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Cancer Pain Management

  • Thomas J. Smith
    Correspondence
    Correspondence: Address to Thomas J. Smith, MD, Harry J. Duffey Family Palliative Care Program, Johns Hopkins Medical Institutions, Sidney Kimmel Comprehensive Cancer Center, 600 N Wolfe St, Blalock 369, Baltimore, MD 21287-0005.
    Affiliations
    Harry J. Duffey Family Palliative Care Program of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Institutions, Baltimore, MD
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  • Catherine B. Saiki
    Affiliations
    Harry J. Duffey Family Palliative Care Program of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Institutions, Baltimore, MD
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      Abstract

      Safe, effective, and evidence-based management of cancer-related pain is a cornerstone of comprehensive cancer care. Despite increasing interest in and efforts to improve its management, pain remains poorly controlled in nearly half of all patients with cancer, with little change in the past 20 years. Limited training in pain assessment and management, overestimation of providers' own skills to treat pain, and failure to refer patients to pain specialists can result in suboptimal pain management with devastating effects on quality of life, physical functioning, and increased psychological distress. From a thorough assessment of cancer-related pain to appropriate treatments that may include opiates, adjuvant medications, nerve blocks, and nondrug interventions, this article is intended as a brief overview of the mechanisms and types of pain as well as a review of current, new, and promising approaches to its management.

      Abbreviations and Acronyms:

      NSAID (nonsteroidal anti-inflammatory drug)
      CME Activity
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      Learning Objectives: On completion of this article, you should be able to (1) understand the etiology of cancer-related pain; (2) differentiate between pain types based on the characteristics; and (3) perform a thorough pain assessment to assist in identifying appropriate treatments(s).
      Disclosures: As a provider accredited by ACCME, Mayo Clinic College of Medicine (Mayo School of Continuous Professional Development) must ensure balance, independence, objectivity, and scientific rigor in its educational activities. Course Director(s), Planning Committee members, Faculty, and all others who are in a position to control the content of this educational activity are required to disclose all relevant financial relationships with any commercial interest related to the subject matter of the educational activity. Safeguards against commercial bias have been put in place. Faculty also will disclose any off-label and/or investigational use of pharmaceuticals or instruments discussed in their presentation. Disclosure of this information will be published in course materials so that those participants in the activity may formulate their own judgments regarding the presentation.
      In their editorial and administrative roles, William L. Lanier, Jr, MD, Terry L. Jopke, Kimberly D. Sankey, and Nicki M. Smith, MPA, have control of the content of this program but have no relevant financial relationship(s) with industry.
      The authors report no competing interests.
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      Questions? Contact [email protected] .
      In 2015, 14.5 million Americans are living with a recent or remote history of cancer.

      American Cancer Society. Cancer Facts & Figures 2015. Atlanta, GA: American Cancer Society. http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf. Accessed June 24, 2015.

      National Cancer Institute. SEER research data 1973-2012—ASCII text data: Surveillance, Epidemiology, and End Results (SEER) Program research data (1973-2012). www.seer.cancer.gov. Published April 15, 2015. Accessed June 24, 2015.

      Worldwide, those estimates were 32.6 million in 2012.
      • Ferlay J.
      • Soerjomataram I.
      • Dikshit R.
      • et al.
      Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.
      Pain is among the most distressing and disabling sequelae of cancer and its related treatments and remains poorly managed across the globe. The prevalence of cancer-related pain has ranged from 14% to 100% in surveys.
      • Goudas L.C.
      • Bloch R.
      • Gialeli-Goudas M.
      • Lau J.
      • Carr D.B.
      The epidemiology of cancer pain.
      The incidence of pain is surprisingly similar across stages of disease, with 64% of those with advanced disease reporting pain vs 53% of patients with all stages of disease. Pain persists in 33% of those who have completed curative treatments.
      • van den Beuken-van Everdingen M.H.
      • de Rijke J.M.
      • Kessels A.G.
      • Schouten H.C.
      • van Kleef M.
      • Patijn J.
      Prevalence of pain in patients with cancer: a systematic review of the past 40 years.
      We see this in our own practice as previously healthy people can be hobbled with poor quality of life after curative treatments leave them with neuropathic pain.
      • Pachman D.R.
      • Barton D.L.
      • Swetz K.M.
      • Loprinzi C.L.
      Troublesome symptoms in cancer survivors: fatigue, insomnia, neuropathy, and pain.
      • Lewis M.A.
      • Zhao F.
      • Jones D.
      • et al.
      Neuropathic symptoms and their risk factors in medical oncology outpatients with colorectal vs. breast, lung, or prostate cancer: results from a prospective multicenter study.
      Safe, effective, and evidence-based management of cancer-related pain is a cornerstone of comprehensive cancer care. Despite increasing interest in and efforts to improve its management, pain remains poorly controlled in nearly half of all patients with cancer.
      • Deandrea S.
      • Montanari M.
      • Moja L.
      • Apolone G.
      Prevalence of undertreatment in cancer pain: a review of published literature.
      The consequences of suboptimal pain management on quality of life, physical functioning, and psychological distress can be devastating. Two-thirds of patients report that pain interferes with their activities of daily living, and half believe that their providers do not prioritize quality of life in their overall plan of care.
      • Breivik H.
      • Cherny N.
      • Collett B.
      • et al.
      Cancer-related pain: a pan-European survey of prevalence, treatment, and patient attitudes.
      These figures stand in stark contrast with oncologists' perceptions of their ability to manage pain. Oncologists rated their training in pain management as a score of 3 (on a scale of 0 to 10) in medical school and 5 in residency but gave themselves a 7 for cancer pain expertise. Oncologists performed worse than pain specialists on pain vignettes, with 60% and 87% giving answers that would be unacceptable to pain specialists on 2 challenging cases.
      • Breuer B.
      • Fleishman S.B.
      • Cruciani R.A.
      • Portenoy R.K.
      Medical oncologists' attitudes and practice in cancer pain management: a national survey.
      A recent update with 8 vignettes was more concerning when oncologists were compared with pain management specialists and palliative medicine specialists.
      • Breuer B.
      • Chang V.T.
      • Von Roenn J.H.
      • et al.
      How well do medical oncologists manage chronic cancer pain? a national survey.
      Oncologists did worse than either group in selection of an opioid, management of opioid adverse effects, management of a pain crisis, use of a coanalgesic to treat neuropathic pain, and use of interventions such as nerve blocks. Despite their lower scores on these vignettes, oncologists rated their own skills at 7 of 10, while pain specialists rated their skills at 6. Contemporary oncology practice results indicate less than optimal management as well. Even in practices that were being self-monitored for pain management, one-third of patients with cancer pain had inadequate prescriptions for pain, despite 20 years of emphasis on cancer pain relief.
      • Fisch M.J.
      • Lee J.W.
      • Weiss M.
      • et al.
      Prospective, observational study of pain and analgesic prescribing in medical oncology outpatients with breast, colorectal, lung, or prostate cancer.
      Minority patients had twice as much difficulty: in this national study of 6 academic and 32 community practices, the chances of a white patient getting inadequate pain prescription was half that of a minority patient (odds ratio, 0.51; 95% CI, 0.37-0.70; P=.002). Of 2700 patients followed up for symptoms, one-third had improvement after consultation with the oncologist, but one-fifth had worsening of their pain.
      • Zhao F.
      • Chang V.T.
      • Cleeland C.
      • et al.
      Determinants of pain severity changes in ambulatory patients with cancer: an analysis from Eastern Cooperative Oncology Group trial E2Z02.
      A persistent theme has been our failure to properly assess pain, especially neuropathic pain, as part of the management process and failure to get help. Even today, 8% of oncologists never and 21% rarely refer patients to a pain specialist.
      • Breuer B.
      • Chang V.T.
      • Von Roenn J.H.
      • et al.
      How well do medical oncologists manage chronic cancer pain? a national survey.
      We can and should do better, whatever our branch of medicine or nursing. We present a brief overview of the mechanisms and types of pain as well as current and new approaches to its management.

