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Breakthrough pain: On the road again
European Journal of Pain 13 (2009) 329–330
Contents lists available at ScienceDirect
European Journal of Pain journal homepage: www.EuropeanJournalPain.com
Editorial
Breakthrough pain: On the road again The term breakthrough pain (BP) appeared in the pain management literature 18 years ago. Since the first definition provided by Portenoy and Hagen (1990), BP has become recognized as an important aspect of overall cancer care, as evidenced by the growing number of review articles and practice recommendation guidelines published in recent years. For some time the meaning of this term remained confusing for many European languages, because no translation existed (Mercadante et al., 2002). However, the term of BP has been progressively adopted in any country to define the temporal pattern of this event. In this issue a task force of experts from UK and Ireland provide recommendations about BP in cancer patients (Davies et al., 2009). As expected, given the paucity of existing data and the kind of questions posed by the expert panel, any specific recommendation remains below a standard level of evidence, most of them being of level D, that is the level of already existing recommendations. While these recommendations could be shared, despite mostly being self-referenced, one point deserves some comments, also because it is reported as the only one substantiated by some evidence (level B). The opioid dose to be administered for BP still remains controversial. From an historical perspective, dosing recommendations have been based for years on anecdotal experience; they suggest that the effective dose of BP medication is a percentage of the patient’s total daily opioid dose with a one-sixth (17%) of the daily dose as a starting point (Hanks et al., 2001). On the other hand, all the trials with transmucosal fentanyl (OTFC) have contradicted this assumption drawn from practical experience, suggesting a lack of relationship between the effective OTFC dose and around the clock (ATC) opioid dose (Christie et al., 1998; Portenoy et al., 1999; Farrar et al., 1998; Coluzzi et al., 2001). According to these studies, recommendation n.8 (level B) states that the dose of opioid for BP should be determined by individual titration. A better critical analysis may help interpreting existing data, as these randomized trials have never specifically examined this issue, and the information gathered is just consequential to the study design aimed to demonstrate superiority of OTFC over placebo, oral morphine or usual oral opioids, or to evaluate the safety and efficacy of ascending doses of OTFC in dose-finding studies. Indeed, observations from data pooled from the same trials of OTFC showed a statistically significant relationship between the BP and ATC opioid dose, despite a large interindividual variability in patients’ dose requirements (Hagen et al., 2007). To scientifically affirm the need of titration a randomized trial should compare efficacy and safety in groups of patients titrated versus groups non-titrated, and this was not the case. For instance, open series or small controlled studies with a specific aim reproducing real clinical situations, may provide better information than randomized controlled trials designed with another goal.
Is the risk of overdosage, and consequently the occurrence of feared adverse effects, that justifies titration? Some open-label studies reflecting daily practice have shown that intravenous morphine (IV-M) used at doses proportional to the ATC dose provided prompt analgesia and was effective in most cases, without evident risks even in aged population (Mercadante et al., 2004, 2008). As IV-M has the highest intrinsic risk for serious adverse event, one could argue that other drugs should be at least similarly safe. In a controlled study, OTFC used in a similar way, that is at a dose proportional to the basal opioid regimen, was safe in all patients experiencing pain exacerbation, even though administered at starting doses of 1600 lg in highly tolerant patients (Mercadante et al., 2007). In a recent study reproducing a clinical scenario of patients receiving opioids for BP, the dose of oral opioids used as rescue medication was 18% of the ATC opioid dose, whereas for OTFC, titrated to determine the effective dose, the rescue dose was about 35% of the ATC dose (Zeppetella, 2008), suggesting that titration process mostly provides even higher doses than those expected by using proportional doses to ATC regimen. A titration process starting with 200 lg of OTFC is likely to produce a limited effect in patients who are receiving high doses of opioids regularly. This practice may discourage patients, particularly outpatients, to continue titration in daily activity. Regardless of the methodological problems with studies which suggested the need for dose titration of OTFC, other factors could influence the outcome, namely the different pain intensity of each episode or the type of BP, which potentially should require titration for each episode, unfeasible in clinical practice. For example, incident pain due to movement is a challenge as it is strongly dependent from physical activity and may spontaneously evanish stopping movement. Potentially, it should be differently assessed in clinical studies. Due to the variability in presentation of pain flares, potentially each episode could need a dose titration. It could be argued that, to cover the majority of episodes, a rapid and intense treatment should be necessary. Previous preliminary studies have shown that in patients receiving opioids for chronic cancer pain the risks of administering about 20% of the daily dose of opioids with rapid modalities, intravenously or transmucosally, are minimal, going back to previous recommendations, based on clinical experience (Hanks et al., 2001). This can be explained by the protective effect offered by opioid tolerance in patients chronically receiving relevant opioid doses for the management of cancer pain. A reliable compromise between the different opinions could be to start with relatively higher doses of opioids in highly tolerant patients skipping some steps of dose titration, until more information will be available to settle the question. Randomized studies with an appropriate design comparing advantages and
1090-3801/$36.00 Ó 2009 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpain.2008.11.021
330
Editorial / European Journal of Pain 13 (2009) 329–330
disadvantage of titration versus fixed doses proportional to ACD opioid doses could reveal the truth. From a practical perspective, to reduce patients’ reluctance to ask for opioid rescue medication (Zeppetella, 2008; Davies et al., 2008), a definite indication should be provided and self-titration is unlikely to be accepted, unless performed in an assisted setting. Practical problems, including the need of titration, has probably limited the use of OTFC, and probably will be the same with other new delivery systems, despite the superiority on oral morphine in terms of onset and the efforts of pharmaceutical industry, regardless of the cost. Many patients will continue to prefer the conventional use of oral morphine, even though most of the episodes will evanish spontaneously (Davies et al., 2009), and an uneventful burst of morphine will be gratuitously given. This hypothesis raises a further question about the effect of BP medication with opioids on opioid receptor activity. At the moment we do not have any information about what happens, and which may be the biochemical consequences of repeated receptor bursts. Again we need to bridge clinical science and biology. May be a new frontier for research? All the researchers in the field are called on the road again.
