Analgesic Effect of Topical Sevoflurane on Venous Leg Ulcer with Intractable Pain M

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Kasuistik © Schattauer 2011 95 Analgesic effect of topical sevoflurane on venous leg ulcer with intractable pain M. Gerónimo-Pardo1; A. Martínez-Monsalve2; M. Martínez-Serrano3 1Department of Anesthesiology, Reanimation and Pain Treatment, Complejo Hospitalario Universitario of Albacete; 2Department of Vascular Surgery, Complejo Hospitalario Universitario of Albacete; 3Department of Clinical Microbiol- ogy and Parasitology, Complejo Hospitalario Universitario of Albacete

and, over this period of time, has proven to Keywords Schlüsselwörter be a very safe drug (4, 5). In addition to its Pain intractable, drug therapy, varicose ulcer, Therapieresistente Schmerzen, medikamen- hypnotic effect, its profile as an analgesic is drug therapy, anesthetics, inhalation, thera- töse Therapie, Ulcus cruris, Anästhesie, Inha- being determined, particularly in spinal ap- peutic use, sevoflurane lation, therapeutischer Nutzen, Sevofluran plications (6, 7). Summary Zusammenfassung The following is a description of our We are presenting the case of a patient with a Wir stellen den Fall eines Patienten mit einem first experience with the compassionate use very painful venous ulcer for whom therapy sehr schmerzhaften venösen Geschwür vor, bei of liquid sevoflurane as a topical irrigation with different analgesic combinations (includ- welchem die Therapie mit verschiedenen in the analgesic management of intractable ing acetaminophen, metamizol, tramadol, Schmerzmittelkombinationen (einschließlich pain in a case of venous ulcer. morphine, fentanyl, buprenorphine, pregabal- Paracetamol, Metamizol, Tramadol, Morphin, in, gabapentin, as well as applications of lido- Fentanyl, Buprenorphin, Pregabalin, Gabapen- caine/prilocaine eutectic cream and infusion tin, sowie der lokalen Anwendung von Lido- Clinical case of epidural ropivacaine) was unsatisfactory. cain/Prilocain Creme und epiduralen Infusio- Analgesic control was finally achieved nen mit Ropivacain) unbefriedigend war. The patient was a 76-year-old woman with through applications of liquid sevoflurane to Schmerzstillende Kontrolle wurde schließlich main antecedents of arterial hypertension, the wound, which resulted in immediate, in- erreicht durch direkte Anwendung von flüssi- chronic atrial fibrillation diagnosed 4 years tense, and long-lasting analgesia. To the pa- gem Sevofluran auf der Wunde, die zur unmit- ago when patient suffered from a deep vein tients satisfaction, the same response was ob- telbaren, intensiven und lang anhaltenden thrombosis of the left lower extremity. tained throughout the 16 days it took the Analgesie führte. Zur Zufriedenheit des Patien- She was admitted to Vascular Surgery ulcer to heal. The compassionate use of sevo- ten wurde eine ähnliche Reaktion während des for intense pain uncontrolled with several flurane in this innovative and promising Zeitraums von 16 Tagen erreicht, in dem das analgesics (acetaminophen, tramadol, manner warrants further research to evaluate Geschwür heilte. Die direkte/topische Anwen- pregabalin, morphine) associated to a ne- its efficacy and safety. dung von Sevofluran mit dieser innovativen crotic left external maleolar ulcer, ischemic und vielversprechenden Methode rechtfertigt etiology being ruled out by the ankle-bra- weitere Untersuchungen zur Bewertung der chial index. Epidural infusion of ropiva- Wirksamkeit und Sicherheit von Sevofluran. caine and fentanyl plus topical application of lidocaine/prilocaine eutectic cream (EMLA®) controlled resting pain, but they Korrespondenzadresse Schmerzstillende Wirkung von topisch angewand- were insufficient to allow tolerance to vac- Manuel Gerónimo-Pardo, PhD tem Sevofluran auf ein venöses Geschwür mit the- uum-assited closure (VAC) therapy. Be- Dep. of Anesthesiology, Reanimation and Pain Treat- rapieresistenten Schmerzen sides, the patient suffered blockage of the ment, Complejo Hospitalario Universitario of Albacete Phlebologie 2011; 40: 95–97 rigth lower extremity, and finally the epidu- Hermanos Falcó, E-02006 Albacete, Spanien Received: November 18, 2010 E-Mail: [email protected] Accepted: January 20, 2011 ral catheter was removed on patient re- quest. The patient was discharged with pregabalin, morphine and transmucosal fentanyl, with regular dose increments be- Venous ulcers are a major health issue. Be- mention the adverse effects that may arise cause of the pain was still poorly con- sides their financial impact (1), a signifi- from these therapies (2, 3). Therefore, a trolled. cant part of this issue stems from the pain new alternative in analgesia would be wel- In this context, she was readmitted to associated with these ulcers. There is a per- come. the Internal Medicine service with diag- centage of patients who suffer intractable Sevoflurane (Sevorane®) is a halogen- noses of opioid poisoning, prerenal acute pain resulting in poor quality of life (in- ated inhalation anesthetic agent that has renal failure, and intractable painful ulcers somnia, immobility, irritability), not to been used in general anesthesia for decades of the lower extremities. Following initial

