Overview Pain is one of the most common tumor-related symptoms. Pain is defined as “the sensory and emotional experience associated with actual or potential tissue damage or similar injury”. Cancer pain or cancer-associated pain affects patients differently than non-malignancy-associated pain. Approximately 1 in 4 patients with newly diagnosed malignancies, 1 in 3 patients undergoing treatment, and 3 in 4 patients with advanced tumors have a combination of pain. Moreover, pain is one of the most dreaded symptoms for patients. If pain is not relieved, it can cause discomfort and greatly affect their activities, motivation, interactions with family and friends, and overall quality of life. The importance of pain relief and the practicality of effective treatment require that physicians and nurses treating these patients be familiar with the assessment and treatment of cancer pain. This requires a strong familiarity with: the pathogenesis of cancer pain; pain assessment techniques; common barriers to the implementation of appropriate analgesic treatment; and pharmacologic, anesthetic, neurosurgical, and behavioral approaches related to cancer pain management. The World Health Organization (WHO) established guidelines for cancer pain are widely accepted. It recommends acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs) as the starting treatment for pain relief in patients with cancer pain. If these drugs are not sufficiently effective, they should be progressively upgraded to “weak opioids” such as codeine, followed by “strong opioids” such as morphine. Although the guidelines have served as an excellent educational tool, the management of cancer pain is far more complex than the “three-step cancer pain treatment” recommendations. This clinical practice guideline was developed by the National Comprehensive Cancer Network (NCCN) Adult Cancer Pain Expert Panel, which has a unique perspective in many important areas. First, it contains several essential elements: ● Pain intensity must be quantified (to the extent possible) because treatment decisions are based on the results of pain intensity scores; ● Formal and comprehensive pain assessment must be performed; ● Pain intensity must be reassessed at regular intervals to ensure that the chosen treatment is achieving the desired effect; ● Social and psychological support must be provided; and Psychosocial support must be provided; and educational materials must be made available to patients. Second, the guideline identifies the complex set of decisions that may be faced in the treatment of these patients. The guideline therefore provides guidelines for the use of NSAIDs, opioids, and adjunctive analgesics. The guideline also gives advice on opioid titration, switching, dosing, management of opioid adverse reactions, and when and how to proceed with other cancer pain treatment techniques/interventions. Pathophysiologic Classification Cancer patients can experience various types of pain. There have been continuous attempts to classify them according to different criteria. The classification of cancer pain should distinguish between tumor-related pain, treatment-related pain, and pain unrelated to either. The differences between acute and chronic pain should also be considered when deciding on treatment options. The treatment strategy depends on the pathophysiological characteristics of the pain, which is determined by examining and evaluating the patient. There are two main pathophysiologic mechanisms of pain: injury-receptive and neuropathic. Injury-receptive pain is caused by injury to somatic and visceral structures that eventually activate injury receptors. Injury receptors are located in the skin, viscera, muscles, and connective tissues. Injury-receptive pain can be further divided into somatic pain and visceral pain. Somatic injury-receptive pain is usually precisely localized, with complaints of cutaneous, pulsating, and pressure-like pain. It is often caused by surgery or bone metastases. Visceral injury-receptive pain is often more diffuse and presents as aching and cramping pain. It often occurs after compression, invasion or pulling of internal organs in the chest and abdomen. Neuropathic pain is caused by injury to the peripheral or central nervous system. This type of pain can be described as burning, knife-like, or electric shock-like pain. Examples of neuropathic pain include pain caused by spinal stenosis or diabetic neuropathy, or as an adverse reaction to chemotherapy (e.g., vincristine) or radiation therapy. Comprehensive pain assessment A comprehensive assessment is essential to determine appropriate pain management. Inadequate multiple pain assessments often result in poor pain control. Treatment decisions are based on the premise that all cancer patients should be screened for pain at the initial evaluation, at the periodic follow-up phase, and at the start of any new treatment. If pain is