Safety and Effectiveness of Intravenous Morphine for Episodic Breakthrough Pain in Patients Receiving Transdermal Buprenorphine

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1 Vol. 32 No. 2 August 2006 Journal of Pain and Symptom Management 175 Original Article Safety and Effectiveness of Intravenous Morphine for Episodic Breakthrough Pain in Patients Receiving Transdermal Buprenorphine Sebastiano Mercadante, MD, Patrizia Villari, MD, Patrizia Ferrera, MD, Giampiero Porzio, MD, Federica Aielli, MD, Lucilla Verna, MD, and Alessandra Casuccio, BS Anesthesia & Intensive Care Unit (S.M., P.V., P.F.) and Pain Relief & Palliative Care Unit (S.M., P.V., P.F.), La Maddalena Cancer Center, Palermo; Palliative Medicine, Department of Anesthesia, Intensive Care & Emergency Medicine (S.M.) and Section of Ophthalmology (A.C.), University of Palermo, Department of Oncology (G.P., F.A., L.V.), University of L Aquila, Palermo, Italy Abstract Supplemental dosing of an opioid is the main treatment suggested to manage breakthrough pain in cancer patients. The intravenous route has been proven to be safe and effective, providing rapid analgesia in patients receiving oral morphine. Transdermal buprenorphine (TTS-BUP) is increasingly used in cancer pain management, but this drug has been labeled as a difficult drug to use in combination with other opioids. The aim of this open-label study was to verify the safety and effectiveness of intravenous morphine (IV-MO) for the treatment of episodic pain in cancer patients receiving TTS-BUP. A consecutive sample of 29 cancer patients, who were treated with TTS-BUP, reported an acceptable basal analgesia, and presented with episodic pains were selected for the study. The IV-MO dose was one-fifth of the morphine equivalent oral daily dose calculated using a ratio of TTS-BUP/oral morphine of 1:75, and a morphine IV/oral ratio of 1:3. For each episode, pain intensity and opioidrelated adverse effects were recorded when severe pain occurred (T0), and 15 minutes after. One hundred six breakthrough events in the 29 patients (3.7 episodes per patient, on average) were recorded during admission. The mean pain intensity decreased from an initial value of 7.3 (confidence interval [CI] 95% ) to 2.9 (CI 95% ) 15 minutes after IV-MO. Ninety-eight episodes (92.4%) were considered treated successfully, defined as a reduction of more than 33% within 15 minutes; 88 of these episodes (83.0%) had more than 50% pain intensity decrease. No differences in age, gender, pain mechanism, and time of events were found. Eight episodes (7.5%) did not respond effectively within 15 minutes, and required further doses. The occurrence of adverse effects for each episode treated was not frequent and intensity was not relevant. IV-MO was effective and safe in most cancer patients receiving TTS-BUP who experienced pain exacerbation. J Pain Symptom Manage 2006;32: Ó 2006 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Address reprint requests to: Sebastiano Mercadante, MD, Anesthesia & Intensive Care Unit, Pain Relief & Palliative Care Unit, La Maddalena Cancer Ó 2006 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved. Center, Via S. Lorenzo 312, Palermo, Italy. terapiadeldolore@la-maddalena.it Accepted for publication: January 27, /06/$--see front matter doi: /j.jpainsymman

2 176 Mercadante et al. Vol. 32 No. 2 August 2006 Key Words Intravenous morphine, transdermal buprenorphine, opioids, breakthrough pain, cancer pain Introduction Although buprenorphine (BUP), a partial mu-receptor agonist, has been used for at least 30 years in the treatment of cancer-related pain, this drug has never gained popularity. The reasons include the adverse event profile of the parenteral and sublingual formulations, the presumed ceiling effect for analgesia, and possible problems if used with other opioids due to its potential antagonist activity when administered to a patient already receiving a full agonist drug. 1 Thus, BUP has been labeled as an atypical opioid, difficult to place on the World Health Organization analgesic ladder, and less easy to use clinically than other strong opioids. 2 Recently, BUP has been formulated as a transdermal patch. With this delivery system, peaks in plasma concentration due to rapid absorption are unlikely and the more constant concentrations may provide a clinical advantage. 1,3,4 No data exist on the treatment of breakthrough pain in patients receiving transdermal BUP (TTS-BUP). Traditional short-acting opioids are commonly used for this purpose. Intravenous morphine (IV-MO) has been reported to be safe and effective in treating breakthrough episodes, using a dose proportional to the basal dosage of oral morphine, in patients receiving oral morphine for their basal pain control. 