Topical Morphine for Analgesia in Patients With Skin Grafts

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.

Study Overview

• Status: Withdrawn
• Conditions: Pain; Skin Transplantation
• Intervention / Treatment: Other: Placebo; Drug: Morphine - .25 mg; Drug: Morphine; Drug: Morphine

Detailed Description

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.

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• Israel
  • Haifa, Israel, 31096
    • Department of Plastic Surgery, Rambam Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Rambam Health Care Campus
• Investigators: Principal Investigator: Yehuda Ullman, M.D., Rambam Health Care Campus

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Anticipated): January 1, 2022
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): December 1, 2024

Study Registration Dates

• First Submitted: August 8, 2006
• First Submitted That Met QC Criteria: August 8, 2006
• First Posted (Estimate): August 9, 2006

Study Record Updates

• Last Update Posted (Actual): May 3, 2022
• Last Update Submitted That Met QC Criteria: April 27, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: pain; morphine; topical; burn; skin-wound; skin-graft; peripheral analgesia
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Morphine
• Other Study ID Numbers: RMC-2468.CTIL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No