Time to Pain Relief After Immediate-Release Morphine in Episodic Pain The TIME Study

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1 ORIGINAL RESEARCH ARTICLE Clin Drug Investig 21; 3 Suppl. 2: /1/2-49/$49.95/ ª 21 Adis Data Information BV. All rights reserved. Time to Pain Relief After Immediate-Release Morphine in Episodic Pain The TIME Study Claudio Lo Presti, 1 Alessandro Roscetti, 2 Davide Muriess 3 and Massimo Mammucari 1 1 Pain Medicine and Intensive-Care Unit, San Filippo Neri Hospital, Rome, Italy 2 Intensive-Care Antalgic Therapy Hospice Unit, San Camillo de Lellis Hospital, Rieti, Italy 3 San Carlo di Nancy, Rome, Italy Abstract Background: Cancer-related and non-cancer chronic pain embodies the most frequent challenge in clinical practice. Management of chronic pain and breakthrough pain (BTP) requires adjustments to the analgesic regimen to achieve adequate pain control. Objective: To examine the time to achieve pain relief in patients who experienced intense episodic pain breakouts despite baseline therapy with analgesics. Methods: This study was based on a 14-day observation period. Patients with either cancer-related or non-cancer pain who experienced >2 intensive episodic pain breakouts per day were prescribed immediate-release (IR) morphine sulphate (1 mg to 2 mg as needed) every 4 hours (around-the-clock) and allowed one rescue dose of IR morphine (equal to one additional administration of the dosage taken at fixed times) for any episodic pain breakouts. Patients recorded time of administration and time taken to achieve partial or total relief of episodic pain breakout in daily diaries; in one study centre the diary was managed with the help of specialized medical attendants. Pain intensity and general wellbeing were assessed by a Numerical Rating Scale (NRS) and Karnofsky Performance Scale, respectively. Adverse events and sleep patterns were also recorded. Results: Of 85 patients (mean age years) enrolled, 14 experienced pain from non-cancer degenerative diseases, and 71 had cancer-related pain. Following stabilization of background pain, the intensity of daily pain improved; NRS decreased from baseline to day 14 for cancer (from 5.63 to 1.98) and non-cancer (from 8. to 1.) groups (both p <.1). Patients general wellbeing increased concomitantly. Around-the-clock therapy resulted in an immediate decrease in the number of intense episodic pain breakouts per day, with 11.8% of patients achieving total pain relief within 24 hours. The mean

2 5 Lo Presti et al. number of intense episodic pain breakouts per day decreased steadily in the cancer group, reaching significance at day 14 (p <.1 vs baseline). Moreover, the time to achieve partial and total pain relief of intense episodic pain breakouts improved significantly. Adverse events and sleep patterns improved over the 14-day observation period. Conclusions: Stabilization of background cancer-related or non-cancer pain with around-the-clock IR morphine therapy resulted in fewer intense episodic pain breakouts, which were more quickly managed with rescue-dose IR morphine, suggesting that end-dose pain should not be classified as BTP. Introduction Periodic exacerbations of chronic cancer-related pain represents one of the largest pharmacological challenges of today, owing to its devastating impact on patients. [1] The mechanisms of chronic pain are numerous and the type of pain, its localization, the emotional component and other variables influence the severity of each clinical case. Treatment of chronic pain and its exacerbations relies on many pharmacological agents, although opioids are considered the gold standard in the management of chronic cancerrelated pain. [2,3] Opioids are mistakenly considered a last frontier, as stated by numerous patients at our specialist consultation who lack acceptable pain control. Other patients, though having been informed of opioids as a treatment option, take insufficient doses, and others are treated with slow-release formulations with no background research on the optimal dose. In our experience, opioid dosages in patients are often established arbitrarily with no regard to individual analgesic dose-response curves. Such an approach can generate a misinterpretation of background pain exacerbations as breakthrough pain (BTP) [with BTP defined as a transient flare of pain despite the management of chronic pain with opioids [4] ] and may lead to emergency treatment with inappropriate opioid dosages. Many authors have suggested