5 As the use of BUP in association with other opioids has been of concern because of a possible antagonistic effect which might reduce analgesia or induce withdrawal symptoms rather than decrease the intensity of a pain flare, the aim of this open-label study was to evaluate the safety and effectiveness of IV-MO in advanced cancer patients who were receiving TTS-BUP. Methods A consecutive sample of 29 cancer patients admitted to a pain relief and palliative care unit were recruited for the study. Patients were receiving TTS-BUP for their basal pain and reported acceptable analgesia. Patients requiring four or more breakthrough doses were excluded. Breakthrough pain had to exceed a pain score of 7/10, so that patients with fluctuations of pain with no clear cut peaks of pain intensity were also excluded. Institutional approval and informed consent were obtained. According to the department policy, an intravenous line was established on admission for emergency treatment of symptoms and hydration, if required. Patients were encouraged to call when their pain became severe (more than seven on a numerical pain scale) and a bolus of IV-MO was administered over 5 minutes The IV-MO dose was one-fifth of the morphine equivalent oral daily dose, using the following conversion ratios: IV-MO:oral MO was 1:3 and TTS-BUP:oral MO was 1:75. 5 For example, a daily dose of TTS-BUP of 52.5 mg/hour (about 1.2 mg/day), was considered equivalent to 90 mg of oral MO. This corresponded to 30 mg of IV-MO (1:3 ratio), so that the final dose (one-fifth of the daily dose) for the episodic pain was to be 6 mg. As the TTS BUP doses used were 35, 52.5, and 70 mg/hour, the equivalent boluses of IV-MO were 4, 6, and 8 mg, respectively. Written orders were given and IV- MO was administered by nurses. For each episode, pain intensity was recorded using a numerical scale from 0 to 10, and opioid-related adverse effects were described using a scale from 0 to 3 (absent, slight, moderate, severe). Data were collected by nurses trained in symptom measurement as part of their daily activity. Daily doses of TTS-BUP were also recorded. Data were recorded at time of the flare (T0) and 15 minutes after (T1). Patients who did not respond satisfactorily 15 minutes after IV-MO (reduction in pain intensity greater than 33%), or were unsatisfied, were considered unresponsive and received further treatments (a half dose of IV-MO). According to previous experience with IV-MO, 15 minutes was considered an acceptable time for evaluating effects. Patients with a pain reduction of at least 33% 15 minutes after IV-MO injection were considered to have a clinical benefit. 6 Statistical Analysis Frequency analysis was performed using the Chi-squared test. The paired Wilcoxon

3 Vol. 32 No. 2 August 2006 IV Morphine in Patients Receiving TTS Buprenorphine 177 signed-rank test and paired samples Student s t-test were used to compare the scores or the means of nonparametric and parametric variables, respectively, at the different time intervals. The one-way analysis of variance and Kruskal Wallis statistic test were used to compare the different parametric or nonparametric variables. All P values were two sided, and P values less than 0.05 were considered statistically significant. Data were analyzed by the Epi Info software, version 3.2.2, (Centers for Disease Control and Prevention) and the Systat Software 8.0 version (SPSS, Inc.). Results Patient characteristics are described in Table 1. One hundred six breakthrough events were recorded in the 29 patients who were receiving TTS-BUP during hospital admission. Most patients presented two or more events during their hospital stay for a mean of 3.7 events per patient. Patients who were receiving a mean TTS-BUP dose of 44.5 mg/hour (95% confidence interval [CI] ) received a mean IV-MO dose of 6.1 mg (95% CI ). In 98 episodes, treatment with IV-MO was successful, yielding a reduction of pain intensity of more than 33% within 15 minutes. There was a decrease in mean intensity from 7.3 (95% CI ) to 2.9 (95% CI ). In 88 episodes (83%), there was more than a 50% decrease in pain intensity 15 minutes after IV-MO. Eight episodes (7.5%) did not subside (less than 33% reduction in pain intensity or unsatisfied patients) within 15 minutes after IV-MO, Table 1 Patient Characteristics Number of patients 29 Age 62.7 (11.6) Gender (M/F) 17/12 Primary tumor Colon-rectum 5 Urogenital 6 Breast 6 Head/neck 3 Lung 2 Others 7 Pain mechanism Somatic 10 Visceral 6 Somatic-neuropathic 6 Neuropathic 3 Visceral-neuropathic 2 Somatic-visceral-neuropathic 2 and required further treatments. This group of patients was receiving a mean dose of TTS- BUP of 49.6 mg/hour (95% CI ), not significantly different