Pain in Patients with Cancer: Part 2

​Sixty percent to 90% of patients with cancer with bone metastasis develop bone pain.^1,2 In turn, bone pain can be the first sign that cancer has spread to the bone. The discomfort may come and go at first, with the pain being worse at night and lessening with movement. However, as the cancer progresses, the pain can become constant and more severe with activity. A patient may describe this type of pain as dull, achy, or “ongoing.”¹

When cancer invades the bone, it results in bone destruction, leading to skeletal complications. The most common sites include the spine, upper arm bone, hip bone, ribs, upper leg bone, and skull.³ Fractures, spinal cord compression, and high blood calcium levels can all be indications of bone metastasis. table 13 shows the most common sites where metastasis can occur.³ In addition, certain kinds of cancer are more likely to spread to the bone. These include breast, prostate, lung, thyroid, and kidney cancer.³ Bone pain can be treated with nonsteroidal anti-inflammatory drug (NSAIDs), corticosteroids, radiation therapy, bisphosphonates, calcitonin, or denosumab.

NSAIDs

NSAIDs are an effective agent for treatment of bone pain, as prostaglandins appear to play a role.² Study results have shown that NSAIDs are more effective than placebo for cancer pain, but that NSAIDs are comparable in safety profile and effectiveness.² Avoid use or use with caution in those with renal failure, liver disease, peptic ulcer disease, or past intolerability to NSAIDs.

Corticosteroids

Dexamethasone is the most commonly used corticosteroid because of its long half-life and lack of mineralocorticoid activity, which causes less fluid retention.^4,5 Other steroids that could be used include prednisone or prednisolone. One advantage of prednisolone is that myopathy occurs less often with its use.⁴ Overall, the most common adverse effects (AEs) of corticosteroid use include insomnia, gastrointestinal (GI) distress, moon face, myopathy or muscle weakness, skin purpura, oral candidiasis, and hyperglycemia or worsening of diabetes.⁵

The risk of osteoporotic fracture associated with long-term steroid use in patients whose bone is already weakened from metastatic cancer can limit their long-term use; however, in the hospice setting, the benefits from long-term use typically outweigh the risks. In cases of acute, severe cancer pain, a large bolus followed by a taper to the lowest effective dosage can be beneficial to patients. The most appropriate dose of dexamethasone has not been determined, but a range of 2 to 8 mg orally or subcutaneously 1 to 3 times daily is generally accepted.⁴

Corticosteroids can also help relieve other symptoms that may occur. For example, they can stimulate appetite, suppress nausea, and alleviate fatigue. See table 25 for corticosteroid doses for common indications in cancer patients.

Bisphosphonates^6-9

Bisphosphonates work by inhibiting osteoclast activity. The literature supports the analgesic efficacy of bisphosphonate use in patients with bone pain due to bone metastases from solid tumors and multiple myeloma.^6-9 Pamidronate, 60 to 90 mg, injected intravenously (IV) and infused over 2 to 4 hours every 3 to 4 weeks, has been well documented for treatment of bone metastasis.² AEs include hypocalcemia and a flulike syndrome. Zoledronic acid is another bisphosphonate used with good tolerability. The recommended dose is 4 mg IV every 3 weeks over at least 15 minutes.^2,9 Patients must be adequately hydrated, and a serum creatinine level should be assessed prior to administration. The analgesic effects should occur in 2 to 4 weeks.¹⁰

Recommendations for patients include taking vitamin D and supplemental calcium daily and having any preventive and invasive dental care completed prior to starting bisphosphonates to reduce the risk of osteonecrosis of the jaw (ONJ).^8,9

Calcitonin^11-13

Calcitonin can be administered either subcutaneously or intranasally. The nasal dose is 200 IU in 1 nostril a day, alternating nostrils.^2,10 The optimal subcutaneous dose is unknown, but 100 IU daily to 200 IU every 6 hours for 48 hours has been used.^11-13 If the subcutaneous route is used, a skin test with 1 IU should be done to screen for hypersensitivity reactions, especially in patients with a history of reactions to salmon or seafood. Nausea and infrequent hypersensitivity reactions are the main AEs with the subcutaneous injections.²

Although a few small studies have shown a beneficial effect, there is minimal literature available to support the use of calcitonin for managing cancer bone pain.^10-14 Calcitonin is not recommended as a first-line agent for bone pain but could be an option when other medications have failed.

