Cancer Breakthrough Pain in the Presence of Cancer-Related Chronic Pain: Fact versus Perceptions of Health-Care Providers and Patients

A significant number of patients suffering from cancer experience these pain flares. In a single-population evaluation of cancer pain (n = 159), it was reported that of those patients with continuous pain, 57 (75%) experienced cancer BTP. More than half (54%) of those patients who experienced cancer pain reported it being related to particular activities, while a little over one-quarter of patients (26%) experienced pain idiopathic in nature and 16% of patients experienced end-of-dose pain.³ In a survey of 545 patients with cancer experiencing fluctuations in pain conducted by the American Pain Foundation, 96% of these patients experienced episodes of cancer BTP at least once a month, more than 70% experienced cancer BTP episodes at least once a week, and more than one-fifth (22%) experienced cancer BTP more than once a day.¹¹

The inadequate treatment of cancer pain is an issue with far-reaching implications; therefore, the purpose of this review is to examine the roles that health-care providers, patients, and family caregivers play in the undertreatment of cancer BTP.

Defining Cancer BTP

Despite the reported prevalence of the condition, questions continue to surround the definition of cancer BTP. The earliest clinical accounts of cancer BTP describe it as a greater than moderate temporary flare in pain that occurs on a baseline of moderate pain in patients receiving opioids for cancer pain.⁸ Presently, descriptions of cancer BTP include statements that flares may occur in the presence of stable persistent pain (regardless of the treatment)¹² having pain levels ranging from moderate to severe, with onset depending on the subtype of pain.¹³

Some controversy centers on the term “breakthrough pain.” The American-English term “breakthrough pain” does not have an exact translation to other languages. Physicians in Europe may use the term “episodic” or “transient” to describe these fluctuations in cancer pain. However, these terms do not capture the idea that the pain is above and beyond persistent pain control (eg, “breaks through baseline analgesia”). Furthermore, if the term “breakthrough pain” is used, it may be limited to descriptions of pain that occur at the end of the dosing cycle.¹⁴ Finally, there are physicians in some countries who do not view exacerbation of cancer pain as a separate clinical entity. Instead, they view spikes of pain as a predictable or normal element of cancer pain.¹⁴

In spite of the questions surrounding cancer BTP, persistent pain must be controlled before management of cancer BTP can proceed. In addition, repeated episodes of cancer BTP may indicate that baseline pain has not been properly assessed and not adequately managed.¹⁰ Therefore, cancer BTP and persistent cancer pain should be assessed independently as they are separate clinical conditions.

Treatment Approaches to Persistent Cancer Pain versus Cancer BTP

Persistent cancer pain requires around-the-clock (ATC) treatment with therapeutic agents that both maximize outcomes and minimize risks. ATC treatment allows maintenance of drug concentrations and prevents peaks and troughs resulting in increased risk of toxicity and lack of efficacy. Opioids such as morphine, oxycodone, methadone, and fentanyl are used extensively for the treatment of cancer pain as they produce an analgesic effect at a minimum dose and are easily titrated.¹⁵ While opioids are administrated orally per World Health Organization recommendations,¹⁵ they may also be administered rectally, intravenously, subcutaneously, intramuscularly, and transdermally. Clinical trials are being conducted to examine the administration of opioids through inhalation.¹⁶ Methadone is an example of a long-acting opioid that has been used to treat persistent pain.¹⁷ Pharmaceutically long-acting drugs such as sustained-release formulations of morphine, oxycodone, oxymorphone, and hydromorphone have been used to treat cancer pain.¹⁸ Adjuvant medications may be coadministered with opioids to treat symptoms that occur concurrently with cancer pain and to augment the analgesic effect. Although few clinical trials have evaluated the efficacy of adjuvants in patients with cancer, local anesthetics (eg, lidocaine), nonsteroidal anti-inflammatory drugs (eg, aspirin, naproxen, and ibuprofen), nonopioid analgesics (eg, acetaminophen), antidepressants (eg, amitriptyline, duloxetine, and venlafaxine), and anticonvulsants (eg, gabapentin, pregabalin, valproate, and lamotrigine) have been used to supplement opioid therapy.¹²

A number of physical and cognitive–behavioral interventions may be used in addition to pharmacological treatments to alleviate some of the pain symptoms experienced in patients with persistent cancer pain. In most patients, heating pads or ice packs may be used to relieve pain and reduce swelling; however, neither heat nor cold should be used on irradiated tissue, and caution should be used when using ice packs on patients with peripheral vascular disease.¹⁹ Exercise may be started or continued to improve physical conditioning. While tumor masses should not be manipulated, other techniques requiring physical stimulation, such as massage, pressure, and vibration, may also be used in the treatment of persistent pain. Either moving an immobile patient or temporarily restricting movement can prevent or alleviate pain. Acupuncture is another treatment that may be used to treat persistent cancer pain. Psychosocial interventions include hypnosis, use of relaxation techniques, biofeedback, and cognitive distraction.¹⁹

Orally administered, short-acting or rapid-acting opioids are used to treat cancer BTP episodes. However, the pharmacokinetic profiles of oral opioids may not match the onset and duration of some cancer BTP episodes.²⁰ An analgesic agent used to treat cancer BTP should match the temporal characteristics of cancer BTP, be easily titrated to higher or lower doses if needed, and, if used appropriately in opioid-tolerant patients, not be associated with undue adverse effects.

Oral transmucosal delivery of opioids is an option for these challenges. Three formulations of the opioid fentanyl are available for transmucosal delivery: oral transmucosal fentanyl citrate (OTFC),²¹ fentanyl buccal tablets (FBTs),²² and fentanyl buccal soluble film (FBSF).²³ OTFC is a fentanyl lozenge that has demonstrated an analgesic effect within 15 minutes of administration. Despite its rapid onset of action, the amount of fentanyl administered with the OTFC lozenge depends on the education provided to the patient on the use of this medication and the ability of the patient to actively use this product.²¹ While FBT (a tablet that utilizes an effervescent reaction to improve absorption) does not require substantial patient participation, its use has been associated with application-site side effects.²² Like OTFC and FBT, FBSF offers a rapid onset of action but does not require active patient participation and has minimal oral adverse side effects.²³ These oral transmucosal fentanyl products should be administered only to opioid-tolerant patients, to avoid the risk of life-threatening respiratory depression.