identified at screening, the patient (if possible) must quantify the intensity of the pain. Because of the subjective nature of pain, the patient’s chief complaint is the standard method of pain intensity assessment. Currently available quantitative methods are 0-10 numeric rating scales, categorical scales, or pictorial scales (e.g., the Facial Expression Pain Rating Scale). The Facial Expression Pain Rating Scale may be more effective for patients who have difficulty using other scales, such as children, older adults, and patients with language or cultural differences or other communication barriers. If the patient is unable to report pain verbally, another method must be used for pain scoring and assessment. In addition to pain intensity, the patient should be asked to describe the nature of the pain (i.e., aching, burning, etc.). If the patient is not in pain, the patient should be screened for pain again at each follow-up visit or as needed. This method of identifying pain through repeated screening is important for implementing effective pain management. If the pain score is >0, then a full pain assessment is initiated. A comprehensive pain assessment involves many components, including primarily the type and nature of pain; pain history (e.g., time of onset, duration, course, etc.); pain intensity (i.e., at rest; during activity; effect of activity on pain intensity); pain localization, referred pain, radiating pain; factors contributing to pain exacerbation or relief, current pain management plan; patient response to current treatment; previous analgesic treatment; important psychosocial factors (e.g., patient stress, family and other personnel support, psychiatric history, risk factors for analgesic abuse, and risk factors for inadequate treatment); other pain-related issues (e.g., meaning of pain to the patient and family, sociocultural influences on pain and pain expression, spiritual or religious philosophy, current distress). Finally, a discussion should also address the patient’s goals and expectations for pain management, including comfort and functional needs. In addition, a physical examination with appropriate laboratory and imaging tests is important for a comprehensive pain assessment. This evaluation may help the health care provider to clarify the presence of an underlying cause that is related to pain and requires specific treatment. For example, the administration of opioids alone is not sufficient for patients who may be presenting with spinal cord compression. Without the administration of glucocorticoids and local radiation therapy, the pain will likely not be well controlled and the patient will still be at high risk for spinal cord damage. The ultimate goal of a comprehensive pain assessment is to determine the etiology and pathophysiological mechanism of pain (somatic, visceral or neuropathic). Pain management is individualized according to the clinical situation and the patient’s wishes, as well as according to the goal of optimizing function and quality of life. Management of pain For the management of cancer pain in adults, this guideline classifies pain intensity in three levels based on a 0-10 numerical rating scale (where 10 is the most painful): severe pain (7-10); moderate pain (4-6); and mild pain (1-3). One important point is to distinguish pain associated with tumor emergencies from pain unrelated to tumor emergencies (e.g., pain caused by fracture or weight-bearing bone fracture precursors, tumor brain metastases, epidural metastases, and soft meningeal metastases; pain caused by infection; and pain caused by obstruction or perforation of a visceral organ). Pain associated with tumor emergencies should be treated immediately along with the treatment of the primary disease for pain. In addition, this guideline distinguishes patients with pain not caused by oncologic emergencies who are not on long-term opioid therapy from patients with cancer pain who have been or are currently on opioid therapy, and takes precautions for pain and anxiety associated with clinical operations. According to the FDA, “An opioid-tolerant patient is one who is taking at least the following doses of medication: oral morphine 60 mg/d, fentanyl transdermal patch 25 μg/h, oral oxycodone 30 mg/d, oral hydromorphone 8 mg/d, oral hydromorphone 25 mg/d, or an equivalent dose of another opioid that for 1 week or longer.” Therefore, patients who do not meet the above definition of opioid tolerance and whose opioid doses do not meet the above criteria and last for 1 week or longer remain as opioid-naïve patients. Treatment of pain unrelated to oncologic emergencies in patients who have not used opioids (not long-term daily opioid use) should receive rapid titration of short-acting opioids if their pain is severe (i.e., pain intensity score 7-10) and the following section on opioid dosing principles, prescribing, titration, and maintenance), short-acting