      Mechanisms and Types of Cancer Pain

      Cancer pain is the result of complex interactions among cancer cells, the peripheral and central nervous systems, and the immune system.
      • Schmidt B.L.
      • Hamamoto D.T.
      • Simone D.A.
      • Wilcox G.L.
      Mechanism of cancer pain.
      • Ellis A.
      • Bennett D.L.
      Neuroinflammation and the generation of neuropathic pain.
      Cancer cells and the local immune cells produce a wide range of substances that mediate or interact with pain receptors (nociceptors). As more is understood about the functioning of these molecules in the pain signal transduction process, they have emerged as important targets for novel analgesic interventions.
      • Ossipov M.H.
      The perception and endogenous modulation of pain.
      Additionally, in animals, and likely in humans, peripheral nociceptors appear to become activated, sensitized, or injured in the presence of certain cancers.
      • Gregory N.S.
      • Harris A.L.
      • Robinson C.R.
      • Dougherty P.M.
      • Fuchs P.N.
      • Sluka K.A.
      An overview of animal models of pain: disease models and outcome measures.
      Once pain receptors are stimulated, impulses are transmitted first by afferent A-delta (thinly myelinated) fibers and then by separate slower (nonmyelinated) C fibers. These fibers end in cell bodies in the dorsal root or trigeminal ganglion, which then interact with neurons in the central nervous system cells in the spinal cord. These cells synapse to the contralateral thalamus from which impulses are transmitted to regions of the cortex via somatosensory pathways. Interactions at the cortical level are highly complex, involving the somatosensory cortex, frontal cortex, and limbic system. Each transmission implies some chance to block the pain signal at that point.
      The observation that perceptions of pain can vary depending on factors (anxiety, depression, distraction) that have no direct relationship to nociceptors or the painful stimulus indicates the presence of additional mechanisms that modulate transduction and response.
      • Jensen M.P.
      A neuropsychological model of pain: research and clinical implications.
      These mechanisms include inhibition at the spinal level by nonpainful input (the gate control theory

      Gate control theory. Wikipedia website. https://en.wikipedia.org/wiki/Gate_control_theory. Updated August 5, 2015. Accessed July 5, 2015.

      ) and descending inhibition from midbrain and higher regions that contain high concentrations of opioid receptors. Visceral pain arising from nociceptors in internal organs is mostly transmitted by C fibers. Often less well localized and less sharp than somatic pain, visceral pain is triggered by direct irritation from the tumor, distention or contraction of an organ, ischemia, necrosis, or inflammatory mediators.
      Neuropathic pain arises from injury to nerve tissue in either the central or peripheral nervous system. It differs from nociceptive pain in several important ways. First, the inciting stimulus may be gone, so there is nothing to “fix” at the nociceptor. Second, the pain stimulus can arise at any place along the pathway, eg, peripheral, spinal cord, or even central areas. Finally, chronic neuropathic pain may serve no protective purpose. These mechanisms are discussed in an excellent review by Cohen and Mao.
      • Cohen S.P.
      • Mao J.
      Neuropathic pain: mechanisms and their clinical implications.
      Such pain is less likely to respond to standard opioid or nonsteroidal anti-inflammatory drug (NSAID)–based therapy.
      • Cohen S.P.
      • Mao J.
      Neuropathic pain: mechanisms and their clinical implications.
      Neuropathic pain is also complicated by the “wind-up” phenomena
      • Herrero J.F.
      • Laird J.M.
      • López-García J.A.
      Wind-up of spinal cord neurones and pain sensation: much ado about something?.
      : repetitive stimulation of the C fibers leads to biochemical and physical genetic changes in the central nervous system.
      • Kerstman E.
      • Ahn S.
      • Battu S.
      • Tariq S.
      • Grabois M.
      Neuropathic pain.
      In fact, the damaged nerves and their undamaged counterparts may both be giving pain signals by cross talk mediated by gap junctions,
      • Wu A.
      • Green C.R.
      • Rupenthal I.D.
      • Moalem-Taylor G.
      Role of gap junctions in chronic pain.
      reinforcing the pain stimulus.
      In patients with cancer, such injury often arises as a result of treatment (chemotherapy, surgical procedure, or radiotherapy) but can also be caused by infection, direct action of the tumor, ischemia, or a combination of these factors. Unlike somatic or visceral pain, the quality of neuropathic pain is often described as burning, numbness, or tingling and may be further diagnosed as allodynic (caused by stimuli that do not normally trigger pain) or hyperalgesic (pain perception that is much greater than would be expected). The distinction between nociceptive pain (somatic and visceral) and neuropathic pain is clinically important because different therapeutic approaches are often needed to achieve relief.
      Cancer pain can be readily categorized on the basis of the mechanism of nerve damage or type of sensation, but most pain is actually mixed (Table 1). In our own study of refractory cancer pain in 5 countries, 60% of patients had mixed pain.
      • Smith T.J.
      • Coyne P.J.
      • Staats P.S.
      • et al.
      An implantable drug delivery system (IDDS) for refractory cancer pain provides sustained pain control, less drug-related toxicity, and possibly better survival compared with comprehensive medical management (CMM).
      It is important to try to discern the cause of the pain—the “pain generator”—because consequences and treatment options vary tremendously. For instance, local pain from a T12 vertebral metastatic tumor should mandate concern about an epidural mass causing spinal cord compression. In addition, the pain may be well controlled with injections of a local anesthetic or, if mostly neuropathic, from a combination of opioids and neuropathic drugs.
      Table 1Types of Commonly Encountered Cancer Pain
      Type of painCauseCharacteristicsExamples
      NociceptivePressure on nervesDeep, dull, aching, constant, and worsening with timePancreas cancer, deep boring, and epigastric
      VisceralDistention of a hollow viscusCramping, bloating pain, intermittentIntestinal obstruction, renal colic
      NeuropathicDirect damage to the nerves from cancer, treatment, or both
      • Wong C.S.
      • Hui G.K.
      • Chung E.K.
      • Wong S.H.
      Diagnosis and management of neuropathic pain.
      Local pain, sharp shooting, burning, stabbing, often with allodynia (painful sensation with normal touch) or hyperalgesiaDiffuse, constant, stabbing pain in bilateral mastectomy scars, “Like wearing a bra made of barbed wire”
      Chemotherapy-induced neuropathic pain; direct damage to the longest nerves with damaged receptors and even loss of nerve fiber densityNumbness, tingling, and pain together; longest nerves affected most, giving a stocking-glove neuropathyIncreasingly common and dose limiting, occurring in 40%-70% of patients receiving modern treatments
      • Pachman D.R.
      • Watson J.C.
      • Loprinzi C.L.
      Therapeutic strategies for cancer treatment related peripheral neuropathies.
      ; duloxetine is the only proven medication. See Table 3
      Incident or movement painPathologic fractures, bone damage from cancer, residual damage left after cancerMinimal pain at rest but excruciating pain with movement “bone on bone”Very difficult to control. See Table 3

