Cancer pain is caused by malignant tumors destroying the tissues of the patient’s body and stimulating the nerve endings. Statistics at home and abroad show that about 50% of all cancer patients have different degrees of pain, about 30% of them have inadequate or no treatment for cancer pain, and about 25% of them have no relief from severe cancer pain before they die. About 80% of cancer patients with suicidal tendencies are related to severe pain. Yang Liqiang, Pain Treatment Center, Xuanwu Hospital, Capital Medical University
Treatment methods for cancer pain are divided into pharmacological treatment and non-pharmacological treatment. Drug treatment is the most common and popular, and the WHO promotes the drug triple-step treatment, which can relieve the pain of about 70-90% of patients. However, the effect of oral drugs is very unsatisfactory due to the destruction of body structure and nerve damage in progressive cancer pain, and the pain is severe and difficult to treat. For such patients, non-pharmacological treatment, i.e. minimally invasive interventional neurodestruction therapy, can be used. Nerve disruption treatment is guided by various imaging devices, and the puncture needle is placed into the corresponding lesion and the nerve in the innervation area, and through physical or chemical methods, the corresponding nerve loses its conduction function, blocking the transmission of pain stimuli to the nerve center, thus eliminating the pain sensation. In addition, for some patients of advanced age and poor physical condition who are not suitable for minimally invasive interventional procedures, a combination of radiation therapy, immunotherapy, and gene therapy can be applied.
I. Drug therapy
Drug therapy can be divided into two types according to the different ways of drug absorption, one is drug metabolism through systemic absorption to produce analgesia, including oral, intramuscular injection, intravenous, rectal, skin, mucous membrane and other drug delivery methods, and the other is drug infusion directly into the spinal canal, so that the drug is in direct contact with the nerve to produce analgesia, including continuous drug infusion in the epidural space, subarachnoid space and other parts of the spinal canal.
1.Three-step treatment method: drug analgesia is the most basic and commonly used method to deal with cancer pain. The principles of using pain relief drugs should follow the five points of WHO recommended three-step therapy for cancer pain treatment, namely, oral administration, on time, according to the step, individualized administration and paying attention to specific details, the core of which is “on time” and “according to the step” administration. The sensitivity of cancer pain patients to narcotic analgesics varies greatly, so there is no standard dose of opioids. The common routes of drug pain relief include oral drug, intramuscular drug, rectal drug, skin and mucous membrane drug.
2.Intraspinal drug administration for cancer pain control.
(1) Continuous infusion of drugs in epidural cavity: when cancer pain does not have sufficient analgesic effect after WHO three-step therapy and opioid analgesic drugs have serious side effects, epidural administration of drugs for analgesia can be used instead. The measures to improve the epidural analgesic effect are.
① opioid analgesics should be used for epidural analgesia, while local anesthetics can be combined once somatic pain, sudden pain, spasmodic visceral pain and spinal cord compression pain occur.
② Epidural injection of colistin and ketamine can enhance the analgesic effect and reduce the side effects. Conventional epidural placement method has inevitable problems of catheter dislodgement and infection due to the long-term exposure of epidural catheter, so the epidural catheter is mostly used clinically to tunnel to the lateral chest or abdominal wall via the skin to fix it, which not only prevents catheter dislodgement, but also makes the catheter stay longer and reduces the number of punctures.
(2) Subarachnoid continuous drug infusion: This method is also known as morphine pump continuous infusion, in which a continuous infusion pump (controlled by a microcomputer chip) is buried under the patient’s skin under the guidance of imaging equipment and connected to the subarachnoid space in the intervertebral space through a thin catheter and pre-drilled subcutaneous tunnel, and the infusion system of the pump can continuously, slowly and uniformly enter the drug into the subarachnoid space. Through the hand-controlled extracorporeal telemetry, a continuous infusion of 1/300 of morphine volume of oral pain medication is given according to the patient’s pain condition, which can achieve satisfactory pain relief while reducing many side effects associated with oral pain medication. In addition, the amount of morphine input can be remotely adjusted outside the body after surgery according to the degree of pain and the pattern of attack of the patient, in order to best meet the analgesic needs of different patients, and the drug reservoir implanted under the skin can be repeatedly injected and the concentration of the drug can be changed. The incidence of nausea and vomiting and constipation is greatly reduced with continuous subarachnoid drug infusion compared with oral administration. Skin pruritus is a common side effect of subarachnoid opioid therapy.
II. Image-guided neurodestructive treatment
(a) Nerve destruction is divided into chemical destruction and physical destruction.
1. Chemical nerve destruction, the drugs or reagents used mainly include 50% to 100% ethanol, 5% to 15% phenol glycerol. Ethanol has the longest duration of action and is mainly used in the ventral plexus, trigeminal ganglion, and spinal column, and is non-selective for nerve damage. Phenol is mostly dissolved in glycerol to make a 5%-15% heavy gravity solution, which is non-selective for nerve damage, but more reversible than ethanol and has a shorter duration of action.
