SciELO - Scientific Electronic Library Online

vol.67 issue7S100B protein expression in the heart of deceased individuals by overdose: a new forensic marker?Clinical pharmacokinetics of vancomycin in the neonate: a review author indexsubject indexarticles search
Home Pagealphabetic serial listing  

Services on Demand




Related links



Print version ISSN 1807-5932

Clinics vol.67 no.7 São Paulo July 2012 



Wound-healing and benzodiazepines: does sleep play a role in this relationship?



Flavia Egydio; Gabriel Natan Pires; Sergio Tufik; Monica Levy Andersen

Universidade Federal de São Paulo (UNIFESP), Departamento de Psicobiologia, São Paulo/SP, Brazil




Patients who have suffered burns frequently experience psychological consequences, among which anxiety disorders are prominent. Benzodiazepines are commonly administered to treat these symptoms. The effects of benzodiazepines on healing may not be direct but rather are modulated by alterations of the sleep architecture. This hypothesis is supported by studies that demonstrate the effects of benzodiazepines on the immune system and the inflammatory profile under both normal sleep conditions and during sleep deprivation, particularly rapid eye movement sleep deprivation.

Keywords: Benzodiazepines; Sleep Deprivation; Wound Healing; Burns; Immune System.




Damage to the skin triggers mechanisms of repair that are collectively called healing. This process commences immediately after injury and is composed of the following three main phases: inflammatory, proliferative, and maturation. The wound-healing process is not linear, and these phases depend on various intrinsic and extrinsic factors. Several factors may influence the healing process, including age, nutritional status, diabetes, atherosclerosis, stress, lack of sleep, and the integrity of the immune system (1-3). The integrity of the immune system is indispensable during the healing process, particularly during the recovery of tissue after burns, when defense cells and inflammatory mediators act in unison to promote tissue regeneration, cytokine production, and bacterial clearance.

Among patients who have suffered burns, a common sequela is the psychological consequences, among which anxiety disorders are the most prevalent (4). A therapeutic option for anxiety is the prescription of benzodiazepines (BDZ) to deal with the ensuing stress caused by the injury. The choice of this drug for burn patients has grown considerably in the past years and 77% of burn patients received this drug in 2001 (5,6).

Recently, some studies examined the effects of midazolam, a commonly used BZD, upon the burn wound. Babcock et al. treated mice with midazolam (1 mg/kg) daily after a burn injury and observed a decrease in IL-1β, TNF-α, IL-6, IL-10, and TGF-β levels compared to saline-treated mice (7). Moreover, the chemokines (MIP-1α,MIP-1α, and MIP-2) in the wound were increased significantly by midazolam. Another study by this group, using the same treatment with midazolam, investigated whether psychological stress (e.g., predator exposure) could alter survival following Pseudomonas aeruginosa infection. The results showed that midazolam had a protective effect in mice (8). Together, these studies suggest that BDZ can modulate the immune system and a host of inflammatory mediators, leading to a detrimental effect on healing and tissue regeneration.

Based on this evidence, we hypothesize that inflammation of wounded tissue may not be a direct effect of midazolam but rather a consequence of sleep alterations caused by the administration of BZD.



An important factor during the treatment of wounded patients is the stress resulting from the injury, which may affect the immune system. Another consideration is the interaction between stress and the immune system. As demonstrated by McGhee et al. (9), lesions caused by burns or other wounds are potentially stressful events and are one reason why the use of BZD among such patients has seen a rise. However, stress, anxiety, and the immune system are intimately associated, especially when dealing with inflammation and healing. Specifically, dermatologic lesions can trigger psychological alterations such as stress (10), and stressful situations may trigger alterations in the immune system as a consequence of the activation of the hypothalamic-pituitary adrenal axis (HPA) and increased glucocorticoids (11; see (16) for review), which may then impact healing.

