Opioid Escalation in Patients with Cancer Pain: The Effect of Age

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1 Vol. 32 No. 5 November 2006 Journal of Pain and Symptom Management 413 Original Article Opioid Escalation in Patients with Cancer Pain: The Effect of Age Sebastiano Mercadante, MD, Patrizia Ferrera, MD, Patrizia Villari, MD, and Alessandra Casuccio, BS Anesthesia & Intensive Care Unit and Pain Relief and Palliative Care Unit (S.M., P.F., P.V.), La Maddalena Clinic for Cancer, Palermo; and Departments of Anesthesiology, Intensive Care & Emergencies (S.M.), and Ophthalmology (A.C.), University of Palermo, Palermo, Italy Abstract Elderly people are commonly considered more susceptible to opioid effects. However, no data regarding the need for opioid escalation in patients already receiving opioids for the management of chronic pain are available. The purpose of this study was to evaluate the differences between younger and older patients during the crucial phase of opioid titration. One hundred consecutive patients with cancer pain requiring further opioid dose refinement were recruited for this cohort study. Pain intensity, dose of opioids, number of opioids used (need to switch), routes of administration used, and opioid-related symptoms were measured from admission until dose stabilization. Opioid escalation indexes (OEIs) were calculated. For the purpose of analysis, patients were divided into three age groups (<65, 65e74, 75 or over). Despite differences in opioid doses at admission (lower in older patients), no differences were found in routes, need to switch, OEI, or other parameters between younger and older patients. Similarly, adverse effects did not significantly differ between the three groups, although an overall distress score worsened in older patients during acute titration and then improved at stabilization time. These data contradict the assumption that older patients who already receive opioids are more susceptible than younger adults to opioid effects during opioid titration. Although the elderly require lower doses, opioid effects do not appear to vary with age in this population. However, the group of patients over 75 was relatively small and data should be interpreted with caution. Careful titration based on the individual response seems appropriate irrespective of age. J Pain Symptom Manage 2006;32:413e419. Ó 2006 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Cancer pain, elderly, opioid titration Address reprint requests to: Sebastiano Mercadante, MD, Anesthesia & Intensive Care Unit and Pain Relief and Palliative Care Unit, La Maddalena Cancer Center, Palermo, Via san Lorenzo 312, Palermo, Italy. terapiadeldolore@la-maddalena.it Accepted for publication: May 11, Ó 2006 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved. Introduction As the world population ages, cancer care will become increasingly important and symptom palliation may be the primary objective of cancer treatment for many. More than 70% of cancer patients develop cancer-related pain during the course of their illness. 1 Furthermore, prevalence rates for chronic noncancer pain increase with age in the general /06/$esee front matter doi: /j.jpainsymman

2 414 Mercadante et al. Vol. 32 No. 5 November 2006 population, and the elderly cancer patient may have different types of pain, often associated with comorbidities typical of advanced age. Regrettably, palliative care is made available increasingly later in the aged population, 2 and pain in the elderly has only recently begun to receive serious consideration. Elderly patients, like minority populations, are less likely than younger adults to receive proper pain management. 1 Pain in older adults may not be treated or even assessed because they are less likely to report it, or because clinicians are hesitant to prescribe analgesics due to concerns about troublesome adverse effect profiles, possibly combined with polypharmacy in a frail elder. 3 It is generally accepted that older patients are more sensitive to all drug effects, including adverse drug reactions. 4 However, a broad range of responses to pain control medications exists, as a result of individually different cell and tissue-specific patterns of gene expression. Elderly adults also demonstrate a slight increase in pain threshold and a moderate to substantial decrease in pain tolerance. 5,6 Opioids are the mainstay of cancer pain management. Patients with cancer pain often require opioid escalation to maintain opioid efficacy. The need for escalating opioid doses may be due to progression of disease, the development of opioid tolerance, or a multitude of other factors that may play a role on an individual basis. 