Use of Strong Opioids in Advanced Cancer Pain: A Randomized Trial

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1 Vol. 27 No. 5 May 2004 Journal of Pain and Symptom Management 409 Original Article Use of Strong Opioids in Advanced Cancer Pain: A Randomized Trial Franco Marinangeli, MD, Alessandra Ciccozzi, MD, Marco Leonardis, MD, Luca Aloisio, MD, Anna Mazzei, MD, Antonella Paladini, MD, Giampiero Porzio, MD, Paolo Marchetti, MD, and Giustino Varrassi, MD Departments of Anesthesiology and Pain Medicine (F.M., A.C., M.L., L.A., A.M., A.P., G.V.), and Oncology (G.P., P.M.), University of L Aquila, L Aquila, Italy Abstract The World Health Organization (WHO) guidelines for the treatment of cancer pain recommend nonopioid analgesics as first-line therapy, so-called weak analgesics combined with nonopioid analgesics as second-line therapy, and so-called strong opioids (with nonopioid analgesics) only as third-line therapy. However, these guidelines can be questioned with regard to the extent of efficacy as well as the rationale for not using strong opioids as first-line treatment, especially in terminal cancer patients. The purpose of this randomized study was to prospectively compare the efficacy and tolerability of strong opioids as first-line agents with the recommendations of the WHO in terminal cancer patients. One hundred patients with mild moderate pain were randomized to treatment according to WHO guidelines or to treatment with strong opioids. Evaluated outcomes included pain intensity, need for change in therapy, quality of life, Karnofsky Performance Status, general condition of the patient, and adverse events. No between-treatment differences were observed for changes in quality of life or performance status, but patients started on strong opioids had significantly better pain relief than patients treated according to WHO guidelines (P 0.041). Additionally, patients started on strong opioids required significantly fewer changes in therapy, had greater reduction in pain when a change was initiated, and reported greater satisfaction with treatment than the comparator group (P 0.041). Strong opioids were safe and well-tolerated, with no development of tolerance or serious adverse events. These data suggest the utility of strong opioids for first-line treatment of pain in patients with terminal cancer. J Pain Symptom Manage 2004;27: U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Oncologic pain, opioids, WHO guidelines Address reprint requests to: Franco Marinangeli, MD, Department of Anesthesiology and Pain Medicine, University of L Aquila, Piazzale S. Tommasi 1, L Aquila, Italy. Accepted for publication: October 13, U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved. Introduction Subsequent to the publication of the World Health Organization s (WHO) therapeutic ladder for the treatment of cancer pain 1 and its validation, 2 6 there has been criticism and debate regarding the evaluation and extent of efficacy of these guidelines. 7 With the emerging importance among physicians and patients of /04/$ see front matter doi: /j.jpainsymman

2 410 Marinangeli et al. Vol. 27 No. 5 May 2004 the need for more effective treatment of cancer pain, discussion among pain clinicians has focused on the appropriateness of initiating therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) or paracetamol (acetaminophen), as suggested by the WHO ladder, rather than on stronger analgesic agents such as opioids. Despite the known efficacy of opioids for cancer pain, there is only limited use of these drugs for this indication. The underutilization of opioids is in part based on the unsubstantiated fear by physicians, patients, and their families of opioid addiction and tolerance. Additionally, the strict regulation and control of these agents in most countries may present prescription difficulties, and legal problems arising from the actual or perceived abuse or addiction to these drugs can also contribute to their limited use. Consequently, it still occurs too often in the clinical setting that a terminal cancer patient presenting with strong pain is treated with massive doses of anti-inflammatory drugs or weak opioids. 8 The first two steps of the WHO guidelines are formally respected, but not the last one, thus raising the following issues regarding appropriate therapy: Is it reasonable to administer massive doses of NSAIDs or weak opioids in order to avoid strong opioids, thus achieving relative efficacy with a potentially greater incidence of side effects? What is the rationale for starting therapy in terminal patients with the weakest analgesic agents and avoiding the use of stronger more effective drugs? The purpose of this study was to try evaluate the use of strong opioids as first-line treatment in patients with terminal cancer and to compare this regimen with the recommended WHO guidelines that suggest the use of strong opioids only as third-line treatment. Methods The study was performed in accordance with the revised Declaration of Helsinki and the protocol was approved by the Ethics Committee of the study center involved. Both the physician and the patients were aware of the goals of the trial and written informed consent was obtained from each patient prior to enrollment and randomization. A total of 100 patients with a diagnosis of cancer, who were not eligible for disease-oriented treatment and were provided with home palliative care, were included in this open randomized study. The same oncologist defined the intractability of disease. In addition to the diagnosis of intractable cancer, inclusion criteria included a minimum age of 15 years and the presence of somatic or visceral pain having an untreated intensity of not greater than 6 on a 10 cm visual analogue scale (VAS; 0 no pain, 10 unbearable pain) over the last week. Exclusion criteria