Increased psychological stress is associated with a higher incidence of skin dermatoses (such as psoriasis and dermatitis) (12-14). This abnormality in the skin may interfere in the healing process and compromise the skin's ability to act as an immune barrier, which is one of its main functions (15). Padgett et al. (17) observed retardation in the healing process in an animal model submitted to immobilization stress. In addition, immobilized mice presented increased corticosterone when compared to controls. Thus, delayed healing was correlated with higher concentrations of corticosterone, suggesting that a perturbation of neuroendocrine homeostasis may modulate the repair process of the lesion. Taken as a whole, these results suggest that alterations in the immune function are associated with stress and may exert further complications that hamper the regeneration and integrity of the skin.



Recently, Kronholm and collaborators (18) showed that average sleep time has fallen approximately two hours per night over the past 50 years. This reduction in sleep time, which is characteristic of a modern lifestyle, may lead to repercussions upon one's health and well-being. In particular, several studies have shown that sleep deprivation (SD) causes marked and adverse alterations in the immune system (19-24). One study demonstrated that forced wakefulness in the first half of the night (from 22:00 to 3:00) and in the second half of the night (from 3:00 to 7:00) promoted a reduction in the activity of natural killer (NK) cells (25). These results suggest that a few hours of sleep deprivation is sufficient to cause adverse effects on the integrity of the immune system. Recently, Ruiz et al. (24) reported that a total of two nights of SD resulted in increased leukocytes and neutrophils in healthy men compared to their baseline values. After 24 hours of sleep recovery, those figures returned to the values observed at baseline. However, the concentrations of monocytes, eosinophils, basophiles, and cytokines (IL-1β, IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ) remained unaltered after the SD protocol. Thus, SD may alter the immune profile. BZD also influence the immune system, affecting cytokines, neutrophils, and macrophages (26-28).



When first administered, hypnotics and anxiolytics of the BZD class improve sleep efficiency by reducing the latency of sleep onset and arousals during the night (29). However, after chronic use, BZDs inhibit the desynchronization process, reducing REM sleep due to a decrease of the neurotransmitter GABA (30). Additionally, BZDs increase slow-wave sleep and, in the long term, lead to a condition of REM-sleep restriction (31).

The relationship between sleep deprivation, immune parameters, and skin integrity remains under investigation. Mostaghimi et al. (32) showed that rats subjected to five days of sleep deprivation by the multiple-platform method did not present a slower healing process when compared to controls. Similarly, Landis and Whitney (33) did not observe any detrimental effects on healing at the cellular level in rats that were sleep-deprived for 72 h using the single-platform method. Although these data cannot be interpreted as that the lack of sleep jeopardizes the healing process, nevertheless it is possible that those effects are mediated by other molecular mechanisms that are currently unidentified.

The wound healing process consists in a perfectly coordinated cascade of cellular and molecular events that interact to produce the reconstitution of the tissue. There are several studies in the literature showing the adverse effects, particularly stress, in wound healing in animal models and humans. It is known that sleep deprivation is an event inherent to stress and we can hypothesize that the stress caused by sleep deprivation results in negative consequences in the healing process. However, it is a challenge for researchers to investigate the effects of sleep deprivation on the healing process due to the complexity of this process.



Recovery from skin lesions, such as burns, is intimately associated with specific inflammatory mediators, which entails a direct association with the immune system. An example of such an association can be found in the formation of granulation tissue as macrophages release a variety of pro-inflammatory cytokines (interleukin 1 and 6) and growth factors (fibroblast growth factor [FGF], epidermal growth factor EGF, transforming growth factor-beta [TGF-β], and platelet-derived growth factor [PDGF]). The formation of granulation tissue is an essential process for the synthesis, deposition, and organization of new extracellular matrix [see review, (34)]. Thus, the efficacy of the healing process is directly dependent upon the integrity of the immune system. However, particularly when the wound is of great extent, depth, or severity, symptoms such as anxiety and stress can be observed, making the relationship between stress and the immune system bidirectional; the patient is stressed by the wound, and stress can compromise the immune system, slowing healing time. Thus, stress itself is responsible for the retardation of healing time (35).