DenosumaB^6,15

Denosumab binds to receptor activator of nuclear factor kappa-B ligand (RANKL), a protein that is needed for the formation and function of osteoclasts, the cells responsible for bone resorption. Denosumab inhibits osteoclast formation, function, and survival, which leads to a decrease in bone resorption and an increase in bone mass. The typical dose is 120 mg every 4 weeks. There are no requirements for renal monitoring. Adverse reactions include dyspnea, fatigue, headache, hypophosphatemia, and nausea. Because ONJ has been reported in patients receiving denosumab invasive dental work should be done prior to starting denosumab and other preventive dental measures should be taken.⁶

Radiation Therapy

Radiation therapy can be used for bone metastases to relieve pain, prevent impending pathologic fractures, and promote healing of pathologic fractures. It successfully relieves pain in 60% to 70% of patients, but can take up to 3 weeks to be fully effective.⁶

Neuropathic Pain^16-20

Neuropathic pain is widely recognized as a common conse- quence of cancer and can result from administration of several common oncology drugs, including oxaliplatin, carboplatin, cisplatin, paclitaxel, docetaxel, bortezomib, lenalidomide, thalidomide, epothilone, and the vinca alkaloid.^2,16 There is currently no approved therapy for the prevention or mitigation of chemotherapy-induced neuropathy. Patients with neuropathic pain may report symptoms of paresthesia, dysesthesias, allodynia, hyperalgesia, and hyperpathia. They may describe the pain as sharp, burning, tingling, prickly, or shooting. Treatment includes the use of anticonvulsants, antidepressants, opioids, and topical agents.¹⁷ The choice of treatment requires evaluation of age, coexisting disease states, drug interactions, and the AE profile of the medication.

Anticonvulsants

Gabapentin and pregabalin have been used successfully in the treatment of cancer-related pain syndromes.^17-20 They are structurally related compounds, so they should not be used concurrently. However, both can be used alone or in combination with morphine for effective pain relief.^20,21 The combination of either agent with morphine can have opioid-sparing effects and a beneficial effect on daily activity, mood, sleep, and quality of life.^19,20

Gabapentin and pregabalin have few drug—drug interactions and are generally well tolerated.¹⁷ Somnolence and dizziness are the most common AEs, but they can be managed by starting at low doses and titrating slowly. Both drugs are renally excreted, so patients with renal impairment require a dosage adjustment. Pregabalin also has anxiolytic effects and may be the first drug of choice in patients with anxiety.¹⁷

The recommended starting dose of gabapentin is 100 to 300 mg at bedtime, titrating as needed every 3 days. The maximum recommended dose is 3600 mg daily. An adequate trial should include 1 to 2 weeks at the maximum-tolerated dose.²² The recommended dose of pregabalin is 75 to 150 mg, 2 times daily (although some cancer studies used doses up to 600 mg/ day in divided doses).²⁰

Other anticonvulsants have been used in the treatment of neuropathic pain, including carbamazepine (particularly for trigeminal neuralgia), lamotrigine, topiramate, and oxcarbazepine. Carbamazepine and oxcarbazepine are first-line drugs for trigeminal neuralgia.²² Trials that have compared the 2 drugs have reported comparable analgesic effects but fewer AEs with oxcarbazepine. Oxcarbazepine also does not induce hepatic enzymes and has fewer drug—drug interactions than carbamazepine. Neither drug is considered a first-line agent in the treatment of cancer-related neuropathic pain.^23,24

Lamotrigine was studied in patients with chemotherapy-induced peripheral neuropathy. The results suggest that it is not effective for relieving neuropathic symptoms in this patient population.²⁵ Therefore, it is not recommended as a first-line agent for neuropathic pain. The potential for severe rash and Stevens-Johnson syndrome also poses some concern.

Some study results have shown topiramate as an effective second- or third-line agent in the treatment of cancer neuropathic pain when other medications have failed.²⁶ AEs include somnolence, changes in vision, dizziness, confusion, slowed thinking, and mood changes.

In some small studies, levetiracetam has been shown to be effective in alieving cancer pain.²⁷ The maximum levetiracetam dose ranged from 500 to 1500 mg twice daily.²⁷ The most common AEs include somnolence, pharyngitis, asthenia, and headache. This agent could be used as an alternative when others have failed.