7 The need for increasing doses of opioids may reflect a critical phase in the treatment of cancer patients with pain, 8 and there may be considerable concern about this need in older patients who are potentially more susceptible to the development of adverse effects due to age-related changes in pharmacokinetics. However, cancer pain is a complex issue and multiple factors may lead to unpredictable individual responses in any specific clinical situation. The aim of this study was to evaluate the responses in older and younger patients who are already receiving opioids for cancer pain and experience the need to escalate opioid doses. Patients and Methods A prospective cohort study was carried out in a sample of 100 consecutive patients who were already receiving opioids and were admitted to an acute palliative care unit for inadequate pain control (considered as pain intensity >4 on a numerical scale from 0e10). Informed consent and institutional approval were obtained. Inclusion criteria were aged >18 years and an expected survival for longer than one month. The exclusion criterion was the inability to gather data from patients due to cognitive failure or important biochemical abnormalities. The management of pain and other symptoms followed a standard protocol. Through opioid titration, patients with poor analgesia had their dosage increased until pain subsided or toxicity developed. Opioid doses were titrated according to the pain level and clinical response. To control dose-related toxicity and allow for optimal titration of opioids, hydration, changes of routes, and opioid switching were used. According to department policy, the conversion ratios used among opioids and routes of administration were as follows: oral morphine 100 ¼ intravenous morphine 33 ¼ TTS fentanyl 1 ¼ intravenous fentanyl 1 ¼ oral methadone 20 ¼ intravenous methadone In cases of switching to another opioid, initial opioid doses after conversion were changed according to the clinical response. Drugs previously administered to control symptoms due to illness or treatment were continued or changed according to the clinical needs. Nonopioid analgesics were also continued if previously administered, at the same doses. No patient received anticancer therapy during the course of the study. All patients were strictly monitored with frequent daily rounds by a team consisting of doctors and nurses experienced in symptom management. Daily doses were changed, according to the amount of drugs consumed as rescue doses in the previous day and clinical judgment, to achieve the best balance between acceptable analgesia with minimal adverse effects. Number of opioids used, routes and doses (expressed as oral morphine equivalents) and the following data were recorded: Gender, primary cancer, known metastases, pain causes and mechanisms, and performance status. The pain syndromes were considered on the basis of clinical history, anatomical site of primary tumor and

3 Vol. 32 No. 5 November 2006 Opioid Escalation and Age 415 known metastases, physical examination, and investigations when available. Pain intensity, measured using the patient s self-report on a numerical 0e10 scale, and symptoms associated with opioid therapy or commonly present in advanced cancer patients, such as nausea and vomiting, drowsiness, confusion, weakness, or dry mouth. Symptoms were measured using a scale from 0 to 3 (not at all, slight, a lot, awful), as assessed by the patient. Symptoms were recorded as follows: intensity at admission (T0), the worst intensity during opioid titration (T1), and symptom intensity at time of hospital discharge (T2). A distress score (DS) was also calculated as a sum of symptom intensity (nausea and vomiting, drowsiness, confusion, weakness, and dry mouth). Opioid escalation index (OEI), in milligrams or as percentage, was calculated from the initial dose at admission until time of dose stabilization, according to the following formula: OEI%: [(x y)/ 1]/days 100, where x is dose at stabilization and y is the dose at admission, both expressed as equivalents of oral morphine. OEImg was (x y)/days. Dose stabilization was considered as the planned daily dose requiring no more than two rescues as needed. The first of two days with a stable dose was considered as time of stabilization. Statistical Analysis For analysis, patients were then divided in three groups: under 65 years (Group 1), 65e74 years (Group 2), and 75 years old or over (Group 3), respectively. Frequency analysis was performed with Chi-squared test. The paired Wilcoxon signed-rank test was used to compare pain intensity scores and symptom intensity scores in the time periods. The paired samples Student s t-test was used to compare opioid mean dose in the time periods. The one-way analysis of variance and Mann-Whitney U statistic test were used for parametric and nonparametric analysis, respectively. All P values were two-sided and P values less than 0.05 were considered to indicate statistical significance. Data were analyzed by the Epi Info software, version (Centers for Disease Control and Prevention) and the Systat Software 8.0 version (SPSS, Inc.). Results One hundred consecutive patients with uncontrolled pain were considered. Five patients had incomplete data. Fifty-eight were under 65 years, 27 patients were 65e74 years old, and 10 were 75 years old or over. No differences in primary tumors; Karnofsky status; gender; metastases sites; type and route of