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Chemoradiotherapy-Induced Esophagitis Pain Relieved by Topical Morphine: Three Cases
Vol. 30 No. 2 August 2005
Journal of Pain and Symptom Management
107
Letters
Chemoradiotherapy-Induced Esophagitis Pain Relieved by Topical Morphine: Three Cases To the Editor: Esophagitis is a frequent and potentially severe complication of radiation therapy, with or without concomitant chemotherapy, in lung cancer patients. It is painful, impairs adequate nutritional intake, and may lead to dose reduction of a cytostatic drug or interruption of radiotherapy. To our knowledge, there is no established method to prevent esophagitis. Systemic analgesics and topical anesthetics are widely and often unsuccessfully used for relieving pain. Experimental1 and clinical2 studies suggest that opioid analgesia in patients with painful inflammatory tissues might be enhanced by a topical action. In prior studies, relief of oral mucositis pain has been obtained by a topical 0.1% morphine solution.3,4 To produce topical analgesia, morphine can be delivered by viscous gel, which might cover esophageal surfaces when it is swallowed. This type of morphine-induced topical analgesia is illustrated by case reports. The three patients had non-small cell lung cancer. The radiotherapy schedule consisted of a total palliative dose of 36 Gy in 12 fractions of 3 Gy. Patients experienced grade III radiotherapy-induced esophagitis. Esophageal toxicities were graded by Radiation Therapy Oncology Group (RTOG) criteria (Table 1). In addition to systemic analgesics, patients swallowed from 2 to 10 mL of 0.1% morphine gel three times a day, 5 to 60 minutes before eating. The morphine sulfate was diluted in the ready-mixed Purilon (carboxymethylcellulose, water) and was prepared by the hospital pharmacy. Patients were asked to rate the intensity of their maximum pain with a numeric scale
쑖 2005 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.
that ranged from 0 (no pain) to 10 (maximum pain), and also to rate the duration of pain relief. Side effects induced by topical morphine were recorded. Patient 1 was a 57-year-old woman hospitalized for an adenocarcinoma of the lung (T1N2M1), with cerebral, bone, adrenal, and renal metastases. She had a previous history of breast cancer in situ treated by surgery. The patient complained of severe back pain and a 10 kg weight loss. She underwent one cycle of chemotherapy with carboplatin and paclitaxel. Spinal cord compression (L2) was treated surgically in November 2003, and the spinal cord (T2 to T8 and T12 to L4) was irradiated (36 Gy with 12 fractions of 3 Gy). She continued to receive cycling chemotherapy with carboplatin and paclitaxel. The patient developed a grade III esophagitis two weeks after the beginning of irradiation. She rated pain with swallowing as 9.5 on a 0 to10 pain scale, movement pain at 3, and pain at rest at 1. She required parenteral nutrition because swallowing was almost impossible. The esophagitis remained painful despite treatment with omeprazole (20 mg per day), acetaminophen (3 g per day), controlled-release morphine (40 mg per day), topical lidocaine, and magnesium aluminum hydroxide. Besides
Table 1 Radiation Therapy Oncology Group Grading for Esophageal Toxicity Score 0 1 2 3
4 5
Description No change over baseline Mild dysphagia or odynophagia: may require topical anesthetic, non-narcotic agents, or soft diet Moderate dysphagia or odynophagia: may require narcotics agents or puree/liquid diet Severe dysphagia or odynophagia with dehydration or weight loss (⬎15% from pretreatment baseline) requiring nasogastric feeding tube, IV fluids, or hyperalimentation Complete obstruction, ulceration, perforation or fistula Death
0885-3924/05/$–see front matter
108
