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The management of pain endured by patients after skin grafting is complex. Pain is the single most distressing symptom but as it is difficult to manage, it is often under-treated. These patients may experience pain from two types of wound: the original injury and from "skin-donor" sites, areas of healthy skin from which skin is surgically removed and used to cover the original injury. As the section of skin which is removed is standardized, the wound created at the donor site is uniform and so provides a model of an acute wound.
Opioids (such as morphine) are the backbone of treating the moderate to severe pain experienced by any patient. But due to their potentially severe side effects and that some patients do not experience sufficient relief from the treatment, optimal treatment schedules are still being sought after.
Topically applied morphine has provided effective and safe analgesia in several clinical models. We, therefore, wish to apply this treatment modality onto skin-graft donor wounds. If found to be effective this could be an appealing non-invasive method to treat the pain of this type of wound.
Administration of morphine into the knee joint is the best-studied clinical procedure documenting the use of topically-applied opioids. When 1-5 mg morphine were injected into the knee joint, patients experienced pain relief for up to 24 hours, whereas similar doses given systemically (i.e. intravenously) were effective for 2-4 hours. Furthermore, the analgesic effect was reversed when the opioid antagonist naloxone was injected into the knee joint. Both these findings indicate that the effect is mediated by local opioid receptors in the knee joint.
Peripheral analgesic effects of opioids are not detectable in normal tissue but appear minutes to hours after initiation of inflammation. This suggests that opioid receptors are already present in the peripheral nerve terminals but under normal conditions they are not functional.
Research on application of opioids to skin wounds is very sparse and has primarily been performed in palliative care patients. These reports demonstrate that topical opioid gel (morphine or diamorphine) provided rapid and effective relief. In some patients pain subsided within 20 minutes after application with a long-lasting (7-8 hours) effect. Fundamental aspects regarding topical application of opioids onto skin wounds are still lacking. For example, issues such as optimal dose and dose-effect relationships have not been investigated. We hope to determine these in this study.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo | Placebo Comparator | Gel with no active ingredient |
|
| Morphine .25 mg | Active Comparator | Gel with 0.25 mg morphine per 100cm2 square of wound |
|
| Morphine - .75 mg. | Active Comparator | Gel with 0.75 mg morphine per 100cm2 square of wound. |
|
| Morphine 1.25 mg. | Active Comparator | Gel with 1.25 mg morphine per 100cm2 square of wound. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Placebo | Other | Gel with no active ingredient. |
| |
| Morphine - .25 mg |
| Measure | Description | Time Frame |
|---|---|---|
| Pain score in first 24 hours | Sum of the differences in pain scores between the skin-donor site vs. original injury site taken over a 24 hour period after application of the medication. | 24 hours after application of the medication |
| Measure | Description | Time Frame |
|---|---|---|
| Pain Score | Pain score at skin-donor site using an abbreviated form of the McGill Pain Questionnaire | 24 hours after surgery |
| Time course of analgesia for each drug concentration | Time course of analgesia for each drug concentration |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Yehuda Ullman, M.D. | Rambam Health Care Campus | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Plastic Surgery, Rambam Medical Center | Haifa | 31096 | Israel |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 10204724 | Background | Krajnik M, Zylicz Z, Finlay I, Luczak J, van Sorge AA. Potential uses of topical opioids in palliative care--report of 6 cases. Pain. 1999 Mar;80(1-2):121-5. doi: 10.1016/s0304-3959(98)00211-5. | |
| 1653901 | Background | Stein C, Comisel K, Haimerl E, Yassouridis A, Lehrberger K, Herz A, Peter K. Analgesic effect of intraarticular morphine after arthroscopic knee surgery. N Engl J Med. 1991 Oct 17;325(16):1123-6. doi: 10.1056/NEJM199110173251602. |
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| ID | Term |
|---|---|
| D010146 | Pain |
| D002056 | Burns |
| ID | Term |
|---|---|
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D014947 | Wounds and Injuries |
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| ID | Term |
|---|---|
| D009020 | Morphine |
| ID | Term |
|---|---|
| D009022 | Morphine Derivatives |
| D009019 | Morphinans |
| D053610 | Opiate Alkaloids |
| D000470 | Alkaloids |
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| Drug |
gel with 0.25 mg morphine per 100cm2 square of wound. |
|
| Morphine | Drug | Gel with 0.75 mg morphine per 100cm2 square of wound. |
|
| Morphine | Drug | Gel with 1.25 mg morphine per 100cm2 square of wound. |
|
| First 24 hours after surgery |
| Side effects | Presence and severity of side effects: (a) central (nausea, vomiting, sedation, purities) and (b) local (burning, tingling, wheal, flare) | First 24 hours after surgery |
| Supplementary analgesic medications | Concurrent, supplementary, "rescue", analgesic medication (i.v.or oral morphine), given during the first 24 hours post operatively | First 24 hours after surgery |
| Analgesic medicine from 2nd post-operative day until dressings are removed. | Analgesic medication (type and dose), given from the second post-operative day until dressings are removed for the first time (= the 12th post-operataive day, on average). | Day 2 post-surgery through 12th post-op day on average |
| Pain score collection | Pain scores at donor and original injury, twice daily, from the second post-operative day until dressings are removed for the first time - up until 8th post-op day | Twice daily from day 2 post-op until day 8 post-op |
| Wound assessment | Assessment of the wound once the dressings are removed | Average day 12 post-operative |
| 16256893 | Background | Porzio G, Aielli F, Verna L, Cannita K, Marchetti P, Ficorella C. Topical morphine in the treatment of painful ulcers. J Pain Symptom Manage. 2005 Oct;30(4):304-5. doi: 10.1016/j.jpainsymman.2005.08.011. No abstract available. |
| 15120772 | Background | Ribeiro MD, Joel SP, Zeppetella G. The bioavailability of morphine applied topically to cutaneous ulcers. J Pain Symptom Manage. 2004 May;27(5):434-9. doi: 10.1016/j.jpainsymman.2003.09.011. |
| 10568861 | Background | Stein A, Yassouridis A, Szopko C, Helmke K, Stein C. Intraarticular morphine versus dexamethasone in chronic arthritis. Pain. 1999 Dec;83(3):525-532. doi: 10.1016/S0304-3959(99)00156-6. |
| 15733803 | Background | Zeppetella G, Ribeiro MD. Morphine in intrasite gel applied topically to painful ulcers. J Pain Symptom Manage. 2005 Feb;29(2):118-9. doi: 10.1016/j.jpainsymman.2004.12.006. No abstract available. |
| 12894165 | Background | Stein C, Schafer M, Machelska H. Attacking pain at its source: new perspectives on opioids. Nat Med. 2003 Aug;9(8):1003-8. doi: 10.1038/nm908. |
| D006571 |
| Heterocyclic Compounds |
| D006572 | Heterocyclic Compounds, Bridged-Ring |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D010616 | Phenanthrenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D011083 | Polycyclic Compounds |