In the survey of cancer pain patients, 80% of them are most afraid of pain rather than death. Therefore, if pain is not effectively addressed, not only is the patient’s self-esteem deprived, but constant pain often causes a series of psychological changes such as despair, restlessness and irritability, leading to increased sensitivity to pain and deterioration of the patient’s condition. This is an extremely serious and easily neglected global public health problem. About one-third of cancer patients worldwide have their cancer pain treated inadequately or not at all, and about 25% of patients have severe cancer pain that is not relieved before they die.
The goals of cancer pain management are: to control pain to an acceptable level for patients; to assess pain and evaluate the effectiveness of treatment in a timely manner; to take into account all factors affecting pain; to relieve pain at night, at rest and during activity; and to provide patients and their health care providers with up-to-date information on analgesic medications. For bone metastatic cancer pain, pain relief remains the primary treatment goal through multidisciplinary efforts. There are various clinical methods for treating cancer pain, which are applied individually or in combination according to patients’ specific conditions, in order to increase the chance of cure, obtain satisfactory analgesic effects with minimum adverse effects, while eliminating symptoms related to cancer pain (such as anxiety and depression) and maintaining patients in a certain state of health.
I. Drug treatment
Pharmacological analgesia is the most basic and commonly used method to deal with cancer pain. The principles of using pain medication should follow the five points recommended by WHO for cancer pain treatment, namely, oral administration, on time, according to a step, individualized administration and paying attention to specific details, the core of which is “on time” and “according to a step”. The sensitivity of cancer pain patients to narcotic analgesics varies greatly, so there is no standard dose of opioids. The common routes of pain relief include oral, intramuscular, rectal, skin and mucous membrane administration.
The World Health Organization (WHO) has proposed a three-step medication principle for cancer pain, and a study of more than 8,000 patients has confirmed the effectiveness of WHO analgesic ladder in cancer pain treatment: more than 71% of cancer pain patients have obtained satisfactory pain relief after appropriate application of WHO analgesic ladder. The first step is to use non-opioid analgesics, mainly non-steroidal anti-inflammatory drugs (NSAIDs) for patients with mild to moderate pain; the second step is to use small doses of weak opioids such as codeine for patients with moderate pain; and the third step is to use high doses of strong opioids such as morphine and fentanyl for patients with moderate to severe pain. The satisfactory standard of cancer pain treatment is pain relief in the 1st week, minimizing the occurrence of explosive pain in the 2nd week, and maintaining stable analgesic efficacy in the 3rd week; pain assessment and targeted treatment should be carried out separately at different times.
1.Non-steroidal anti-inflammatory drugs
Prostanoids have been shown to play an important role in the modulation of inflammation, tumor angiogenesis, and many other cellular responses and pathophysiological processes. The main mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs) is the inhibition of (COX) and thus prostanoid synthesis.COX-1 is expressed in a variety of tissues, including the gastrointestinal tract, platelets and kidneys, and exerts a cytoprotective effect.COX-2 plays an important role in inflammation, growth factor and tumor stimulation. COX-2 is rapidly activated in response to growth factors and tumor stimuli and is highly expressed on tumor cells and macrophages that accumulate around them.
Specific COX-2 inhibitors do not affect the action of COX-1, but 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 the similar drug 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 for cancer pain cases with increased prostaglandins, NSAIDs play a key role in analgesia. Side effects can occur in the gastrointestinal tract, hematopoietic system, kidney, central nervous system, and cardiovascular system. Two new NSAIDs, rofecoxib and valdexcoxib, have been banned in the United States because of the potential for increased incidence of stroke and myocardial infarction at high doses.
2. Tramadol (Tramadol)
Tramadol has an affinity for mu-opioid receptors that is 1/6000 of morphine, and also has an effect on amine receptors (α2-adrenergic receptors and 5-HT), with both mechanisms synergistically producing strong analgesia 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. It can be used in the treatment of severe cancer pain and postoperative pain up to 600mg daily dose.
3.Bisphosphonates (bisphosphonate)
Bisphosphonates have been developed more than a dozen products, according to their molecular structure can be divided into three generations: the first generation of molecular structure of the side chain is straight hydrocarbon such as clodronate (clodronate), etidronate (etidronate); the second generation in the side chain of the introduction of amino, also known as amino bisphosphonates, such as alendronate (alendronate), pamidronate (pamidronate), ibandronate (ibandronate) and Opal. The third generation has a cyclic side chain, such as risedronate, tiludronate, incadronate and zoledronate. The most commonly used bisphosphonates for the treatment of metastatic bone pain are: clodronate, pamidronate, zoledronate, and ibandronate.