opioids have a rapid onset of analgesia Short-acting opioids have the advantage of rapid onset of analgesia. Choose the most appropriate route of opioid administration (oral or intravenous) based on the patient’s current analgesic needs. Opioid therapy must be accompanied by treatment for intestinal adverse reactions and non-opioid analgesic therapy. Regimens related to prevention of intestinal adverse reactions and antiemetic medications; management measures for these common opioid adverse reactions should be concurrent with the initiation of opioid therapy. For example, opioid-induced bowel dysfunction should be considered in advance and laxatives should be used prophylactically to promote bowel motility, and stool softeners should be decided as needed. Treatment options for patients who have not used opioids and have a pain score of 4-6 at the time of presentation are very similar to those for patients with a pain intensity of 7-10 (as above). The main differences between the two included slower titration of short-acting opioids used at the start of treatment. Patients who have not used opioids should receive NSAID or acetaminophen therapy or consider a slower titration of short-acting opioids if they have only mild pain (1-3). For all types of patients, the addition of adjuvant analgesic therapy needs to be considered for those with specific pain syndromes. Adjuvant analgesics are used to augment the efficacy of opioids or NSAIDs, and for all patients with pain, health care providers should also provide psychosocial support and initiate educational activities. The need for psychosocial support is to ensure that patients can receive appropriate help if they encounter barriers to performing related pain management (e.g., fear of addiction or adverse effects, inability to purchase opioids) or if they need help in dealing with other problems (e.g., depression, rapid decline in functional status). It is important that patients and families receive education about pain management and its related issues. Although analgesic medications are the cornerstone of cancer pain management, these medications do not always provide complete pain control and are associated with many adverse effects, so a combination of other medications or treatments is often necessary. Optimal use of nonpharmacologic interventions may be a useful complement to analgesic medications. Nonpharmacologic interventions include physical and cognitive modalities, and interventional treatment strategies are described in the following sections. Opioid Dosing Principles, Prescribing, Titration, and Maintenance Choosing an appropriate opioid When initiating treatment, one should try to identify the underlying pain mechanism and diagnose the presence of a pain syndrome. The choice of the optimal analgesic depends on the intensity of the patient’s pain, the current analgesic treatment, and the concomitant disease. Morphine, hydromorphone, and fentanyl with oxycodone are the commonly used opioids in the United States. The starting dose of opioids, frequency of administration, and titration should be individualized to obtain a balance between analgesia and adverse effects. Morphine is usually the standard initial treatment drug for patients who have not used opioids previously. For patients who have not used opioids, the recommended starting dose of oral morphine sulfate is 5-15 mg or equivalent, or the starting dose of intravenous morphine sulfate is 2-5 mg or equivalent. Pure agonists (e.g., codeine, oxycodone, hydromorphone, and fentanyl) are the most commonly used drugs for cancer pain treatment. Short half-life opioid receptor agonists (morphine, hydromorphone, fentanyl, and oxycodone) are preferred because they are easier to titrate than longer half-life analgesics (methadone and levomorphone). Fentanyl transdermal patches should not be used for rapid titration of opioid doses and are recommended only after other opioids have been used for pain control. The conversion ratio of intravenous fentanyl to fentanyl transdermal patches is 1:1. Morphine should be avoided in patients with renal disease and hepatic insufficiency. This is because patients with renal insufficiency are prone to morphine-6-glucosinolate (the active metabolite of morphine) accumulation, which has analgesic effects and exacerbates adverse effects. The large individual differences in methadone pharmacokinetics (long half-life, ranging from 8-120+ hours) make its use in cancer patients very difficult. Because of the long half-life, high potency, and individual differences in pharmacokinetics, the starting dose of methadone should be lower than the expected dose, slowly increased during titration, and accompanied by sufficient short-acting medication to control flare pain. Consultation with a pain specialist should be considered prior to application. The following medications are not recommended for cancer patients: 1) mixed agonist-antagonists (e.g., bupropion, pentazocine), 2) propoxyphene and pethidine and 3) placebo. For severe pain, mixed agonist-antagonists have limited efficacy and may cause withdrawal symptoms in patients who are using pure agonist analgesics. Chronic pain is a contraindication to propoxyphene and pethidine, especially in patients with renal insufficiency or dehydration, because metabolites excreted via the kidneys accumulate in the body and cause neurotoxicity or cardiac arrhythmias. Placebo treatment of pain is not ethical. Propoxyphene is an inhibitor of the hepatic enzyme CYP2D6. Since some data suggest that CYP2D6 inhibitors increase the risk of recurrence in breast cancer patients treated with tamoxifen, we believe that propoxyphene may have the same effect. Therefore, propoxyphene should be avoided in patients taking tamoxifen. In general, propoxyphene should be avoided for the treatment of cancer pain because the risks far outweigh the benefits. Choosing the route of administration To ensure that effective analgesia is achieved, the least invasive, easiest, and safest form of opioid administration should be used. Oral administration is the preferred route of chronic pain management. Oral administration should be considered first for patients who are able to take the drug orally, unless rapid analgesia is needed or the patient has an adverse reaction to oral administration. Continuous parenteral infusion, intravenous (IV) or subcutaneous (SC) administration is recommended for patients who are unable to swallow or have impaired intestinal absorption of opioids. Compared to oral or transdermal administration, opioids given parenterally can rapidly achieve effective blood levels. Rapid analgesia should be administered intravenously because of the short lag time from injection to onset of action (analgesic effect peaks at 15 minutes) and the long lag time for onset of action when given orally (analgesic effect peaks at 60 minutes). In China, transdermal patch administration is a commonly used non-invasive route of drug delivery. Currently, the widely used analgesic delivery methods in clinical practice are: “on-time”, “on-demand” and “patient-controlled analgesia”. “On-time” dosing is designed to provide continuous pain relief to patients with chronic pain. For patients receiving an “on-time” regimen, a “relief dose” should also be used as a follow-up treatment. For pain that cannot be relieved by regular “on-time” dosing, short-acting opioid rescue therapy should be given. Opioid “on-demand” dosing is used for patients with intermittent pain with pain-free intervals. The “on-demand” approach is also used for patients who require rapid dose titration. Patient-controlled analgesia technology allows patients to self-titrate opioids “as soon as needed” (the device’s titration dose is controlled by physician-set parameters). Adverse reactions to opioids Constipation, nausea and vomiting, pruritus, delirium, respiratory depression, motor and cognitive impairment, and excessive sedation are common, especially when used in combination with multiple drugs. Each adverse reaction is carefully evaluated and treated. Take appropriate management measures to avoid and mitigate adverse reactions to analgesic medications. Opioid therapy almost always leads to constipation, and measures to prevent gastrointestinal adverse reactions are recommended. However, there is little evidence to help us choose the best preventive measures. One study showed that a laxative (senna) combined with a stool softener (docusate sodium) was less effective than a laxative (senna) alone. Therefore, the NCCN clinical practice guideline for adults with cancer pain recommends stimulant laxatives in combination with or without stool softeners. Specific details of prevention of gastrointestinal adverse effects, additional measures to prevent constipation, and antiemetic medications. Opioid Switching No single opioid is appropriate for all patients. If the opioid currently being used has significant adverse effects, it may be replaced with an equivalent dose of another opioid to obtain a balance between analgesia and adverse effects. This approach is known as opioid switching. It is important to consider the relative efficacy when switching between oral and parenteral routes of administration to avoid overdose or underdose. Methods for opioid equivalent dose conversion (dose ratio), titration, and maintenance dosing, as well as examples, are outlined in this guide. The initial application of short-acting opioids in patients who have not used opioids is based on the patient’s choice of opioid route of administration (oral or intravenous). For patients who have not used opioids, the initial dose is 5-15 mg morphine sulfate orally or 1-5 mg morphine sulfate intravenously or equivalent if the pain score is ≥4, or if the pain score is less than 4 but pain control and functional goals are not met. Efficacy and adverse