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Morphine in Intrasite Gel Applied Topically to Painful Ulcers
118
Letters
7. Folstein MF, Folstein SE, McHugh PR. “Minimental state.” A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198.
Morphine in Intrasite Gel Applied Topically to Painful Ulcers To the Editor: There have been a number of publications reporting the use of topical morphine for painful ulcers, including some randomized controlled studies.1 We have reported the results of a pilot study,2 following which we undertook a larger study. Although this study was terminated early because of administrative problems, the preliminary results are presented here, which may be informative. Hospice inpatients with painful ulcers were randomly assigned to receive either morphine (morphine sulfate injection 10mg/ml in 8g Intrasite gel) or placebo (water for injection 1 ml in 8g Intrasite gel) topically to their ulcer. Patients were treated for two days followed by a two-day washout period after which they were crossed over to the alternative treatment. Patients assessed analgesia by completing a numerical rating score (NRS) daily. Patients, and nursing staff, also recorded any local or systemic
Vol. 29 No. 2 February 2005
adverse effects experienced during the course of the study. Twenty-one patients were recruited; five did not complete the study (deterioration (3), protocol violation (2)). Demographic details for the remaining 16 patients are shown in Table 1. The mean (⫾ SD) NRS scores for patients pretreatment, with morphine, and with placebo were 6.6 ⫾ 1.6, 2.8 ⫾ 1.3 and 5.5 ⫾ 1.9, respectively (Table 2). Topically applied morphine produced significantly lower NRS scores compared to pre-treatment and placebo treatment (P ⬍ 0.001). Patients reported some local effects, such as itching, burning and discomfort, but none were specifically attributable to morphine; neither patients nor nursing staff documented any systemic adverse effects. Most patients (69%) preferred morphine to placebo and there was no difference in the patients’ use of rescue medication during the two treatment arms. This study is consistent with the previous reports describing an analgesic effect when morphine has been applied topically to painful malignant and benign ulcers. Furthermore, topically applied morphine appears to be safe and well tolerated by patients. The mechanism may be a local action as the bioavailability of topically applied morphine is low3 and the same dose appears effective across a range of oral opioid analgesics. Although this is the largest randomized, double-blind, placebo-controlled
Table 1 Patient Characteristics
Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Sex
Age
ECOG
Primary cancer
Female Male Male Female Male Female Male Female Male Male Male Female Male Female Male Male
72 78 71 75 70 85 89 92 79 82 71 80 65 75 80 66
3 3 4 3 4 2 3 4 3 3 3 3 3 3 3 3
Lung Prostate Lung Esophagus Lung Lung Stomach Lung Mesothelioma Lung Colon Mesothelioma Bladder Esophagus Anus Pancreas
Ulcer characteristics
24-hr morphine equivalent (mg)
Size (cm )
Etiology
Sterling score
25 60 40 Nil 160 240 80 60 20 Nil 20 120 40 60 60 90
6 8.9 5.2 12.5 14 38 5 14 22.4 9 15 8 30 6.5 24 4.5
Pressure Pressure Pressure Pressure Pressure Pressure Pressure Pressure Pressure Pressure Malignant Pressure Malignant Pressure Malignant Pressure
2.2 2.3 2.3 3.1 3.2 2.3 2.2 2.2 2.3 2.2 2.3 3.1 3.2 2.2 2.2 3.1
2
Vol. 29 No. 2 February 2005
Letters
119
Table 2 Patient Numerical Rating Scores Following Morphine and Placebo Numerical Rating Scores Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
First treatment
Baseline
Opioid Day 1
Opioid Day 2
Placebo Day 1
Placebo Day 2
Preference
Morphine Morphine Placebo Placebo Placebo Placebo Morphine Placebo Morphine Morphine Morphine Morphine Placebo Morphine Placebo Morphine
6 6 9 7 5 6 8 5 8 10 6 4 6 5 7 7
4 2 6 4 3 4 2 5 3 3 2 3 2 2 2 3
3 3 4 2 1 3 1 4 5 4 1 2 3 0 1 2
8 4 5 9 4 8 7 4 4 9 4 3 5 4 6 5
7 6 3 6 5 8 9 7 3 7 5 3 4 3 5 6
Morphine Morphine Placebo Morphine Morphine Morphine Morphine None Placebo None Morphine None Morphine Morphine Morphine Morphine
study to date, the sample size is relatively small and larger studies are required to confirm these findings. Giovambattista Zeppetella, BSc, MRCGP St. Clare Hospice Hastingwood, United Kingdom Maria D.C. Ribeiro, MRCP Peace Hospice Watford, United Kingdom doi:10.1016/j.jpainsymman.2004.12.006
References 1. Zeppetella G. Topical morphine for painful ulcers. Does it work? Eur J Pall Med 2004;11:93–96. 2. Zeppetella G, Paul J, Ribeiro MDC. Analgesic efficacy of morphine applied topically to painful ulcers. J Pain Symptom Manage 2003;25:555–558. 3. Ribeiro MDC, Joel SP, Zeppetella G. The bioavailability of morphine applied topically to cutaneous ulcers. J Pain Symptom Manage 2004;27:434–439.
