Background and Definitions

The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”[2] Pain is commonly experienced by cancer patients. Its proper assessment requires measuring pain intensity; clarifying the impact of pain on patients’ psychological, social, spiritual, and existential domains; and establishing treatment adherence and responsiveness.

A commonly used approach to pain management employs the World Health Organization (WHO) pain relief ladder, which categorizes pain intensity according to severity and recommends analgesic agents based on their strength.[3] Pain intensity is often assessed using a numeric rating scale (NRS) of 0 to 10. On this scale, 0 indicates no pain, 1 to 3 indicates mild pain, 4 to 6 indicates moderate pain, and 7 to 10 indicates severe pain.[4]

Step 1 on the WHO pain relief ladder treats mild pain. Patients in this category receive nonopioid analgesics such as acetaminophen, nonsteroidal anti-inflammatory drugs, or an adjuvant analgesic, if necessary. Step 2 treats patients experiencing mild to moderate pain who are already taking a nonopioid analgesic, with or without an adjuvant analgesic, but who are still experiencing poor analgesia. Step 2 agents include tramadol and acetaminophen products containing hydrocodone, oxycodone, and codeine. Step 3 treats moderate to severe pain with strong analgesics. Step 3 opioids include morphine, hydromorphone, fentanyl, levorphanol, methadone, oxymorphone, and oxycodone.

Familiarity with opioid pharmacokinetics, equianalgesic dosing, and adverse effects is necessary for their safe and effective use. The appropriate use of adjuvant pharmacological and nonpharmacological interventions is needed to optimize pain management.

Prevalence

Pain occurs in 20% to 50% of patients with cancer.[5] Roughly 80% of patients with advanced-stage cancer have moderate to severe pain.[6] One meta-analysis looking at pooled data from 52 studies found that more than half of patients had pain.[7] Younger patients are more likely to experience cancer pain and pain flares than are older patients.[8]

Cancer patients often have multiple sites of pain.[9] Patients rated pain from 4 to 6 (severe) on the NRS, with exacerbations rated as high as 7.

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.[9] Most pain was somatic, and pain was as likely to be continuous as intermittent.

Pain can be caused by cancer therapies, including surgery, radiation therapy, chemotherapy, targeted therapy, supportive care therapies, and/or 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.[10] Pain unrelated to cancer is relatively common in cancer patients, occurring in 16% of patients in one study.[9]

Impact on Function and Quality of Life

Cancer pain is associated with increased emotional distress. Both pain duration and pain severity correlate with risk of developing depression. Cancer patients are disabled an average of 12 to 20 days per month, with 28% to 55% unable to work because of their cancer.[28] Cancer survivors may experience distress when their pain unexpectedly persists after completion of cancer treatments.[29] Survivors also experience loss of support from their previous health care team as oncologists transition their care back to primary care providers.

In one study, between 20% and 50% of cancer patients continued to experience pain and functional limitations years posttreatment.[30] Untreated pain leads to requests for physician-assisted suicide.[31] Untreated pain also leads to unnecessary hospital admissions and visits to emergency departments.[32]

