Topical Morphine for Analgesia in Patients With Skin Grafts

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Topical Morphine for Analgesia in Patients With Skin Grafts

Conditions
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Skin Transplantation, Pain

Intervention / Treatment
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* Other: Placebo
* Drug: Morphine - .25 mg
* Drug: Morphine
* Drug: Morphine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients undergoing skin-grafting American Society of Anesthesiologists (ASA) classification I-II Written consent Either sex Able to self-asses and report their pain level Exclusion Criteria: Alcohol abuse or addiction - current Opioids and benzodiazepines abuse - life time Known hypersensitivity to morphine Major renal or hepatic dysfunction Pregnancy or lactation Sleep-apnoea-syndrome Diabetes Participation in other clinical studies

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Gel with no active ingredient | Other: Placebo<br>* Gel with no active ingredient.<br>|
| Active Comparator: Morphine .25 mg<br>Gel with 0.25 mg morphine per 100cm2 square of wound | Drug: Morphine - .25 mg<br>* gel with 0.25 mg morphine per 100cm2 square of wound.<br>|
| Active Comparator: Morphine - .75 mg.<br>Gel with 0.75 mg morphine per 100cm2 square of wound. | Drug: Morphine<br>* Gel with 0.75 mg morphine per 100cm2 square of wound.<br>|
| Active Comparator: Morphine 1.25 mg.<br>Gel with 1.25 mg morphine per 100cm2 square of wound. | Drug: Morphine<br>* Gel with 1.25 mg morphine per 100cm2 square of wound.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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 | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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topical, morphine, pain, skin-wound, skin-graft, peripheral analgesia, burn