miércoles, 10 de abril de 2019

Cancer Pain (PDQ®) 4/4 —Health Professional Version - National Cancer Institute

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

National Cancer Institute

Cancer Pain (PDQ®)–Health Professional Version



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.)
References
  1. McHugh ME, Miller-Saultz D, Wuhrman E, et al.: Interventional pain management in the palliative care patient. Int J Palliat Nurs 18 (9): 426-8, 430-3, 2012. [PUBMED Abstract]
  2. Tei Y, Morita T, Nakaho T, et al.: Treatment efficacy of neural blockade in specialized palliative care services in Japan: a multicenter audit survey. J Pain Symptom Manage 36 (5): 461-7, 2008. [PUBMED Abstract]
  3. Bhatnagar S, Khanna S, Roshni S, et al.: Early ultrasound-guided neurolysis for pain management in gastrointestinal and pelvic malignancies: an observational study in a tertiary care center of urban India. Pain Pract 12 (1): 23-32, 2012. [PUBMED Abstract]
  4. Chambers WA: Nerve blocks in palliative care. Br J Anaesth 101 (1): 95-100, 2008. [PUBMED Abstract]
  5. Smyth CE, Jarvis V, Poulin P: Brief review: Neuraxial analgesia in refractory malignant pain. Can J Anaesth 61 (2): 141-53, 2014. [PUBMED Abstract]
  6. Smith TJ, Staats PS, Deer T, et al.: Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: impact on pain, drug-related toxicity, and survival. J Clin Oncol 20 (19): 4040-9, 2002. [PUBMED Abstract]
  7. Smith TJ, Coyne PJ: Implantable drug delivery systems (IDDS) after failure of comprehensive medical management (CMM) can palliate symptoms in the most refractory cancer pain patients. J Palliat Med 8 (4): 736-42, 2005. [PUBMED Abstract]
  8. Reddy A, Yennurajalingam S, de la Cruz M, et al.: Factors associated with survival after opioid rotation in cancer patients presenting to an outpatient supportive care center. J Pain Symptom Manage 48 (1): 92-8, 2014. [PUBMED Abstract]
  9. Siegfried J: Electrostimulation and neurosurgical measures in cancer pain. Recent Results Cancer Res 108: 28-32, 1988. [PUBMED Abstract]
  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 Abstract]
  11. Lahuerta J, Lipton S, Wells JC: Percutaneous cervical cordotomy: results and complications in a recent series of 100 patients. Ann R Coll Surg Engl 67 (1): 41-4, 1985. [PUBMED Abstract]
  12. Fadul N, Elsayem A, Palmer JL, et al.: Supportive versus palliative care: what's in a name?: a survey of medical oncologists and midlevel providers at a comprehensive cancer center. Cancer 115 (9): 2013-21, 2009. [PUBMED Abstract]
  13. Dalal S, Palla S, Hui D, et al.: Association between a name change from palliative to supportive care and the timing of patient referrals at a comprehensive cancer center. Oncologist 16 (1): 105-11, 2011. [PUBMED Abstract]
  14. Temel JS, Greer JA, Muzikansky A, et al.: Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 363 (8): 733-42, 2010. [PUBMED Abstract]
  15. Zimmermann C, Swami N, Krzyzanowska M, et al.: Early palliative care for patients with advanced cancer: a cluster-randomised controlled trial. Lancet 383 (9930): 1721-30, 2014. [PUBMED Abstract]
  16. Bakitas M, Lyons KD, Hegel MT, et al.: The project ENABLE II randomized controlled trial to improve palliative care for rural patients with advanced cancer: baseline findings, methodological challenges, and solutions. Palliat Support Care 7 (1): 75-86, 2009. [PUBMED Abstract]
  17. Bakitas MA, Tosteson TD, Li Z, et al.: Early Versus Delayed Initiation of Concurrent Palliative Oncology Care: Patient Outcomes in the ENABLE III Randomized Controlled Trial. J Clin Oncol 33 (13): 1438-45, 2015. [PUBMED Abstract]
