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Morphine-Infused Silver Sulfadiazine (MISS) Cream for Burn Analgesia: A Pilot Study

Morphine-Infused Silver Sulfadiazine (MISS) Cream for Burn Analgesia: A Pilot Study Abstract Pain is considered the most distressing symptom of a burn wound, with analgesia usually provided via oral or parenteral medications. Use of systemic opioids can be complicated by fluctuations in bioavailability, absorption, and clearance of drugs caused by the burn. There has been little research done in the area of topical medications for burn analgesia. The following is a double-blind, placebo-controlled pilot study assessing the safety (side effects) and efficacy (pain ratings and medications administered) of morphine-infused silver sulfadiazine cream for burn pain. Four patients are reported on (2 in each group). Only participants taking placebo reported side effects related to morphine and necessitated anxiolytic medications. Pain ratings in the treatment group ranged from 0 to 7 with a mean of 2.1, whereas the placebo group's ratings ranged from 2 to 8 with a mean of 5.6. The placebo group averaged 55.3 mg oral morphine per half day, whereas the treatment group averaged 42.9 mg. It is estimated that approximately 1.25 million burn injuries occur per year, 25% of these resulting in acute hospital admissions. 1 The average inpatient stay for the treatment of burns is 13.5 days 2 per incident. Pain is, without a doubt, the single most distressing symptom of any burn, yet it is often underrecognized and more often undertreated, because it is difficult to manage. Burn wounds are painful initially and longitudinally. 3 Severe pain is felt during acute treatment and rehabilitation, especially during dressing changes, debridements, and skin grafting, and continues through long-term follow-up. 3,4 Burn pain is not caused by a single physiologic mechanism, but is felt to have components of both nociceptive and neuropathic pain. 3 There has been a common misconception in the medical community that because of destruction of peripheral nociceptors, full-thickness (3rd degree) burns are less painful than partial-thickness burns. This notion has been refuted by other researchers, 5 who found that larger areas of full-thickness burns were associated with higher pain ratings. The backbone of burn analgesia is opioid therapy, administered via oral or parenteral routes. 4 The use of medications with these patients is complicated by the fluctuation in bioavailability of drugs, protein binding, volume of distribution, and clearance related to the hemodynamic and volume shifts that occur with burn injury. Intestinal absorption of hydrophilic compounds or macromolecules may be affected for the first few days after a burn, with increased permeability to bacteria. Patients with burns exhibit decreased albumin and increased α-1-acid glycoprotein levels, which affect the distribution, elimination, and even pharmacologic effect of drugs. Consequently, the distribution of those drugs with high protein binding may be altered, and renal clearance of drugs may be altered. The latter may be affected by plasma clearance, variation in glomerular filtration rate, tubular secretion, and tubular reabsorption. Additionally, both filtration and secretory clearance are substantially increased during the hypermetabolic phase of burns. 6 Adding to the difficulty of predicting drug levels, the hepatic clearance of high-extraction drugs is increased, although that of low-extraction drugs may be decreased, so that the elimination half-life of medications is largely unknown. 7 Studies of the opioid pharmacokinetics and pharmacodynamics of burn patients is sparse, with varied results. In studying the use of alfentanil with burn patients, researchers found a decreased volume of distribution, free drug, and clearance, rendering dose adjustment unclear. 8 In a similar study of morphine, Furman et al 9 reported a decreased volume of distribution and clearance, as well as an increased half-life necessitating a dose adjustment downward. Denson et al 10 studied methadone pharmacokinetics in burn patients and noted that because of an unchanged volume of distribution and increased clearance, methadone should be loaded as usual, but maintenance doses should be increased. Such varied responses to oral and parenteral opioids makes topical application of analgesics an attractive alternative for this population. Topical treatment is presumed to provide analgesia at the peripheral opioid receptors with minimal absorption. There are several characteristics of burn wounds that change during the course of healing. In a study of burns in mice, 11 changes in the permeability of burn eschar was evaluated. There was a 50% increase in permeability that persisted for the first 4 to 5 days postburn, and increased further through approximately Day 10, after which it began to diminish. As early as 1968 the topical absorptive qualities of burn wounds were studied. Stone et al 12 compared the absorption of gentamicin sulfate using both a water-miscible cream and a petrolatum-based ointment. The systemic levels of gentamicin varied depending on the age of the burn wound and the base in which the drug was applied. Highest absorption was found using the water-miscible base. There was immediate and great absorption, which slowed gradually until equilibrium was reached. Similarly, Aoyama et al 13 studied the absorption of tobramycin when applied with a water-miscible cream, polyethylene glycol, or a petrolatum ointment. These researchers also found rapid absorption when cream or polyethylene glycol were used and minimal absorption with the ointment. Silver-sulfadiazine cream is a commonly-used topical antimicrobial agent used on burn wounds to reduce the incidence of infection. Absorption from this agent has been investigated by several authors. In one study 14 the absorption of sulfadiazine was compared after application of silver-sulfadiazine (water-insoluble), sulfadiazine (water-insoluble) creams, or sodium sulfadiazine (water-soluble) cream. Researchers found that absorption was greater with the sodium-based cream than with the other 2 compounds. Despite this lower absorption, when silver-sulfadiazine cream is used, significantly higher and persistent levels of silver are measurable in treated subjects. 