Breakthrough cancer pain (BTcP) is common, particularly in patients with advanced disease . The reported prevalence of BTcP, however, varies widely and has been difficult to determine because of a lack of a clear consensus on its definition . Although several definitions have been used over the past 20 years, the Association for Palliative Medicine of Great Britain and Ireland (APM) has recently proposed that BTcP should be defined as ‘a transient exacerbation of pain that occurs either spontaneously or in relation to a specific predictable or unpredictable trigger, despite relatively stable or adequately controlled background pain’ [3•].
A pan-European survey of cancer patients with pain suggests that BTcP occurs in over 60% of cancer patients prescribed analgesics for their pain [4••]. Furthermore, despite advances in the treatment of cancer pain, there is increasing evidence that assessment and diagnosis of BTcP is often poor and treatment suboptimal [4••,5•]. It appears that BTcP is often undertreated not only due to a lack of consensus on its definition but also because of unwarranted concerns among healthcare professionals and patients about overmedicating  and difficulties among healthcare professionals in differentiating BTcP from poorly controlled background pain [5•]. The successful treatment of BTcP, however, is important because it has been shown to significantly affect patients' quality of life and have an enormous impact on the cost of healthcare if poorly controlled .
BTcP has been traditionally managed with normal-release opioids, also known as rescue medication, given in addition to regularly scheduled around-the-clock analgesics. Control of BTcP, however, is problematic because the pain relief afforded by morphine and other normal-release oral opioids, such as oxycodone and hydromorphone, does not appear to match the characteristics of the BTcP episode itself [6••]. Optimal management of BTcP therefore requires independent assessment and targeted treatment [6••]. Integral to this approach is the appropriate use of BTcP medication and risk management strategies to improve quality of life and reduce the number of adverse incidents experienced by patients.
The aim of this article is to increase understanding of BTcP and the profound impact it can have on patients' quality of life if treatment is suboptimal and to discuss potential management strategies that could improve pain control in clinical practice.
Impact of breakthrough cancer pain
Two types of BTcP exist: incident pain, which can be precipitated by predictable volitional factors (e.g. walking) or unpredictable nonvolitional factors (e.g. coughing), and spontaneous pain that occurs unexpectedly . Incident pain is more common than spontaneous pain, whereas spontaneous pain generally lasts longer [8•]. It is important that BTcP is distinguished from end-of-dose pain, which can occur before a scheduled dose of background analgesic and generally arises due to an inadequate dose of analgesic or extended dosing interval [8•]. The clinical features of BTcP vary from individual to individual; some patients experience one type of pain, whereas others experience several distinct pains [8•]. Nevertheless, BTcP is often of sudden onset, short duration and severe or excruciating, which makes management difficult [6••].
There is increasing evidence that BTcP is a significant clinical problem, which, if poorly controlled, can have an enormous impact on cancer patients' daily lives [4••,9,10•]. Impact of BTcP on patients' quality of life is as follows:
- Sleep is disrupted.
- Emotional health is affected.
- Personal relationships are affected.
- Ability to perform everyday activities is affected.
- Concentration and thought are stopped.
- Work performance is impacted.
In a pan-European survey of patients aged 18 years or over with all stages and types of cancer, 63% (281 of 441) reported BTcP or inadequate pain relief despite being prescribed analgesics [4••]. Of these patients, over half (58%) reported inadequate pain relief all the time, every hour, several times daily, daily or several times per week, and yet, only a third (33%) of them were treated with additional analgesic medication. Many of the patients surveyed reported pain-related difficulties with everyday activities and work performance [4••].
Similarly, in a recent survey conducted by the American Pain Foundation [10•], 85% of patients who responded stated that BTcP negatively affects their quality of life, including their physical health, interpersonal relationships and ability to engage in certain activities. The majority of respondents (91%) believed that if they could get their BTcP under control, their quality of life would improve [10•]. Data suggest, however, that healthcare professionals often do not consider patients' quality of life in their overall care [4••], and some clinicians described patients' BTcP as a normal side-effect of cancer and its treatment [10•]. Some nurses too have difficulty defining BTcP as a distinct pain subtype, as highlighted in a recent small, qualitative study undertaken in specialist palliative care units [5•]. Although nurses were aware of the range of drugs available for the treatment of BTcP and the differing routes of administration, the study found that most of them were unable to differentiate BTcP from poorly controlled background pain [5•]. These data clearly demonstrate that treatment continues to be suboptimal, highlighting training needs to improve the management of BTcP [4••,5•,10•].