included the inability to perform follow-up, impaired sensory or cognitive function, and the use of strong opioids in a prior therapeutic step. Following a baseline evaluation, patients were randomly assigned to one of the two treatment groups. Patients in Group A were treated according to the WHO therapeutic ladder that utilizes nonopioid analgesics in Step I, so-called weak analgesics combined with nonopioid analgesics in Step II, and so-called strong opioids combined with nonopioid analgesics only in Step III. Patients assigned to Group B were immediately started on strong opioids, with dosages determined on a per case basis. The two treatment protocols were comparable because of the demonstrated efficacy of all the study drugs for VAS 6. In both groups, opioids could be combined with nonopioid analgesics. If immediate-release drugs were used, the evening dose was doubled in order to reduce the risk of nighttime pain breakthrough, and rescue medication in the form of higher dosage or additional drugs was available to treat incident pain. Co-analgesic drugs with indications different from pain were used in some cases because of a demonstrated efficacy in some painful syndromes. The choice of co-analgesic drugs was based on the specific characteristics of pain syndrome. The anticonvulsants, antidepressants, corticosteroids, bisphosphonates, and spasmolytic drugs were administered when neuropathic pain component, depression, edema associated with neoplastic lesion, osteolytic metastasis, and visceral spasms, respectively, were present. The predominance of neuropathic pain was a criterion for exclusion. Adjuvant drugs were prescribed for the treatment of cancer symptoms

3 Vol. 27 No. 5 May 2004 Use of Strong Opioids in Advanced Cancer Pain 411 or for the prophylaxis and/or treatment of side effects. A complete list of drugs used in the study is shown in Table 1. The least invasive route of administration (oral, transdermal patch) was always preferred, with subcutaneous or intravenous routes used only if necessary, such as in patients with dysphagia, persistent nausea and/or vomiting, ileus, or periods of transient mental distraction. The intrathecal route of administration was used only if oral or parenteral administration was ineffective or there were serious side effects not responsive to adjunctive therapy. In such cases, spinal opioids were combined with local anesthetics. If necessary, anesthetic and neurolytic blocks, psychotherapy, and physiotherapy were provided. Indications for neuroablative procedures were considered when pain was not controlled with noninvasive procedures or when the pharmacologic treatment was associated with intolerable side effects. In this case, the patient was excluded from the study. The necessity of palliative antineoplastic treatment (radiotherapy, Table 1 Analgesic, Co-Analgesic, and Adjuvant Drugs Used Drug Class Drug Systemic analgesics Nonopioids Weak opioids Strong opioids Co-analgesic drugs Anticonvulsants Antidepressants Corticosteroids Diphosphonates Spasmolytics Adjuvant drugs Antiemetics Anxiolytics Hypnotics Laxatives Prokinetics Neuroleptics paracetamol (acetaminophen) nimesulide diclofenac ibuprofen ketorolac codeine/acetaminophen tramadol buprenorphine fentanyl methadone morphine clonazepam carbamazepine gabapentin amitriptyline fluvoxamine dexamethasone pamidronate, butiscopolamine metoclopramide ondansetron diazepam flunitrazepam lactulose cisapride chlorpromazine haloperidol chemotherapy, hormonal therapy, or surgery) was assessed in collaboration with an oncologist. All patients were evaluated by the same pain clinician once a week, either as outpatients or, if the subject was not self-sufficient, during a home visit. The following parameters were evaluated at baseline, at each visit, and at any therapeutic change (change in drug or dosage): 1) patient s quality of life (QOL) by means of a multidimensional questionnaire; 9 2) side effects associated with treatment; 3) drug tolerability; 4) satisfaction with the analgesic treatment of the previous week (verbal report of satisfied or not satisfied in response to physician s query); and 5) Karnofsky Performance Status. 10 During periods of transient confusion, the QOL questionnaire and satisfaction score were omitted. Patients were also provided with a diary and requested to make a daily record of the following parameters:1) intensity of pain using a 10- cm VAS (0 no pain, 10 unbearable pain); 2) general condition using a 0 10-cm VAS (0 worst possible condition, 10 best possible condition); 3) occurrence of side effects or adverse events (the intensity was defined by a three point scale: 0 mild, 1 moderate, 2 severe); and 4) problems arising during the day. Only the side effects possibly linked to therapy and reported by the patients in their diary were registered by the pain physician. A responsible relative was also delegated the task of providing an evaluation on a daily basis in the same diary. The relative was requested to note his/her perception of the patient s overall condition on a 0 10-cm visual analogue scale (0 worst possible condition, 10 best possible condition). The study was considered concluded at the time of the patient death. Endpoints used to evaluate efficacy included: pain intensity (VAS), general condition (VAS), Karnofsky Performance Status, QOL, and patient satisfaction with the therapy of the previous week, number of weeks described as satisfactory, and incidence of therapeutic change. Data for the above endpoints were collected from the patient diary, records from the weekly visits, and at end of study. Mean values were obtained for the duration of treatment and were compared with baseline. Safety and tolerability were evaluated by comparing the type and incidence of side effects in the two groups, and discontinuation due to side effects.