from doses used for responsive patients. No relationship between TTS-BUP doses and the response to IV-MO was found. No differences in age, gender, pain mechanism, and time of events were found. Acute adverse effects occurring after IV-MO were those commonly observed with opioid therapy. The occurrence of adverse effects was not relevant in frequency and intensity. Adverse effects occurred only in 18% of episodes treated. Adverse effects (nausea and/or drowsiness) were mild in all but five of 29 patients; these five reported drowsiness of moderate intensity (graded as 2), but this was devoid of any relevant clinical consequence. The occurrence of such adverse effects was not significantly related to the TTS-BUP basal dose and, as a consequence, with the IV-MO dose. The same dose of IV-MO that was found to be effective was successfully converted to oral equivalents of morphine and used before being prescribing for use at home. Data after this conversion were not recorded, but the general impression was that it was still working. Discussion In cancer patients, breakthrough pain is a transient flare of pain, severe in intensity, which is superimposed on an otherwise stable pain pattern in patients treated with opioids. 7 The availability of supplemental doses of a short-acting opioid (rescue medication) in addition to the continuous analgesic medication is the main treatment suggested to manage these pain flares. 8 Current dosing recommendations for breakthrough pain generally suggest that the effective dose of an oral or intravenous breakthrough pain medication must be a percentage of a patient s total daily opioid dose. 9 This was confirmed in a preliminary experience by using IV-MO in doses proportional to the basal oral morphine dose. Such an approach that resulted was effective and safe when using 20% of the basal regimen. 5 The use of BUP in association with other opioids, as for example during opioid switching, has been of concern because of a possible antagonistic effect, which might reduce analgesia or induce withdrawal symptoms. BUP binds to

4 178 Mercadante et al. Vol. 32 No. 2 August 2006 the opioid receptor avidly and has a slow dissociation, which could potentially impede the full effectiveness of the added opioid. However, recent data suggest that no interference between BUP and other opioids mu-agonists exists. 3 The persistent occupancy of mu-receptors may be an in vitro observation only seen in isolated receptor preparation. Under in vivo conditions, the accessibility of mu-receptor sites is regained within the time course of the analgesic activity of BUP. 3 Clinically, the combination of BUP with MO in the analgesic dose range results in a magnitude of effect compatible with an additive type of interaction. MO, when given after the decline of the acute effect of BUP, maintains full efficacy, 10 independent of the order of the administration of the opioids. 11 As shown by isobolographic and detoxification studies, crosstolerance between mu-agonists and BUP exists, and a combination of drugs results in an additive effect, rather than antagonism. 10 Recent experiments have shown no indication of a subadditive effect or antagonistic interaction, which might have been presumed in regard to a partial agonistic property or the slow receptor dissociation attributed to BUP. 3 Thus, the occurrence of withdrawal symptoms is unlikely. In the current study, IV-MO provided a strong and rapid analgesic effect in patients presenting with severe pain flares and having basal pain responsive to the TTS-BUP regimen. Neither interference between the two opioids nor withdrawal symptoms occurred. The outcome also was not influenced by the pain mechanism, timing of the event, or the TTS-BUP dose. Dose did not influence the outcome, probably because of the low range of equivalent morphine doses used. Of interest, before discharge, IV-MO was switched to the oral route (after back conversion) to facilitate the use at home, and this appeared to be successful. However, data were not recorded, as the intent was just to provide preliminary information. The use of oral morphine or transmucosal fentanyl for treating breakthrough pain in patients receiving TTS-BUP should be explored in future studies. Only eight episodes (7.5%) in six patients were not responsive to the selected dose of IV-MO. According to department policy, this group of patients received a further half-dose of IV-MO at 15 minutes. If not successful, the dose to be administered was reevaluated and treatment individualized. The response to the treatment was independent of the doses used, as unresponsive patients were receiving a mean dose of TTS-BUP of 49.6 mg/hour (95% CI ), not significantly different from doses used for responsive