administration of opioids at admission, during titration phase, and at stabilization time; and other adjuvant drugs and doses used were observed. In Group 1, the mean opioid dose at admission and the mean dose at stabilization (expressed as oral morphine equivalents) were 175 mg (95% CI 107e244) and 270 mg (95% CI 188e353), respectively. In Group 2, the same parameters were 159 mg (95% CI 44e274) and 173 mg (95% CI 72e274), respectively, and in Group 3, the values were 44 mg (95% CI 0e105) and 86 mg (95% CI 7e165), respectively. Data on patient characteristics, time to achieve opioid dose stabilization, admission time, changes in dose, route, or drugs, OEI%, and OEImg calculated from admission (T0) until the time of dose stabilization (T1) and time of hospital discharge (T2) are reported in Table 1. Although the doses at stabilization were significantly lower in Group 2 and in Group 3, no statistical differences were found between the three groups in OEI, changes in doses, or routes of administration. No differences in the number of changes in opioids or routes of administration required were found among the three groups: 3.1 (95% IC 2.5e3.6), 3.2 (95% IC 2.2e4.1), and 3.0 (95% IC 1.7e4.2), respectively. Data on changes of opioids or routes of administration are presented in Table 2. No differences in opioid doses at the intervals examined or OEI were found among the groups, when considering the number of changes in opioids or routes of administration used (Table 3). In all the groups, the highest number of changes of opioids or routes used, the longest time to find the final dose, or the longest time of hospital stay (P < 0.01). Pain mechanisms did not

4 416 Mercadante et al. Vol. 32 No. 5 November 2006 Table 1 Patient Characteristics, Days Required to Reach Dose Stabilization, Hospital Stay, Number of Therapeutic Changes, OEI%, and OEImg in the Three Groups Group 1 Group 2 Group 3 P Patients Age 51.9 (49e54) 69.5 (68e71) 78.6 (76e81) Karnofsky 47.8 (46e49) 44.8 (41e48) 46.5 (42e51) Stabilization (days) 3 (2.3e3.6) 2.6 (1.7e3.4) 2.5 (1.3e3.6) Discharge (days) 5.2 (4.5e6) 5.5 (4.4e6.6) 5.3 (3.9e6.7) Changes (drug-route-dose) 3.1 (2.5e3.6) 3.2 (2.2e4.1) 3.0 (1.7e4.3) OEI% (dose-finding) 47 (21e72) 12 ( 5e30) 28 ( 77e134) OEImg (dose-finding) 25 ( 1e52) 7 ( 23e37) 16 (0e32) influence the parameters examined or the number of changes in opioid or routes. No gender differences among the three groups in parameters taken into consideration were found. No specific differences were found in the worse symptom intensity measured during the titration phase among the three groups. Although DS significantly worsened in comparison with admission values at time of dose stabilization, a significant improvement in DS was observed in all groups (Table 4). Discussion Many variables have been examined in terms of pain management outcomes in the cancer population. Age, however, has seldom been investigated. In particular, the relationship between age and opioid response in patients receiving opioids and undergoing opioid titration for uncontrolled pain has never been assessed. Data from this study contradict the assumption that older patients are more susceptible to opioid effects than younger adults, at least in the acute setting of opioid titration in opioid-tolerant patients. Although the doses were lower in older patients, opioid response did not differ between younger and older patients, as determined by dose escalation, number of opioids, or routes of administration necessary to optimize the balance between analgesia and adverse effects in the clinical setting. Adverse effects developed in a similar way, although in older patients the DS score worsened during titration to return to previous value at time of stabilization. Information gathered from different settings, while offering different evaluations, has substantially demonstrated the large individual variability in opioid response. This variation reduces the influence of age. In postoperative pain, age was the best predictor of morphine requirement in the first 24 hours, but the wide interpatient variation in further dose requirements suggested that subsequent doses still had to be titrated according to the effect of morphine. 10 In the long-term monitoring of the opioid response in advanced cancer patients followed at home, advanced age was associated with lower opioid doses, but with similar adverse effects. 11,12 However, the setting of patients already receiving opioids and requiring an increase in dose is unique and no data from an identical scenario to compare with the present findings exist. In a setting similar to that of this study, elderly cancer patients required Table 2 Frequency of Opioid Switching and Number of Opioids Used in the Three Groups Number of Changes in Opioid or Route Used No Changes a One Change Two Changes Three Changes Total Group 1 34 (58.6%) 19 (32.7%) 4 (6.9%) 1 (1.7) 58 Group 2 16 (59.2%) 6 (22.2%) 3 (11.1%) 2 (7.4%) 27 Group 3 5 (50%) 5 (50%) Total 55 (57.9%) 30 (31.5%) 7 (7.3%) 3 (3.1%) 95 a Titration of the same opioid using the same route.