this treatment, celecoxib (200 mg per day) and controlled-release ketoprofen (300 mg per day) were administered for bone pain. She began topical morphine 26 days after the end of the radiotherapy. Pain on movement and at rest disappeared after 8 days of treatment. Pain with swallowing declined to below 4 after 10 days of treatment. Pain relief lasted about one hour after each dose. She complained of nausea and loss of appetite. On discharge at home, she was able to swallow and she did not need any analgesics but ketoprofen. Patient 2 was a 36-year-old man who developed a large cell carcinoma of the lung with liver, bone, and mesenteric metastases (T4N3M1). He underwent three cycles of chemotherapy at three-week intervals with cisplatin (Day 1: 80 mg/m2) and gemcitabine (Day 1, 8: 1250 mg/m2). Then a palliative bone flash irradiation was delivered on T2-T8 and left ribs (18 Gy in 3 fractions) with concomitant chemotherapy (paclitaxel and carboplatin). The patient complained of a Grade III esophagitis 10 days after the beginning of irradiation. He scored swallowing pain at 10 despite treatment with parenteral omeprazole (40 mg per day). He was also treated for bone pain with methylprednisolone (80 mg per day), ketoprofen (1500 mg per day), oral acetaminophen (1500 mg per day), morphine (30 mg per day), and transdermal fentanyl (100 µg per hour, one patch every three days). He received oral morphine gel 2.5 mL for four days. Pain level fell immediately under 4, and further declined below 2 after 6 days. The analgesic effect of topical morphine lasted for two hours. He complained of nausea after swallowing. The patient died the following month due to the primary disease. Patient 3 was a 51-year-old man with lung carcinoma (T4N3M1). He received two cycles of chemotherapy with cisplatin and vinorelbine. He also received chemotherapy with carboplatin and paclitaxel. The paclitaxel and carboplatin doses were reduced during radiotherapy. He underwent mediastinal and clavicular palliative irradiation (2.5 Gy in 5 fractions) then 6 fractions in 5 days to T12 (4 Gy in 4 fractions). Grade III esophagitis began two weeks after the end of the first radiotherapy. He scored pain with swallowing at 9 and perceived no benefit from the following treatment: omeprazole (40 mg per day), acetaminophen
Letters
Vol. 30 No. 2 August 2005
(6 g per day), and controlled-release morphine (120 mg per day). He had controlled-release ketoprofen (300 mg per day) for bone pain. Significant analgesic benefit was achieved immediately with 3 ml morphine gel and lasted for four hours. No adverse effects were reported. The patient died in one month due to the primary disease. Grade III esophagitis causes severe dysphagia or odynophagia with dehydration or weight loss (⬎15% from pre-treatment baseline). All patients underwent concurrent chemoradiotherapy, with a low irradiation dose. The incidence of esophageal toxicity is almost 90% of patients treated by concurrent chemoradiotherapy.5,6 Choy et al. reported a 46% incidence of acute Grade III-IV esophagitis during treatment with 66 Gy of radiotherapy and concurrent weekly paclitaxel and carboplatin.5 Usual topical treatments include antacids, viscous lidocaine, aluminum hydroxide-magnesium carbonate, and acetaminophen. The benefits from these treatments, like the efficacy of systemic analgesics, are known to be limited. Peripheral morphine analgesia has been demonstrated in dental surgery patients,2 and some clinical trials suggest that topical morphine is effective in mucositisassociated pain following concomitant chemoradiotherapy in head and neck carcinoma.3,4 There are no published data on topical morphine in esophagitis. Although peripheral opioid receptors are not detectable in normal tissue, they appear in inflamed tissue1 and the analgesic effect of peripheral opioids in an experimental model increases linearly with the duration of inflammation.7 Moreover, the number of peripheral sensory-nerve terminals is increased in inflamed tissues.8 Analgesia would be expected where topical morphine gel covers inflamed gastrointestinal mucosa. It might be possible that some of the topical morphine is absorbed systemically. All patients were treated with oral morphine, however, and demonstrated no effect on esophagitis pain. One patient reported nausea after swallowing morphine gel, but this side effect disappeared while taking very small volumes. The nausea was also probably due to the primary disease and to chemotherapy. Clinical trials are needed to confirm this observation. The major advantages that could be achieved with topical morphine administration
Vol. 30 No. 2 August 2005
