Cancer Pain (PDQ®)–Health Professional Version - National Cancer Institute

Cancer Pain (PDQ®)–Health Professional Version

General Approaches to Pain Treatment

Decision-making Approach

Pain management varies widely in complexity. The decision-making process involves a careful consideration of many patient-related and pain-related factors. These may include, but are not limited to, the pain mechanism, pain expression, previous treatments, available options, and prognosis. Recognition of specific pain syndromes can be useful in guiding management.

Approach to Somatic Pain

Damage and/or inflammation involving the muscles, skin, joints, connective tissue, or bones can lead to activation of the nociceptive pathways that result in somatic pain. This type of pain is often well localized; may be described as sharp, achy, throbbing, and/or stabbing in nature; and often worsens with movement. It can often be managed with acetaminophen, anti-inflammatories, and opioids. Bone pain related to metastases is particularly common in cancer patients and is discussed below in more detail.

Bone pain

Bone pain due to metastatic disease is one of the most common causes of pain in cancer patients.[1,2] Bone is highly innervated tissue with receptors sensitive to mechanical damage.[3] The entrapment of nerve fibers in the collapsing bony matrix caused by increased osteoclastic activity and the release of inflammatory cytokines by cancer cells and immune cells are also central to the pathophysiology of bone pain.[3] Patients typically describe the pain as continuous, deep, and throbbing, with brief episodes of more-severe pain often precipitated by movement (i.e., a type of incident pain).

Most patients will require morphine or an equivalent opioid for adequate pain relief, although incident pain is less responsive. Adjunctive agents such as nonsteroidal anti-inflammatory drugs and corticosteroids are often prescribed and appear moderately effective and safe.[4]

In addition to providing analgesia, the clinician introduces treatments designed 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 (refer to the Bisphosphonates and denosumab section of this summary for more information) have been demonstrated to reduce future skeletal-related events and to reduce the likelihood of increased pain or increased use of opioids in patients with advanced cancer.[5]

Palliative radiation therapy produces complete or partial pain relief in up to 80% of treated patients; the median duration of relief exceeds 6 months.[6] (Refer to the External-Beam Radiation Therapy section of this summary for more information.)

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

Approach to Visceral Pain

Visceral pain is a type of nociceptive pain that originates in nociceptors innervating visceral organs. Several features of visceral pain inform the therapeutic approach:

Not all internal organs have nociceptors. 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.[7]
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.[8] Also important are radiographic studies to look for underlying causes that may be amendable to other interventions (e.g., bowel obstruction).

Approach to Neuropathic Pain

Pain with features suggestive of 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. These patients reported worse physical, cognitive, and social functioning than did those with nociceptive pain; were on more analgesic medications and higher doses of opioids; and had a worse performance status.[9] Neuropathic pain is considered less responsive to opioids. Multiple therapeutic options instead of or in addition to opioids have been studied. Most of these studies were conducted in patients with nonmalignant sources of neuropathic pain and may not be applicable to patients with cancer with different etiologies 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. Gabapentin improved analgesia when added to opioids for uncontrolled cancer-related neuropathic pain.[10,11] When gabapentin was used adjuvantly to an opioid regimen, improvement in pain control was seen within 4 to 8 days.[12] 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.[13] Compared with monotherapy with amitriptyline, gabapentin, or placebo, pregabalin use resulted in a significant decrease in pain score when studied in neuropathic cancer pain.[14]

Notably, in a systemic review of neuropathic pain that included mostly patients with a nonmalignant source of neuropathic pain, the effect of gabapentin and pregabalin appeared less robust.[15] Data comparing gabapentin or pregabalin directly with TCAs and serotonin–norepinephrine reuptake inhibitors (SNRIs) are limited, especially in patients with cancer. Efficacy of TCAs and SNRIs appears to be comparable and, in some cases, superior to gabapentin or pregabalin (refer to the Chemotherapy-induced peripheral neuropathy (CIPN) section of this summary for more information). Because of concerns about side effects and drug-drug interactions, many practitioners tend to start with gabapentin or pregabalin as first-line treatment for neuropathic pain. However, as noted below, certain neuropathic syndromes may be less responsive to these agents. (Refer to the Postthoracotomy pain syndrome and Chemotherapy-induced peripheral neuropathy (CIPN) sections of this summary for more information.) Studies have also examined the use of lidocaine patches, tramadol, topically applied capsaicin, and botulinum toxin A for use in patients with neuropathic pain [15] with inconclusive results.