5 Vol. 32 No. 5 November 2006 Opioid Escalation and Age 417 Table 3 Opioid Doses a at Admission, Initial Titration Doses, and Final Doses (Stabilization) in the Three Groups, Depending on the Number of Opioids Used No Change One Change Two Changes Three Changes Group 1 (58 patients) n ¼ 34 n ¼ 19 n ¼ 4 n ¼ 1 Previous dose 173 (65e281) 203 (112e294) 67 ( 30e165) 180 Final dose 266 (145e387) 290 (153e428) 165 (82e247) 450 Group 2 (27 patients) n ¼ 16 n ¼ 6 n ¼ 3 n ¼ 2 Previous dose 118 ( 12e248) 92 (8e177) 600 ( 766e1966) 30 (30) Final dose 173 (13e334) 131 (10e253) 317 ( 404e1038) 75 ( 116e266) Group 3 (10 patients) n ¼ 5 n ¼ 5 d d Previous dose 12 ( 21e45) 76 ( 66e219) Final dose 54 ( 34e142) 118 ( 55e292) a Expressed as morphine equivalents in mg: mean and CI 95%). a lower amount of opioids than adults, while obtaining similar pain relief. However, at Day 7, which more or less should correspond to the end of opioid titration, no differences between older and younger people were found, confirming the results of the present study. 13 Substantial interindividual variation in opioid requirements in advanced cancer patients was confirmed. Unfortunately, these data are not fully comparable, as the records were reviewed retrospectively and opioid doses at Day 7 seem to be similar to doses recorded at Day 2. As initial doses at admission are not reported, it also is difficult to establish true opioid escalation. In a similar setting, no single parameter, including age, convincingly predicted the opioid consumption and the pain outcome during the first week of specialized palliative care. 14 Both age-related pharmacokinetic and pharmacodynamic factors have been claimed to explain the presumed decrease in opioid requirements in the elderly. 15 Changes in drug metabolism, protein binding, distribution, and clearance associated with aging may result in a diminished rate of elimination, thereby amplifying drug effects. In contrast to these pharmacokinetic effects, however, pharmacodynamic data have rarely been explored. A tendency for tolerance to be more prominent in the younger groups than in the elderly groups has been claimed. In animal models, enhanced molecular and cellular neuroplasticity in younger neurons would allow for a more rapid development of tolerance to opioids compared to older neurons. 16 Aging also may affect the function of molecular substrates thought to play critical roles in the development of opioid tolerance. 17 In a retrospective analysis of chronic pain patients, age was an important variable in opioid-dose escalation. 18 However, in studies dealing with the pharmacodynamic effects of opioids in the elderly, the rate of drug delivery rather than the absolute dose over time influenced both analgesia and adverse effects. 19 This is even true in patients with evolving pain syndromes who were already receiving opioids and required dose increments to achieve better pain relief. Moreover, the relationship between progression of disease, changes in neuroplasticity, and opioid-receptor activity is more complex in cancer patients than in animals or the noncancer population. 20 The complex network of factors involved in the opioid response make the evaluation of a single element, such as age, more difficult. 7 Moreover, some investigations have reported age-related differences in Table 4 Distress Scores in the Three Groups Group 1 Group 2 Group 3 Admission 5.4 (4.6 to 6.2) 6.3 (5.0 to 7.6) 3.2 (1.6 to 4.8) The worst during titration 6.0 (5.1 to 6.8) 7.3 (5.9 to 8.7) 5.7 (3.8 to 7.6) a Discharge 3.4 (2.8 to 4.1) b,c 4.5 (3.2 to 5.7) b,c 3.2 (1.3 to 5.1) c a P < 0.01 (T0 vs. T1). b P < 0.01 (T0 vs. T2). c P < 0.01 (T1 vs. T2).