References

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3. Davis MP, Walsh D: Epidemiology of cancer pain and factors influencing poor pain control. Am J Hosp Palliat Care 21 (2): 137-42, 2004 Mar-Apr. [PubMed: 15055515]
4. Oldenmenger WH, de Raaf PJ, de Klerk C, et al.: Cut points on 0-10 numeric rating scales for symptoms included in the Edmonton Symptom Assessment Scale in cancer patients: a systematic review. J Pain Symptom Manage 45 (6): 1083-93, 2013. [PubMed: 23017617]
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8. Green CR, Hart-Johnson T: Cancer pain: an age-based analysis. Pain Med 11 (10): 1525-36, 2010. [PubMed: 21199305]
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10. van den Beuken-van Everdingen MH, de Rijke JM, Kessels AG, et al.: Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol 18 (9): 1437-49, 2007. [PubMed: 17355955]
11. Sauerland C, Engelking C, Wickham R, et al.: Vesicant extravasation part I: Mechanisms, pathogenesis, and nursing care to reduce risk. Oncol Nurs Forum 33 (6): 1134-41, 2006. [PubMed: 17149396]
12. Pucino F, Danielson BD, Carlson JD, et al.: Patient tolerance to intravenous potassium chloride with and without lidocaine. Drug Intell Clin Pharm 22 (9): 676-9, 1988. [PubMed: 3063479]
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16. Lacouture ME, Anadkat MJ, Bensadoun RJ, et al.: Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer 19 (8): 1079-95, 2011. [PMC free article: PMC3128700] [PubMed: 21630130]
17. Boers-Doets CB, Epstein JB, Raber-Durlacher JE, et al.: Oral adverse events associated with tyrosine kinase and mammalian target of rapamycin inhibitors in renal cell carcinoma: a structured literature review. Oncologist 17 (1): 135-44, 2012. [PMC free article: PMC3267813] [PubMed: 22207567]
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19. Coleman RE, Bolten WW, Lansdown M, et al.: Aromatase inhibitor-induced arthralgia: clinical experience and treatment recommendations. Cancer Treat Rev 34 (3): 275-82, 2008. [PubMed: 18082328]
20. Lynch TJ Jr, Kim ES, Eaby B, et al.: Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist 12 (5): 610-21, 2007. [PubMed: 17522250]
21. Portenoy RK, Duma C, Foley KM: Acute herpetic and postherpetic neuralgia: clinical review and current management. Ann Neurol 20 (6): 651-64, 1986. [PubMed: 3545049]
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25. Chu D, Lacouture ME, Fillos T, et al.: Risk of hand-foot skin reaction with sorafenib: a systematic review and meta-analysis. Acta Oncol 47 (2): 176-86, 2008. [PubMed: 18210295]
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28. Brown LF, Kroenke K, Theobald DE, et al.: The association of depression and anxiety with health-related quality of life in cancer patients with depression and/or pain. Psychooncology 19 (7): 734-41, 2010. [PMC free article: PMC2888919] [PubMed: 19777535]
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30. Harrington CB, Hansen JA, Moskowitz M, et al.: It's not over when it's over: long-term symptoms in cancer survivors--a systematic review. Int J Psychiatry Med 40 (2): 163-81, 2010. [PubMed: 20848873]
31. Foley KM: The relationship of pain and symptom management to patient requests for physician-assisted suicide. J Pain Symptom Manage 6 (5): 289-97, 1991. [PubMed: 1856503]
32. Mayer DK, Travers D, Wyss A, et al.: Why do patients with cancer visit emergency departments? Results of a 2008 population study in North Carolina. J Clin Oncol 29 (19): 2683-8, 2011. [PMC free article: PMC3139372] [PubMed: 21606431]

Total Pain

The concept of total pain captures its multidimensional nature by explicitly including the physical, psychological, social, and spiritual components of pain.[1-4] The immediate implications for the clinician are severalfold:

1. A complete assessment of pain requires screening for psychological distress, social disruption, and existential crises, to treat the pain effectively and to anticipate barriers to pain relief.
2. Patients’ descriptions of pain that seem out of proportion to the known pathology may reflect other syndromes such as depression and existential distress.[5]
3. Patients suffering from pain often require multidimensional interventions from supportive services such as palliative care, chaplaincy, or psychotherapy.[6]
4. The concept of total pain does not suggest that pain is solely caused by psychological or existential distress, but that psychological and spiritual components can exacerbate or ameliorate the experience of pain. If the clinician suspects somatization, then referral for psychiatric or psychological evaluation is indicated.

Pain Mechanisms

Pain is classified on the basis of the mechanism underlying the perception of pain, the duration of pain, or the description of recognizable syndromes associated with pain.[7] The three mechanisms underlying the perception of pain are nociceptive, neuropathic, and psychogenic.

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 that 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).[8] 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 normally experienced.

Psychogenic pain is the physical sensation of pain caused by psychological distress or other mental or behavioral disorders. Psychogenic pain is not a precise term and may also be used to communicate that physical pain (nociceptive or neuropathic) may be exacerbated by similar factors.

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.[9] 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; or results from lesions unlikely to regress or heal.[9] The transition from acute to chronic pain may be understood as a series of relatively discrete changes in the CNS,[9] but there are also clearly behavioral confounders in the genesis of chronic pain. 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.