      The First Step: Assessment of Pain

      An editorial commenting on an article in the Journal of Clinical Oncology that reported no progress in pain management in the past 20 years called for “ensuring that every consultation includes the patient's rating of pain, that the oncologist pays attention to the answer, and that there is an agreed-upon plan to increase analgesia when it is inadequate.”
      • Stockler M.R.
      • Wilcken N.R.
      Why is management of cancer pain still a problem [editorial]?.
      We agree but believe that a pain rating alone is insufficient. Table 2 listed the common questions that we use in our pain assessment, modified to be practical and usable.
      Table 2Questions for Pain Assessment in Adults With Cancer Pain
      Data from UpToDate.

      Portenoy RK, Dhingra LK. Assessment of cancer pain. UpToDate website. http://www.uptodate.com/contents/assessment-of-cancer-pain?source=search_result&search=Assessment+of+cancer+pain&selectedTitle=1∼150. Updated May 15, 2015. Accessed August 23, 2015.

      QuestionSearching forWhat to do with the response
      Describe your pain to meGet the patient's own words, rather than presuming some mechanismSuccessful pain management requires a trusting relationship with a health care professional. In a recent study, trust in the physician, higher education level, and white race were all strongly correlated with better knowledge about how to control cancer pain
      • Baker T.A.
      • O'Connor M.L.
      • Krok J.L.
      Experience and knowledge of pain management in patients receiving outpatient cancer treatment: what do older adults really know about their cancer pain?.
      When did it start?Searching for the cause of the painDetermine if it started before or after the surgery, radiation, chemotherapy, or shingles
      Where is it?Searching for the cause

      Symmetry? Nerve, plexus, root or cord?
      Try to isolate the pain origin to control it with nerve blocks, local treatments
      What does it feel like?Dull, aching (nociceptive) or sharp and stabbing associated with tingling (neuropathic)Neuropathic pain requires nerve medications. We describe it to patients as being like treating seizures: we are trying to quiet down the nerve over some weeks
      How long does it last?Searching for pain generatorsPain that lasts seconds, only with bone movement, indicates bone instability or damage
      What makes it better or worse?Searching for pain generators and mechanismIf heat, cold, or massage works, then local treatments may help
      Does touching the skin hurt?Allodynia—pain on normal touch—indicates neuropathic painTreat with neuropathic drugs and look for a spot to administer a local nerve block or try topical treatments
      Is there associated numbness and tingling?Indicates nerve damage such as a plexopathy or chemotherapy-induced peripheral neuropathyPatients may not tell you about these symptoms unless you ask
      What has worked or not before?Make a list of potential things to try; do not include things that the patient has tried that were not effectiveIt is very hard to convince a patient with a serious adverse reaction to a drug, eg, delirium or urinary hesitancy, to try it again
      What adverse effects have you experienced with pain medications?Sedation, constipation, delirium, pruritus, nauseaUnderstanding predictable adverse effects allows for better teaching
      What impact has it had on your life?Does the pain restrict activity? The pain may be less because the person never goes outside or tries to walkDo they think it means the cancer is growing and so will not report it? Is their pain controlled but they never go outside anymore?
      Please rate your pain on a scale of 0 to 10A number. Every patient can at least say if the pain is well controlled or not well controlledEven though this is the fifth vital sign, the score is less important than the mechanism. Getting the pain score down to 0 is often impossible, but patients function well if the pain score is ≤4
      Are there major risks of respiratory or organ dysfunction that limit choice?Liver disease, kidney disease, allergies, high doses of serotonin drugsInfluences prescribing and may need consultation with a pain or palliative care expert and pharmacist
      Are there red flags for potential abuse?Prior drug addiction or misuse,

      multiple prescribers, pain out of keeping with the known anatomy and physiology
      Every prescriber should be able to use their available prescription drug monitoring plan. A full review of their use is beyond the scope of this review
      Modified from questions used by Judith Paice, RN, MSN, PhD, Northwestern University.

