Japanese Journal of Clinical Oncology Advance Access originally published online on October 24, 2008
Japanese Journal of Clinical Oncology 2008 38(12):857-860; doi:10.1093/jjco/hyn110
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© The Author (2008). Published by Oxford University Press. All rights reserved
Potential Utility of Peripherally Applied Loperamide in Oral Chronic Graft-versus-host Disease Related Pain
1 Department of Anesthesiology and Palliative medicine, Chiba University Graduate School of Medicine, Chiba
2 Department of Anesthesiology and Palliative medicine, National Cancer Center Hospital, Tokyo, Japan
For reprints and all correspondence: Natsuko Nozaki-Taguchi, Department of Anesthesiology and Palliative medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo, Chiba 260-8677, Japan. E-mail: nnoztag{at}faculty.chiba-u.jp
Received June 18, 2008; accepted September 16, 2008
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Abstract |
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Four patients with oral chronic graft-versus-host disease pain were treated with loperamide oral-rinse solution. Two-week continued use of the drug solution improved not only the pain scores but also the pain-causing disabilities associated with eating, drinking and sleeping, with no noticeable side effects. Current results suggest that the mu-opioid agonist, loperamide, has a potential analgesic effect that could be clinically used as a peripheral analgesic agent for stomatits pain. However, these observations will need to be further confirmed in a randomized-controlled trial.
Key Words: loperamide • chronic graft-versus-host disease • stomatitis
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INTRODUCTION |
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Chronic graft-versus-host disease (cGVHD) is a common long-term complication of allogeneic hematopoietic stem cell transplantation. Of the many cGVHD features seen in patients, oral cGVHD can significantly affect the quality of life due to discomfort and the impairment of oral intake, which can lead to malnutrition and, in some instances, increased morbidity (1). The initial and continued symptoms that present in oral cGVHD are pain and dryness of the oral cavity. Various local treatment therapies designed to treat one area of the body intensively while sparing the patient from systemic side effects, have been attempted. For example, palliative rinses, topical immunosuppressive agents, steroids and phototherapy have all been tried in oral cGVHD. We report on four patients suffering from oral cGVHD pain who were successfully treated using locally applied loperamide.
The loperamide solution was prepared by the Chiba University Hospital (CUH) Pharmacy as follows: Loperamide hydrochloride (Sigma: 1 g) was dissolved in 900 ml of boiling distilled water. After the solution cooled, distilled water was further added to make a 1 l solution. Carboxymethylcellulose sodium (CMC-Na) (Maruishi: 10 g) was added to the solution, which was then maintained at 4°C overnight. The following day, after thoroughly mixing the solution, a 50–100 ml portion was taken out and mixed with a small amount of lecithin, which was used as a bitterness inhibitor (2) (Kao: BMI-40). The modified mixture was returned to the original solution, and the same procedure continued repeatedly until a total of 50 g of lecithin had been mixed into the solution. Finally, 100 ml aliquots of the solution were placed in individual containers that were kept at –80°C until use. The Ethics Committee of the National Cancer Center Hospital and CUH approved the protocol for this study and all patients provided written informed consent prior to enrollment in the study.
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CASE 1 |
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A 33-year-old man with acute myeloid leukemia underwent successful bone marrow transplantation treatment from an unrelated donor 4 months previously. At the time of enrollment into the study, he was suffering from oral cGVHD that was being treated with tacrolimus hydrate (1.2 mg) and betamethasone mouthwash. However, the treatment provided no apparent pain relief. The maximum, minimum and average pain levels experienced during the 24-h assessment period were 3, 0, and 1, respectively, when using a 0 to 10 numerical pain scale (NRS), where 0 denoted no pain and 10 denoted the worst pain possible. The effects of his oral pain on daily activities (eating, drinking, sleeping, pastime activities and general activities) were also assessed by a brief pain inventory (3). These were expressed as numerical scores ranging from 0 to 10, with 0 denoting no disturbance of the activity and 10 denoting total disturbance of the activity. The patient’s scores were: eating, 10; drinking, 7; sleeping, 9; pastime activities, 5; and general activities, 0. The treatment using the loperamide oral-rinse solution (15 ml) consisted of rinsing the oral cavity three times a day at 30 min prior to each scheduled meal. The patient was instructed to keep the oral-rinse solution in the oral cavity for at least 2 minutes and moreover, he was told not to swallow the solution. While the first mouthwash had no effect on his oral pain, with continued use his pain-causing disturbance scores started to improve. At 2 weeks his scores were: eating, 4; drinking, 2; sleeping, 0; pastime activities, 1; and general activities, 0 (Fig. 1). No improvement was seen in his stomatitis condition and no notable side effects were observed. He continued using the oral-rinse solution for several months until worsening of other systemic cGVHD symptoms required further hospitalization.