Breakthrough Pain

In caring for patients with pain, breakthrough pain is distinguished from background pain. Breakthrough pain is a transitory increase or flare of pain in the setting of relatively well-controlled acute or chronic pain.[10] 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 such pain effectively because of its episodic nature.[11] 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 etiologies.[12]

References

1. Richmond C: Dame Cicely Saunders. Br Med J 331 (7510): 238, 2005. Also available online. Last accessed July 29, 2015.
2. Mehta A, Chan LS: Understanding of the concept of “total pain”: a prerequisite for pain control. J Hosp Palliat Nurs 10 (1): 26-32, 2008.
3. Syrjala KL, Jensen MP, Mendoza ME, et al.: Psychological and behavioral approaches to cancer pain management. J Clin Oncol 32 (16): 1703-11, 2014. [PMC free article: PMC4031190] [PubMed: 24799497]
4. Merskey H, Bogduk N, eds.: Classification of Chronic Pain: Description of Chronic Pain Syndromes and Definitions of Pain Terms. 2nd ed. Seattle, Wash: IASP Press, 1994. Also available online. Last accessed July 22, 2015.
5. Porter LS, Keefe FJ: Psychosocial issues in cancer pain. Curr Pain Headache Rep 15 (4): 263-70, 2011. [PubMed: 21400251]
6. Wachholtz A, Makowski S: Spiritual dimensions of pain and suffering. In: Moore RJ, ed.: Handbook of Pain and Palliative Care: Biobehavioral Approaches for the Life Course. New York, NY: Springer, 2013, pp 697-713.
7. Chang VT, Janjan N, Jain S, et al.: Update in cancer pain syndromes. J Palliat Med 9 (6): 1414-34, 2006. [PubMed: 17187550]
8. Dworkin RH, Backonja M, Rowbotham MC, et al.: Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 60 (11): 1524-34, 2003. [PubMed: 14623723]
9. Voscopoulos C, Lema M: When does acute pain become chronic? Br J Anaesth 105 (Suppl 1): i69-85, 2010. [PubMed: 21148657]
10. Caraceni A, Martini C, Zecca E, et al.: Breakthrough pain characteristics and syndromes in patients with cancer pain. An international survey. Palliat Med 18 (3): 177-83, 2004. [PubMed: 15198130]
11. Mercadante S: Managing difficult pain conditions in the cancer patient. Curr Pain Headache Rep 18 (2): 395, 2014. [PubMed: 24407750]
12. Gutgsell T, Walsh D, Zhukovsky DS, et al.: A prospective study of the pathophysiology and clinical characteristics of pain in a palliative medicine population. Am J Hosp Palliat Care 20 (2): 140-8, 2003 Mar-Apr. [PubMed: 12693647]

Patient-Reported Outcomes

Effective pain treatment begins with screening at every visit and a thorough assessment if pain is present. Patient self-report is the standard of care for evaluating pain.[1]

Many tools have been developed to quantify the intensity of pain. The most commonly used tools include the numerical rating scale (0–10: 0 = no pain, 10 = worst pain imaginable); the categorical scale (none, mild, moderate, severe); and the visual analog scale (0–100 mm: 0 mm = no pain, 100 mm = worst pain imaginable). Multidimensional pain assessment tools such as the McGill Pain Questionnaire, the Brief Pain Inventory,[2] and the PROMIS-PI (Patient-Reported Outcomes Measurement Information System—Pain Interference) [3] have been developed to evaluate pain and its interference with daily functions. Although these tools are important, they may be best applied in the research setting, given their complexity and significant time requirements.

Pain assessment tools have been developed for special populations such as children and those with cognitive impairment (refer to the Special Considerations section of this summary for more information).

Pain intensity may be assessed for different time frames, such as “now,” “last 24 hours,” or “last week.” In addition to the average pain intensity, the worst or lowest intensity may be assessed. Evaluation of pain intensity at each visit would allow clinicians to monitor for changes and treatment response. Pain intensity scales can also be used to develop a personalized pain goal.[4]

Clinician Assessment

Failure to assess pain adequately leads to undertreatment. Assessment involves both clinician observation and patient report. The goal of the initial pain assessment is to characterize the pathophysiology of the pain and to determine the intensity of the pain and its impact on the patient’s ability to function. It is important to recognize that psychosocial issues can either exacerbate or ameliorate the experience of pain.[5] These psychosocial issues cannot be easily treated through pharmacologic approaches; therefore, it is critical that clinicians include these in initial and subsequent examinations of patients with pain to ensure referrals to appropriate treatment resources. Furthermore, distinct cultural components may need to be incorporated into a multidimensional assessment of pain, including how culture influences the pain experience, pain communication, and provider response to pain expression.[6-9]

Identifying the etiology of pain is important to its management. Clinicians treating patients with cancer need to recognize the common cancer pain syndromes. (Refer to the Approach to Somatic Pain, Approach to Visceral Pain, and Approach to Neuropathic Pain sections of this summary for more information.)