Antidepressants

Antidepressants may be the first choice for treating neuropathic pain in patients with coexisting depression. Both venlafaxine and duloxetine are newer agents that have proven beneficial for patients with neuropathy.^28,29 Venlafaxine has been used for the management of hot flashes and can be quite helpful to patients who have breast cancer with neuropathic pain, menopausal flashes, and depression.¹⁷ Because there is a risk of elevated arterial pressure with venlafaxine use, however, regular monitoring is recommended. Venlafaxine also should be prescribed with dosage adjustment in patients with renal or hepatic insufficiency.

Duloxetine has proven to be effective in the treatment of chemotherapy-induced peripheral neuropathy (CIPN).^17,30 Its effects were present from week 1, and the most effective dosage associated with the fewest AEs was 60 mg once daily.^17,30 The most common AEs include nausea, fatigue, dizziness, constipation, anorexia, dry mouth, and sexual dysfunction. Duloxetine should be avoided in patients with hepatic insufficiency.

Tricyclic antidepressants (TCAs) have been shown to be effective for neuropathic pain. When compared with some of the new agents, the TCAs are just as effective.³¹ The limiting factor with these medications are the anticholinergic AEs: dry mouth, constipation, urinary retention, sweating, and blurred vision. Somnolence and confusion can be a concern when initiating treatment, particularly in elderly patients and those on other sedating medications. Orthostatic hypotension and gait disturbances are also common and need to be monitored in elderly patients. Desipramine and nortriptyline may be better tolerated than amitriptyline. Initiation of TCA treatment is best done slowly, starting with 10 to 25 mg daily and slowly increasing up to 50 mg to 150 mg daily.

Lidocaine²²

Lidocaine patches have become a useful add-on treatment for patients with cancer-related neuropathic pain, especially where allodynia is present. It can also help with CIPN that affects the feet with in post—breast surgery pain syndromes. A dose of up to 3 patches may be applied for 12 hours per day. AEs are mild, with skin irritation being the most common.

Opioids^{1,2,6,10,17,32-34}

Because the discomfort from cancer can be neuropathic and occur concurrently with pain that is highly opioid responsive, opioids can be a good choice for treatment of neuropathic pain associated with cancer. In fact, some patients may achieve a better analgesia or AE profile with an opioid rather than an adjuvant for neuropathic pain¹⁷. Neuropathic pain has been reported to respond to opioids with an effect similar to antidepressants, gabapentin, or pregabalin, with no proven difference between various opioids (eg, oxycodone, morphine, methadone, tramadol)¹⁷. Several different opioids are available, and all of them can produce sedation, constipation, drowsiness, physical dependence, tolerance, and respiratory depression.

N-Methyl D-Asparate Antagonists

A painful stimulus can release the excitatory amino acid glutamate that can interact with the N-methyl-d-aspartate (NMDA) receptor. Activation of this receptor can lead to hyperalgesia, neuropathic pain, and reduced functionality of opioid receptors. Blocking these receptors by antagonists leads to a reduction in pain. There are several NMDA receptor antagonists available: ketamine, methadone, memantine, amantadine, and dextromethorphan.

Ketamine^35-37

Oral or parenteral ketamine use should be reserved for treating resistant pain. It reduces opioid consumption, helps relieve neuropathic pain, and has been successfully used in cancer pain. Dosages ranged from 0.25 mg/kg or 0.5 mg/kg to 100 to 300 mg per day.^36-37 The limiting factor is its AE profile, which appears dose related and produces hallucinations, agitation, and confusion.

Methadone⁶

Methadone is an effective option for relieving neuropathic pain. Methadone has unique properties, including a variable half-life, a long list of drug interactions, and QT prolongation. There is no single recommended equi-analgesic dosing con- version when dosing methadone, which is beyond the scope of this article.