Physician-Related Factors in Clinical Inertia

Three elements shape physicians' perceptions of the severity of cancer BTP and influence prescribing practices: technical knowledge, attitudes concerning use of opioids, and regulatory restrictions.^{[24], [25], [26] and [27]}

The medical training of most physicians may not include courses in pain management. Instead, practitioners' education is a result of inpatient experience during the postgraduate years and is generally geared toward management of acute injuries, postoperative pain, and cardiovascular events such as myocardial infarctions.²⁸ More evidence of this lack of knowledge among physicians is presented in a survey of British Columbian physicians.²⁹ Among those doctors who responded, only 32% were aware of the dose that would produce an equal analgesic effect when a switch between morphine and acetaminophen is required. Furthermore, only 55% of physicians correctly stated that doses of opioids for cancer BTP should be 10% of the total daily dose and administered every 1 or 2 hours as needed per National Comprehensive Cancer Network guidelines. These findings suggest that when patients need stronger analgesics, physicians may not be skilled in converting to a more potent opioid or calculating a dose for cancer BTP management.²⁹ Indiscriminate polypharmacy presents additional complications, whereby coadministration of multiple opioids exposes patients to an increased risk of toxicity and distorts the clinician's interpretation of outcomes.³⁰

In addition to training, the communication skills of the practitioner play a role in effective treatment of cancer BTP and persistent cancer pain. Discussions regarding treatment can significantly influence a patient's decision to use opioids. In an interview study conducted during a cancer pain management trial, patients were reportedly occasionally “suspicious about the idea of choice” in the use of opioids.³¹ These patients favored thorough discussions of pain treatment options with physicians who were knowledgeable and confident about the use of opioids. The likelihood of patients participating in a pain management trial also increased if the physician stated that a lower dose of opioid would be used initially and treatment would cease if side effects developed.

Health-care providers' attitudes about the side effects of opioid treatment also impact treatment of persistent cancer pain and cancer BTP.³² In addition, although clinical studies do not support the assertion that patients may become addicted to opioids used to treat acute and persistent cancer pain, the belief that these patients are at risk for addiction prevents some health-care providers from prescribing opioids.³³ The perceived relationship between opioid tolerance and addiction is one of the sources of confusion. One of the complications of opioid therapy is pharmacological tolerance, the loss of analgesic effect. Tolerance to an opioid may be determined genetically or acquired after metabolic changes, changes to receptors, or by learned behavior.³³ The result of tolerance is decreasing pain relief, in spite of persistent doses over time.^{[34] and [35]} Pharmacological tolerance is associated with incomplete cross-tolerance to other opioids. In contrast, addiction is a psychological syndrome characterized by uncontrolled and persistent use of the drug despite harm.^{[34], [35] and [36]} Physical dependence on opioids is characterized by a withdrawal syndrome that occurs when the dose is stopped or decreased suddenly or an antagonist is administered.³⁶ Pharmacological dependence is not synonymous with addiction; pharmacological tolerance occurs with many commonly prescribed drugs (such as nitrates) and does not indicate addiction.³⁴

The prevalence of opioid addiction among a population of patients with cancer pain varies. In a meta-review of opioid addiction studies, authors reported a 0%–7.7% prevalence rate of addiction in patients with cancer depending on the population studied and the diagnostic measure used.³⁷ This corresponds with the rate of addiction prevalent in the population at large—it does not support a cause-and-effect relationship between opioid administration and addiction.

Assessing and treating both persistent pain and cancer BTP in special populations such as the elderly and pediatric patients understandably presents a number of concerns for physicians. Although preclinical studies show that aging often correlates with increased pain sensitivity,^{[38], [39], [40] and [41]} pain is often underdiagnosed in older patients.⁴² Age bias often shapes physicians' attitudes toward pain in the elderly. In a survey of 386 physicians to examine the attitudes, knowledge, and psychological factors that contribute to pain management decisions, about 31% believed that older patients were less likely to report pain than patients who were younger. The lack of studies designed to assess the efficacy of pain treatments in elderly patients and the unavailability of meta-analyses and systemic reviews to investigate use of opioids in the elderly are two reasons physicians are often hesitant in treating elderly patients with opioids.³⁸ Another reason for the inadequate treatment of pain in the elderly is concern surrounding drug–drug interactions and uncontrolled side effects resulting from polypharmacy and variability in the patient population.⁴³ The aging process results in impaired kidney and liver function and changes in body composition (including increases in body fat and changes in protein binding), which lead to alterations in drug distribution, metabolism, and elimination. Aging affects receptor responses and substrate intake in older individuals, and thus, the biological processes of increasing age influence the pharmacodynamics of drugs. Most elderly patients experience multiple comorbidities that require medications in addition to treatments for persistent pain and cancer BTP. It is not always possible to predict the drug–drug interactions and side effects that will often result from concomitant medications in this patient population.³⁸ Finally, cognitive impairment and the inability to effectively communicate by the elderly make it difficult for physicians to properly assess pain in this patient population.⁴⁴

Cancer BTP in children is often insufficiently treated because it is rarely assessed and poorly investigated. Additional research in this area would be useful in determining the true degree of risk associated with the use of opioids in children with cancer.^{[45] and [46]}

Finally, practitioners working within the constraints of stringent laws and guidelines surrounding the allowed use of opioids may be reluctant to prescribe opioids given concerns over repercussions or uncertainty regarding appropriate protocols and documentation for use.^{[12], [47] and [48]} Since cancer BTP episodes are not always properly assessed or recognized as separate clinical entities, opioids may not be prescribed in dosages sufficient to treat flares of persistent pain or more appropriate opioids that would best match the cancer BTP experience may not be considered.³⁰ Risk evaluation and mitigation strategies⁴⁹ and programs that require extensive documentation (such as writing prescriptions in triplicate²⁹) may prevent health-care providers from prescribing opioids to patients experiencing cancer BTP. Physicians may also be hesitant to prescribe opioids because of the time and effort required for reimbursement by managed health-care companies.⁵⁰

Patient-Related Factors in Clinical Inertia

Patient perceptions and beliefs about pain medication are similar to those of clinicians in some respects. In a study of patients in not-for-profit community hospitals and outpatients, both groups (27% of inpatients and 37% of outpatients) expressed a fear of addiction to pain medication.⁵¹ These patients also expressed the belief that medication should be saved until pain gets worse and that medication may interfere with daily activities.⁵¹ Like doctors, patients expected concerns about the side effects of pain medications including drowsiness, constipation, nausea, and difficulty breathing. Unlike doctors, a significant number of these patients also expressed concern about the cost of medication.⁵¹