are simplicity, low incidence of side effects, and low cost. Anne Cecile Gairard-Dory, PharmD Carine Schaller, PharmD Bertrand Mennecier, MD Anita Molard, MD Be´ne´dicte Gourieux, Pharm D Lavrence Beretz, Pharm D Elisabeth Quoix, MD University Hospital Strasbourg, France doi: 10.1016/j.jpainsymman.2005.05.008
References 1. Schafer M, Imai Y, Uhl GR, Stein C. Inflammation enhances peripheral µ-opioid analgesia, but not µ-opioid receptor transcription in dorsal root ganglia. Eur J Pharmacol 1995;279:165–169. 2. Likar RL, Koppert W, Blatnig H, et al. Efficacy of peripheral morphine analgesia in inflamed, noninflamed and perineural tissue of dental surgery patients. J Pain Symptom Manage 2001;21:330–337. 3. Cerchietti LC, Navigante AH, Bonomi MR, et al. Effect of topical morphine for mucositis-associated pain following concomitant chemoradiotherapy for head and neck carcinoma. Cancer 2002;95: 2230–2236. 4. Cerchietti LC, Navigante AH, Ko¨rte MW, et al. Potential utility of the peripheral analgesic properties of morphine in stomatitis-related pain: a pilot study. Pain 2003;105:265–273. 5. Choy H, Akerly W, Graziano S. Multi-institutional phase II trial of paclitaxel, carboplatin and concurrent radiation therapy for locally advanced non-small cell lung cancer. J Clin Oncol 1998;16:3316–3322. 6. Singh AK, Lockett MA, Bradley JD. Predictors of radiation-induced esophageal toxicity in patients with non-small-cell lung cancer treated with threedimensionnal conformal radiotherapy. Int J Radiation Oncology Biol Phys 2003;55(2):337–341. 7. Zhou L, Shang Q, Stein C, Schafer M. Contribution of opioid receptors on primary afferent versus sympathetic neurons to peripheral opioid analgesia. J Pharmacol Exp Ther 1998;286:1000–1006. 8. Stein C. The control of pain in peripheral tissue by opioids. N Eng J Med 1995;332:1685–1690.
Is Research Really Problematic in Palliative Care? A Pilot Study To the Editor: Clinical research on patients at the end of life is necessary to improve the care they receive.1
Letters
109
However, it has been argued that palliative care patients are too ill and too vulnerable to allow meaningful scientific research.2 Others have objected to this position because palliative care patients should not be considered special cases because they should benefit from research based on ethical principles leading to wellgrounded clinical guidelines.3–6 In addition, to deny palliative care patients access to take part in clinical research may well be unethical. We conducted a pilot study to determine the expectations concerning research of nurses and of advanced cancer patients. Two different case studies were presented as semi-structured interviews during one day to all patients hospitalized in two palliative care units. The same cases with the same questions were then presented as individual questionnaires to all nurses working in these units. Case A (Mrs. T) was about including a woman with advanced breast cancer in a research protocol studying a new pharmacological treatment against anorexia. Questions were: Should the patient agree to be included? If yes or no, why? Should the patient ask the family for advice? Would you agree to be included in the study? Case B (Mr. V) was about including a confused patient with advanced prostate cancer in a research protocol studying a new intravenous treatment for delirium. Questions were: Should the patient’s wife accept the inclusion of her husband? If yes or no, why? Is the patient’s wife allowed to decide for her husband? Would you accept a proxy to include you—or to be included—in the study? On the study day, 29 patients were hospitalized. Ten patients could not be interviewed, five because of poor general condition, three because they didn’t speak the local language and two because of cognitive failure (MiniMental State Examination [MMSE] ⬍ 21). One patient declined. Eighteen patients were included (8F/10M). The mean age was 68.9 ⫾ 11.9 years. Mean MMSE was 24.7 ⫾ 3.6. Fourteen (10F, 4M) of the 19 nurses sent back the questionnaire. Mean age was 39.6 ⫾ 7.7. Mean working experience time was 16.4 ⫾ 8.6 years and 8.4 ⫾ 5.5 years in palliative care units. Quantitative results of the responses are summarized in Table 1.