4 412 Marinangeli et al. Vol. 27 No. 5 May 2004 Bivariate statistical analyses were performed by using chi-square and t-tests, as appropriate. P 0.05 was considered significant. Results Of the 100 patients enrolled, 8 were excluded (2 in Group A, 6 in Group B) for the following reasons: 3 patients (1 Group A, 2 Group B) for refusal to continue in the study; 2 patients (1 in each group) who underwent neuroablative therapy with subsequent pain resolution; 1 patient (Group B) who was lost to follow-up; and 2 patients (Group B) whose duration of treatment was less than 15 days. Thus, 48 patients who were treated according to the WHO guidelines (Group A) and 44 patients who were treated with strong opioids (Group B) are included in the analysis. The baseline demographic and disease characteristics of these patients are shown in Table 2; there were no significant differences between the two Table 2 Baseline and Disease Characteristics of Randomized and Treated Patients Group A Group B (n 48) (n 44) Age, years Mean SD Range Sex, % Male Female Diagnosis by organ system, % Respiratory Gastrointestinal/biliary Genito-urinary Musculoskeletal Primary site of pain, n Head/neck 2 1 Chest 7 5 Abdomen Back 12 7 Upper extremities 0 1 Lower extremities 8 9 Perineum 2 1 Duration of treatment, days mean ( SD) range Quality of life mean SD Karnofsky Performance Status Index, mean SD VAS pain score, mean SD groups. The cumulative evaluated weeks of treatment for all patients were 503 for Group A and 467 for Group B. The overall patient evaluation over the duration of treatment demonstrated significant reduction from baseline in Karnofsky Performance Status and disease-related QOL (Table 3). However, both treatment strategies resulted in significant improvements from baseline in pain intensity (VAS scores) (Table 3). Although these changes were similar in both treatment groups for QOL and performance status, firstline treatment with strong opioids (Group B) resulted in improvement in pain severity that was significantly better than that obtained in patients who were treated according to the WHO therapeutic ladder (Group A). Similarly, Group B was significantly superior to Group A for both the percentage of cumulative weeks that the patient defined treatment as satisfactory (85.6% vs. 80.5%, P 0.041), as well as for the percentage of cumulative weeks without a therapeutic change (48.9% vs. 59.3%, P 0.001) (Figure 1). The patient s general condition, assessed by the patients themselves using the VAS scale throughout the period of observation and recorded in the diary, was significantly better in Group B compared with Group A ( vs ; P 0.007). The condition of the patients in both groups according to the assessment by the responsible relative didn t show any statistically significant difference ( of Group B vs of Group A). The number of cumulative weeks during which a change in therapy was initiated was significantly lower in Group B (190 weeks) than in Group A (257 weeks; P 0.001). For Group A, 49.4% of the changes were drug switches, and 50.6% were changes in dosage. In contrast, Table 3 Mean Change from Baseline in the Overall Patient Evaluation Group A Group B P QOL ns Karnofsky ns Performance Status Pain intensity (VAS) Note: All changes reflect significant differences (P 0.05) from baseline; decreases in QOL and performance status indicate worsening condition, decrease in pain intensity indicates improvement.