Effective assessment and management
Although complete pain relief is usually an unrealistic expectation, the aim is to lessen the impact of pain episodes on the patient's quality of life [8•]. Initially, it is important to differentiate patients with uncontrolled background pain experiencing transient exacerbations of that pain from patients with controlled background pain experiencing episodes of BTcP [3•]. Patients with BTcP should then have this pain specifically assessed [3•]. During assessment, it is important to ascertain the temporal pattern of pain, any precipitating or exacerbating factors, any relieving factors, the response to opioid analgesics and the response to other therapeutic manoeuvres . Currently, there is no validated clinical risk assessment tool, so the diagnosis is usually made based on several sources, including taking a detailed history, performing a thorough examination and using standard pain questions to determine the clinical features of BTcP. The objectives of assessment are to determine the cause and pathophysiology of the pain and any factors that would indicate or contraindicate specific interventions [3•]. The assessment of pain depends primarily on basic clinical skills; however, a simple algorithm (Fig. 1) can aid with the diagnosis [8•].
Case 1: cancer patients with pain should be assessed for the presence of breakthrough cancer pain
Eileen, a 72-year-old woman with breast cancer and bone metastases, describes severe episodes of pain, which occur even when she uses pain medication. Following an initial evaluation and assessment of her background pain, it was decided to increase her around-the-clock medication from 8 to 12 mg of oral hydromorphone daily. Although the patient's overall pain was better controlled, she still experienced transient exacerbations of pain that were usually of sudden onset, lasted from a few minutes to a couple of hours, and were primarily related to movement (e.g. walking and turning over in bed). These episodes were particularly distressing, as they affected her ability to do household chores and sleep. The patient was specifically assessed for the presence of BTcP and was subsequently diagnosed as having incident BTcP, which was related to her bone metastases.
The optimal management of BTcP requires an individual approach and depends on a variety of pain-related and patient-related factors (Table 1) . In addition, good pain management requires a comprehensive multidisciplinary approach and a combination of treatment strategies, which may include pharmacological and nonpharmacological treatment modalities. It is also important that patients and their carers are reassured about pain relief and encouraged to participate in the management of their BTcP .
The cornerstone of management of BTcP episodes is the use of rescue medication, which is taken as required, rather than on a regular basis [3•]. Traditionally, the most common form of rescue medication has been the oral normal-release formulations of morphine and other relevant opioid analgesics [3•]. Although the oral route is often preferred for rescue medication, the typical characteristics of BTcP suggest that responsiveness to an oral drug may not be optimal because the analgesia provided occurs after the BTcP has spontaneously subsided [8•]. Undesirable effects of the drug (i.e. fatigue, sedation, confusion) may also become problematic due to effects of the medication that persist long after the pain has resolved [8•,9].
Barriers to effective pain management
A number of perceived barriers to effective pain management have been identified, which may be physician-related , patient-related [13,14•] or regulatory barriers [4••]. Physician-related barriers include a lack of knowledge of BTcP, inadequate appreciation by the physician of the intensity of the pain, concerns about side-effects of opioids, prescription of ineffective doses of opioids and failure to adequately address the undesirable effects of opioids [4••,12]. Patient-related barriers include patients' inadequate communication of pain, fear of the adverse effects of opioids and their adherence to analgesic regimen [4••,14•]. It has also been proposed that regulatory barriers (e.g. formulary approvals) to opioid prescription and dispensing may account for the poor care of cancer pain [4••]. Even when prescribed, data from a recent prospective survey demonstrated that some patients with BTcP do not take their oral formulations of rescue medication (morphine, oxycodone, hydromorphine, methadone or oral transmucosal fentanyl citrate) for all BTcP episodes, primarily because it was not deemed to be effective . Other reasons included concerns about adverse effects or overdosing, concerns that the rescue medication would affect their daily routines and because no instructions were provided by the healthcare professional . Similar findings were reported in a prospective, observational study that was undertaken to determine utilization of BTcP medication among 120 oncology patients aged 29–84 years . In this study, patients were asked about their experience of using BTcP medication (oral morphine, oral oxycodone, oral transmucosal fentanyl citrate or oral methadone) and, for those who took the medication intermittently, the main reasons for not using the treatment. Eighty-seven (72.5%) of the patients were experiencing BTcP (median number of two episodes per day). Of these patients, 81 had been prescribed a strong opioid as BTcP medication; however, 63 of them used the opioid only some of the time. The most common reason given was that the pain was not always severe or intense (Fig. 2). In many instances, however, the reason patients took their BTcP intermittently was that restrictions had been imposed on the frequency of use of BTcP . These findings suggest the ongoing need to educate healthcare professionals about the prevalence, impact and importance of treating BTcP and for improved patient education about the usage of BTcP .