Re: Olanzapine-Induced Delirium To the Editor: In response to the letter by Morita and coworkers in a previous issue of this journal,1 I would like to address several points regarding the treatment of emesis in advanced cancer, use of olanzapine as an antiemetic, and olanzapine-induced delirium.
Olanzapine is an atypical neuroleptic drug of the thienobenzodiazepine class that is structurally related to clozapine. Olanzapine is a selective monoaminergic antagonist with highaffinity binding to serotonin 5-HT2A, 5-HT2c, 5-HT3, 5-HT6, dopamine (D1-D4), and muscarinic, histaminergic, and α1-adrenergic receptors.2 The approach to treating nausea and vomiting in advanced cancer may be based either on current understanding of the neuropharmacology of the emetic pathway or on empiric evidence (using various antiemetics without regard to the underlying mechanism).3 The second approach can be successful, especially if a broad-spectrum antiemetic is used. Either approach is valid, although a recent review suggests that approaching vomiting from an etiology-based approach may be more valid as well.3 In this patient, nausea and vomiting was attributed to radiation, opioids, and cachexia. The mechanism of radiation-induced nausea and vomiting is thought to be due to radiation-induced injury to the GI tract, with release of serotonin, stimulation of vagal afferents, and subsequent stimulation of the area postrema, nucleus tractus solitarius, dorsal motor nucleus of the vagus, and the central pattern generator leading to emesis, nausea, or both.4 The serotonin 5-HT3 receptor subtype is the receptor involved in acute nausea and vomiting associated with cis-platinum chemotherapy.4 In the current case, older agents did not provide significant 5-HT3 serotonin blocking activity, save for metoclopramide (which can block
Letters
7. Folstein MF, Folstein SE, McHugh PR. “Minimental state.” A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198.
Morphine in Intrasite Gel Applied Topically to Painful Ulcers To the Editor: There have been a number of publications reporting the use of topical morphine for painful ulcers, including some randomized controlled studies.1 We have reported the results of a pilot study,2 following which we undertook a larger study. Although this study was terminated early because of administrative problems, the preliminary results are presented here, which may be informative. Hospice inpatients with painful ulcers were randomly assigned to receive either morphine (morphine sulfate injection 10mg/ml in 8g Intrasite gel) or placebo (water for injection 1 ml in 8g Intrasite gel) topically to their ulcer. Patients were treated for two days followed by a two-day washout period after which they were crossed over to the alternative treatment. Patients assessed analgesia by completing a numerical rating score (NRS) daily. Patients, and nursing staff, also recorded any local or systemic
Vol. 29 No. 2 February 2005
adverse effects experienced during the course of the study. Twenty-one patients were recruited; five did not complete the study (deterioration (3), protocol violation (2)). Demographic details for the remaining 16 patients are shown in Table 1. The mean (⫾ SD) NRS scores for patients pretreatment, with morphine, and with placebo were 6.6 ⫾ 1.6, 2.8 ⫾ 1.3 and 5.5 ⫾ 1.9, respectively (Table 2). Topically applied morphine produced significantly lower NRS scores compared to pre-treatment and placebo treatment (P ⬍ 0.001). Patients reported some local effects, such as itching, burning and discomfort, but none were specifically attributable to morphine; neither patients nor nursing staff documented any systemic adverse effects. Most patients (69%) preferred morphine to placebo and there was no difference in the patients’ use of rescue medication during the two treatment arms. This study is consistent with the previous reports describing an analgesic effect when morphine has been applied topically to painful malignant and benign ulcers. Furthermore, topically applied morphine appears to be safe and well tolerated by patients. The mechanism may be a local action as the bioavailability of topically applied morphine is low3 and the same dose appears effective across a range of oral opioid analgesics. Although this is the largest randomized, double-blind, placebo-controlled
