Cancer pain

Contents

Cancer pain

Cancer pain

Pain is an unpleasant physical feeling. Pain is also personal, meaning what’s painful for one person may not be painful for another person. The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” ¹. When there is damage to any part of your body, nerves in that part of the body send messages to your brain. When your brain receives these messages, you feel pain. This includes pain caused by cancer. Cancer pain is often cited as one of the most feared complications in cancer patients ². However, not everyone with cancer has cancer pain, but some do. If you have cancer that’s spread or recurred, your chance of having pain is higher. In a cross-sectional study, pain occurs in 20% to 50% of patients with cancer ³. Roughly 80% of patients with advanced-stage cancer have moderate to severe pain ⁴. One meta-analysis looking at pooled data from 52 studies found that more than half of patients with cancer had pain ⁵. Younger patients are more likely to have cancer pain and pain flares than older patients ⁶. Patients with advanced cancer have more severe pain, and many cancer survivors have pain that continues after cancer treatment ends ⁵.

Pain that is severe or continues after cancer treatment ends increases the risk of psychological helplessness, anxiety, and depression ⁷. If you feel depressed or have anxiety, your pain may feel worse and make it harder to control. Uncontrolled pain interferes with patients’ ability to perform daily life activities and work because of the pain. Therefore, pain should be managed properly.

Cancer pain takes many forms. Cancer pain can be dull, achy, sharp or burning. Cancer pain can be constant, intermittent, mild, moderate or severe. How much pain you feel depends on a number of factors, including the type of cancer you have, how advanced it is, where it’s situated and your pain tolerance.

Cancer pain is a broad term for the different kinds of pain people may experience when they have cancer ⁸. Even people with the same type of cancer can have different experiences. The way you feel pain will be affected by ⁹:

Type of cancer
Cancer stage (how advanced it is)
Cancer treatment you receive. For example, tumors surgery, intravenous chemotherapy, radiation therapy, targeted therapy, therapies such as bisphosphonates, and diagnostic procedures may cause you pain.
Other health issues you have e.g., substance use disorder, emotional distress, depression, anxiety
Your attitudes and beliefs about pain
The significance of the pain to you.
Combination of the above factors.

Pain can be experienced at any stage of the disease ¹⁰:

Before diagnosis – cancer can cause pain before a diagnosis and the pain may come and go. In some cases, pain comes from the tumour itself, such as abdominal pain from the tumour pressing on bones, nerves or organs in the body.
Diagnosis – tests to diagnose cancer can sometimes cause short-term pain or feel uncomfortable (e.g. you may need surgery to remove a sample of tissue for examination). Most pain caused by tests can be relieved.
During treatment – some treatments cause pain, for example radiation therapy may lead to skin redness and irritation.
After treatment – pain may continue for months or years. Causes include scars after surgery, numbness in the hands or feet, lymphoedema, and pain in a missing limb or breast.
Advanced cancer – if the cancer has spread, it can cause pain by a tumour pressing on a part of the body such as a nerve, bone or organ.

Most cancer pain is manageable and there are ways to lessen pain in most patients and controlling your pain is an essential part of your treatment. Pain control can improve your quality of life during cancer treatment and after it ends.

Each person’s diagnosis, cancer stage, response to pain, and personal likes and dislikes are different. For this reason, each patient needs a personal plan to control cancer pain. You, your family, and your health care team can work together to manage your pain. As part of your pain control plan, your doctor, pain specialist or palliative care specialist can give you and your family members written instructions to manage your pain at home. Ask your doctor, pain specialist or palliative care specialist who you should call if you have questions about your pain.

A number of treatments are available for cancer pain. Your options may depend on what’s causing your cancer pain and the intensity of the pain you’re feeling. You may need a combination of pain treatments to find the most relief.

Cancer pain treatment options include ¹¹:

Over-the-counter (OTC) pain relievers (analgesics). For mild and moderate levels of pain, pain relievers that don’t require a prescription may help. Examples include aspirin, acetaminophen (paracetamol) and non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Advil, Motrin IB, others). Used either alone or in combination, depending on clinical assessment and pain severity in order to achieve rapid, effective and safe pain control.
Medications derived from opium (opioids). Opioids are prescription medications used to treat moderate to severe pain. Examples of opioids include morphine (Kadian, Ms Contin, others) and oxycodone (Oxycontin, Roxicodone, others). Some opioids are short-acting medicines, so pain relief comes quickly but you may need to take them more often. Other opioid drugs are long-acting medicines, so pain relief takes longer but the medicine doesn’t need to be taken as often. Sometimes short-acting and long-acting opioids are used together.
Other prescription medicines. Other types of medicine can help relieve pain, including antidepressants, anti-seizure drugs and steroids.
Procedures to block pain signals. A nerve block procedure can be used to stop pain signals from being sent to your brain. In this procedure, a numbing medicine is injected around or into a nerve.
Alternative therapies. Some people find some pain relief through acupuncture, massage, physical therapy, relaxation exercises, meditation, hypnosis, spiritual or social interventions.

Other treatments may be available for your particular situation. In some places, it may be legal to use medical marijuana (cannabis oil) for cancer pain.

All pain medicines have side effects. Work with your doctor to understand the benefits and risks of each pain treatment and how to manage the side effects. Together you can decide which treatments may be best for you.

Who helps manage my cancer pain?

Different health professionals help manage pain. Health professionals you may see include a surgeon, medical oncologist, pain specialist, palliative care specialist, pharmacist, social worker and nurse practitioner, among others. They will often discuss ways to manage pain at a multidisciplinary team meeting.

If your pain is not well controlled, ask your family doctor or palliative care specialist for a referral to a pain medicine specialist who is part of a multidisciplinary pain team.

If you’re not getting the answers you need, request a referral to a facility skilled in the care of cancer pain. All major cancer centers have pain management programs. The medications and treatment for pain are generally covered by standard insurance.

What are the most common causes of cancer pain?

Cancerous tumors that are growing or spreading in parts of your body often cause cancer pain. For example, a tumor that spreads to your bones may put pressure on your nerves, causing painful nerve damage. A tumor growing in your pancreas may stretch organ walls and cause pain. Other cancer pain causes include:

Pain from cancer surgery: People often have post-surgical pain if they needed surgery to remove a cancerous tumor.
Pain from cancer treatment: Cancer treatments such as chemotherapy or radiation therapy may have painful side effects. For example, someone receiving chemotherapy may have severe bouts of vomiting that can be painful. Other types of chemotherapy may cause peripheral neuropathy leading to numbness and pain in your fingers and toes.
Breakthrough pain: Breakthrough pain is sudden severe pain that’s not controlled with the medications you’ve been prescribed.

What cancer causes the most pain?

That’s hard to say. Pain is very personal. One person’s mild pain may be moderate pain for someone else. That said, one analysis of cancer pain research indicates pancreatic cancer causes the most pain. Data show 72% of people with pancreatic cancer reported cancer pain. Between 80% and 100% of people with advanced cancer reported cancer pain.

What are some reasons for not receiving adequate treatment for cancer pain?

Unfortunately cancer pain is often inadequately treated. Many factors can contribute to that, some of which include ¹²:

Reluctance of doctors to ask about pain or offer treatments. Doctors should ask people with cancer about pain at every visit. Some doctors don’t know enough about pain treatment. In that case, request a referral to a palliative care or pain specialist. Given current concerns about opioid use and abuse, many doctors might be reluctant to prescribe these opioid medications. Maintaining a close working relationship with your cancer specialists is essential to proper use of these medications.
Reluctance of people to mention their pain. Some people don’t want to “bother” their doctors, or they fear that the pain means the cancer is worsening. Others are worried their doctors will think of them as complainers or that they can’t afford pain medications.
Fear of addiction to opioids (narcotic analgesics). The risk of addiction for people with advanced cancer who take pain medications as directed for cancer pain is low. Your doctor or pain specialist will help you choose the type and dose of opioid that best controls your pain. It depends on the pain you have and the amount of drug you need to control it. For example, when morphine is used for a long time, it may become habit-forming, causing mental or physical dependence. However, people who have continuing pain should not let the fear of dependence keep them from using narcotics to relieve their pain. Mental dependence (addiction) is not likely to occur when narcotics are used for this purpose. You might develop a tolerance for your pain medication, which means you might need a higher dose to control your pain. Tolerance isn’t addiction. If your medication isn’t working as well as it once did, talk to your doctor about a higher dose or a different drug. Don’t increase the dose on your own.
Fear of side effects. Some people fear being sleepy, being unable to communicate, acting strangely or being seen as dependent on medications. You might have these side effects when you start taking strong pain medications, but they often resolve once your doctors find the correct dose of pain medications for you and once you achieve a steady level of pain medicine in your body.

Will I become addicted to opioids?

One reason that some people don’t use opioids is because they worry about becoming addicted. When people take morphine or other opioids to relieve cancer pain or for palliative care, they may experience withdrawal symptoms when they stop taking a drug, but this is not addiction.

A person with a drug addiction problem takes drugs to fulfill physical or emotional needs, despite the drugs causing harm.

Some people who take opioids long term for pain relief are at risk of becoming addicted. The risk is higher for people who have a history of misusing opioids or other medicines before their cancer diagnosis.

People who use opiods to manage chronic pain over a long period of time are also at risk of becoming addicted. Talk to your doctor if you are concerned about drug dependence.

Will my body get used to the opioids?

Some people with cancer stop getting pain relief from their usual opioid dose if they use it for a long time. This is known as tolerance and it means that the body has become used to the dose.

Your doctor will need to increase the dose or give you a different opioid to achieve the same level of pain control. You can develop tolerance without being addicted.

If I start opioids now, will they still work well later?

Some people try to avoid taking pain medicine until the pain is severe, thinking it is better to hold out for as long as possible so the medicine works better later. However, this may change the way your central nervous system (brain and spinal cord) processes the pain, causing you to experience pain long after the cause of the pain is gone. It is better to take pain medicine as prescribed, rather than just at the time you feel the pain.

Can I stop taking opioids at any time?

Stopping opioids suddenly can cause side effects. You should only reduce your dose or stop taking opioids after talking with your health care team. Your doctor will develop a withdrawal plan called a taper to gradually reduce the amount of medicine you take. It may take a few weeks to safely reduce the dose.

If I’m given opioids, does that mean the cancer is advanced?

People with cancer at any stage can develop severe pain that needs to be managed with strong opioids, such as morphine. Opioids are also commonly prescribed after surgery.

Being prescribed opioids doesn’t mean you will always need to take them. If your pain improves, you may be able to take a milder pain medicine such as acetaminophen (paracetamol) and non-steroidal anti-inflammatory drugs (NSAIDs) or try other ways to manage your pain, or you may be able to stop taking strong pain medicines.

Types of pain

There are many types of pain. Pain can be described or categorized depending on how long it lasts or what parts of the body are affected.

Acute pain

Acute pain is pain that starts suddenly and lasts a short time, possibly for a few days or weeks ¹³. It may be mild or severe. Acute pain usually occurs because the body is hurt or injured in some way, but it generally disappears when the body has healed. The treatment of acute pain focuses on blocking pain signal pathways while the tissue heals.

Chronic pain

Chronic pain is pain that lasts longer than three months ¹³. Chronic pain may be due to an ongoing problem but can also develop after any tissue or nerve damage has healed. It is also called persistent pain. For example, you may have ongoing tissue damage and therefore experience chronic pain.

The transition from acute to chronic pain may be understood as a series of relatively discrete changes in your brain and spinal cord (central nervous system) ¹³. Chronic pain involves the activation of secondary mechanisms such as the sensitization of second-order neurons by upregulation of N-methyl-D-aspartic acid (NMDA) channels and alteration in microglia cytoarchitecture. Chronic pain, with its multiple factors for perpetuation, often benefits from a multidisciplinary approach to treatment ¹⁴.

Breakthrough pain

Breakthrough pain is a sudden flare-up of pain that can occur despite taking regular pain medicine (analgesic) in the setting of relatively well-controlled acute or chronic pain ¹⁵, ¹⁶, ¹⁷. Breakthrough pain may happen because the dose of medicine is not high enough or because the pain changes when you move around also called incident pain. Other causes include stress, anxiety or other illnesses. In one study, 75% of patients experienced breakthrough pain; 30% of this pain was incidental, 26% was nonincidental, 16% was caused by end-of-dose failure, and the rest had mixed causes ¹⁸.

Incident pain

Incident pain is a type of breakthrough pain related to certain often-defined activities or factors such as movement increasing vertebral body pain from metastatic disease. It is often difficult to treat incident pain effectively because of its episodic nature ¹⁹.

Nerve pain (neuropathic pain)

Nerve (neuropathic) pain is pain caused by pressure on nerves or the spinal cord, or by nerve damage. The nerve damage or pressure can be in the peripheral nervous system (the nervous system outside the brain and spinal cord) or the central nervous system (spinal cord or brain). People often describe nerve pain as numbness, burning or tingling, or ‘pins and needles’. Nerve pain can occur anywhere nerves get damaged, and the pain may come and go.

Causes of neuropathic (nerve) pain of particular relevance to cancer include chemotherapy (e.g., vinca alkaloids), infiltration of the nerve roots by tumor, or damage to nerve roots (radiculopathy) or groups of nerve roots (plexopathy) due to tumor masses or treatment complications (e.g., radiation plexopathy) ²⁰. Nerve (neuropathic) pain may be evoked by stimuli or spontaneous. Patients who experience pain from nonnoxious stimuli are classified as having allodynia. Allodynia is a condition where a stimulus that normally wouldn’t cause pain results in pain. For example, a light touch from a feather might feel painful instead of just a sensation. Other examples include pain from wearing clothing, temperature changes, or someone gently tapping your shoulder. Hyperalgesia is an abnormally increased sensitivity to feeling pain and an extreme response to pain, which may be caused by damage to pain receptors (nociceptors) or peripheral nerves and can cause hypersensitivity to stimulus. Pain receptors are found in somatic (e.g., muscles, skin, joints, connective tissue, or bones) and visceral tissues (internal organs).

Bone pain

Bone pain is pain caused by cancer spreading to the bones and damaging bone tissue in one or more areas. It is often described as dull, aching or throbbing, and it may be worse at night.

Soft tissue pain

Soft tissue pain is pain caused by damage to or pressure on soft tissue, including muscle. The pain is often described as sharp, aching or throbbing.

Visceral pain

Visceral pain is pain caused by damage to or pressure on internal organs. Visceral pain can be difficult to pinpoint. It may cause some people to feel sick in the stomach and is often described as having a throbbing sensation.