effects of oral morphine sulfate were assessed every 60 minutes and of intravenous morphine sulfate every 15 minutes to determine the subsequent dose. If pain scores remain unchanged or increase, a 50%-100% increase in opioid dose is recommended for good analgesia. If the pain score decreases to 4-6, then repeat the same dose and assess again after 60 minutes of oral medication and 15 minutes of intravenous medication. If reassessment after 2-3 dose cycles reveals poor control of moderate to severe pain, then change the route of administration from oral to intravenous, or consider a follow-up treatment strategy. If the pain score drops to 1-3, administer the drug as needed at the current effective dose for the initial 24 hours and then proceed to follow-up treatment. Management of opioid-tolerant patients with pain unrelated to oncologic emergencies An opioid-tolerant patient is one who has been taking opioids for a long time for pain relief. According to the FDA, “An opioid-tolerant patient is one who takes at least the following doses of medication: oral morphine 60 mg/d, fentanyl transdermal patch 25 μg/h, oral oxycodone 30 mg/d, oral hydromorphone 8 mg/d, oral hydromorphone 25 mg/d, or an equivalent dose of another opioid for 1 week or longer.” For opioid-tolerant patients with pain intensity ≥4 or pain intensity <4 but not meeting pain control and functional goals, increase the "relief" dose by 10%-20% in order to achieve good pain control by calculating the total amount of oral or intravenous opioids administered in the previous 24 hours. The efficacy and adverse effects of oral morphine sulfate were assessed every 60 minutes, and the efficacy and adverse effects of intravenous morphine sulfate were assessed every 15 minutes to determine the subsequent dose. If pain scores remain unchanged or increase, a 50%-100% increase in opioid relief dose is recommended for good analgesia. If the pain score decreases to 4-6, then repeat the same dose and reassess after 60 minutes of oral medication and 15 minutes of intravenous medication. If there is no change in pain scores in patients with moderate to severe pain after 2-3 dose cycles, then change the route of administration from oral to intravenous, or consider a follow-up treatment strategy. If the pain score drops to 1-3, administer as needed at the current effective dose (oral or intravenous opioid) for the first 24 hours before proceeding to follow-up treatment. Follow-up pain management for opioid-tolerant patients Follow-up treatment is determined based on the patient's continuous pain score. All treatments indicated for any pain intensity should be administered in conjunction with psychosocial support and patient and family education. If the pain is severe, unchanged, or worsening at this point, the current diagnosis should be reassessed and a comprehensive pain assessment should be performed. Consider changing opioid class (opioid switch, for patients who experience adverse reactions and are unable to increase their current opioid dose. Reevaluate the addition of adjunctive analgesic medications to increase the analgesic effect of opioids or to mitigate opioid adverse effects. Because of the multifaceted nature of cancer pain, other interventions may be considered for specific cancer pain syndromes in order to achieve good pain control, and consultation with a pain specialist may be considered. In case of moderate pain with a score of 4-6, repeat the same dose or increase the dose if the pain is well controlled with the current opioid dose. In addition, consistent with severe pain, consider adding adjuvant analgesic medications and for specific cancer pain syndromes other interventions may be considered, consider consulting a pain specialist. For opioid-tolerant patients with mild pain who have good analgesia but are unable to tolerate or manage adverse effects, reduce the dose by 25% from the current dose. Consider adding adjunctive analgesic medications. Ongoing monitoring Although pain intensity needs to be assessed frequently to evaluate the need for increasing the opioid dose, the patient's goals for comfort and functional requirements should be formally reassessed at each follow-up visit. If patient satisfaction with comfort and function is achieved and the 24-hour opioid dose is stable, the NCCN Adult Cancer Pain Panel recommends switching to extended-release oral medications (if feasible) or other extended-release dosage forms (e.g., fentanyl transdermal patches), or other long-acting medications (e.g., methadone). Develop a follow-up treatment plan based on the patient's persistent pain score. If an extended-release opioid does not provide complete pain relief, a short-acting dosage form of the same long-acting drug is allowed as relief therapy during maintenance therapy. Follow-up visits are recommended. Outpatients should be followed up at each visit, and inpatients may be followed up at least