Table 1 Patient Characteristics
Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Sex
Age
ECOG
Primary cancer
Female Male Male Female Male Female Male Female Male Male Male Female Male Female Male Male
72 78 71 75 70 85 89 92 79 82 71 80 65 75 80 66
3 3 4 3 4 2 3 4 3 3 3 3 3 3 3 3
Lung Prostate Lung Esophagus Lung Lung Stomach Lung Mesothelioma Lung Colon Mesothelioma Bladder Esophagus Anus Pancreas
Ulcer characteristics
24-hr morphine equivalent (mg)
Size (cm )
Etiology
Sterling score
25 60 40 Nil 160 240 80 60 20 Nil 20 120 40 60 60 90
6 8.9 5.2 12.5 14 38 5 14 22.4 9 15 8 30 6.5 24 4.5
Pressure Pressure Pressure Pressure Pressure Pressure Pressure Pressure Pressure Pressure Malignant Pressure Malignant Pressure Malignant Pressure
2.2 2.3 2.3 3.1 3.2 2.3 2.2 2.2 2.3 2.2 2.3 3.1 3.2 2.2 2.2 3.1
2
Vol. 29 No. 2 February 2005
Letters
119
Table 2 Patient Numerical Rating Scores Following Morphine and Placebo Numerical Rating Scores Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
First treatment
Baseline
Opioid Day 1
Opioid Day 2
Placebo Day 1
Placebo Day 2
Preference
Morphine Morphine Placebo Placebo Placebo Placebo Morphine Placebo Morphine Morphine Morphine Morphine Placebo Morphine Placebo Morphine
6 6 9 7 5 6 8 5 8 10 6 4 6 5 7 7
4 2 6 4 3 4 2 5 3 3 2 3 2 2 2 3
3 3 4 2 1 3 1 4 5 4 1 2 3 0 1 2
8 4 5 9 4 8 7 4 4 9 4 3 5 4 6 5
7 6 3 6 5 8 9 7 3 7 5 3 4 3 5 6
Morphine Morphine Placebo Morphine Morphine Morphine Morphine None Placebo None Morphine None Morphine Morphine Morphine Morphine
study to date, the sample size is relatively small and larger studies are required to confirm these findings. Giovambattista Zeppetella, BSc, MRCGP St. Clare Hospice Hastingwood, United Kingdom Maria D.C. Ribeiro, MRCP Peace Hospice Watford, United Kingdom doi:10.1016/j.jpainsymman.2004.12.006
References 1. Zeppetella G. Topical morphine for painful ulcers. Does it work? Eur J Pall Med 2004;11:93–96. 2. Zeppetella G, Paul J, Ribeiro MDC. Analgesic efficacy of morphine applied topically to painful ulcers. J Pain Symptom Manage 2003;25:555–558. 3. Ribeiro MDC, Joel SP, Zeppetella G. The bioavailability of morphine applied topically to cutaneous ulcers. J Pain Symptom Manage 2004;27:434–439.
Re: Olanzapine-Induced Delirium To the Editor: In response to the letter by Morita and coworkers in a previous issue of this journal,1 I would like to address several points regarding the treatment of emesis in advanced cancer, use of olanzapine as an antiemetic, and olanzapine-induced delirium.
Olanzapine is an atypical neuroleptic drug of the thienobenzodiazepine class that is structurally related to clozapine. Olanzapine is a selective monoaminergic antagonist with highaffinity binding to serotonin 5-HT2A, 5-HT2c, 5-HT3, 5-HT6, dopamine (D1-D4), and muscarinic, histaminergic, and α1-adrenergic receptors.2 The approach to treating nausea and vomiting in advanced cancer may be based either on current understanding of the neuropharmacology of the emetic pathway or on empiric evidence (using various antiemetics without regard to the underlying mechanism).3 The second approach can be successful, especially if a broad-spectrum antiemetic is used. Either approach is valid, although a recent review suggests that approaching vomiting from an etiology-based approach may be more valid as well.3 In this patient, nausea and vomiting was attributed to radiation, opioids, and cachexia. The mechanism of radiation-induced nausea and vomiting is thought to be due to radiation-induced injury to the GI tract, with release of serotonin, stimulation of vagal afferents, and subsequent stimulation of the area postrema, nucleus tractus solitarius, dorsal motor nucleus of the vagus, and the central pattern generator leading to emesis, nausea, or both.4 The serotonin 5-HT3 receptor subtype is the receptor involved in acute nausea and vomiting associated with cis-platinum chemotherapy.4 In the current case, older agents did not provide significant 5-HT3 serotonin blocking activity, save for metoclopramide (which can block