Study Case A Eighty-six percent of patients and 100% of nurses thought that Mrs. T should agree to be
Journal of Pain and Symptom Management
107
Letters
Chemoradiotherapy-Induced Esophagitis Pain Relieved by Topical Morphine: Three Cases To the Editor: Esophagitis is a frequent and potentially severe complication of radiation therapy, with or without concomitant chemotherapy, in lung cancer patients. It is painful, impairs adequate nutritional intake, and may lead to dose reduction of a cytostatic drug or interruption of radiotherapy. To our knowledge, there is no established method to prevent esophagitis. Systemic analgesics and topical anesthetics are widely and often unsuccessfully used for relieving pain. Experimental1 and clinical2 studies suggest that opioid analgesia in patients with painful inflammatory tissues might be enhanced by a topical action. In prior studies, relief of oral mucositis pain has been obtained by a topical 0.1% morphine solution.3,4 To produce topical analgesia, morphine can be delivered by viscous gel, which might cover esophageal surfaces when it is swallowed. This type of morphine-induced topical analgesia is illustrated by case reports. The three patients had non-small cell lung cancer. The radiotherapy schedule consisted of a total palliative dose of 36 Gy in 12 fractions of 3 Gy. Patients experienced grade III radiotherapy-induced esophagitis. Esophageal toxicities were graded by Radiation Therapy Oncology Group (RTOG) criteria (Table 1). In addition to systemic analgesics, patients swallowed from 2 to 10 mL of 0.1% morphine gel three times a day, 5 to 60 minutes before eating. The morphine sulfate was diluted in the ready-mixed Purilon (carboxymethylcellulose, water) and was prepared by the hospital pharmacy. Patients were asked to rate the intensity of their maximum pain with a numeric scale
쑖 2005 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.
that ranged from 0 (no pain) to 10 (maximum pain), and also to rate the duration of pain relief. Side effects induced by topical morphine were recorded. Patient 1 was a 57-year-old woman hospitalized for an adenocarcinoma of the lung (T1N2M1), with cerebral, bone, adrenal, and renal metastases. She had a previous history of breast cancer in situ treated by surgery. The patient complained of severe back pain and a 10 kg weight loss. She underwent one cycle of chemotherapy with carboplatin and paclitaxel. Spinal cord compression (L2) was treated surgically in November 2003, and the spinal cord (T2 to T8 and T12 to L4) was irradiated (36 Gy with 12 fractions of 3 Gy). She continued to receive cycling chemotherapy with carboplatin and paclitaxel. The patient developed a grade III esophagitis two weeks after the beginning of irradiation. She rated pain with swallowing as 9.5 on a 0 to10 pain scale, movement pain at 3, and pain at rest at 1. She required parenteral nutrition because swallowing was almost impossible. The esophagitis remained painful despite treatment with omeprazole (20 mg per day), acetaminophen (3 g per day), controlled-release morphine (40 mg per day), topical lidocaine, and magnesium aluminum hydroxide. Besides
Table 1 Radiation Therapy Oncology Group Grading for Esophageal Toxicity Score 0 1 2 3
4 5
Description No change over baseline Mild dysphagia or odynophagia: may require topical anesthetic, non-narcotic agents, or soft diet Moderate dysphagia or odynophagia: may require narcotics agents or puree/liquid diet Severe dysphagia or odynophagia with dehydration or weight loss (⬎15% from pretreatment baseline) requiring nasogastric feeding tube, IV fluids, or hyperalimentation Complete obstruction, ulceration, perforation or fistula Death
0885-3924/05/$–see front matter
108