A specific type of visceral pain is referred pain, which is explained by the commingling of nerve fibers from somatic (e.g., muscles, skin, joints, connective tissue, or bones) and visceral pain receptors (nociceptors) at the level of the spinal cord. Patients mistakenly interpret the pain as originating from the innervated somatic tissue (e.g., muscles, skin, joints, connective tissue, or bones). Visceral pain may be accompanied by autonomic signs such as sweating, pallor, or bradycardia. Somatic pain is more easily localized.

Referred pain

Referred pain is pain that is felt in a different area of the body from the area that is damaged.

Localized pain

Localized pain is pain at the spot where there’s a problem.

Phantom pain

Phantom pain is a pain sensation in a body part that is no longer there, such as breast pain after the breast has been removed. This type of pain is very real.

Cancer pain causes

Cancer pain can be caused by the cancer itself, by the cancer treatment, or by other health issues not related to cancer, such as emotional distress, depression, anxiety, substance use disorder or arthritis. Pain could happen if the cancer grows into or destroys nearby tissue. As a tumor grows, it can press on nerves, bones or organs. The tumor can also release chemicals that can cause pain.

Treatment of the cancer can help the pain in these situations. However, cancer treatments, including surgery, radiation and chemotherapy, can also cause pain.

A study evaluating the characteristics of patients with advanced cancer presenting to a palliative care service found the primary tumor as the chief cause of pain in 68% of patients ¹⁸. Most pain was somatic (pain that originates in the soft tissues of the body, such as the skin, muscles, bones, joints, and connective tissues) and the pain was as likely to be continuous as intermittent ¹⁸.

Cancer pain can be caused by the following ²¹:

Surgery (postoperative pain).
Radiation therapy and radiation-induced pain.
Chemotherapy. Chemotherapy-related musculoskeletal pain and chemotherapy-induced peripheral neuropathy
Targeted therapy.
Supportive care therapies.
Diagnostic procedures.
Treatment-related mucositis.
White blood cell growth factor–related bone pain.
Skin complications and chemotherapy.
Cancer metastasis (spread of cancer cells from the original tumor to other parts of the body).

Cancer treatments

Cancer treatments may cause pain. The pain you experience depends on the treatments you receive, including ²²:

Postoperative pain.
Spasms, stinging, and itching caused by intravenous chemotherapy.
Mucositis (inflammation of the mucous membranes) caused by chemotherapy or targeted therapy.
Ostealgia (bone pain) caused by filgrastim or pegfilgrastim, which are granulocyte colony-stimulating factors that help the body make more white blood cells.
Peripheral neuropathy caused by chemotherapy or targeted therapy.
Pain in joints and muscles caused by paclitaxel or aromatase inhibitor therapy.
Osteonecrosis of the jaw caused by bisphosphonates given for cancer that has spread to the bone.
Avascular necrosis caused by long-term use of corticosteroids.
Pain syndromes caused by radiation therapy, including:
- Pain from brachytherapy. Brachytherapy, also called implant radiation therapy, internal radiation therapy, and radiation brachytherapy, is a type of radiation therapy in which a radioactive substance is sealed inside materials that can be implanted, such as pellets, seeds, ribbons, wires, needles, or capsules, and placed inside your body, directly into or near a tumor or within a body cavity. The implant may be placed through a small flexible tube called a catheter or through an applicator device. It may be kept in place for a few minutes, for many days, or for the rest of a person’s life. Brachytherapy is often used to treat cancers of the head and neck, breast, cervix, prostate, and eye.
- Pain from lying in the same position during treatment.
- Mucositis (inflammation of the mucous membranes in areas that were treated with radiation).
- Dermatitis (inflammation of the skin).
- Pain flares.

Postoperative pain

Postoperative pain is a normal part of the surgical experience and is a response to tissue injury caused by surgery. It can feel like an unpleasant physical and psychological experience. The type of surgery you have can affect how much pain you experience. Complex surgeries that involve more tissue dissection, bone cutting, and joint manipulation can cause more pain. Other factors that can affect pain include your sex, whether you smoke, and whether you have a mental health disorder.

Pain is usually worst in the first 24–48 hours after surgery, but it can last for weeks or months. Your doctor will likely prescribe oral pain medication. Other options include non-steroidal anti-inflammatory drugs (NSAIDs), opioids, and regional analgesia.

Chemotherapy-induced peripheral neuropathy

Peripheral neuropathy is a common toxic effect of chemotherapy and is predominantly a sensory neuropathy ¹⁴. Patients with chemotherapy-induced peripheral neuropathy (CIPN) report numbness and tingling in a stocking-and-glove distribution. Chemotherapy-induced peripheral neuropathy is most commonly associated with the following ²³:

Platinum compounds (e.g., oxaliplatin, cisplatin, and carboplatin, in descending order of severity).
Taxanes (e.g., paclitaxel, docetaxel, and cabazitaxel).
Thalidomide.
Proteasome inhibitor (e.g., bortezomib, carfilzomib, and ixazomib).
Vinca alkaloids.

Other agents, including ixabepilone, lenalidomide, and pomalidomide, are common sources of chemotherapy-induced peripheral neuropathy ¹⁴. With any of these agents, chemotherapy-induced peripheral neuropathy may limit the dose of chemotherapy delivered, which may affect the outcomes of treatment ²³. In one series of women treated with docetaxel, approximately one in four reported chemotherapy-induced peripheral neuropathy ²⁴. Although chemotherapy-induced peripheral neuropathy often improves after discontinuation or completion of chemotherapy, symptoms can linger for years for some patients, especially those treated with taxanes, with one study demonstrating a median 6.5-year duration of symptoms after diagnosis ²⁵, ²⁶. Newer immune checkpoint inhibitor therapy, such as pembrolizumab and nivolumab, can produce peripheral neuropathies ²⁷. The prevalence may become clear as more patients are treated with these agents ²⁷.

In two studies of women with breast cancer, peripheral neuropathy correlated negatively with quality of life (QOL) ²⁸, ²⁹. The effect of a docetaxel regimen and patient characteristics on peripheral neuropathy and quality of life was evaluated in a substudy of the NASBP B-30 trial ²⁹. The B-30 trial randomly assigned women with lymph node-positive, early-stage breast cancer to one of three regimens: four cycles of doxorubicin plus cyclophosphamide every three weeks, followed by four cycles of docetaxel 100 mg/m² (AC→T); four cycles of doxorubicin plus docetaxel 60 to 75 mg/m²; or four cycles of doxorubicin plus cyclophosphamide plus docetaxel 60 to 75 mg/m² ²⁹. Overall, 41.9% of patients reported peripheral neuropathy 24 months after beginning treatment, with 10.3% reporting a severe symptom (“quite a bit”/“very much”/“bother” level) ²⁹. Treatment with doxorubicin plus cyclophosphamide every three weeks, followed by four cycles of docetaxel, the regimen with the highest cumulative dose of docetaxel, resulted in increased severity of peripheral neuropathy compared with the other two regimens. Women who reported worse peripheral neuropathy symptoms had a statistically significant decreased quality of life (QOL) ²⁹.

Preventing and reducing risk of chemotherapy-induced peripheral neuropathy

In 2020, the American Society of Clinical Oncology released a guideline update on the prevention and management of chemotherapy-induced peripheral neuropathy. At the time, there were no studies whose outcomes supported the recommendation of any neuropathy-preventive agents. A previously documented benefit of venlafaxine was refuted in a subsequent randomized, placebo-controlled, double-blind study, in which 50 patients were randomly assigned to receive venlafaxine extended-release 37.5 mg twice daily or a placebo. The study demonstrated no significant benefit for those who received venlafaxine ³⁰.

It is recommended that doctors assess the risks and benefits of agents known to cause chemotherapy-induced peripheral neuropathy among patients with underlying neuropathy and with conditions that predispose to neuropathy. These conditions include the following ³¹, ³²:

Older age.
Obesity.
Lower physical activity.
Diabetes.
Longer planned duration of treatment.
A family or personal history of hereditary peripheral neuropathy.
Symptom burden.
Alcohol intake.

The risk of long-term chemotherapy-induced peripheral neuropathy has also been documented. At 24 months after treatment initiation for early-stage breast cancer, women with the following characteristics were at an increased risk of continued peripheral neuropathy ²⁹:

Preexisting peripheral neuropathy.
Older age.
Obesity.
Mastectomy.
Greater number of positive lymph nodes.

In a genome-wide association study, African American ancestry was the most significant predictor of taxane-induced peripheral neuropathy ³³. It should be noted that the impact of risk-factor profiles may differ between racial and ethnic groups, as reported in one observational study of African American patients ³⁴. Eligible African American cancer survivors were surveyed to determine if there was an association between nongenetic risk factors and comorbidities with chemotherapy-induced peripheral neuropathy. Patients with chemotherapy-induced peripheral neuropathy were more likely to report hypertension, hypercholesterolemia, depression, diabetes, or increased body mass index (BMI). In contrast, alcohol consumption and tobacco use were not associated with increased risk of chemotherapy-induced peripheral neuropathy.

Chemotherapy infusion-related pain syndromes

The infusion of intravenous chemotherapy causes four pain syndromes ³⁵, ³⁶, ³⁷:

Venous spasm, which is treated by the application of a warm compress or a decrease in the infusion rate.
Chemical phlebitis, which may result from chemotherapy or nonchemotherapy infusions such as potassium chloride and hyperosmolar solutions ³⁶
Vesicant extravasation, which may cause intense pain followed by desquamation and ulceration ³⁵
Anthracycline-associated flare, a venous flare reaction that may be caused by doxorubicin and includes local urticaria, pain, or stinging ³⁷

Some chemotherapy agents such as vinorelbine may cause pain at the tumor site ³⁸.

Peripheral neuropathy

Peripheral neuropathy happens when the nerves that are located outside of your brain and spinal cord (peripheral nerves) are damaged. Peripheral neuropathy can cause pain, weakness, numbness, and tingling in your hands and feet. Peripheral neuropathy is a type of pain that can be caused by chemotherapy. Patients on chemotherapy may have chemotherapy-induced peripheral neuropathy (CIPN). In some patients, chemotherapy-induced peripheral neuropathy may continue after chemotherapy has ended.

Studies of drugs and natural products used to treat chemotherapy-induced peripheral neuropathy have shown mixed results. Duloxetine is a drug that has been studied to treat chemotherapy-induced peripheral neuropathy.

Treatment-related mucositis

Severe mucositis (inflammation of the mucosa, the mucous membranes that line your mouth and your entire gastrointestinal tract) often occurs as a consequence of bone marrow cells destroying chemotherapy and standard-intensity therapy ³⁹. Cytotoxic agents commonly associated with mucositis are cytarabine, doxorubicin, etoposide, fluorouracil (5-FU), and methotrexate ²¹. Epidermal growth factor receptor (EGFR) inhibitors, multitargeted tyrosine kinase inhibitors, and mammalian target of rapamycin inhibitors also cause mucositis ⁴⁰, ⁴¹. Risk factors for mucositis include preexisting oral pathology, poor dental hygiene, and younger age ³⁹.

White blood cell growth factor–related bone pain

Filgrastim and pegfilgrastim are recombinant granulocyte colony-stimulating factors (G-CSFs) that increase in the number and differentiation of neutrophil precursors. Bone pain is a significant adverse effect caused by granulocyte colony-stimulating factors (G-CSFs) that can occur in 20% to 71% of patients ⁴². This bone pain starts within 2 days of a pegfilgrastim dose and lasts for 2 to 4 days. Although the mechanism by which granulocyte colony-stimulating factors (G-CSFs) cause bone pain is largely unknown, it is hypothesized that histamine release, creating local inflammation and edema, may play a role. A phase 2 trial randomly assigned patients who had experienced bone pain with pegfilgrastim to receive either daily loratadine 10 mg for 7 days or matching placebo after subsequent doses of pegfilgrastim ⁴³. There was no statistically significant difference between the two arms.

A second phase 2 trial randomly assigned patients receiving pegfilgrastim to receive naproxen, loratadine, or no preventative medications ⁴⁴. The percentage of patients experiencing any grade bone pain was 40.3% in the naproxen group, 42.5% in the loratadine group, and 46.6% in the no-prophylaxis group ⁴⁴. Although there was no statistically significant difference between treatment groups, the authors concluded that loratadine administration has a favorable risk-to-benefit profile and should be considered ⁴⁴.

Conventional pain medications have also been studied in this area. A phase 3, double-blind, placebo-controlled trial of naproxen for the prevention of pegfilgrastim-induced bone pain randomly assigned patients to receive either naproxen 500 mg twice daily for 5 to 8 days after pegfilgrastim administration or placebo ⁴⁵. Naproxen reduced overall pain intensity and duration of pain, compared with placebo.

Chemotherapy-related musculoskeletal pain

Paclitaxel generates a syndrome of diffuse pain in one or more joints and muscle aches and pain in 10% to 20% of patients ⁴⁶. Diffuse pain in joints and muscles appears 1 to 2 days after Paclitaxel infusion and lasts a median of 4 to 5 days ⁴⁶. Pain originates in the back, hips, shoulders, thighs, legs, and feet ⁴⁶. Weight bearing, walking, or tactile contact worsens the pain. Steroids may reduce the tendency to develop muscle aches and pain and joints pain. Among hormonal therapies, aromatase inhibitors cause musculoskeletal symptoms, osteoporotic fractures, joints pain, and muscle aches and pain ⁴⁷

Skin complications and chemotherapy

Epidermal growth factor receptor (EGFR) inhibitors cause skin inflammation with ensuing pain ⁴⁸. Acute herpetic neuralgia (neuropathic pain that occurs due to damage to a peripheral nerve caused by the the varicella zoster virus) occurs with a significantly increased incidence among cancer patients, especially those with blood cancers and those receiving immunosuppressive therapies ⁴⁹. The pain usually resolves within 2 months but can persist and become postherpetic neuralgia.

The palmar-plantar erythrodysesthesia syndrome is observed in association with continuously infused 5-FU, capecitabine ⁵⁰, liposomal doxorubicin ⁵¹, and paclitaxel ⁵².

Targeted agents such as sorafenib and sunitinib are also associated with hand-foot–like syndrome ⁵³. Patients develop tingling or burning in their palms and soles, followed by an erythematous rash. Management often requires discontinuing therapy or reducing the treatment dose.

Supportive care therapies pain

Supportive care therapies can cause pain, as typified by bisphosphonate-associated osteonecrosis of the jaw ⁵⁴. Corticosteroid use has also been associated with the development of avascular necrosis ⁵⁵.

