Pain is a major factor that can impair the quality of life in patients with advanced cancer [1]. About 75% of cancer patients experience transitory exacerbation of pain despite appropriate treatment with around-the-clock (ATC) opioids [2]. This breakthrough pain (BTP) is also a serious problem for advanced cancer patients because of the rapid onset and often unpredictable nature in pain episodes. Although BTP is a specific condition for individual patients, BTP is generally defined as a transitory exacerbated pain that occurs over and above controlled background pain [2]. The duration is usually brief and reaches peak intensity within 10 to 15 minutes [3,4]. BTP is associated with adverse effects on patient mood and function [5]. Because of their onset time and duration, oral opioids are considered unsuitable for treating BTP events; therefore, several analyses have suggested that fentanyl formulations are a more efficacious treatment option than oral morphine [6,7].

Fentanyl buccal tablet (FBT; Fentanyl citrate, Fentora, Teva-Handok, Seoul, Korea) is a rapid-onset opioid (ROO) indicated for managing BTP in cancer patients with opioid tolerance [8]. Transmucosal delivery of fentanyl leads to rapid absorption across the buccal mucosa [9]. Treatment with FBT can significantly relieve pain within as few as 10 minutes after administration, resulting in an improved patient satisfaction [10]. For BTP management, a rescue dose of a short-acting opioid (SAO) is generally recommended 10% to 20% of 24-hour ATC opioids dose; however, when using FBTs, a dose titration process starting at the lowest dose, such as 100 μg, has been commonly recommended to provide effective pain control while minimizing the risk of clinically significant adverse effects [10-12]. The titration process of FBTs was attributed to the finding that the effective dose of transmucosal fentanyl opioids could not be predicted from the maintenance dose of the ATC opioids [13]. Interindividual variations in opioid metabolism and response to opioids have also been suggested to affect the efficacy of these drugs [10].

However, a straightforward dose titration process using lowest starting dose can be time consuming for determining the appropriate FBT dose and may result in poor compliance [10]. Thus, a faster and simplified management of BTP is needed. The initial FBT dose also remains controversial similar to the optimal starting doses of transdermal fentanyl for chronic cancer pain [14]. Therefore, several Western studies evaluated the initial FBT doses proportional to the high doses of ATC opioids used for background pain and determined that it was effective and well tolerated [15-17]. In addition, a recent randomized study conducted in Europe compared a starting dose of FBTs at 100 or 200 μg in the titration process, and established non-inferiority in terms of achieving an effective dose by starting with 200 μg of FBTs (81.4%) compared with 100 μg (75.2%) [18]. Adverse events (AEs) during the titration period were also similar between the two groups (5.5% in 100 μg group, 7.2% in 200 μg). Taken together, these results suggested that a starting titration at 200 μg of FBTs is a possible strategy in European clinical practice.

Asian cancer patients differ from Western patients in terms of body weight and body mass index (BMI) [19]. It was not known whether initiating titration of FBTs at a dose of 200 μg will be safe and feasible in Asian patients. Additionally, in clinical practice settings, 100 μg FBTs was not available in about 20% of hospitals in Korea, including at our institution. Therefore, we aimed to evaluate the safety and efficacy of initiating 200 μg FBT for BTP in Korean cancer patients.

This study was a retrospective analysis of the safety and efficacy of using an initial dose of 200 μg FBTs in Korean cancer patients. Most patients well-tolerated the initial exposure to 200 μg FBT, and, for most, the final effective dose was 200 μg. Dizziness and nausea/vomiting were the most common causes of FBT discontinuation.

