Treatment of breakthrough cancer pain: to titrate or to proportionate?

Abstract

Breakthrough cancer pain can be treated effectively by rapid-onset opioids, such as sublingual fentanyl. However, it remained unclear how the optimal dose of sublingual fentanyl should be determined. Dosing proportional to basic opioid regimen is now proposed as an alternative to dose titration.

Key words::

• Breakthrough cancer pain
• Fentanyl
• Pain
• Rapid-onset formulation

Breakthrough pain occurs in 33–65% of patients suffering from cancer-related pain syndromes1–3. Besides being a common clinical problem it also markedly reduces the quality of life in these patients4. Despite the abundance of publications on this topic in medical literature, there still remains much confusion about the proper definition of breakthrough pain. Several organizations, such as the European Association for Palliative Care (EAPC), have previously suggested that the term breakthrough pain should be changed into ‘transient pain’ or ‘episodic pain’. Nevertheless, the term breakthrough pain is still commonly used in scientific publications as well as in clinical practice.

Breakthrough cancer pain (BTcP) is a transitory pain in patients with cancer (reaching maximum severity in about 15 minutes and lasting less than 60 minutes), who have relatively stable and well controlled baseline pain with long-term around-the-clock analgesia. Many patients suffer several episodes a day. Although the median duration of BTcP is only 30–60 minutes and it is generally self-limiting, BTcP is widely recognized as placing a highly significant burden on patients, their families, caregivers, health-care systems, and society as a whole5. For patients with cancer, BTcP is associated with decreased functional status and increased levels of anxiety and depression. Several types of BTcP can be distinguished, such as spontaneous pain (idiopathic), incident pain (with an identifiable cause, such as movement or voiding), and end of dose pain (when dosing of drug drops below analgesic level). The treatment for BTcP episodes that is recommended in current guidelines involves extended-release formulations in combination with rapid-onset and short-acting opioids4,6–8. For a long time, only immediate-release formulations such as morphine, oxycodone, or hydromorphone were available, which start to act within about half an hour. According to current evidence-based treatment recommendations, these substances are indicated when BTcP is expected to occur, e.g., as incident pain is triggered by movement, or when a single episode lasts for more than an hour (which is rather unusual)9,10. Traditional recommendations (such as to use 1/6th of total daily morphine dose) are hereby based on strategies developed when only immediate-release morphine was available on the market and has – due to its pharmacokinetic properties – to be given six times per day. However, these immediate-release opioid formulations have pharmacokinetic profiles that do not correlate with the sudden onset and the short time to maximum severity characteristic of BTcP. In line with such a time course, a fast and short-lasting elevation of the opioid plasma concentration seems to be more reasonable. Although in a recent European survey breakthrough pain attacks in the majority of cancer pain patients were sufficiently treated with immediate-release opioids11, recent clinical trials have been examining whether the application of transmucosal or intranasal fentanyl, with their known reduced time to maximum plasma concentrations, show a possible advantage in comparison to immediate-release opioids12–14. In these clinical trials the intensity of breakthrough pain episodes was significantly reduced following transmucosal or intranasal fentanyl. However, the magnitude of the observed effects does not convincingly appear to be clinically relevant15. Among other reasons this may be related to the fact that those patients who would perhaps benefit from such treatment have not yet been identified.

Fentanyl, a rapid-onset opioid, potentially offers an advantageous pharmacological profile for the treatment of the different types of BTcP. However, its enteral bioavailability is no more than moderate. Over the past few years, therefore, various oromucosal and nasal application forms have been developed. Newer formulations, such as an intrapulmonary deposition, are currently under development. Treating physicians, however, need to be aware of the significant clinical differences between the newer fentanyl preparations and immediate-release opioids.

For clinical purposes, an important and unique finding is that, unlike with traditionally used opioid drugs such as morphine, for the fentanyl preparations, no correlation was found between extended-release daily dose and the dosage of the rapid-onset on-demand medication16. Individually tailored, gradually increasing dose titration is therefore recommended. But such a titration poses significant practical problems. Since this titration process reduces compliance, the possibility has been contemplated of skipping over the lowest dosages in high-dose opioid therapy or even skipping the titration process entirely and providing patients with theoretically determined (median-dose) fentanyl formulations in order to stay on the safe side and not induce significant side effects or even overdosing. Moreover, such titration demands great expertise and knowledge of the specific pharmacokinetic profiles of the applied drugs, rendering such titration extremely difficult for non-pain-specialists. Additionally, it remains unclear how patients with low to average background pain but displaying high intensity BTcP have to be treated by means of such titration process. Solid scientific details concerning this titration are still largely lacking.

