Consensus statement on the management of breakthrough cancer pain: Assessment, treatment and monitoring recommendations

Consensus statement on the management of breakthrough cancer pain: Assessment, treatment and monitoring recommendations María Dolores López Alarcón1*, Francisco Villegas Estevez2, Vicente Domingo Triado3, Pilar Blasco Segura1, Genoveva Hernández Comes4, Alfonso Berrocal Jaime1, Ana Blasco Cordellat1, Jorge Pastor Peidro1, José López Torrecilla1, Carlos Ferrer Albiach2, Almudena Ruiz Sastre1 and Manuel Hernández Peris3

and indeed, a systematic literature review found that study designs and clinical settings were highly variable across regions. As a result, nearly 50% of patients were undertreated, affecting their daily life [8].
The main objective of this review was to present the current evidence on the management of BTcP, and to provide an action protocol to properly diagnose, treat and follow-up BTcP patients based on practical experience, to help healthcare specialists in making therapeutic decisions, thereby improving patient quality of care.

Considerations on the defi nition of BTcP
Breakthrough cancer pain was fi rst defi ned by Portenoy et al. in 1990 [7], as 'a transitory exacerbation of pain experienced by patients undergoing long-term opioid treatment for cancerrelated pain whose baseline pain is adequately controlled', but there has been controversy with respect to this defi nition over the past two decades. Some international guidelines recommend the defi nition of BTcP derived from the original by Portenoy [9][10][11][12], whereas others have established their own defi nition [13][14][15]. The main discrepancy is the fact that BTcP can also occur in the absence of background cancer pain and regardless of opioid treatment [16,17]. So far, there has been no global agreement on the defi nition of BTcP [18]. This lack of consensus has generated different criteria for diagnosing cancer pain, which explains the large variability found in BTcP prevalence rates, ranging from 12% to 93%, depending on the study [8,[19][20][21][22].
In 2012, an association of Spanish medical doctors, composed of palliative care and pain specialists, oncologists and radiation oncology experts, produced a consensus document with a series of guidelines to properly diagnose and treat BTcP patients. BTcP at that time was defi ned as 'a transient, highly intense exacerbation of pain of short duration (less than 20-30 minutes) appearing through a stable pain baseline that can be controlled by opioid treatment' [13].
Although this defi nition is still valid, some clarifi cations are needed. First, how exactly is stable baseline pain defi ned? Some specialists consider that baseline pain is stable when the intensity is very low or there is no pain at all for more than 12 hours, but it can also be interpreted as pain with stable intensity for at least 48 hours, or when there are no more than fi ve daily BTcP episodes. Second, we also need to delimit the length of a 'transient episode'. BTcP episodes are extremely variable, both between and within individuals, and, although it is generally considered that the average duration of a BTcP event is around 30 minutes, it can last more than 1 hour [23].
Lastly, one should distinguish between BTcP and end-of-dose pain. End-of dose pain occurs just before the next scheduled dose of opioid treatment, indicating an inadequate dose or too prolonged interval between subsequent administrations.
All medical specialties involved in the management of BTcP should agree on a practical defi nition for BTcP, identifying all possible variables and drawing up an international consensus for the proper diagnosis and management of BTcP.

Recommendations for the treatment of BTcP
The following recomendations were generated with the goal of assisting healthcare professionals in their therapeutic decision-making in patients with cancer pain.

Diagnostic criteria
For patients with cancer, BTcP is associated with decreased functional status and increased levels of anxiety and depression, greatly affecting the patient's quality of life [24]. In fact, a study by the American Pain Foundation showed that living with pain negatively infl uences emotional health and causes suffering in 82% of patients [25]. However, despite its prevalence and impact on patients, BTcP is sometimes unrecognized and often undertreated [26][27][28]. Prompt and effi cient diagnosis is therefore essential.
Pain levels can currently be evaluated using different scales and questionnaires, including a visual analog scale (VAS), the SF-36 pain scale and a neuropathic pain diagnostic questionnaire (DN4) [29,30]. There are different tools for the diagnosis of BTcP [31][32][33], although the standard one used is the Davies algorithm. Figure 2 shows the most widely used algorithm, modifi ed from the original published in 2009 [23,34,35]. Although it has a good positive predictive value, its sensitivity is still limited due to patient variability. A complete clinical evaluation is still the preferred method to diagnose BTcP [36]. Increase the daily basal analgesic dose (25% to 50%), to minimize the intensity and number of BTcP episodes [40].
Previous studies on patient tolerability and adverse events at higher levels of basal analgesics should be performed before applying this measure.