Treatment decisions may be based on a number of factors including the patient's understanding of the diagnosis and confidence in the effectiveness of treatments.⁵² Patients may believe that pain is part of the cancer diagnosis and is to be expected. Some patients believe that use of opioids signifies that the “end of life” is near. They may believe that side effects related to opioids are unavoidable and the burden of the use of opioids outweighs the benefits.⁵³

Another factor to consider when examining patient barriers to effective pain medication is the inability to effectively communicate pain to health-care professionals. The health-care setting may play a role in effectively describing pain. Patients in hospitals have the benefit of health-care providers being available to ask questions about their pain experience, which aids in describing the pain experience. Outpatients, on the other hand, may have difficulty in explaining their level of pain to family members and health-care providers.⁵¹ Patients may also be reluctant to describe their pain to family members or health-care professionals for fear of causing distress or appearing to be “weak”.⁵⁴

Summary and Considerations

Many health-care professionals are not aware of the dual components of cancer pain: persistent pain and cancer BTP. This lack of understanding results in underdiagnosis and undertreatment of persistent cancer pain and cancer BTP, which can have significant repercussions on the patient–physician relationship. In a pan-European survey to examine the treatment of cancer pain, many patients reported feeling that clinicians did not prioritize the treatment of cancer pain highly enough; instead, treatment of cancer was given greater emphasis. The consequence of the lack of time committed to pain assessment and discussions geared toward the treatment options was that patients felt that their quality of life was not important to clinicians, their pain was not appreciated, and the physician did not know how to treat their pain.⁵⁵

Several steps may be taken to close the gap between patients and physicians in the treatment of cancer BTP. Continuing education of physicians and other health-care professionals about the importance of persistent cancer pain and cancer BTP is essential to overcoming this obstacle.¹⁰ Properly prescribing opioids as treatments for cancer BTP and adherence to analgesic guidelines can prevent the undertreatment of this condition.⁵⁶ Proper documentation of doses previously prescribed, side effects observed after dosing, and the severity of pain experienced may decrease the risk of adverse events.⁵⁷

Improved pain management by practitioners can be achieved through knowledge and application of a number of validated pain assessment tools (Table 2). The patient self-report (in the form of a pain diary) is one of the most reliable methods of assessing persistent pain and cancer BTP; however, physicians must be careful to ensure accurate documentation of pain flares in patients who experience mental impairment or do not understand the concept of cancer BTP.¹⁰ Also, physical examination and appropriate tests are required to determine the pathophysiology of pain.¹² In addition to the patient diary and the physical examination, there are a number of tools available to assess persistent pain and cancer BTP (Table 2).^{[58], [59] and [60]}

Pain assessments may be unidimensional or multidimensional. Unidimensional assessments such as the Visual Analogue Scale and the Numerical Rating Scale⁶⁰ offer simple measurements for changes in pain intensity,⁶¹ are easy to use, and require minimal health-care provider involvement. Multidimensional pain assessment instruments like the Brief Pain Inventory and the McGill Pain Questionnaire, on the other hand, consider not only pain intensity but also dimensions such as changes or fluctuations in pain, treatments, location of pain, physical descriptions of pain sensations, emotions and feelings related to pain, duration of pain, and history of pain.⁶¹

An additional resource to utilize would be the pain knowledge of nurses. Performance-based testing to examine the deficiencies in assessment and management of cancer show that hospice-care nurses were more proficient in assessing pain intensity and pain location than resident and family physicians.^{[62], [63] and [64]} Nurses also have the opportunity to spend more time with the patient and to assess response to treatment plans.⁵⁶

Conclusions

Cancer BTP is underdiagnosed and undertreated due to a number of patient and health-care provider–related factors. By identifying misconceptions; providing education to health-care providers, patients, and family caregivers; and accessing all available resources to improve pain diagnosis and management, steps can be taken to ensure that patients experiencing persistent cancer pain and cancer BTP are properly treated.

Acknowledgments

Funding for the preparation of this article was provided by Meda Pharmaceuticals, Inc. Editorial support was provided by M. K. Grandison, PhD, of inScience Communications, a part of the Wolters Kluwer organization.

A significant number of patients suffering from cancer experience these pain flares. In a single-population evaluation of cancer pain (n = 159), it was reported that of those patients with continuous pain, 57 (75%) experienced cancer BTP. More than half (54%) of those patients who experienced cancer pain reported it being related to particular activities, while a little over one-quarter of patients (26%) experienced pain idiopathic in nature and 16% of patients experienced end-of-dose pain.³ In a survey of 545 patients with cancer experiencing fluctuations in pain conducted by the American Pain Foundation, 96% of these patients experienced episodes of cancer BTP at least once a month, more than 70% experienced cancer BTP episodes at least once a week, and more than one-fifth (22%) experienced cancer BTP more than once a day.¹¹

The inadequate treatment of cancer pain is an issue with far-reaching implications; therefore, the purpose of this review is to examine the roles that health-care providers, patients, and family caregivers play in the undertreatment of cancer BTP.

Defining Cancer BTP

Despite the reported prevalence of the condition, questions continue to surround the definition of cancer BTP. The earliest clinical accounts of cancer BTP describe it as a greater than moderate temporary flare in pain that occurs on a baseline of moderate pain in patients receiving opioids for cancer pain.⁸ Presently, descriptions of cancer BTP include statements that flares may occur in the presence of stable persistent pain (regardless of the treatment)¹² having pain levels ranging from moderate to severe, with onset depending on the subtype of pain.¹³

Some controversy centers on the term “breakthrough pain.” The American-English term “breakthrough pain” does not have an exact translation to other languages. Physicians in Europe may use the term “episodic” or “transient” to describe these fluctuations in cancer pain. However, these terms do not capture the idea that the pain is above and beyond persistent pain control (eg, “breaks through baseline analgesia”). Furthermore, if the term “breakthrough pain” is used, it may be limited to descriptions of pain that occur at the end of the dosing cycle.¹⁴ Finally, there are physicians in some countries who do not view exacerbation of cancer pain as a separate clinical entity. Instead, they view spikes of pain as a predictable or normal element of cancer pain.¹⁴

In spite of the questions surrounding cancer BTP, persistent pain must be controlled before management of cancer BTP can proceed. In addition, repeated episodes of cancer BTP may indicate that baseline pain has not been properly assessed and not adequately managed.¹⁰ Therefore, cancer BTP and persistent cancer pain should be assessed independently as they are separate clinical conditions.