15,–17 These findings indicate that the application of topical agents to burns can be expected to produce measurable blood levels of some substances included in those agents. In efforts to treat neuropathic and overall burn pain, the use of topical anesthetic agents has been tried. Adriani and Dalili 18 studied the analgesia obtained when topical local anesthetic agents were applied to superficial burns and found that these agents offered no relief. In 1984 Wehner et al 19 reported seizures after the topical application of local anesthetics on 2 burn patients. Both cases were infants who also received drugs with the potential to cause seizures. Brofeldt et al 20 studied the application of topical lidocaine to partial-thickness burns. These researchers used a 5% lidocaine cream applied at a concentration of 1 mg/cm2, followed by the analysis of blood lidocaine levels. The highest blood level obtained was 5.8 μg/ml in a patient with 28% total body surface area (TBSA) burn. The level was constant, and was associated with significant decrease in pain ratings. We first used morphine-infused silver sulfadiazine (MISS) cream on a burn patient at a 0.5% morphine/cream wt/wt concentration. The analgesia achieved was remarkable (pain ratings dropped to a level of “0”). However, after 1 dose, the patient's skin became erythematous, he became sedated, and the medication was discontinued. This cream was then used in a double-blind study at a 0.005% wt/wt concentration with what seemed to be little efficacy. After the fourth subject was given the MISS 0.005% cream for 4 days, the morphine concentration was increased to 0.01% concentration. Only 1 dressing change was done with the 0.01% MISS cream because this patient's wound required a change in dressing to xeroform (bismuth tribromophenate) gauze. Before the use of MISS 0.01%, the patient received 109 mg (oral morphine equivalent) of break-through medications, and only 39 mg after the MISS 0.01% was applied. Before using MISS 0.01%, the patient required lorazepam 2 and 3 times per day. While the MISS 0.01% was applied to the wound, no anxiolytics were needed. The following double-blind placebo-controlled pilot study was conducted to assess whether the addition of morphine to silver-sulfadiazine cream in a 0.01% concentration seems safe and effective in producing analgesia for burn patients. The effectiveness was measured by pain ratings, the amount of medications administered, and the use of anxiolytics. Safety was assessed by the tracking of side effects. METHODS Subjects Potential subjects were referred to the study by the burn unit staff after obtaining permission from the attending physician for the patient's enrollment. Patients were included if they were 18 years of age or older, their burn had occurred within the past 72 hours, and the burn covered 25% or less total body surface area (TBSA). Exclusion criteria included surgical intervention (which precluded the presence of a donor site at the time of the study), known hypersensitivity to morphine or its metabolites, and cognitive impairment sufficient to limit ability to give informed consent and ratings of pain. Measures Brief Pain Inventory. The Brief Pain Inventory (BPI) is a questionnaire that allows for standardized collection of information related to a painful medical condition. This pain inventory was developed in 1983 21 and was demonstrated to be a valid and reliable self-report measure. As reported by Cleeland and Ryan, 22 this questionnaire is a powerful tool that has demonstrated reliability and validity in different countries, with different cultures, in different languages, in various different pain populations, and in studies assessing the efficacy of pain treatments. The Brief Pain Inventory-Pain Scale (BPI-PS) was used to assess pain throughout the study. This is a numerical scale that ranges from 0 to 10, 0 anchored by “No pain,” and 10 anchored by “Pain as bad as you can imagine.” Opioid Side Effects Questionnaire (OSEQ). An adjective list similar to that used by Preston and colleagues 23,–28 at Johns Hopkins University School of Medicine was used to assess the side effects of topically applied morphine. The following side effects were rated between 0 (not present) to 10 (as bad as you can imagine): constipation, dry mouth, urinary retention, drowsiness, confusion, hallucinations, nausea, itching, and depression. Each side effect was listed individually and rated by the patient in conjunction with study personnel. Morphine-Infused Silver Sulfadiazine Cream. Silver-sulfadiazine is a topical sulfonamide compound of silver nitrate and sodium sulfadiazine prepared in a 1% water-miscible cream. It is the most frequent dressing agent applied to deep partial-thickness and full-thickness burns. Morphine powder was added to silver-sulfadiazine 1% cream to achieve a concentration of 0.01% morphine by weight. The investigational pharmacy formulated, dispensed, and tracked the amount of cream applied. Procedures Once identified by staff on the burn unit and referred for the study, consent for participation was obtained in writing, and the inclusion and exclusion criteria were documented. The investigational pharmacist at the university hospital was then contacted and advised that there was a patient enrolled in this study. The investigational pharmacist, who had run a computer-generated randomization chart, supplied blinded study cream to the burn unit, identified only by patient initials, study patient number, day, date, and whether it was to be applied with the morning or evening dressing change. After dressing wounds, nurses were instructed to place the gloves used to apply the cream along with anything left in the jar in a bag provided so that these could be weighed, and an accurate amount of morphine applied calculated. Burn patients were to receive MISS cream or placebo for 4 days with their morning and evening dressing changes, rating their pain 4 times per day with the BPI-PS before the morning dressing change, 6 hours later, before the evening dressing change, and 6 hours after that. Documentation forms for pain ratings were provided to the burn unit nurses, and an investigator was available by pager 24 hours per day to answer any questions; however, not all pain ratings were completed. Side effects were assessed once per day and documented on study records, and concomitant medications were obtained from the official