strategies for the management of BTP. [5-8] The gradual start of therapy with fixed doses of morphine was shown to be efficient and well tolerated. [9-11] Moreover, the application of start therapy with fixed doses of immediate-release (IR) morphine followed by a rotation to slow-release opioids was shown to stabilize background pain, reduce the number of episodes of intense pain and provide rapid control of episodic pain breakouts with rescue doses; this strategy is relevant for both cancer and non-cancer patients. [11] Stabilization of background pain is imperative in order to avoid misdiagnosing episodic pain breakout as BTP, for example, where end-dose pain is often misdiagnosed as BTP. Despite stabilization of background pain, BTP is nevertheless a frequent clinical condition causing reduced quality of life and an increased use of medical resources. [3,12] In this regard, we selected both cancer and non-cancer patients who experienced intense episodic pain breakouts despite therapy with analgesics. The primary objective of this study was to assess the time needed to achieve a satisfactory analgesic response before and after background pain stabilization with IR morphine. We also aimed to emphasize that end-dose pain should not be classified as BTP. Methods This was a prospective, open-label, noncomparative, multicentre study. Patients were managed on an outpatient or ambulatory basis at the Pain Medicine and Intensive-Care Unit, San Filippo Neri Hospital, Rome and the Pain Therapy Unit, San Carlo di Nancy, Rome, and on an inpatient basis at the Intensive-Care Antalgic Therapy Hospice Unit, San Camillo de Lellis Hospital, Rieti.

3 Pain Relief with IR Morphine 51 Patients This study consecutively enrolled patients with moderate-to-severe pain due to cancer or to noncancer degenerative diseases (i.e. degenerative osteoarticular) from September to December 29. Male and female patients, who were receiving pharmacological treatment but experiencing two or more intense episodic pain breakouts per day, were selected for inclusion in the study. Patients had to be over the age of 18 years, have a mean pain intensity of >4 on the previous day as assessed by a Numerical Rating Scale (NRS) [NRS from to 1, where = no pain and 1 = maximum pain] and be able to express their state of pain and the effects of analgesic therapy. The Karnofsky Performance Scale (KPS) index was used to assess a patient s general wellbeing, where 1%=perfect health and %=death. All patients provided written informed consent. Patients were assessed at baseline and on days 7 and 14 of the observation period. Treatment was aimed at stabilizing background pain and involved the oral administration of IR morphine sulphate (1 mg to 2 mg as needed) every 4 hours (six times a day, i.e. around-the-clock). For each episode of intense pain breakout, the patient was allowed to take one rescue dose of IR morphine (equal to one additional administration of the dosage taken at fixed times). Constipation prevention therapy was prescribed at baseline. Patients were asked to record the time of administration and time needed to achieve partial (reduction of NRS by 5% with respect to baseline) or total relief of the episodic pain breakout in their personal diaries from the start of treatment (day 1) to the end of the 14-day observation period. Administration of this scheme was accompanied by detailed instructions for patients (or caregivers). The diaries of inpatients at the Intensive-Care Antalgic Therapy Hospice Unit, San Camillo de Lellis Hospital, Rieti, were managed with the help of specialized medical attendants, who helped the older patients with diary entries and were specifically dedicated to the study. During the study, information on adverse events and sleep patterns was also recorded on the clinical report form. Statistical Analysis Data were collected and stored in a relational database that was appropriately designed and structured with Microsoft Access 27, in accordance with clinical-therapeutic items and methodologies foreseen by the protocol. Information boxes concerning the basal assessment, follow-up visits and patient diaries were created. The paper forms received were compiled onto the database master file. After a quality analysis, univariate and bivariate descriptive analyses were conducted to obtain frequency distributions, means and standard deviations. Select queries were produced using longitudinal data (from baseline to the last follow-up visit, or throughout the 14-day