Memantine^38,39

A few limited studies have looked at memantine in the treatment of pain. One used memantine (5 to 20 mg/day) for 4 weeks starting 2 weeks prior to mastectomy.³⁹ Patients showed a decrease in postmastectomy pain intensity, used less rescue pain medication, and had a better emotional state. An improvement of pain symptoms induced by cancer chemotherapy was also reported.³⁹

Amantadine⁴⁰

A small study looked at amantadine versus placebo in relieving surgical neuropathic pain in patients with cancer. Amantadine was given as an infusion of 200 mg, and pain levels were measured before, during, and following treatment. Pain was reduced by 85% with the infusion. The difference in pain relief between the 2 treatments was statistically significant (P = .009).40 Amantadine’s place in pain has not be established, but could be an option when other medications have failed or a patient is unable to tolerate AEs from other medications.

Capsaicin^22,41

Capsaicin is thought to deplete substance P, leading to decreased pain perception. The cream has been shown to be effective in cancer pain when patients applied a 0.075% capsaicin cream to the site 4 times daily.⁴¹ A trial of several weeks is needed to see maximal benefit, however. Patients may experience severe burning pain after the first application, but this should diminish as time progresses.

Miscellaneous Adjuvants

Baclofen can be used to treat spasticity, which can help relieve pain associated with muscle spasms. Benzodiazepines also can reduce pain by relieving anxiety associated with pain or related to the cancer itself.

Mucositis

Mucositis is mucosal damage that occurs in the oral cavity; pharyngeal, laryngeal, and esophageal regions; and other areas of the GI tract. It typically presents as erythema or ulceration of the oral mucosa and can be very painful and limit oral intake and quality of life. GI symptoms include pain, nausea or vomiting, and diarrhea. Causes include chemotherapy and radiation therapy: approximately 20% to 40% of patients receiving chemotherapy, 80% of patients receiving high-dose chemotherapy, and most patients receiving head and neck radiation therapy will experience mucositis. Severe mucositis can necessitate a reduction in the chemotherapy dose or a treatment break in radiation therapy.

The Multinational Association of Supportive Care in Cancer and the International Society of Oral Oncology have recommended the following specific guidelines based on the evidence:

Recommended guidelines for oral mucositis (strong evidence supports)⁴²:

1. Use 30 minutes of oral cryotherapy to prevent oral mucositis in patients receiving bolus 5-fluorouracil chemotherapy.

2. Use recombinant human keratinocyte growth factor-1 to prevent oral mucositis (60 mcg/kg per day for 3 days prior to conditioning treatment and for 3 days post transplant) in patients receiving high-dose chemotherapy and total body irradiation, followed by autologous stem cell transplantation, for a hematological malignancy.

3. Use low-level laser therapy to prevent oral mucositis in patients receiving hematopoietic stem cell transplantation (HSCT) conditioned with high-dose chemotherapy, with or without total body irradiation.

4. Use patient-controlled analgesia with morphine to treat pain from oral mucositis in patients undergoing hematopoietic stem cell transplantation.

5. Use benzydamine mouthwash to prevent oral mucositis in patients with head and neck cancer receiving moderate dose radiation therapy, without concomitant chemotherapy.

Oral mucositis suggestions (weaker evidence supports)42:

1. Use oral care protocols to prevent oral mucositis in all age groups and across all cancer treatment modalities.

2. Use cryotherapy to prevent oral mucositis in patients receiving high-dose melphalan, with or without total body irradiation, as conditioning for HSCT.

3. Use low-level laser therapy to prevent oral mucositis in patients undergoing radiotherapy, without concomitant chemotherapy, for head and neck cancer.

4. Transdermal fentanyl may be effective for treating pain from oral mucositis in patients receiving conventional or high-dose chemotherapy, with or without total body irradiation.

5. The panel suggests that 0.2% morphine mouthwash may be effective for treating pain from oral mucositis in patients receiving chemoradiation for head and neck cancer.

6. The panel suggests that 0.5% doxepin mouthwash may be effective for treating pain from oral mucositis.

7. Systemic zinc supplements administered orally may be of benefit to prevent oral mucositis in oral cancer patients receiving radiation therapy or chemoradiation.

Oral mucositis suggestions; recommendations against (strong evidence indicates lack of effectiveness)⁴²:

1. Do not use PTA (polymyxin, tobramycin, amphotericin B) and BCoG (bacitracin, clotrimazole, gentamicin) antimicrobial lozenges and PTA paste to prevent oral mucositis in patients receiving radiation therapy for head and cancer.

