CANCER PAIN

Pain occurs in 20% to 50% of patients with cancer. Roughly 80% of patients with advanced-stage cancer have moderate to severe pain. One meta-analysis examining pooled data from 52 studies found that more than half of patients had pain. Younger patients are more likely than older patients to experience cancer pain and pain flares.

Causes of Cancer Pain: Cancer, Cancer Treatments, and Comorbidities

A study evaluating the characteristics of patients (N = 100) with advanced cancer presenting to a palliative care service found the primary tumor as the chief cause of pain in 68% of patients. Most pain was somatic, and pain was as likely to be continuous as intermittent.

Pain can be caused by the following:

Surgery.
Radiation therapy.
Chemotherapy.
Targeted therapy.
Supportive care therapies.
Diagnostic procedures.

A systematic review of the literature identified reports of pain occurring in 59% of patients receiving anticancer treatment and in 33% of patients after curative treatments. The prevalence of chronic nonmalignant pain—such as chronic low back pain, osteoarthritis pain, fibromyalgia, and chronic daily headaches—has not been well characterized in cancer patients. It has been reported to range from 2% to 76%, depending on the patient population and how pain was assessed.

Postoperative pain

Pain is an expected consequence of surgery. Concerns about the prevalence of opioid misuse have drawn increasing attention to how opioids are prescribed in common settings, including postoperatively. Studies suggest widespread variation in the prescribing patterns of opioids in the postoperative setting. One study of opioid use after orthopedic and general surgery procedures found that, on average, only between 19% and 34% of the opioids prescribed were used and that the quantity of opioids prescribed after a given procedure varied widely by provider. This finding led to the evaluation of utilization data and recommendations for standardizing the quantity of opioids prescribed for five common general surgery procedures. An educational intervention based on those recommendations was associated with a 53% decrease in prescribed opioids after those five general surgery procedures, with only 1 patient in a cohort of 246 patients requiring an opioid refill.

The opioid epidemic has also raised questions about whether postoperative use of opioids can lead to misuse. New, persistent opioid use develops in 6% to 8% of patients who have never used opioids after noncancer surgery. In a large retrospective analysis of patients undergoing curative-intent cancer surgery, 10.4% of opioid-naïve patients developed new persistent opioid use, defined as filling opioid prescriptions 90 to 180 days after surgery. At 1 year postsurgery, these patients were using an average of six 5-mg hydrocodone (or equivalent) tablets per day. Among the risk factors evaluated, only the use of adjuvant chemotherapy increased the risk of new persistent opioid use (15%–21% risk with adjuvant chemotherapy vs. 7%–11% risk with no chemotherapy). In summary, one in ten patients undergoing curative-intent cancer surgery may be at risk of postoperative persistent opioid use.

Infusion-related pain syndromes

The infusion of intravenous chemotherapy causes four pain syndromes:

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.
Vesicant extravasation, which may cause intense pain followed by desquamation and ulceration.
Anthracycline-associated flare, a venous flare reaction that may be caused by doxorubicin and includes local urticaria, pain, or stinging.

Treatment-related mucositis

Severe mucositis often occurs as a consequence of myeloablative chemotherapy and standard-intensity therapy. Cytotoxic agents commonly associated with mucositis are cytarabine, doxorubicin, etoposide, fluorouracil (5-FU), and methotrexate. Epidermal growth factor receptor (EGFR) inhibitors, multitargeted tyrosine kinase inhibitors, and mammalian target of rapamycin inhibitors also cause mucositis. Risk factors for mucositis include preexisting oral pathology, poor dental hygiene, and younger age.

White blood cell growth factor–related bone pain

Filgrastim and pegfilgrastim are recombinant granulocyte colony-stimulating factors (G-CSFs) that increase proliferation and differentiation of neutrophil precursors. Ostealgia is a significant adverse effect caused by G-CSFs that can occur in 20% to 71% of patients. This bone pain starts within 2 days of a pegfilgrastim dose and lasts for 2 to 4 days. Although the mechanism by which 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 II trial randomly assigned patients who had experienced bone pain with pegfilgrastim to receive either daily loratadine 10 mg for 7 days or a matching placebo after subsequent doses of pegfilgrastim. There was no statistically significant difference between the two arms.

A second phase II trial randomly assigned patients receiving pegfilgrastim to receive naproxen, loratadine, or no preventative medications. 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. 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.

Conventional pain medications have also been studied in this area. A phase III, 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 a placebo. Naproxen reduced overall pain intensity and duration of pain, compared with placebo.