      The Second Step: Management of the Pain

      Once pain is assessed, treatment may begin. The World Health Organization's cancer pain ladder for adults

      WHO's cancer pain ladder for adults. World Health Organization website. http://www.who.int/cancer/palliative/painladder/en/. Accessed August 8, 2014.

      recognizes 3 fundamental categories of analgesics—nonopioids (aspirin, acetaminophen, paracetamol, or NSAIDs), “weak” opioids (codeine), and strong opioids (morphine, hydromorphone, and others)—and 3 levels of pain (mild, mild-moderate, and moderate-severe). Mild pain is treated with nonopioids, mild-moderate pain with “weak” opioids with or without a nonopioid, and moderate-severe pain with strong opioids with or without nonopioids. Adjuvant medications are recommended on an ad hoc basis. The World Health Organization's cancer pain ladder for adults recommends around-the-clock dosing of analgesics with provision for break-through or rescue doses, adaption of regimens based on individual needs, patient education, and administration via the oral route when possible. We commonly use some modifications to these recommendations. These modifications include the use of low doses of strong opioids for mild-moderate pain (elimination of step 2 on the ladder, especially the use of codeine, because 10% of patients do not metabolize these medications to the active component, as now recommended by the National Comprehensive Cancer Network

      National Comprehensive Cancer Network. Cancer Pain Guidelines version 2.2015:28. http://www.nccn.org/professionals/physician_gls/pdf/pain.pdf. Accessed July 5, 2015.

      ), concerns about long-term use of NSAIDs on renal and cardiac health, validation of various routes of administration, the addition of a fourth step of interventions for severe and intractable pain, and specific recognition of neuropathic pain requiring a different approach.
      • Vargas-Schaffer G.
      Is the WHO analgesic ladder still valid? twenty-four years of experience.
      • Mercadante S.
      • Fulfaro F.
      World Health Organization guidelines for cancer pain: a reappraisal.
      Some available modalities of treatment are provided in Tables 3 and 4.
      Table 3Standard Ways of Relieving Cancer Pain With Drugs
      MethodCurrent usesEffectivenessComments
      OpioidsSomatic pain

      Neuropathic pain

      Mixed pain
      For morphine, 63% of patients have “treatment success” (very satisfied, very good, or excellent patient reports)
      • Wiffen P.J.
      • Wee B.
      • Moore R.A.
      Oral morphine for cancer pain.
      All the available drugs (morphine, oxycodone, hydrocodone, hydromorphone and oxymorphone) have efficacy with no randomized trial evidence of superiority. In the one randomized trial, methadone had no more effect than morphine in neuropathic pain, but the study was underpowered to detect small improvements
      • Bruera E.
      • Palmer J.L.
      • Bosnjak S.
      • et al.
      Methadone versus morphine as a first-line strong opioid for cancer pain: a randomized, double-blind study.
      Mixed-mechanism drugs (bind to μ-opioid receptor and some blockade of serotonin and norepinephrine)Most of the world has inexpensive tramadol when opiates are not available.

      Tapentadol is new drug that has proven efficacy with fewer gastrointestinal adverse effects than morphine
      • Kress H.G.
      • Koch E.D.
      • Kosturski H.
      • et al.
      Tapentadol prolonged release for managing moderate to severe, chronic malignant tumor-related pain.
      Moderately effective against pain and some cancer-related neuropathic painConversion ratio of tramadol to morphine is 10:1 but variable

      GlobalRPh calculator. GlobalRPh website. http://www.globalrph.com/narcotic.cgi. Updated August 25, 2015. Accessed July 5, 2015



      Use with caution because these drugs lower seizure threshold and can cause serotonin syndrome

      Tapentadol is substantially more expensive ($132) vs oxycodone ($27)
      • Erlich D.R.
      • Bodine W.
      Tapentadol (Nucynta) for treatment of pain.
      Adjuvant drugs

      Antidepressants

      Neuroleptics/seizure medications

      Corticosteroids
      Somatic pain, neuropathic pain, mixed painOne systematic review reported that a reduction in cancer pain intensity of >1 point was unlikely.
      • Bennett M.I.
      Effectiveness of antiepileptic or antidepressant drugs when added to opioids for cancer pain: systematic review.
      Pain relief occurred in 4-8 d, if it occurred
      All have some efficacy, but sequential trials may be required.
      • Cohen S.P.
      • Mao J.
      Neuropathic pain: mechanisms and their clinical implications.
      New drugs are needed because the number needed to treat is often equal to the number who are harmed with adverse effects
      • Finnerup N.B.
      • Sindrup S.H.
      • Jensen T.S.
      The evidence for pharmacological treatment of neuropathic pain.
      Bone strengthenersBisphosphonates50%-70% of patients report benefit.
      • Wong R.
      • Wiffen P.J.
      Bisphosphonates for the relief of pain secondary to bone metastases.
      Six of 11 randomized trials reported benefit
      • Wong M.H.
      • Stockler M.R.
      • Pavlakis N.
      Bisphosphonates and other bone agents for breast cancer.
      Patients with cancer who have lytic bone metastases should receive these drugs routinely.
      • von Moos R.
      • Sternberg C.
      • Body J.J.
      • Bokemeyer C.
      Reducing the burden of bone metastases: current concepts and treatment options.
      Whether added doses provide benefit is unknown
      DenosumabDelays onset of bone pain 4 mo longer than bisphosphonates
      • Stopeck A.T.
      • Lipton A.
      • Body J.J.
      • et al.
      Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study.
      Substantially more expensive than bisphosphonates ($2500 per dose vs $600)
      CalcitoninReduced pain from acute osteoporotic compression fractures by 3 points at 1 wk and by 6 points at 4 wk. No effect on chronic pain.
      • Knopp-Sihota J.A.
      • Newburn-Cook C.V.
      • Homik J.
      • Cummings G.G.
      • Voaklander D.
      Calcitonin for treating acute and chronic pain of recent and remote osteoporotic vertebral compression fractures: a systematic review and meta-analysis.
      Reduced pain associated with aromatase inhibitors more than placebo, from 5 to 2
      • Liu P.
      • Yang D.Q.
      • Xie F.
      • Zhou B.
      • Liu M.
      Effect of calcitonin on anastrozole-induced bone pain during aromatase inhibitor therapy for breast cancer.
      Does not work for chronic metastatic bone pain
      • Martinez-Zapata M.J.
      • Roqué M.
      • Alonso-Coello P.
      • Català E.
      Calcitonin for metastatic bone pain.
      Corticosteroids in addition to other pain drugsMethylprednisolone 32-mg/d did not improve pain compared with placebo in patients with cancer but did improve fatigue, nausea, and well-being.
      • Paulsen O.
      • Klepstad P.
      • Rosland J.H.
      • et al.
      Efficacy of methylprednisolone on pain, fatigue, and appetite loss in patients with advanced cancer using opioids: a randomized, placebo-controlled, double-blind trial.
      A Cochrane systematic review found a mean difference in reduction in pain of 0.84 at 1 week
      • Haywood A.
      • Good P.
      • Khan S.
      • et al.
      Corticosteroids for the management of cancer-related pain in adults.
      If you use a corticosteroid, use for 1 wk and reevaluate. There may be good reasons to use corticosteroids to treat fatigue and improve quality of life.
      • Yennurajalingam S.
      • Frisbee-Hume S.
      • Palmer J.L.
      • et al.
      Reduction of cancer-related fatigue with dexamethasone: a double-blind, randomized, placebo-controlled trial in patients with advanced cancer.
      Use 8 mg of dexamethasone before any stereotactic bone radiation to prevent a pain flare