Ideal treatment for breakthrough cancer pain episodes
The ideal treatment for most BTcP episodes is a rescue dose of strong opioid with pharmacokinetic properties that closely match the temporal characteristics of the BTcP [8•]. Features of the ideal BTcP medication are as follows:
- It is effective.
- It closely matches the temporal characteristics of the BTcP.
- It has rapid onset of action.
- It has relatively short duration of action.
- It is patient-friendly – noninvasive, simple to administer.
- It has minimal adverse effects.
Fentanyl is a lipophilic opioid that is rapidly absorbed across mucosal membranes, with the promise of a rapid onset that more closely matches the profile of the ideal rescue treatment [8•]. The administration of this drug via the buccal [16•,17,18••], sublingual [19•] or nasal [20•–22•] routes provides more rapid drug absorption and onset of action compared with the oral route and with oral morphine. Five fentanyl preparations are currently licensed for the treatment of BTcP: oral transmucosal fentanyl citrate (Actiq, Flynn Pharma Ltd, Dublin, UK), fentanyl buccal tablets (FBTs) [Effentora, Cephalon (UK) Ltd, Welwyn Garden City, UK], fentanyl sublingual tablets (FST) (Abstral, ProStrakan, Galashiels, UK), fentanyl intranasal spray (Instanyl, Nycomed UK Ltd, Marlow, UK) and fentanyl pectin nasal spray (PecFent, Archimedes Pharma Ltd, Reading, UK). Clinical trials have shown these fentanyl preparations to be effective and well tolerated in the treatment of BTcP [16•,17,18••,19•–22•,23–26]. Onset of analgesia that can be termed clinically relevant has been shown to occur as early as 10 min after administration of these agents [17,19•,21•,22•]. These effective therapies have a significant role in the management of BTcP.
Case 2: rapid-onset fentanyl preparations specifically developed and licensed for the treatment of breakthrough cancer pain are a more appropriate rescue medication than oral opioids
Helen, a 38-year-old woman with metastatic ovarian cancer and mother of two children, presented with frequent (five to six per day) episodes of BTcP in her axilla. She was initially prescribed normal-release morphine 10 mg as rescue medication. However, she found that the oral morphine worked too slowly to adequately control her BTcP episodes and the multiple doses she was taking each day were causing her excess drowsiness and fatigue, which had a profound negative impact on her quality of life. After careful re-assessment, her background medication (60 mg oral morphine daily) was modified with the subsequent introduction of pregabalin 150 mg twice a day, which reduced her BTcP to two to three episodes per day. Her rescue medication was then switched to FBTs, which were titrated to an effective dose of 400 μg per BTcP episode. Her mood improved as she felt more in control of her pain and less drowsy, and she was able to spend more quality time with her children at home.
Current evidence-based, clinical guidelines from the APM recommend that the decision to use a specific opioid preparation should be based on a combination of the pain characteristics, the product characteristics, the patient's previous response to opioids in terms of efficacy and tolerability and, above all, the patient's preferences for an individual preparation [3•]. In the past, it has been advised that the dose of opioid rescue medication should be a fixed proportion of the dose of the opioid background medication, typically one-sixth of the daily background opioid dose [8•]. However, based on clinical trial data, the APM guidelines recommend that the dose of all opioid rescue medications should be determined by individual titration [3•]. In addition, the APM guidelines recommend that patients should have their BTcP specifically re-assessed in order to determine the efficacy and tolerability of the treatment and any change in the nature of the BTcP [3•].
Case 3: the dosage of breakthrough cancer pain (rescue) medication should be determined by titration
James, a 53-year-old taxi driver with metastatic carcinoma of the prostate, was finding it increasingly difficult to work because of breakthrough sacral pain, which he described as severe, of rapid onset and lasted for about half an hour. He was referred to the hospice and after a thorough assessment was started on FSTs 100 μg, which was titrated upwards in a step-wise fashion. He was allowed to take no more than two tablets per breakthrough pain episode, with 15–30 min between tablets to determine if additional pain relief was required. The patient was titrated to a successful maintenance dose of 600 μg, which he found to be effective and well tolerated. Soon after, he was discharged and was able to return to work part-time.