Medication Administration Record. RESULTS Four subjects were entered. After breaking the blind, we found that the first 2 subjects had received placebo cream, and the last 2 had been given the MISS cream. All subjects were male. The 2 who received placebo were 20 and 36 years of age, with 3.5 and 18.1% TBSA burns, respectively. The former had a third-degree burn on the arm, the latter a second-degree burn on the trunk. The men who received MISS cream were 22 and 51 years of age, with 25 and 17.5% TBSA burns, respectively. The younger participant had a second-degree burn to his upper extremities, chest, knee, and right thigh, and the other had a third-degree burn to the left arm. Randomization resulted in groups with comparable characteristics. Surgery intervention was required for 3 participants, and the other's dressing was changed to xeroform; therefore, no one was treated for the full 4 days intended. All subjects received scheduled opioids (MS Contin®, Purdue Pharma, Norwak, CT) for pain, as well as intravenous morphine for breakthrough pain, and to premedicate for dressing changes. These are standard medications ordered upon admission to the burn unit. Other standard orders are for stool softener or laxative, and an anxiolytic, on an as-needed basis. After completion of the study, all medical records were reviewed to document exactly what medications were administered. To standardize opioid use, pain medications were changed to an equianalgesic dose of oral morphine using the Agency for Health Care Policy and Research (AHCPR) Clinical Practice Guidelines for Management of Cancer Pain: Adults. 29 Equianalgesic doses were then totaled to reflect what was given after 1 dressing change up to the next (approximately a 12-hour period). All the subjects in this study were given oral or parenteral opioids. It was not possible to differentiate those that were given routinely, with dressing changes, or at the request of the patient, which is why they are reported as a single amount. Because the MISS cream was applied topically, the morphine did not undergo extensive first-pass metabolism as with oral medications. Because this was a pilot study, pain medications were not controlled in such a way that would allow our determination of the amount of morphine absorbed systemically, nor were these assayed. Consequently, we report the amount of morphine applied in the MISS cream as calculated by the investigational pharmacy (Table 1). Table 1. Doses, effects, and side effects of medicines given View Large Table 1. Doses, effects, and side effects of medicines given View Large Subject A participated in this study for 3 days because on Day 4 his dressing was changed to xeroform. On Day 1, this first (placebo) participant received a total of 40 mg of morphine during the day between the morning and night dressing changes and 60 mg between the first night's dressing change and the next morning's. The following day the morphine equivalents were 78 and 72 mg, day and night respectively, and 65 and 40 mg on the last day this patient was in the study. This individual required anxiolytics on the first 2 days of study, but none on Day 3. During the course of the 3 days, this person's pain ratings ranged from 4 to 8, with an average of 6. Side effects reported while in the study include drowsiness, constipation, and confusion. Subject B (placebo) was studied for only 2 days, because he required surgical intervention on Day 3. He used a total of 66 mg of equianalgesic morphine between the morning and evening dressing change and 72 mg between the evening and next morning's change. On the second day, this participant was only given a total of 60 mg for the entire 24-hour period. Pain ratings were in the moderate range, with individual ratings recorded between 2 and 5, with an average of 3. He also required an anxiolytic on the first day and complained of side effects (sleepiness and sedation). Subject C (MISS cream), like the former participant, was only enrolled in the study for 2 days because he necessitated surgical intervention. This individual only required a morphine equianalgesic amount of 60 mg per half day for the 2 days he was in the study. Pain ratings were reported to be 0 for the first day of the study, and 3 and 2 on the second day. This patient did not require an anxiolytic and complained of no medication-induced side effects. Subject D (MISS cream) first began using study cream with an evening dressing change, unlike the other participants. This person was only given 54 mg of morphine during the first 24 hours and 36 mg during the second 24-hour period. Pain ratings were reported at a mild to moderate level (3 to 7) on the first day, dropping to mild on the second (2 to 4). No anxiolytics were required, and no side effects were reported. Because the small sample size was only 4, 2 participants per group, statistical analyses were not facilitated. Exploratory Mann-Whitney U tests were conducted on each pain rating and half-day medication totals documented between the 2 groups. This was done in violation of the assumption of independence between scores on the test variable. The results of the Mann-Whitney U test on the pain variable were significant (z = −3.187;P =.001), with the placebo group data points having an average rank of 16.77 and the MISS group with an average pain rank of 7.35. The Mann-Whitney U test conducted on the medications taken was near significance (z = −1.797;P = .072); the placebo group data points had a mean rank of 10.80, and the MISS group had a mean of 6.43. The placebo-treated subjects received anxiolytics during the study, yet no participant in the MISS group required anxiolytics while enrolled in the study. No side effects from pain medications were reported in the MISS group, whereas both subjects in the placebo group experienced side effects. DISCUSSION Trends noted in this study indicate that MISS cream could potentially decrease pain, the use of anxiolytics, and side effects associated with systemic opioid medications. It also seems to decrease the amount of oral and parenteral analgesics needed. It is as yet unclear exactly how much morphine is systemically absorbed from this formulation. Based upon the results of Brofeldt et al, 20 remarkable levels would not be expected. In addition, given the paucity of side effects in the active cream group, we hesitate to treat the