6 418 Mercadante et al. Vol. 32 No. 5 November 2006 endogenous pain modulation and diminished tolerance for certain types of experimental pain models among the elderly. Older adults demonstrated facilitation rather than inhibition during painful stimulation, suggesting decrements in endogenous analgesic response. 21 It is commonly reported that an increased risk of drug reactions occurs in older patients and the risks rise as the number of medications increases. 3 Evidence suggests that sensitivity to drugs in the central nervous system increases with age. 15 Of interest, symptom intensity did not differ among groups. This finding was unexpected, given the presumed vulnerability of older patients. Thus, these effects could be mitigated in tolerant patients already receiving opioids. Careful titration associated with an appropriate use of symptomatic drugs also may improve the opioid response, both in younger adults and older patients. This is also confirmed by the finding of similar numbers, routes, and doses of opioids used for switching in case of unfavorable responses, in most cases due to the development of adverse effects. In a similar population, no association between age and cognitive failure (one of the most feared adverse effects in the elderly) was found. 22 In a previous study, opioid-related adverse effects recorded among older patients during longterm monitoring were similar in intensity to those observed in younger patients. 23 On the other hand, a decrease in pain intensity induced by opioid titration does not necessarily produce changes in symptoms, as their intensity could be positively balanced by the indirect benefit of pain control on some symptoms. 24,25 These findings were confirmed in this study, where a tendency to worsened DS was observed during opioid titration in both groups (more intense in older patients), followed by a subsequent improvement in DS at the time of stabilization in both groups, at an even better level compared to admission values. There are some limitations to this study. Patient recruitment was consecutive and not matched in a randomized way, so that the distribution of data in the three groups was not uniform. On the other hand, this approach was chosen to reflect the clinical setting so that the outcomes obtained should have a real and practical impact and should be more reproducible. It is possible that differences would have appeared in a larger group of patients. However, data also showed that time for stabilization and discharge, as well as adverse effects intensity, expressed as DS, are quite similar after opioid titration, thereby confirming that older patients present similar responses to titration at different levels of dosage. Many older patients are treated within community hospitals, where anticancer therapies are less likely to be given and the palliation of symptoms should be of primary importance. Unfortunately, many patients are not referred to supportive care teams. Many physicians are reluctant to prescribe appropriate doses of opioids to the elderly because of the fear of adverse effects and the belief that this population certainly requires less opioid to achieve analgesia. This hesitation could result in undertreatment in a group of minority patients, such as older patients, who are already at risk because they are poorly assessed and often do not report pain complaints. 1 As in younger people, many factors influence the need for opioid escalation in unpredictable ways. Though older patients require careful opioid titration to limit the consequences of the well-known reduced pharmacokinetic capabilities, and more attention should be paid to the development of adverse effects, they should not be labeled as more responsive to opioids, either for analgesia or adverse effects, and require individualization of opioid doses during titration just as younger patients. References 1. Cleeland C, Gonin R, Hatfield AK, et al. Pain and its treatment in outpatients with metastatic cancer. N Engl J Med 1994;330:592e De Conno F, Boffi R, Brunelli C, Panzeri C. Age-related differences in patients admitted to a palliative home care service. Tumori 2002;88:117e Gloth FM. Geriatric pain. Factors that limit pain relief and increased complication. Geriatrics 2000; 55:46e Portenoy RK. Optimal pain control in elderly cancer patients. Geriatrics 1987;42:33e Gagliese L, Melzack R. Chronic pain in elderly people. Pain 1997;70:3e Gibson SJ, Helme RD. Age-related differences in pain perception and report. Clin Geriatr Med 2001;17:433e456.

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