once a day depending on their condition or hospital rules. Patients should be provided with a written follow-up plan and informed of the importance of adherence to the medication plan, adherence to outpatient visits and physician follow-up, and if the patient's comfort and functional needs are not at an acceptable level, a thorough screening and evaluation to consider adding additional measures for pain relief. Management of Clinical Operation-Related Pain and Anxiety Clinical operation-related pain is an acute, transient experience that can be accompanied by significant anxiety. Operations that have been reported to cause pain include: bone marrow aspiration, trauma care, lumbar puncture, skin and bone marrow biopsy, static/arterial placement and central venous placement and injections. Most of the available information on operation-related pain comes from studies of pediatric cancer patients and is further extended to adult patients. The management of operation-related pain should take into account the type of operation, the expected level of pain, and the patient's individual circumstances such as age and physical condition. Treatment can be provided by a variety of means, including pharmacological and/or non-pharmacological treatments. The therapeutic effect of local anesthetics for operation-related pain can be maintained for a sufficiently long period of time as long as they are used with reference to the instructions. Such medications include lidocaine, proparacaine, and bupivacaine. Physical methods such as skin warming, laser or jet injections, and ultrasound can accelerate the onset of skin anesthetics. Sedation can also be used, although deep sedation and general anesthesia can only be administered by professionals. In addition, the use of nonpharmacologic interventions may be helpful in managing pain and anxiety associated with clinical operations. Non-pharmacological interventions include mainly physical and cognitive therapies to increase the confidence of cancer pain patients to control their pain and reduce the feeling of helplessness. Patients are usually better able to tolerate operations if they know what is going to be performed, so written instructions for analgesia should be given to patients and families. It is important to educate patients prior to the operation, including the specific details of the operation and strategies for pain management. Patients and families should be given written information about pain management. Interventional Treatment Strategies Some patients receive medications but have inadequate pain control or are unable to tolerate opioid titration regimens due to adverse effects. Other patients may prefer interventional therapy over a long-term drug delivery regimen. The primary indications for interventional therapy are patients who are likely to have pain relief by nerve block (e.g., pancreatic/epigastric pain relief by abdominal plexus block, lower abdominal pain relief by inferior epigastric plexus block, intercostal nerve block, or peripheral nerve block) and/or who do not have intolerable adverse effects but have poor pain control. For example, pancreatic cancer patients who are intolerant to opioids or whose pain is not adequately controlled may opt for an abdominal plexus block. If patients do not achieve good analgesia, some interventional strategies may be considered. Local infusion of analgesics (epidural, intrathecal and local plexus) is one option. This approach minimizes the binding of analgesic drugs to receptors in the brain, thus potentially avoiding the adverse effects of systemic administration. Intrathecal administration should be considered for patients who are unable to tolerate excessive sedation, mental confusion, and/or inadequate pain control due to systemic administration of opioids. This approach can provide significant improvement in pain at various local anatomic sites (e.g., head and neck, upper and lower extremities, trunk). Neurodestruction for precisely localizable pain syndromes (e.g., back pain due to intervertebral microarthropathy, sacroiliac arthropathy; visceral pain due to abdominal or pelvic tumors), percutaneous vertebroplasty/posterior vertebral kyphoplasty, nerve stimulation (for peripheral neuralgia), and radiofrequency ablation of bone lesions have been shown to be effective in analgesia, particularly in patients with poor pain control without intolerable adverse effects. patients. These techniques have been shown in some cases to eliminate pain or significantly reduce pain levels and/or may significantly reduce the systemic dosage of analgesics. Patients who are reluctant, or who have infections, clotting abnormalities, or very short survival are not candidates for interventional therapy. Also, any medications that the patient is taking that may increase the risk of bleeding [e.g., anticoagulants (warfarin, heparin), antiplatelet agents (clopidogrel, dipyridamole), or