this treatment, celecoxib (200 mg per day) and controlled-release ketoprofen (300 mg per day) were administered for bone pain. She began topical morphine 26 days after the end of the radiotherapy. Pain on movement and at rest disappeared after 8 days of treatment. Pain with swallowing declined to below 4 after 10 days of treatment. Pain relief lasted about one hour after each dose. She complained of nausea and loss of appetite. On discharge at home, she was able to swallow and she did not need any analgesics but ketoprofen. Patient 2 was a 36-year-old man who developed a large cell carcinoma of the lung with liver, bone, and mesenteric metastases (T4N3M1). He underwent three cycles of chemotherapy at three-week intervals with cisplatin (Day 1: 80 mg/m2) and gemcitabine (Day 1, 8: 1250 mg/m2). Then a palliative bone flash irradiation was delivered on T2-T8 and left ribs (18 Gy in 3 fractions) with concomitant chemotherapy (paclitaxel and carboplatin). The patient complained of a Grade III esophagitis 10 days after the beginning of irradiation. He scored swallowing pain at 10 despite treatment with parenteral omeprazole (40 mg per day). He was also treated for bone pain with methylprednisolone (80 mg per day), ketoprofen (1500 mg per day), oral acetaminophen (1500 mg per day), morphine (30 mg per day), and transdermal fentanyl (100 µg per hour, one patch every three days). He received oral morphine gel 2.5 mL for four days. Pain level fell immediately under 4, and further declined below 2 after 6 days. The analgesic effect of topical morphine lasted for two hours. He complained of nausea after swallowing. The patient died the following month due to the primary disease. Patient 3 was a 51-year-old man with lung carcinoma (T4N3M1). He received two cycles of chemotherapy with cisplatin and vinorelbine. He also received chemotherapy with carboplatin and paclitaxel. The paclitaxel and carboplatin doses were reduced during radiotherapy. He underwent mediastinal and clavicular palliative irradiation (2.5 Gy in 5 fractions) then 6 fractions in 5 days to T12 (4 Gy in 4 fractions). Grade III esophagitis began two weeks after the end of the first radiotherapy. He scored pain with swallowing at 9 and perceived no benefit from the following treatment: omeprazole (40 mg per day), acetaminophen
Letters
Vol. 30 No. 2 August 2005
(6 g per day), and controlled-release morphine (120 mg per day). He had controlled-release ketoprofen (300 mg per day) for bone pain. Significant analgesic benefit was achieved immediately with 3 ml morphine gel and lasted for four hours. No adverse effects were reported. The patient died in one month due to the primary disease. Grade III esophagitis causes severe dysphagia or odynophagia with dehydration or weight loss (⬎15% from pre-treatment baseline). All patients underwent concurrent chemoradiotherapy, with a low irradiation dose. The incidence of esophageal toxicity is almost 90% of patients treated by concurrent chemoradiotherapy.5,6 Choy et al. reported a 46% incidence of acute Grade III-IV esophagitis during treatment with 66 Gy of radiotherapy and concurrent weekly paclitaxel and carboplatin.5 Usual topical treatments include antacids, viscous lidocaine, aluminum hydroxide-magnesium carbonate, and acetaminophen. The benefits from these treatments, like the efficacy of systemic analgesics, are known to be limited. Peripheral morphine analgesia has been demonstrated in dental surgery patients,2 and some clinical trials suggest that topical morphine is effective in mucositisassociated pain following concomitant chemoradiotherapy in head and neck carcinoma.3,4 There are no published data on topical morphine in esophagitis. Although peripheral opioid receptors are not detectable in normal tissue, they appear in inflamed tissue1 and the analgesic effect of peripheral opioids in an experimental model increases linearly with the duration of inflammation.7 Moreover, the number of peripheral sensory-nerve terminals is increased in inflamed tissues.8 Analgesia would be expected where topical morphine gel covers inflamed gastrointestinal mucosa. It might be possible that some of the topical morphine is absorbed systemically. All patients were treated with oral morphine, however, and demonstrated no effect on esophagitis pain. One patient reported nausea after swallowing morphine gel, but this side effect disappeared while taking very small volumes. The nausea was also probably due to the primary disease and to chemotherapy. Clinical trials are needed to confirm this observation. The major advantages that could be achieved with topical morphine administration
Vol. 30 No. 2 August 2005