      Khan L, Chiang A, Zhang L, et al. Prophylactic dexamethasone effectively reduces the incidence of pain flare following spine stereotactic body radiotherapy (SBRT): a prospective observational study [published online ahead of print March 10, 2015]. Support Care Cancer. http://dx.doi.org/10.1007/s00520-015-2659-z.

      Acetaminophen in addition to opioidsThere are conflicting data. A small (N=22) randomized trial of paracetamol added to strong opioids found no benefit.
      • Israel F.J.
      • Parker G.
      • Charles M.
      • Reymond L.
      Lack of benefit from paracetamol (acetaminophen) for palliative cancer patients requiring high-dose strong opioids: a randomized, double-blind, placebo-controlled, crossover trial.
      A slightly larger (N=30) trial found some benefit to adding paracetamol vs placebo, a 0.6-point change in pain with a 0.7-point improvement in well-being
      • Stockler M.
      • Vardy J.
      • Pillai A.
      • Warr D.
      Acetaminophen (paracetamol) improves pain and well-being in people with advanced cancer already receiving a strong opioid regimen: a randomized, double-blind, placebo-controlled cross-over trial.
      If you add acetaminophen, evaluate at 48 h for benefit. Do not expect much change
      NSAIDs in addition to opioidsThe majority of trials report some additional benefit
      • Mercadante S.
      • Giarratano A.
      The long and winding road of non steroidal antinflammatory drugs and paracetamol in cancer pain management: a critical review.
      • Nabal M.
      • Librada S.
      • Redondo M.J.
      • Pigni A.
      • Brunelli C.
      • Caraceni A.
      The role of paracetamol and nonsteroidal anti-inflammatory drugs in addition to WHO Step III opioids in the control of pain in advanced cancer: a systematic review of the literature.
      Getting an 15% additional pain relief may be welcomed and possible, given different mechanisms of action
      Special situation: incident pain (pain on movement of bones)Opioids, NSAIDsOpioids are only partially effective, at the cost of oversedation)
      • Mercadante S.
      • Villari P.
      • Ferrera P.
      • Casuccio A.
      Optimization of opioid therapy for preventing incident pain associated with bone metastases.
      A few patients have been treated with opioid switching and “burst” ketamine at 100 mg/d
      • Mercadante S.
      • Villari P.
      • Ferrera P.
      • Arcuri E.
      • David F.
      Opioid switching and burst ketamine to improve the opioid response in patients with movement-related pain due to bone metastases.
      Topical drugsMenthol 1% twice dailyEffective in one large nonrandomized study and nontoxic, with 82% of patients reporting clinically significant relief and better mood
      • Fallon M.T.
      • Storey D.J.
      • Krishan A.
      • et al.
      Cancer treatment-related neuropathic pain: proof of concept study with menthol—a TRPM8 agonist.
      Randomized trials are ongoing. Do not use 10% menthol creams like Bengay or Tiger Balm—dilute to 1%
      Baclofen-amitriptyline-ketamine gel twice dailyIn RCTs, improvements in pain and sensation; worked better on hands
      • Barton D.L.
      • Wos E.J.
      • Qin R.
      • et al.
      A double-blind, placebo-controlled trial of a topical treatment for chemotherapy-induced peripheral neuropathy: NCCTG trial N06CA.
      Works best on the hands, not the feet. Trials of higher concentrations are needed
      GabapentinThere are no randomized trials. Relieves pain of vulvodynia, postherpetic neuropathy, and other local pain problems. In a recent series, 20 of 23 patients benefited with pain scores falling from 8.2 to 5.6 at 1 mo, and 11 of 23 achieved a clinically meaningful 30% reduction in pain
      • Hiom S.
      • Patel G.K.
      • Newcombe R.G.
      • Khot S.
      • Martin C.
      Severe postherpetic neuralgia and other neuropathic pain syndromes alleviated by topical gabapentin.
      Most centers use 6% gabapentin, compounded, applied 3 times daily. It does affect local nociception,
      • Bryson E.
      • Asbill S.
      • Sweitzer S.
      Skin permeation and antinociception of topical gabapentin formulations.
      so there is rationale for it working
      Lidocaine 5% patchLimited randomized trials. A recent study reported a reduction in pain of 0.3 points compared with placebo for peripheral neuropathic pain

      Demant DT, Lund K, Finnerup NB, et al. Pain relief with lidocaine 5% patch in localized peripheral neuropathic pain in relation to pain phenotype [published online ahead of print June 18, 2015]. Pain. http://dx.doi.org/10.1097/j.pain.0000000000000266.

      Expensive—$10 per patch generic. Try for 1 d and evaluate before commitment
      NSAID = nonsteroidal anti-inflammatory drug; RCT = randomized controlled trial.
      Table 4Nondrug Pain Treatments
      Modified from Springer-Verlag.
      • O'Neill J.
      • Smith T.J.
      Fundamentals of Cancer Pain Management, “Supportive Cancer Care”.
      MethodCurrent usesEffectivenessComments
      Radiation therapyBone pain60% or more patients experience pain relief in days
      • Kane C.M.
      • Hoskin P.
      • Bennett M.I.
      Cancer induced bone pain.
      that may last months
      Important to emphasize that pain relief will not occur in just 1 day but takes several days to kill enough cancer cells to relieve pain. Single-fraction radiation is strongly recommended if possible for convenience, efficacy, and cost
      • Fischberg D.
      • Bull J.
      • Casarett D.
      • et al.
      HPM Choosing Wisely Task Force
      Five things physicians and patients should question in hospice and palliative medicine.
      Surgical procedureObstruction, abdominal painVery little actual data because many patients die before reevaluation
      • Badgwell B.
      • Krouse R.
      • Cormier J.
      • Guevara C.
      • Klimberg V.S.
      • Ferrell B.
      Frequent and early death limits quality of life assessment in patients with advanced malignancies evaluated for palliative surgical intervention.


