lunes, 11 de marzo de 2019

Cancer Pain (PDQ®) 2/2 —Health Professional Version - National Cancer Institute

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

National Cancer Institute

Cancer Pain (PDQ®)–Health Professional Version

Opioids and risk of addiction

In the United States, the number of opioid prescriptions and deaths from painkillers quadrupled between 1999 and 2013.[86] In 2013 alone, two million Americans were estimated to have either abused or been dependent on opioids, with 22,767 deaths related to prescription drug overdose. Although most cancer patients prescribed opioids are using them safely, one study estimated that up to 8% of cancer patients may be addicted to opioids.[87] Thus, it is important for clinicians treating cancer patients for pain to provide careful monitoring and to adopt safe opioid-prescribing practices.[88]
Most patients begin opioid therapy after an acute event such as a pain crisis from cancer progression or surgery.[89] Sometimes cancer treatment and its effects will lead to increased opioid use, with approximately 10% of patients continuing to take the equivalent of 30 mg of hydrocodone per day at 1 year post–curative surgery.[90] All patients taking opioids require assessment for risk of abuse or addiction.[89]
Addiction is defined as continued, compulsive use of a drug despite harm. Many other conditions may be misidentified as addiction, and it is important that clinicians distinguish between the two.[91] These conditions include:[92,93]
  • Aberrant behavior: a behavior outside the boundaries of the agreed-on treatment plan that is established as early as possible in the doctor-patient relationship.[94]
  • Chemical coping: the use of opioids to cope with emotional distress, characterized by inappropriate and/or excessive opioid use.[93]
  • Diversion: redirection of a prescription drug from its intended user to another individual.
  • Misuse: inappropriate use of a drug, whether deliberate or unintentional.
  • Physical dependence: condition in which abrupt termination of drug use causes withdrawal syndrome.
  • Pseudo-addiction: condition characterized by behaviors such as drug hoarding that mimic addiction but are driven by a desire for pain relief; usually signals undertreated pain or anxiety that future pain will be untreated.
  • Self-medication: use of a drug without consulting a health care professional to alleviate stressors or disorders such as depression or anxiety.
  • Substance abuse: maladaptive pattern of substance use leading to considerable impairment or distress.
  • Tolerance: phenomenon in which analgesia decreases as the body grows tolerant to a given dosage of a drug, requiring an increased dose to achieve the same analgesic effect.[92]
The following aberrant behaviors may suggest addiction or abuse; further assessment is required to make the diagnosis:
  • Aggressive complaining about the need for more drugs.
  • Drug hoarding during periods of reduced symptoms.
  • Acquiring similar drugs from other medical sources.
  • Requesting specific drugs.
  • Reporting psychic effects not intended by the physician.
  • Resistance to a change in therapy associated with tolerable adverse effects accompanied by expressions of anxiety related to the return of severe symptoms.
  • Resistance to referral to a mental health professional.
  • Unapproved use of the drug to treat another symptom or use of the drug for a minor symptom (e.g., use of fentanyl for mild headache pain).
  • Unsanctioned dose escalation or other nonadherence to therapy on one or two occasions.
  • Unconfirmed multiple allergies to multiple opioids.
Table 6. Risk Mitigation Tools for Evaluating Opioid Misusea
ToolDescriptionComments
aAdapted from DiScala SL, Lesé MD: Chronic pain. In Murphy JE, Lee MW, eds.: Pharmacotherapy Self-Assessment Program. Book 2: CNS/Pharmacy Practice. Lenexa, Kan: American College of Clinical Pharmacy, 2015, p. 102.