morphine administered topically as though it were “parenteral,” with dose equivalents comparable to intravenous or intramuscular dosing. If we were to do this, Subject C would be considered as having an additional 39.6 mg morphine from the MISS on the first study day and 73.2 mg on the second day (using a 3:1 oral to parenteral conversion ratio). This would increase the daily morphine dose by 33 and 61%, respectively, while achieving what seems to be superior analgesia with lower side effects. Addition of the morphine applied topically to Subject D's daily morphine intake increases the later by 19.5 mg (36%) for the first day and 66.6 mg (approximately 200%) for the second day. Again, this is accompanied by a lower side-effect profile and superior analgesia. We are aware that the very low number of subjects in this study makes extrapolation of these results suspect. Recruitment was much lower than expected, in part owing to the restrictions we placed on study entry (less than 25% burn, less that 72 hours old, age over 18 years). Our inpatient burn unit typically handles burns of greater TBSA than allowed in the inclusion criteria. We attempted to remedy this by opening the study to the outpatient burn clinic, but here found most of the burns to be of greater than 72 hours in age. The topical application of morphine for analgesia seems to be a viable alternative for patients with open wounds, such as burns. The research that we have conducted thus far with MISS cream is promising. Because of financial constraints, we were not able to conduct a more controlled study including the measurement of morphine blood levels and morphine metabolites to determine the amount of morphine absorbed systemically from the MISS cream while carefully documenting and controlling oral and parenteral opioids. If routine and dressing change pain medications could be used as needed rather than preventively, we would be able to discern the effects of MISS cream more clearly. If found to be effective without these standard medications, MISS cream could significantly decrease the amount of oral and parenteral opioids that are administered to burn patients, whose metabolism and absorption are complicated by the burn wound itself. Further research is needed with larger sample sizes to assess the systemic absorption of morphine from silver sulfadiazine cream, efficacy and safety of slightly higher morphine concentrations for pain relief, use with 2nd vs 3rd degree burns, and use with different percentages of TBSA. Our future research will focus on the effect this cream might have on wound healing. Studies on graft acceptance should also be performed. Particular weaknesses of this study were its small sample size, limited treatment period, and lack of pharmacokinetic and pharmacodynamic information. Peculiar constraints of this patient population (widely varying wound sizes, need for surgery, grafting, etc) made recruitment and maintenance of subjects in this study difficult. Although pharmacologic information is needed, our hope was to address this in future studies. DISCLAIMER The authors of this article wish to emphasize the limitations of this study as they apply to the clinical use of morphine-infused silver sulfadiazine cream (MISS). We have yet to study the systemic absorption of opioid from MISS. The wounds treated in this study were limited in size and scope because of this uncertainty. We would not advise general clinical use of this cream until pharmacokinetic and pharmacodynamic studies have been completed and would particularly caution against its use in larger wounds until this data is available. Use of MISS on large burns may lead to high levels of systemic opioid. References 1. Brigham P, McLoughlin E Burn incidence and medical care use in the United States: estimate, trends, and data sources. J Burn Care Rehabil.  1996; 17: 95– 107. Google Scholar CrossRef Search ADS PubMed  2. Saffle J, Davis B, Williams P Recent outcomes in the treatment of burn injury in the United States: a report from the American Burn Association Patient Registry. J Burn Care Rehabil.  1995; 16: 219– 32. Google Scholar CrossRef Search ADS PubMed  3. Latarjet J, Choine're M Pain in burn patients. Burns.  1995; 5: 344– 8. Google Scholar CrossRef Search ADS   4. Ashburn MA Burn pain: the management of procedure-related pain. J Burn Care Rehabil.  1995; 16: 365– 71. Google Scholar CrossRef Search ADS PubMed  5. Atchison N, Osgood P, Carr B, Szyfelbein S Pain during burn dressing change in children: relationship to burn area, depth and analgesic regimens. Pain.  1991; 47: 41– 5. Google Scholar CrossRef Search ADS PubMed  6. Rybak M, Albrecht L, Berman J Vancomycin pharmacokinetics in burn patients and intravenous drug abusers. Antimicrob Agents Chemother.  1990; 34: 792– 5. Google Scholar CrossRef Search ADS PubMed  7. Jaehde U, Sorgel F Clinical pharmacokinetics in patients with burns. Clin Pharmacokinet.  1995; 29: 15– 28. Google Scholar CrossRef Search ADS PubMed  8. Macfie A, Magides A, Reillyu D Disposition of alfentanil in burns patients. Br J Anaesth.  1992; 69: 447– 50. Google Scholar CrossRef Search ADS PubMed  9. Furman W, Munster A, Cone E Morphine pharmacokinetics during anesthesia and surgery in patients with burns. J Burn Care Rehabil.  1990; 11: 391– 4. Google Scholar CrossRef Search ADS PubMed  10. Denson D, Concilur R, Wardern G Pharmacokinetics of continuous intravenous infusion of methadone in the early postburn period. J Clin Pharmacol.  1990; 30: 70– 5. Google Scholar CrossRef Search ADS PubMed  11. Flynn G, Behl C, Linn E, Higuchi W, Jo N Permeability of thermally damaged skin v: permeability over the course of maturation of a deep partial-thickness wound. Burns.  1982; 8: 196– 202. Google Scholar CrossRef Search ADS   12. Stone H, Kolb L, Pettit J, Smith R The systemic absorption of an antibiotic from the burn wound surface. Am Surg.  1968; 34: 639– 44. Google Scholar PubMed  13. Aoyama H, Nishizaki A, Aoki Y, Izawa Y The effect of some ointment bases on the systemic absorption of tobramycin from various wound surfaces of burned patients. Burns.  1984; 10: 290– 9. Google Scholar CrossRef Search ADS   14. Aoyama H, Yokoo K, Fujii K Systemic absorption of sulphadiazine, silver sulphadiazine and sodium sulphadiazine through human burn wounds. Burns.  