Many studies have shown that FBT is effective for managing BTP and is generally well-tolerated in cancer patients with opioid tolerance [13,21,22]. Currently, management of cancer pain guidelines suggest considering rapidly acting transmucosal fentanyl in opioid-tolerant patients for BTP, and always initiating transmucosal fentanyl with lowest dose in chosen formulation and titrate to effect [12]. Although individualized treatment is important, the dose titration process from lowest dose to determine the effective dose in each patient may complicate the practical use of FBT, particularly in outpatient settings [16]. Patients already receiving high doses of opioids for background pain could have trouble managing BTP with dose titration using minimal initial doses of FBT because they are opioid-tolerant [5]. Trying different doses of FBT for each BTP episode may be time-consuming due to the repeated need for dose calculation and adjustments [11,16]. Patients may also be unwilling to attempt the titration process and avoid using the ROOs such as FBT, ultimately preferring traditional oral opioids such as SAOs [23]. Therefore, several studies have been performed to facilitate effective control of BTP using FBT. A European study reported that initiating a titration of FBTs at a 200-μg dose may lead patients to be more rapidly titrated to an effective dose compared with starting at a 100-μg dose [18]. Another multicenter prospective randomized study also indicated that doses proportional to the basal opioids for background pain might be safe and effective, and there is no evidence for the use of FBT dose titration [17].

In the present analysis, 200 μg was the most common dose for the final effective regimen of FBT. Although data from Western clinical studies of FBT show that the effective dose ranged from 100 to 800 μg per episode [13,21,24], the final effective doses of FBT for Asian patients, including our data, are slightly lower than those for Western patients [25]. This could be because Asian cancer patients have lower BMI (20 to 21) and body weights (54 to 59 kg) than Western patients (BMI, 24 to 27; weight, 70 to 80 kg) [13,18,22,25,26] or because clearance of fentanyl differs between lean and obese patients [27].

The most frequent treatment-related AEs were nausea/vomiting, somnolence, and dizziness. The prevalence of these AEs was comparable to previous Western reports [18,22]. About 5% of patients could not tolerate the 200-μg dose, which was also similar to the results of a previous European study [18]. Although factors that predicted intolerance of the initial 200 μg FBTs could not be defined, some clinical features in common for the patients were female sex, advanced age, low BMI (or body weight), and low MEDD. According to pharmacogenomics data, it is known that the μ-opioid receptors are more sensitive in females, so women usually require lower dose of opioids for pain relief and can suffer more from the AEs of opioids compared with male [28]. Another important clinical factor that can affect drug tolerance is patient age. There are changes in body composition with aging: an increase in adipose tissue, decrease in lean body mass and decrease in total body water. These changes can affect drug distribution, and lipophilic drugs such as fentanyl could have a greater volume of distribution and take more time to be eliminated from the body [29]. The elderly also have limitations in physical and functional capacity, so there were considerable interindividual heterogeneities in response to drugs [30]. Therefore, attention is needed when FBT titration is carried out in cancer patients who are female, elderly, underweight, and/or have lower MEDD.

In this study, some opioid-naïve patients were administered FBTs although they are currently indicated only for opioid-tolerant patients [8]. All patients were given FBTs in an inpatient setting by resident physicians in the oncology ward. Fortunately, there were no severe or critical AEs, as fentanyl-related deaths happen not infrequently [31]. Therefore, more education about cancer pain management should be emphasized, especially for non-oncology doctors.

Our study had several limitations that are inherent to the retrospective design and analysis. There were a small number of patients, and all were treated at a single institution. Not all patients were opioid tolerant, which was defined as receiving > 60 mg/day of oral morphine, > 30 mg/day of oral oxycodone, > 8 mg/day of oral hydromorphone, and > 25 mg/hour of transdermal fentanyl or an equivalent dose of opioid [12]. Not all patients had stable and adequately controlled background pain, which was defined as an average pain intensity score < 4/10 on the NRS [32]. Data regarding BTP intensity at and after initial titration with FBTs were not available, and supplemental medication information was not provided. Despite these limitations, this analysis provides practical information on the prevalence of AEs and tolerance to an initial 200-μg dose of FBTs in Korean patients.

In conclusion, an initial dose of 200 μg FBTs was well-tolerated in a clinical practice setting in Korean patients. Further prospective studies are needed to determine the appropriate initiating doses of FBT in Korean cancer patients to develop a safe and effective titration strategy for BTP.