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CASE 2 |
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A 40-year-old woman with acute myeloid leukemia underwent a successful peripheral blood stem cell transplantation (PBSCT) treatment using stem cells obtained from her brother. Oral cGVHD pain continued for 9 months after the original transplantation. Ciclosporin and betamethasone mouthwash treatments provided no pain relief. Her maximum, minimum and average pain scores during the 24-h assessment period were 5, 0, and 3, respectively. A brief pain inventory revealed her scores for disturbance in daily activities to be: eating, 10; drinking, 10; sleeping, 0; pastime activities, 5; and general activities, 0. A gradual improvement in her pain was noted after she started using the loperamide mouthwash (same solution and schedule as used in Case 1). Maximum and average pain scores decreased to 3 and 1, respectively. While her scores for disturbances in eating (7) and drinking (2) improved, there were no improvements noted for any of her other activities (Fig. 1). After the drug was stopped, the oral pain resumed, suggesting that there was no improvement in her stomatitis after the 2-week treatment period. Though no systemic side effects were observed, she complained that the bitterness of the mouthwash solution caused alterations in her taste, and in addition, she also noted slight nausea upon use of the solution.
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CASE 3 |
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A 46-year-old man with chronic lymphocytic leukemia underwent successful bone marrow transplantation (HLA full match) from an unrelated donor 9 months prior to the study enrollment. Although his oral cGVHD pain was severe, he was not taking any immunosuppressants or steroids since there were no other relevant cGVHD symptoms. His maximum, minimum and average pain scores during the 24-h assessment period were 6, 4, and 5, respectively. Pain-causing daily activity disturbances were: eating, 8; drinking, 8; sleeping, 6; pastime activities, 5; and general activities, 7. After 2 weeks of continued use of the loperamide mouthwash, his maximum, minimum and average pain scores dropped to 4, 2, and 3, respectively. While scores for daily activity disturbances improved for eating (6), drinking (6) and sleeping (3), there were no changes noted for any of his other activities (Fig. 1). There were also no changes in the condition of his stomatitis or any apparent local side effects. Systemically, he experienced a more constipated state during the experimental trial, although this did not require any additional pharmacological treatment.
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CASE 4 |
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A 61-year-old female with acute lymphocytic leukemia underwent successful PBSCT treatment after receiving stem cells from her brother, 2 years and 4 months prior to the study enrollment. After the onset of the oral cGVHD, the severity of the symptoms fluctuated. She was systemically treated with the immunosuppressant ciclosporin (10 mg), and locally treated with betamethasone mouthwash. Due to the oral pain, there was a decrease in oral food intake, leading to her reliance on a fluid diet. She was admitted to the hospital due to malnutrition and a depressed mental state. Her maximum, minimum and average on the NRS were 5, 2, and 3. Ratings for daily activity disturbances due to pain were: eating, 8; drinking, 3; sleeping, 5; pastime activities, 3; and general activities, 3. After the first mouthwash, she noted no change in her oral pain at rest. However, she noted significant improvement in pain upon eating (NRS 1/10). After 2 weeks of continued use, although her maximum, minimum and average pain scores did not change (5, 1 and 3, respectively), there was improvement in the scores for her daily activity disturbances due to pain for eating (5), sleeping (3) and general activities (2). She noted no changes for drinking or pastime activities (Fig. 1), and in addition, there was no improvement in her stomatitis condition. While she complained of the bitter taste and the thick texture of the rinse solution, there were no apparent side effects observed and subsequently, she was discharged from the hospital and continued to use the mouthwash.
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DISCUSSION |
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TOPAbstractINTRODUCTIONCASE 1CASE 2CASE 3CASE 4DISCUSSIONCONCLUSIONFundingAcknowledgementsReferences |
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Use of the peripherally acting opioid agonist, loperamide, as an oral-rinse solution in oral cGVHD patients effectively relieved the stomatitis pain and improved scores for the daily activity disturbances due to pain. No noticeable side effects were observed except for complaints concerning the bitter taste and the unpleasantness of the thick texture of the drug. In 3 patients, betamethasone mouthwash was initially used, but did not provide any relief from pain. Therefore, the anti-hyperalgesic effect of the loperamide mouthwash is most likely a specific effect of the oral wash. When attempting to increase the quality of life in patients with oral pain, analgesic effects need to be effective without any concurrent loss of taste and sensation, which are often sacrificed when using oral-rinse solutions combined with local anesthetics. In the current study, use of peripheral loperamide appears to have achieved this goal.