1990; 16: 163– 5. Google Scholar CrossRef Search ADS PubMed  15. Boosalis M, McCall J, Ahrenhalz D, Solem L, McClain C Serum and urinary silver levels in thermal injury patients. Surgery.  1987; 101: 40– 3. Google Scholar PubMed  16. Wan A, Conyers R, Coombs C, Masterton J Determination of silver in blood, urine, and tissues of volunteers and burn patients. Clin Chem.  1991; 37: 1683– 7. Google Scholar PubMed  17. Fuller F, Parrish M, Nance F A review of the dosimetry of 1% silver sulfadiazine cream in burn would treatment. J Burn Care Rehabil.  1991; 15: 213– 23. Google Scholar CrossRef Search ADS   18. Adriani J, Dalili H Penetration of local anesthetics through epithelial barriers. Anesth Analg.  1971; 50: 834– 41. Google Scholar CrossRef Search ADS PubMed  19. Wehner D, Hamilton G Seizures following topical application of local anesthetics to burn patients. Ann Emerg Med.  1984; 13: 456– 8. Google Scholar CrossRef Search ADS PubMed  20. Brofeldt B, Cornwell P, Doherty D, Batra K, Guntehr R Topical lidocaine in the treatment of partial-thickness Burns. J Burn Care Rehabil.  1989; 10: 63– 8. Google Scholar CrossRef Search ADS PubMed  21. Daut RL, Cleeland CS, Flanner RC Development of the Wisconsin Brief Pain Questionnaire to assess pain in cancer and other diseases. Pain.  1983; 17: 197– 210. Google Scholar CrossRef Search ADS PubMed  22. Cleeland CS, Ryan KM Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore.  1994; 23: 129– 38. Google Scholar PubMed  23. Preston KL, Bigelow GE, Liebson IA Butorphanol-precipitated withdrawal in opioid-dependent human volunteers. (NIDA Research Monograph Vol 76.) Washington, DC: US Government Printing Office; 1987. 24. Preston KL, Bigelow GE, Bickel WK, Liebson IA Drug discrimination in human postaddicts: agonist-antagonist opioids. J Pharm Exp Ther.  1989; 250: 184– 96. 25. Preston KL, Bigelow GE, Liebson IA Discrimination of butorphanol and nalbuphine in opioid-dependent humans. Pharm Biochem Behav.  1990; 37: 511– 22. Google Scholar CrossRef Search ADS   26. Preston KL, Jasinski DR, Testa M Abuse potential and pharmacological comparison of tramadol and morphine. Drug Alcohol Depend.  1991; 27: 7– 17. Google Scholar CrossRef Search ADS PubMed  27. Walsh SL, Preston KL, Bigelow GE, Stitzer ML Acute administration of buprenorphine in humans: partial agonist and blockade effects. J Pharm Exp Ther.  1995; 274: 361– 72. 28. Strain EC, Preston KL, Liebson IA, Bigelow GE Opioid antagonist effects of dezocine in opioid-dependent humans. Clin Pharm Ther.  1996; 60: 206– 17. Google Scholar CrossRef Search ADS   29. Jacox A, Carr DB, Payne R, et al.   Management of Cancer Pain. Clinical Practice Guideline No. 9.  AHCPR Publication No. 94-0592. Rockville, Md. Agency for Health Care Policy and Research, U.S. Department of Health and Human Services, Public Health Service, March 1994. Footnotes ‡ Supported by the University of Kansas Research Institute. Copyright © 2001 by the American Burn Association http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Burn Care & Research Oxford University Press

Morphine-Infused Silver Sulfadiazine (MISS) Cream for Burn Analgesia: A Pilot Study

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Copyright
Copyright © 2001 by the American Burn Association
ISSN
1559-047X
eISSN
1559-0488
DOI
10.1097/00004630-200103000-00006
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Abstract

Abstract Pain is considered the most distressing symptom of a burn wound, with analgesia usually provided via oral or parenteral medications. Use of systemic opioids can be complicated by fluctuations in bioavailability, absorption, and clearance of drugs caused by the burn. There has been little research done in the area of topical medications for burn analgesia. The following is a double-blind, placebo-controlled pilot study assessing the safety (side effects) and efficacy (pain ratings and medications administered) of morphine-infused silver sulfadiazine cream for burn pain. Four patients are reported on (2 in each group). Only participants taking placebo reported side effects related to morphine and necessitated anxiolytic medications. Pain ratings in the treatment group ranged from 0 to 7 with a mean of 2.1, whereas the placebo group's ratings ranged from 2 to 8 with a mean of 5.6. The placebo group averaged 55.3 mg oral morphine per half day, whereas the treatment group averaged 42.9 mg. It is estimated that approximately 1.25 million burn injuries occur per year, 25% of these resulting in acute hospital admissions. 1 The average inpatient stay for the treatment of burns is 13.5 days 2 per incident. Pain is, without a doubt, the single most distressing symptom of any burn, yet it is often underrecognized and more often undertreated, because it is difficult to manage. Burn wounds are painful initially and longitudinally. 3 Severe pain is felt during acute treatment and rehabilitation, especially during dressing changes, debridements, and skin grafting, and continues through long-term follow-up. 3,4 Burn pain is not caused by a single physiologic mechanism, but is felt to have components of both nociceptive and neuropathic pain. 3 There has been a common misconception in the medical community that because of destruction of peripheral nociceptors, full-thickness (3rd degree) burns are less painful than partial-thickness burns. This notion has been refuted by other researchers, 5 who found that larger areas of full-thickness burns were associated with higher pain ratings. The backbone of burn analgesia is opioid therapy, administered via oral or parenteral routes. 4 The use of medications with these patients is complicated by the fluctuation in bioavailability of drugs, protein binding, volume of distribution, and clearance related to the hemodynamic and volume shifts that occur with burn injury. Intestinal absorption of hydrophilic compounds or macromolecules may be affected for the first few days after a burn, with increased permeability to bacteria. Patients with burns exhibit decreased albumin and increased α-1-acid glycoprotein levels, which affect the distribution, elimination, and even pharmacologic effect of drugs. Consequently, the distribution of those drugs with high protein binding may be altered, and renal clearance of drugs may be altered. The latter may be affected by plasma clearance, variation in glomerular filtration rate, tubular secretion, and tubular reabsorption. Additionally, both filtration and secretory clearance are substantially increased during the hypermetabolic phase of burns. 