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Cancer pain

Introduction

Cancer patients commonly experience pain, which often leads to a negative impact on patients’ functional status and quality of life. Management of cancer pain, including breakthrough and refractory pain, usually involves treatment with non-opioid and opioid analgesics, and must take into account the increased risk of adverse effects with these drugs.

This collection comprises a selection of recent high-quality full-text review articles from the Springer Nature portfolio that discuss cancer-related pain, including its clinical significance, methods for assessment and strategies for management. These are accompanied by additional selected full-text articles sourced from other prominent publishers.

Pathophysiology, epidemiology and clinical significance

Mechanisms in cancer pain

This chapter provides an overview of the types of pain experienced by patients with cancer and discusses the underlying mechanisms and pathophysiology.

Summary points
  • The mechanisms involved in the pain of cancer patients are complex and multifactorial.
  • Pain in the cancer patient is caused primarily by the development of the disease process (tumors, metastases), which in turn causes, amongst other things, infiltration of soft tissues, bones, nervous system structures, and serous membranes.
  • Pain in the cancer patient may also be the consequence of anticancer therapy.
  • Pain in a cancer patient can be classified as nociceptive (somatic, visceral), neuropathic, or mixed.
  • A significant negative impact on the quality of life of cancer patients is exerted by acute pain due to both diagnostic (e.g. biopsy, blood sampling) and therapeutic procedures (e.g. acute postoperative pain).
  • Understanding the underlying mechanisms of pain in the cancer patient should be the goal for effective management pathways rather than the current empirical treatment strategy.
  • Complex pain mechanisms in cancer patients will require multimodal pharmacological and non-pharmacological treatment.

Wordliczek J, Zajaczkowska R. In: Cancer Pain. Edited by Hanna M, Zylicz Z. Springer-Verlag London 2013. DOI 10.1007/978-0-85729-230-8_5.

Update on prevalence of pain in patients with cancer: systematic review and meta-analysis

The aim of this review was to study the present status of the prevalence of pain in patients with cancer and explore the determinants of pain prevalence.

Summary points
  • Pain has a severe impact on patients' quality of life, and numerous psychosocial responses are associated with cancer pain.
  • Recent studies suggest that treatment of cancer pain has improved during the last decade.
  • A systematic search of the literature published between September 2005 and January 2014 was performed using the databases PubMed, Medline, Embase, CINAHL, and Cochrane.
  • 122 studies were selected for the meta-analyses on pain (117 studies, n = 63,533) and pain severity (52 studies, n = 32,261).
  • Pain prevalence rates were 39.3% after curative treatment; 55.0% during anticancer treatment; and 66.4% in advanced, metastatic, or terminal disease.
  • Moderate to severe pain (numerical rating scale score ≥5) was reported by 38.0% of all patients.
  • Despite increased attention on assessment and management, pain continues to be a prevalent symptom in patients with cancer.

van den Beuken-van Everdingen MHJ et al. J Pain Symptom Manage. 2016;51:1070-1090.e9. DOI: 10.1016/j.jpainsymman.2015.12.340

Biology of Bone Cancer Pain

This chapter reviews the complex, multifactorial processes involved in the pathophysiology of bone cancer pain.

Summary points
  • Pain is the most common presenting symptom in patients with skeletal metastases and is directly proportional to the patient’s quality of life.
  • Bone cancer pain is a multifactorial process that is initiated by a complex interaction between the host cells within the affected bone and the tumor cells.
  • Pain occurs during tissue damage as the result of release of neurotransmitters, cytokines, and other factors from damaged cells, reactive or activated inflammatory cells, adjacent blood vessels, and nociceptive terminals.
  • Bone is densely innervated by sensory nerve fibers within the bone marrow, mineralized bone, and periosteum.
  • Tumor-derived cytokines, growth factors, and peptides have been shown to stimulate primary afferent nerve fibers that innervate bone, resulting in cancer pain.
  • Most metastatic skeletal malignancies are destructive in nature and produce regions of significant osteolysis via activation, recruitment, and proliferation of osteoclasts at tumor-bearing sites.
  • Research targeting pain-related cytokines, antiosteoclastic medications, and ion channels has shown significant clinical progress in the treatment of cancer-related bone pain.

O’Donnell PW, Clohisy DR. In: Metastatic Bone Disease. Edited by Randall RL, Springer Science+Business Media New York 2016. DOI 10.1007/978-1-4614-5662-9_3

Assessment and diagnosis

AAPT diagnostic criteria for chronic cancer pain conditions

This review article discusses a proposed taxonomy for the classification and diagnosis of three chronic cancer pain syndromes; cancer-induced bone pain, pancreatic cancer pain and chemotherapy-induced peripheral neuropathy.