Effective pain management requires close monitoring of patient response after treatment is initiated. In a review of 1,612 patients referred to an outpatient palliative care center, more than half of patients with moderate to severe pain did not show pain relief (a reduction in 2 out of 10 points or a 30% decrease on the pain scale) after the initial palliative care consultation.[10] In addition, one-third of patients with mild pain progressed to moderate to severe pain by the time of their first follow-up visit. The study also identified baseline pain intensity, fatigue, and Edmonton Symptom Assessment System symptom burden as factors predicting response.[10]

Ideally, comprehensive pain assessment includes a discussion about the patient’s goals and expectations for pain management. This conversation may lead to a fruitful discussion about balancing pain levels and other patient goals, such as mental alertness. Comprehensive pain assessment also includes pain history, pain intensity, quality of pain, and location of pain. For each pain location, the pattern of pain radiation is assessed. Also important is provider awareness of the patient’s current pain management treatment plan and how the patient has responded to treatment; this includes how adequately the current treatment plan addresses any breakthrough or episodic pain. A full assessment also reviews previously attempted pain therapies and reasons for discontinuation, relevant clinical records, laboratory data, and results of diagnostic imaging. A focused physical examination includes clinical observation of pain behaviors, pain location, and functional limitations.

Psychosocial factors that affect pain are also assessed and appropriately treated. Depression and anxiety can have a large influence on the pain experience. Across many different types of pain, research has shown the importance of considering a patient’s sense of self-efficacy over their pain: low self-efficacy, or focus on solely pharmacologic solutions, is likely to increase the use of pain medication.[11,12] In addition, patients who repeatedly catastrophize pain (e.g., patient reports pain higher than 10 on a 10-point scale) are more likely to require higher doses than are patients who do not catastrophize. Catastrophizing is strongly associated with low self-efficacy and reliance on chemical coping strategies.[13-17] Furthermore, assessing the impact of pain on the individual’s life and associated factors that exacerbate or relieve pain can reveal how psychosocial issues are affecting the patient’s pain levels.

A pain assessment includes a review of any patient and family history of substance use and the extent of the patient’s chemical coping strategies before and since the cancer diagnosis. The extent of chemical coping strategies, including reliance on legal substances (e.g., nicotine, alcohol, and sleeping pills), may indicate a history of reliance on chemicals to alleviate distress. It can also provide the clinician with information about the patient’s nicotine use, which may affect how certain opioids may be differentially metabolized and the amount of opioids required to achieve pain control.[18] A remote history of substance abuse can still affect current pain levels and analgesic requirements. Remote substance use may have long-term implications for pain sensitivity, even if the patient has a history of prolonged abstinence from opioid use.[19] Together, personal and family substance use can inform a risk assessment for potential abuse of medications, potential analgesic requirements, and diversion of prescriptions.

Pain Prognostic Scores

A number of pain-related factors and patient-related factors predict response to pain treatment. Specifically, a high baseline pain intensity, neuropathic pain, and incident pain are often more difficult to manage.[20] Furthermore, several patient characteristics such as a personal or family history of illicit drug use, alcoholism ,[21,22] smoking,[23-25] somatization,[26] mental health issues such as depression or anxiety,[27] and cognitive dysfunction [28-30] are associated with higher pain expression, higher opioid doses, and longer time to achieve pain control.

On the basis of these predictive factors, several risk scores have been developed to assist clinicians in clinical practice, such as the Edmonton Classification System for Cancer Pain (ECS-CP) [20,31] and the Cancer Pain Prognostic Scale (CPPS).[32]

• The ECS-CP consists of (1) neuropathic pain, (2) incident pain, (3) psychological distress, (4) addiction, and (5) cognitive impairment. The presence of any of these factors indicates that pain may be more difficult to control. The ECS-CP has been validated in various cancer pain settings.[33]
• The CPPS includes four variables in a formula to determine the risk score, including worst pain severity (Brief Pain Inventory), Functional Assessment of Cancer Therapy - General (FACT-G) emotional well-being, initial morphine equivalent daily dose (≤60 mg/day; >60 mg/day), and mixed pain syndrome. The CPPS score ranges from 0 to 17, with a higher score indicating a higher possibility of pain relief.

Predictive factors can help to personalize cancer pain management. Especially for patients with a poor pain prognosis, clinicians may consider discussing realistic goals for alleviating pain, focusing on function and use of multimodality interventions. Repeated or frequent escalation of analgesic doses without improvement of pain may trigger clinicians to consider an alternative approach to pain.