Postmastectomy pain syndrome

Rates of postmastectomy pain range between 25% and 33%,[16-19] making this a common complication. Women with postmastectomy pain note more role limitations due to physical, emotional, and mental health issues.[16] Associations of postmastectomy pain with extent of surgery, radiation therapy, and chemotherapy are inconsistent across studies. One cross-sectional study found associations between postmastectomy pain and psychosocial factors such as depression, anxiety, somatization, and catastrophizing.[17,19]

A number of small studies have examined the effect of an anesthetic administered intraoperatively or immediately postoperatively, with varying results;[20] one group found a decrease in pain during the infusion but no benefits after the infusion until 12 months.[21,22] The use of venlafaxine or gabapentin for 10 days, starting 1 day before surgery, may decrease postmastectomy pain,[23] but confirmatory studies are needed.

Postthoracotomy pain syndrome

Defined as pain occurring 2 months after thoracotomy, postthoracotomy pain syndrome occurs in approximately 50% of patients and may be underreported and undertreated. The pain is thought to be related to damage to the intercostal nerve during surgery and from postoperative drainage via chest tubes. The pain includes both neuropathic and nonneuropathic components.[24]

Opioid and nonopioid analgesics are part of the standard approach to treatment. Several approaches in the immediate postoperative period are being investigated. An open-label noncontrolled study of 5% lidocaine patches showed improvement in pain scores 1 month postoperatively.[25] A small randomized trial of transcutaneous electrical nerve stimulation demonstrated decreased pain and reduced use of morphine and nonopioid analgesia in the immediate postoperative period.[26] Patients randomly assigned to receive intraoperative cryoanalgesia versus placebo were found to have less pain at time points up to 60 days postoperatively and reduced analgesic use in the first 3 days.[27] Further work is needed to confirm these results. In a randomized, double-blinded, placebo-controlled study of gabapentin started preoperatively and titrated over 5 days postoperatively, gabapentin failed to show benefit.[28]

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 platinum compounds (e.g., oxaliplatin, cisplatin, and carboplatin, in descending order of severity), taxanes (e.g., paclitaxel, docetaxel), thalidomide, and vinca alkaloids. Among newer agents, ixabepilone, lenalidomide, pomalidomide, and bortezomib are common sources. With these agents, CIPN limits the dose of chemotherapy delivered, which may affect the outcomes of treatment.[29] In one series of women treated with taxanes, approximately one in four reported CIPN.[30] Although CIPN often improves after discontinuation or completion of chemotherapy, symptoms can linger for a year or longer for some patients, especially those treated with taxanes.[31]

Studies evaluating treatment for CIPN have been plagued by methodologic flaws such as small size and open-label comparisons. Differences in the defined endpoints have also made it difficult to compare across studies. Duloxetine is the only agent whose efficacy in treating CIPN is supported by data from a large phase III study.[32] One group of investigators found 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.[32] 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.[32,33]

Investigators studied the use of venlafaxine for prevention and relief of oxaliplatin-induced acute neuropathy and found both a significant decrease in acute neuropathy and an increased relief at 3 months after treatment.[34] There is hesitation to use venlafaxine preventively because its antioxidative effects may decrease the efficacy of oxaliplatin. American Society of Clinical Oncology (ASCO) CIPN guidelines do not recommend routine use of venlafaxine for CIPN because of a lack in strength of the existing data.[35]

Evidence of the efficacy of nortriptyline and amitriptyline in CIPN is limited to small and frequently underpowered trials with mixed results.[36-38] ASCO guidelines [35] recommend against the use of many commonly prescribed agents for the treatment of existing CIPN and do not recommend any agent for CIPN prevention. For treatment, the guidelines suggest that the best current evidence supports the use of duloxetine, on the basis of the randomized controlled trial mentioned above.[32] Despite inconclusive trials, the authors suggest 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.[39]

Approach to Acute Procedural Pain

Bone marrow biopsy and aspiration

Bone marrow biopsy and aspiration cause pain in 84% of patients, with intensity reported as severe in 8% to 35%.[40] Factors associated with greater pain are the duration of the procedure (taking longer than 10 minutes), younger age, higher body mass index, female sex, anxiety, site of examination (sternum being the most painful), inadequate information given before procedure, and lack of physician experience.[41] Pharmacologic interventions for pain control vary from local anesthesia,[42] to intravenous sedation with benzodiazepines and/or opioids,[43] to the use of inhaled nitrous oxide,[44] to premedication with opioids. Addressing anxiety is an important nonpharmacologic intervention.[41]

Lumbar puncture

Lumbar puncture is a diagnostic and staging tool for hematologic malignancies and solid tumors involving the central nervous system. Patients can develop post–lumbar puncture headache. Headaches usually develop hours to days after the procedure and are caused by leakage of cerebrospinal fluid, possible compensatory intracranial vessel dilatation, or increased tension on brain and meninges.[45] The use of an atraumatic small-bore needle has been found to reduce to incidence of post–lumbar puncture headaches.[46,47] A Cochrane review that included 13 small randomized trials mostly in noncancer patients reported some evidence to support the use of caffeine, gabapentin, hydrocortisone, and theophylline to treat post–lumbar puncture headache, and a lack of efficacy for sumatriptan, adrenocorticotropic hormone, pregabalin, and cosyntropin.[48]

Treatment of Pain in Specific Patient Populations

Pediatric cancer patients

Refer to the PDQ summary on Pediatric Supportive Care for more information.