Given the detrimental effects of stress in these situations, BZDs are commonly administered as a means of attenuating anxiety and stress symptoms (36). However, chronic consumption of BZD also provokes significant immunological disorders in humans (37) and alterations in sleep that may also affect immune function.

Therefore, we propose that the effects of BZD on healing are not direct, but rather are modulated by alterations of sleep, which then affect the immune system (Figure 1). This hypothesis is supported by studies that demonstrate the effects of BZD on the characteristics of the immune system and the inflammatory profile in normal sleep and sleep deprivation, particularly in REM sleep deprivation.



The potential damage caused by BZD to the healing process in patients who have skin wounds contradicts the use of these compounds in such cases (6). BZDs are used in such cases to improve the mental state of the patient and, as a consequence, promote better tissue regeneration; however, that advantage is offset by these potentially detrimental effects.

There are two important considerations that follow from our hypothesis. The first is that the hypothesis presents a novel manner of approaching the clinical condition in a patient with skin lesions. In this scenario, sleep becomes an important factor for that patient's improvement. The second is that this investigation opens a debate on the use of BZD for patients with skin lesions. BZDs are not the only drugs available as a therapeutic option for patients with anxiety. Medications such as buspirone, tricyclic antidepressants, and beta-blockers may be employed. Additionally, the effects of these medications on sleep differ from the effects of BZD; thus, they may reduce the negative effects on healing. This difference is particularly important when considering sleep deprivation and especially REM sleep deprivation. In these cases, the use of non-BZD hypnotics may be an option.

The physiological integrity of the skin is essential for the health of living creatures. Sleep is also a biological process that is fundamental for the quality of an individual's mental, emotional and physical life. Thus, our hypothesis combines the interaction of BZD with sleep and the possible influence on the healing process. However, additional studies, conducted in animals and humans, are necessary to test this hypothesis. This hypothesis opens opportunities for new discussions regarding this theme.



This work was supported by grants from Associação Fundo de Incentivo a Pesquisa (AFIP), CNPq, and Fundação de Amparo à Pesquisa do Estado de Sao Paulo-FAPESP (No. 2011/14462-0 to F.E., No. #2010/14768-0 to G.N.P and CEPID #98/14303-3 to S.T.). M.L.A. and S.T. are recipients of CNPq fellowships.



Egydio F contributed to the idea conception, the bibliographic review, the writing, and the final approval. Pires GN contributed to the idea conception, the writing, and the final approval. Tufik S contributed to the idea conception and the final approval. Andersen ML contributed to the idea conception, the writing, and the final approval.



1. Guo S, Dipietro LA. Factors affecting wound healing. J Dent Res. 2010; 89(3):219-29.         [ Links ]

2. Kahan V, Andersen ML, Tomimori J, Tufik S. Stress, immunity and skin collagen integrity: evidence from animal models and clinical conditions. Brain Behav Immun. 2009;23(8):1089-95,         [ Links ]

3. Wild T, Rahbarnia A, Kellner M, Sobotka L, Eberlein T. Basics in nutrition and wound healing. Nutrition. 2010;26(9):862-6,         [ Links ]

4. Ter Smitten MH, de Graaf R, Van Loey NE. Prevalence and co-morbidity of psychiatric disorders 1-4 years after burn. Burns. 2011;37(5):753-61,         [ Links ]

5. Tcheung WJ, Robert R, Rosenberg L, Rosenberg M, Villarreal C, Thomas C, et al. Early treatment of acute stress disorder in children with major burn injury. Pediatr Crit Care Med. 2005;6(6):676-81,         [ Links ]

6. Ratcliff SL, Brown A, Rosenberg L, Rosenberg M, Robert RS, Cuervo LJ, et al. The effectiveness of a pain and anxiety protocol to treat the acute pediatric burn patient. Burns 2006;32(5):554-62,         [ Links ]