Phlebologie 2/2011 96 M. Gerónimo-Pardo et al.: Effect of sevoflurane on leg ulcer with intractable pain

clinical improvement in her general condi- not performed. These findings strongly use of sevoflurane in this particular patient tion, the pain again became the primary supported the venous etiology for both was obtained from the Pharmacy Depart- problem, despite analgesic therapy with ulcers, and the patient was diagnosed of ment and from the authorities of our insti- transdermal buprenorphine and sublin- chronic venous insufficiency (class 6 of tution. The patient gave us written consent gual buprenorphine tablets for rescue anal- CEAP classification). to undergo an initial trial application on gesia, and the patient was transferred back Right ulcer pain was adequately con- the more painful left leg ulcer, with the op- to Vascular Surgery. trolled, numerical pain scale (NPS) <4/10, tion to have the application repeated if the Upon examination, two supramaleolar but pain from left ulcer was severe, result was satisfactory. The first treatment ulcers were noted on the posteroexternal NPS = 8/10. This pain was interfering with consisted of removing the macroscopic de- surface of the distal third of both legs, the the patient’s rest at night, and she was in a bris using a normal saline-humidified gas left also having exudate and clinical signs of very bad mood. Furthermore, local treat- and irrigating the ulcer bed with 5 ml of superinfection (ǠFig. 1). Ischemic etiology ments to the left leg ulcer were so painful liquid sevoflurane. The patient reported an was ruled out based on preserved plethys- that the patient was refusing them. Reinser- immediate feeling of coolness and then, mographic curves and normal ankle-bra- tion of an epidural catheter was offered to about 2 minutes later, intense analgesia chial index (left 0’93, right 0’86). Bilateral the patient, but this she also refused be- (NPS = 4/10) that lasted for a period of venous ultrasound study performed on cause of her previous bad experience. about 12 hours before returning to the pre- deep venous system and mayor saphenous In this desperate context the patient was treatment score (NPS = 8/10). During the veins showed important venous reflux (du- offered the compassionate use of local se- period of analgesia, the patient was able to ration higher than 3 seconds and speed voflurane irrigations in an attempt to con- rest and sleep. After this, the patient herself equal to 35 cm . sec-1). Histologic study was trol the pain. Permission for the off-label requested that the sevoflurane treatments be repeated daily, which lasted 16 days. The only undesirable effect that appeared was a mild pruriginous irritation of the healthy skin around the wound, which could be minimized by keeping the sevoflurane con- fined within the wound edges. Even so, the patient’s subjective degree of satisfaction was very high. The progress of the left leg ulcer was also very favorable. The ulcer was markedly im- proved in appearance, showing a moderate reduction in area but an almost total resol- ution of its depth. As stated above, on the sixteenth day of sevoflurane applications, Fig. 1 the left leg ulcer was considered closed Venous ulcer prior to (ǠFig. 2) and the sevoflurane treatment initiating sevoflurane applications. concluded. The patient’s clinical progress was very slow, however, owing to complications with the right leg ulcer, which was treated con- ventionally with silver sulfadiazine applications and dressings. This ulcer developed a MRSA superinfection. The patient was treated with intravenous vancomycin and developed a generalized, bullous exanthem diagnosed as vancomycin-induced linear IgA dermatosis. This necessitated her ad- mission to ICU where she remained for three months due to subsequent compli- Fig. 2 cations – respiratory and urinary infec- Appearance after 16 tions, renal and respiratory insufficiency, days of sevoflurane pulmonary bleeding due to vascular mal- applications, when it formations in the bronchial and intercostal was considered clini- trunks – before being transferred back to cally cured. the ward.