angiogenesis inhibitors (bevacizumab)] should be communicated to the interventionalist. In these cases, the patient should discontinue these drugs for a period of time before starting the pain intervention and restart them only after a period of time has elapsed following the pain intervention. Interventions should not be performed if the physician is not skilled. Other treatments Other treatment strategies may be considered for specific pain conditions. Inflammatory pain, bone pain, nerve compression or inflammation, neuropathic pain, pain due to intestinal obstruction, and pain that may be responsive to antineoplastic therapy are listed. Overall, neuropathic pain is less responsive to opioids than pain caused by other pathophysiologic causes. Other treatments, including specific nontraditional analgesics, are often indicated for the treatment of neuropathic pain syndromes. For example, adjunctive analgesics may be tried in patients with neuropathic pain that cannot be adequately relieved by opioids. Clinically, there is a wide range of adjunctive analgesics, including anticonvulsants (e.g., gabapentin, pregabalin), antidepressants (e.g., tricyclic antidepressants), corticosteroids, and local anesthetics (e.g., topical lidocaine patches). Some antidepressants are known to inhibit drug metabolism in the liver by inhibiting cytochrome P450 enzymes, particularly CYP2D6. Tamoxifen is an estrogen receptor blocker and is commonly used in patients with hormone receptor-positive breast cancer. Tamoxifen is primarily metabolized by the liver, so CYP2D6 inhibitors may reduce the production of active metabolites of tamoxifen, thereby affecting its efficacy. Clinical studies have shown that patients receiving tamoxifen with concomitant use of selective 5-hydroxytryptamine reuptake inhibitor (SSRI) antidepressants have an increased risk of breast cancer recurrence compared to those on tamoxifen alone. If SSRIs are required in patients using tamoxifen, weak CYP2D6 inhibitors (sertraline, citalopram, venlafaxine, edipram) should be chosen over moderate-to-potent CYP2D6 inhibitors (paroxetine, fluoxetine, fluvoxamine, bupropion, duloxetine). Adjuvant analgesics are commonly used as adjuncts for the treatment of bone pain, neuropathic pain, and visceral pain, to reduce systemic administration of opioids, and are particularly important for opioid-resistant neuropathic pain. Acetaminophen, NSAIDs including selective COX-2 inhibitors, tricyclic antidepressants (TCAs), anticonvulsants, bisphosphonates, and hormones are the most commonly used adjuvant analgesics.NSAID and acetaminophen prescribing guidelines. A history of peptic ulcer, advanced age (>60 years), male, and ongoing corticosteroid use should be considered prior to NSAID use to prevent upper gastrointestinal bleeding and perforation. Well-tolerated proton pump inhibitors are recommended to mitigate NSAID-induced gastrointestinal adverse effects. NSAIDs should be used with caution in patients older than 60 years, with imbalanced fluid status, renal insufficiency, concomitant use of other nephrotoxic drugs, and use of transrenal excretion of chemotherapeutic agents to avoid nephrotoxicity. Non-pharmacologic specialty therapies such as physical modalities (e.g., massage, physical therapy) and cognitive modalities (e.g., hypnosis, relaxation) may be fruitful in combination with pharmacologic interventions. Special attention should also be given to psychosocial support, providing education to patients and their families, and reducing the adverse effects of opioid analgesics. Ongoing pain scores should be documented in the case to ensure that the patient’s pain is consistently well controlled and that treatment goals are met. In addition, specialty consultations can be helpful in providing interventions for difficult cancer pain problems. The main indication for referral to a specialist is if the specialist treatment will provide pain relief or help improve the patient’s ability to perform daily activities. These treatments need to be provided by professionals and include first identifying individualized treatment goals, then providing patients with targeted treatment and patient education. These specialized treatments may include physical therapy, occupational therapy, psychosocial support, or interventional therapy. In summary, cancer pain can be effectively managed in most patients with appropriate methods and safe medications. The full range of pain management approaches covered in this guideline is comprehensive. It is based on routine pain assessment, integrates pharmacologic and non-pharmacologic interventions, and requires ongoing reassessment of the patient. the NCCN expert panel on clinical practice guidelines for adult cancer pain recommends that cancer pain can be well controlled in most patients if guidelines are systematically applied, carefully monitored, and individual patient needs are adequately considered.