7. Babcock GF, Hernandez L, Yadav E, Schwemberger S, Dugan A. The burn wound inflammatory response is influenced by midazolam. Inflammation. 2012;35(1):259-70,         [ Links ]

8. Dugan AL, Gregerson KA, Neely A, Gardner J, Noel GJ, Babcock GF, et al. Mice treated with a benzodiazepine had an improved survival rate following Pseudomonas aeruginosa infection. J Burn Care Res. 2010;31(1):1-12,         [ Links ]

9. McGhee LL, Maani CV, Garza TH, DeSocio PA, Gaylord KM, Black IH. The relationship of intravenous midazolam and posttraumatic stress disorder development in burned soldiers. The Journal of trauma. 2009;66(4 Suppl):186-90.         [ Links ]

10. Gouin JP, Kiecolt-Glaser JK. The impact of psychological stress on wound healing: methods and mechanisms. Immunol Allergy Clin North Am. 2011;31(1):81-93,         [ Links ]

11. Heijnen CJ, Kavelaars A. The contribution of neuroendocrine substances to the immune response. Neth J Med. 1991;39(3-4):281-94.         [ Links ]

12. Rostenberg A Jr. The role of psychogenic factors in skin diseases. Arch Dermatol. 1960;81:81-6,         [ Links ]

13. Tausk FA, Nousari H. Stress and the skin. Arch Dermatol. 2001; 137(1):78-82.         [ Links ]

14. Sugarman JL, Fluhr JW, Fowler AJ, Bruckner T, Diepgen TL, Williams ML. The objective severity assessment of atopic dermatitis score: an objective measure using permeability barrier function and stratum corneum hydration with computer-assisted estimates for extent of disease. Arch Dermatol. 2003;139(11):1417-22,         [ Links ]

15. Altemus M, Rao B, Dhabhar FS, Ding W, Granstein RD. Stress-induced changes in skin barrier function in healthy women. J Invest Dermatol. 2001;117(2):309-17,         [ Links ]

16. Stahn C, Buttgereit F. Genomic and nongenomic effects of glucocorticoids. Nat Clin Pract Rheumatol. 2008;4:525-33,         [ Links ]

17. Padgett DA, Marucha PT, Sheridan JF. Restraint stress slows cutaneous wound healing in mice. Brain Behav Immun. 1998;12(1):64-73,         [ Links ]

18. Kronholm E, Partonen T, Laatikainen T, Peltonen M, Härmä M, Hublin C, et al. Trends in self-reported sleep duration and insomnia-related symptoms in Finland from 1972 to 2005: a comparative review and re-analysis of Finnish population samples. J Sleep Res. 2008;17(1):54-62,         [ Links ]

19. Palma BD, Gabriel A Jr, Colugnati FA, Tufik S. Effects of sleep deprivation on the development of autoimmune disease in an experimental model of systemic lupus erythematosus. Am J Physiol Regul Integr Comp Physiol. 2006;291(5):1527-32,         [ Links ]

20. Perry JC, D'Almeida V, Souza FG, Schoorlemmer GH, Colombari E, Tufik S. Consequences of subchronic and chronic exposure to intermittent hypoxia and sleep deprivation on cardiovascular risk factors in rats. Respir Physiol Neurobiol. 2007;156(3):250-8,         [ Links ]

21. Zager A, Andersen ML, Ruiz FS, Antunes IB, Tufik S. Effects of acute and chronic sleep loss on immune modulation of rats. Am J Physiol Regul Integr Comp Physiol. 2007;293(1):R504-9,         [ Links ]

22. Zager A, Andersen ML, Lima MM, Reksidler AB, Machado RB, Tufik S. Modulation of sickness behavior by sleep: the role of neurochemical and neuroinflammatory pathways in mice. Eur Neuropsychopharmacol. 2009;19(8):589-602,         [ Links ]