Radiation-induced pain

Radiation is associated with several distinct pain syndromes. First, patients may experience pain from brachytherapy (a type of radiation therapy that involves placing radioactive devices near or inside a tumor to treat cancer) and from positioning during treatment (i.e., placement on a radiation treatment table). Second, delayed tissue damage such as mucositis, mucosal inflammation in areas receiving radiation, and skin inflammation (dermatitis) may be painful. Third, a temporary worsening of pain in the treated area (a pain flare) is a potential side effect of radiation treatment for bone metastases ⁵⁶. A randomized trial demonstrated that dexamethasone (8 mg on day of radiation therapy and daily for the following 4 days) reduces the incidence of pain flares, compared with placebo ⁵⁷.

What affects pain?

As well as the physical cause of the pain, your environment, fatigue levels, emotions and thoughts can affect how you feel and react to pain.

It’s important for your health care team to understand the way these factors affect you.

Where you are – things and people in your environment can have a positive or negative impact on your experience of pain.
How tired you feel – extreme tiredness (fatigue) can make it harder for you to manage pain. Lack of sleep can increase your pain. Ask your health care team for help if you are not sleeping well.
How you feel – you may worry or feel easily discouraged when in pain. Some people feel hopeless, helpless, embarrassed, angry, inadequate, irritable, anxious, frightened or frantic. You may notice your mood changes. Some people become more withdrawn and isolated.
What you’re thinking – how you think about pain can affect how you experience the pain, for example whether you believe it is overwhelming or manageable.

If the pain interferes with your life or is persistent, report it. It might help to keep track of your pain by jotting down:

How severe the pain is
What type of pain (stabbing, dull, achy) you have
Where you feel the pain
What brings on the pain
What makes the pain worse or better
What pain relief measures you use, such as medication, massage, and hot or cold packs, how they help and any side effects they cause

Using a pain-rating scale from 0 to 10 — with 0 being no pain and 10 being the worst pain imaginable — might help you to report your pain to your doctor.

Cancer pain diagnosis

Your health care team will ask you about your pain to determine the cause of your pain and find the best treatment. A complete assessment of pain requires screening for psychological distress, social disruption, and existential crises, in order to treat the pain effectively and to anticipate barriers to pain relief.

Patients’ descriptions of pain that seem out of proportion to the known pathology may reflect other syndromes such as depression and existential distress ⁵⁸.

Medical history

To learn about your pain, the health care team will ask you the following questions:

When did the pain start?
Where in your body do you feel pain or discomfort? You will be asked to show exactly where the pain is on your body or on a drawing of a body.
How would you describe the pain?
How long does the pain last?
What makes the pain better or worse?
How does it compare to pain you have felt in the past?
Have there been changes in where or when the pain occurs?
How strong is the pain? You will be asked to rate your pain between 1-10, with 10 being the strongest.
What does it feel like? For example, is it dull, throbbing, aching, shooting, stabbing or burning? Are there any pins and needles or tingling? Are there areas where it feels numb?
Does your pain spread from one area to another (radiate)?
When did the pain or discomfort begin?
How often are you in pain? How long does the pain last each time it occurs? (Try timing the pain). What makes the pain better or worse?
Is the pain worse during certain times of the day or night?
Do you have trouble sleeping, or do you feel tired, depressed, or anxious?
Do you have any flare-ups of pain?
Does pain get in the way of activities of daily life (e.g. eating, getting up, dressing, concentrating, bending down, walking, sitting for long periods, exercising, carrying things, driving, sleeping, having sex)?
What activities would you like to do if the pain improves?
How does the pain make you feel emotionally?
What pain relief methods have you tried? What helped or didn’t help?
Did you have any side effects from pain medicines?
What have you done in the past to relieve pain? How did this work?
What does the pain mean to you?

A family member or caregiver may be asked to give answers for a patient who has problems with speech, language, or understanding.

Your health care team will also review your health history, including the following information:

Past and current pain treatments.
Prognosis.
Other conditions you may have, such as kidney, liver, or heart disease.
Past and current use of nicotine, alcohol, or sleeping pills.
Personal or family history of substance use disorder.
Personal history of mental health disorders or abuse.
Your choices for your pain control plan.

The information you give your health care team will be used to decide how to help relieve your pain.

Pain assessment

Pain assessment involves both clinician observation and your pain report. The goal of the initial pain assessment is to characterize the underlying pathophysiologic mechanisms of your pain and to determine the intensity of your pain and its impact on your ability to function. Pain assessment includes a discussion about the your goals and your expectations for pain management, which also includes your pain history, pain intensity, quality of your pain, and location of your pain. For each pain location, the pattern of pain radiation is assessed. It is important to recognize that psychosocial issues (psychological issues includes your thought, your beliefs, your behavior and your surrounding social environment) can either worsen or reduce the experience of pain ⁵⁹. These psychosocial issues cannot be easily treated with pain medications; therefore, it is critical that your doctor include these in his/her initial and subsequent examinations of you to ensure referrals to appropriate treatment resources. Furthermore, cultural components may need to be incorporated into a multidimensional assessment of pain, including how culture influences the pain experience, pain communication, and healthcare provider response to pain expression ⁶⁰, ⁶¹, ⁶², ⁶³.

Also important is your doctor’s awareness of your current pain management treatment plan and how you have responded to the treatment; this includes how adequately the current treatment plan addresses any breakthrough or episodic pain. A full pain assessment also reviews previously attempted pain therapies and reasons for discontinuation; other associated symptoms such as sleep difficulties, fatigue, depression, and anxiety; functional impairment; and any relevant laboratory data and diagnostic imaging. A focused physical examination includes clinical observation of pain behaviors, pain location, and functional limitations ¹⁴.

Pain severity

You can use different pain scales to describe your pain and how it is affecting you. These can help your health care team find the best pain control methods for you.

There are different kinds of pain scales or tools to quantify the intensity of pain, including ⁶⁴, ¹⁴:

Word scale: Rates the pain from none or mild through to moderate or severe. For example, none, mild, moderate and severe pain
Number scale: Rates the pain from 1–10, where the higher the number, the worse the pain. For example, pain scale 0 to 10: where 0 = no pain; 10 = worst pain imaginable.
Activity tolerance scale: Rates how much the pain affects what you can do, for example thinking, walking, carrying things
Facial scale: Facial scales uses facial expressions to show how the pain makes you feel.

Physical and neurological exams

Physical and neurological exams will be done to help plan pain control.

The following exams will be done:

Physical exam: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual.
Neurological exam: A series of questions and tests to check the brain, spinal cord, and nerve function. The exam checks your mental status, coordination, and ability to walk normally, and how well the muscles, senses, and reflexes work. This may also be called a neuro exam or a neurologic exam.

Your health care team will also assess your psychological, social, and spiritual needs. Psychological and spiritual factors can exacerbate or reduce the experience of pain ¹⁴.

If your doctor suspects somatization, which is the manifestation of psychological distress by the presentation of physical symptoms such as pain, then referral for psychiatric or psychological evaluation is indicated.

Cancer pain management

The way cancer pain is managed depends on the cause, but relief is still possible even if the cause is unknown. Treatment may include drugs or non-drug therapies. In some cases, patients are referred to pain or palliative care specialists. Your health care team will work with you to decide whether the benefits of treatment outweigh any risks. They will also let you know how much relief to expect from your pain treatment. Your doctor will continue to ask you how well your treatment is working and make changes if needed.

Often a combination of methods is used to manage cancer pain, including ¹¹:

Medicines specifically for pain
Surgery, radiation therapy and cancer drug therapies
Procedures to block pain signals such as nerve blocks or spinal injections
Other therapies, such as physiotherapy, psychological support and complementary therapies
Pain management plans.

It might take time to find the right pain relief for you, and you may need to continue taking pain medicines while waiting for some treatments to take effect. Different pain relief methods might work at different times, so you may need to try a variety.

The World Health Organization (WHO) estimates that the right medicine, in the right dose, given at the right time, can relieve 80 to 90% of cancer pain ¹¹.

If you have a new pain, a sudden increase in pain or pain that doesn’t improve after taking medicines, let your doctor or nurse know. Like a cancer diagnosis, pain that is not well controlled can make you feel anxious or depressed.

Sometimes cancer pain can be difficult to relieve completely with medicines or you may need to stop taking a pain medicine because of its side effects. If you continue to have pain, let your health care team know. There are other ways to reduce your pain that don’t involve medicine. Often a combination of treatments and therapies are more effective than just one.

Cancer treatments can sometimes reduce pain by helping to remove its cause. This will depend on the cancer, the type of pain and where the pain is.

Pain can sometimes be managed with other medical procedures. This can include simple options such as nerve blocks to more complex procedures such as implanted pumps. These options are not suitable for everyone, but can be particularly useful for treating nerve pain or pain that has been difficult to control with other medicines.

Talk to your doctor about referring you to a pain specialist. The specialist can explain the risks and benefits of each procedure.

Cancer treatment aimed at relieving pain, rather than curing the disease, is called palliation or palliative treatment.

Cancer pain medicines

Medicines that relieve pain are called analgesics, also known as pain medicines or pain relievers ⁶⁵, ⁶⁶, ⁶⁷, ⁶⁸. Analgesics (pain relievers) do not affect the cause of your pain, but they can help reduce your pain. Different types of medicine may be used, depending on your type and intensity of your pain (e.g., mild, moderate, or severe pain).

There are different types of pain medicines or analgesics, including:

Non-opioids – often available over the counter without a prescription. Examples include acetaminophen (paracetamol) and non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen. Paracetamol (Tylenol) is used to help with bone pain, muscle pain, pain in the skin or in the lining of the mouth. Non-steroidal anti-inflammatory drugs (NSAIDs) are used to reduce inflammation or swelling.
Opioids – there are different types of opioids depending on the type of pain. Opioids need a prescription. Examples include oxycodone, morphine and fentanyl.
Adjuvant (add-on) analgesics – can help control some types of pain. Often used with non-opioid and opioid medicines.

Your health care team will compare the expected pain relief against possible side effects and the impact on your quality of life. Let them know what you’d like to be able to do, for example being able to stay awake during the day.

The aim is for pain to be continuously controlled. You should take your pain medicine as prescribed, even if that means taking medicine even when you don’t feel pain.

If pain lasts longer than a few days without much relief, or you are in more pain than usual, see your doctor. It’s better to get relief early rather than allowing it to get worse. This makes it easier to control and means you are likely to have less pain overall.

Your doctor will talk to you about how much medicine to take (the dose) and how often to take it (the frequency).

Many people believe they should put up with pain for as long as possible and only use pain medicines when it becomes unbearable. If you do this, it can mean that you are in pain when you don’t need to be.

There is no need to save pain medicines until your pain is severe. Severe pain can cause anxiety and difficulty sleeping. These things can make the pain feel worse and harder to control.

If you think your pain medicine isn’t working or the pain returns before the next dose, it’s important to let your doctor know. They may need to adjust the dose, prescribe a different medicine or give an extra dose of medicine. Don’t change the dose yourself.

Acetaminophen and Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Often initiated when a person has mild pain, acetaminophen and NSAIDs are useful in managing moderate and severe pain as adjunct (add-on) agents to opioids ¹⁴. No single NSAID is preferred over others, and all are better than placebo for analgesia ⁶⁹. As opioid adjuncts (add-ons), acetaminophen and NSAIDs have shown benefit both in improved analgesia and in decreased opioid use ¹⁴. These agents are used with care or avoided in older patients or those who have kidney, liver, or cardiac disease ⁶⁹.

While acetaminophen and NSAIDs provide pain relieve on their own, a number of randomized controlled trials have reported that the addition of either agent to opioids may improve pain control and decrease opioid need in cancer patients ⁶⁶, ⁶⁷, ⁶⁸. However, these benefits were not consistently observed across trials ⁷⁰, ⁷¹.

High-potency NSAIDs such as ketorolac and diclofenac are more studied and have shown benefit in the management of cancer pain. However, there are no comparative data with older agents to show superiority of one product over others. Prominent side effects of ketorolac and diclofenac are gastrointestinal irritation, ulcer formation, and dyspepsia. Other side effects of concern include heart toxicity, kidney toxicity, liver toxicity, and hematologic effects ⁷², ⁷³. Cyclooxygenase-2 (COX-2)–specific agents such as celecoxib may have a more favorable gastrointestinal side effect profile at a higher monetary cost ⁷². Long-term safety and efficacy data remain unclear ¹⁴.

Table 1. Acetaminophen and Selected Nonsteroidal Anti-Inflammatory (NSAIDs) Analgesics

Drug	Dosage	Comments	Reference(s)
Acetaminophen (paracetamol)	<4,000 mg/day	Dosed every 4 to 8 hours, depending on dose and product used.	⁶⁶
Celecoxib	200–400 mg/day	COX-2 specific. Minimal antiplatelet effects compared with nonselective NSAIDs.	⁷²
Diclofenac	100–200 mg/day	Available as immediate- and delayed/extended–release products.	⁷⁴
Ibuprofen	600–2,400 mg/day		⁷⁴
Ketoprofen	100–300 mg/day	Available as parenteral in some parts of the world, which may be preferred.	⁷².
Ketorolac	40–60 mg/day, generally dosed every 6 hours	Parenteral (IV, IM) ketorolac is used ≤5 days because of concerns about GI adverse events. May also be given PO.	⁷².

Abbreviations: COX-2 = cyclooxygenase-2; GI = gastrointestinal; IM = intramuscular; IV = intravenous; NSAIDs = nonsteroidal anti-inflammatory drugs; PO = by mouth.

[Source ¹⁴ ]

Opioids

Opioids are medicines made from the opium poppy or created in a laboratory. Opioids block pain messages between your brain and spinal cord and your body. Opioids can be used to reduce some types of pain, such as acute pain and chronic cancer pain. The use of opioids for the relief of moderate to severe cancer pain is considered necessary for most patients ⁶⁵.

There are different types of opioids and they come in varying strengths. The type you have depends on: what kind of pain you have; how much pain you are in; whether you can take oral (by mouth) medicines; other factors such as how well your kidney and liver work.

For moderate pain, weak opioids (e.g., codeine or tramadol) or lower doses of strong opioids (e.g., morphine, oxycodone, or hydromorphone) are often administered and frequently combined with nonopioid analgesics such as acetaminophen and NSAIDs ⁶⁵.
For severe pain, strong opioids are routinely used. Although no agent appears to be more effective than another, morphine is often considered the opioid of choice because of provider familiarity, broad availability, and lower cost ⁶⁵.

Opioids may include:

Hydrocodone (Vicodin).
Hydromorphone (Dilaudid).
Oxycodone (Oxycontin, Percocet).
Methadone (Dolophine).
Fentanyl skin patch (Duragesic).
Buprenorphine transdermal patch(Butrans).
Buprenorphine buccal film (Belbuca).
Buprenorphine (Suboxone).
Morphine (MS Contin).