Prescription of opioid analgesics as rescue medication for
BTcP. Strong opioids, such as immediate-release morphine, have traditionally been used to treat BTcP [41], and indeed it is still the fi rst treatment option for some scientifi c societies, including the National Institute for Health and Care Excellence (NICE) [42]. However, the pharmacokinetic/pharmacodynamic profi les of opioids do not always follow the temporal characteristics of most breakthrough pain episodes [43]. Oral opioids need around 30-40 minutes to take effect, while the maximum pain intensity of BTcP is reached very fast (often in less than 10 minutes) [44]. Rapid-onset opioids (ROOs), specifi cally fentanyl formulations, are the current gold standard in BTcP treatment because they act very quickly, and are very effective [45,46]. In fact, the European Society for Medical Oncology (ESMO) guidelines for the management of cancer pain recommends the use of fentanyl forms for the treatment of BTcP (level of evidence I, degree of recommendation A), whilst morphine is given a level of evidence of II and degree of recommendation of B [34]. Moreover, fentanyl forms are also generally better tolerated, which is particularly important in patients with renal and hepatic disease, since they cannot tolerate strong opioids due to known accumulation of toxic metabolites [47]. Thus, fentanyl formulations are presently the fi rst option in the treatment of BTcP recommended by most medical oncology societies [34,48].

Fentanyl selection: Administration options and dose titration procedure
As previously mentioned, rescue treatment for BTcP involves taking an extra dose (usually at 5%-20% of the total daily dose) of the opioid used around-the-clock (ATC) to relieve baseline pain [47,49,50]. This approach, which is based on years of clinical experience, might not always work because

Therapeutic management
Given the wide inter-and intra-individual variability that characterizes BTcP patients [12,23], it is crucial to perform an individualized and very exhaustive initial evaluation to provide them with the best possible management approach. The etiology of the cancer pain will determine the best treatment option. However, regardless of the treatment, therapeutic management should be multimodal, combining preventive measures with both pharmacological and non-pharmacological methods. Support from family and health professionals will also be essential for a successful outcome.

Non-pharmacological approaches:
Interventional strategies can be used prior to or alongside pharmacological therapy.
Specialists have traditionally followed the original analgesic stepladder algorithm (WHO), in which pharmacological measures are fi rst applied and nonpharmacological techniques are used only when the analgesic ladder fails [37,38]. More recently, though, some clinicians are advocating the early application of non-pharmacological techniques, arguing that it could be benefi cial for pain control [39]. Regardless of the time of application, professionals the pharmacokinetics of ATC opioids might not match the onset of the BTcP episode [43]. For this reason, ROOs, specifi cally fentanyl formulations, are the treatments of choice at present. Clinicians should take into consideration different variables to choose the correct transmucosal fentanyl form from among buccal, sublingual or intranasal preparations [51].
Patient preferences and personal circumstances should fi rst be considered (Table 1). For instance, in the case of patients with frequent vomiting or mucositis, intranasal or sublingual forms of fentanyl administration are recommended. Patients taking buccal tablets or fi lms are advised not to eat or drink anything until the medication has completely dissolved inside the buccal cavity. Having a dry mouth, as well as breaking or sucking the tablets, will decrease their clinical effi cacy.
Previous moisturization of the oral mucosa has been proven to effectively improve fentanyl absorption [52]. Additionally, the pain specialist should also evaluate the drug pharmacokinetic  Figure 3. If, for any reason, patients do not obtain suffi cient relief, the concentration should be gradually increased until the pain is adequately controlled without side effects, with an interval of at least two hours between doses of sublingual fentanyl tablets and four hours in other fentanyl forms. In older adults, the method for trialing the opioid treatment is not exactly the same [54].
These patients are usually more susceptible to the medication effects, and many analgesic guides recommend a "start slow and go slow" approach [55]; however, this dosing strategy is often misinterpreted as "start low, stay low", entailing the risk of inadequate analgesia [56]. To avoid excess sedation, it is recommended to use half the starting dose used for younger adults and proceed with smaller dose increments when needed [56]. If patients of any age present adverse effects or tolerability issues, it is advised to change to another fentanyl formulation.
In these cases, a new dosage adjustment protocol should be drawn up, because each fentanyl preparation has different absorption profi les.
To evaluate treatment effi cacy and tolerability, patients should be advised to keep track of their in-home fentanyl use by keeping a daily diary [13]. They should record all the variables that could affect medication performance, as summarized in Table 2. Keeping this pain diary can be helpful to reinforce patient treatment adherence. Ultimately, the objective is that the patients identify the most appropriate

Follow-up
Physicians should do an early assessment by telephone 48 hours after treatment initiation [11,57]. It is also recommended that patients contact their specialist if they have more than four BTcP episodes per day. Subsequent follow-up can be done through scheduled visits or appointments at the patient's request.
Optimal cancer pain management will require continuous

The need for a multidisciplinary approach
Cancer pain can be extremely diffi cult to manage because it is very heterogenous and can vary signifi cantly from one patient to another [12,23]. It is essential that patients and their families receive appropriate health education. Physicians should focus on explaining the different treatment options and the importance of early treatment initiation, to prevent low adherence rates to medication due to lack of confi dence in the treatment or fear of possible side effects.
The most successful way to diagnose, treat and monitor patients suffering from BTcP is to establish a multidisciplinary approach. Since cancer pain occurs throughout the course of the disease, it is essential that all specialists who treat cancer patients are familiar with its detection and management. Close

Conclusions
In   Medical writing and editing services were provided by Medical Statistics Consulting (MSC) and funded by a grant from Kyowa Kirin Farmacéutica S.L.U.

Confl ict of Interest
All authors, as members of the scientifi c committee, were responsible and participated in data collection and interpretation and had access to full data and reports. In addition, all authors revised the manuscript versions and approved the fi nal draft.