Clinical risk management strategies
Clinical risk management strategies aim to reduce the risk of adverse effects of medical treatment and enhance the safety of patients by identifying circumstances that put patients at risk of harm and by preventing or controlling those risks. The management of patients with BTcP presents a number of challenges to treating clinicians and other healthcare professionals. Opioids, such as morphine and fentanyl, are often associated with concerns about their risks, including undesirable effects and the potential for substance abuse and addiction. As a result, some clinicians may avoid using these agents, which can lead to the risk of continued undertreatment of pain [27••]. It is important, therefore, that patients, caregivers and clinicians receive appropriate education to dispel the fears and myths surrounding opioids . Healthcare professionals also need to strike a balance between appropriate use of opioids and prevention of misuse  and to develop effective approaches to manage both types of risk . Most patients with BTcP can be managed successfully in the community, but it is important that patients' drug use is monitored, with particular attention to their maintenance opioid therapy and potential accidental exposure.
In an effort to reduce the risk of medical error and improve patient safety, pharmaceutical packaging is subject to more demanding requirements from a regulatory point of view, including pack size, clarity of patient information leaflets and child-resistant packaging. Healthcare professionals should instruct patients and their caregivers that fentanyl is an opioid and, as such, can be fatal to a child and therefore must be kept out of their reach.
Differences in administration may make one BTcP medication more favourable than the other. Formulations of fentanyl that use advanced delivery systems provide efficacious pain therapy with minimal side-effects and are often preferred by patients compared with traditional oral opioids used for the treatment of BTcP. Experience with FBT and oral transmucosal fentanyl citrate shows that many patients favour these agents compared with their previous BTcP medication (oxycodone, morphine, methadone and fentanyl) because of the faster time to onset of pain relief, ease of administration and convenience of use [18••,31].
The wide range of fentanyl products currently available makes it easier to individualize treatment for each patient. However, as bioavailability between products differs significantly, care must be taken while switching from one fentanyl product to another, as they are not interchangeable. It is also advised that the brand name should be used when prescribing [8•], especially as a prescription for ‘fentanyl tablet, to be used sublingually’, can be filled by one of two products (FST or FBT).
Case 4: risk management is an important consideration when prescribing rescue medication
Sarah, a 45-year-old accountant with metastatic colorectal cancer and mother of three young children, developed sharp stabbing pains in her rectum, particularly during bowel movements. Her clinician diagnosed her with BTcP and decided to prescribe her FBT. For titration, FBT is available in child-resistant blister cards containing four tablets, which can help in minimizing wastage. The tablets take approximately 15–25 min to disintegrate in the mouth, so can be removed early by the patient, if required (e.g. if the pain relief is adequate or the patient is feeling excess drowsiness, etc.). Pharmacokinetic studies [32,33] indicate that fentanyl is released rapidly from the FBT and that tablet residue is comprised largely of inert excipients rather than active drug. Hence, delayed removal of the tablet might not result in reduced exposure to fentanyl. The tablets also have a mildly salty taste, such that if mistakenly placed in the mouth by a child, the tablet is likely to be expelled before fully releasing its contents. The patient found FBT effectively controlled the BTcP and noticed an improvement in her functionality and quality of life.
Despite the introduction of a range of effective fentanyl products for the treatment of BTcP, which are generally well tolerated and favoured by patients, BTcP continues to be underrecognized and undertreated. The successful management of BTcP requires a multidisciplinary approach, careful patient assessment and a treatment strategy tailored for the individual patient that considers the cause and type of BTcP, as well as patient preferences. As with any opioids, it is important that risk management strategies are in place to reduce the risk of abuse, misuse and diversion.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 65–66).
This study was sponsored by Cephalon (UK) Ltd. Strategen Ltd provided writing and editorial support to the author. Strategen Ltd received a fee in this regard from Cephalon (UK) Ltd. Cephalon (UK) Ltd were not involved in the drafting, preparation, reviewing or writing of this manuscript.
The author has undertaken consultancy work for Archimedes Pharma Ltd, Cephalon (UK) Ltd, Flynn Pharma Ltd, Nycomed (UK) Ltd and ProStrakan.
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