Summary points
  • Cancer pain is often classified by its intensity (i.e. mild, moderate or severe), expected duration (i.e. acute vs chronic), location (e.g. head and neck pain), putative mechanism (e.g. tumor- or treatment-related) or presumed pathophysiology (e.g. nociceptive vs neuropathic).
  • The working group proposed new core diagnostic criteria for three chronic pain syndromes in patients with cancer; cancer-induced bone pain, pancreatic cancer pain and chemotherapy-induced peripheral neuropathy (CIPN).
  • The core diagnostic criteria for cancer-induced bone pain must include a diagnosis of cancer and imaging evidence of primary or metastatic bone disease.
  • Pancreatic cancer pain diagnostic criteria include a diagnosis of pancreatic cancer and imaging evidence of an epigastric mass and/or biopsy findings that confirm the diagnosis.
  • The diagnostic criteria for CIPN include a temporal relationship between the onset of symptoms and the start, end and duration of cancer treatment.
  • Future work will investigate the validity and reliability of these proposed diagnostic criteria.

Paice JA et al. J Pain. 2017;18:233-246. DOI: 10.1016/j.jpain.2016.10.020

Pain outcomes in patients with bone metastases from advanced cancer: assessment and management with bone-targeting agents

This review article discusses pain and analgesic use assessment in patients with cancer-related pain and summarises pain outcomes in clinical studies of bone-targeting agents (e.g. bisphosphonates and denosumab).

Summary points
  • Without systematic pain monitoring with validated patient-reported outcome assessments, cancer pain may be under-reported and inadequately managed.
  • Effective pain assessment, ideally with at least two different variables to determine the impact of pain worsening/improving, is essential for optimal management of patients with bone metastases.
  • Several methods of cancer pain and analgesic use assessment have been used in randomised controlled trials (RCTs).
  • The World Health Organisation (WHO) pain ladder is a four-point scale based on analgesic use: 0 = no analgesic; 1 = non-opioid; 2 = weak opioid; and 3 = strong opioid.
  • The Analgesic Quantification Algorithm is an expanded version of the WHO ladder with eight points; no analgesic, non-opioid analgesic, weak opioids and strong opioids (oral morphine equivalent of ≤75 mg, >75–150 mg, >150–300 mg, >300–600 mg or >600 mg daily).
  • The Brief Pain Inventory-Short Form is a 15-point questionnaire on pain severity (0 = no pain; 1–4 = mild pain; 5–6 = moderate pain; 7–10 = severe pain) and pain interference (0 = no interference; 10 = complete interference).
  • In RCTs, bone-targeting agents (e.g. bisphosphonates and denosumab) were shown to reduce skeletal-related events (e.g. pathological fractures), thereby improving patient outcomes and reducing the need for strong opioid analgesics.

Patrick DL. Support Care Cancer 2015; 23: 1157. DOI:10.1007/s00520-014-2525-4

Management strategies for cancer pain

Multidimensional Treatment of Cancer Pain

In this review article, Liu et al provide an overview of the recent literature discussing the assessment and treatment options of cancer pain.

Summary points
  • Although numerous treatment options are available to address cancer pain, inadequate management continues to be an ongoing problem worldwide.
  • Comprehensive pain assessment should note the pain location, characteristics, mechanisms, expression, and function, including assessment of the psychosocial factors and the current analgesic treatment.
  • Pain intensity should be regularly assessed to determine the severity of the pain as well as to monitor responses to analgesic treatment.
  • A comprehensive, holistic treatment plan which includes a team of trained specialists employing both pharmacological (eg, opioids, nonsteroidal anti-inflammatory drugs) as well as other treatments (eg, psychosocial interventions) would be most beneficial. Though numerous modalities are available, care plans must be individualized for each specific patient.
  • Few adequate studies evaluate current treatments of cancer pain, but this is probably a reflection of the difficulty in conducting adequately powered randomized controlled trials in this heterogeneous patient population.

Liu WC et al. Curr Oncol Rep 2017; 19: 10. DOI:10.1007/s11912-017-0570-0

Opioids and Chronic Pain: Where Is the Balance?

This chapter reviews the array of approaches to treat cancer pain and discusses likely future trends.