In one well-designed review, most individuals with moderate to severe cancer pain obtained significant pain relief from oral morphine ⁷⁵. One study has also noted that low-dose morphine (up to 30 mg orally per day) provided better analgesia than did weak opioids (codeine, tramadol) ⁷⁶. A 2022 update to a Cochrane review of oxycodone for cancer-related pain concluded that there were no differences in pain intensity, pain relief, and adverse effects between oxycodone and other strong opioids, including morphine ⁷⁷. However, based on low certainty of evidence, constipation and hallucinations occurred less often with long-acting oxycodone than with long-acting morphine ⁷⁷.

The management of acute pain begins with an immediate-release opioid formulation. Once pain is stabilized, opioid consumption is converted to a extended-release or longer-acting opioid on the basis of the patient’s previous 24-hour opioid consumption. The morphine milligram equivalent (MME) can then be used to convert to an alternative opioid, if desired. Randomized controlled trials have shown that long-acting opioids given every 12 hours provide efficacy similar to that of scheduled short-acting opioids given every 4 hours ⁷⁸, ⁷⁹. The dosing of long-acting opioids may lead to increased adherence. This finding is based on evidence from a cross-sectional study showing that analgesic medications taken at longer dose intervals (e.g., 8, 12, or 24 hours) were associated with increased adherence, adjusting for pain, symptom, demographic, and setting variables in the model ⁸⁰. Use of the immediate-release product is continued for the management of breakthrough pain ⁶⁵.

During ongoing pain management, the immediate-release opioids inform the titration of long-acting medications. Rapid-acting oral, buccal, sublingual, transmucosal, rectal, and intranasal products are all acceptable for the treatment of breakthrough pain ¹⁴. In people who are unable to take oral medications, a subcutaneous method of delivery is as effective as the intravenous route for morphine and hydromorphone ¹⁴.

Opioids can affect people in different ways, but you may have some of the following common side effects:

Constipation – opioids slow down the muscle contractions that move food through your colon, which can cause hard faeces (stools or poo). To keep stools soft, your treatment team will suggest you take a laxative or stool softener at the same time as the opioids. Drinking 6–8 glasses of water a day, eating a high-fibre diet and getting some exercise can help.
Feeling sick (nausea) – this usually improves when you get used to the dose or can be relieved with other medicines. Sometimes you may need to try a different opioid.
Drowsiness – feeling sleepy is typical when you first start taking opioids, but usually improves once you are used to the dose. If you continue to feel drowsy, you may need to adjust the dose or change medicines. Alcohol can make drowsiness worse and is best avoided. Opiods can affect your ability to drive.
Dry mouth – opioids can reduce the amount of saliva in your mouth, which can cause tooth decay. Chewing gum or drinking plenty of liquids can help. Visit your dentist regularly.
Tiredness – your body may feel physically tired, so you may need to ask for help you with household tasks and other responsibilities. Research shows that stretching or a short walk helps you maintain a level of independence and can give you some energy.
Itchy skin – if you have itchy skin, sometimes it may feel so irritated that it is painful. A moisturiser may help, or ask your doctor if there is an anti-itch medicine or a different opioid you can try.
Poor appetite – you may not feel like eating. Small, frequent meals or snacks and supplement drinks may help. If the loss of appetite is ongoing, see a dietitian.
Breathing problems – opioids can slow your breathing, but this usually improves as your body gets used to the dose. Your doctor may advise you not to drink alcohol or take sleeping tablets.
Hallucinations (seeing or hearing things that aren’t there) – this is rare. It is important to tell your doctor immediately if this occurs.

Your health care team will closely monitor you while you’re using opioids. Let them know about any side effects you have. They will change the medicine if necessary.

If you stop taking opioids suddenly, you will usually have withdrawal symptoms or a withdrawal response. This is because your body has become used to the dose (physical dependence). Withdrawal symptoms may include:

agitation
nausea
abdominal cramping
diarrhoea
heart palpitations
sweating.

To avoid opioid withdrawal symptoms, your doctor will reduce your dose gradually to allow your body to adjust to the change in medicine. Don’t reduce your dose or stop taking opioids without talking to your doctor first. They will develop a plan to gradually reduce the opioid dose.

Table 2. Opioid Analgesics

Opioid Drug	Equianalgesic Dosing	Comments
Buprenorphine	No consensus.	Transdermal product and sublingual available. May cause less constipation and nausea than do other opioids.
Codeine	Oral: 200 mg	Maximum of 360 mg/d. Used with or without acetaminophen.
Fentanyl	Transdermal: 12 µg/h × 24 h ~ 25 mg oral morphine/day. Transmucosal: no consensus; varies by product.	Delivered transdermally, transmucosally, or intravenously. Cachectic patients may have decreased absorption from transdermal patch.
Hydrocodone	Immediate release formulation with acetaminophen: 20 mg	Equianalgesic dose calculations for extended-release products vary; see prescribing information.
Hydromorphone	Oral: 6-7.5 mg, IV: 1.5 mg
Methadone	Equianalgesic ratio varies widely by dose.	Used primarily for severe pain in non–opioid-naïve patients. Unusual pharmacokinetics require experienced practitioner.
Morphine	Oral: 30 mg, IV: 10 mg	Randomized trials supporting use. First-choice opioid because of familiarity, availability, and cost.
Oxycodone	20 mg	Randomized trials supporting use.
Oxymorphone	10 mg
Tapentadol	100 mg	Similar to morphine, 30-40 mg.
Tramadol	150 mg ~ 25 mg oral morphine	Use at <400 mg/d with or without acetaminophen. Used for moderate pain. Inhibits reuptake of norepinephrine and serotonin. Caution with concomitant antidepressant use.

[Source ¹⁴ ]

Table 3. Routes of Opioid Administration

Route	Agent	Comments
Buccal	Fentanyl	Used primarily for breakthrough pain.
Epidural	Opioids, local anesthetics	Consider if inadequate analgesia or intolerable side effects with oral or intravenous analgesics.
Intramuscular injection	Opioids, acetaminophen, ketorolac	Typically avoided because of pain from injection.
Intranasal	Fentanyl	Onset faster than that of transmucosal fentanyl or oral morphine. Used for breakthrough pain.
Intrathecal	Opioids	Consider if inadequate analgesia or intolerable side effects with oral or intravenous analgesics.
Intravenous	Most strong opioids (except oxycodone) and some nonsteroidal anti-inflammatory drugs (NSAIDs)	Availability varies by world region.
Oral	Most opioids except fentanyl and buprenorphine	Most common and preferred method of administration.
Rectal	Morphine, methadone	Onset similar to that of oral; possibly better absorption. May be useful for pediatric and end-of-life patients.
Subcutaneous	Morphine, fentanyl, hydromorphone, ketoprofen, methadone	Benefit similar to that of intravenous; considered an alternative if no oral capacity.
Sublingual	Fentanyl, buprenorphine, concentrated morphine solution, methadone	Used primarily for breakthrough pain.
Topical	Lidocaine	Primarily application of topical anesthetics.
Transdermal	Fentanyl, buprenorphine	Efficacy similar to that of oral agents for moderate to severe pain in opioid-naïve patients.
Transmucosal	Fentanyl	Used primarily for breakthrough pain.

[Source ¹⁴ ]

Rapid-onset fentanyl formulations

Rapid-onset opioids are developed to provide fast analgesia without using a parenteral route. Fentanyl, a synthetic opioid 50 to 100 times more potent than morphine, is available in a variety of delivery methods to offer additional options for management of breakthrough pain (Table 4) ⁸¹. Along with rapid onset of action, these products avoid first-pass liver metabolism and intestinal digestion.

All rapid-acting fentanyl products are intended for use only in patients already tolerant to opioids and are not initiated in opioid-naive patients ¹⁴. However, none are bioequivalent to others, making dose interchange complicated and requiring dose titration of each product individually, without regard to previous doses of another fentanyl product ¹⁴. The dose titration schedule is unique to each product, and it is critical that product information is reviewed individually when each product is used ¹⁴. The risk of addiction with these rapid-onset agents has not been elucidated. In the United States, prescription of these agents requires enrollment in the U.S. Food and Drug Administration’s (FDA’s) Risk Evaluation and Mitigation Strategies (REMS) program ¹⁴.

Table 4. Routes of Fentanyl Administration

Drug	Starting Dose (µg)	Tmax (median, minutes)	Comments	Evidence
Transmucosal fentanyl lozenges (Actiq, generic)	200	20–40	Lozenge on stick, rubbed against cheek. Sugar content may increase dental caries.	Multiple randomized controlled trials showing benefit over placebo and oral morphine.
Fentanyl buccal tablet (Fentora)	100, 200, or 400	35–45	Absorption may be affected by mucositis. Before use, wet mouth if dry.	randomized controlled trial showing benefit over placebo, and open-label study showing benefit for pain rescue; more rapid than oxycodone.
Fentanyl buccal film (Onsolis)	200	60	Before use, wet mouth if dry.	double blinded, placebo controlled, randomized controlled trial showing benefit.
Fentanyl nasal spray (Lazanda)	100	15–21	Vial contains residual fentanyl when empty, requiring special disposal. Do not use with decongestant sprays.	double blinded, placebo controlled, randomized controlled trial showed benefit. Open-label randomized controlled trial showed benefit over transmucosal fentanyl and oral morphine. Most rapid onset.
Fentanyl sublingual spray (Subsys)	100	40–75	Contains residual fentanyl when empty, requiring special disposal.	Open-label and placebo controlled randomized controlled trial showing benefit.
Fentanyl sublingual tablet (Abstral)	100	30–60	Absorption may be affected by mucositis. Before use, wet mouth if dry.	Multiple placebo controlled randomized controlled trials showing benefit.

Footnote: Tmax = time to maximum blood concentration.

[Source ¹⁴ ]

Methadone

Given the complexities related to methadone administration, it is important that this opioid be prescribed by experienced clinicians who can provide careful monitoring ¹⁴. Referral to a pain specialist or a palliative care team may be indicated ¹⁴.

Methadone is both a mu (μ) opioid receptor agonist and an N-methyl-D-aspartate (NMDA) receptor antagonist. Methadone can be given via multiple routes (oral, intravenous, subcutaneous, and rectal); has a long half-life (13 to 58 hours) and rapid onset of action; and is inexpensive, making it an attractive option for cancer pain control ¹⁴. Because of methadone’s NMDA properties, methadone may be particularly useful for the management of opioid-induced neurotoxicity (OIN), hyperalgesia, and neuropathic pain, although further studies are needed to confirm these theoretical benefits ¹⁴. Opioid-induced neurotoxicity (OIN) is a broad term used to encompass the neuropsychiatric effects that result from opioid use, including:

Sedation.
Hallucinations.
Delirium.
Myoclonus.
Seizures.
Hyperalgesia.

The mechanism behind opioid-induced neurotoxicity may be attributed to opioids’ anticholinergic activity, endocytosis of opioid receptors, and stimulation of N-methyl-D-aspartate (NMDA) receptors ⁸², ⁸³. Patients are at increased risk of opioid-induced neurotoxicity if they are receiving an opioid with active metabolites such as morphine or codeine, are older adults, have kidney dysfunction or active infection, or are dehydrated ¹⁴.

Methadone is safer than other opioids for patients with kidney dysfunction, given that it is minimally renally excreted ¹⁴. Methadone is preferred for those with known opioid allergies because it is a synthetic opioid. Additionally, it is long acting, whether given in crushed or liquid form, an important benefit when patients require drug administration via enteral tubes. However, methadone also has several distinct disadvantages, including drug interactions, the risk of QT prolongation, and a variable equianalgesic ratio, making rotation more challenging ¹⁴.

Methadone is metabolized by CYP2B6, CYP2C19, CYP3A4, and CYP2D6 ¹⁴. The principal enzyme responsible for methadone levels and drug clearance is CYP2B6 ⁸⁴. CYP3A4 inducers (e.g., certain anticonvulsants and antiretroviral agents) can potentially reduce its analgesic effect ⁸⁵. In contrast, enzyme inhibitors may increase methadone’s activity, including side effects. For clinicians, the potential for significant drug-drug interactions may mean that some medications need to be replaced and that patients need extra monitoring. Furthermore, because methadone is a substrate of P-glycoprotein, medications that inhibit the activity of this transporter, such as verapamil and quinidine, may increase methadone’s bioavailability ¹⁴.

Methadone is associated with QT prolongation ¹⁴. QT prolongation increases in patients receiving high doses (especially >100 mg/day) or with preexisting risk factors, including treatment with some anticancer agents. For patients with risk factors for QT prolongation, it is important to conduct a baseline electrocardiogram (ECG) before treatment with methadone. A follow-up ECG is recommended at 2 to 4 weeks after methadone initiation if the patient has known risk factors, with the occurrence of new risk factor(s) for all patients, and when the doses of methadone reach 30 to 40 mg/day and 100 mg/day for all patients regardless of risk, if consistent with goals of care ⁸⁵, ⁸⁴.

Because the equianalgesic ratio between methadone and other opioids is unpredictable, most health care professionals recommend starting at a low dose twice daily, with gradual dose escalation every 3 to 5 days or at longer intervals ⁸⁴. Short-acting opioids, not methadone, should also be available for breakthrough pain.

A systematic review has highlighted three approaches to methadone conversion in the literature ⁸⁶, ⁸⁷. However, the quality of the evidence was low, making it difficult to conclude which approach was superior ¹⁴. Rapid titration of methadone may result in delayed respiratory depression because of its long half-life ⁸⁸.

Medicinal cannabis

Medicinal cannabis is a medicine that comes from the cannabis plant also known as marijuana. Cannabis makes a resin (thick substance) that contains compounds called cannabinoids. The highest concentration of cannabinoids is found in the female flowers of the plant ⁸⁹. Two of these, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) – are found in most medicinal cannabis products. Cannabidiol (CBD) does not produce the characteristic altered consciousness associated with Cannabis. Cannabidiol (CBD) is thought to have potential therapeutic effectiveness and has recently been approved in the form of the pharmaceutical Epidiolex for the treatment of refractory seizure disorders in children. Other cannabinoids that are being investigated for potential medical benefits include cannabinol (CBN), cannabigerol (CBG), and tetrahydrocannabivarin (THCV).

Cannabinoids are chemicals that act on certain receptors found in your brain and spinal cord (central nervous system), similar to how opioids interact with your body. Research studies have looked at the potential benefits of using medicinal cannabis to relieve symptoms and treatment side effects of cancer. However, the U.S. Food and Drug Administration (FDA) has not approved Cannabis (marijuana) as a treatment for cancer, side effect of cancer therapy or any other medical condition. Two cannabinoids (dronabinol and nabilone) are approved by the FDA for the treatment of nausea and vomiting caused by chemotherapy in patients who have not responded to antiemetic therapy.