23. Ruiz FS, Andersen ML, Zager A, Martins RC, Tufik S. Sleep deprivation reduces the lymphocyte count in a non-obese mouse model of type 1 diabetes mellitus. Braz J Med Biol Res. 2007;40(5):633-7,         [ Links ]

24. Ruiz FS, Andersen ML, Martins RC, Zager A, Lopes JD, Tufik S. Immune alterations after selective rapid eye movement or total sleep deprivation in healthy male volunteers. Innate Immun. 2012;18(1):44-54,         [ Links ]

25. Irwin M, Mascovich A, Gillin JC, Willoughby R, Pike J, Smith TL. Partial sleep deprivation reduces natural killer cell activity in humans. Psychosomatic medicine. 1994;56(6):493-8.         [ Links ]

26. Zavala F, Taupin V, Descamps-Latscha B. In vivo treatment with benzodiazepines inhibits murine phagocyte oxidative metabolism and production of interleukin 1, tumor necrosis factor and interleukin-6. J Pharmacol Exp Ther. 1990;255(2):442-50.         [ Links ]

27. Schreiber AA, Frei K, Lichtensteiger W, Schlumpf M. The effect of prenatal diazepam exposure on TNF-alpha production by rat splenocytes. Agents and actions. 1993;38(3-4):265-72,         [ Links ]

28. Sakai M, Fonseca ES, Dagli ML, Palermo-Neto J. Diazepam effects on Ehrlich tumor growth and macrophage activity in mice. Life sciences. 2006;78(16):1777-83,         [ Links ]

29. Roehrs R RT. Hypnotics: Efficacy and adverse events. In: Kryger TR MH, Dement eWC, ed. Principles and practices of sleep medicine. New York: 3rd ed; 2000:pp.414-8.         [ Links ]

30. Xi MC, Morales FR, Chase MH. Evidence that wakefulness and REM sleep are controlled by a GABAergic pontine mechanism. J Neurophysiol. 1999;82(4):2015-9.         [ Links ]

31. Marks GA, Sachs OW, Birabil CG. Blockade of GABA, type A, receptors in the rat pontine reticular formation induces rapid eye movement sleep that is dependent upon the cholinergic system. Neuroscience. 2008;156(1):1-10,         [ Links ]

32. Mostaghimi L, Obermeyer WH, Ballamudi B, Martinez-Gonzalez D, Benca RM. Effects of sleep deprivation on wound healing. J Sleep Res. 2005;14(3):213-9,         [ Links ]

33. Landis CA, Whitney JD. Effects of 72 hours sleep deprivation on wound healinginthe rat. Res Nurs Health. 1997;20(3):259-67,<259::AID-NUR8>3.0.CO;2-H.         [ Links ]

34. Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M. Growth factors and cytokines in wound healing. Wound Repair Regen. 2008;16(5):585-601,         [ Links ]

35. Kiecolt-Glaser JK, Glaser R. Psychological stress and wound healing: Kiecolt-Glaser, et al. (1995). Adv Mind Body Med. 2001;17(1):15-6,         [ Links ]

36. Goyal R, Anil K. Protective effect of alprazolam in acute immobilization stress-induced certain behavioral and biochemical alterations in mice. Pharmacological reports. 2007;59(3):284-90.         [ Links ]

37. Lechin F, van der Dijs B, Vitelli-Flores G, Báez S, Lechin ME, Lechin AE, et al. Peripheral blood immunological parameters in long-term benzodiazepine users. Clin Neuropharmacol. 1994;17(1):63-72,         [ Links ]



Received for publication on January 10, 2012
First review completed on January 31, 2012
Accepted for publication on February 22, 2012
No potential conflict of interest was reported.



E-mail: /
Tel.: 55-11 21490155

Creative Commons License All the contents of this journal, except where otherwise noted, is licensed under a Creative Commons Attribution License