      May be used more for obstruction
      The disease situation carries a high mortality, so this should be an automatic hospice or palliative referral “trigger”
      Nerve blocksCeliac and other plexus blocks, local injectionsIn general, about a 75% chance of success, with the ability to repeat in the future if neededSee Table 5
      AcupunctureCancer painThere is good evidence for benefit in nausea/vomiting but less for cancer pain because of the high risk of bias in studies or underpowered trials
      • Garcia M.K.
      • McQuade J.
      • Haddad R.
      • et al.
      Systematic review of acupuncture in cancer care: a synthesis of the evidence.
      Pain is the most common cancer symptom for which acupuncture is used. Nine of 11 trials of acupuncture reported positive results but had a high risk of bias. Because the risks are low, acupuncture is worth a trial for most patients
      Advanced locoregional pain techniquesSpinal cord stimulationOver half of patients experience significant benefit
      • Deer T.R.
      • Krames E.
      • Mekhail N.
      • et al.
      Neuromodulation Appropriateness Consensus Committee
      The appropriate use of neurostimulation: new and evolving neurostimulation therapies and applicable treatment for chronic pain and selected disease states.
      Pain relief can be instantaneous and dramatic, without opioid and drug side effects, but requires a referral to a pain specialist
      Peripheral nerve stimulationAppears similar to spinal cord stimulation but with no randomized trialsInsertion of sterile electrodes around the painful area, with stimulation across the area of pain. Not widely available
      Intrathecal infusionRandomized trial found better pain control, less drug toxicity, and longer survival compared with conventional best pain management
      • Smith T.J.
      • Coyne P.J.
      • Staats P.S.
      • et al.
      An implantable drug delivery system (IDDS) for refractory cancer pain provides sustained pain control, less drug-related toxicity, and possibly better survival compared with comprehensive medical management (CMM).
      Preservative-free morphine is the only FDA-approved drug, but fentanyl, hydromorphone, bupivacaine, and clonidine are commonly added
      Scrambler therapyOne randomized trial and 16 uncontrolled trials found some relief of pain with minimal adverse effects (Mathia et al 2015; unpublished data)Better designed placebo-controlled trials are needed to reduce risk of bias
      Integrative therapiesMusic therapy, massage, and healing touch have definable benefitAn excellent review documented no harm and modest evidence of improvement
      • Greenlee H.
      • Balneaves L.G.
      • Carlson L.E.
      • et al.
      Society for Integrative Oncology Guidelines Working Group
      Clinical practice guidelines on the use of integrative therapies as supportive care in patients treated for breast cancer.
      Widely available, but not usually require out of pocket payment. Welcomed by patients as no side effects and gives a sense of control
      FDA = US Food and Drug Administration.
      At least 15% of patients will not experience pain relief with pain medication or will have severe adverse effects. In these patients, nerve blocks or other interventional procedures are needed (Table 5). In our experience, many health care professionals have little experience with the power of nerve blocks. We describe a splanchnic nerve block to our patients in simple terms: “Remember when the dentist put some Novocain into your cheek and your teeth suddenly stopped feeling pain? Same principle. You will know if it works right away, and if it does, you will ask why we did not do this months ago.”
      Table 5Summary of Evidence for Intra-abdominal and Ganglion Nerve Blocks
      CRPS = complex regional pain syndrome; IV = intravenous; PHN = postherpetic neuralgia.
      Modified from Ann Oncol.
      • Aslakson R.
      • Brookman J.C.
      • Smith T.J.
      When should nerve blocks be used for pain management?.
      Type of blockIndicationEffect on painAdverse effects
      Celiac plexus
      Only visceral pain responds, not bone or muscle pain from the same region.
      Deep visceral pain especially from the pancreas or nearby organs70%-96% success in pancreas cancer,
      • Eisenberg E.
      • Carr D.B.
      • Chalmers T.C.
      Neurolytic celiac plexus block for treatment of cancer pain: a meta-analysis.
      often lasting months

      May be very successful in pancreatitis
      • Wong G.Y.
      • Sakorafas G.H.
      • Tsiotos G.G.
      • Sarr M.G.
      Palliation of pain in chronic pancreatitis: use of neural blocks and neurotomy.
      Hypotension, diarrhea