Treatment Approaches to Persistent Cancer Pain versus Cancer BTP

Persistent cancer pain requires around-the-clock (ATC) treatment with therapeutic agents that both maximize outcomes and minimize risks. ATC treatment allows maintenance of drug concentrations and prevents peaks and troughs resulting in increased risk of toxicity and lack of efficacy. Opioids such as morphine, oxycodone, methadone, and fentanyl are used extensively for the treatment of cancer pain as they produce an analgesic effect at a minimum dose and are easily titrated.¹⁵ While opioids are administrated orally per World Health Organization recommendations,¹⁵ they may also be administered rectally, intravenously, subcutaneously, intramuscularly, and transdermally. Clinical trials are being conducted to examine the administration of opioids through inhalation.¹⁶ Methadone is an example of a long-acting opioid that has been used to treat persistent pain.¹⁷ Pharmaceutically long-acting drugs such as sustained-release formulations of morphine, oxycodone, oxymorphone, and hydromorphone have been used to treat cancer pain.¹⁸ Adjuvant medications may be coadministered with opioids to treat symptoms that occur concurrently with cancer pain and to augment the analgesic effect. Although few clinical trials have evaluated the efficacy of adjuvants in patients with cancer, local anesthetics (eg, lidocaine), nonsteroidal anti-inflammatory drugs (eg, aspirin, naproxen, and ibuprofen), nonopioid analgesics (eg, acetaminophen), antidepressants (eg, amitriptyline, duloxetine, and venlafaxine), and anticonvulsants (eg, gabapentin, pregabalin, valproate, and lamotrigine) have been used to supplement opioid therapy.¹²

A number of physical and cognitive–behavioral interventions may be used in addition to pharmacological treatments to alleviate some of the pain symptoms experienced in patients with persistent cancer pain. In most patients, heating pads or ice packs may be used to relieve pain and reduce swelling; however, neither heat nor cold should be used on irradiated tissue, and caution should be used when using ice packs on patients with peripheral vascular disease.¹⁹ Exercise may be started or continued to improve physical conditioning. While tumor masses should not be manipulated, other techniques requiring physical stimulation, such as massage, pressure, and vibration, may also be used in the treatment of persistent pain. Either moving an immobile patient or temporarily restricting movement can prevent or alleviate pain. Acupuncture is another treatment that may be used to treat persistent cancer pain. Psychosocial interventions include hypnosis, use of relaxation techniques, biofeedback, and cognitive distraction.¹⁹

Orally administered, short-acting or rapid-acting opioids are used to treat cancer BTP episodes. However, the pharmacokinetic profiles of oral opioids may not match the onset and duration of some cancer BTP episodes.²⁰ An analgesic agent used to treat cancer BTP should match the temporal characteristics of cancer BTP, be easily titrated to higher or lower doses if needed, and, if used appropriately in opioid-tolerant patients, not be associated with undue adverse effects.

Oral transmucosal delivery of opioids is an option for these challenges. Three formulations of the opioid fentanyl are available for transmucosal delivery: oral transmucosal fentanyl citrate (OTFC),²¹ fentanyl buccal tablets (FBTs),²² and fentanyl buccal soluble film (FBSF).²³ OTFC is a fentanyl lozenge that has demonstrated an analgesic effect within 15 minutes of administration. Despite its rapid onset of action, the amount of fentanyl administered with the OTFC lozenge depends on the education provided to the patient on the use of this medication and the ability of the patient to actively use this product.²¹ While FBT (a tablet that utilizes an effervescent reaction to improve absorption) does not require substantial patient participation, its use has been associated with application-site side effects.²² Like OTFC and FBT, FBSF offers a rapid onset of action but does not require active patient participation and has minimal oral adverse side effects.²³ These oral transmucosal fentanyl products should be administered only to opioid-tolerant patients, to avoid the risk of life-threatening respiratory depression.

Physician-Related Factors in Clinical Inertia

Three elements shape physicians' perceptions of the severity of cancer BTP and influence prescribing practices: technical knowledge, attitudes concerning use of opioids, and regulatory restrictions.^{[24], [25], [26] and [27]}

The medical training of most physicians may not include courses in pain management. Instead, practitioners' education is a result of inpatient experience during the postgraduate years and is generally geared toward management of acute injuries, postoperative pain, and cardiovascular events such as myocardial infarctions.²⁸ More evidence of this lack of knowledge among physicians is presented in a survey of British Columbian physicians.²⁹ Among those doctors who responded, only 32% were aware of the dose that would produce an equal analgesic effect when a switch between morphine and acetaminophen is required. Furthermore, only 55% of physicians correctly stated that doses of opioids for cancer BTP should be 10% of the total daily dose and administered every 1 or 2 hours as needed per National Comprehensive Cancer Network guidelines. These findings suggest that when patients need stronger analgesics, physicians may not be skilled in converting to a more potent opioid or calculating a dose for cancer BTP management.²⁹ Indiscriminate polypharmacy presents additional complications, whereby coadministration of multiple opioids exposes patients to an increased risk of toxicity and distorts the clinician's interpretation of outcomes.³⁰

In addition to training, the communication skills of the practitioner play a role in effective treatment of cancer BTP and persistent cancer pain. Discussions regarding treatment can significantly influence a patient's decision to use opioids. In an interview study conducted during a cancer pain management trial, patients were reportedly occasionally “suspicious about the idea of choice” in the use of opioids.³¹ These patients favored thorough discussions of pain treatment options with physicians who were knowledgeable and confident about the use of opioids. The likelihood of patients participating in a pain management trial also increased if the physician stated that a lower dose of opioid would be used initially and treatment would cease if side effects developed.