Current Opioid Misuse Measure (COMM)17-item self-assessment tool for patientsIdentifies aberrant behaviors; for those with chronic pain who are already on opioids.
Diagnosis, Intractability, Risk, Efficacy (DIRE)8-item toolDetermines risk of long-term opioid use in those with chronic pain; evaluates regimen efficacy.
Opioid Risk Tool (ORT)5-item toolPredicts aberrant or drug-related behaviors.
Prescription Drug Use Questionnaire (Self-Report) (PDUQp)31-item self-assessment toolEvaluates and predicts opioid misuse in those with chronic pain.
Pain Medication Questionnaire (PMQ)26-item toolEvaluates risk of opioid misuse in those with chronic pain.
Screening Instrument for Substance Abuse Potential (SISAP)5-item toolEvaluates those with history of substance abuse and risk of opioid misuse; used in primary care setting.
Screener and Opioid Assessment for Patients with Pain (SOAPP) Version 1.024-item self-assessmentEvaluates risk of long-term opioid therapy in those with chronic pain.
Screener and Opioid Assessment for Patients with Pain—Revised (SOAPP-R)24-item self-assessmentEvaluates those already taking opioids, or those about to begin (before initiation of therapy).
Risk factors for opioid abuse include smoking, psychiatric disorders, history of childhood sexual abuse, and personal or family history of substance abuse.[91] Screening tools help in risk assessment. Common tools include the Opioid Risk Tool (ORT),[95] the Screener and Opioid Assessment for Patients with Pain–Revised (SOAPP-R),[96] and the Screening Instrument for Substance Abuse Potential (SISAP).[92,97] The choice of which tool to use depends on the type of practice. The ORT is short and useful for busy practices.[92]
Risk assessment determines the structure of therapy, which can range from minimal structure to more structure. Highly structured opioid therapy requires approaches such as frequent visits, limiting pills per prescription, use of other specialists, and urine drug testing.[91] Opioid agreements outline what is expected of the patient, educate about drug storage, and delineate acceptable and unacceptable behavior.[98] Patients are taught that they must safeguard their medications “like their wallets” to protect against diversion. In addition, state guidelines for chronic opioid use, state prescription monitoring, and the use of pharmacists may reduce the potential for worsening addictive behavior.[99]
Random urine drug testing is used for patients with an inadequate response to opioid therapy and those receiving opioids long term.[100] A urine drug test demonstrating absence of prescribed opioid can be useful because it suggests either diversion or stockpiling; a urine drug test revealing concurrent use of other nonprescribed medications or illicit substances can also be informative. Because many different types of urine drug tests are available, clinicians may want to become familiar with the types and interpretation of tests available locally. A clinician’s laboratory can identify the substance in question. Clinicians use urine drug testing differently, with some requiring it at the initiation of therapy, episodically, or at the transition to long-term opioid therapy. Risk assessment helps to determine frequency of urine drug testing.[100]
Pharmacologic deterrence has emerged as another option designed to dissuade misuse and abuse by making it difficult to obtain euphoric effects from opioid use.[100] Creating barriers to increasing the bioavailability of opioids is one method of pharmacologic deterrence. Approaches have included adding an opioid antagonist to the formulation [101] or adding niacin to create a bad taste in the mouth if too many pills are taken.[102] Embedding opioid into a matrix that cannot be obtained by crushing or chemical extraction is another pharmacologic deterrent.[103]