References Christie J, Simmonds M, Patt R, Coluzzi P, Busch M, Nordbrock E, et al. Dosetitration multicenter study of transmucosal fentanyl citrate for the treatment of breakthrough pain in cancer patients using transdermal fentanyl for persistent pain. J Clin Oncol 1998;16:3238–45. Coluzzi P, Schwartzberg L, Conroy J, Chaparata S, Gay M, Busch M, et al. Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulphate immediate release (MSIR). Pain 2001;91:123–30. Davies A, Dickman A, Reid C, Stevens A, Zeppetella J. The management of cancerrelated breakthrough pain: recommendations of a task group of the Association of palliative medicine of Great Britain and Ireland. Eur J Pain 2009;13:330–7. Davies AN, Vriens J, Kennett A, McTaggart M. An observational study of oncology patients’ utilization of breakthrough pain medication. J Pain Symptom Manage 2008;35:406–11.
Farrar J, Cleary J, Rauck R, Busch M, Nordbrock E. Oral transmucosal fentanyl citrate: a randomized, double-blinded, placebo-controlled trial for treatment of breakthrough pain in cancer patients. J Natl Cancer Inst 1998;90: 611–6. Hagen NA, Fisher K, Victorino C, Farrar JT. A titration strategy is needed to manage breakthrough cancer pain effectively: observations from data pooled from three clinical trials. J Palliat Med 2007;10:47–55. Hanks GW, De Conno F, Cherny N, Hanna M, Kalso E, McQuay HJ, et al. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Brit J Cancer 2001;84:587–93. Mercadante S, Radbruck L, Caraceni A, Cherny N, Kaasa S, Nauck F, et al. Episodic (breakthrough pain) consensus conference of an expert working group of the European Association of Palliative Care. Cancer 2002;94:832–9. Mercadante S, Villari P, Ferrera P, Bianchi M, Casuccio A. Safety and effectiveness of intravenous morphine for episodic-breakthrough pain, using a fixed ratio with the oral daily morphine dose. J Pain Symptom Manage 2004;27:352–9. Mercadante S, Villari P, Ferrera P, Casuccio A, Mangione S, Intravaia G. Transmucosal fentanyl vs intravenous morphine in doses proportional to basal opioid regimen for episodic-breakthrough pain. Brit J Cancer 2007;96:1828–33. Mercadante S, Intravaia G, Villari P, Ferrera P, Riina S, Mangione S. Intravenous morphine for breakthrough (episodic) pain in an acute palliative care unit: a confirmatory study. J Pain Symptom Manage 2008;35:307–13. Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalence and characteristics. Pain 1990;41:273–81. Portenoy RK, Payne R, Coluzzi P, et al. Oral transmucosal fentanyl citrate (OTFC) for the treatment of breakthrough pain in cancer patients: a controlled dose titration study. Pain 1999;79:303–12. Zeppetella G. Opioids for cancer breakthrough pain: a pilot study reporting patient assessment of time to meaningful pain relief. J Pain Symptom Manage 2008;35:563–7.