Summary points
  • Pain is the most common and most feared symptom among cancer patients. At least 75% of cancer patients will have significant pain, and the pain usually increases as the disease progresses and the end of life nears.
  • Pain in cancer is the result of complex interactions between cancer cells themselves, the peripheral and central nervous systems, and the immune system.
  • One of the most significant challenges facing the clinician is to build an objective framework from which to assess and monitor the patient’s subjective, or self-reported, experience of pain. Without it, measuring the progression of disease and understanding the impact and efficacy of therapeutic interventions are difficult.
  • Various interview techniques, assessment tools, technologies, and scales have been evaluated and deployed for assessing pain in patients with cancer.
  • The basic World Health Organization approach recognizes three fundamental categories of analgesics: non-opioids (aspirin, acetaminophen, paracetamol, or NSAIDs), ‘weak’ opioids (codeine), and strong opioids (morphine, hydromorphone and others) – and three levels of pain (mild, mild-moderate, and moderate-severe).
  • Opioids are the backbone of most all strategies to control cancer pain. Opioid dosing can be highly variable from patient to patient and must be tailored to individual responses and characteristics.
  • Adjuvant non-opioid pharmacotherapies are used most often in conjunction with opiates to treat nociceptive pain.
  • The clinician should be especially vigilant to identify bone pain and to rule out or address impending pathological fractures (especially if there is spinal disease and a potential for spinal cord compression).
  • Advances in cancer pain management will come from a better understanding of the pathophysiology of pain, discovery of novel medications and techniques to treat pain, and smarter educational and public policies directed at promulgating pain management techniques into healthcare systems.

Davis MP, Mehta Z. Curr Oncol Rep 2016; 18: 71. DOI:10.1007/s11912-016-0558-1

Fundamentals of Cancer Pain Management

This chapter reviews the array of approaches to treat cancer pain and discusses likely future trends.

Summary points
  • Pain is the most common and most feared symptom among cancer patients. At least 75% of cancer patients will have significant pain, and the pain usually increases as the disease progresses and the end of life nears.
  • Pain in cancer is the result of complex interactions between cancer cells themselves, the peripheral and central nervous systems, and the immune system.
  • One of the most significant challenges facing the clinician is to build an objective framework from which to assess and monitor the patient’s subjective, or self-reported, experience of pain. Without it, measuring the progression of disease and understanding the impact and efficacy of therapeutic interventions are difficult.
  • Various interview techniques, assessment tools, technologies, and scales have been evaluated and deployed for assessing pain in patients with cancer.
  • The basic World Health Organization approach recognizes three fundamental categories of analgesics: non-opioids (aspirin, acetaminophen, paracetamol, or NSAIDs), ‘weak’ opioids (codeine), and strong opioids (morphine, hydromorphone and others) – and three levels of pain (mild, mild-moderate, and moderate-severe).
  • Opioids are the backbone of most all strategies to control cancer pain. Opioid dosing can be highly variable from patient to patient and must be tailored to individual responses and characteristics.
  • Adjuvant non-opioid pharmacotherapies are used most often in conjunction with opiates to treat nociceptive pain.
  • The clinician should be especially vigilant to identify bone pain and to rule out or address impending pathological fractures (especially if there is spinal disease and a potential for spinal cord compression).
  • Advances in cancer pain management will come from a better understanding of the pathophysiology of pain, discovery of novel medications and techniques to treat pain, and smarter educational and public policies directed at promulgating pain management techniques into healthcare systems.

Smith TJ, O'Neil J. In: Supportive Cancer Care. Edited by Alberts D et al.  Springer International Publishing Switzerland 2016. DOI 10.1007/978-3-319-24814-1_7

New Cancer Pain Treatment Options

The goals of this review are to draw attention to the critical role that regional anesthetic nerve blocks and interventional pain management techniques play in treating malignancy-related pain.

Summary points
  • The consequences of implementing suboptimal treatment are far-reaching; therefore, effective treatment methods are in a great demand.
  • A large proportion of cancer patients continues to struggle with an inadequately treated pain despite a strict adherence to the World Health Organisation analgesic step ladder.
  • Interventional procedures have become an integral part of providing multimodal analgesia in cancer pain treatment.
  • The previous pain treatment algorithm has been modified to include peripheral neural blockade, neuro-destructive techniques, neuromodulatory device use, and intrathecal drug delivery systems.
  • Frequently, the interventions provide life-saving benefits afforded when ameliorating the pain without the attendant side effects of opioids including mental obtundation and respiratory and circulatory suppression.

Candido KD et al. Curr Pain Headache Rep 2017; 21: 12. DOI:10.1007/s11916-017-0613-0

Management strategies for breakthrough cancer pain

Breakthrough Cancer Pain

This review examines the important topical publications on breakthrough cancer pain.