diary entries) which were exported to SPSS version 1., a statistical application used to perform multivariate and inferential analyses to identify statistical significance. Chi-square tests were performed for bivariate analyses of dichotomic items and Student s t-distribution and ANOVA tests for quantitative items. A p-value of <.5 was considered significant. Results In total, 85 patients (42 inpatients and 43 outpatients) were enrolled (48 males and 37 females; mean SD age years). Fourteen patients experienced pain from non-cancer degenerative diseases and 71 had cancer-related pain (35 with metastasis). Analgesic therapy prior to study entry included opioids, as monotherapy or in combination with other analgesics such as nonsteroidal anti-inflammatory drugs or paracetamol. Fifteen patients died during the study (all were inpatients at the Intensive-Care Antalgic Therapy Hospice Unit in Rieti), leaving 7 patients to complete the 14-day study. At baseline (day 1 of the observational period), patients experienced approximately 2.6 episodes of intense pain breakouts per day. The mean SD daily dosage of oral IR morphine sulphate administered for stabilizing background pain was mg. The mean dosage of oral IR morphine sulphate administered for each episodic

4 52 Lo Presti et al. Mean NRS Baseline Day 7 Day 14 Cancer Non-cancer Fig. 1. Mean daily pain levels, assessed by a Numerical Rating Scale (NRS), at baseline and days 7 and 14 in cancer and noncancer patients. p <.1 vs baseline. pain breakout was mg during the 14-day observation period. Overall, the mean SD daily pain NRS score at baseline was , with a mean of for cancer patients and 8..5 for patients with non-cancer degenerative diseases. Pain levels decreased significantly at days 7 and 14 for cancer and non-cancer patient groups (all p <.1 vs baseline) [figure 1]. The overall mean SD KPS index at baseline was 59.7% 36.4%; patients from clinical practice and those in hospice care had a mean SD KPS index of 65.5% 15.1% and 25.7% 13.1%, respectively. The KPS index increased from 63.% to 69.1% (p-value not statistically significant) and from 42.5% to 82.5% (p <.5) for cancer and non-cancer patient groups from baseline to day 14, respectively (figure 2). There was an immediate decrease in the number of episodic pain breakouts after 1 day of treatment with IR morphine; 1 of the 85 patients experienced total relief with no outbreaks of pain during the first 24 hours of treatment. Six of these patients had no pain outbreaks for the remainder of the study period, while four patients had one or two episodic pain breakouts during the study period. Of the 75 patients (88.2% of the enrolled population) who did not have total pain relief on the first day of treatment, 21 of 62 (33.9%) patients with cancer-related pain reported an average of 1.5 episodes of episodic pain breakouts daily, while only one patient from the non-cancer group experienced an episodic pain breakout throughout the observation period. In the cancer group, the mean number of episodic pain breakouts per day decreased steadily, reaching significance at day 14 compared with baseline (p <.1) [figure 3]. On day 1, the time to pain relief onset was on average 16 minutes for a reduction of 5% of pain (partial pain relief) and 4 minutes for total pain relief, according to an evaluation of patient daily diaries. From day 2, the mean response time to the single rescue doses decreased even further, reaching significance for days 6, 7, 1, 12, 13 and 14 compared with day 1 (all p <.5); all times p <.1 versus day 1 for both total and partial pain relief (figure 4). Night-time rest improved noticeably in patients who were treated. Indeed, compared with baseline, all 85 patients reported improved satisfaction levels with sleep patterns after treatment was completed. Only 37 patients (33 cancer patients and 4 non-cancer patients) correctly completed entries for sleep satisfaction in their daily diaries; while the majority of these patients were dissatisfied with sleep patterns at baseline, almost 6% were very satisfied with sleep patterns after 14 days treatment (figure 5). The incidence of adverse events, consistent with opioid use, decreased from baseline to the end of the observation period, and there were no discontinuations due to adverse events (figure 6). Mean KPS Baseline Day 7 Day 14 Cancer Non-cancer Fig. 2. Mean Karnofsky Performance Scale (KPS) index at baseline and days 7 and 14 in cancer and non-cancer patients. p <.5 vs baseline.