6 Adding to the difficulty of predicting drug levels, the hepatic clearance of high-extraction drugs is increased, although that of low-extraction drugs may be decreased, so that the elimination half-life of medications is largely unknown. 7 Studies of the opioid pharmacokinetics and pharmacodynamics of burn patients is sparse, with varied results. In studying the use of alfentanil with burn patients, researchers found a decreased volume of distribution, free drug, and clearance, rendering dose adjustment unclear. 8 In a similar study of morphine, Furman et al 9 reported a decreased volume of distribution and clearance, as well as an increased half-life necessitating a dose adjustment downward. Denson et al 10 studied methadone pharmacokinetics in burn patients and noted that because of an unchanged volume of distribution and increased clearance, methadone should be loaded as usual, but maintenance doses should be increased. Such varied responses to oral and parenteral opioids makes topical application of analgesics an attractive alternative for this population. Topical treatment is presumed to provide analgesia at the peripheral opioid receptors with minimal absorption. There are several characteristics of burn wounds that change during the course of healing. In a study of burns in mice, 11 changes in the permeability of burn eschar was evaluated. There was a 50% increase in permeability that persisted for the first 4 to 5 days postburn, and increased further through approximately Day 10, after which it began to diminish. As early as 1968 the topical absorptive qualities of burn wounds were studied. Stone et al 12 compared the absorption of gentamicin sulfate using both a water-miscible cream and a petrolatum-based ointment. The systemic levels of gentamicin varied depending on the age of the burn wound and the base in which the drug was applied. Highest absorption was found using the water-miscible base. There was immediate and great absorption, which slowed gradually until equilibrium was reached. Similarly, Aoyama et al 13 studied the absorption of tobramycin when applied with a water-miscible cream, polyethylene glycol, or a petrolatum ointment. These researchers also found rapid absorption when cream or polyethylene glycol were used and minimal absorption with the ointment. Silver-sulfadiazine cream is a commonly-used topical antimicrobial agent used on burn wounds to reduce the incidence of infection. Absorption from this agent has been investigated by several authors. In one study 14 the absorption of sulfadiazine was compared after application of silver-sulfadiazine (water-insoluble), sulfadiazine (water-insoluble) creams, or sodium sulfadiazine (water-soluble) cream. Researchers found that absorption was greater with the sodium-based cream than with the other 2 compounds. Despite this lower absorption, when silver-sulfadiazine cream is used, significantly higher and persistent levels of silver are measurable in treated subjects. 15,–17 These findings indicate that the application of topical agents to burns can be expected to produce measurable blood levels of some substances included in those agents. In efforts to treat neuropathic and overall burn pain, the use of topical anesthetic agents has been tried. Adriani and Dalili 18 studied the analgesia obtained when topical local anesthetic agents were applied to superficial burns and found that these agents offered no relief. In 1984 Wehner et al 19 reported seizures after the topical application of local anesthetics on 2 burn patients. Both cases were infants who also received drugs with the potential to cause seizures. Brofeldt et al 20 studied the application of topical lidocaine to partial-thickness burns. These researchers used a 5% lidocaine cream applied at a concentration of 1 mg/cm2, followed by the analysis of blood lidocaine levels. The highest blood level obtained was 5.8 μg/ml in a patient with 28% total body surface area (TBSA) burn. The level was constant, and was associated with significant decrease in pain ratings. We first used morphine-infused silver sulfadiazine (MISS) cream on a burn patient at a 0.5% morphine/cream wt/wt concentration. The analgesia achieved was remarkable (pain ratings dropped to a level of “0”). However, after 1 dose, the patient's skin became erythematous, he became sedated, and the medication was discontinued. This cream was then used in a double-blind study at a 0.005% wt/wt concentration with what seemed to be little efficacy. After the fourth subject was given the MISS 0.005% cream for 4 days, the morphine concentration was increased to 0.01% concentration. Only 1 dressing change was done with the 0.01% MISS cream because this patient's wound required a change in dressing to xeroform (bismuth tribromophenate) gauze. Before the use of MISS 0.01%, the patient received 109 mg (oral morphine equivalent) of break-through medications, and only 39 mg after the MISS 0.01% was applied. Before using MISS 0.01%, the patient required lorazepam 2 and 3 times per day. While the MISS 0.01% was applied to the wound, no anxiolytics were needed. The following double-blind placebo-controlled pilot study was conducted to assess whether the addition of morphine to silver-sulfadiazine cream in a 0.01% concentration seems safe and effective in producing analgesia for burn patients. The effectiveness was measured by pain ratings, the amount of medications administered, and the use of anxiolytics. Safety was assessed by the tracking of side effects. METHODS Subjects Potential subjects were referred to the study by the burn unit staff after obtaining permission from the attending physician for the patient's enrollment. Patients were included if they were 18 years of age or older, their burn had occurred within the past 72 hours, and the burn covered 25% or less total body surface area (TBSA). Exclusion criteria included surgical intervention (which precluded the presence of a donor site at the time of the study), known hypersensitivity to morphine or its metabolites, and cognitive impairment sufficient to limit ability to give informed consent and ratings of pain. Measures Brief Pain Inventory. The Brief Pain Inventory (BPI) is a questionnaire that allows for standardized collection of information related to a painful