According to the different sites of chemical destruction drugs, chemical nerve destruction can be divided into the following categories: cribriform nerve destruction, intrathecal and epidural nerve destruction, pituitary destruction, sympathetic nerve destruction (including stellate ganglion, thoracic sympathetic, lumbar sympathetic nerve destruction), visceral plexus destruction (including ventral plexus, superior inferior abdominal plexus, odd nerve and other destruction), etc.
2.Physical nerve destruction, the main application of radiofrequency thermal coagulation technology, the technology is through the radiofrequency instrument emits high frequency radiofrequency current, by the instrument connected to the radiofrequency needle to the disease site of the nerve tissue can produce heat, to block the pain signal to the spinal nerve conduction, destroy the pain conduction pathway, so that it can not be transmitted to the brain, can not produce pain sensation and experience, so as to achieve the purpose of pain control.
According to the different radiofrequency sites, they can be divided into the following categories: radiofrequency thermocoagulation of the trigeminal ganglion, percutaneous dorsal root ganglion dissection, and radiofrequency destruction of the thoracolumbar sympathetic nerve, and percutaneous radiofrequency destruction of the anterolateral nerve of the cervical medulla.
(ii) Application of various image-guided techniques
In recent years, the physical and chemical nerve destruction treatment techniques for different sites described above have been continuously improved, but the key to improvement is not the updating of chemical drugs or the upgrading of radiofrequency instruments, but the continuous progress and diversification of various image-guided techniques. It is the emergence of various imaging guidance techniques that has led to the improvement of the efficacy and reduction of complications of neurodestructive treatment for cancer pain. At present, the widely used imaging guidance devices include: C-arm X-ray machine, CT, MRI, extracorporeal ultrasound, endoscopic ultrasound and other devices
1, C-arm guided into: C-arm X-ray equipment is small, easy to use, simple and easy to implement, can improve the success rate, X-ray fluoroscopy under the nerve block or destruction, the image is clear, intuitive, strong sense of the whole and dynamic observation, so X-ray fluoroscopy is still the basic image guidance method for nerve block destruction. However, C-arm-guided imaging cannot indicate whether or not to puncture a blood vessel or organ, nor can it determine the exact distance of the needle tip in front of the vertebral body or the actual diffusion range of the injected solution, so there are certain shortcomings.
(2) CT-guided: CT-guided puncture has the following advantages: (1) CT is cross-sectional imaging, which avoids anterior-posterior overlap of images and allows thin-layer scanning to ensure the accuracy of puncture. (2) CT has high density resolution and can clearly show the puncture path and the surrounding arteries, veins, internal organs, lymph nodes and other important structures, which is very important for selecting the puncture point, needle route and depth. During the puncture process, the position of the needle tip can be accurately displayed to avoid damaging important organs and ensure the efficacy of treatment. (3) The puncture point, needle angle and depth can be simulated and marked on the CT display to guide the operator in accurate needle insertion. (4) CT can accurately display the diffusion range of ethanol (mixed contrast agent) to determine whether the amount of ethanol is sufficient and whether there is leakage of ethanol, etc.
(3) MRI-guided: Among all the auxiliary methods, MRI can provide the closest image to the actual anatomical structure. In clinical work, some physicians use it as an image guidance method for minimally invasive interventional procedures. MRI images can provide sagittal images, allowing the operator to fully understand the anatomical structure and the location of the puncture needle. Special puncture needles must be applied during the procedure, and ordinary metal needles cannot be used. In addition MRI can clearly show soft tissue images such as the kidney, ureter, spinal cord and aorta. No contrast agent needs to be injected, and saline can be used instead. It can also provide three-dimensional images. All these advantages can significantly reduce the complications caused by inaccurate puncture, and also shorten the operation time.
4. Guided by ultrasound.
Body surface ultrasound: B ultrasound-guided percutaneous puncture nerve-destructive block for cancer pain can clearly display various arteriovenous vessels and surrounding structures, and can find and effectively destroy nerves based on vascular markers and relying on the diffusion effect of chemical drugs. b ultrasound can clearly obtain complete two-dimensional images of blood vessels, so indirect localization for various ganglia can be performed through ultrasound imaging. Ultrasound scans of the puncture site are usually performed first, and the skin puncture site is located according to the ultrasound image, then the needle is inserted into the target area under dynamic ultrasound monitoring, and the nerve-destroying drug is injected after a diagnostic block.