5 Pain Relief with IR Morphine 53 Mean number of episodes Discussion Baseline Day 7 Day 14 Cancer Fig. 3. Mean number of intense episodic pain breakouts per day in cancer patients. p <.1 vs baseline. Our data, collected from cancer and noncancer patients, suggest that stabilization of background pain with fixed doses of IR morphine sulphate improved patients daily mean pain intensity and general wellbeing and decreased the number of episodic pain breakouts that cannot be defined as BTP but as underlying pain due to inadequate treatment. Cancer patients are likely to have a history of experiencing episodes of intense pain, which may not be questioned as long as they are classified as true BTP, as defined by Portenoy and Hagen. [4] As mentioned previously, [2] confusion is also generated by the fact that in some countries the term breakthrough pain is translated as episodic pain or transitory pain. In addition, it must be noted that most pain episodes appear as incident pain (55%), followed by a lower percentage of cases in which pain is idiopathic (27%) or enddose (29%). [4] Therefore from a practical point of view, it is important to consider the predictability of episodic pain and to identify the situations that provoke pain appearance (predictable incident pain or end-dose pain) with clinical anamnesis and detailed pharmacology. This could provide precise indications for the adjustment of base therapy and prevent incident pain with a rescue dose. At other times (idiopathic or spontaneous pain) it is difficult to predict pain appearance; therefore, the use of immediate-release drugs with a limited effect is helpful when combined with a stabilized base therapy. As shown in the current study, a residual number of pain episodes persist despite stabilization therapy with fixed-dose around-the-clock therapy of oral IR morphine sulphate; 74.1% of enrolled patients had no episodic breakthrough pain at the end of the observation period. Therefore, 25.9% of patients could have benefited from a further increase in daily dose of morphine; however, it was judged best to manage the single 45 4 Partial pain relief Total pain relief 35 3 Time (min) Day Fig. 4. Time to achieve partial and total pain relief of intense episodic pain breakouts following administration of rescue-dose IR morphine. p <.5 for days 6, 7, 1, 12, 13, 14 vs day 1 for pain relief onset; all times p <.1 vs day 1 for both total and partial pain relief.

6 54 Lo Presti et al. episodic pain with an extra dose of IR morphine when needed, given that patients had already obtained a significant reduction of median pain level, a net improvement of sleep patterns, an analgesic effect within a few minutes from rescue dose administration and a good level of tolerability. This holds true for cancer patients owing to the many drugs taken simultaneously, thus putting them at risk of pharmacological interactions once they exceed the minimum interacting dose of opioid. [13] While our data are not conclusive, yet based on recent studies, [9-11] we show here that oral administration of IR morphine for start therapy in a clinical setting provides a good level of background pain control, normalizes the frequency of episodic pain, reduces the relief time after each rescue dose and improves sleep. Hence, IR morphine sulphate administered orally allows faster onset of pain relief for episodic pain breakouts, when background pain is adequately treated; this could explain the different data provided by other authors. [14,15] We are convinced that end-dose pain cannot be considered as BTP, but must be seen as illcontrolled background pain. Therefore, it is common agreement that incorrect use of more potent therapies could lead to over-medication, an escalation of the posology needed to treat BTP, increased adverse effects and episodes of hyperalgesia from opioids. [16] Percentage of patients Baseline Day 14 Dissatisfied Satisfied Very satisfied Fig. 5. The proportion of patients with satisfaction of sleep patterns at baseline and after 14 days treatment. Data are from 37 patients who correctly completed entries for sleep satisfaction in their daily diaries Proportion of patients Nausea Vomiting Moreover, we would like to mention a practical aspect deemed essential for better management of chronic pain and its recrudescence. This aspect is characterized by the involvement of a nurse or caregiver, who, in the current study, allowed proper management of patient diaries; when specialized medical attendants were involved, patients exerted a greater will to fill out their diaries more precisely and properly. This is fundamental if there is to be an accurate interpretation of around-the-clock therapy. However, the completion of diaries, which absorbs many resources and excessive time, may seem to be a mere auxiliary instrument to the clinician. Nonetheless, our study has detected that greater attention placed on administration and patient diary processing yields increased compliance and reliability of collected data. Limitations of this study include the small number of patients included; hence, larger clinical studies are necessary to confirm our results. Conclusions Mental confusion Constipation Gastralgia Baseline Day 14 Other Fig. 6. Frequency (in %) of adverse events at baseline and after 14 days treatment. We have shown here that stabilization of cancer-related or non-cancer pain with aroundthe-clock IR morphine therapy resulted in fewer episodic pain breakouts, which were more quickly managed with rescue doses of IR morphine, suggesting that end-dose pain should not be classified as BTP.