Recent studies have shown that bisphosphonates have direct anticancer properties while achieving a certain level of analgesia. Their mechanism of action is through promoting apoptosis of tumor cells. It can also affect the invasion, adhesion, migration and degeneration of tumor cells in vitro, thus the application of these drugs for the adjuvant treatment of bone metastases is under clinical investigation. In vitro studies have shown that pamidronate and zoledronic acid have inhibitory effects on multiple myeloma, breast cancer and prostate cancer cells. Among them, zoledronic acid has the broadest and most potent antitumor activity, promoting apoptosis in human breast and prostate cancer cells.
Bisphosphonates were originally used to treat hypercalcemia caused by bone tumors and are also effective analgesics, with 50% of patients experiencing pain relief. Bisphosphonates induce apoptosis in breast cancer and myeloma cells, inhibit osteoclast activity, osteoblast and tumor cell proliferation, and production of the cytokines IL-6 and MMP-1 (Matrix-metallo-proteinase-1), concentrating their action on the bone site due to their strong affinity for calcium ions. The effectiveness of disodium pamidronate, a second-generation bisphosphonate compound, on bone metastatic cancer pain has been confirmed. In a rat model of tibial cancer pain, the application of the third generation bisphosphonate, i.e. zoledronic acid 30 mg/kg subcutaneously, significantly inhibited the proliferation of tumor cells and bone destruction, greatly reduced the number of osteoclasts, reduced painful behavior, and maintained the normal level of bone mineral content and density.
4.Narcotic analgesics
More than 80% of cancer patients need opioids to control pain. Codeine and morphine are important analgesics, but side effects such as tolerance of their analgesic effects and euphoria, drowsiness, constipation, nausea, vomiting and respiratory depression can occur. 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 cancer pain patients in contrast to other drugs. Morphine is the most commonly chosen analgesic drug for advanced cancer pain, and its metabolite morphine-6-glucuronide (M6G) is also used to produce analgesic effects. It is easily absorbed orally and has a bioavailability of about 25%. The plasma half-life of morphine is 3 hours, and the plasma half-life of M6G in healthy people is more than 3 hours, but will be significantly prolonged in patients with renal insufficiency. The duration of action of oral morphine controlled-release tablets can be as long as 12 hours. After the patient’s pain is controlled, the morphine dosage stabilizes within 48 hours, and can be converted to extended-release morphine dosage form at this time. The main feature of Morphine sulfate extended release capsules is that the effect lasts for 24 hours and can be given once a day.
(2) Fentanyl: Transdermal fentanyl patch (TTS-Fentanyl) is an important drug for the treatment of advanced cancer pain. Fentanyl is also a strong opioid and μ agonist, and its analgesic strength is 70-100 times that of morphine. Because of its small molecular weight, high lipid solubility and low skin irritation, it is suitable for making slow-release transdermal patches and is therefore suitable for patients who cannot take it orally. The absorption rate of transdermal fentanyl patch is 92-94%, and the plasma peak concentration is reached in 6-12 hours after the first dose, and the plasma steady-state concentration is 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 reactions are similar to morphine, such as nausea and vomiting, constipation, etc., but occur less frequently than morphine.
Fentanyl mucosal patch (Oral transmucosal fentanyl citrate, OTFC) through the oral mucosa with an onset of action of 5 to 15 minutes and a duration of action of about 2 hours. This is a new method of treating explosive pain. However, it is expensive.
(3) Pethidine: Pethidine is not suitable for the treatment of chronic pain and cancer pain, because its metabolism in the body after demethylation produces norethindrone, the half-life of this metabolite is 2-3 times that of pethidine, long-term use can lead to accumulation in the body, causing a series of adverse reactions in the central nervous system, such as tremor, myoclonus and even seizures, and naloxone can not antagonize the adverse reactions caused by norethindrone. There is even a tendency to aggravate.
(4) methadone (methadone): the application of methadone in cancer pain is gradually gaining attention, it is a synthetic opioid, which can 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 tolerance to morphine, and methadone agonizes both μ and δ receptors, which has a better analgesic effect and does not produce aggregation of metabolites.
(5) Hydromorphone and oxycodone: Hydromorphone and oxycodone are similar to morphine in extended-release dosage forms. The efficacy and tolerability of hydromorphone and morphine are similar. The active ingredient of hydromorphone 24-hour controlled-release tablets is a semi-synthetic strong opioid analgesic, with an analgesic effect 5-715 times stronger than morphine. Oxycodone is an effective alternative to morphine, and its side effects and analgesic efficacy are similar to those of morphine. The bioavailability of oxycodone is higher (60% to 90%), and its equivalent dose is 1/2 to 2/3 of the oral morphine dose.