are simplicity, low incidence of side effects, and low cost. Anne Cecile Gairard-Dory, PharmD Carine Schaller, PharmD Bertrand Mennecier, MD Anita Molard, MD Be´ne´dicte Gourieux, Pharm D Lavrence Beretz, Pharm D Elisabeth Quoix, MD University Hospital Strasbourg, France doi: 10.1016/j.jpainsymman.2005.05.008
References 1. Schafer M, Imai Y, Uhl GR, Stein C. Inflammation enhances peripheral µ-opioid analgesia, but not µ-opioid receptor transcription in dorsal root ganglia. Eur J Pharmacol 1995;279:165–169. 2. Likar RL, Koppert W, Blatnig H, et al. Efficacy of peripheral morphine analgesia in inflamed, noninflamed and perineural tissue of dental surgery patients. J Pain Symptom Manage 2001;21:330–337. 3. Cerchietti LC, Navigante AH, Bonomi MR, et al. Effect of topical morphine for mucositis-associated pain following concomitant chemoradiotherapy for head and neck carcinoma. Cancer 2002;95: 2230–2236. 4. Cerchietti LC, Navigante AH, Ko¨rte MW, et al. Potential utility of the peripheral analgesic properties of morphine in stomatitis-related pain: a pilot study. Pain 2003;105:265–273. 5. Choy H, Akerly W, Graziano S. Multi-institutional phase II trial of paclitaxel, carboplatin and concurrent radiation therapy for locally advanced non-small cell lung cancer. J Clin Oncol 1998;16:3316–3322. 6. Singh AK, Lockett MA, Bradley JD. Predictors of radiation-induced esophageal toxicity in patients with non-small-cell lung cancer treated with threedimensionnal conformal radiotherapy. Int J Radiation Oncology Biol Phys 2003;55(2):337–341. 7. Zhou L, Shang Q, Stein C, Schafer M. Contribution of opioid receptors on primary afferent versus sympathetic neurons to peripheral opioid analgesia. J Pharmacol Exp Ther 1998;286:1000–1006. 8. Stein C. The control of pain in peripheral tissue by opioids. N Eng J Med 1995;332:1685–1690.
Is Research Really Problematic in Palliative Care? A Pilot Study To the Editor: Clinical research on patients at the end of life is necessary to improve the care they receive.1
Letters
109
However, it has been argued that palliative care patients are too ill and too vulnerable to allow meaningful scientific research.2 Others have objected to this position because palliative care patients should not be considered special cases because they should benefit from research based on ethical principles leading to wellgrounded clinical guidelines.3–6 In addition, to deny palliative care patients access to take part in clinical research may well be unethical. We conducted a pilot study to determine the expectations concerning research of nurses and of advanced cancer patients. Two different case studies were presented as semi-structured interviews during one day to all patients hospitalized in two palliative care units. The same cases with the same questions were then presented as individual questionnaires to all nurses working in these units. Case A (Mrs. T) was about including a woman with advanced breast cancer in a research protocol studying a new pharmacological treatment against anorexia. Questions were: Should the patient agree to be included? If yes or no, why? Should the patient ask the family for advice? Would you agree to be included in the study? Case B (Mr. V) was about including a confused patient with advanced prostate cancer in a research protocol studying a new intravenous treatment for delirium. Questions were: Should the patient’s wife accept the inclusion of her husband? If yes or no, why? Is the patient’s wife allowed to decide for her husband? Would you accept a proxy to include you—or to be included—in the study? On the study day, 29 patients were hospitalized. Ten patients could not be interviewed, five because of poor general condition, three because they didn’t speak the local language and two because of cognitive failure (MiniMental State Examination [MMSE] ⬍ 21). One patient declined. Eighteen patients were included (8F/10M). The mean age was 68.9 ⫾ 11.9 years. Mean MMSE was 24.7 ⫾ 3.6. Fourteen (10F, 4M) of the 19 nurses sent back the questionnaire. Mean age was 39.6 ⫾ 7.7. Mean working experience time was 16.4 ⫾ 8.6 years and 8.4 ⫾ 5.5 years in palliative care units. Quantitative results of the responses are summarized in Table 1.
Study Case A Eighty-six percent of patients and 100% of nurses thought that Mrs. T should agree to be