patients. To evaluate the effectiveness of the treatment, 33%--50% cut-off points for the percentage of decrease in pain intensity were used. These are simple endpoints of clinically meaningful benefit, easily understood by professionals and patients. These levels of change in pain intensity have been commonly used to evaluate clinical differences in patients, 6 although they cannot be equated to patients satisfaction. Acute adverse effects occurring after IV-MO were those commonly observed with opioid therapy. Only minor opioid-induced adverse effects were observed. The occurrence of adverse effects was not relevant in frequency and intensity. Only in five of 29 patients was drowsiness of moderate intensity (graded as 2, in the scale chosen), and no clinical consequences were observed. The occurrence of such adverse effects was independent of the basal TTS-BUP regimen and, as a consequence, of the IV-MO dose administered as needed. This may reflect the presence of some crosstolerance between the two drugs. These data confirm the findings of a previous trial of patients receiving morphine as the regular opioid regimen. 5 There are obvious limitations of this study, principally the lack of blinding and a control group. Therefore, the results should be interpreted with caution. However, the strict selection criteria for defining episodic pain, using a minimal intensity of 7/10 on a numerical scale, and a fixed time to evaluate the impact of the treatment, should reinforce the meaning of the data. Although the use of placebo and a double-blind design would provide additional information, this solution was not taken due to ethical concerns in such patients, and because the intent was to provide preliminary information on safety and efficacy of the treatment. In contrast to a previous experience, where it was decided to record the time for pain relief when the pain reached a level of about the basal pain, timing for evaluation in this study was fixed at 15 minutes. This approach seems to be more objective and reasonably acceptable for judging

5 Vol. 32 No. 2 August 2006 IV Morphine in Patients Receiving TTS Buprenorphine 179 the effect of a treatment for breakthrough pain on the basis of data reported in the literature. Similarly, to collect such acute data in real time, it was preferable to use very simple tools, avoiding other instruments, such as pain relief intensity, which would have confused the monitoring to be repeated in a short time and introduced a further burden for patients. Sublingual buprenorphine tablets also may be a natural option for the treatment of episodic pain during TTS-BUP therapy. However, doses as needed have never been determined in patients receiving TTS-BUP, and the prolonged effect of the rescue doses may add problems to the therapy. In conclusion, IV-MO at a dose equivalent to 20% of the oral morphine equivalent of TTS- BUP (using a TTS-BUP:oral MO ratio of 1:75) is safe and effective in most patients experiencing pain exacerbation. Possible conflicts when using two drugs with different receptor characteristics, such as MO and BUP, were not clinically evident in this clinical context. These preliminary data should be confirmed in future studies with appropriate designs. References 1. Johnson R, Fudala P, Payne R. Buprenorphine: considerations for pain management. J Pain Symptom Manage 2005;29: Mercadante S. Cancer pain/palliative care. In: Raffa R, Budd K, eds. Buprenorphine in pain therapy. New York: Thieme, 2005: Kogel B, Christoph T, Straburger W, Friderichs E. Interaction of mu-opioid receptor agonists and antagonists with the analgesic effect of buprenorphine in mice. Eur J Pain 2005;9: Sorge J, Sittl R. Comparison of transdermal and sublingual buprenorphine: results from a phase III, randomized, double-blind, placebo-controlled multicenter study in patients with chronic pain. J Pain Symptom Manage 2000;20:S 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: Farrar J, Portenoy RK, Berlin J, et al. Defining the clinically important difference in pain outcome measures. Pain 2000;88: Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalence and characteristics. Pain 1990;41: Mercadante S, Radbruch L, Caraceni A, et al. Episodic (breakthrough) pain. Cancer 2002;94: Hanks GW, Expert Group of EAPC. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer 2001;84: Cowan A, Friderichs E, Straburger W, Raffa RB. Basic pharmacology of buprenorphine. In: Raffa R, Budd K, eds. Buprenorphine in pain therapy. New York: Thieme, New York, 2005: Atkinson R, Schofield P, Mellor P. The efficacy in sequential use of buprenorphine and morphine in advanced cancer pain. In: Doyle D, ed. Opioids in the treatment of cancer pain. London: Royal Society of Medicine, 1990: