosing interval According to the different pharmacokinetics of the drug, the development of appropriate dosing interval, regular administration, so that the body to maintain a constant concentration of analgesic drugs, can improve the analgesic effect of the drug, but also to reduce the occurrence of tolerance. The analgesic effect of various morphine hydrochloride and morphine sulfate controlled-release tablets can appear 1 hour after administration, peak at 2-3 hours, and last for 12 hours, and can also be combined with the application of NSAIDs.The analgesic effect of transdermal fentanyl patches often occurs 12 hours after administration, peaks at 24-48 hours, and lasts for about 72 hours. Transvenous administration of morphine can have an onset of effect within 5 minutes and last for 1-2 hours. For activities, stress, disease progression caused by explosive pain can be given on the basis of timed additional amount of analgesic drugs. 5.Ketamine Ketamine (ketamine) is a kind of general anesthetic with analgesic, sedative and anesthetic effects, which can treat bone cancer pain. It can act on opioid, adrenaline, choline and NMDA receptor, and is the antagonist of NMDA receptor. No matter it is injected intravenously or taken orally, intrathecal medication can effectively reduce the degree of bone cancer pain. Colistin is a central α2 agonist, and its analgesic mechanism may be related to the release and activity of central and peripheral neurotransmitters. Coladin is used for analgesia mainly to central drug delivery. Combined intrathecal use with morphine and local anesthetics can effectively relieve neuralgia of tumors and bone metastatic cancer pain. Side effects include hypotension, bradycardia, dry mouth and sedation. The so-called adjuvant therapy jointly adopts some non-analgesic drugs, improves the analgesic effect of opioids, reduces the dosage of opioids, and thus also reduces their adverse reactions. For the conventional analgesic drugs can not control refractory pain adjuvant therapy is particularly important. (1) Tricyclic antidepressants: represented by amitriptyline, analgesic effect and antidepressant effect. (2) Corticosteroids: their analgesic effect may be related to the anti-inflammatory effect. Due to the presence of systemic side effects, they are mostly used for acute nerve compression with inflammatory edema or for nerve block therapy. (3) Anticonvulsants: Gabapentin can act on calcium channels, sodium channels and NMDA receptors, inhibit neuronal discharge and play an analgesic effect on neuropathic pain. It is reported that the maximum dose can reach 1800-3600mg, and it can be used for the treatment of bone cancer pain in adults and children. Radiotherapy: About 40% of all radiotherapy patients are treated to control cancer pain. Radiotherapy is effective in treating pain caused by cancer compression or infiltration of nerves and limited bone metastases. Commonly used radiotherapy modalities that are helpful in controlling cancer pain include: distant radiotherapy, brachytherapy, systemic radionuclide and indirect therapy. Surgery Surgery can remove the tumor to remove the cause of pain; for the obstructive pain caused by tumor compression and stimulation, surgery is also a necessary and effective treatment method, even palliative surgery can make the pain last for the longest time with the best effect of relief. Even palliative surgery can provide the longest and most effective relief of pain. It can achieve the purpose of eliminating and alleviating pain, prolonging the life span, reducing the rate of disability and improving the quality of life. IV. Nerve block and nerve destruction Nerve destroying drugs such as ethanol and phenol can chemically block the abnormal impulse conduction of nerves to achieve the purpose of treating cancer pain. At present, peripheral nerve, nerve root, subarachnoid space, abdominal plexus and pituitary gland destruction are commonly used in clinic. Abdominal plexus destruction is mainly used for pain caused by tumors in the abdominal cavity, and the best effect is the application of abdominal plexus destruction to treat pain caused by pancreatic cancer when the effect of other methods is not good. Radiofrequency plexus destruction can also be used to destroy the conduction tracts in the spinal cord, such as the thalamic tracts of the spinal cord and some nuclei in the brain, to treat some intractable cancer pain. Nerve block and nerve disruption are neither the only techniques nor the last resort for the treatment of cancer pain, and their effectiveness and possible side effects (e.g. local anesthesia, etc.) must be comprehensively evaluated before selection and informed consent must be obtained from the patients, and follow-up is also needed after application, including the effect of analgesia, side effects and complications, etc. Chemotherapy is a method to control the pain caused by cancer. Chemotherapy Chemotherapy is a necessary means to control cancer pain, which can eliminate the pain caused by tumor from the cause. Chemotherapy is mainly applicable to patients with tumors that cannot be resected by surgery and multiple foci, especially for the pain caused by compression or infiltration of nerves or bone tissues caused by osteosarcoma, lymphoma, small-cell lung cancer, leukemia and so on, which can show rapid effect. Hormone therapy Beatson considered the relationship between ovary and breast cancer proliferation a century ago, and also observed that the removal of ovary in premenopausal women with bone metastasis of breast cancer can lead to temporary lesion shrinkage and prolong the survival time. With the discovery of estrogen synthesis and, estrogen receptor (ER), estrogen receptor modulators (SERMs), it has been found that: ERa and ERβ may be associated with different target sites of action of SERMs. Raloxifene and Arzoxifene are synthetic second-generation estrogen antagonists with proven efficacy in the prevention and treatment of breast cancer; Toremifene is structurally similar to triamcinolone acetonide and has been shown to be effective in the treatment of breast cancer in postmenopausal women; GW 5638 is also a SERM used in the treatment of triamcinolone-resistant breast cancer and bone metastases. Removal of androgens (depot) is an effective treatment for bone metastases of prostate cancer and can also effectively relieve bone cancer pain. Psychotherapy: Patients with malignant tumors are often accompanied by anxiety and depression, which aggravate their conditions. The purpose of psychotherapy for patients with cancer pain is to reduce the psychological barriers of patients with cancer pain, enhance the patients' confidence in treatment, improve the patients' sense of pain, and improve the patients' ability to cope with pain. Psychotherapy can be combined with pain-relieving drugs to control pain, but it cannot replace drug treatment for cancer pain. Psychotherapy methods include hypnosis, relaxation, biofeedback regulation, psychotherapy and cognitive behavioral therapy. Other treatments, such as skin stimulation, exercise, immobilization, transcutaneous electrical nerve stimulation, acupuncture, traditional Chinese medicine, etc., can significantly reduce or stop the patients' demand for narcotic analgesic drugs.