7 Pain Relief with IR Morphine 55 Acknowledgements The authors have no conflicts of interest relating to the contents of this article; no external funding was received. English-language and editorial assistance for the preparation of this article was provided by Melanie Gatt of inscience Communications, a Wolters Kluwer business, and was funded by Molteni Farmaceutici, Inc. We thank Ennio Sarli (Centro Consulenze, Florence, Italy) for data management and Cristina Camisola (Intensive Care Antalgic Therapy Hospice Unit, San Camillo de Lellis Hospital, Rieti, Italy) for coordinating the nurses who participated in this study. References 1. Zeppetella G. Impact and management of breakthrough pain in cancer. Curr Opin Support Palliat Care 29 Mar; 3 (1): Hanks GW, Conno F, Cherny N, et al. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer 21 Mar 2; 84 (5): Zeppetella G, Ribeiro MD. Opioids for the management of breakthrough (episodic) pain in cancer patients. Cochrane Database Syst Rev 26; (1): CD Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalence and characteristics. Pain 199 Jun; 41 (3): Mercadante S, Radbruch L, Caraceni A, et al. Episodic (breakthrough) pain: consensus conference of an expert working group of the European Association for Palliative Care. Cancer 22 Feb 1; 94 (3): Bennett D, Burton AW, Fishman S, et al. Consensus panel recommendations for the assessment and management of breakthrough pain. Part 2: management. P & T 25; 3 (6): Davies AN, Dickman A, Reid C, et al. The management of cancer-related breakthrough pain: recommendations of a task group of the Science Committee of the Association for Palliative Medicine of Great Britain and Ireland. Eur J Pain 29 Apr; 13 (4): Casuccio A, Mercadante S, Fulfaro F. Treatment strategies for cancer patients with breakthrough pain. Expert Opin Pharmacother 29 Apr; 1 (6): De Conno F, Ripamonti C, Fagnoni E, et al. The MERITO Study: a multicentre trial of the analgesic effect and tolerability of normal-release oral morphine during titration phase in patients with cancer pain. Palliat Med 28 Apr; 22 (3): Ripamonti CI, Campa T, Fagnoni E, et al. Normal-release oral morphine starting dose in cancer patients with pain. Clin J Pain 29 Jun; 25 (5): Gatti A, Reale C, Occhioni R, et al. Standard therapy with opioids in chronic pain management: ORTIBER study. Clin Drug Investig 29; 29 Suppl. 1: Fortner BV, Okon TA, Portenoy RK. A survey of painrelated hospitalizations, emergency department visits, and physician office visits reported by cancer patients with and without history of breakthrough pain. J Pain 22 Feb; 3 (1): Geppetti P, Benemei S. Pain treatment with opioids: achieving the minimal effective and the minimal interacting dose. Clin Drug Investig 29; 29 Suppl. 1: McCarberg BH. The treatment of breakthrough pain. Pain Med 27 Jan-Feb; 8 Suppl. 1: S Zeppetella G. Opioids for cancer breakthrough pain: a pilot study reporting patient assessment of time to meaningful pain relief. J Pain Symptom Manage 28 May; 35 (5): Jumbelic MI. Deaths with transdermal fentanyl patches. Am J Forensic Med Pathol 21 Mar; 31 (1): Correspondence: Dr Claudio Lo Presti, San Filippo Neri Hospital, Via Giovanni Martinotti 135 Rome, Italy. clopclop@tiscali.it