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 (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.[10,104]

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.[105] 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.[106]
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 venlafaxine, 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 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.[107] A small but well-designed study showed no benefit to adding corticosteroids to opioid analgesia in the short term (7 days).[108]
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.[109]
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,[110] to dexamethasone 10 mg twice daily.[111] 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.[112] (Refer to the External-Beam Radiation Therapy section of this summary for more information.) 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.[113-116] 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.[117,118] 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.[119-121] 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.[122] 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% confidence interval, 0.77–0.91).[123]
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.[124]

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.[125]
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.[126] Adverse drug reactions include hypertension, tachycardia, psychotomimetic effects, increased intracranial and intraocular pressure, sedation, delirium, and impaired bladder function.
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  85. 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 Abstract]
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  88. Koyyalagunta D, Burton AW, Toro MP, et al.: Opioid abuse in cancer pain: report of two cases and presentation of an algorithm of multidisciplinary care. Pain Physician 14 (4): E361-71, 2011 Jul-Aug. [PUBMED Abstract]
  89. 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 Abstract]
  90. Lee JS, Hu HM, Edelman AL, et al.: New Persistent Opioid Use Among Patients With Cancer After Curative-Intent Surgery. J Clin Oncol 35 (36): 4042-4049, 2017. [PUBMED Abstract]
  91. Passik SD: Issues in long-term opioid therapy: unmet needs, risks, and solutions. Mayo Clin Proc 84 (7): 593-601, 2009. [PUBMED Abstract]
  92. 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 Abstract]
  93. 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. [PUBMED Abstract]
  94. Gourlay DL, Heit HA: Pain and addiction: managing risk through comprehensive care. J Addict Dis 27 (3): 23-30, 2008. [PUBMED Abstract]
  95. 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 Abstract]
  96. 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. [PUBMED Abstract]
  97. 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.
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  100. 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 Abstract]
  101. 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 Abstract]
  102. Katz N: Abuse-deterrent opioid formulations: are they a pipe dream? Curr Rheumatol Rep 10 (1): 11-8, 2008. [PUBMED Abstract]
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  104. 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. [PUBMED Abstract]
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Modalities for Pain Control: Other Approaches

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.

Nerve blocks

The celiac plexus block, used primarily for patients with upper abdominal pain from pancreatic cancer, is the most commonly employed neurolytic blockade of the sympathetic axis, followed by the superior hypogastric plexus block and the ganglion of impar block for patients with lower abdominal or pelvic pain. Traditionally, the autonomic neural blockade was reserved for patients with inadequate response to oral opioids, but some researchers have suggested that the intervention—which is associated with decreased pain, reduced opioid consumption, improved performance status, and few complications—is considered a first-line approach.[2,3]
For patients with regional pain, a peripheral nerve block infusing a local anesthetic can achieve local pain control. This approach can be applied to any peripheral nerve, including the femoral, sciatic, paravertebral, brachial plexus, and interpleural nerves.[4]

Neuroaxial delivery of analgesia

When patients have pain that persists despite high doses of opioids and other analgesics or have intolerable side effects to oral opioids—such as delirium, sedation, or nausea—an alternative route of delivery may be considered. Compared with intravenous administration of opioids, epidural and intrathecal routes of delivery are 10 and 100 times more potent, respectively. Such routes of delivery allow high doses of analgesics to be administered with less systemic absorption and fewer side effects.[5]
One study that randomly assigned patients to receive either an implantable drug delivery system or comprehensive medical management found that patients receiving the analgesic through the implantable pump had less pain, less toxicity, and longer survival at 6 months.[6] While the survival benefit did not persist in other studies, the intrathecal pump may be an option for selected patients with refractory pain and a life expectancy longer than 3 months.[7] However, intrathecal pumps may make it difficult for patients to access hospice care because of care needs and cost issues, and they cannot effectively treat pain that is predominantly related to psychological distress.[8] For patients with shorter life expectancies, placement of an epidural catheter may be a safe and effective technique.[4]

Cordotomy

Cordotomy is reserved for pain refractory to other approaches and is done less commonly today. It is most effective in treating unilateral somatic pain from the torso to the lower extremities. The available literature suggests a high rate of efficacy, with 60% to 80% complete pain relief immediately after the procedure, falling to 50% at 12 months. Cordotomy is generally reserved for patients considered to be in the last 2 years of life, with pain refractory to other approaches, and may be done via the open route or the percutaneous route.[9-11]
For patients with either regional pain syndromes or pain refractory to escalating systemic medications, the cancer clinician may consult with a pain specialist or neurosurgeon to consider an interventional approach to pain control.