(6) New perspectives of narcotic analgesics for analgesia in bone cancer pain.
Reducing the applied dose of opioids, expanding their safety range, slowing down the occurrence of tolerance and dependence, and synergistically applying small doses of opioid antagonists to improve analgesic effects are the development directions of opioid analgesics for cancer pain.
Replacement of opioid drugs Some reported individual differences to different opioid drugs are related to the different pain sensitivity and responsiveness to opioid drug therapy caused by the difference of alternate genes, so the drugs should be replaced timely according to the treatment response. Some studies have shown that most cancer pain patients need to change 2-3 opioid analgesics to achieve more satisfactory analgesia. The ratio of the strength of morphine to fentanyl is 1:70~1:100; the ratio of 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 strength of different drugs and different routes of administration.
Opioid-Induced Abnormal Pain Sensitivity and Opioid Tolerance Opioid-induced abnormal nociceptive sensitization (Opioid-Induced Abnormal Pain Sensitivity) may occur in both animals and humans after long-term administration of opioids. This pain sensitivity is similar to the characteristics of neuropathic pain caused by nerve injury or disease, with mechanisms related to NMDA receptors and the presence of neuropathic pain and neuronal mechanism interactions. This phenomenon should be considered when a patient fails to achieve effective analgesia or experiences opioid toxicity despite incremental opioid doses, when increasing the dose only exacerbates the pain.
Since opioid use in advanced cancer patients is mainly for analgesic purposes, drug tolerance and somatic dependence may occur, but they are different from psychological dependence of drug addicts. Tolerance and somatic dependence should not be a barrier to the use of opioids for adequate relief of cancer pain; a 2003 US survey found that patients with advanced bone cancer pain were severely under-medicated with opioids (<60%) in the last year before death, resulting in inadequate analgesia.
Oral administration is the preferred route of administration for patients with advanced cancer pain, and can also be administered sublingually or rectally. Fentanyl transdermal patch is an effective non-invasive method of drug delivery. For pain that cannot be controlled by transgastrointestinal administration, transvenous administration can be considered. After failure of oral, intravenous, or transdermal routes or when uncontrollable side effects occur, intrathecal administration or complex local nerve block therapy may be used instead.
According to the different pharmacokinetics of drugs, a suitable interval of drug administration should be formulated and administered regularly to maintain a constant analgesic drug concentration in the body, which can improve the analgesic effect of drugs and 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 NSAIDs. the analgesic effect of transdermal fentanyl patch often appears 12 hours after administration, peaks at 24-48 hours, and can last for about 72 hours. Transvenous administration of morphine can have an onset of effect within 5 minutes and lasts 1-2 hours. For explosive pain caused by activity, stress and disease progression, a certain amount of analgesic drug can be added on top of the regular administration.
5.Ketamine
Ketamine is a general anesthetic drug with analgesic, sedative and anesthetic effects, and can treat bone cancer pain. It can act on opioid, adrenaline, choline and NMDA receptors, and is an antagonist of NMDA receptors. No matter intravenous injection or oral or intrathecal administration, it can effectively reduce the degree of bone cancer pain.
6.Collidine
It is a central α2 agonist, and the mechanism of analgesic effect may be related to the change of central and peripheral neurotransmitter release and activity. Colistin is mainly used for central administration for analgesia. Combined with morphine and local anesthetics intravertebral use can effectively relieve neuralgia of tumors and bone metastatic cancer pain. Side effects include hypotension, bradycardia, dry mouth and sedation.
7.Adjuvant therapy drugs
The so-called adjuvant therapy jointly adopts some non-analgesic drugs to improve the analgesic effect of opioids and reduce the dosage of opioids, which can also reduce their adverse effects. Adjuvant therapy is especially important for refractory pain that cannot be controlled by conventional analgesics.
(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 treatment.
(3) Anticonvulsants: Gabapentin can act on calcium channels, sodium channels and NMDA receptors to inhibit neuronal firing and play an analgesic effect on neuropathic pain. The maximum dose of Gabapentin can be 1800-3600mg, and it can be used for the treatment of bone cancer pain in adults and children.
II. Radiotherapy
About 40% of all radiotherapy patients are treated for the purpose of controlling cancer pain. Radiotherapy is effective in the treatment of pain caused by cancer compression or infiltration of nerves and limited bone metastasis. The common radiotherapy methods that can help control cancer pain are: distant radiotherapy, brachytherapy, systemic radionuclide and indirect therapy.
3.Surgical treatment
Surgery is also a necessary and effective treatment for obstructive pain caused by tumor compression and irritation, and even palliative surgery can provide the longest and most effective pain relief. It can achieve the purpose of eliminating and reducing pain, prolonging life span, reducing disability rate and improving the quality of life.