medical condition. This pain inventory was developed in 1983 21 and was demonstrated to be a valid and reliable self-report measure. As reported by Cleeland and Ryan, 22 this questionnaire is a powerful tool that has demonstrated reliability and validity in different countries, with different cultures, in different languages, in various different pain populations, and in studies assessing the efficacy of pain treatments. The Brief Pain Inventory-Pain Scale (BPI-PS) was used to assess pain throughout the study. This is a numerical scale that ranges from 0 to 10, 0 anchored by “No pain,” and 10 anchored by “Pain as bad as you can imagine.” Opioid Side Effects Questionnaire (OSEQ). An adjective list similar to that used by Preston and colleagues 23,–28 at Johns Hopkins University School of Medicine was used to assess the side effects of topically applied morphine. The following side effects were rated between 0 (not present) to 10 (as bad as you can imagine): constipation, dry mouth, urinary retention, drowsiness, confusion, hallucinations, nausea, itching, and depression. Each side effect was listed individually and rated by the patient in conjunction with study personnel. Morphine-Infused Silver Sulfadiazine Cream. Silver-sulfadiazine is a topical sulfonamide compound of silver nitrate and sodium sulfadiazine prepared in a 1% water-miscible cream. It is the most frequent dressing agent applied to deep partial-thickness and full-thickness burns. Morphine powder was added to silver-sulfadiazine 1% cream to achieve a concentration of 0.01% morphine by weight. The investigational pharmacy formulated, dispensed, and tracked the amount of cream applied. Procedures Once identified by staff on the burn unit and referred for the study, consent for participation was obtained in writing, and the inclusion and exclusion criteria were documented. The investigational pharmacist at the university hospital was then contacted and advised that there was a patient enrolled in this study. The investigational pharmacist, who had run a computer-generated randomization chart, supplied blinded study cream to the burn unit, identified only by patient initials, study patient number, day, date, and whether it was to be applied with the morning or evening dressing change. After dressing wounds, nurses were instructed to place the gloves used to apply the cream along with anything left in the jar in a bag provided so that these could be weighed, and an accurate amount of morphine applied calculated. Burn patients were to receive MISS cream or placebo for 4 days with their morning and evening dressing changes, rating their pain 4 times per day with the BPI-PS before the morning dressing change, 6 hours later, before the evening dressing change, and 6 hours after that. Documentation forms for pain ratings were provided to the burn unit nurses, and an investigator was available by pager 24 hours per day to answer any questions; however, not all pain ratings were completed. Side effects were assessed once per day and documented on study records, and concomitant medications were obtained from the official Medication Administration Record. RESULTS Four subjects were entered. After breaking the blind, we found that the first 2 subjects had received placebo cream, and the last 2 had been given the MISS cream. All subjects were male. The 2 who received placebo were 20 and 36 years of age, with 3.5 and 18.1% TBSA burns, respectively. The former had a third-degree burn on the arm, the latter a second-degree burn on the trunk. The men who received MISS cream were 22 and 51 years of age, with 25 and 17.5% TBSA burns, respectively. The younger participant had a second-degree burn to his upper extremities, chest, knee, and right thigh, and the other had a third-degree burn to the left arm. Randomization resulted in groups with comparable characteristics. Surgery intervention was required for 3 participants, and the other's dressing was changed to xeroform; therefore, no one was treated for the full 4 days intended. All subjects received scheduled opioids (MS Contin®, Purdue Pharma, Norwak, CT) for pain, as well as intravenous morphine for breakthrough pain, and to premedicate for dressing changes. These are standard medications ordered upon admission to the burn unit. Other standard orders are for stool softener or laxative, and an anxiolytic, on an as-needed basis. After completion of the study, all medical records were reviewed to document exactly what medications were administered. To standardize opioid use, pain medications were changed to an equianalgesic dose of oral morphine using the Agency for Health Care Policy and Research (AHCPR) Clinical Practice Guidelines for Management of Cancer Pain: Adults. 29 Equianalgesic doses were then totaled to reflect what was given after 1 dressing change up to the next (approximately a 12-hour period). All the subjects in this study were given oral or parenteral opioids. It was not possible to differentiate those that were given routinely, with dressing changes, or at the request of the patient, which is why they are reported as a single amount. Because the MISS cream was applied topically, the morphine did not undergo extensive first-pass metabolism as with oral medications. Because this was a pilot study, pain medications were not controlled in such a way that would allow our determination of the amount of morphine absorbed systemically, nor were these assayed. Consequently, we report the amount of morphine applied in the MISS cream as calculated by the investigational pharmacy (Table 1). Table 1. Doses, effects, and side effects of medicines given View Large Table 1. Doses, effects, and side effects of medicines given View Large Subject A participated in this study for 3 days because on Day 4 his dressing was changed to xeroform. On Day 1, this first (placebo) participant received a total of 40 mg of morphine during the day between the morning and night dressing changes and 60 mg between the first night's dressing change and the next morning's. The following day the morphine equivalents were 78 and 72 mg, day and night respectively, and 65 and 40 mg on the last day this patient was in the study. This individual required anxiolytics on the first 2 days of study, but none on Day 3. During the course of the 3 days, this person's pain ratings ranged from 4 to 8, with an average of 6. Side effects