Health-care providers' attitudes about the side effects of opioid treatment also impact treatment of persistent cancer pain and cancer BTP.³² In addition, although clinical studies do not support the assertion that patients may become addicted to opioids used to treat acute and persistent cancer pain, the belief that these patients are at risk for addiction prevents some health-care providers from prescribing opioids.³³ The perceived relationship between opioid tolerance and addiction is one of the sources of confusion. One of the complications of opioid therapy is pharmacological tolerance, the loss of analgesic effect. Tolerance to an opioid may be determined genetically or acquired after metabolic changes, changes to receptors, or by learned behavior.³³ The result of tolerance is decreasing pain relief, in spite of persistent doses over time.^{[34] and [35]} Pharmacological tolerance is associated with incomplete cross-tolerance to other opioids. In contrast, addiction is a psychological syndrome characterized by uncontrolled and persistent use of the drug despite harm.^{[34], [35] and [36]} Physical dependence on opioids is characterized by a withdrawal syndrome that occurs when the dose is stopped or decreased suddenly or an antagonist is administered.³⁶ Pharmacological dependence is not synonymous with addiction; pharmacological tolerance occurs with many commonly prescribed drugs (such as nitrates) and does not indicate addiction.³⁴

The prevalence of opioid addiction among a population of patients with cancer pain varies. In a meta-review of opioid addiction studies, authors reported a 0%–7.7% prevalence rate of addiction in patients with cancer depending on the population studied and the diagnostic measure used.³⁷ This corresponds with the rate of addiction prevalent in the population at large—it does not support a cause-and-effect relationship between opioid administration and addiction.

Assessing and treating both persistent pain and cancer BTP in special populations such as the elderly and pediatric patients understandably presents a number of concerns for physicians. Although preclinical studies show that aging often correlates with increased pain sensitivity,^{[38], [39], [40] and [41]} pain is often underdiagnosed in older patients.⁴² Age bias often shapes physicians' attitudes toward pain in the elderly. In a survey of 386 physicians to examine the attitudes, knowledge, and psychological factors that contribute to pain management decisions, about 31% believed that older patients were less likely to report pain than patients who were younger. The lack of studies designed to assess the efficacy of pain treatments in elderly patients and the unavailability of meta-analyses and systemic reviews to investigate use of opioids in the elderly are two reasons physicians are often hesitant in treating elderly patients with opioids.³⁸ Another reason for the inadequate treatment of pain in the elderly is concern surrounding drug–drug interactions and uncontrolled side effects resulting from polypharmacy and variability in the patient population.⁴³ The aging process results in impaired kidney and liver function and changes in body composition (including increases in body fat and changes in protein binding), which lead to alterations in drug distribution, metabolism, and elimination. Aging affects receptor responses and substrate intake in older individuals, and thus, the biological processes of increasing age influence the pharmacodynamics of drugs. Most elderly patients experience multiple comorbidities that require medications in addition to treatments for persistent pain and cancer BTP. It is not always possible to predict the drug–drug interactions and side effects that will often result from concomitant medications in this patient population.³⁸ Finally, cognitive impairment and the inability to effectively communicate by the elderly make it difficult for physicians to properly assess pain in this patient population.⁴⁴

Cancer BTP in children is often insufficiently treated because it is rarely assessed and poorly investigated. Additional research in this area would be useful in determining the true degree of risk associated with the use of opioids in children with cancer.^{[45] and [46]}

Finally, practitioners working within the constraints of stringent laws and guidelines surrounding the allowed use of opioids may be reluctant to prescribe opioids given concerns over repercussions or uncertainty regarding appropriate protocols and documentation for use.^{[12], [47] and [48]} Since cancer BTP episodes are not always properly assessed or recognized as separate clinical entities, opioids may not be prescribed in dosages sufficient to treat flares of persistent pain or more appropriate opioids that would best match the cancer BTP experience may not be considered.³⁰ Risk evaluation and mitigation strategies⁴⁹ and programs that require extensive documentation (such as writing prescriptions in triplicate²⁹) may prevent health-care providers from prescribing opioids to patients experiencing cancer BTP. Physicians may also be hesitant to prescribe opioids because of the time and effort required for reimbursement by managed health-care companies.⁵⁰

Patient-Related Factors in Clinical Inertia

Patient perceptions and beliefs about pain medication are similar to those of clinicians in some respects. In a study of patients in not-for-profit community hospitals and outpatients, both groups (27% of inpatients and 37% of outpatients) expressed a fear of addiction to pain medication.⁵¹ These patients also expressed the belief that medication should be saved until pain gets worse and that medication may interfere with daily activities.⁵¹ Like doctors, patients expected concerns about the side effects of pain medications including drowsiness, constipation, nausea, and difficulty breathing. Unlike doctors, a significant number of these patients also expressed concern about the cost of medication.⁵¹

Treatment decisions may be based on a number of factors including the patient's understanding of the diagnosis and confidence in the effectiveness of treatments.⁵² Patients may believe that pain is part of the cancer diagnosis and is to be expected. Some patients believe that use of opioids signifies that the “end of life” is near. They may believe that side effects related to opioids are unavoidable and the burden of the use of opioids outweighs the benefits.⁵³

Another factor to consider when examining patient barriers to effective pain medication is the inability to effectively communicate pain to health-care professionals. The health-care setting may play a role in effectively describing pain. Patients in hospitals have the benefit of health-care providers being available to ask questions about their pain experience, which aids in describing the pain experience. Outpatients, on the other hand, may have difficulty in explaining their level of pain to family members and health-care providers.⁵¹ Patients may also be reluctant to describe their pain to family members or health-care professionals for fear of causing distress or appearing to be “weak”.⁵⁴

Summary and Considerations

Many health-care professionals are not aware of the dual components of cancer pain: persistent pain and cancer BTP. This lack of understanding results in underdiagnosis and undertreatment of persistent cancer pain and cancer BTP, which can have significant repercussions on the patient–physician relationship. In a pan-European survey to examine the treatment of cancer pain, many patients reported feeling that clinicians did not prioritize the treatment of cancer pain highly enough; instead, treatment of cancer was given greater emphasis. The consequence of the lack of time committed to pain assessment and discussions geared toward the treatment options was that patients felt that their quality of life was not important to clinicians, their pain was not appreciated, and the physician did not know how to treat their pain.⁵⁵

Several steps may be taken to close the gap between patients and physicians in the treatment of cancer BTP. Continuing education of physicians and other health-care professionals about the importance of persistent cancer pain and cancer BTP is essential to overcoming this obstacle.¹⁰ Properly prescribing opioids as treatments for cancer BTP and adherence to analgesic guidelines can prevent the undertreatment of this condition.⁵⁶ Proper documentation of doses previously prescribed, side effects observed after dosing, and the severity of pain experienced may decrease the risk of adverse events.⁵⁷

