By: Katharine Cimmino, Editor-in-Chief

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Pressure ulcers can be a painful condition decreasing the quality of life of patients and prolonging hospital stays.¹ About 10% of hospital inpatients and 26% of hospice admissions have pressure sores.² Pressure ulcers are injuries that occur when pressure is applied for prolonged periods of time over bony prominences.¹ There are many factors that play into the development of pressure ulcers including the pressure applied to the area, the lack of oxygen being supplied to the tissue, shear force applied to a patient, friction to superficial skin, moisture (mostly from perspiration, feces, or urine), immobility, incontinence, circulatory factors, nutritional status, neurologic disease, and more.³ The severity of the pressure ulcer can range from redness of the skin to deep ulcers that extend to the bone. While the best relief would come from a completely healed ulcer, this can be a slow process and may not always be achievable, especially in a palliative care setting.² Since this condition is mainly prevalent in the elderly and critically ill, therapy should be tailored that provides the most pain relief with the least amount of side effects. Because of this, topical morphine can be considered a good pharmacologic option for patients who suffer from pressure ulcer wounds. Opioid receptors are generally found in the central nervous system, however after inflammation, they can be found in normal tissues in the nerve terminals.^{2, 4-5} 

One study examined six hospice patients with their treatment of ulcers, averaging a size of 12.8 cm². In a randomized order, the patients were either given morphine sulfate 10 mg in intrasite gelTM or morphine sulfate 10 mg subcutaneous over 4 hours. In this crossover study, each drug was given at least 48 hours apart. Afterwards morphine and its metabolites (morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G)) were measured. This study showed that when using the topical formulation, morphine, M3G, and M6G were only detectible in 1 out of 6 patients; however, that patient had the largest ulcer size (60 cm²). In this patient, the calculated morphine and M6G bioavailability was approximately 20%. It should be noted that the patient’s bioavailability is still relatively small and the side effects should therefore be negligible. In addition, neither the patients nor the nursing staff reported adverse effects, local or systemic.⁶ If the wound has a large surface area, the study concludes that the absorption of morphine is not significant enough to potentiate systemic side effects.

Many case reports state how patients are admitted to the hospital due to inadequate pain control from oral opioids when they have pressure ulcers. After therapy of topical morphine gel these patients are able to resume functions of daily living such as feeding or bathing. In addition, they report a decrease in pain and most patients even decrease their dose of oral opioids.^{4, 7,8} Twillman et al reported eight out of nine patients had a reduction in pain. Most morphine intrasite gelTM compounds are made with a 0.1% w/w composition with the recommendation to start the application twice a day.⁴ Back and Finlay reported that after application of diamoprhine intrasite gelTM, pain relief was achieved in three of their patients, no deterioration occurred to the area of application, and one patient continued treatment for over 2 months.⁷ Porzio G, Aielli F, Verna L, et al reported five patients who were uncontrolled on systemic opioids, and after being given 10 mg in 8 g intrasite gelTM (0.125% w/w) three times a day, patients reported prompt relief that was maintained throughout the stay. Prior to the application the ulcers were washed with lactated ringers and metronidazole solution.⁸ The critical review by Graham T, Grocott P, Probst S, et al examined 27 articles, both controlled studies and case reports, which included 170 patients. Most importantly, pain relief was achieved with topical opioids for patients who had pressure or malignant wounds.⁹ Overall, the use of topical morphine is a very common practice; it yields good pain relief for ulcer wounds without the systemic side effects of nausea, constipation, drowsiness, and sedation.