      (usually a good sign that the right area was reached and blocked)
      Superior hypogastric plexus block
      Only visceral pain responds, not bone or muscle pain from the same region.
      Pelvic pain from recurrent rectal, bladder, uterine, cervical cancerIf diagnostic block is successful, long-lasting pain relief occurs in 72% of patients
      • Eisenberg E.
      • Carr D.B.
      • Chalmers T.C.
      Neurolytic celiac plexus block for treatment of cancer pain: a meta-analysis.
      whether done early or late in the disease course
      • de Oliveira R.
      • dos Reis M.P.
      • Prado W.A.
      The effects of early or late neurolytic sympathetic plexus block on the management of abdominal or pelvic cancer pain.
      Hypotension, diarrhea
      Splanchnic nerve block
      Only visceral pain responds, not bone or muscle pain from the same region.
      Deep visceral pain for more diffuse metastases or sites of diseaseGood to excellent success
      • Erdine S.
      Celiac ganglion block.
      The splanchnic nerves are “upstream” of the celiac plexus, and block may cover more of the entire upper abdomen
      Stellate ganglion blockMenopausal hot flashes, upper extremity pain, PHN, angina, Raynaud disease, angina pectoris, phantom limb pain, CRPSSafe, with 64% reduction in hot flashes.
      • Haest K.
      • Kumar A.
      • Van Calster B.
      • et al.
      Stellate ganglion block for the management of hot flashes and sleep disturbances in breast cancer survivors: an uncontrolled experimental study with 24 weeks of follow-up.
      Safe and effective but few randomized or large trials
      • Deandrea S.
      • Montanari M.
      • Moja L.
      • Apolone G.
      Prevalence of undertreatment in cancer pain: a review of published literature.
      Paresthesias, anesthesias
      Ganglion impar block, anterior to the sacrococcygeal junctionPerineal painGood to excellent relief for perineal and coccyx pain, 90% response with >50% reduction in pain
      • Agarwal-Kozlowski K.
      • Lorke D.E.
      • Habermann C.R.
      • Am Esch J.S.
      • Beck H.
      CT-guided blocks and neuroablation of the ganglion impar (Walther) in perineal pain: anatomy, technique, safety, and efficacy.
      Can treat pain including pelvic, genital, perineal, anal pain, and visceral pain in these areas
      Brachial plexus block or infusionChronic pain from cancer, scar, radiation, accidentsFew large series but small reports detail excellent pain relief
      • Mukherji S.K.
      • Wagle A.
      • Armao D.M.
      • Dogra S.
      Brachial plexus nerve block with CT guidance for regional pain management: initial results.
      Thoracic ganglion blocks may also be highly effective in similar patients
      • Yoo H.S.
      • Nahm F.S.
      • Lee P.B.
      • Lee C.J.
      Early thoracic sympathetic block improves the treatment effect for upper extremity neuropathic pain.
      Lumbar sympathetic blockLower extremity cancer pain, phantom limb pain, CRPS, PHN, pelvic/urogenic pain, vertebral fracture painFew large series. In a recent randomized trial, L2 block for osteoporosis/fracture pain helped for 2 wk but not beyond that time
      • Ohtori S.
      • Yamashita M.
      • Inoue G.
      • et al.
      L2 spinal nerve-block effects on acute low back pain from osteoporotic vertebral fracture.
      Can relieve lower back or leg pain, especially if due to the abnormal vascular tone of complex regional pain syndrome
      Peroneal or popliteal nerveChronic ischemia-related or cancer-related painGood results in chronic ischemia with either local anesthetic or combined with morphine
      • Keskinbora K.
      • Aydinli I.
      Perineural morphine in patients with chronic ischemic lower extremity pain: efficacy and long-term results.
      Few to no trials in chronic pain. IV ketamine may be a better choice for ischemic pain based on small single-arm trials, either as a single infusion
      • Mitchell A.C.
      • Fallon M.T.
      A single infusion of intravenous ketamine improves pain relief in patients with critical limb ischaemia: results of a double blind randomised controlled trial.
      or low-dose continuous infusion
      • Tawfic Q.A.
      • Eipe N.
      • Penning J.
      Ultra-low-dose ketamine infusion for ischemic limb pain.
      a CRPS = complex regional pain syndrome; IV = intravenous; PHN = postherpetic neuralgia.
      b Only visceral pain responds, not bone or muscle pain from the same region.
      Some common practices in pain management that should be avoided are presented in Table 6.
      Table 6Common Mistakes in Cancer Pain Management
      MistakeRemedyEvidence
      Not assessing for neuropathic pain and treating everything with opioids without trying gabapentin firstAlways do a full assessment including for neuropathic painOpioids alone help neuropathic pain as does gabapentin, but the combination is more effective than either alone
      • Gilron I.
      • Bailey J.M.
      • Tu D.
      • Holden R.R.
      • Weaver D.F.
      • Houlden R.L.
      Morphine, gabapentin, or their combination for neuropathic pain.
      Treating chemotherapy-induced peripheral neuropathy (CIPN) like any other type of neuropathic pain such as diabetic neuropathyDo use duloxetine. Do not use gabapentin or other drugs for CIPN until proven beneficial in randomized trials
      • Hershman D.L.
      • Lacchetti C.
      • Dworkin R.H.
      • et al.
      Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline.
      The only drug to date with significant activity in CIPN is duloxetine, which reduced pain scores from 6 to 5 in 6 wk.
      • Smith E.M.
      • Pang H.
      • Cirrincione C.
      • et al.
      Alliance for Clinical Trials in Oncology. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial.
      Do not use acetyl-L-carnitine, which looked promising in phase 2 trials but is actually harmful
      • Hershman D.L.
      • Unger J.M.
      • Crew K.D.
      • et al.
      Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy in women undergoing adjuvant breast cancer therapy.
      Not sending patients with pancreas cancer or other serious pain for consultation with a pain specialistDo refer patients to a pain specialist early. Develop a working relationship with a pain management team, just like with radiation oncologyPain relief from splanchnic block is often immediate (minutes to hours), is long-lasting (months), and can be repeated if needed. The initial randomized trial found that patients who underwent chemical splanchnicectomy had longer survival,
      • Lillemoe K.D.
      • Cameron J.L.
      • Kaufman H.S.
      • Yeo C.J.
      • Pitt H.A.
      • Sauter P.K.
      Chemical splanchnicectomy in patients with unresectable pancreatic cancer: a prospective randomized trial.
      but a modern trial reported only markedly better pain relief with neurolytic block vs opioids, with 16% vs 6% of patients alive at 2 years
      • Wong G.Y.
      • Schroeder D.R.
      • Carns P.E.
      • et al.
      Effect of neurolytic celiac plexus block on pain relief, quality of life, and survival in patients with unresectable pancreatic cancer: a randomized controlled trial.
      Not performing single-fraction radiation for painful bone metastasesInstruct radiation therapists to give single-fraction radiation whenever possibleIt works just as well as 10 fractions in most people, with 60% of patients having pain relief and 25% being pain free.
      • Kane C.M.
      • Hoskin P.
      • Bennett M.I.
      Cancer induced bone pain.
      One in 8 patients may need retreatment, but repeated single-fraction radiation is also effective and has less toxicity than multiple-fraction radiation.
      • Chow E.
      • van der Linden Y.M.
      • Roos D.
      • et al.
      Single versus multiple fractions of repeat radiation for painful bone metastases: a randomised, controlled, non-inferiority trial.
      Single-fraction radiation is recommended by all national guidelines, works quickly, is much easier to perform, and is less costly for families
      Putting a lidocaine patch on anything that hurtsLidocaine patches work slightly better than placebo for myofascial pain
      • Lin Y.C.
      • Kuan T.S.
      • Hsieh P.C.
      • Yen W.J.
      • Chang W.C.
      • Chen S.M.
      Therapeutic effects of lidocaine patch on myofascial pain syndrome of the upper trapezius: a randomized, double-blind, placebo-controlled study.
      at 7 d but not at 1 mo. They may help with postthoracotomy or mastectomy pain or for local recurrences,
      • Garzón-Rodríguez C.
      • Casals Merchan M.
      • Calsina-Berna A.
      • López-Rómboli E.
      • Porta-Sales J.
      Lidocaine 5 % patches as an effective short-term co-analgesic in cancer pain: preliminary results.
      but randomized trials are lacking, and a Cochrane database review found no convincing evidence for efficacy
      • Derry S.
      • Wiffen P.J.
      • Moore R.A.
      • Quinlan J.
      Topical lidocaine for neuropathic pain in adults.
      Even generic patches are $10 each, and because they often are not covered by insurance, they can be a financial burden. If you must use them, try one to see if it works before committing your patient to the expense