In this issue of Current Medical Research and Opinion the findings of a study performed by Mercadante et al. concerning the implementation of proportional dosing of sublingual fentanyl are published16. Patients admitted to an acute palliative care unit and presenting breakthrough pain despite stable opioid dosing for background pain were selected to assess the efficacy and safety of sublingual fentanyl in doses proportional to the basal opioid regimen instead of completing a titration process to identify optimal dosing of rescue medication. The study by Mercandante and colleagues has a number of appealing features. In particular, the complex titration process is abandoned for a much simpler proportional dosing. Furthermore, the study protocol approximates routine clinical circumstances, increasing the clinical validity of its findings. In addition, multiple BTcP episodes were evaluated in single patients (with a mean of 2.5 periods per patient), which is also rather unusual in most registration studies. Finally, pain intensity (or decrease in pain intensity) was measured on several time points after the dosing of sublingual fentanyl. Such repeated measurements of pain intensity are often lacking in the previously published registration studies. The results of this study indicate that proportional dosing is not only efficacious (92% of BTcP periods were treated successfully without further request for additional analgesics) but also safe, while effective analgesia is achieved much faster than with the more ‘traditional’ titration process. Such proportional dosing features several important clinical advantages. Firstly, proportional dosing is applicable across all doses of baseline opioid treatment. Secondly, proportional dosing can safely be applied in a variety of environments, even the less controlled ones such as at the patient’s home (as shown by the same authors in another recent publication)17, in nursing homes and outpatient units. The authors of this study clearly demonstrate that such proportional dosing significantly simplifies the application of sublingual fentanyl in cancer patients suffering from BTcP. Interestingly, they also provide several plausible explanations for the somewhat ambiguous findings of previous studies on titration of rapid acting fentanyl in cancer patients. Based on their proposals, future pharmaceutical trials in BTcP should be specifically powered to investigate dose titration.

The findings of this study on proportional dosing should of course be further validated for other galenic fentanyl preparations as well as in earlier stages of cancer and even in non-cancer pain conditions. In addition, the clinical validity of its findings would be further augmented if proportional dosing of fentanyl preparations would be compared to proportional dosing of more conventional immediate-release preparations. Indeed, only such a comparative study design, although not easily achievable in practice, can unequivocally demonstrate the clinical superiority of galenic fentanyl preparations compared to the more conventional opioid formulations with morphine and oxycodone. Taking into account the impending introduction of even newer formulations of fentanyl on the market, registration studies for these drugs should also include proportional dosing schedules into their respective study protocols.

Although the results of this study by Mercadante and colleagues, to say the least, are very exciting, an important point remains the matter of cost. Although fentanyl itself is very cheap, the new galenic preparations are considerably more expensive than existing alternatives. Immediate-release hydromorphone, oxycodone, and morphine cost about €0.95 to €1.82 per single dose, while the prices of rapid-onset fentanyl preparations range from €6.63 to €11.22 per single administration. The scientific evidence indicating the superiority of rapid-onset fentanyl formulations, compared to the more conventional immediate release opioid formulations, becomes increasingly powerful, but their use in routine daily clinical practice is still hampered for several reasons. In many countries rapid-onset fentanyl formulations are still not reimbursed due to their high cost (as detailed above). Although their pharmacokinetic features make them more suitable for application in BTcP, they are up to ten times more expensive than the more conventional alternatives such as immediate release morphine preparations and rapid-acting oxycodone. Such additional cost is often considered too high for the gain in quality of life by government agencies and insurance companies.

In these times of budgetary constraints and growing interest in cost-utility of drugs, several solutions can be identified by which pharmaceutical companies could (easily) overcome the current oppositions by reimbursement and insurance agencies. First of all, pharmaceutical companies should initiate larger-scale, long-term studies of higher methodological quality, performed in the specific patient groups for which these analgesics are (or will be when reimbursed) marketed. Including mainly non-cancer patients in registration studies for a drug used to treat cancer-induced breakthrough pain will hardly contribute to its reimbursement in cancer pain conditions. Furthermore, long-term follow-up (with an absolute minimum of 12 weeks) will become crucial in such studies in order to determine unequivocally the impact of rapid onset fentanyl preparations on overall quality of life (and perhaps even survival) in cancer patients. Thirdly, study protocols should include simple – yet highly specific – primary and secondary outcome parameters which make it possible to calculate the actual gain in health from the use of these rapid onset fentanyl agents, as well as the costs associated with this health gain (net benefit). Such measurements would allow the unambiguous determination of cost-effectiveness outcome measures, such as quality-adjusted life years (QALY). QALY of galenic fentanyl preparations should then be compared to conventional immediate-release opioid formulations, instead of the often applied equation to placebo. Finally, development and fabrication costs of these new galenic formulations of fentanyl should become much more transparent. On the other hand, reimbursement agencies and insurance companies should stop monetizing health effects and take the remarkable changes in overall quality of life, induced by distinct treatment of BTcP episodes, under consideration, instead of focusing solely on the question of whether a perceived decrease in pain intensity is clinically relevant or not. Drug companies and health care organizations should join hands together so that optimal pain treatment, in all its aspects, indeed becomes a privilege for cancer patients worldwide.

Transparency

Declaration of funding

The author received no payment in preparation of this manuscript.

Declaration of financial/other relationships

G.H.H. has disclosed that he has no significant relationships with or financial interests in any commercial companies related to this editorial.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed no relevant financial relationships.