5 Vol. 27 No. 5 May 2004 Use of Strong Opioids in Advanced Cancer Pain 413 Fig. 1. Percent of cumulative weeks that the patient defined treatment as satisfactory *P 0.041, and percent of cumulative weeks with no changes in therapy. **P Group B versus Group A. 96.3% of the changes in Group B were dosage changes, with only 3.7% of patients switching drugs (five patients switched from morphine to fentanyl and two patients switched from morphine to methadone). When a therapeutic change was initiated, both the pain intensity reported by the patient and the difference in the patient s general condition reported by the family member in the week after the change compared to the week before the change were significantly superior in Group B compared with Group A (Figure 2). In both groups, the change resulted in a significant reduction in pain intensity in the week after the change compared with the week prior to the change. However, only in Group B was there a significant improvement in the patient s general condition subsequent to the change in therapy (Figure 2). Several side effects considered to be related to therapy were reported by patients (Table 4). Of these events, only the incidence of nausea was significantly different between the two groups, being lower in Group A (315 episodes versus 437 episodes; P ). The type and mean dose of opioids being administered to patients at the time of death is shown in Table 5 for both groups. In the group treated using the WHO algorithm (Group A), half of the patients (48%) progressed to treatment with strong opioids. There wasn t any statistically significant difference in the dose of strong opioids required by the patients of both groups at the end of the study. No patients required any intrathecal analgesic administration or palliative antineoplastic treatment (radiotherapy, chemotherapy, hormonal therapy, or surgery). There were no statistically significant differences between the two study groups in the use of the co-analgesic drugs. No patient was treated with bisphosphonates. Discussion The problem in treating chronic pain, and cancer pain in particular, is not to finding effective therapies, but rather the appropriate choice and use of these therapies. All previous Fig. 2. Mean visual analogue scale scores (VAS) of pain intensity reported by the patient and general condition reported by the patient s relative in the week preceding and subsequent to a change in therapy. Note that a higher value in VAS for pain denotes increased pain, whereas a higher value for the general condition denotes improvement. *P versus previous week; P versus Group A.

6 414 Marinangeli et al. Vol. 27 No. 5 May 2004 Table 4 Episodes of Side Effects Possibly Linked to Therapy and Reported by Patients in Their Diaries Number of Events Adverse Event Group A Group B Nausea 315 a 437 Vomiting Constipation Gastro-enteric bleeding 2 0 Periods of mental confusion (excluding the period immediately before death) P versus Group B. efficacy assessments of the WHO step ladder have been case control studies or retrospective reviews of patients files, but not randomized trials. This is a randomized, but not a doubleblind, study, with the aim to compare two different methods of treatment. A double-blind study is particularly difficult to realize when a number of drugs, with different routes of administration and different delivery systems are used. It could be more feasible when only two drugs are compared. In 1998, Grond et al. underlined that the use of weak opioids has great educational impact and has helped spread the use of the WHO guidelines. 11 Furthermore, weak opioids are more freely available and are expected to have a better side-effect profile. At the same time, they stated the necessity of controlled long-term studies for confirmation. The results of the current study demonstrated the potential efficacy but questionable tolerability and acceptability of NSAIDs alone and in combination with weak opioids for the treatment of mild and/or moderate pain in terminal cancer patients. It is important to underline the choice of VAS score as inclusion criteria. It was justified by the main goal of the study: the feasibility to use strong opioids from Table 5 Type and Mean Dose ( SD) of Opioid Being Administered at Time of Death Opioid Group A (n) Group B (n) Tramadol (mg/d) (13) Codeine (mg/d) (12) Morphine (mg/d) (12) (15) Fentanyl TTS (µg/h) (8) (23) Methadone (mg/d) (3) (6) the beginning of the symptoms (mild and moderate pain), and to make the groups homogeneous. Moreover, the necessity of strong opioids in the treatment of severe pain (VAS 7) is well established in the literature and suggested by WHO. Given a less intense pain, strong opioids appear to be at least as effective and better tolerated. This was demonstrated not only by significantly superior pain relief, but also by the significantly greater number of weeks of patient satisfaction and fewer therapeutic changes among patients treated with strong opioids as first line pain therapy. This superiority is especially important in the treatment of patients affected by an advanced disease and for whom disease-oriented treatment is not likely to be an option. These