2. Do not use iseganan antimicrobial mouthwash to prevent oral mucositis in patients receiving high-dose chemotherapy, with or without total body irradiation, for HSCT or in patients receiving radiation therapy or concomitant chemoradiation for head and neck cancer.

3. Do not use sucralfate mouthwash to prevent oral mucositis in patients receiving chemotherapy for cancer or in patients receiving radiation therapy or concomitant chemoradiation for head and neck cancer.

4. Do not use sucralfate mouthwash to treat oral mucositis in patients receiving chemotherapy for cancer or in patients receiving radiation therapy for head and neck cancer.

5. Do not use IV glutamine to prevent oral mucositis in patients receiving high-dose chemotherapy, with or without total body irradiation, for HSCT.

Oral mucositis suggestions; recommendations against (weaker evidence indicates lack of effectiveness)⁴²:

1. Do not use chlorhexidine mouthwash to prevent oral mucositis in patients receiving radiation therapy for head and neck cancer.

2. Do not use granulocyte macrophage colony-stimulating factor (GM-CSF) mouthwash to prevent oral mucositis in patients receiving high-dose chemotherapy, for autologous or allogeneic stem cell transplantation.

3. Do not use misoprostol mouthwash to prevent oral mucositis in patients receiving radiation therapy for head and neck cancer.

4. Do not use systemic pentoxifylline, administered orally, to prevent oral mucositis in patients undergoing bone marrow transplantation.

5. Do not use systemic pilocarpine, administered orally, to prevent oral mucositis in patients receiving radiation therapy for head and neck cancer or in patients receiving highdose chemotherapy, with or without total body irradiation, for HSCT.

GI mucositis (other than the oral cavity): recommendations in favor (strong evidence supports effectiveness)⁴²:

1. Use IV amifostine ≥340 mg/m2 to prevent radiation proctitis in patients receiving radiation therapy.

2. Use Octreotide ≥100 mcg, administered subcutaneously twice daily, to treat diarrhea induced by standard- or high-dose chemotherapy associated with HSCT, if loperamide is ineffective.

GI mucositis (other than the oral cavity): suggestions in favor (weaker evidence supports effectiveness)⁴²:

1. Use IV amifostine to prevent esophagitis induced by concomitant chemotherapy and radiation therapy in patients with non—small cell lung carcinoma.

2. Use sucralfate enemas to treat chronic radiation-induced proctitis in patients with rectal bleeding.

3. Use systemic sulfasalazine 500 mg, administered orally twice daily, to prevent radiation-induced enteropathy in patients receiving radiation therapy to the pelvis.

4. Use probiotics containing Lactobacillus species to prevent diarrhea in patients receiving chemotherapy and/or radiation therapy for a pelvic malignancy.

5. Use hyperbaric oxygen to treat radiation-induced proctitis in patients receiving radiation therapy for a solid tumor.

GI mucositis (other than the oral cavity): recommendations against (strong evidence indicates lack of effectiveness)42:

1. Do not use systemic sucralfate, administered orally, to treat GI mucositis in patients receiving radiation therapy for a solid tumor.

2. Do not use salicylic acid (ASA) and the related compounds mesalazine and olsalazine, administered orally, to prevent acute radiation induced diarrhea in patients receiving radiation therapy for a pelvic malignancy.

3. Do not use misoprostol suppositories to prevent acute radiation-induced proctitis in patients receiving radiation therapy for prostate cancer.

Topical Agents for Mucositis

Magic mouthwash, typically a combination of Maalox or Mylanta, diphenhydramine, and lidocaine, has been used to treat mucositis. Five to 10 mL can be swished and spit or swallowed every 4 hours as needed for the pain. It is unclear how effective this medication is for mucositis; typically, these agents are short acting and do not cover the entire painful area. AEs of magic mouthwash may include problems with taste, a burning or tingling sensation in the mouth, drowsiness, constipation, diarrhea, and nausea. Lidocaine and benzocaine have also been used to coat the mouth to relieve pain. Caution must be used if eating or drinking afterward. Typically, opioid pain medications are needed to relieve pain.

End Note

​Pain can present in many different forms during cancer. It is important to take an accurate history and treat the correct pain. The choice of medication will depend on age, other disease states, and drug interactions. With the correct pain medication, dose, and frequency, pain can be controlled, even relieved.

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