Special Considerations

Self-report is accepted as the gold standard of pain assessment; however, for certain vulnerable populations, such as children, those with learning disabilities, and those who are cognitively impaired, self-report may not be feasible or reliable.

While adults and children older than 7 years can effectively utilize the numerical rating scale, young children and those with cognitive impairment may benefit from using a pictorial scale such as the Faces Pain Scale.[34] (Refer to the PDQ summary on Pediatric Supportive Care for more information.)

Cognitive impairment may impede a person’s ability to describe pain, recall pain events, or understand the tools used to assess pain, leading such patients to receive more or less analgesia.[35-37] The American Society for Pain Management Nursing has developed a position statement on pain assessment in the nonverbal patient that includes clinical recommendations.[38] Pain assessment can be evaluated via direct observation, family/caregiver report, and evaluation of response to pain relief interventions. For patients with advanced dementia, tools relying on professional caregiver assessment of pain through the observation of patient behaviors have been developed.[39-41] Although the validity and reliability of these tools have been questioned, the tools are often recommended for patients with advanced dementia who cannot report pain and, in combination with self-report by other cognitively impaired groups, as a means to enhance pain assessment and avoid undertreatment of pain.

Cognitive impairment extends beyond patients with a diagnosis of dementia, such as those with brain tumors and delirium, which are common complications of advanced cancer. In such patients, the Faces Pain Scale [42] and the Coloured Analogue Scale [43] as well as vertical instead of horizontal orientation of scales may be preferable to the numeric rating scales.[44]

Culture also plays a role in the patient experience of pain and the reporting of pain. For example, among some Asian cultures, patients tend not to report pain.[6] Complaining of pain may be perceived as a sign of weakness. Individuals may hide pain from family members to avoid burdening the family. For some patients, pain may have spiritual value, leading them to accept pain rather than dull the experience with medication.[45] Thus, understanding an individual patient’s spiritual and cultural background without making assumptions is important in approaching pain assessment.

In a cross-sectional study, the cancer pain experience of white patients was individual and independent, while that of ethnic minority patients was family oriented. Minority patients received support from their families during the cancer treatment, and they fought cancer for their families. The families were involved deeply in their decision making related to cancer treatment and pain management.[7]

Other studies indicate that Asian patients have greater barriers to pain management and display more fatalism than do Western patients.[8,9]

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Acetaminophen and Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Often initiated when an individual has mild pain, acetaminophen and NSAIDs are useful in managing moderate and severe pain as adjunct agents to opioids. No single NSAID is preferred over others, and all are better than placebo for analgesia.[1] As opioid adjuncts, acetaminophen and NSAIDs have shown benefit both in improved analgesia and in decreased opioid use. These agents are used with care or perhaps avoided in patients who are elderly or have renal, hepatic, or cardiac disease.[1]

While acetaminophen and NSAIDs provide analgesia 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.[2-4] However, these benefits were not consistently observed across trials.[5,6]

High-potency NSAIDs such as ketorolac and diclofenac are more studied and have shown benefit in the management of cancer pain, but there are no comparative data with older agents to show superiority of one product over others. Prominent side effects are gastrointestinal irritation, ulcer formation, and dyspepsia, with other side effects of concern being cardiotoxicity, nephrotoxicity, hepatotoxicity, and hematologic effects.[7,8] Cyclooxygenase-2 (COX-2)–specific agents such as celecoxib may have a more favorable gastrointestinal side effect profile at a higher monetary cost.[7] Long-term safety and efficacy data remain unclear.

Opioids

Gabapentin and Pregabalin

Gabapentin and pregabalin are structural derivatives of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and decrease neuronal excitability in pain-associated sensory neurons. These drugs have been widely studied in the treatment of neuropathic pain syndromes (refer to the Approach to Neuropathic Pain section of this summary for more information) and as adjunctive agents with opioids.

These medications may cause sedation, dizziness, peripheral edema, nausea, ataxia, and 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.[10,95]

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 (SNRIs) originally approved for depression; however, both are used off-label for the treatment of chemotherapy-induced peripheral neuropathy (CIPN). Both serotonin and norepinephrine have important roles in analgesia.

Common dosing for duloxetine ranges from 30 mg to 60 mg per day. Side effects include nausea, headache, fatigue, dry mouth, and constipation.[96] 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.[97]

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.