Chemotherapy-related musculoskeletal pain

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

Dermatologic complications and chemotherapy

EGFR inhibitors cause dermatitis with ensuing pain. Acute herpetic neuralgia occurs with a significantly increased incidence among cancer patients, especially those with hematologic malignancies and those receiving immunosuppressive therapies. 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, liposomal doxorubicin, and paclitaxel. Targeted agents such as sorafenib and sunitinib are also associated with hand-foot–like syndrome. 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 and pain

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

Radiation-induced pain

Radiation is associated with several distinct pain syndromes. First, patients may experience pain from brachytherapy 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 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. A randomized trial demonstrated that dexamethasone (8 mg on the day of radiation therapy and daily for the following 4 days) reduces the incidence of pain flares, compared with placebo. For more information, see the External-Beam Radiation Therapy section.

Nociceptive pain, which may be either somatic or visceral in nature, originates with a chemical, mechanical, or thermal injury to tissue that stimulates pain receptors, which transmit a signal to the central nervous system (CNS), causing the perception of pain. Pain receptors are found in somatic (e.g., cutaneous, bone) and visceral tissues. The amount of visceral sensory innervation and the diffusion of visceral pain signals within the brain explain the difficulty experienced by patients in describing or localizing visceral pain compared with somatic pain. A specific type of visceral pain is referred pain, which is explained by the commingling of nerve fibers from somatic and visceral nociceptors at the level of the spinal cord. Patients mistakenly interpret the pain as originating from the innervated somatic tissue. Visceral pain may be accompanied by autonomic signs such as sweating, pallor, or bradycardia. Somatic pain is more easily localized.

Neuropathic pain is pain caused by damage to the peripheral nervous system or the CNS (spinal cord or brain). Causes of neuropathic 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). The pain may be evoked by stimuli or spontaneous. Patients who experience pain from nonnoxious stimuli are classified as having allodynia. Hyperalgesia connotes increased sensations of pain out of proportion to what is usually experienced.

Emotional distress may also contribute to the pain experience. Most patients with cancer and pain do not have somatic symptom disorder. However, if pain complaints appear to be disproportionate to the underlying pain stimulus, it is important to evaluate for psychological and existential distress contributing to the pain complaint, chemical coping, and substance use disorder.

Acute and Chronic Cancer Pain

Pain is often classified as either acute or chronic or by how it varies over time with terms such as breakthrough, persistent, or incidental. Acute pain is typically induced by tissue injury, begins suddenly with the injury, and diminishes over time with tissue healing. There is no definite length but, in general, acute pain resolves within 3 to 6 months. The treatment of acute pain focuses on blocking nociceptive pathways while the tissue heals.

Chronic pain typically persists even after the injury has healed, although patients with chronic joint disease, for example, may have ongoing tissue damage and therefore experience chronic pain. Pain becomes chronic when it:

Continues for more than 1 month after the healing of precipitating lesions.
Persists or becomes recurrent over months.
Results from lesions unlikely to regress or heal.

The transition from acute to chronic pain may be understood as a series of relatively discrete changes in the CNS,[9] but the genesis of chronic pain also includes clearly behavioral confounders. Chronic pain involves the activation of secondary mechanisms such as the sensitization of second-order neurons by upregulation of N-methyl-D-aspartic acid channels and alteration in microglia cytoarchitecture. Chronic pain, with its multiple factors for perpetuation, often benefits from a multidisciplinary approach to treatment.

Adjuvant Pain Medications

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. These drugs have been widely studied in the treatment of neuropathic pain syndromes and as adjunctive agents with opioids. For more information, see the Approach to Neuropathic Pain section.

These medications may cause the following symptoms:

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

Gradual upward titration of gabapentin to a maximum of 3,600 mg per day and pregabalin to 300 mg per day can help with dose-dependent sedation and dizziness. 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 renal dysfunction.[10,116]

Venlafaxine and duloxetine

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

Common dosing for duloxetine ranges from 30 to 60 mg per day. Side effects include the following:[117]

Nausea.
Headache.
Fatigue.
Dry mouth.
Constipation.

Duloxetine is avoided in patients with hepatic impairment and severe renal 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 CIPN.

Venlafaxine can be started at 37.5 mg, with a maximum dose of 225 mg per day. 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 or a history of seizures and is dose-adjusted for patients with renal or hepatic insufficiency. If the decision is made to discontinue either venlafaxine or duloxetine, a slow tapering course may help to minimize withdrawal symptoms.

Tricyclic antidepressants (TCAs)

The TCAs amitriptyline, desipramine, and nortriptyline are used to treat many neuropathic pain syndromes. These drugs enhance pain inhibitory pathways by blocking serotonin and norepinephrine reuptake.