Oral cGVHD commonly occurs and is reported to impede the quality of life of long-term survivors of hematological malignancies. While systemic immunosuppressive therapy is indicated for cGVHD treatment, there are great disadvantages of this therapeutic approach including significant side effects such as an increased frequency of opportunistic infections and renal insufficiency. Even with routine systemic treatments, resolution of oral cGVHD is often not achieved and thus, can lead to a decreased oral intake. Unfortunately, systemic non-steroidal anti-inflammatory drugs, as well as opioids, are not able to sufficiently control the incidental pain induced by eating and drinking. In many cases, the slightest amount of pain can decrease a patient’s quality of life, and if the pain creates difficulty in eating and drinking, this can subsequently lead to a patient becoming malnourished. Thus, better control of oral cGVHD pain is crucial when trying to improve the quality of life in survivors of hematological malignancies.
While our results are promising, our current study has several limitations including a very small sample size, the lack of a control group, and the fact that no dose-dependency was shown. In addition, only subjective scores were used to assess the effect of the drug, and there were no objective scores such as changes in body weight or nutritional state assessed. Although this study was conducted in two hospitals over a period of 2 years, the sample size was indeed very limited. This was not because oral cGVHD is not relevant or rare, but was because of the difficulties in finding patients who have no other systemic cGVHD manifestations while undergoing treatment. In the current study, we chose a dosing of 0.1% because a 0.1% dose of morphine oral wash has been reported to be effective in treating oral stomatitis pain induced by chemoradiation for head and neck malignancies (4). Loperamide was chosen over morphine in this study, because despite increased morphine concentrations having a better analgesic effect, they can also produce systemic absorption, which inevitably results in a systemic analgesic effect. When using the same concentration, loperamide appears to be more potent with regard to its receptor affinity, as well as its limited central action (5,6). Therefore, we expected to see a stronger peripheral analgesic effect. However, due to the as yet very limited number of patients tested, we have not been able to examine other dosing levels. Even with all of the above-discussed limitations, we consider it important to report the results of these few successful cases. Stomatitis pain is not relegated to only those patients with cGVHD, but in fact, is more frequent and of a more severe nature in acute GVHD and in chemotherapy and/or radiation-induced stomatitis cases. Thus, it is important that in future we expand upon these results to include all patients suffering from treatment-induced stomatitis pain. At present, we are currently designing a trial that will use a preparation with an improved taste and texture that may very well be the key that will allow a more general use of this drug as a painkiller for cancer treatment-induced oral mucositis.
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CONCLUSION |
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TOPAbstractINTRODUCTIONCASE 1CASE 2CASE 3CASE 4DISCUSSIONCONCLUSIONFundingAcknowledgementsReferences |
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We present four cases in which a loperamide mouthwash was found to be effective in relieving oral cGVHD pain, suggesting that this therapy might have the potential to improve the quality of life in bone marrow transplantation treatment survivors.
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Funding |
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TOPAbstractINTRODUCTIONCASE 1CASE 2CASE 3CASE 4DISCUSSIONCONCLUSIONFundingAcknowledgementsReferences |
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This study was supported by Grant-in-Aid for Cancer Research from the Japanese Ministry of Health, Labor and Welfare (15–23).
Conflict of interest statement
None declared.
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Acknowledgements |
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TOPAbstractINTRODUCTIONCASE 1CASE 2CASE 3CASE 4DISCUSSIONCONCLUSIONFundingAcknowledgementsReferences |
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We would like to thank the CUH pharmacy staff members, Ms. H Saeki, Ms. M Tanaka and Mr. H Nakasa for their help in preparing the study drug, Nurse M Araki and Dr. Fukuda for their help in recruiting patients at National Cancer Center, and Prof. T Nishino for his advice in preparing this manuscript.
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References |
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1 Woo S-B, Lee JS, Schubert MM. Graft vs. host disease. Crit Rec Oral Biol Med (1997) 8:201–16.[CrossRef]
2 Katsuragi Y, Mitsui Y, Umeda T, Otsugi K, Yamasawa S, Kurihara K. Basic studies for the practical use of bitterness inhibitors: selective inhibition of bitterness by phospholipids. Pharmaceutical Res (1997) 14:724–8.
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4 Cerchietti LC, Navigante AH, Korte MW, Cohen AM, Quiroga PN, Villaamil EC, et al. Potential utility of the peripheral analgesic properties of morphine in stomatitis-related pain: a pilot study. Pain (2003) 105:265–73.[CrossRef][Web of Science][Medline]
5 Nozaki-Taguchi N, Yaksh TL. Characterization of the anti-hyperalgesic action of a novel peripheral mu-opioid receptor agonist loperamide. Anesthesiology (1999) 90:225–34.[CrossRef][Web of Science][Medline]
6 Menendez L, Lastra A, Meana A, Hidalgo A, Baamonde A. Analgesic effects of loperamide in bone cancer pain in mice. Pharmacol Biochem Behav (2005) 81:114–21.[CrossRef][Web of Science][Medline]
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