patients are often in the worst possible physical condition and are at risk for the side effects of drugs, such as NSAIDs, which have a narrow therapeutic range. Although there are no established guidelines for the definition of disease intractability, in this study the evaluation was always performed by the same oncologist, on the basis of clinical evaluation and response to therapy. The present study also evaluated the concept of patient QOL. This concept may be difficult to recognize in terminal cancer patients, but endof-life QOL has become increasingly important in the management of such patients, and may also be considered to be the basis of palliative care. Although the instrument used in this study may capture disease-related physical components of QOL based on its use of health-related questions, the non-specific VAS scales used to assess the patient s general condition, both from the patient s and the relative s perspective, may capture non-physical aspects of QOL. These scales provide a useful instrument because of their ease and rapidity of use on a daily basis. 7,9 12 Although there was deterioration from baseline in the Karnofsky Performance Status and QOL, as might be expected in this population of patients, the magnitude of deterioration was similar with both treatment strategies. Despite the reduction in these endpoints, the reduction in pain and the greater patient satisfaction in Group B support the use of strong opioids at an appropriate dosing schedule. Additionally, the lack of improvement in the patients general condition following a therapeutic change in Group A would suggest that

7 Vol. 27 No. 5 May 2004 Use of Strong Opioids in Advanced Cancer Pain 415 treatment with weak opioids may cause patient discomfort, at least during the week following the change. This does not occur in the group of patients treated with strong opioids, probably because of continuous titration, which is related to disease evolution; the majority of the therapeutic changes in Group B were related to changes in dose rather than change in drug (96.3% vs. 3.7%). In a rapidly worsening pathology, the use of drugs with a limited range of therapeutic efficacy can potentially increase the risk of ineffective treatment and continuous changes in dosage. In the group treated according to the WHO guidelines, the overall therapeutic efficacy was good during the entire disease evolution, consistent with the studies that validating the WHO guidelines. However, this therapeutic efficacy was still significantly lower compared to the efficacy of patients initiated on treatment with strong opioids. Furthermore, the wide range of strong opioids currently available in a range of doses and routes of administration, suggests the possibility of effective and well-tolerated treatment with strong opioids even for mild/ moderate pain. Although a 0.69 difference in change pain intensity could seem clinically not important, it could influence the therapeutic choice, especially when WHO guidelines are used. Because of physician fear of administering strong opioids, the prescription of nonopioid drugs (e.g., NSAIDs) or of weak opioids at the highest dosages, may result in the occurrence of side effects, which may present a greater risk to the patient than that of strong opioids. Although this study was not powered to show statistically significant differences in uncommon but serious side effects, the worst side effects were noted with the use of NSAIDs (two bleeding ulcers). This is consistent with the known gastrointestinal toxicity of these drugs. 11,13,14 Only the incidence of the nausea was significantly higher in Group A patients. This result could be related both to the analgesic drugs and higher pain intensity. One of the aims of the study was to assess the incidence of tolerance or addiction to strong opioids in incurable patients. The potential for tolerance and addiction and the possible induction of respiratory depression represent the main barriers to the use of these drugs in countries such as Italy, where the use of opioids for analgesic purposes remains low. 15 During the current study, there was an increase in the consumption of strong opioids in Group B, but, as showed by Schug et al. in a long-term survey of morphine in cancer pain patients, this result could be explained by progression of the terminal disease. 16 Despite this increase in consumption, the dose of these drugs was generally lower than patients in Group A who progressed to strong opioids, although these differences were not statistically significant. It has been demonstrated that tolerance is a relative problem, because in many patients even with very severe pain, it is only necessary to increase the initial dosage only during the process of disease evolution. 17 This has been confirmed in the current study during which the physician was always able to attribute the increase in dosages to disease progression. It should also be noted that no patient attained dose levels of analgesics responsible for tolerance; continuous dose modifications were always performed in order to follow disease evolution. Furthermore, the short period of survival together with the combination of effective adjuvant drugs may also eliminate fears of tolerance and addiction. Finally, with regard to the fear of respiratory depression, it should be stressed that morphine is actually indicated as a useful adjuvant drug in the control of respiratory symptoms associated with heart failure and myocardial infarction. 