Summary points
  • Breakthrough cancer pain is a transient exacerbation of pain which occurs during/despite stable and adequately controlled background pain. This type of pain is common in patients with cancer pain and is associated with significant morbidity.
  • A systematic review and pooling of study results revealed that breakthrough cancer pain had a prevalence of 59.2%; 39.9% in outpatient clinics and 80.5% in hospice settings.
  • The clinical features of breakthrough cancer pain reveal that is not a single clinical entity, but a range of entities that vary between individuals and can vary within an individual over time. Generally breakthrough cancer pain is rated as severe by the majority of patients and occurs during the daytime.
  • The appropriate management of breakthrough pain incorporates factors relating to both the pain type (etiology, clinical features and pathophysiology) and the patient (disease stage, performance status and personal preferences).
  • An opioid analgesic is the most appropriate rescue medication in the majority of cases (as opposed to a non-opioid or adjuvant analgesic).
  • Transmucosal and intranasal formulations of opioids provide more rapid pain relief than traditional oral opioids (which do not have an onset or duration of effect that matches the characteristics of most breakthrough pain episodes).

Davies AN. Curr Pain Headache Rep 2014; 18: 420. DOI:10.1007/s11916-014-0420-9

Practical Approach to the Management of Cancer Breakthrough Pain

Using a case-based approach, this chapter reviews practical approaches to the treatment of cancer breakthrough pain.

Summary points
  • At the initiation of treatment and throughout treatment, the clinician and healthcare team should always tailor and individualize their treatment methods to the patient.
  • After it is determined that a patient has cancer and pain flares, the clinician should then assess whether the patient’s background pain is adequately controlled by an around-the-clock (ATC) medication.
  • In most situations, if flares of pain are occurring more than four times per day then the physician should consider titration of the ATC medication; however, some patients may not tolerate increasing the ATC dose and might do better with more frequent cancer breakthrough pain (cBTP) medication dosing.
  • Once the ATC medication has been optimally titrated to control the patient’s background pain, then it must be determined if the patient is opioid tolerant.
  • The patient should also be screened for aberrant drug behavior during initial examination, and their risk factors should be reviewed.
  • If the background pain is under adequate control, the patient is opioid tolerant, they are compliant with treatment, and episodes of pain require treatment with opioids, then a rapid-onset opioid (ROO) or standard opioid may be considered for the treatment of their cBTP.
  • The ROOs are most helpful when the pain flares are unpredictable and/or rise rapidly to maximum intensity.

Taylor D. In: Managing Cancer Breakthrough Pain. Edited by Taylor D. Springer Healthcare, 2013. DOI: 10.1007/978-1-908517-83-8_4

Management strategies for refractory cancer pain

Pharmacological options for the management of refractory cancer pain—what is the evidence?

In their review of the literature and evidence for treatments commonly employed for managing refractory pain, Afsharimani and colleagues aimed to develop evidence-based guidelines for patient with refractory cancer pain.

Summary points
  • Refractory cancer pain is that related to cancer or its treatment that has lasted for at least 3 months and does not respond to standard analgesics.
  • Occurring in 10–20% of patients with cancer, refractory pain has been associated with factors such as young age, pain type (neuropathic or incident), psychological distress, previous opioid use, high tolerance, a history of addiction and impaired cognition.
  • Using knowledge gleaned from surveys, personal experience, Cochrane Database reviews, systematic reviews and controlled clinical trials, these guidelines were established for pharmacological interventions in refractory cancer pain.
  • Opioids are the sole analgesic with proven efficacy in cancer pain. Adverse effects often limit the use of higher doses; however a number of methods exist to minimize these, such as actively managing adverse effects, rotating opioids and using co-analgesia.
  • Non-opioid analgesics, such as paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs), are recommended for use in mild cancer pain and can also be used in more severe forms of pain as an adjuvant to opioids.
  • Other compounds have been examined in various chronic pain states, including the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine, cannabinoids, lignocaine and corticosteroids. However, there is a lack of clear robust data to support their use in this indication.

Afsharimani B et al. Support Care Cancer 2015; 23: 1473. DOI:10.1007/s00520-015-2678-9.

Interventional options for the management of refractory cancer pain—what is the evidence?

This systematic review compiles the latest evidence on interventional refractory pain management in cancer patients – i.e. those that differ from standardised clinical approaches.