Endoscopic ultrasound: Endoscopic ultrasound can guide intra-abdominal nerve block or destruction, and the application of linear ultrasound endoscopy can inject drugs into the abdominal nerve region for the treatment of severe abdominal pain caused by abdominal diseases such as pancreatic cancer. The abdominal ganglion is adjacent to the gastric cavity, the puncture distance is close, the localization is accurate, the injury and complications are less, and its operation is simple and less painful for the patient. An endoscopic ultrasound puncture needle filled with saline was placed into the endoscope through the biopsy channel and punctured into the nerve region under real-time monitoring, 2 % lidocaine was injected first, followed by anhydrous ethanol, and a cloudy echo was visible through endoscopic ultrasound after the injection. This is repeated in the area of the plexus on the other side of the abdominal aorta. Application of this method even allows for outpatient treatment, requiring only light sedation of the patient.
III. Other minimally invasive interventional treatment methods
1.Permanent implantation of stereotactic radioactive I125 particles: Because of the disadvantages of external radiation such as high interference with patients’ daily life, high cost, large side effects and difficulties in radiation protection, the method of minimally invasive inter-tissue radioactive particle implantation is gradually developed, which has the advantages of accurate target, small damage to normal tissues, simple method and economy. This method can be combined with surgical treatment, or be implanted under CT, B-type ultrasound guidance or endoscopic or laparoscopic direct vision, which is a method of combining tumor surgery and tumor radiation therapy. The application of radiation particle implantation method to treat tumors that cannot be removed by surgery can improve the survival time and quality of life of patients and significantly reduce the pain symptoms. Particle implantation adopts template method or suture method, and is implanted by particle implantation gun and special source applicator under direct vision according to the treatment plan formulated before surgery.
2.Tumor radiofrequency therapy: Radiofrequency therapy is a common method for the treatment of solid tumor at present. At present, RF ablation has been widely used in the treatment of liver cancer, lung cancer and other solid tumors, and has achieved better efficacy and is superior to microwave and ethanol injection and other therapies. Currently there are many clinicians apply this method to treat cancer pain, through intraoperative or under the guidance of imaging equipment. The effect of radiofrequency can simultaneously coagulate the blood vessels around the tumor, further aggravate the ischemic necrosis of the tumor, slow down the growth of the tumor, and help prevent the metastasis of the tumor. Radiofrequency treatment can be performed under CT and B-ultrasound guidance and monitoring, which can clearly observe the degree of adhesion between tumor and surrounding large blood vessels and the surrounding relationship, fully reveal the tumor boundary, and effectively avoid damage to surrounding organs and bleeding at the puncture site. The main mechanism of its pain relief is to destroy the tumor, reduce the compression and directly destroy the local nerves.
Prospects
1. New analgesic therapies at the cellular and genetic levels
The two main approaches for pain treatment at the cellular level are cell implantation therapy and gene therapy. Cell implantation is the transplantation of autologous cells cultured in vitro into the human body, and through a biological micropump-like effect, these transplanted cells continuously secrete antinociceptive proteins, antinociceptive protein regulatory factors, enzymes or signal transduction factors to achieve analgesic effects, such as bovine adrenal cystic cells implanted into the subarachnoid space of the spinal cord of patients with cancer pain, which can achieve long-term analgesic effects by secreting opioid peptides, catecholamines, neurotrophic factors, etc. Gene therapy interferes specifically with the biological behavior of pain by altering gene expression in the body for therapeutic purposes. There are two directions of gene therapy in pain research: upregulation of antinociceptive gene expression and downregulation of pain gene expression for pain control. Preliminary studies have shown that these approaches have definite analgesic effects and provide a new direction for the treatment of cancer pain.
2. osteoprotegerin: Honore et al. reported that osteoprotegerin has good anti-injury effects. The osteoprotegerin is a member of the soluble TNF receptor family, which can bind and block the OPG ligand (OPGL). oPG inhibits bone destruction by inhibiting the activation of osteoclasts by OPGL. oPG, when applied in a mouse femoral cancer pain model, can completely block tumor-induced bone destruction, remove osteoclasts from the tumor site, and reduce but not completely eliminate pain behavior and neurochemical changes. , spinal cord forcible peptide and GFAP were restored to baseline levels, and c-fos and SPR endocytosis were reduced, but not to baseline levels.
3. nerve growth factor (NGF) receptor antagonist: anti-NGF treatment in bone cancer pain model mice, 10mg/kg anti-NGF monoclonal antibody intraperitoneal injection, analgesic effect is greater than or equivalent to 10mg/kg morphine.
4. Other new drugs
Other new drugs for bone cancer pain are: transient receptor potential vanilloid type -Ⅰantagonists; antibody therapy against tumor angiogenesis, ET receptor antagonists, VRl antagonists, ASIC antagonists, NMDA2B subtype receptor antagonists, P2 X3 receptor inhibitors, nicotinic receptor agonists, capsaicinoids, sodium channel blockers, bradykinin blockers, 5-HT blockers, growth factor inhibitors, etc. Experimental studies have shown promising applications.