Geriatric cancer patients

Geriatric patients are defined as persons aged 65 years or older, with a significant increase in incidence of comorbidity after age 75 years.[49,50] Up to 80% of geriatric cancer patients have pain over the course of their disease.[51] There are unique concerns in the treatment of cancer pain in this patient population, resulting from a narrowed therapeutic index of many analgesic and adjunctive medications. Age-related physiologic changes alter pharmacodynamics and pharmacokinetic drug properties (refer to Table 7).[52-55] Increased comorbidities and the resulting polypharmacy put patients at risk of drug-disease and drug-drug interactions. In addition, few clinical trials have been performed in patients older than 65 years to confirm drug safety and efficacy. For geriatric patients, analgesic medications need to be started at low doses and titrated up gradually. The rationales behind this approach include higher pain thresholds,[56] differences in pain expression,[57] and greater effects on physical and psychosocial function in this patient population.[58] (Refer to the Pain Assessment section of this summary for more information.)

Table 7. Pharmacokinetic and Pharmacodynamic Changesa

Age-Related Physiologic Change	Example of Affected Drugs
NSAID = nonsteroidal anti-inflammatory drug.
aAdapted from American Geriatrics Society Panel on Pharmacological Management of Persistent Pain in Older Persons,[52] Miller,[53] Bosilkovska et al.,[54] and Lexicomp Online.[55]
Decreased renal function	Increased accumulation of morphine metabolites
Decreased renal function	Increased risk of NSAID-induced renal dysfunction
Increased body fat/decreased body water	Delayed elimination of lipophilic drugs such as methadone
Cachexia	Decreased fentanyl absorption from transdermal fentanyl patches [59]
Decreased hepatic function	Results in increased oral bioavailability and half-life of opioids
	– Decrease dose: hydromorphone, oxycodone
	– Increase dose interval: morphine, oxycodone
Reduced protein binding	Increased drug sensitivity/side effects
Reduced cytochrome P450 enzyme activity	Increased drug concentrations of fentanyl and methadone
Decreased gastrointestinal motility	Increased risk of opioid-induced constipation

Geriatric patients are also at risk of undertreatment because of underreported pain, difficulty communicating, and physician concerns about adverse effects and aberrant behavior. Persistent, inadequately controlled pain leads to poor outcomes in older patients, including the following:[52]

Functional impairment.
Slower rehabilitation.
Sleep and appetite changes.
Increased use of health care resources.

Treatment of an underlying depression can help facilitate pain treatment.[60]

The American Geriatrics Society (AGS) recommends the use of acetaminophen over nonsteroidal anti-inflammatory drugs (NSAIDs), when possible, for the treatment of mild to moderate musculoskeletal pain.[52] Compared with acetaminophen, NSAIDs carry an increased risk of gastrointestinal bleed/peptic ulcer disease, and exacerbating hypertension and heart failure. The maximum recommended dose of acetaminophen is 3 to 4 g per day. When the use of NSAIDs is necessary, as in cases of chronic inflammatory pain, particular caution should be used in patients with reduced renal function, gastropathy, cardiovascular disease, or dehydration.

Strategies to prevent gastrointestinal adverse effects include the following:[52]

Co-administration of a gastroprotective agent such as an H2 receptor antagonist or a proton pump inhibitor.
Use of a COX-2–selective NSAID.
Use of a topical NSAID.

Opioids continue to be the mainstay of treating moderate to severe pain in geriatric patients. Elderly patients may be more sensitive to opioids because of the decreased renal and hepatic clearance of these drugs and their metabolites.[61,62] Geriatric patients may also need lower doses because they achieve greater analgesia from opioids. One retrospective study of opioid consumption in geriatric patients found that they need less opioid with acute and chronic pain therapy; they require less opioid regardless of route of administration; and incidental pain and/or neuropathic pain did not confound the correlation between age and opioid consumption but was associated with higher doses of opioids.[63] Geriatric patients are more susceptible to opioid adverse effects such as sedation and constipation. Guidelines recommend starting with lower opioid doses and increasing time between doses, with frequent reassessment of pain control to prevent underdosing. Meperidine should be avoided because of a lack of efficacy and increased risk of adverse effects, including seizure.[52]