Sebastiano Mercadante Director Anesthesia and Intensive Care Unit, Pain Relief and Palliative Care Unit, La Maddalena Cancer Center, University of Palermo, Via San Lorenzo 312, 90146 Palermo, Italy Tel.: +39 091 6806521; fax: +39 091 6806110 E-mail address: [email protected] Available online 11 February 2009
Contents lists available at ScienceDirect
European Journal of Pain journal homepage: www.EuropeanJournalPain.com
Editorial
Breakthrough pain: On the road again The term breakthrough pain (BP) appeared in the pain management literature 18 years ago. Since the first definition provided by Portenoy and Hagen (1990), BP has become recognized as an important aspect of overall cancer care, as evidenced by the growing number of review articles and practice recommendation guidelines published in recent years. For some time the meaning of this term remained confusing for many European languages, because no translation existed (Mercadante et al., 2002). However, the term of BP has been progressively adopted in any country to define the temporal pattern of this event. In this issue a task force of experts from UK and Ireland provide recommendations about BP in cancer patients (Davies et al., 2009). As expected, given the paucity of existing data and the kind of questions posed by the expert panel, any specific recommendation remains below a standard level of evidence, most of them being of level D, that is the level of already existing recommendations. While these recommendations could be shared, despite mostly being self-referenced, one point deserves some comments, also because it is reported as the only one substantiated by some evidence (level B). The opioid dose to be administered for BP still remains controversial. From an historical perspective, dosing recommendations have been based for years on anecdotal experience; they suggest that the effective dose of BP medication is a percentage of the patient’s total daily opioid dose with a one-sixth (17%) of the daily dose as a starting point (Hanks et al., 2001). On the other hand, all the trials with transmucosal fentanyl (OTFC) have contradicted this assumption drawn from practical experience, suggesting a lack of relationship between the effective OTFC dose and around the clock (ATC) opioid dose (Christie et al., 1998; Portenoy et al., 1999; Farrar et al., 1998; Coluzzi et al., 2001). According to these studies, recommendation n.8 (level B) states that the dose of opioid for BP should be determined by individual titration. A better critical analysis may help interpreting existing data, as these randomized trials have never specifically examined this issue, and the information gathered is just consequential to the study design aimed to demonstrate superiority of OTFC over placebo, oral morphine or usual oral opioids, or to evaluate the safety and efficacy of ascending doses of OTFC in dose-finding studies. Indeed, observations from data pooled from the same trials of OTFC showed a statistically significant relationship between the BP and ATC opioid dose, despite a large interindividual variability in patients’ dose requirements (Hagen et al., 2007). To scientifically affirm the need of titration a randomized trial should compare efficacy and safety in groups of patients titrated versus groups non-titrated, and this was not the case. For instance, open series or small controlled studies with a specific aim reproducing real clinical situations, may provide better information than randomized controlled trials designed with another goal.
Is the risk of overdosage, and consequently the occurrence of feared adverse effects, that justifies titration? Some open-label studies reflecting daily practice have shown that intravenous morphine (IV-M) used at doses proportional to the ATC dose provided prompt analgesia and was effective in most cases, without evident risks even in aged population (Mercadante et al., 2004, 2008). As IV-M has the highest intrinsic risk for serious adverse event, one could argue that other drugs should be at least similarly safe. In a controlled study, OTFC used in a similar way, that is at a dose proportional to the basal opioid regimen, was safe in all patients experiencing pain exacerbation, even though administered at starting doses of 1600 lg in highly tolerant patients (Mercadante et al., 2007). In a recent study reproducing a clinical scenario of patients receiving opioids for BP, the dose of oral opioids used as rescue medication was 18% of the ATC opioid dose, whereas for OTFC, titrated to determine the effective dose, the rescue dose was about 35% of the ATC dose (Zeppetella, 2008), suggesting that titration process mostly provides even higher doses than those expected by using proportional doses to ATC regimen. A titration process starting with 200 lg of OTFC is likely to produce a limited effect in patients who are receiving high doses of opioids regularly. This practice may discourage patients, particularly outpatients, to continue titration in daily activity. Regardless of the methodological problems with studies which suggested the need for dose titration of OTFC, other factors could influence the outcome, namely the different pain intensity of each episode or the type of BP, which potentially should require titration for each episode, unfeasible in clinical practice. For example, incident pain due to movement is a challenge as it is strongly dependent from physical activity and may spontaneously evanish stopping movement. Potentially, it should be differently assessed in clinical studies. Due to the variability in presentation of pain flares, potentially each episode could need a dose titration. It could be argued that, to cover the majority of episodes, a rapid and intense treatment should be necessary. Previous preliminary studies have shown that in patients receiving opioids for chronic cancer pain the risks of administering about 20% of the daily dose of opioids with rapid modalities, intravenously or transmucosally, are minimal, going back to previous recommendations, based on clinical experience (Hanks et al., 2001). This can be explained by the protective effect offered by opioid tolerance in patients chronically receiving relevant opioid doses for the management of cancer pain. A reliable compromise between the different opinions could be to start with relatively higher doses of opioids in highly tolerant patients skipping some steps of dose titration, until more information will be available to settle the question. Randomized studies with an appropriate design comparing advantages and
1090-3801/$36.00 Ó 2009 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpain.2008.11.021
330
Editorial / European Journal of Pain 13 (2009) 329–330
disadvantage of titration versus fixed doses proportional to ACD opioid doses could reveal the truth. From a practical perspective, to reduce patients’ reluctance to ask for opioid rescue medication (Zeppetella, 2008; Davies et al., 2008), a definite indication should be provided and self-titration is unlikely to be accepted, unless performed in an assisted setting. Practical problems, including the need of titration, has probably limited the use of OTFC, and probably will be the same with other new delivery systems, despite the superiority on oral morphine in terms of onset and the efforts of pharmaceutical industry, regardless of the cost. Many patients will continue to prefer the conventional use of oral morphine, even though most of the episodes will evanish spontaneously (Davies et al., 2009), and an uneventful burst of morphine will be gratuitously given. This hypothesis raises a further question about the effect of BP medication with opioids on opioid receptor activity. At the moment we do not have any information about what happens, and which may be the biochemical consequences of repeated receptor bursts. Again we need to bridge clinical science and biology. May be a new frontier for research? All the researchers in the field are called on the road again.