By federal law, possessing Cannabis (marijuana) is illegal in the United States outside of approved research settings. Recently, a growing number of states, territories, and the District of Columbia have passed laws to legalize medical and/or recreational marijuana ⁹⁰. And many cancer patients turn to medical Cannabis in states where it has not been legalized. Researchers from the Medical University of South Carolina conducted a survey study that explored the prevalence, patterns, and motivations behind Cannabis use among cancer patients and survivors in a state without legal access to Cannabis as of 2023 ⁹¹. Despite the absence of legal access, a significant proportion of cancer patients reported using Cannabis for symptom management including pain, nausea, and other symptoms ⁹¹. Moreover, cancer patients reported improvements in mood, sleep, and overall better quality of life. This study gives insight into why many cancer patients and survivors use Cannabis for symptom management, highlighting the importance of understanding and addressing patient’ needs even in states with no legal access to Cannabis.

The potential benefits of medicinal Cannabis for people living with cancer include the following ⁹²:

Antiemetic effects (a drug that prevents or reduces nausea and vomiting).
Appetite stimulation.
Pain relief.
Improved sleep.

In a survey of 934 adult cancer patients at a National Cancer Institute, the top five reasons for Cannabis use included sleep (57%), stress (56%), pain (51%), appetite (49%), and nausea (38%) ⁹³. It appears that doctors caring for patients with cancer in the United States who recommend medicinal Cannabis do so predominantly for symptom management ⁹⁴.

Data from 2,970 Israeli cancer patients who used government-issued Cannabis were collected over a 6-month period to assess for improvement in baseline symptoms ⁹⁵. The most improved symptoms from baseline in large population of patients with cancer include the following ⁹⁵:

Nausea and vomiting (91.0%).
Sleep disorders (87.5%).
Restlessness (87.5%).
Anxiety and depression (84.2%).
Pruritus (82.1%).
Headaches (81.4%).

Before treatment initiation, 52.9% of patients reported pain scores in the 8 to 10 range, while only 4.6% of patients reported this intensity at the 6-month assessment time point ⁹⁵. It is difficult to assess from the observational data if the improvements were caused by the Cannabis or the cancer treatment ⁹⁵. Similarly, a study of a subset of cancer patients in the Minnesota medical Cannabis program explored changes in the severity of eight symptoms (i.e., anxiety, appetite loss, depression, disturbed sleep, fatigue, nausea, pain, and vomiting) experienced by these patients ⁹⁶. Significant symptomatic improvements were noted (38.4% to 56.2%) in patients with each symptom. Because of the observational and uncontrolled nature of this study, the findings are not generalizable, but as the authors suggested, may be useful in designing more rigorous research studies in the future ⁹⁶.

Forty-two percent of women (257 of 612) with a diagnosis of breast cancer within the past 5 years who participated in an anonymous online survey reported using Cannabis for the relief of symptoms, particularly pain (78%), insomnia (70%), anxiety (57%), stress (51%), and nausea and vomiting (46%) ⁹⁷. Among Cannabis users, 79% used Cannabis during their cancer treatment, and 75% reported that Cannabis was extremely or very helpful for relieving symptoms ⁹⁷. Forty-nine percent of Cannabis users felt that Cannabis could be useful in treating the cancer itself. Only 39% of the participants reported discussing Cannabis use with their physicians ⁹⁷.

Few studies have been done to find out how Cannabis interacts with conventional treatment ⁹⁸. A retrospective observational study in Israel showed that Cannabis reduced the effect of immunotherapy ⁹⁸. A prospective observational study of immunotherapy and Cannabis in patients with metastatic cancer reported that the Cannabis users did not benefit from immunotherapy as much as those who did not use Cannabis ⁹⁹, ⁹⁸. 140 patients with advanced melanoma, non-small cell lung cancer, and renal cell carcinoma received the checkpoint inhibitor nivolumab (89 patients received nivolumab alone and 51 patients received nivolumab plus Cannabis) ⁹⁹. Cannabis was the only significant factor that reduced the response rate to immunotherapy (37.5% in patients who received nivolumab alone compared with 15.9% in patients who received nivolumab plus Cannabis) ⁹⁹. There was no difference in progression-free survival or overall survival. A subsequent prospective observational study from the same investigators followed 102 patients with metastatic cancers initiating immunotherapy ¹⁰⁰. 68 patients received immunotherapy alone while 34 patients used Cannabis during immunotherapy ¹⁰⁰. Over half of the patients in each group had stage 4 non-small cell lung cancer. Cannabis users were less likely to receive immunotherapy as a first-line intervention (24%) compared with nonusers (46%) ¹⁰⁰. Cannabis users showed a significantly lower percentage of clinical benefit (39% of Cannabis users with complete or partial responses or stable disease compared with 59% of nonusers) ¹⁰⁰. In this analysis, the median time to tumor progression was 3.4 months in Cannabis users compared with 13.1 months in nonusers and the overall survival was 6.4 months in Cannabis users compared with 28.5 months in nonusers ¹⁰⁰. The investigators also noted that Cannabis users reported a lower rate of overall treatment-related adverse experiences compared with nonusers, with fewer immune-related adverse events ¹⁰⁰. The investigators postulated that this finding may be related to the possible immunosuppressive effects of Cannabis and concluded that Cannabis consumption should be carefully considered in patients with advanced cancers who are treated with immunotherapy ¹⁰⁰. Limitations noted by the authors that may be confounders in this analysis include the observational nature of the study, the relatively small sample size, and the high heterogeneity of the participants ¹⁰⁰.

Side effects of Cannabis and cannabinoids can include ⁹⁸:

Fast heartbeat.
Low blood pressure.
Muscle relaxation.
Bloodshot eyes.
Slow digestion.
Dizziness.
Drowsiness.
Depression.
Hallucinations.
Paranoia.

Both Cannabis and cannabinoids may be addictive. Symptoms of withdrawal from cannabinoids include ⁹⁸:

Being easily annoyed or angered.
Trouble sleeping.
Unable to stay still.
Hot flashes.
Nausea and cramping (rare).

These symptoms are mild compared with symptoms of withdrawal from opiates and usually go away after a few days ⁹⁸.

Antiemetic Effects

Preclinical research suggests that emetic circuitry is controlled by endocannabinoids ⁹⁰. The antiemetic action of cannabinoids is believed to be mediated via interaction with the 5-hydroxytryptamine 3 (5-HT3) receptor ⁹⁰. Cannabinoid 1 (CB1) receptors and 5-hydroxytryptamine 3 (5-HT3) receptors are colocalized on gamma-aminobutyric acid (GABA)-ergic neurons, where they have opposite effects on GABA release ¹⁰¹. There also may be direct inhibition of 5-HT3 gated ion currents through non–CB1 receptor pathways. CB1 receptor antagonists have been shown to elicit emesis in the least shrew that is reversed by cannabinoid agonists. ¹⁰². The involvement of CB1 receptor in vomiting prevention has been shown by the ability of CB1 antagonists to reverse the effects of delta-9-tetrahydrocannabinol (THC) and other synthetic cannabinoid CB1 agonists in suppressing vomiting caused by cisplatin in the house musk shrew and lithium chloride in the least shrew. In the latter model, cannabidiol (CBD) was also shown to be efficacious ¹⁰³, ¹⁰⁴.

Cannabis and cannabinoids have been studied in the treatment of nausea and vomiting caused by cancer or cancer treatment ⁹⁸:

Delta-9-tetrahydrocannabinol (THC) taken by mouth: Two cannabinoid drugs, dronabinol and nabilone, approved by the U.S. Food and Drug Administration (FDA), are given to treat nausea and vomiting caused by chemotherapy in patients who have not responded to standard antiemetic therapy. Clinical trials have shown that both dronabinol and nabilone work as well as or better than other drugs to relieve nausea and vomiting.
Oral spray with delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD): Nabiximols, a Cannabis extract given as a mouth spray, was shown in a small randomized, placebo-controlled, double-blinded clinical trial in Spain to treat nausea and vomiting caused by chemotherapy.
Inhaled Cannabis: Small trials have studied inhaled Cannabis for the treatment of nausea and vomiting caused by chemotherapy.

Appetite Stimulation

Many animal studies have previously demonstrated that delta-9-tetrahydrocannabinol (THC) and other cannabinoids have a stimulatory effect on appetite and increase food intake. It is believed that the endogenous cannabinoid system may serve as a regulator of feeding behavior. The endogenous cannabinoid anandamide potently enhances appetite in mice ¹⁰⁵. Moreover, CB1 receptors in the hypothalamus may be involved in the motivational or reward aspects of eating ¹⁰⁶.

The ability of cannabinoids to increase appetite has been studied ⁹⁸:

Delta-9-tetrahydrocannabinol (THC) taken by mouth: A clinical trial compared delta-9-THC (dronabinol) and a standard drug (megestrol, an appetite stimulant) in patients with advanced cancer and loss of appetite. Results showed that delta-9-THC did not help increase appetite or weight gain in patients with advanced cancer compared with megestrol.
Inhaled Cannabis: There are no published studies of the effect of inhaled Cannabis on patients with cancer who have loss of appetite.

Pain relief

Understanding the mechanism of cannabinoid-induced analgesia has been increased through the study of cannabinoid receptors, endocannabinoids, and synthetic agonists and antagonists. Cannabinoids produce analgesia through supraspinal, spinal, and peripheral modes of action, acting on both ascending and descending pain pathways ¹⁰⁷. The CB1 receptor is found in both the central nervous system (brain and spinal cord) and in peripheral nerve terminals. Similar to opioid receptors, increased levels of the CB1 receptor are found in regions of the brain that regulate nociceptive processing ¹⁰⁸. CB2 receptors, located predominantly in peripheral tissue, exist at very low levels in the central nervous system (brain and spinal cord). With the development of receptor-specific antagonists, additional information about the roles of the receptors and endogenous cannabinoids in the modulation of pain has been obtained ¹⁰⁹, ¹¹⁰.

Cannabinoids may also contribute to pain modulation through an anti-inflammatory mechanism; a CB2 effect with cannabinoids acting on mast cell receptors to attenuate the release of inflammatory agents, such as histamine and serotonin, and on keratinocytes to enhance the release of analgesic opioids has been described ¹¹¹, ¹¹², ¹¹³. One study reported that the efficacy of synthetic CB1- and CB2-receptor agonists were comparable with the efficacy of morphine in a murine model of tumor pain ¹¹⁴.

Cannabinoids have been shown to prevent chemotherapy-induced neuropathy in animal models exposed to paclitaxel, vincristine, or cisplatin ¹¹⁵, ¹¹⁶, ¹¹⁷.

Cannabis and cannabinoids have been studied in the treatment of pain ⁹⁸:

Vaporized Cannabis with opioids: In a study of 21 patients with chronic pain, vaporized Cannabis given with morphine relieved pain better than morphine alone, while vaporized Cannabis given with oxycodone did not give greater pain relief. Further studies are needed.
Inhaled Cannabis: Randomized controlled trials of inhaled Cannabis in patients with peripheral neuropathy or other nerve pain found that inhaled Cannabis relieved pain better than inhaled placebo. A retrospective study of patients who received an anticancer drug for gastrointestinal cancers found that those who also inhaled Cannabis had less nerve pain, including those who took Cannabis before they began the anticancer drug.
Cannabis plant extract: A study of Cannabis extract that was sprayed under the tongue found it helped patients with advanced cancer whose pain was not relieved by strong opioids alone. In another study, patients who were given lower doses of cannabinoid spray showed better pain control and less sleep loss than patients who received a placebo. Control of cancer-related pain in some patients was better without the need for higher doses of Cannabis extract spray or higher doses of their other pain medicines. Adverse events were related to high doses of cannabinoid spray.
Delta-9-tetrahydrocannabinol (THC) taken by mouth: Two small clinical trials of oral delta-9-THC showed that it relieved cancer pain. In the first study, patients had good pain relief, less nausea and vomiting, and better appetite. A second study showed that delta-9-THC could relieve pain as well as codeine. An observational study of nabilone also reported less cancer pain along with less nausea, anxiety, and distress when compared with no treatment. Neither dronabinol nor nabilone is approved by the FDA for pain relief.
Non-specific Cannabis products: A randomized controlled trial studied patients with advanced cancer who used Cannabis in addition to opioids early in treatment compared to patients who added Cannabis later in treatment. Patients who were given Cannabis later showed an increase in opioid use during the 3-month study. Opioid use was stable in patients who began Cannabis use earlier. There were no changes in symptoms or adverse effects between the two groups. Over 100 different Cannabis products were given during the study.

Anxiety and sleep

The endocannabinoid system is believed to be centrally involved in the regulation of mood and the extinction of aversive memories. Animal studies have shown cannabidiol (CBD) to have anxiolytic properties. It was shown in rats that these anxiolytic properties are mediated through unknown mechanisms ¹¹⁸. Anxiolytic effects of cannabidiol (CBD) have been shown in several animal models ¹¹⁹, ¹²⁰.

The endocannabinoid system has also been shown to play a key role in the modulation of the sleep-waking cycle in rats ¹²¹, ¹²².

Cannabis and cannabinoids have been studied in the treatment of anxiety ⁹⁸:

Inhaled Cannabis: A small case series found that patients who inhaled Cannabis had improved mood, improved sense of well-being, and less anxiety. In another study, 74 patients newly diagnosed with head and neck cancer who were Cannabis users were matched to 74 nonusers. The Cannabis users had lower anxiety or depression and less pain or discomfort than the nonusers. The Cannabis users were also less tired, had more appetite, and reported greater feelings of well-being.
Oral Cannabis oil: A randomized controlled trial studied two different doses of oral Cannabis oil in patients with brain cancer that could not be removed by surgery or had come back. Physical side effects such as sleep were noted to be better in the 1:1 ratio dose group. Both doses were well tolerated without any adverse effects.

Relief of cancer symptoms with cannabidiol oil

Cannabidiol (CBD) is a Cannabis compound that does not produce a “high” linked to Cannabis, but is felt to have possible health benefits. CBD oil has been studied for relief of cancer symptoms. A randomized, placebo-controlled, double-blinded trial of 144 patients studied the effect of oral CBD oil on cancer symptoms ⁹⁸. All patients were treated by palliative care specialists. No difference was found in relief of cancer symptoms between the oral CBD group and the placebo group after 14 and 28 days. This trial has several limiting factors involving patients who participated, low levels of symptoms, and high levels of patients who did not complete the study ⁹⁸.