      Step 3: Prevention and Management of Adverse Effects

      There are important opiate-induced adverse effects to anticipate, prevent, and educate patients and families about. Some are predictable and expected such as constipation, fuzzy-headedness, and mild nausea. Most patients with pain will need a stool stimulant or softener; however, for hospice patients, there is no advantage to using a stool softener.
      • Tarumi Y.
      • Wilson M.P.
      • Szafran O.
      • Spooner G.R.
      Randomized, double-blind, placebo-controlled trial of oral docusate in the management of constipation in hospice patients.
      If opioid induced, constipation refractory to an aggressive bowel regimen can also be managed with the use of methylnaltrexone, a modification of naltrexone that does not cross the blood-brain barrier and therefore will not reverse analgesia. In the most recent placebo-controlled trial, 63% of patients achieved a bowel movement with use of methylnaltrexone compared with just 9% in those receiving placebo.
      • Bull J.
      • Wellman C.V.
      • Israel R.J.
      • Barrett A.C.
      • Paterson C.
      • Forbes W.P.
      Fixed-dose subcutaneous methylnaltrexone in patients with advanced illness and opioid-induced constipation: results of a randomized, placebo-controlled study and open-label extension.
      The primary adverse effect of methylnaltrexone is the expense.
      The management of nausea and vomiting associated with opioid use is based on practical experience and nonrandomized trials. The available evidence suggests that dopamine antagonists such as prochlorperazine or metoclopramide may be the most effective, available, and inexpensive; serotonin-blocking ondansetron can be effective but is much more expensive and can be constipating.

      Portenoy RK, Mehta Z, Ahmed E. Cancer pain management with opioids: prevention and management of side effects. UpToDate website. http://www.uptodate.com/contents/cancer-pain-management-with-opioids-prevention-and-management-of-side-effects?source=search_result&search=Cancer+pain+management+with+opioids&selectedTitle=2∼150. Updated August 4, 2015. Accessed July 4, 2015.

      Unresolved Clinical Questions and Future Directions

      The biggest unresolved issue in pain management is neuropathic pain because of relatively ineffective drugs, some placebo response, publication bias, and no major “winners.”
      • Finnerup N.B.
      • Attal N.
      • Haroutounian S.
      • et al.
      Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis.
      Long after the stimulus is gone, the nerve is still sending a danger signal that can be disabling.
      We and others have had good clinical success with a novel method of cutaneous electrical stimulation. The machine synthesizes 16 different electrical currents, assembles them into packages, and transmits them to the existing nerves using modified electrocardiogram pads for 30 minutes a day. In the largest review, Mayo Clinic researchers included 16 clinical trials (Mathia et al 2015; unpublished data) with some positive effect ranging from 25% pain relief in low back pain, 50% to 60% relief of refractory chemotherapy-induced peripheral neuropathy,
      • Smith T.J.
      • Coyne P.J.
      • Parker G.L.
      • Dodson P.
      • Ramakrishnan V.
      Pilot trial of a patient-specific cutaneous electrostimulation device (MC5-A Calmare®) for chemotherapy-induced peripheral neuropathy.
      • Pachman D.R.
      • Weisbrod B.L.
      • Seisler D.K.
      • et al.
      Pilot evaluation of Scrambler therapy for the treatment of chemotherapy-induced peripheral neuropathy.
      and 95% pain relief in postherpetic neuralgia, failed back syndrome, and spinal cord stenosis
      • Marineo G.
      • Iorno V.
      • Gandini C.
      • Moschini V.
      • Smith T.J.
      Scrambler therapy may relieve chronic neuropathic pain more effectively than guideline-based drug management: results of a pilot, randomized, controlled trial.
      with no toxicity. However, randomized trials are still needed. High-intensity light treatments (photon therapy that penetrated 4 cm into the tissue with no adverse effects) has been reported to improve quality of life and sensation in patients with diabetic neuropathy while not affecting pain significantly
      • Swislocki A.
      • Orth M.
      • Bales M.
      • et al.
      A randomized clinical trial of the effectiveness of photon stimulation on pain, sensation, and quality of life in patients with diabetic peripheral neuropathy.
      ; further trials in patients with cancer are ongoing and demonstrate how much we still have to learn about nerves.
      An unexplored but highly promising field is mindfulness-based stress reduction and cognitive therapy, which had positive effects on stress and on mental and some physical functioning in multiple randomized trials.
      • Gotink R.A.
      • Chu P.
      • Busschbach J.J.
      • Benson H.
      • Fricchione G.L.
      • Hunink M.G.
      Standardised mindfulness-based interventions in healthcare: an overview of systematic reviews and meta-analyses of RCTs.
      Recent data reveal that mindfulness-based stress reduction is effective for cancer-related fatigue and chemotherapy-induced cognitive dysfunction,
      • Bower J.E.
      • Crosswell A.D.
      • Stanton A.L.
      • et al.
      Mindfulness meditation for younger breast cancer survivors: a randomized controlled trial.
      but effects on pain have been nonsignificant
      • Ledesma D.
      • Kumano H.
      Mindfulness-based stress reduction and cancer: a meta-analysis.
      ; we are not aware of any trial with cancer pain as a primary end point.

      Conclusion

      Cancer pain remains an unresolved problem 20 years after initiation of a campaign to make pain the fifth vital sign. The primary barriers for effective pain management include (1) inadequate pain assessment and management training (lack of awareness of one's own knowledge deficits), (2) failure to refer patients to pain management specialists, (3) patient reluctance and poor adherence (not covered in this review), and (4) poor reimbursement for nonprocedural pain management (not covered in this review). These barriers are in addition to the complexities of pain itself.
      Specific actions that providers can take are to always do a thorough pain assessment, learn to use both opioids and adjunctive medications, tailor neuropathic pain treatments to the cause of the pain, and refer patients to pain specialists earlier and more often.

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