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 dry mouth, drowsiness, weight gain, and 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 elderly 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.[98] A small but well-designed study showed no benefit to adding corticosteroids to opioid analgesia in the short term (7 days).[99]

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.[100]

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,[101] to dexamethasone 10 mg twice daily.[102] Immediate side effects include hyperglycemia, insomnia, immunosuppression, and psychiatric disorders. Serious long-term effects of myopathy, peptic ulceration, osteoporosis, and Cushing syndrome encourage short-term use. 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.[103-106] 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 nonpharmacologic interventions.[107,108] 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.[109-111] Doses are adjusted for patients with renal dysfunction.

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% confidence interval, 0.77–0.91).[112]

Denosumab is avoided in myeloma patients because a subgroup analysis in one trial suggested increased mortality in that patient population.[110] 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.[113]

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.[114] Adverse drug reactions include hypertension, tachycardia, psychomimetic effects, increased intracranial and intraocular pressure, sedation, delirium, and impaired bladder function.

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80. Lee MA, Leng ME, Tiernan EJ: Retrospective study of the use of hydromorphone in palliative care patients with normal and abnormal urea and creatinine. Palliat Med 15 (1): 26-34, 2001. [PubMed: 11212464]
81. Paice JA, Von Roenn JH: Under- or overtreatment of pain in the patient with cancer: how to achieve proper balance. J Clin Oncol 32 (16): 1721-6, 2014. [PubMed: 24799468]
82. Passik SD: Issues in long-term opioid therapy: unmet needs, risks, and solutions. Mayo Clin Proc 84 (7): 593-601, 2009. [PMC free article: PMC2704131] [PubMed: 19567713]
83. Passik SD, Kirsh KL: The need to identify predictors of aberrant drug-related behavior and addiction in patients being treated with opioids for pain. Pain Med 4 (2): 186-9, 2003. [PubMed: 12873265]
84. Kwon JH, Hui D, Bruera E: A Pilot Study To Define Chemical Coping in Cancer Patients Using the Delphi Method. J Palliat Med 18 (8): 703-6, 2015. [PMC free article: PMC4522949] [PubMed: 25922879]
85. Gourlay DL, Heit HA: Pain and addiction: managing risk through comprehensive care. J Addict Dis 27 (3): 23-30, 2008. [PubMed: 18956526]
86. Webster LR, Webster RM: Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the Opioid Risk Tool. Pain Med 6 (6): 432-42, 2005 Nov-Dec. [PubMed: 16336480]
87. Butler SF, Fernandez K, Benoit C, et al.: Validation of the revised Screener and Opioid Assessment for Patients with Pain (SOAPP-R). J Pain 9 (4): 360-72, 2008. [PMC free article: PMC2359825] [PubMed: 18203666]
88. Coambs RB, Jarry JL, Santhiapillai AC, et al.: The SISAP: a new screening instrument for identifying potential opioid abusers in the management of chronic nonmalignant pain within general medical practice. Pain Res Manag 1 (3): 155-62, 1996.
89. The use of opioids for the treatment of chronic pain. A consensus statement from the American Academy of Pain Medicine and the American Pain Society. Clin J Pain 13 (1): 6-8, 1997. [PubMed: 9084947]
90. Wiedemer NL, Harden PS, Arndt IO, et al.: The opioid renewal clinic: a primary care, managed approach to opioid therapy in chronic pain patients at risk for substance abuse. Pain Med 8 (7): 573-84, 2007 Oct-Nov. [PubMed: 17883742]
91. Gourlay DL, Heit HA, Almahrezi A: Universal precautions in pain medicine: a rational approach to the treatment of chronic pain. Pain Med 6 (2): 107-12, 2005 Mar-Apr. [PubMed: 15773874]
92. Chindalore VL, Craven RA, Yu KP, et al.: Adding ultralow-dose naltrexone to oxycodone enhances and prolongs analgesia: a randomized, controlled trial of Oxytrex. J Pain 6 (6): 392-9, 2005. [PubMed: 15943961]
93. Katz N: Abuse-deterrent opioid formulations: are they a pipe dream? Curr Rheumatol Rep 10 (1): 11-8, 2008. [PubMed: 18457606]
94. Setnik B, Roland CL, Cleveland JM, et al.: The abuse potential of Remoxy(®), an extended-release formulation of oxycodone, compared with immediate- and extended-release oxycodone. Pain Med 12 (4): 618-31, 2011. [PubMed: 21463474]
95. Dworkin RH, O'Connor AB, Audette J, et al.: Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc 85 (3 Suppl): S3-14, 2010. [PMC free article: PMC2844007] [PubMed: 20194146]
96. Pachman DR, Watson JC, Loprinzi CL: Therapeutic strategies for cancer treatment related peripheral neuropathies. Curr Treat Options Oncol 15 (4): 567-80, 2014. [PubMed: 25119581]
97. Pachman DR, Barton DL, Watson JC, et al.: Chemotherapy-induced peripheral neuropathy: prevention and treatment. Clin Pharmacol Ther 90 (3): 377-87, 2011. [PubMed: 21814197]
98. Paulsen Ø, Aass N, Kaasa S, et al.: Do corticosteroids provide analgesic effects in cancer patients? A systematic literature review. J Pain Symptom Manage 46 (1): 96-105, 2013. [PubMed: 23149084]
99. Paulsen O, Klepstad P, Rosland JH, et al.: Efficacy of methylprednisolone on pain, fatigue, and appetite loss in patients with advanced cancer using opioids: a randomized, placebo-controlled, double-blind trial. J Clin Oncol 32 (29): 3221-8, 2014. [PubMed: 25002731]
100. Leppert W, Buss T: The role of corticosteroids in the treatment of pain in cancer patients. Curr Pain Headache Rep 16 (4): 307-13, 2012. [PMC free article: PMC3395343] [PubMed: 22644902]
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102. Watanabe S, Bruera E: Corticosteroids as adjuvant analgesics. J Pain Symptom Manage 9 (7): 442-5, 1994. [PubMed: 7822883]
103. Rosen LS, Gordon D, Antonio BS, et al.: Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J 7 (5): 377-87, 2001 Sep-Oct. [PubMed: 11693896]
104. Wardley A, Davidson N, Barrett-Lee P, et al.: Zoledronic acid significantly improves pain scores and quality of life in breast cancer patients with bone metastases: a randomised, crossover study of community vs hospital bisphosphonate administration. Br J Cancer 92 (10): 1869-76, 2005. [PMC free article: PMC2361764] [PubMed: 15870721]
105. Rosen LS, Gordon D, Tchekmedyian S, et al.: Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial--the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 21 (16): 3150-7, 2003. [PubMed: 12915606]
106. Weinfurt KP, Anstrom KJ, Castel LD, et al.: Effect of zoledronic acid on pain associated with bone metastasis in patients with prostate cancer. Ann Oncol 17 (6): 986-9, 2006. [PubMed: 16533874]
107. Van Poznak CH, Temin S, Yee GC, et al.: American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol 29 (9): 1221-7, 2011. [PubMed: 21343561]
108. Kyle RA, Yee GC, Somerfield MR, et al.: American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol 25 (17): 2464-72, 2007. [PubMed: 17515569]
109. Qi WX, Tang LN, He AN, et al.: Risk of osteonecrosis of the jaw in cancer patients receiving denosumab: a meta-analysis of seven randomized controlled trials. Int J Clin Oncol 19 (2): 403-10, 2014. [PubMed: 23605142]
110. Henry DH, Costa L, Goldwasser F, et al.: Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 29 (9): 1125-32, 2011. [PubMed: 21343556]
111. Sivolella S, Lumachi F, Stellini E, et al.: Denosumab and anti-angiogenetic drug-related osteonecrosis of the jaw: an uncommon but potentially severe disease. Anticancer Res 33 (5): 1793-7, 2013. [PubMed: 23645723]
112. Peddi P, Lopez-Olivo MA, Pratt GF, et al.: Denosumab in patients with cancer and skeletal metastases: a systematic review and meta-analysis. Cancer Treat Rev 39 (1): 97-104, 2013. [PMC free article: PMC3691016] [PubMed: 22898302]
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114. Hardy J, Quinn S, Fazekas B, et al.: Randomized, double-blind, placebo-controlled study to assess the efficacy and toxicity of subcutaneous ketamine in the management of cancer pain. J Clin Oncol 30 (29): 3611-7, 2012. [PubMed: 22965960]

Pain Procedures

While pharmacologic therapy using the World Health Organization (WHO) guidelines effectively manages most cancer pain, approximately 10% to 20% of patients will have refractory pain or excessive side effects.[1] For patients with refractory pain or specific regional pain syndromes, an interventional approach to treating pain has been proposed as the fourth step on the WHO pain relief ladder. Some common interventions and their evidence of benefit are discussed below.