  18. Sze WM, Shelley M, Held I, et al.: Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy - a systematic review of the randomised trials. Cochrane Database Syst Rev (2): CD004721, 2004. [PUBMED Abstract]
  19. Chow E, Zeng L, Salvo N, et al.: Update on the systematic review of palliative radiotherapy trials for bone metastases. Clin Oncol (R Coll Radiol) 24 (2): 112-24, 2012. [PUBMED Abstract]
  20. van der Linden YM, Lok JJ, Steenland E, et al.: Single fraction radiotherapy is efficacious: a further analysis of the Dutch Bone Metastasis Study controlling for the influence of retreatment. Int J Radiat Oncol Biol Phys 59 (2): 528-37, 2004. [PUBMED Abstract]
  21. van der Linden YM, Steenland E, van Houwelingen HC, et al.: Patients with a favourable prognosis are equally palliated with single and multiple fraction radiotherapy: results on survival in the Dutch Bone Metastasis Study. Radiother Oncol 78 (3): 245-53, 2006. [PUBMED Abstract]
  22. Wong E, Hoskin P, Bedard G, et al.: Re-irradiation for painful bone metastases - a systematic review. Radiother Oncol 110 (1): 61-70, 2014. [PUBMED Abstract]
  23. Chow R, Ding K, Ganesh V, et al.: Gender and age make no difference in the re-irradiation of painful bone metastases: A secondary analysis of the NCIC CTG SC.20 randomized trial. Radiother Oncol 126 (3): 541-546, 2018. [PUBMED Abstract]
  24. Chow E, van der Linden YM, Roos D, et al.: Single versus multiple fractions of repeat radiation for painful bone metastases: a randomised, controlled, non-inferiority trial. Lancet Oncol 15 (2): 164-71, 2014. [PUBMED Abstract]
  25. Chow E, Meyer RM, Ding K, et al.: Dexamethasone in the prophylaxis of radiation-induced pain flare after palliative radiotherapy for bone metastases: a double-blind, randomised placebo-controlled, phase 3 trial. Lancet Oncol 16 (15): 1463-72, 2015. [PUBMED Abstract]
  26. Serafini AN, Houston SJ, Resche I, et al.: Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: a double-blind placebo-controlled clinical trial. J Clin Oncol 16 (4): 1574-81, 1998. [PUBMED Abstract]
  27. Sartor O, Reid RH, Bushnell DL, et al.: Safety and efficacy of repeat administration of samarium Sm-153 lexidronam to patients with metastatic bone pain. Cancer 109 (3): 637-43, 2007. [PUBMED Abstract]
  28. Resche I, Chatal JF, Pecking A, et al.: A dose-controlled study of 153Sm-ethylenediaminetetramethylenephosphonate (EDTMP) in the treatment of patients with painful bone metastases. Eur J Cancer 33 (10): 1583-91, 1997. [PUBMED Abstract]
  29. Parker C, Nilsson S, Heinrich D, et al.: Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 369 (3): 213-23, 2013. [PUBMED Abstract]
  30. Bloch R: Rehabilitation medicine approach to cancer pain. Cancer Invest 22 (6): 944-8, 2004. [PUBMED Abstract]
  31. Richardson MA, Sanders T, Palmer JL, et al.: Complementary/alternative medicine use in a comprehensive cancer center and the implications for oncology. J Clin Oncol 18 (13): 2505-14, 2000. [PUBMED Abstract]
  32. Bardia A, Barton DL, Prokop LJ, et al.: Efficacy of complementary and alternative medicine therapies in relieving cancer pain: a systematic review. J Clin Oncol 24 (34): 5457-64, 2006. [PUBMED Abstract]

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)
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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.

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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]
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  • Updated: March 6, 2019
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