18 The present study also assessed disease evolution based on the evaluation of the patient s relative during therapeutic changes. This may be of particular clinical importance because the physician often complies with the requests of such a person rather than with those of the patient, who sometimes accepts pain or is unable to express his/her opinion. Although several studies have suggested that there is a tendency of relatives to overestimate pain, 19,20 other studies have demonstrated that the perception of a relative may provide a more accurate index of the patient s conditions. 21,22 In summary, the data obtained in this study support the fundamental assertions of the WHO guidelines. Nevertheless, such guidelines exclude disease progression and this may prove to be a limitation. In fact, there are often situations where the disease quickly evolves and where therapeutic changes may not be tolerated by

8 416 Marinangeli et al. Vol. 27 No. 5 May 2004 the patient and his/her relatives. Consequently, it may be necessary to modify these guidelines to take into account both disease outcomes and patient-centered outcomes. The data from this study should further reassure the physician about the need and use of strong opioids in appropriate circumstances. Moreover, the quick progression of disease, reduced life-expectancy, and the demonstrated safety of opioid analgesics are reason enough to administer strong opioids in all incurable oncologic patients, independent of the intensity of pain. Strong opioids, because of their wide therapeutic efficacy and tolerability, should be considered as a very important instrument in the ethical care of the intractable patient. References 1. World Health Organization. Cancer pain relief. Geneva: World Health Organization, Ventafridda V, Tamburini M, Caraceni A, et al. A validation study of the WHO method for cancer pain relief. Cancer 1987;59: Schug SA, Zech D, Dörr U. Cancer pain management according to WHO analgesic guidelines. J Pain Symptom Manage 1990;5: Grond S, Zech D, Schug SA, et al. Validation of World Health Organization guidelines for cancer pain relief during the last days and hours of life. J Pain Symptom Manage 1991;6: Grond S, Zech D, Lynch J, et al. Validation of World Health Organization guidelines for pain relief in head and neck cancer. A prospective study. Ann Otol Rhinol Laryngol 1993;102: Zech D, Grond S, Lynch J, et al. Validation of World Health Organization Guidelines for cancer pain relief: a 10-year prospective study. Pain 1995;63: Jadad AR, Browman GP. The WHO analgesic ladder for cancer pain management. Stepping up the quality of its evaluation. JAMA 1995;274: Cascinu S, Giordani P, Agostinelli R, et al. Pain and its treatment in hospitalized patient with metastatic cancer. Supp Care Cancer 2003;11: Ferrell BR, Wisdom C, Wenzl C. Quality of life as an outcome variable in the management of cancer pain. Cancer 1989;63: Conill C, Verger E, Salamero M. Performance status assessment in cancer patients. Cancer 1990; 65: Grond S, Meuser T. Weak opioids an educational substitute for morphine? Curr Opin Anaesthesiol 1998;11: Donnelly S, Rybicki L, Walsh D. Quality of life measurement in the palliative management of advanced cancer. Support Care Cancer 2001;9: García Rodríguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual nonsteroidal anti-inflammatory drugs. Lancet 1994;343: Hernandez-Diaz S, Garcia Rodriguez LA. Association between nonsteroidal anti-inflammatory drugs and upper gastrointestinal tract bleeding/perforation. An overview of epidemiologic studies published in the 1990 s. Arch Intern Med 2000;160: Blengini C, Ventafridda V. Use and cost of opioids in Italy. J Pain Symptom Manage 2000;20: Schug SA, Zech D, Grond S, et al. A long-term survey of morphine in cancer pain patients. J Pain Symptom Manage 1992;7: Brescia FJ, Portenoy RK, Ryan M, et al. Pain, opioid use, and survival in hospitalized patients with advanced cancer. J Clin Oncol 1992;10:149v Mazzocato C, Buclin T, Rapin CH. The effects of morphine on dyspnea and ventilatory function in elderly patients with advanced cancer: a randomized double-blind controlled trial. Ann Oncol 1999;10: Lobchuk MM, Kristjanson L, Degner L, et al. Perceptions of symptom distress in lung cancer patients: I. Congruence between patients and primary family caregivers. J Pain Symptom Manage 1997;14: Kristjanson LJ, Nikoletti S, Porock D, et al. Congruence between patients and family caregivers perceptions of symptom distress in patients with terminal cancer. J Palliat Care 1998;14: Dar R, Beach CM, Barden PL, Cleeland CS. Cancer pain in the marital system: a study of patients and their spouses. J Pain Symptom Manage 1992;7: Lin CC. Congruity of cancer pain perceptions between Taiwanese patients and family caregivers: relationship to patients concerns about reporting pain and using analgesics. J Pain Symptom Manage 2001; 21:18 26.