Adjuvant (add-on) pain medications

Adjuvant (add-on) pain medications used in conjunction with opioids have been found to be beneficial in the management of many cancer pain syndromes; however, they are currently
underutilized. Adjuvant medicines may be necessary to enhance pain relief such as corticosteroids in nerve compression or sedatives and antidepressants to treat concomitant psychological disturbances such as insomnia, anxiety and depression ¹²³.

Gabapentin and pregabalin

Gabapentin and pregabalin are structurally related to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) but have no effect on GABA binding. Instead, they bind to the alpha2delta-1 subunit of voltage-gated calcium channels, which may result in decreased neuronal excitability in pain-associated sensory neurons ¹⁴. These drugs have been widely studied in the treatment of neuropathic pain syndromes and as adjunctive agents with opioids.

Gabapentin and pregabalin may cause the following symptoms ¹²⁴:

Sedation.
Dizziness.
Peripheral edema.
Nausea.
Ataxia.
Dry mouth.

Gradual upward titration of gabapentin to a maximum of 3,600 mg per day (in 3 divided doses) and pregabalin to 300 mg per day can help with dose-dependent sedation and dizziness ¹⁴. In addition, starting doses of gabapentin may be given at bedtime to assist with tolerating any sedation. Doses of both agents need to be adjusted for patients with kdiney dysfunction ¹²⁴

Venlafaxine and duloxetine

The antidepressant medications venlafaxine and duloxetine have demonstrated some efficacy in the treatment of neuropathic pain syndromes ¹⁴. Venlafaxine and duloxetine are serotonin and norepinephrine reuptake inhibitors (SNRIs) originally approved for depression; however, both are used off-label for the treatment of chemotherapy-induced peripheral neuropathy (CIPN) ¹⁴. In addition, duloxetine is indicated for musculoskeletal pain. Both serotonin and norepinephrine have important roles in analgesia.

Common dosing for duloxetine ranges from 30 mg to 60 mg per day ¹⁴.

Duloxetine side effects include the following ¹²⁵:

Nausea.
Headache.
Fatigue.
Dry mouth.
Constipation.

Duloxetine is avoided in patients with liver impairment and severe kidney impairment, and it carries an increased risk of bleeding.

Venlafaxine inhibits serotonin reuptake more intensely at low doses, and norepinephrine more intensely at higher doses; higher doses may be necessary for relief of chemotherapy-induced peripheral neuropathy (CIPN) ¹²⁶. Venlafaxine can be started at 37.5 mg, with a maximum dose of 225 mg per day ¹⁴. Adverse effects include nausea, vomiting, headache, somnolence, and hypertension at higher doses. These effects decrease with the use of the long-acting formulations. Venlafaxine is used with caution in patients with bipolar disorder (BPD) or a history of seizures and is dose-adjusted for patients with kidney or liver insufficiency ¹⁴. If the decision is made to discontinue either venlafaxine or duloxetine, a slow tapering course may help to minimize withdrawal symptoms ¹⁴.

Tricyclic antidepressants (TCAs)

Tricyclic antidepressants (TCAs) such as amitriptyline, desipramine, and nortriptyline are used to treat many neuropathic pain syndromes. These drugs enhance pain inhibitory pathways by blocking serotonin and norepinephrine reuptake ¹⁴.

Tricyclic antidepressants (TCAs) have anticholinergic, antihistaminic, and antiadrenergic effects that result in the following:

Dry mouth.
Drowsiness.
Weight gain.
Orthostatic hypotension.

Significant drug interactions are a concern, including interactions with anticholinergics, psychoactive medications, class IC antiarrhythmics, and selective serotonin reuptake inhibitors (SSRIs). Because of these adverse effects and drug interactions, tricyclic antidepressants (TCAs) are used with caution in older patients, patients with seizure disorders, and those with preexisting heart disease.

Corticosteroids

There is a lack of high-quality data demonstrating the efficacy of corticosteroids in treating cancer pain ¹⁴. A systematic review of the literature resulted in four randomized controlled trials and concluded that there is low-grade evidence to suggest corticosteroids have moderate activity in the treatment of cancer pain ¹²⁷. A small but well-designed study showed no benefit to adding corticosteroids to opioid analgesia in the short term (7 days) ¹²⁸.

Despite the lack of good evidence, corticosteroids are often used in the clinical setting ¹⁴. Corticosteroids (dexamethasone, methylprednisolone, and prednisone) may be used as adjuvant (add-on) analgesics for cancer pain originating in bone, neuropathy, and malignant intestinal obstruction ¹⁴. Mechanisms of analgesic action include decreased inflammation, decreased peritumoral edema, and modulation of neural activity and plasticity ¹²⁹.

Although there is no established corticosteroid dose in this setting, recommendations range from a trial of low-dose therapy such as dexamethasone 1 mg to 2 mg or prednisone 5 mg to 10 mg once or twice daily ¹³⁰, to dexamethasone 10 mg twice daily ¹³¹. A randomized trial demonstrated that dexamethasone (8 mg on day of radiation therapy and daily for the following 4 days) reduces the incidence of pain flares, compared with placebo ⁵⁷.

The immediate side effects of corticosteroid use include:

Hyperglycemia.
Insomnia.
Immunosuppression.
Psychiatric disorders.

Serious long-term effects—myopathy, peptic ulceration, osteoporosis, and Cushing syndrome—encourage short-term use of corticosteroids ¹⁴. If taken for more than 3 weeks, corticosteroids are tapered upon improvement in pain, if possible ¹⁴. If corticosteroids are to be continued long term, anti-infective prophylaxis can be considered ¹⁴. Dexamethasone is preferred because it has reduced mineralocorticoid effects, resulting in reduced fluid retention; however, it does exhibit cytochrome P450–mediated drug interactions ¹⁴.

Ketamine

Ketamine is an FDA-approved dissociative general anesthetic that has been used off-label in subanesthetic doses to treat opioid-refractory cancer pain ¹⁴. A 2012 Cochrane review of ketamine used as an adjuvant (add-on) to opioids in the treatment of cancer pain concluded there is insufficient evidence to evaluate its efficacy in this setting ¹³².

Lack of demonstrated clinical benefit, significant adverse events, and CYP3A4-associated drug interactions limit ketamine’s utility in the treatment of cancer pain ¹⁴. Ketamine is an NMDA receptor antagonist that, at low doses, produces analgesia, modulates central sensitization, and circumvents opioid tolerance. However, a randomized placebo-controlled trial of subcutaneous ketamine in patients with chronic uncontrolled cancer pain failed to show a net clinical benefit when ketamine was added to the patients’ opioid regimen ¹³³.

Ketamine adverse drug reactions include the following:

Hypertension.
Tachycardia.
Psychotomimetic effects.
Increased intracranial and intraocular pressure.
Sedation.
Delirium.
Impaired bladder function.

Surgery

Whether surgery is an option depends on several factors, including your overall health and fitness. Some people may have an operation to remove part or all of a tumour from the body. It can be a major, invasive operation or a relatively minor procedure. Surgery can improve quality of life if the pain is caused by a tumor pressing on a nerve or blocking an organ. Examples include unblocking the bile duct to relieve jaundice which can occur with pancreatic cancer, or removing a bowel obstruction which can occur with ovarian or bowel cancer.

Radiation therapy

Radiation therapy uses a controlled dose of radiation, usually in the form of x-ray beams, to kill or damage cancer cells so they cannot grow, multiply or spread. Radiation therapy will cause tumors to shrink and stop causing discomfort. For example, radiation therapy can relieve pain if cancer has spread to your bones, or headaches if cancer has increased the pressure in your brain.

When radiation is used for pain management, often only a short course of treatment of a few days to a week or two is required. It can take a few days or weeks before your pain improves. You will need to keep taking your pain medicines during this time. In some cases, the pain may get worse before it gets better. Your doctor will be able to prescribe different medicines to manage this.

The dose of radiation therapy used to treat pain is low, and the treatment has very few side effects other than tiredness.

Cancer drug therapies

Drug therapies for cancer may be used to control the cancer’s growth and stop it spreading. The drugs reach cancer cells throughout your body, this is called systemic treatment, and it includes:

Chemotherapy – use of drugs to kill cancer cells or slow their growth
Hormone therapy – use of synthetic hormones to stop the body’s natural hormones from helping some cancers to grow
Targeted therapy – use of drugs to attack specific features of cancer cells to stop the cancer growing and spreading
Immunotherapy – use of the body’s own immune system to fight cancer.

In some cases, drug therapies can shrink tumors that are causing pain, such as a tumor on the spine that cannot be operated on, to help improve quality of life.

In other cases, drug therapies can reduce inflammation and relieve symptoms of advanced cancer, such as bone pain. They can also be used to prevent the cancer coming back.

Bone pain treatment

Bone pain due to metastatic cancer or stage 4 cancer (when cancer cells spread from the original tumor to other parts of the body) is one of the most common causes of pain in cancer patients ¹³⁴, ¹³⁵. Bone is highly innervated tissue with receptors sensitive to mechanical damage ¹³⁶. The entrapment of nerve fibers in the collapsing bony matrix caused by increased osteoclastic activity (break down bone tissue) and the release of inflammatory cytokines by cancer cells and immune cells are also central to the pathophysiology of bone pain ¹³⁶. Patients typically describe bone pain due to metastatic cancer or stage 4 cancer as continuous, deep, and throbbing, with brief episodes of more-severe pain often precipitated by movement (i.e., a type of incident pain) ¹⁴.

Most patients will require morphine or an equivalent opioid for adequate pain relief, although incident pain (type of breakthrough pain related to movement increasing bone pain from metastatic disease) is less responsive ¹⁴. Adjunctive (add-on) agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are often prescribed and appear moderately effective and safe ⁷⁴.

In addition to providing pain relieve, additional treatments are needed to prevent further weakening of skeletal integrity, which may lead to loss of functional status or further pain. Bone-targeting agents such as the bisphosphonates (zoledronic acid or pamidronate) or denosumab have been shown to reduce future skeletal-related events and to reduce the likelihood of increased pain or increased use of opioids in patients with advanced cancer ¹³⁷.

Palliative radiation therapy produces complete or partial pain relief in up to 80% of treated patients; the median duration of relief exceeds 6 months ¹³⁸.

Lastly, orthopedic consultation is frequently necessary to determine whether operative intervention is required to prevent and/or treat pathological fractures ¹⁴.

Bisphosphonates and denosumab

Bisphosphonates are drugs that inhibits osteoclastic bone resorption (bone breakdown), decreasing bone pain and skeletal-related events associated with cancer that has metastasized to the bone ¹⁴. Pamidronate and zoledronic acid decrease cancer-related bone pain, decrease analgesic use, and improve quality of life in patients with bone metastases ¹³⁹, ¹⁴⁰, ¹⁴¹, ¹⁴². American Society of Clinical Oncology guidelines for the use of these bone-modifying agents in patients with breast cancer and multiple myeloma specify they should be used not as monotherapy but as part of a treatment regimen that includes analgesics and nonpharmacological interventions ¹⁴³, ¹⁴⁴. Bisphosphonates can cause an acute phase reaction characterized by fever, flu-like symptoms, arthralgia, and myalgia that may last for up to 3 days after administration. Additional side effects include kidney toxicity, electrolyte imbalances, and osteonecrosis of the jaw ¹⁴⁵, ¹⁴⁶, ¹⁴⁷. Doses are adjusted for patients with kidney dysfunction.

A single dose of ibandronate 6 mg was compared with a single fraction of radiation for localized metastatic bone pain in 470 prostate cancer patients ¹⁴⁸. Patients were allowed to cross over if they failed to respond at 4 weeks. Pain was assessed at 4, 8, 12, 26, and 52 weeks. Pain response was not statistically different between the two groups at 4 or 12 weeks; however, a faster onset of pain response was seen in the radiation therapy group ¹⁴⁸. Interestingly, patients who crossed over and received both treatments had a longer overall survival than did patients who did not cross over ¹⁴⁸. The authors concluded that ibandronate provides a feasible alternative to radiation therapy for the treatment of metastatic bone pain when radiation therapy is not an option ¹⁴⁸.

Denosumab is a fully human monoclonal antibody that inhibits the receptor activator of nuclear factor kappa beta ligand (RANKL), prevents osteoclast precursor activation, and is primarily used in the treatment of bone metastases. A review of six trials comparing zoledronic acid with denosumab demonstrated a greater delay in time to worsening pain for denosumab ¹⁴⁹. Compared with zoledronic acid, denosumab has similar side effects with less kidney toxicity and increased hypocalcemia. There is no adjustment for kidney dysfunction; however, patients with a creatinine clearance lower than 30 mL/min are at a higher risk of developing hypocalcemia. Denosumab may be more convenient than zoledronic acid because it is a subcutaneous injection and not an intravenous infusion; however, it is significantly less cost-effective ¹⁵⁰.

Palliative radiation therapy

Pain related to bone metastases, skin lesions, or isolated tumor lesions may be relieved by a short course of radiation therapy ¹⁵¹. Patient selection can be important regarding the likelihood of benefit from radiation therapy ¹⁵¹. In one study, patients with hematologic tumors, a neuropathic pain, and no previous treatment with opioid analgesics before radiation therapy were more likely to experience pain palliation after radiation therapy ¹⁵².

For bone metastases, radiation is often delivered as 8 gray (Gy) in a single fraction, 20 Gy in five fractions, 24 Gy in six fractions, or 30 Gy in ten fractions ¹⁴. A Cochrane review that included 11 randomized trials consisting of 3,435 patients ¹⁵³. showed that single-fraction radiation therapy for bone pain provided a similar overall response rate (60% vs. 59%) and complete response rate (34% vs. 32%), compared with multifraction radiation therapy. However, patients who received single-fraction radiation therapy had a higher rate of re-treatment (22% vs. 7%) and a higher rate of pathological fracture (3% vs. 1.6%) ¹⁵³. This finding was consistent with other systematic reviews ¹⁵⁴. In the Dutch Bone Metastasis Study ¹⁵⁵, ¹⁵⁶, the average time to first pain relief was 3 weeks; the peak effect was achieved in 4 to 6 weeks; and the mean duration of response was approximately 30 weeks.

Single-fraction radiation has several potential advantages:

Greater convenience.
Lower cost.
Less breakthrough pain associated with transportation to the radiation facility and with getting on and off the radiation table.