Very few trials have been conducted on the use of topical opioids in pressure ulcers.  However, after the success stories of individual case studies, a randomized, double-blind, placebo-controlled crossover trial was conducted at the St. Christopher’s Hospice inpatient unit in the United Kingdom. This study entered 13 patients who had Stage II or Stage III pressure ulcers (which meant that the skin had been affected, but the damage had not yet spread to the bone), of which only seven patients completed the trial. Diamorphine gel (a 0.1% w/w composition containing diamorphine as the active ingredient and intrasite gelTM as the base) was compared to the placebo or just intrasite gelTM.¹⁰ In the UK, diamorphine (also known as heroin) can be legally used for severe pain associated with surgical procedures, pain in the terminally ill, myocardial infarction, and for the relief of dyspnea in acute pulmonary edema.¹¹ In the study, gels were applied once daily and covered with a dressing. Pain was measured using a standardized score. The pain scores that were counted were those that had at least a 2-day washout period to ensure that the active diamorphine gel never influenced the placebo. Pain scores improved significantly in the diamorphine group compared to baseline both after 1 hour (P = 0.003) and after 12 hours (P = 0.005). No statistically significance was found in the placebo group. The most common side effects were pruritus and skin irritation. One to two patients experience systemic side effects of drowsiness, hallucinations, and nightmares, however it should be noted that their fentanyl dose was changed and the side effects were most likely attributed to this factor. In addition, all patients were receiving some form of oral opioid medicine and non-steroidal anti-inflammatory medication (NSAIDs).¹⁰ Although this study did not examine morphine gel directly, few controlled trials are conducted using topical opioid creams because these drugs must be compounded. Based upon the case reports, the results from this trial can be extrapolated so that morphine gel can be safely and effectively used in patients with pressure ulcers wounds who do not receive adequate pain control on their conventional regimen.

In another pilot study, the effects of topical morphine were assessed in patients with painful ulcers in a randomized, double-blind, placebo-controlled crossover study where five patients were treated with either 10 mg of morphine sulfate or placebo for two days with a two day wash-out period. Most patients were on scheduled opioid treatment for pain. No local adverse effects could be attributed specifically to morphine. The study found that patients found more relief with topical morphine compared to placebo.²

While the case reports and both of these studies show the efficacy of topical morphine, further studies need to be conducted before clinical guidelines are made. It should be noted that while both studies may be disposed to Type II error (or the error of being too small to detect a difference), significant pain scores were still achieved among patients in the study conducted by Flock. ¹⁰ Others may argue that patients were receiving other drugs such as oral narcotics and NSAIDs which could also reduce their pain. While these medications may have reduced the patients’ pain scores, the fact is that the placebo gel had little to no effect on the pain score of the patients. In addition, these patients already had uncontrolled pain levels while on oral narcotics, which is why other options were sought out.^{2, 10} Since the drug of choice for pressure ulcers seems to be morphine in a gel base, studies should be done to determine pharmacokinetic parameters such as onset of action, duration of action, absorption, etc… to better help determine dosing intervals and titration methods. In addition, long-term efficacy should be assessed. For now these factors are overlooked since the patient population being treated is general those with terminal conditions, in hospice, or the elderly.

It is also important to note that the side effects could be due to the gel base. Most of the studies and case reports used intrasite gelTM, a gel already commonly used in skin ulcer care management. Intrasite gelTM is a pre-made gel containing water, propylene glycol, and carboxy methyl cellulose. This gel absorbs excess exudates to produce a moist environment around the wound area.⁶ Common side effects, most likely due to the gel, are local irritation and itching.^{2. 5}

Morphine is not commercially available in a topical gel formulation and must therefore be compounded. Although other opioids can be used, morphine is relatively inexpensive and available in liquid formulation making it easier to compound. Other narcotics such as methadone powder (when mixed with inert powder such as Stomahesive® powder)^{2, 5, 12} or diamorphine (however when mixed with instrasite gelTM has shown to degrade quicker6) have been used. Also, other bases such as metronidazole gel and silver sulfadiazine cream have been used.^2,5 Most practitioners prefer using morphine in the intrasite gelTM since it has the most evidence surrounding its use.