References Christie J, Simmonds M, Patt R, Coluzzi P, Busch M, Nordbrock E, et al. Dosetitration multicenter study of transmucosal fentanyl citrate for the treatment of breakthrough pain in cancer patients using transdermal fentanyl for persistent pain. J Clin Oncol 1998;16:3238–45. Coluzzi P, Schwartzberg L, Conroy J, Chaparata S, Gay M, Busch M, et al. Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulphate immediate release (MSIR). Pain 2001;91:123–30. Davies A, Dickman A, Reid C, Stevens A, Zeppetella J. The management of cancerrelated breakthrough pain: recommendations of a task group of the Association of palliative medicine of Great Britain and Ireland. Eur J Pain 2009;13:330–7. Davies AN, Vriens J, Kennett A, McTaggart M. An observational study of oncology patients’ utilization of breakthrough pain medication. J Pain Symptom Manage 2008;35:406–11.
Farrar J, Cleary J, Rauck R, Busch M, Nordbrock E. Oral transmucosal fentanyl citrate: a randomized, double-blinded, placebo-controlled trial for treatment of breakthrough pain in cancer patients. J Natl Cancer Inst 1998;90: 611–6. Hagen NA, Fisher K, Victorino C, Farrar JT. A titration strategy is needed to manage breakthrough cancer pain effectively: observations from data pooled from three clinical trials. J Palliat Med 2007;10:47–55. Hanks GW, De Conno F, Cherny N, Hanna M, Kalso E, McQuay HJ, et al. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Brit J Cancer 2001;84:587–93. Mercadante S, Radbruck L, Caraceni A, Cherny N, Kaasa S, Nauck F, et al. Episodic (breakthrough pain) consensus conference of an expert working group of the European Association of Palliative Care. Cancer 2002;94:832–9. Mercadante S, Villari P, Ferrera P, Bianchi M, Casuccio A. Safety and effectiveness of intravenous morphine for episodic-breakthrough pain, using a fixed ratio with the oral daily morphine dose. J Pain Symptom Manage 2004;27:352–9. Mercadante S, Villari P, Ferrera P, Casuccio A, Mangione S, Intravaia G. Transmucosal fentanyl vs intravenous morphine in doses proportional to basal opioid regimen for episodic-breakthrough pain. Brit J Cancer 2007;96:1828–33. Mercadante S, Intravaia G, Villari P, Ferrera P, Riina S, Mangione S. Intravenous morphine for breakthrough (episodic) pain in an acute palliative care unit: a confirmatory study. J Pain Symptom Manage 2008;35:307–13. Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalence and characteristics. Pain 1990;41:273–81. Portenoy RK, Payne R, Coluzzi P, et al. Oral transmucosal fentanyl citrate (OTFC) for the treatment of breakthrough pain in cancer patients: a controlled dose titration study. Pain 1999;79:303–12. Zeppetella G. Opioids for cancer breakthrough pain: a pilot study reporting patient assessment of time to meaningful pain relief. J Pain Symptom Manage 2008;35:563–7.
Sebastiano Mercadante Director Anesthesia and Intensive Care Unit, Pain Relief and Palliative Care Unit, La Maddalena Cancer Center, University of Palermo, Via San Lorenzo 312, 90146 Palermo, Italy Tel.: +39 091 6806521; fax: +39 091 6806110 E-mail address: [email protected] Available online 11 February 2009