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, TCAs are used with caution in older patients, patients with seizure disorders, and those with preexisting cardiac disease.

Corticosteroids

There is a lack of high-quality data demonstrating the efficacy of corticosteroids in treating cancer pain. 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. A small but well-designed study showed no benefit to adding corticosteroids to opioid analgesia in the short term (7 days).

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

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, to dexamethasone 10 mg twice daily. 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.

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. If taken for more than 3 weeks, corticosteroids are tapered upon improvement in pain, if possible. If corticosteroids are to be continued long term, anti-infective prophylaxis can be considered. Dexamethasone is preferred because it has reduced mineralocorticoid effects, resulting in reduced fluid retention; however, it does exhibit cytochrome P450–mediated drug interactions.

Bisphosphonates and denosumab

The bisphosphonate class of drugs inhibits osteoclastic bone resorption, decreasing bone pain and skeletal-related events associated with cancer that has metastasized to the bone. Pamidronate and zoledronic acid decrease cancer-related bone pain, decrease analgesic use, and improve quality of life in patients with bone metastases. American Society of Clinical Oncology (ASCO) guidelines for the use of these bone-modifying agents in patients with breast cancer and myeloma specify they should be used not as monotherapy, but as part of a treatment regimen that includes analgesics and nonpharmacological interventions.

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 adverse effects include renal toxicity, electrolyte imbalances, and osteonecrosis of the jaw. Doses are adjusted for patients with renal 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. 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. Interestingly, patients who crossed over and received both treatments had a longer overall survival than did patients who did not cross over. 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.

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 (relative risk, 0.84; 95% CI, 0.77–0.91).

Compared with zoledronic acid, denosumab has similar adverse effects with less nephrotoxicity and increased hypocalcemia. There is no adjustment for renal 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.

Ketamine

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

Lack of demonstrated clinical benefit, significant adverse events, and CYP3A4-associated drug interactions limit ketamine’s utility in the treatment of cancer pain. It 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. Adverse drug reactions include the following:

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

Chemotherapy-induced peripheral neuropathy (CIPN)

Peripheral neuropathy is a common toxic effect of chemotherapy and is predominantly a sensory neuropathy. Patients report numbness and tingling in a stocking-and-glove distribution. CIPN is most commonly associated with the following:[31]

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 CIPN. With any of these agents, CIPN may limit the dose of chemotherapy delivered, which may affect the outcomes of treatment. In one series of women treated with docetaxel, approximately one in four reported CIPN. Although CIPN 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. Newer immunotherapies, such as pembrolizumab and nivolumab, can produce peripheral neuropathies. The prevalence may become clear as more patients are treated with these agents.

In two studies of women with breast cancer, peripheral neuropathy correlated negatively with QOL.[36][Level of evidence: II]; The effect of a docetaxel regimen and patient characteristics on peripheral neuropathy and QOL was evaluated in a substudy of the NASBP B-30 trial. The B-30 trial randomly assigned women with 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. 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). Treatment with AC→T, 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 QOL.

Preventing and reducing risk of CIPN

In 2020, the American Society of Clinical Oncology (ASCO) released a guideline update on the prevention and management of CIPN. 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.

It is recommended that clinicians assess the risks and benefits of agents known to cause CIPN among patients with underlying neuropathy and with conditions that predispose to neuropathy. These conditions include the following:[39,40]

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 CIPN 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:[37]

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

In a genome-wide association study, genetically determined African American ancestry was the most significant predictor of taxane-induced peripheral neuropathy. 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. Eligible African American cancer survivors were surveyed to determine if there was an association between nongenetic risk factors and comorbidities with CIPN. Patients with CIPN 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 CIPN.

Treatment modalities for CIPN

Pharmacological treatments

ASCO guidelines recommend against the use of many commonly prescribed agents for the treatment of existing CIPN. The exception is duloxetine because it is the only agent whose efficacy in treating CIPN is evidence based.[44] One large phase III 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 QOL. 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.

Gabapentin failed to provide a benefit in CIPN when used as monotherapy in a randomized, double-blind, placebo-controlled trial.

Evidence of the efficacy of nortriptyline and amitriptyline in CIPN is limited to small and frequently underpowered trials with mixed results. Despite inconclusive trials, the authors suggested that a trial of 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.

Nonpharmacological treatments

Scrambler therapy

Scrambler therapy is the application of electrical currents to discrete areas of the body as guided by the patient’s report of pain. The therapy is usually applied in ten consecutive sessions, although guidelines permit the skipping of weekend days. The technique 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.[52] 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.