Palliative Care Referral

Palliative care, which is specialized medical care for people with serious illnesses with the goal to maximize quality of life for both patients and families, can provide expert assessment and management of pain and other nonpain symptoms. Palliative care providers work in interdisciplinary teams that include physicians, nurses, mental health specialists, chaplains, and sometimes pharmacists and dieticians. For patients with refractory pain, prominent nonpain symptoms, or intense psychosocial distress, a referral to palliative care may be appropriate, where available.

Palliative care specialists may also help manage patients with multiple comorbidities, those requiring higher doses of opioids, and those with a history of substance abuse or complex psychosocial dynamics that can complicate the management of pain and adherence to recommended medications. 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 for both patients and families [12-15] and may prolong life.[12] (Refer to the PDQ summary on Planning the Transition to End-of-Life Care in Advanced Cancer for more information.)

External-Beam Radiation Therapy

Palliative radiation therapy represents an effective modality for pain related to advanced cancer. Pain related to bone metastases, skin lesions, or isolated tumor lesions may be relieved by a short course of radiation therapy.

For bone metastases, radiation is often delivered as 8 Gy in a single fraction, 20 Gy in five fractions, 24 Gy in six fractions, or 30 Gy in ten fractions. A Cochrane review that included 11 randomized trials consisting of 3,435 patients 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.[16] 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%).[16] This finding was consistent with other systematic reviews.[17] In the Dutch Bone Metastasis Study, 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.[18,19]

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. Re-irradiation typically occurs at least 4 weeks after the first radiation treatment. 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%.[20] Re-irradiation was generally well tolerated. Serious adverse effects such as spinal cord compression and pathological fracture were infrequent (<3%). 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%; P = .02).[21]

Radionuclides

Patients with multiple sites of symptomatic osteoblastic bone metastases may consider radionuclides such as strontium-89 or samarium-153, which are beta-emitters. Two double-blind randomized trials support the superiority of samarium-153 over placebo in providing pain control and reducing analgesic use.[22,23] The overall response varies between 30% and 80%, with onset of pain relief within the first week; some patients report a long-lasting benefit (up to 18 months). The most common toxicities are pain flare and cytopenias. 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.[24] 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).

Radium-223 (an alpha-emitter) is approved for use in patients with castration-resistant prostate cancer. A phase III randomized trial compared radium-223 with placebo in a 2:1 ratio. Among the 921 symptomatic patients enrolled, those who received radium-223 had a prolonged time to first symptomatic skeletal event (15.6 months vs. 9.8 months, P < .0001), in addition to prolonged overall survival (14.9 months vs. 11.3 months, P < .001).[25]

Physical Medicine and Rehabilitation

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). Therefore, pain and functional status may improve with physical or occupational therapy, treatments for strengthening and stretching, and the use of assistive devices.[26] 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.

Complementary Therapy

Patients with cancer frequently use complementary or alternative medicines or interventions (CAM).[27] One of the stated benefits of CAM is pain relief. However, a meta-analysis of multi-institutional, randomized, controlled trials for cancer-related pain concluded that methodological flaws hampered interpretation of the few available studies. There were brief positive effects in favor of CAM for acupuncture, support groups, hypnosis, and herbal supplements.[28] (Refer to the PDQ summaries on Complementary and Alternative Medicine for more information.)

References

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10. Lahuerta J, Bowsher D, Lipton S, et al.: Percutaneous cervical cordotomy: a review of 181 operations on 146 patients with a study on the location of "pain fibers" in the C-2 spinal cord segment of 29 cases. J Neurosurg 80 (6): 975-85, 1994. [PubMed: 8189278]
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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.

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:

1. 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.
2. There is a limited correlation between the degree of visceral injury and the intensity of the perceived pain.[7]
3. 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).
4. 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 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 are not responsive to these agents. 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.

Approach to Acute Procedural Pain

Approach to Special Populations

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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:

• Joseph Bubalo, PharmD, BCPS, BCOP (Oregon Health and Science University Hospital)
• Mary K. Buss, MD (Beth Israel Deconess Medical Center)
• David Hui, MD, MSC (M.D. Anderson Cancer Center)
• Eric E. Prommer, MD (UCLA School of Medicine)
• Megan Reimann, PharmD, BCOP (Indiana University Simon Cancer Center)
• Amy Wachholtz, PhD (University of Massachusetts Medical School & UMass 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:

National Cancer Institute: PDQ® Cancer Pain. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/about-cancer/treatment/side-effects/pain/pain-hp-pdq. Accessed <MM/DD/YYYY>.

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