Improved pain management by practitioners can be achieved through knowledge and application of a number of validated pain assessment tools (Table 2). The patient self-report (in the form of a pain diary) is one of the most reliable methods of assessing persistent pain and cancer BTP; however, physicians must be careful to ensure accurate documentation of pain flares in patients who experience mental impairment or do not understand the concept of cancer BTP.¹⁰ Also, physical examination and appropriate tests are required to determine the pathophysiology of pain.¹² In addition to the patient diary and the physical examination, there are a number of tools available to assess persistent pain and cancer BTP (Table 2).^{[58], [59] and [60]}

Pain assessments may be unidimensional or multidimensional. Unidimensional assessments such as the Visual Analogue Scale and the Numerical Rating Scale⁶⁰ offer simple measurements for changes in pain intensity,⁶¹ are easy to use, and require minimal health-care provider involvement. Multidimensional pain assessment instruments like the Brief Pain Inventory and the McGill Pain Questionnaire, on the other hand, consider not only pain intensity but also dimensions such as changes or fluctuations in pain, treatments, location of pain, physical descriptions of pain sensations, emotions and feelings related to pain, duration of pain, and history of pain.⁶¹

An additional resource to utilize would be the pain knowledge of nurses. Performance-based testing to examine the deficiencies in assessment and management of cancer show that hospice-care nurses were more proficient in assessing pain intensity and pain location than resident and family physicians.^{[62], [63] and [64]} Nurses also have the opportunity to spend more time with the patient and to assess response to treatment plans.⁵⁶

Conclusions

Cancer BTP is underdiagnosed and undertreated due to a number of patient and health-care provider–related factors. By identifying misconceptions; providing education to health-care providers, patients, and family caregivers; and accessing all available resources to improve pain diagnosis and management, steps can be taken to ensure that patients experiencing persistent cancer pain and cancer BTP are properly treated.

Acknowledgments

Funding for the preparation of this article was provided by Meda Pharmaceuticals, Inc. Editorial support was provided by M. K. Grandison, PhD, of inScience Communications, a part of the Wolters Kluwer organization.

A significant number of patients suffering from cancer experience these pain flares. In a single-population evaluation of cancer pain (n = 159), it was reported that of those patients with continuous pain, 57 (75%) experienced cancer BTP. More than half (54%) of those patients who experienced cancer pain reported it being related to particular activities, while a little over one-quarter of patients (26%) experienced pain idiopathic in nature and 16% of patients experienced end-of-dose pain.³ In a survey of 545 patients with cancer experiencing fluctuations in pain conducted by the American Pain Foundation, 96% of these patients experienced episodes of cancer BTP at least once a month, more than 70% experienced cancer BTP episodes at least once a week, and more than one-fifth (22%) experienced cancer BTP more than once a day.¹¹

The inadequate treatment of cancer pain is an issue with far-reaching implications; therefore, the purpose of this review is to examine the roles that health-care providers, patients, and family caregivers play in the undertreatment of cancer BTP.

Defining Cancer BTP

Despite the reported prevalence of the condition, questions continue to surround the definition of cancer BTP. The earliest clinical accounts of cancer BTP describe it as a greater than moderate temporary flare in pain that occurs on a baseline of moderate pain in patients receiving opioids for cancer pain.⁸ Presently, descriptions of cancer BTP include statements that flares may occur in the presence of stable persistent pain (regardless of the treatment)¹² having pain levels ranging from moderate to severe, with onset depending on the subtype of pain.¹³

Some controversy centers on the term “breakthrough pain.” The American-English term “breakthrough pain” does not have an exact translation to other languages. Physicians in Europe may use the term “episodic” or “transient” to describe these fluctuations in cancer pain. However, these terms do not capture the idea that the pain is above and beyond persistent pain control (eg, “breaks through baseline analgesia”). Furthermore, if the term “breakthrough pain” is used, it may be limited to descriptions of pain that occur at the end of the dosing cycle.¹⁴ Finally, there are physicians in some countries who do not view exacerbation of cancer pain as a separate clinical entity. Instead, they view spikes of pain as a predictable or normal element of cancer pain.¹⁴

In spite of the questions surrounding cancer BTP, persistent pain must be controlled before management of cancer BTP can proceed. In addition, repeated episodes of cancer BTP may indicate that baseline pain has not been properly assessed and not adequately managed.¹⁰ Therefore, cancer BTP and persistent cancer pain should be assessed independently as they are separate clinical conditions.

Treatment Approaches to Persistent Cancer Pain versus Cancer BTP

Persistent cancer pain requires around-the-clock (ATC) treatment with therapeutic agents that both maximize outcomes and minimize risks. ATC treatment allows maintenance of drug concentrations and prevents peaks and troughs resulting in increased risk of toxicity and lack of efficacy. Opioids such as morphine, oxycodone, methadone, and fentanyl are used extensively for the treatment of cancer pain as they produce an analgesic effect at a minimum dose and are easily titrated.¹⁵ While opioids are administrated orally per World Health Organization recommendations,¹⁵ they may also be administered rectally, intravenously, subcutaneously, intramuscularly, and transdermally. Clinical trials are being conducted to examine the administration of opioids through inhalation.¹⁶ Methadone is an example of a long-acting opioid that has been used to treat persistent pain.¹⁷ Pharmaceutically long-acting drugs such as sustained-release formulations of morphine, oxycodone, oxymorphone, and hydromorphone have been used to treat cancer pain.¹⁸ Adjuvant medications may be coadministered with opioids to treat symptoms that occur concurrently with cancer pain and to augment the analgesic effect. Although few clinical trials have evaluated the efficacy of adjuvants in patients with cancer, local anesthetics (eg, lidocaine), nonsteroidal anti-inflammatory drugs (eg, aspirin, naproxen, and ibuprofen), nonopioid analgesics (eg, acetaminophen), antidepressants (eg, amitriptyline, duloxetine, and venlafaxine), and anticonvulsants (eg, gabapentin, pregabalin, valproate, and lamotrigine) have been used to supplement opioid therapy.¹²