reported while in the study include drowsiness, constipation, and confusion. Subject B (placebo) was studied for only 2 days, because he required surgical intervention on Day 3. He used a total of 66 mg of equianalgesic morphine between the morning and evening dressing change and 72 mg between the evening and next morning's change. On the second day, this participant was only given a total of 60 mg for the entire 24-hour period. Pain ratings were in the moderate range, with individual ratings recorded between 2 and 5, with an average of 3. He also required an anxiolytic on the first day and complained of side effects (sleepiness and sedation). Subject C (MISS cream), like the former participant, was only enrolled in the study for 2 days because he necessitated surgical intervention. This individual only required a morphine equianalgesic amount of 60 mg per half day for the 2 days he was in the study. Pain ratings were reported to be 0 for the first day of the study, and 3 and 2 on the second day. This patient did not require an anxiolytic and complained of no medication-induced side effects. Subject D (MISS cream) first began using study cream with an evening dressing change, unlike the other participants. This person was only given 54 mg of morphine during the first 24 hours and 36 mg during the second 24-hour period. Pain ratings were reported at a mild to moderate level (3 to 7) on the first day, dropping to mild on the second (2 to 4). No anxiolytics were required, and no side effects were reported. Because the small sample size was only 4, 2 participants per group, statistical analyses were not facilitated. Exploratory Mann-Whitney U tests were conducted on each pain rating and half-day medication totals documented between the 2 groups. This was done in violation of the assumption of independence between scores on the test variable. The results of the Mann-Whitney U test on the pain variable were significant (z = −3.187;P =.001), with the placebo group data points having an average rank of 16.77 and the MISS group with an average pain rank of 7.35. The Mann-Whitney U test conducted on the medications taken was near significance (z = −1.797;P = .072); the placebo group data points had a mean rank of 10.80, and the MISS group had a mean of 6.43. The placebo-treated subjects received anxiolytics during the study, yet no participant in the MISS group required anxiolytics while enrolled in the study. No side effects from pain medications were reported in the MISS group, whereas both subjects in the placebo group experienced side effects. DISCUSSION Trends noted in this study indicate that MISS cream could potentially decrease pain, the use of anxiolytics, and side effects associated with systemic opioid medications. It also seems to decrease the amount of oral and parenteral analgesics needed. It is as yet unclear exactly how much morphine is systemically absorbed from this formulation. Based upon the results of Brofeldt et al, 20 remarkable levels would not be expected. In addition, given the paucity of side effects in the active cream group, we hesitate to treat the morphine administered topically as though it were “parenteral,” with dose equivalents comparable to intravenous or intramuscular dosing. If we were to do this, Subject C would be considered as having an additional 39.6 mg morphine from the MISS on the first study day and 73.2 mg on the second day (using a 3:1 oral to parenteral conversion ratio). This would increase the daily morphine dose by 33 and 61%, respectively, while achieving what seems to be superior analgesia with lower side effects. Addition of the morphine applied topically to Subject D's daily morphine intake increases the later by 19.5 mg (36%) for the first day and 66.6 mg (approximately 200%) for the second day. Again, this is accompanied by a lower side-effect profile and superior analgesia. We are aware that the very low number of subjects in this study makes extrapolation of these results suspect. Recruitment was much lower than expected, in part owing to the restrictions we placed on study entry (less than 25% burn, less that 72 hours old, age over 18 years). Our inpatient burn unit typically handles burns of greater TBSA than allowed in the inclusion criteria. We attempted to remedy this by opening the study to the outpatient burn clinic, but here found most of the burns to be of greater than 72 hours in age. The topical application of morphine for analgesia seems to be a viable alternative for patients with open wounds, such as burns. The research that we have conducted thus far with MISS cream is promising. Because of financial constraints, we were not able to conduct a more controlled study including the measurement of morphine blood levels and morphine metabolites to determine the amount of morphine absorbed systemically from the MISS cream while carefully documenting and controlling oral and parenteral opioids. If routine and dressing change pain medications could be used as needed rather than preventively, we would be able to discern the effects of MISS cream more clearly. If found to be effective without these standard medications, MISS cream could significantly decrease the amount of oral and parenteral opioids that are administered to burn patients, whose metabolism and absorption are complicated by the burn wound itself. Further research is needed with larger sample sizes to assess the systemic absorption of morphine from silver sulfadiazine cream, efficacy and safety of slightly higher morphine concentrations for pain relief, use with 2nd vs 3rd degree burns, and use with different percentages of TBSA. Our future research will focus on the effect this cream might have on wound healing. Studies on graft acceptance should also be performed. Particular weaknesses of this study were its small sample size, limited treatment period, and lack of pharmacokinetic and pharmacodynamic information. Peculiar constraints of this patient population (widely varying wound sizes, need for surgery, grafting, etc) made recruitment and maintenance of subjects in this study difficult. Although pharmacologic information is needed, our hope was to address this in future studies. 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Journal

Journal of Burn Care & ResearchOxford University Press

Published: Mar 1, 2001

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