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, social workers, 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. Many palliative care teams now call themselves supportive care teams because this term is more acceptable to many referring providers and to some patients and families.[12,13]
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 [14-17] and may prolong life.[14] (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.[18] 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%).[18] This finding was consistent with other systematic reviews.[19] 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.[20,21] Single-fraction radiation has several potential advantages: greater convenience, lower cost, and less breakthrough pain associated with transportation to the radiation facility and with getting on and off the radiation table.
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%.[22] Re-irradiation was generally well tolerated.[22] In a secondary analysis of the National Cancer Institute of Canada Clinical Trials Group Symptom Control Trial SC.20, which examined outcomes of 847 patients who underwent palliative re-irradiation of painful bone metastases, the team found no differences in pain relief or side effects across age or gender demographics. Women and younger patients reported greater improvements in quality of life.[23] 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).[24]
A potential side effect of palliative radiation for painful bone metastases is a temporary increase in pain level, i.e., a pain flare. Pain flares occur in about 40% of patients and may be quite distressing. One study [25] randomly assigned 298 patients, who were scheduled to receive a single 8-Gy dose of radiation, to receive either placebo or dexamethasone 8 mg on days 0 to 4. Fewer patients in the dexamethasone group experienced pain flares (26% vs. 35%; P = .05). Potentially serious hyperglycemia was seen in only two patients in the dexamethasone group. The study supports the use of prophylactic dexamethasone in this setting.

Radionuclides

Patients with multiple sites of symptomatic osteoblastic bone metastases may consider radionuclides such as strontium chloride Sr 89 or samarium Sm 153 (153Sm), which are beta-emitters. Two double-blind randomized trials support the superiority of 153Sm over placebo in providing pain control and reducing analgesic use.[26,27] 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.[28] 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 Ra 223-dichloride (223Ra-dichloride) (an alpha-emitter) is approved for use in patients with castration-resistant prostate cancer. A phase III randomized trial compared 223Ra-dichloride with placebo in a 2:1 ratio. Among the 921 symptomatic patients enrolled, those who received 223Ra-dichloride had a prolonged time to first symptomatic skeletal event (15.6 months vs. 9.8 months, P < .0001), in addition to prolonged overall survival (14.9 months vs. 11.3 months, P < .001).[29]

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.[30] 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).[31] 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.[32] (Refer to the PDQ summaries on Integrative, Alternative, and Complementary Therapies for more information.)
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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:
  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 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 ChangeExample 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 functionIncreased accumulation of morphine metabolites
Increased risk of NSAID-induced renal dysfunction
Increased body fat/decreased body waterDelayed elimination of lipophilic drugs such as methadone
CachexiaDecreased fentanyl absorption from transdermal fentanyl patches [59]
Decreased hepatic functionResults in increased oral bioavailability and half-life of opioids
– Decrease dose: hydromorphone, oxycodone
– Increase dose interval: morphine, oxycodone
Reduced protein bindingIncreased drug sensitivity/side effects
Reduced cytochrome P450 enzyme activityIncreased drug concentrations of fentanyl and methadone
Decreased gastrointestinal motilityIncreased 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/ClassExampleRationale
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 antidepressantsAmitriptyline, clomipramine, imipramineAnticholinergic effects, sedation, orthostatic hypotension
Meperidine Decreased efficacy, potential neurotoxicity
Non–COX-2–selective NSAIDsIbuprofen, diclofenac, naproxenGastrointestinal bleed risk, increased blood pressure, renal toxicity
Skeletal muscle relaxantsCyclobenzaprine, metaxalone, methocarbamolAnticholinergic effects, sedation, risk of fracture
CNSAvoid/reduce dose in renal impairment:CNS adverse effects
– Gabapentin
– Pregabalin
– Duloxetine
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Changes to This Summary (03/06/2019)

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.
Modalities for Pain Control: Other Approaches
Added text about a secondary analysis of the National Cancer Institute of Canada Clinical Trials Group Symptom Control Trial SC.20 (cited Chow et al. as reference 23).
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 Deconess 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.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.
  • Updated: March 6, 2019
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