IV. Nerve block and nerve destruction
Nerve-destroying drugs such as ethanol and phenol can achieve the purpose of treating cancer pain by chemically blocking the abnormal impulse conduction of nerves. At present, peripheral nerve, nerve root, subarachnoid, abdominal plexus and pituitary destruction are commonly used in clinical practice. Abdominal plexus disruption is mainly used for pain caused by tumors in the abdominal organs, and the best results are achieved by using abdominal plexus disruption for pain caused by pancreatic cancer. Radiofrequency disruption can also be used to destroy the conduction tracts in the spinal cord such as the thalamus tract 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 treating cancer pain, and their effectiveness and possible side effects (such as local anesthesia) must be evaluated comprehensively before selection and informed consent of patients must be obtained.
V. Chemotherapy
Chemotherapy is a necessary means to control cancer pain, which can eliminate the pain caused by tumor from the etiology. Chemotherapy is mainly applied to patients with tumors that cannot be removed by surgery and multiple lesions, especially for pain caused by compression or infiltration of nerve or bone tissue caused by osteosarcoma, lymphoma, small cell lung cancer and leukemia, etc. It can show rapid effect.
VI. Hormone therapy
Beatson considered the relationship between ovarian and breast cancer proliferation a century ago, and also observed that removal of ovaries in premenopausal women with bone metastases from breast cancer could lead to temporary lesion reduction and prolonged survival.
With the discovery of estrogen synthesis and, estrogen receptor (ER), estrogen receptor modulator (SERM), it was 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 and has been shown to be effective in postmenopausal women with breast cancer; GW 5638 is also a SERM agent that can be used in the treatment of triamcinolone resistant breast cancer and bone metastases.
De-androgenization (depot) is an effective treatment for bone metastases from prostate cancer and can also be effective in relieving bone cancer pain.
VII. Psychotherapy
Patients with malignant tumors are often accompanied by anxiety and depression which aggravate their conditions. The purpose of psychotherapy for cancer pain patients is to reduce the psychological barriers of cancer pain patients, enhance patients’ confidence in treatment, improve patients’ nociception and enhance patients’ ability to cope with pain. Psychotherapy can be combined with pain medication to control pain, but it cannot replace cancer pain medication. Psychotherapy methods include hypnosis, relaxation, biofeedback, psychotherapy and cognitive-behavioral therapy, etc.
Other treatments
Separate or integrated application of skin stimulation, exercise, immobilization, transcutaneous electrical nerve stimulation, acupuncture therapy, Chinese herbal medicine and other methods can significantly reduce or stop patients’ need for narcotic analgesic drugs.
IX. Outlook
1. New analgesic therapies at the cellular and genetic levels
There are two main methods of pain treatment at the cellular level, namely cell implantation therapy and gene therapy. Cell implantation is the transplantation of autologous cells cultured in vitro into human body, and through the role of similar biological micro-pump, these transplanted cells can 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 spinal cord of patients with cancer pain, which can achieve long-term analgesic effects by secreting opioid peptides, catecholamines and neurotrophic factors. 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, providing 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 close the OPG ligand (OPGL). oPG inhibits the activation of osteoclasts by inhibiting OPGL to play the role of inhibiting bone destruction. oPG applied in the mouse femoral cancer pain model can completely block the tumor-induced bone destruction, remove the osteoclasts at the tumor site, reduce but not completely eliminate the 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 for 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 include: transient receptor potential vanilloid type -Ⅰantagonists; antibody therapy for tumor angiogenesis, ET receptor antagonists, VRl antagonists, ASIC antagonists, NMDA2B subtype receptor antagonists, P2 X3 receptor inhibitors, nicotinic receptor agonists, capsaicinoids, sodium channel blockers, and other new drugs for bone cancer pain. capsaicinoids, sodium channel blockers, bradykinin blockers, 5-HT blockers, growth factor inhibitors, etc. Experimental studies have shown good prospects for application.
5.Long-term intraspinal pumping analgesics
The most successful one is the spinal subarachnoid implantation of morphine pump, the effect is precise, and the patient’s quality of life is significantly improved without pain, and some patients can go to work with the pump, but the price is expensive.
6.The establishment of pain service institutions
In order to improve the analgesic effect of cancer pain patients and reduce the side effects, many foreign medical institutions have established pain service institutions, which are composed of experienced doctors, nurses and pharmacists, to provide analgesic drugs and analgesic techniques for patients with advanced cancer pain (some of them are in the community or geriatric hospitals), which is worth learning from.