A number of physical and cognitive–behavioral interventions may be used in addition to pharmacological treatments to alleviate some of the pain symptoms experienced in patients with persistent cancer pain. In most patients, heating pads or ice packs may be used to relieve pain and reduce swelling; however, neither heat nor cold should be used on irradiated tissue, and caution should be used when using ice packs on patients with peripheral vascular disease.¹⁹ Exercise may be started or continued to improve physical conditioning. While tumor masses should not be manipulated, other techniques requiring physical stimulation, such as massage, pressure, and vibration, may also be used in the treatment of persistent pain. Either moving an immobile patient or temporarily restricting movement can prevent or alleviate pain. Acupuncture is another treatment that may be used to treat persistent cancer pain. Psychosocial interventions include hypnosis, use of relaxation techniques, biofeedback, and cognitive distraction.¹⁹

Orally administered, short-acting or rapid-acting opioids are used to treat cancer BTP episodes. However, the pharmacokinetic profiles of oral opioids may not match the onset and duration of some cancer BTP episodes.²⁰ An analgesic agent used to treat cancer BTP should match the temporal characteristics of cancer BTP, be easily titrated to higher or lower doses if needed, and, if used appropriately in opioid-tolerant patients, not be associated with undue adverse effects.

Oral transmucosal delivery of opioids is an option for these challenges. Three formulations of the opioid fentanyl are available for transmucosal delivery: oral transmucosal fentanyl citrate (OTFC),²¹ fentanyl buccal tablets (FBTs),²² and fentanyl buccal soluble film (FBSF).²³ OTFC is a fentanyl lozenge that has demonstrated an analgesic effect within 15 minutes of administration. Despite its rapid onset of action, the amount of fentanyl administered with the OTFC lozenge depends on the education provided to the patient on the use of this medication and the ability of the patient to actively use this product.²¹ While FBT (a tablet that utilizes an effervescent reaction to improve absorption) does not require substantial patient participation, its use has been associated with application-site side effects.²² Like OTFC and FBT, FBSF offers a rapid onset of action but does not require active patient participation and has minimal oral adverse side effects.²³ These oral transmucosal fentanyl products should be administered only to opioid-tolerant patients, to avoid the risk of life-threatening respiratory depression.

Physician-Related Factors in Clinical Inertia

Three elements shape physicians' perceptions of the severity of cancer BTP and influence prescribing practices: technical knowledge, attitudes concerning use of opioids, and regulatory restrictions.^{[24], [25], [26] and [27]}

The medical training of most physicians may not include courses in pain management. Instead, practitioners' education is a result of inpatient experience during the postgraduate years and is generally geared toward management of acute injuries, postoperative pain, and cardiovascular events such as myocardial infarctions.²⁸ More evidence of this lack of knowledge among physicians is presented in a survey of British Columbian physicians.²⁹ Among those doctors who responded, only 32% were aware of the dose that would produce an equal analgesic effect when a switch between morphine and acetaminophen is required. Furthermore, only 55% of physicians correctly stated that doses of opioids for cancer BTP should be 10% of the total daily dose and administered every 1 or 2 hours as needed per National Comprehensive Cancer Network guidelines. These findings suggest that when patients need stronger analgesics, physicians may not be skilled in converting to a more potent opioid or calculating a dose for cancer BTP management.²⁹ Indiscriminate polypharmacy presents additional complications, whereby coadministration of multiple opioids exposes patients to an increased risk of toxicity and distorts the clinician's interpretation of outcomes.³⁰

In addition to training, the communication skills of the practitioner play a role in effective treatment of cancer BTP and persistent cancer pain. Discussions regarding treatment can significantly influence a patient's decision to use opioids. In an interview study conducted during a cancer pain management trial, patients were reportedly occasionally “suspicious about the idea of choice” in the use of opioids.³¹ These patients favored thorough discussions of pain treatment options with physicians who were knowledgeable and confident about the use of opioids. The likelihood of patients participating in a pain management trial also increased if the physician stated that a lower dose of opioid would be used initially and treatment would cease if side effects developed.

Health-care providers' attitudes about the side effects of opioid treatment also impact treatment of persistent cancer pain and cancer BTP.³² In addition, although clinical studies do not support the assertion that patients may become addicted to opioids used to treat acute and persistent cancer pain, the belief that these patients are at risk for addiction prevents some health-care providers from prescribing opioids.³³ The perceived relationship between opioid tolerance and addiction is one of the sources of confusion. One of the complications of opioid therapy is pharmacological tolerance, the loss of analgesic effect. Tolerance to an opioid may be determined genetically or acquired after metabolic changes, changes to receptors, or by learned behavior.³³ The result of tolerance is decreasing pain relief, in spite of persistent doses over time.^{[34] and [35]} Pharmacological tolerance is associated with incomplete cross-tolerance to other opioids. In contrast, addiction is a psychological syndrome characterized by uncontrolled and persistent use of the drug despite harm.^{[34], [35] and [36]} Physical dependence on opioids is characterized by a withdrawal syndrome that occurs when the dose is stopped or decreased suddenly or an antagonist is administered.³⁶ Pharmacological dependence is not synonymous with addiction; pharmacological tolerance occurs with many commonly prescribed drugs (such as nitrates) and does not indicate addiction.³⁴

The prevalence of opioid addiction among a population of patients with cancer pain varies. In a meta-review of opioid addiction studies, authors reported a 0%–7.7% prevalence rate of addiction in patients with cancer depending on the population studied and the diagnostic measure used.³⁷ This corresponds with the rate of addiction prevalent in the population at large—it does not support a cause-and-effect relationship between opioid administration and addiction.

Assessing and treating both persistent pain and cancer BTP in special populations such as the elderly and pediatric patients understandably presents a number of concerns for physicians. Although preclinical studies show that aging often correlates with increased pain sensitivity,^{[38], [39], [40] and [41]} pain is often underdiagnosed in older patients.⁴² Age bias often shapes physicians' attitudes toward pain in the elderly. In a survey of 386 physicians to examine the attitudes, knowledge, and psychological factors that contribute to pain management decisions, about 31% believed that older patients were less likely to report pain than patients who were younger. The lack of studies designed to assess the efficacy of pain treatments in elderly patients and the unavailability of meta-analyses and systemic reviews to investigate use of opioids in the elderly are two reasons physicians are often hesitant in treating elderly patients with opioids.³⁸ Another reason for the inadequate treatment of pain in the elderly is concern surrounding drug–drug interactions and uncontrolled side effects resulting from polypharmacy and variability in the patient population.⁴³ The aging process results in impaired kidney and liver function and changes in body composition (including increases in body fat and changes in protein binding), which lead to alterations in drug distribution, metabolism, and elimination. Aging affects receptor responses and substrate intake in older individuals, and thus, the biological processes of increasing age influence the pharmacodynamics of drugs. Most elderly patients experience multiple comorbidities that require medications in addition to treatments for persistent pain and cancer BTP. It is not always possible to predict the drug–drug interactions and side effects that will often result from concomitant medications in this patient population.³⁸ Finally, cognitive impairment and the inability to effectively communicate by the elderly make it difficult for physicians to properly assess pain in this patient population.⁴⁴