A study published in 2019 ¹⁵⁷ evaluated a higher-dosage (Gy) single-fraction stereotactic body radiation therapy (SBRT) versus multifraction radiation therapy (MFRT), in which patients with primarily nonspine bone metastases received either single-fraction SBRT (12 Gy for ≥4-cm lesions or 16 Gy for <4-cm lesions) or MFRT to 30 Gy in ten fractions. This randomized phase 2 trial demonstrated improved pain at 2 weeks, 3 months, and 9 months, without differences in treatment-related toxicity and with no increase with re-treatment rates that had been seen in previous single-fraction studies, done largely with 8 Gy ¹⁵⁷. Patients who received the higher-dose single-fraction stereotactic body radiation therapy (SBRT) had improved 1- and 2-year survival rates. The authors concluded that the higher dose of single-fraction single-fraction stereotactic body radiation therapy (SBRT) is safe and suggested that this could become the standard of care, if confirmed in phase 3 studies ¹⁵⁷.

Re-irradiation may be considered for selected patients who derive no or partial pain relief with first-time radiation therapy, or who develop worsening pain after an initial response ¹⁴. Re-irradiation typically occurs at least 4 weeks after the first radiation treatment ¹⁴. A systematic review that examined re-irradiation for bone metastases included 15 studies and reported a complete response rate of 20% and a partial response rate of 50% ¹⁵⁸. Re-irradiation was generally well tolerated ¹⁵⁸. In a secondary analysis of the National Cancer Institute of Canada Clinical Trials Group Symptom Control Trial SC.20 ¹⁵⁹, which examined outcomes of 847 patients who underwent palliative re-irradiation of painful bone metastases, the team found no differences in pain relief or side effects across age or gender demographics. Women and younger patients reported greater improvements in quality of life (QOL) ¹⁵⁹. Serious adverse effects such as spinal cord compression and pathological fracture were infrequent (<3%) ¹⁵⁹. A randomized controlled trial compared a single fraction (8 Gy) with multiple fractions (20 Gy over 5 days) of re-irradiation and found similar response rates at 2 months in an intention-to-treat analysis (28% vs. 32%) ¹⁶⁰.

A potential side effect of palliative radiation for painful bone metastases is a temporary increase in pain level, i.e., a pain flare ¹⁴. Pain flares occur in about 40% of patients and may be quite distressing ¹⁴. One study randomly assigned 298 patients, who were scheduled to receive a single 8-Gy dose of radiation, to receive either placebo or dexamethasone 8 mg on days 0 to 4 ⁵⁷. Fewer patients in the dexamethasone group experienced pain flares (26% vs. 35%) ⁵⁷. Potentially serious hyperglycemia was seen in only two patients in the dexamethasone group. The study supports the use of prophylactic dexamethasone in this setting ⁵⁷, ¹⁴.

In a secondary analysis of the National Cancer Institute of Canada Clinical Trials Group Symptom Control Trial SC.23, the authors investigated pain and quality of life (QOL) at days 10 and 42 after radiation therapy, with the aim of determining whether there are differences in quality of life (QOL) between responders and nonresponders ¹⁶¹. Overall, 40% of patients experienced pain reduction and improvement in quality of life at day 10, with continued improvement in quality of life at day 42 ¹⁶¹. Compared with baseline, patients responding to radiation experienced significantly increased improvements in the physical, emotional, and global domains of the day-42 quality of life tool ¹⁶¹.

Radionuclides

Patients with multiple sites of symptomatic osteoblastic bone metastases may consider radionuclides such as strontium chloride Sr 89 or samarium Sm 153 (153Sm) ¹⁴. Two double-blind randomized trials support the superiority of samarium Sm 153 (153Sm) over placebo in providing metastatic bone cancer pain control and reducing analgesic use ¹⁶², ¹⁶³. The overall response varies between 30% and 80%, with onset of metastatic bone cancer pain relief within the first week; some patients report a long-lasting benefit (up to 18 months) ¹⁴. The most common toxicities are pain flare and cytopenias ¹⁴. Pain flare typically occurs in approximately 10% of patients within the first 24 to 48 hours of administration and may be treated with corticosteroids or opioids ¹⁶⁴. Leukopenia and thrombocytopenia are sometimes seen, with a nadir of 4 weeks posttreatment and recovery by 8 weeks. Contraindications to radionuclide therapy include a poor performance status (Karnofsky Performance Status score <50%) and a short life expectancy (<3 months) ¹⁴.

Radium Ra 223-dichloride (223Ra-dichloride) (an alpha-emitter) is approved for use in patients with castration-resistant prostate cancer ¹⁴. A phase 3 randomized trial compared 223Ra-dichloride with placebo in a 2:1 ratio. Among the 921 symptomatic patients enrolled, those who received 223Ra-dichloride had a prolonged time to first symptomatic skeletal event (15.6 months vs. 9.8 months), in addition to prolonged overall survival (14.9 months vs. 11.3 months) ¹⁶⁵.

Visceral Pain treatment

Visceral pain is a type of pain that originates in pain receptors innervating visceral organs, which are internal organs of your body such as your heart, lungs, and organs of the digestive, excretory, reproductive, and circulatory systems. Several features of visceral pain determine the therapeutic approach:

Not all internal organs have pain receptors. Typically, the hollow viscera (stomach, bowel, bladder, and ureters) are innervated and respond to mechanical-, inflammation-, and chemical-induced damage. For example, sensations originating from the liver or spleen are typically caused by distension of the capsule.
There is a limited correlation between the degree of visceral injury and the intensity of the perceived pain ¹⁶⁶.
The source of visceral pain is often difficult to localize. Referred pain may be perceived as remote from the actual affected organ (e.g., shoulder pain with splenic injury).
In the phenomenon of sensitization, the normal activity of an organ is perceived as painful, such as stomach inflammation causing hyperawareness or hyperalgesia-related peristalsis of the stomach.

Opioids remain the core treatment for severe or distressing visceral pain ¹⁶⁷. Also important are radiographic studies to look for underlying causes that may be corrected to other interventions (e.g., bowel obstruction).

Nerve pain (neuropathic pain) treatment

Pain with features suggestive of nerve (neuropathic) pain is common among patients with cancer and can have substantial negative consequences. One study of 1,051 patients with cancer found that 17% had neuropathic pain ¹⁶⁸. These patients reported worse physical, cognitive, and social functioning than did those with nociceptive pain (pain caused by damage to non-nerve tissue and is due to the activation of pain receptor); were on more analgesic medications and higher doses of opioids; and had a worse performance status ¹⁶⁸. Nerve (neuropathic) pain is considered less responsive to opioids ¹⁴. Multiple therapeutic options instead of or in addition to opioids have been studied. Most of these studies were conducted in patients with non-cancer sources of neuropathic pain and may not be applicable to patients with cancer with different causes for their neuropathic pain.

Gabapentin can be used as monotherapy in the first-line setting for neuropathic pain or in combination therapy if opioids, tricyclic antidepressants (TCAs), or other agents do not provide adequate relief ¹⁴. Gabapentin improved pain relief when added to opioids for uncontrolled cancer-related neuropathic pain ¹⁶⁹, ¹⁷⁰. When gabapentin was used as an add-on (adjuvant) to an opioid regimen, improvement in pain control was seen within 4 to 8 days ¹⁷¹. In an open-label trial of pregabalin compared with fentanyl in 120 cancer patients with “definite” neuropathic pain, patients on pregabalin were twice as likely (73.3%) than those on fentanyl (36.7%) to report 30% or more reduction in pain, as measured by a visual analog scale (VAS) ¹⁷². Compared with monotherapy with amitriptyline, gabapentin, or placebo, pregabalin use resulted in a significant decrease in pain score when studied in neuropathic cancer pain ¹⁷³. In a randomized clinical trial of patients with head and neck cancer who were undergoing radiation therapy, pregabalin was shown to improve radiation therapy–related neuropathic pain, mood, and quality of life (QOL), with good tolerability ¹⁷⁴.

In a systemic review of neuropathic pain that included mostly patients with a non-cancer source of neuropathic pain, the effect of gabapentin and pregabalin appeared less robust ¹⁷⁵. Data comparing gabapentin or pregabalin directly with tricyclic antidepressants (TCAs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) are limited, especially in patients with cancer. Efficacy of tricyclic antidepressants (TCAs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) appears to be comparable and, in some cases, superior to gabapentin or pregabalin ¹⁴. Because of concerns about side effects and drug-drug interactions, many doctors tend to start with gabapentin or pregabalin as first-line treatment for neuropathic pain ¹⁴. However, certain neuropathic syndromes may be less responsive to these agents ¹⁴. Studies have also examined the use of lidocaine patches, tramadol, topically applied capsaicin, and botulinum toxin A for use in patients with neuropathic pain with inconclusive results ¹⁷⁵.

Chemotherapy-induced peripheral neuropathy treatment

American Society of Clinical Oncology guidelines recommend against the use of many commonly prescribed agents for the treatment of existing chemotherapy-induced peripheral neuropathy ³¹, ¹⁷⁶. The exception is duloxetine because it is the only agent whose efficacy in treating chemotherapy-induced peripheral neuropathy is evidence based ¹⁷⁷. One large phase 3 trial identified an average decrease of 0.73 in the pain scores of patients who titrated up to 60 mg of duloxetine daily, when compared with placebo. Patients also had improvements in daily functioning and quality of life ¹⁷⁷. Some argue that, while statistically significant, the difference of less than 1 (0.73) on a pain scale of 0 to 10 may not be clinically important ¹⁴.

Gabapentin failed to provide a benefit in chemotherapy-induced peripheral neuropathy when used as monotherapy in a randomized, double-blind, placebo-controlled trial ¹⁷⁷, ¹⁷⁸. The Cancer and Leukemia Group B prospective observational study evaluated 2,450 patients with stage 3 colon cancer. Increased severity of oxaliplatin-induced peripheral neuropathy may be linked to higher body mass index (BMI), lower physical activity, diabetes mellitus, and a longer planned duration of treatment. Celecoxib and vitamin B6 intake did not attenuate oxaliplatin-induced peripheral neuropathy ¹⁷⁹.

Evidence of the efficacy of nortriptyline and amitriptyline in chemotherapy-induced peripheral neuropathy is limited to small and frequently underpowered trials with mixed results ¹⁸⁰, ¹⁸¹, ¹⁸². Despite inconclusive trials, the authors suggested that a trial of tricyclic antidepressants (TCAs), gabapentin, and topical baclofen/amitriptyline/ketamine may be reasonable in light of evidence supporting the benefit of these agents in other types of neuropathy and the relative lack of effective alternatives in this setting ¹⁸³.

Importantly, a large, randomized, multicenter, double-blind, placebo-controlled trial comparing the use of acetyl-L-carnitine with placebo in 409 women receiving taxane-based chemotherapy for breast cancer showed worsened chemotherapy-induced peripheral neuropathy. This worsening persisted over 2 years ¹⁸⁴.

Acupuncture

Several studies have investigated the use of acupuncture to treat persistent chemotherapy-induced peripheral neuropathy from taxane or platinum-based chemotherapy. Preliminary evidence from two small non–placebo-controlled studies (N = 5 and N = 6) has shown that manual acupuncture can improve chemotherapy-induced peripheral neuropathy symptoms ¹⁸⁵, ¹⁸⁶.

A three-arm randomized controlled trial (RCT) (N = 90) examined the use of auricular acupuncture for the treatment of chronic neuropathic pain in cancer patients after receiving cancer treatment. The study found a significant reduction in pain at 2 months in patients who were treated with acupuncture compared with patients who received the sham treatment ¹⁸⁷.

A multicenter observational study of 168 cancer patients who received taxanes or other neuropathy-inducing agents (i.e., bortezomib) compared acupuncture with acupuncture mind-body or control. The study found improvement in chemotherapy-induced peripheral neuropathy and related symptoms ¹⁸⁸.

In more recent studies, several randomized controlled trials found further promising effects of acupuncture in treating chemotherapy-induced peripheral neuropathy.

A three-arm RCT (N = 75) of solid tumor patients with moderate to severe chemotherapy-induced peripheral neuropathy that compared real acupuncture to sham acupuncture and usual care showed that RA reduced pain significantly more than usual care and at a greater degree than SA at the end of 8 weeks of treatment, and that pain reduction persisted at week 12 follow-up ¹⁸⁹. The analysis of quality of life end points showed that both real acupuncture and sham acupuncture significantly improved quality of life measured by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX), Hospital Anxiety and Depression Scale, and Insomnia Severity Index, compared with usual care, but no difference between real acupuncture and sham acupuncture was found ¹⁹⁰.
A randomized sham-controlled trial (N = 84) of colorectal cancer patients undergoing oxaliplatin-based chemotherapy that is currently in progress seeks to find if acupuncture can improve Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) scores as the primary outcome, and numerical rating scale (NRS) and vibration and light touch sense test scores as secondary outcomes (NCT03582423) ¹⁹¹.
A pilot study (N = 33) of cancer patients with chemotherapy-induced peripheral neuropathy treated with 10 sessions of acupuncture found statistical differences in groups in physical and function domains as assessed by the European Organization for Research and Treatment Quality of Life Questionnaire (EORTC QLQ-C30) and improved neuropathy sensory symptoms as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events scale (NCT02309164) ¹⁹².
A small pilot study (N = 10) of breast cancer patients with taxane-induced chemotherapy-induced peripheral neuropathy found that 12 sessions of acupuncture over 4 weeks significantly reduced chemotherapy-induced peripheral neuropathy pain as assessed by the Neuropathic Pain Symptom Inventory (NPSI) and improved sensory outcome as assessed by the Nerve Conduction Study ¹⁹³.

Scrambler therapy

Scrambler therapy is a non-invasive, FDA-approved treatment for chronic pain that uses electrical stimulation to replace pain signals with non-pain signals. Electrodes are placed on your skin above and below the painful area, and small electrical currents are transmitted into your skin. Scrambler therapy sends non-pain messages along the same nerve fibers that are sending pain signals to your brain, retraining your brain to understand the normal signal.

Scrambler therapy is usually applied in ten consecutive sessions, although guidelines permit the skipping of weekend days. Scrambler therapy is operator dependent, given the importance of identifying the area to treat and the application of the electrical current through five electrodes (referred to as artificial neurons). Furthermore, before daily scrambler therapy sessions, adjustments of the electrode placement and dose, titrated to pain relief, are required. Finally, it has been observed that misapplication of the currents induces worse pain.

The proposed mechanism of scrambler therapy begins with the observation that chronic pain may represent dysregulation of the somatosensory nervous system ¹⁹⁴. The application of the electrical currents activates surface receptors (synthetic pain) and provides an opportunity for the patient to reinterpret signals as nonpain. The proposed mechanism depends on patients decoding pain information as nonpainful.