When prepared under sterile conditions, the morphine and intrasite gelTM combination is stable for up to 28 days, but when compounded under non-sterile conditions, it should not be used for more than 7 days due to concerns about infection control.^2,5

The Journal of Supportive Oncology released a treatment algorithm that explains how to treat a patient with painful ulcers. The general approach is to start a patient on an “as needed” oral pain medication with or without long acting analgesics. Since skin ulcers are extremely painful, the patient either exhibits dose-limiting side effects or has uncontrolled pain which results in higher doses of the medication (and eventually is admitted to the hospital due to inadequate pain control). The next step is to add the morphine gel. It is recommended to apply a concentration of 10 mg morphine sulfate injection with 8g of neutral water-based gel (0.125% w/w) twice daily for Stage 2 – 3 ulcers. For Stage 4 ulcers, it is suggested to apply a concentration of 10 mg of morphine sulfate injection with 10g of neutral water-based gel (0.1% w/w) daily. The practitioner can titrate the gel by increasing the concentration of the mixture or increasing the dosing frequency. It is recommended to titrate up to 10 mg of morphine sulfate injection with 5g of a neutral water-based gel (0.2% w/w) two to three times a day.⁵ The amount of gel depends on the size of the ulcer. It is important to irrigate the wound first before applying the gel. Make sure enough of the gel is applied to cover the whole surface of the wound.¹³

Therefore, topical morphine can be a safe alternative in patients with pressure ulcers and it often has shown to provide more relief than systemic opioids. Although a larger trial should be conducted to determine clinical guidelines, topical morphine can be applied in a 0.1% w/w concentration two to three times a day under supervision until adequate pain relief is obtained. Proper wound care should always be practiced while applying the drug and changing the dressing. Since pressure ulcers are more prevalent in the bed-bound, hospice patient, and elderly, this drug is a good option. Topical opioids achieve greater pain relief, thus reducing the need for systemic opioids, which have the side effects of constipation, sedation, confusion, respiratory depression, and drowsiness.

SOURCES:

1. Berlowitz, D. Treatment of pressure ulcers. UpToDate web site. April 8, 2013. Accessed January 29, 2013. http://www.uptodate.com/contents/treatment-of-pressure-ulcers?source=search_result&search=pressure+ulcer&selectedTitle=1%7E115.
2. Zeppetella G, Paul J, Ribeiro MD. Analgesic efficacy of morphine applied topically to painful ulcers. Journal of Pain and Symptom Management. 2003; 25:555.
3. Berlowitz, D. Pressure ulcers: Epidemiology, pathogenesis, clinical manifestations, and staging. UpToDate web site. May 8, 2013. Accessed January 29, 2013. http://www.uptodate.com/contents/pressure-ulcers-epidemiology-pathogenesis-clinical-manifestations-and-staging?source=search_result&search=pressure+ulcer&selectedTitle=2%7E115.
4. Twillman R. Long T, Cathers C, Mueller D. Treatment of painful skin ulcers with topical opioids. Journal of Pain and Symptom Management. 1999; 17 (4): 288- 292
5. Quy T, Fancher T. Achieving analgesia for painful ulcers using topically applied morphine gel. The Journal of Supportive Oncology. 2007; 5 (6): 289-293.
6. Ribeiro M, Joel S, Zeppetell G. The bioavailability of morphine applied topically to cutaneous ulcers. Journal of Pain and Symptom Management 2004; 27 (5): 434–439
7. Back I, Finlay I. Letter: Analgesic effect of topical opioids painful skin ulcers. Journal of Pain and Symptom Management. 1995; 10 (7): 493
8. Porzio G, Aielli F, Verna L, et al. Letters: Topical morphine in the treatment of painful ulcers. Journal of Pain and Symptom Management. 2005; 30 (4): 304-305
9. Graham T, Grocott P, Probst S, et al. How are topical opioids used to manage painful cutaneous lesions in palliative care? A critical review. Pain. 2013; 154 (10): 1920–1928.
10. Flock P. Pilot study to determine the effectiveness of diamorphine gel to control pressure ulcer pain. Journal of Pain and Symptom Management. 2003; 25:547.
11. Diamoprhine HCl [package insert]. Maidenhead, UK: ViroPharma; 2014. http://www.medicines.org.uk/emc/medicine/28259/SPC/
12. Gallagher R, Arndt D, Hunt K. Analgesic effects of topical methadone. Clinical Journal of Pain. 2005; 21 (2): 190-192
13. Gallagher R. Management of painful wounds in advanced disease. Can Fam Physician. 2010;56(9):883-5, e315-7.

[pubmed_related keyword1=”pressure” keyword2=”ulcer” keyword3=”opioid”]

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