Summary points
  • For patients with refractory cancer pain for whom standard analgesic strategies aren’t suitable, interventional analgesic techniques can be used in an attempt to control refractory pain. However, because these techniques usually involve an invasive procedure and necessitate the involvement of specialist clinical staff, a thorough benefit:risk evaluation is very important.
  • Initially used for osteoporotic fractures in the spine, cement fixation of bones has been used in malignant bone disease to relieve pain and stabilise fractured vertebra. Some results indicate that the procedure can provide pain relief, but drawing a clear conclusion is not possible due to the lack of high-quality data.
  • Neuraxial analgesia is a technique involving a percutaneous or implanted catheter delivering local anaesthetics, opioids or co-analgesics directly to the epidural or intrathecal space. This method is common among patients who do not respond to or are intolerant of conventional analgesic treatments.
  • Trigger point injection, whereby local anaesthetics or corticosteroids are delivered directly to a painful muscle or joint, could be a useful treatment modality for patients with cancer pain.
  • Injecting anaesthetic or analgesic directly into the epidural cavity near a nerve plexus or peripheral nerve – a nerve block – can interrupt nociceptive pain and provide analgesia for a longer period than the drug’s duration of action.
  • As a last resort for patients with intractable pain, neuro-destructive procedures can be used to provide long-term pain relief. The injection of ethanol or phenol into a nerve plexus has been used to cause neurolysis in patients with refractory cancer pain. However, given the destructive nature of this approach and the potential for severe adverse events, this treatment should be approached very cautiously.

Vayne-Bossert P et al. Support Care Cancer 2016; 24: 1429. DOI:10.1007/s00520-015-3047-4.

The future of cancer pain – improving management strategies

Access to opioid analgesics and pain relief for patients with cancer

Despite knowledge and availability of palliative strategies for cancer pain, many patients have unrelieved pain. This review examines the barriers to effective management and gives key areas of focus in the drive to improve palliative pain care for patients with cancer.

Summary points
  • Of all cancer symptoms, pain that is not controlled is one of the most frequent and feared symptoms.
  • Cancer pain is associated with considerable burden for patients, giving rise to greater impairment and decreased quality of life. Given that pain can be effectively managed in the vast majority of patients with cancer, the burden of unrelieved pain is regrettable.
  • Cancer pain is not a single entity, rather a description for a complex and varied group of pain syndromes; for each patient cancer pain is a multidimensional construct comprised of elements of disease pathology/tumour activity, cancer treatment, each patient’s own psychological thresholds, social and physical functioning and familial support network.
  • Numerous barriers exist to the effective management of cancer pain, from institutional regulations, a lack of established patient-care initiatives and the attitudes of health-care professionals, to national and international regulations that limit the availability of opioids.
  • Improvements in the management of cancer pain could be made in four general areas. 
    • Examine current barriers in existing regulatory and drug distribution at national, state and institutional levels to enhance opioid availability.
    • Make low-cost opioids available in developing countries; in developed countries remove limits on insurance claims for opioids in patients with cancer pain.
    • Monitor and continually improve the knowledge of health professionals involved in pain management (physicians, nurses and pharmacists).
    • Ensure that healthcare structures and processes are available for the delivery of palliative care (in the home, outpatient and inpatient setting). Continually assess pain prevalence and the current state of care delivered for pain.

Dalal S & Bruera E. Nature Reviews Clinical Oncology 2013; 10: 108-116. DOI:10.1038/nrclinonc.2012.237

Optimal patient education for cancer pain: a systematic review and theory-based meta-analysis

This meta-analysis examines the influence that patient education can have on the management of cancer pain. Although only a moderate effect was observed, the authors recommend that patient education should be a component of all pain management strategies for patients with cancer pain.

Summary points
  • A number of evidence-based guidelines recommend providing patient education because they have been shown to be efficacious in clinical studies.
  • This meta-analysis was performed on English-language articles published in peer-reviewed journals that reported on the impact of patient education on intensity of cancer pain.
  • A total of 15 studies were included in the meta-analysis. A small to moderate effect on cancer pain was observed on patient education, whereby education intervention was associated with better outcomes than usual care. However, this effect was associated with a large degree of heterogeneity.
  • Interestingly, educational programmes that were individualized to specific patients were not associated with a significant improvement in intensity of cancer pain when compared with non-individualised programmes.
  • Patient education had a small to moderate effect on the intensity of cancer pain; the size of the effect was similar to that observed with some analgesics, which suggests that pain education should be incorporated into the standard approach to managing cancer pain.

Marie N et al. Support Care Cancer 2013; 21: 3529. DOI:10.1007/s00520-013-1995-0