Cancer BTP in children is often insufficiently treated because it is rarely assessed and poorly investigated. Additional research in this area would be useful in determining the true degree of risk associated with the use of opioids in children with cancer.^{[45] and [46]}

Finally, practitioners working within the constraints of stringent laws and guidelines surrounding the allowed use of opioids may be reluctant to prescribe opioids given concerns over repercussions or uncertainty regarding appropriate protocols and documentation for use.^{[12], [47] and [48]} Since cancer BTP episodes are not always properly assessed or recognized as separate clinical entities, opioids may not be prescribed in dosages sufficient to treat flares of persistent pain or more appropriate opioids that would best match the cancer BTP experience may not be considered.³⁰ Risk evaluation and mitigation strategies⁴⁹ and programs that require extensive documentation (such as writing prescriptions in triplicate²⁹) may prevent health-care providers from prescribing opioids to patients experiencing cancer BTP. Physicians may also be hesitant to prescribe opioids because of the time and effort required for reimbursement by managed health-care companies.⁵⁰

Patient-Related Factors in Clinical Inertia

Patient perceptions and beliefs about pain medication are similar to those of clinicians in some respects. In a study of patients in not-for-profit community hospitals and outpatients, both groups (27% of inpatients and 37% of outpatients) expressed a fear of addiction to pain medication.⁵¹ These patients also expressed the belief that medication should be saved until pain gets worse and that medication may interfere with daily activities.⁵¹ Like doctors, patients expected concerns about the side effects of pain medications including drowsiness, constipation, nausea, and difficulty breathing. Unlike doctors, a significant number of these patients also expressed concern about the cost of medication.⁵¹

Treatment decisions may be based on a number of factors including the patient's understanding of the diagnosis and confidence in the effectiveness of treatments.⁵² Patients may believe that pain is part of the cancer diagnosis and is to be expected. Some patients believe that use of opioids signifies that the “end of life” is near. They may believe that side effects related to opioids are unavoidable and the burden of the use of opioids outweighs the benefits.⁵³

Another factor to consider when examining patient barriers to effective pain medication is the inability to effectively communicate pain to health-care professionals. The health-care setting may play a role in effectively describing pain. Patients in hospitals have the benefit of health-care providers being available to ask questions about their pain experience, which aids in describing the pain experience. Outpatients, on the other hand, may have difficulty in explaining their level of pain to family members and health-care providers.⁵¹ Patients may also be reluctant to describe their pain to family members or health-care professionals for fear of causing distress or appearing to be “weak”.⁵⁴

Summary and Considerations

Many health-care professionals are not aware of the dual components of cancer pain: persistent pain and cancer BTP. This lack of understanding results in underdiagnosis and undertreatment of persistent cancer pain and cancer BTP, which can have significant repercussions on the patient–physician relationship. In a pan-European survey to examine the treatment of cancer pain, many patients reported feeling that clinicians did not prioritize the treatment of cancer pain highly enough; instead, treatment of cancer was given greater emphasis. The consequence of the lack of time committed to pain assessment and discussions geared toward the treatment options was that patients felt that their quality of life was not important to clinicians, their pain was not appreciated, and the physician did not know how to treat their pain.⁵⁵

Several steps may be taken to close the gap between patients and physicians in the treatment of cancer BTP. Continuing education of physicians and other health-care professionals about the importance of persistent cancer pain and cancer BTP is essential to overcoming this obstacle.¹⁰ Properly prescribing opioids as treatments for cancer BTP and adherence to analgesic guidelines can prevent the undertreatment of this condition.⁵⁶ Proper documentation of doses previously prescribed, side effects observed after dosing, and the severity of pain experienced may decrease the risk of adverse events.⁵⁷

Improved pain management by practitioners can be achieved through knowledge and application of a number of validated pain assessment tools (Table 2). The patient self-report (in the form of a pain diary) is one of the most reliable methods of assessing persistent pain and cancer BTP; however, physicians must be careful to ensure accurate documentation of pain flares in patients who experience mental impairment or do not understand the concept of cancer BTP.¹⁰ Also, physical examination and appropriate tests are required to determine the pathophysiology of pain.¹² In addition to the patient diary and the physical examination, there are a number of tools available to assess persistent pain and cancer BTP (Table 2).^{[58], [59] and [60]}

Pain assessments may be unidimensional or multidimensional. Unidimensional assessments such as the Visual Analogue Scale and the Numerical Rating Scale⁶⁰ offer simple measurements for changes in pain intensity,⁶¹ are easy to use, and require minimal health-care provider involvement. Multidimensional pain assessment instruments like the Brief Pain Inventory and the McGill Pain Questionnaire, on the other hand, consider not only pain intensity but also dimensions such as changes or fluctuations in pain, treatments, location of pain, physical descriptions of pain sensations, emotions and feelings related to pain, duration of pain, and history of pain.⁶¹

An additional resource to utilize would be the pain knowledge of nurses. Performance-based testing to examine the deficiencies in assessment and management of cancer show that hospice-care nurses were more proficient in assessing pain intensity and pain location than resident and family physicians.^{[62], [63] and [64]} Nurses also have the opportunity to spend more time with the patient and to assess response to treatment plans.⁵⁶

Conclusions

Cancer BTP is underdiagnosed and undertreated due to a number of patient and health-care provider–related factors. By identifying misconceptions; providing education to health-care providers, patients, and family caregivers; and accessing all available resources to improve pain diagnosis and management, steps can be taken to ensure that patients experiencing persistent cancer pain and cancer BTP are properly treated.

Acknowledgments

Funding for the preparation of this article was provided by Meda Pharmaceuticals, Inc. Editorial support was provided by M. K. Grandison, PhD, of inScience Communications, a part of the Wolters Kluwer organization.