Adjunct agents are often used with opioids to improve pain control for geriatric patients. Many of these adjunct agents are listed in the AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults, to be avoided or used with caution in geriatric patients because of their increased risk of adverse effects [49] (refer to Table 8). For example, because of their high rate of anticholinergic effects, sedation, and risk of syncope and falls, tricyclic antidepressants commonly used to treat neuropathic pain conditions should be avoided in geriatric patients. Suggested alternatives for the treatment of neuropathic pain include duloxetine, gabapentin, topical capsaicin, and the lidocaine patch.[64]

Table 8. Potentially Inappropriate Medications Based on Beers Criteriaa

Drug/Class	Example	Rationale
CNS = central nervous system; COX-2 = cyclooxygenase-2; NSAIDs = nonsteroidal anti-inflammatory drugs.
aAdapted from American Geriatrics Society 2015 Beers Criteria Update Expert Panel.[49]
Tricyclic antidepressants	Amitriptyline, clomipramine, imipramine	Anticholinergic effects, sedation, orthostatic hypotension
Meperidine		Decreased efficacy, potential neurotoxicity
Non–COX-2–selective NSAIDs	Ibuprofen, diclofenac, naproxen	Gastrointestinal bleed risk, increased blood pressure, renal toxicity
Skeletal muscle relaxants	Cyclobenzaprine, metaxalone, methocarbamol	Anticholinergic effects, sedation, risk of fracture
CNS	Avoid/reduce dose in renal impairment:	CNS adverse effects
	– Gabapentin
	– Pregabalin
	– Duloxetine

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Hanlon JT, Semla TP, Schmader KE: Alternative Medications for Medications in the Use of High-Risk Medications in the Elderly and Potentially Harmful Drug-Disease Interactions in the Elderly Quality Measures. J Am Geriatr Soc 63 (12): e8-e18, 2015. [PUBMED Abstract]

Changes to This Summary (09/12/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

General Information About Cancer Pain

Revised text to state that if opioids are considered, fear of opioids and the risks of opioid use and misuse should be addressed.

Added a new subsection on white blood cell growth factor–related bone pain.

Pain Assessment

Added text about catastrophizing.

Added text to state that these studies describe larger cultural responses to pain that may inform assessments or improve understanding of pain communication by providers. Also added that in addition to a broad cultural understanding, it should be noted that subcultural differences or individual differences within each ethnic group may affect the experience or expression of pain.

Pharmacologic Therapies for Pain Control

In Table 2, revised equianalgesic dosing information for diamorphine, fentanyl, and methadone.

In Table 3, revised agent information for sublingual route of administration.

In Table 4, added comment for fentanyl nasal spray (Lazanda) to note that it achieves the most rapid onset.

Revised text to state that methadone is safer for patients with renal dysfunction, given that it is minimally renally excreted.

Revised text to state that methadone is metabolized by CYP2B6, CYP2C19, CYP3A4 and CYP2D6. Also added text to state that the principal enzyme responsible for methadone levels and drug clearance is CYP2B6 (cited McPherson et al. as reference 28).

Revised text to state that a follow-up electrocardiogram 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.

Added text to state that factors contributing to opioid-induced respiratory depression include obstructive sleep apnea, obesity, and concomitant sedating medications.

Revised text on constipation to state that patients are encouraged to maintain adequate hydration, increase dietary fiber intake, and exercise regularly, in addition to taking laxatives.

Revised text to state that a scheduled stimulant laxative, such as senna, is started with opioid initiation.

The subsection on Hyperalgesia was extensively revised.

Revised text to state that renal insufficiency affects the excretion of morphine, codeine, oxycodone, hydromorphone, oxymorphone, and hydrocodone.

Added text to state that none of the screening tools have been validated in an oncology population.

Added Adjuvant Pain Medications as a new subsection.

Modalities for Pain Control: Other Approaches

Added text to state that patient selection can be important regarding the likelihood of benefit from radiation therapy. Also added that in one study, patients with hematologic tumors, a neuropathic component of the index pain, and no previous treatment with opioid analgesics before radiation therapy were more likely to experience pain palliation after radiation therapy (cited Saito et al. as reference 18).

This summary is written and maintained by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the pathophysiology and treatment of pain. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

be discussed at a meeting,
be cited with text, or
replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Cancer Pain are:

Mary K. Buss, MD, MPH (Beth Israel Deaconess Medical Center)
Heather C. Justice, MSPAP, PA-C (Milligan College)
Alison Palumbo, PharmD, MPH, BCOP (Oregon Health and Science University Hospital)
Megan Reimann, PharmD, BCOP (Indiana University Simon Cancer Center)
Amy Wachholtz, PhD, MDiv, MS (University of Colorado)
Jason A. Webb, MD, FAPA (Duke University Medical Center)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Supportive and Palliative Care Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Supportive and Palliative Care Editorial Board. PDQ Cancer Pain. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/treatment/side-effects/pain/pain-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389387]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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