Phlebologie 2/2011 © Schattauer 2011 M. Gerónimo-Pardo et al.: Effect of sevoflurane on leg ulcer with intractable pain 97

Discussion volunteers (9, 10). It is reasonable to suppose References that, when a halogenated agent is adminis- In this clinical experience, we were able to tered by inhalation, the partial pressure it 1. Langer A, Rogowski W. Systematic review of econ- confirm repeatedly that sevoflurane topi- reaches in peripheral nociceptors may not be omic evaluations of human cell-derived wound care products for the treatment of venous leg and cally applied to an ulcer with refractory high enough to block transmission of a diabetic foot ulcers. BMC Health Services Research pain has a rapid and intense analgesic effect painful stimulus to any clinically significant 2009; 9: 115. that lasts for hours. Moreover, the fact that degree, especially if it is administered at sub- 2. Süleyman H, Demircan B, Karagöz Y. Anti-inflam- this occurred in the context of the patient anesthetic dosages (9, 10). matory and side effects of cyclooxygenase in- hibitors. Pharmacol Rep 2007; 59: 247–258. refusing other therapeutic options – the On the other hand, Fassoulaki et al. 3. Benyamin R, Trescot AM, Datta S et al. Opioid com- opioids because of the poisoning she suf- found a mild local analgesic effect of iso- plications and side effects. Pain Physician 2008; fered, the epidural because of her previous flurane solution applied on the forearm of 11(2 Suppl): S105-S120. 4. Patel SS, Goa KL. Sevoflurane. A review of its phar- bad experience, and the cream because of healthy volunteers, what suggests that iso- macodynamics and pharmacokinetic properties the discomfort its application causes – flurane may have an analgesic effect in the and its clinical use in general anaesthesia. Drugs makes it all the more worthy of further peripheral tissues (11). Even more, Chu et 1996; 51: 658–700. evaluation. al. found that, after subcutaneous injection, 5. Behne M, Wilke HJ, Harder S. Clinical pharmacoki- netics of sevoflurane. Clin Pharmacokinet 1999; 36: The classical thinking has been that the several inhaled anesthetics (isoflurane, ha- 13–26. effect of inhalation anesthetic agents can- lothane, enflurane) produced a reversible, 6. Antognini JF, Kien ND. Potency (minimum alveolar not be explained by a depression of periph- concentration-dependent cutaneous anal- anesthetic concentration) of isoflurane is indepen- eral receptors (8), which implies that, from gesic effect at the site of injection (12). Re- dent of peripheral anesthetic effects. Anesth Analg 1995; 81: 69–72. a physiological standpoint, an analgesic ef- garding our patient it is reasonable to sup- 7. Matute E, Rivera-Arconada I, López-García JA. Ef- fect such as that described in this case pose that, with direct irrigation of a wound, fects of propofol and sevoflurane on the excitability would not be possible. the nociceptors were exposed to a very high of rat spinal motoneurones and nociceptive reflexes partial pressure of sevoflurane, high in vitro. Br J Anaesth 2004; 93(3): 422–427. 8. Koblin DD. Mechanism of action. In: Miller RD, ed. In our opinion, this apparent contradiction enough to block the transmission of pain- Anesthesia. 5th ed. Filadelfia, USA: Churchill Liv- can be easily explained by considering the ful stimuli. ingstone, 2000: 48–73. difference between administering sevoflur- In conclusion, we would like to empha- 9. Tomi K, Mashimo T, Tashiro C, Yagi M, Pak M, Nis- ane by inhalation and administering it by size that, in this case, the compassionate use himura S et al. Alterations in pain threshold and psychomotor response associated with subanaes- local irrigation. of topical sevoflurane was critical to the thetic concentrations of inhalation anaesthetics in management of an ulcer that was causing humans. Br J Anaesth 1993; 70: 684–686. To date, the studies that have evaluated the intractable pain. In our opinion, this calls 10. Petersen-Felix S, Arendt-Nielsen L, Bak P, Fischer M, Bjerring P, Zbinden M. Analgesic effect in hu- possible peripheral analgesic effect of the ha- for future studies and communications to mans of subanaesthetic isoflurane concentrations logenated anesthetic agents administered by evaluate the efficacy and safety of this inno- evaluated by experimentally induced pain. Br J An- inhalation have found no such analgesic ef- vative and promising use of sevoflurane as a aesth 1995; 75: 55–60. fect, both in animal models (6) and healthy topical anesthetic/analgesic. 11. Fassoulaki A, Sarantopoulus C, Karabinis G, Derve- niotis C. Skin application of isoflurane attenuates the responses to a mechanical and a electrical stimulation. Can J Anaesth 1998; 45: 1151–1155. 12. Chu CC, Wu SZ, Su WL, Shieh JP, Kao CH, Ho ST, et al. Subcutaneous injection of inhaled anesthetics produces cutaneous analgesia. Can J Anesth 2008; 55: 290–294.