There are two relevant randomized trials of scrambler therapy. One study randomly assigned 52 patients with chemotherapy-induced peripheral neuropathy to receive either standard guideline–consistent therapy (opioids, gabapentinoids, tricyclic antidepressants) or scrambler therapy ¹⁹⁵. The primary outcome was the mean visual analog scale (VAS) pain score at 1 month. The mean scores before treatment were 8.1 in the control group and 8.0 in the scrambler group. The mean scores in both groups decreased, but the improvement was greater for scrambler therapy: from 5.8 to 0.7. The visual analog scale (VAS) pain scores were maintained at 2 and 3 months. The lack of an effective sham control is a significant limitation, as is the potential that the attention paid to the patient may have a salutary effect.

A subsequent trial randomly assigned 50 patients to either scrambler therapy or a conventional transcutaneous electrical nerve stimulation (TENS) therapy ¹⁹⁶. The primary endpoint of the study was the proportion of patients who experienced a reduction of more than 50% in either pain or tingling at 2 weeks, compared to baseline. Fifty-six percent of patients who received scrambler therapy achieved the goal, compared with 28% of those who received TENS therapy ¹⁹⁶. There was a corresponding improvement in Global Impression of Change scores for neuropathy symptoms. Patients in the scrambler therapy arm were more likely to recommend the therapy to friends. The choice of transcutaneous electrical nerve stimulation (TENS) therapy as a control is confounded by the lack of data related to its efficacy in treating chemotherapy-induced peripheral neuropathy.

Pain Procedures

While medicines can effectively manage most cancer pain, approximately 10% to 20% of people with cancer will have refractory cancer pain or excessive side effects ¹⁹⁷. For people with refractory cancer pain or specific regional pain syndromes, medical procedures or interventional approach to treating pain has been proposed ¹⁴. For patients with either regional pain syndromes or cancer pain refractory to escalating systemic medications, your cancer doctor may consult with a pain specialist or neurosurgeon to consider medical procedures to pain control. This can include simple options such as nerve blocks to more complex procedures such as implanted pumps. However, these options are not suitable for everyone, but can be particularly useful for treating nerve pain or pain that has been difficult to control with other medicines.

Talk to your doctor about referring you to a pain specialist. The pain specialist can explain the risks and benefits of each procedure.

Nerve blocks

A nerve block numbs the nerve sending pain signals to the brain. It is usually an injection of local anaesthetic, similar to when a dentist numbs a painful tooth. Sometimes an x-ray or ultrasound machine is used to help guide the needle. In most cases, the numbing effect lasts for a few hours, but it sometimes lasts for days. A nerve block is generally used to provide short-term pain relief or to help diagnose which nerve is sending the pain signals. This can be used to help with pain after an operation.

Celiac plexus block, used primarily for people with upper abdominal pain from pancreatic cancer, is the most commonly employed neurolytic blockade of the sympathetic axis, followed by the superior hypogastric plexus block and the ganglion of impar block for patients with lower abdominal or pelvic pain. The ganglion of impar is the meeting point of the two sides of the pelvic sympathetic nerves, at the junction between the sacrum and the coccyx ¹⁹⁸. A ganglion of impar block is an injection of local anaesthetic and steroid around the nerves supplying the coccyx (or tailbone) area ¹⁹⁸. Traditionally, the autonomic nerve blockade was reserved for patients with inadequate response to oral opioids, but some researchers have suggested that the intervention—which is associated with decreased pain, reduced opioid consumption, improved performance status, and few complications—is considered a first-line approach ¹⁹⁹, ²⁰⁰.

For patients with regional pain, a peripheral nerve block infusing a local anesthetic can achieve local pain control. This approach can be applied to any peripheral nerve (nerves that lies outside your brain and spinal cord), including the femoral, sciatic, paravertebral, brachial plexus, and interpleural nerves ²⁰¹.

Radiofrequency ablation (RFA) or pulsed radiofrequency

Radiofrequency ablation (RFA) or pulsed radiofrequency can be used after some nerve blocks to provide longer-lasting pain relief. Pulsed radiofrequency ablation (RFA) applies electric pulses to change how your brain senses the pain signal. Thermal radiofrequency ablation (RFA) uses heat to damage the nerve and block it from sending pain signals to your brain.

Your treating pain specialist will let you know what type of radiofrequency is most suitable for you.

Relief from radiofrequency ablation (RFA) is instant for some people, but for others may take up to two months to work. It can last for nine months to more than two years.

Neuroaxial delivery of analgesia (epidural and intrathecal)

When patients have cancer pain that persists despite high doses of opioids and other analgesics or have intolerable side effects to oral opioids—such as delirium, sedation, or nausea—an alternative route of delivery may be considered. Compared with intravenous (IV) administration of opioids, epidural and intrathecal routes of delivery are 10 and 100 times more potent, respectively. Epidural and intrathecal routes of pain medicine delivery allow high doses of pain medicines to be administered with less systemic absorption and fewer side effects ²⁰².

Epidural injection of local anaesthetic and sometimes with other pain medicines near the nerves in your back can provide pain relief for up to two weeks.

If longer-term pain control is needed, a small tube (epidural catheter) may be placed a little deeper in you back. This is connected to an opening (port), which allows pain medicine to be dripped in continuously.

If pain is likely to last longer than six months, the catheter is attached to a small pump under the skin of the abdomen (known as an intrathecal pump). This pump is refilled about every three months with pain medicine. The pump can be adjusted depending on how much pain relief you need.

One study that randomly assigned patients to receive either an implantable drug delivery system or comprehensive medical management found that patients receiving the analgesic through the implantable pump had less pain, less toxicity, and longer survival at 6 months ²⁰³. While the survival benefit did not persist in other studies, the intrathecal pump may be an option for selected patients with refractory cancer pain and a life expectancy longer than 3 months ²⁰⁴. However, intrathecal pumps may make it difficult for patients to access hospice care because of care needs and cost issues, and they cannot effectively treat pain that is predominantly related to psychological distress ²⁰⁵. For patients with shorter life expectancies, placement of an epidural catheter may be a safe and effective technique ²⁰¹.

Spinal cord stimulator

Spinal cord stimulator is an implanted spinal cord stimulation device that sends low levels of electricity directly into your spinal cord to relieve pain. Spinal cord stimulator consists of thin wires (the electrodes) and a small, pacemaker-like battery pack (the generator). The electrodes are placed between your spinal cord and the vertebrae (the epidural space), and the generator is placed under your skin, usually near your buttocks or abdomen. Spinal cord stimulation is used most often after nonsurgical pain treatment options have failed to provide sufficient relief. Spinal cord stimulators require two procedures to test and implant the device: the trial and the implantation.

Spinal cord stimulator is a long-lasting procedure to treat nerve pain problems. A device is implanted into the spine, and a remote control is used to send low levels of electricity. It causes tingling against the nerves in the back or neck, which reduces the amount of pain felt.

The procedure is done in two steps, with the first step as a trial to see if it provides relief. If pain relief is above 60%, the second step is to permanently implant the device.

Experts still don’t fully understand the mechanisms behind spinal cord stimulation, but they know that spinal cord stimulator may target multiple muscle groups directly from the spine and even alter how the brain senses pain.

Traditional spinal cord stimulators replace the sensation of pain with light tingling, called paresthesia. For patients who find these paresthesiae uncomfortable, newer devices offer “sub-perception” stimulation that cannot be felt.

Many of the latest devices are placed by physicians with highly specialized training in interventional pain management under X-ray and/or ultrasound guidance.

Cordotomy

A cordotomy is a surgical procedure that involves cutting nerves in the spinal cord to relieve pain. Cordotomy is a palliative option for patients with severe cancer pain that doesn’t respond to other treatments. Cordotomy is reserved for pain refractory to other approaches and is done less commonly today ¹⁴. Cordotomy is most effective in treating unilateral somatic pain from the trunk to the lower limbs. The available literature suggests a high rate of efficacy, with 60% to 80% complete pain relief immediately after the procedure, falling to 50% at 12 months ¹⁴. Cordotomy is generally reserved for patients considered to be in the last 2 years of life, with cancer pain refractory to other approaches, and may be done via the open route or the percutaneous route ²⁰⁶, ²⁰⁷, ²⁰⁸.

Physical and occupational therapy

Patients with cancer and pain may experience loss of strength, mobility, and, ultimately, functional status secondary to the cause of pain, (e.g., vertebral metastases, incident pain, and chronic nonmalignant pain) ¹⁴. Pain and functional status may improve with physical or occupational therapy, treatments for strengthening and stretching, and the use of assistive devices ²⁰⁹. Referral to a physiatrist (a physician who specializes in rehabilitation medicine) who could create a comprehensive plan may benefit the patient. In addition, some physiatrists practice interventional pain medicine.

Psychological therapy

Professionals such as psychologists and counsellors can provide therapies such as cognitive behavioral therapy (CBT), acceptance and commitment therapy, and mindfulness-based cognitive therapy.

Psychologists and counsellors help you understand how your thoughts and emotions affect your response to pain or identify any worries that are making the pain worse. They can help you build new coping skills and get you back to your usual activities as much as possible.

A psychologist can teach you to use techniques such as desensitisation. This involves focusing on the pain and relaxing at the same time.

Desensitization is sometimes used for neuropathic pain (e.g. numbness or tingling). Other ways to temporarily focus on something other than the pain include counting, drawing and reading.

Complementary therapies

Complementary therapies are designed to be used alongside conventional treatments (i.e., surgery, radiation therapy, drug therapies such as chemotherapy, hormone therapy, targeted therapy and immunotherapy). Complementary therapies may help you cope better with pain, increase your sense of control, decrease anxiety, and improve your quality of life. Examples include acupuncture, hypnotherapy, reflexology, and mindful meditation, among others.

Mind-body practices are based on the belief that what we think, and feel can affect our physical and mental wellbeing. Examples include art therapy, counselling, hypnotherapy, laughter yoga, meditation, mindfulness, music therapy, relaxation, spiritual practices.
Body-based practices work directly on your body. Examples include acupuncture, aromatherapy, massage, Qi gong, reflexology, tai chi, yoga.
Energy therapies are based on the belief that the body has an invisible energy field that when blocked, can make you sick. Examples include touch, reiki.
Therapies using herbs and plants are also known as botanical medicine and are produced from all parts of the plant. Examples include bush remedies, Chinese herbal medicine, flower remedies, medicinal cannabis, Western herbal medicine.

Let your doctor know about any complementary therapies you are using or thinking about trying, as some may cause reactions or unwanted side effects.

You should also tell the complementary therapist about your cancer diagnosis, as some therapies may need to be adjusted.

Chronic pain or persistent pain treatment

After treatment for cancer, some 40% of survivors of cancer will have ongoing pain or chronic pain or persistent pain for months or years. Chronic pain or persistent pain may be caused by your cancer treatments, cancer-related changes (e.g. reduced strength, injuries) or other conditions not related to your cancer such as arthritis, depression, anxiety, fatigue and trouble sleeping that can make your pain worse.

While opioids are sometimes prescribed for chronic pain, research shows that using opioids for a long time is not safe. However, for people with advanced cancer and who are receiving palliative care, opioids usually work well and are safe for managing cancer-related pain.

Evidence shows that opioids are not very useful or safe for managing chronic non-cancer pain. Chronic cancer pain after cancer treatment needs to be managed in a similar way to chronic non-cancer pain. This means looking at the physical, emotional and social impacts of your pain, and managing all these factors. Your doctor may recommend you see a pain management specialist in a multidisciplinary pain clinic. The specialist can recommend a range of pain-relieving therapies and help create a pain management plan to improve your quality of life and return you to your normal activities.

If the pain cannot be well controlled, the focus will shift to improving your ability to function despite the pain.

Palliative Care

Palliative care is specialized medical care for people living with a serious illnesses with the goal to maximize quality of life (QOL) for both patients and families, can provide expert assessment and management of pain and other nonpain symptoms ²¹⁰. Palliative care is focused on providing relief from the symptoms and stress of the illness. The goal is to improve quality of life for both the patient and the family. People at any stage of advanced cancer may benefit from seeing a palliative care team.

Palliative care is based on the needs of the patient, not on the patient’s prognosis ²¹⁰. Palliative care is appropriate at any age and at any stage in a serious illness, and it can be provided along with curative treatment.

Palliative care is provided by a specially-trained team of doctors, nurses, social workers, chaplains or spiritual care practitioners, mental health specialists, physiotherapists, occupational therapists, psychologists, pharmacists and dieticians who work together with a patient’s other doctors to provide an extra layer of support.

The palliative care team work together to:

Maintain your quality of life by relieving physical symptoms.
Support your emotional, cultural, social and spiritual needs.
Provide support to families and carers.
Help you feel in control of your situation.
Make decisions about your treatment and ongoing care.

For patients with refractory cancer pain, prominent nonpain symptoms, or intense psychosocial distress, a referral to palliative care may be appropriate ¹⁴. Your cancer specialist or nurse can put you in touch with a palliative care team for treatment in hospital or at home. Palliative care can improve quality of life from the time of diagnosis and can be given alongside other cancer treatments.

Many palliative care teams now call themselves supportive care teams because this term is more acceptable to many referring providers and to some patients and families ²¹¹, ²¹².

Palliative care specialists may also help manage patients with multiple comorbidities, those requiring higher doses of opioids, and those with a history of substance use disorder or complex psychosocial dynamics that can complicate the management of pain and adherence to recommended medications ²¹⁰. Most palliative care specialists have experience using methadone for pain.

The role of specialty palliative care integrated into cancer care has been well studied, with studies showing that early integration of specialty palliative care into cancer care reduces symptom burden and enhances quality of life (QOL) for both patients and families and may prolong life ²¹³, ²¹⁴, ²¹⁵, ²¹⁶.

Cancer pain monitoring

Effective pain management requires close monitoring of you, your pain intensity and your quality of life after treatment is initiated. You may have regular pain assessments to see how well the medicines and other ways of controlling your pain are working, and to manage new or changed pain. Your doctor should track your pain with a pain scale, assessing how strong it is. The goal should be to keep you comfortable. If you aren’t comfortable, talk to your doctor.

Only you can describe your pain. How it feels and how it affects what you can do will help your doctor and other specialist plan the most appropriate way to treat your pain. This is called a pain assessment.

Make a note of triggers – write down what seems to cause or increase your pain. This is called a trigger, and it may be a specific activity or situation. Knowing what triggers your pain might help you find ways to manage these triggers.
Keep a pain diary – a written record of your pain can help you and those caring for you understand more about your pain and how it can be managed. Note down how the pain feels at different times of the day, what you have tried for relief and how it has worked.
Keep a contact list – make a list of the health professionals in your team and their contact details. Keep this handy in case you or your carer need to get in touch.
Know when to seek help – talk to your doctors about what should prompt you to call them and who you can call, particularly after hours. For example, you may be instructed to call if you are feeling very sick or sleepy.

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