FOCUSED REVIEW

Neuraxial Morphine and Oral Herpes Reactivation in the Obstetric Population

Jeanette R. Bauchat, MD
Neuraxial morphine administration is a common strategy for providing postcesarean delivery analgesia. Morphine delivered via this route increases the risk of herpes labialis (oral herpes) reactivation, a disease common in women of childbearing age. A primary concern is risk of transmission to the neonate from maternal reactivation. The benefits to the mother of this form of analgesia outweigh the risk of neonatal herpes acquired postpartum from maternal recurrence because serious neonatal morbidity from recurrent herpes has not been described. (Anesth Analg 2010;111:1238 41)

dministration of neuraxial morphine for postcesarean delivery analgesia increases the risk for herpes labialis reactivation (oral herpes). The prevalence of herpes labialis in women of childbearing age ranges from 56% to 73%.1 Thirty-three percent of women in the United States have a cesarean delivery. Neuraxial morphine, as part of a multimodal postoperative analgesic regimen, is one of the most widely used and effective methods of providing pain relief.2 6 This focused review describes the pathophysiology and prevalence of herpes simplex virus (HSV), the evidence supporting the link between neuraxial opioids and increased HSV-1 reactivation rates, and the risk to the fetus of maternal HSV reactivation in the postpartum period. Postulated mechanisms for this association are also briefly discussed.

changing. HSV-1 currently accounts for 78% of new cases of genital herpes in college-age women in the United States.14 The true prevalence of oral lesions caused by HSV-2 is unknown. It is believed to be rare, acquired through sexual contact, and activated in the setting of a primary infection or recurrence of HSV-2 genital herpes.15 HSV infection can be diagnosed by sending vesicular fluid for culture or viral polymerase chain reaction but accurate results are dependent on collection technique.16 Serologic testing for HSV antibodies can distinguish HSV-1 from HSV-2, and helps to determine exposure history in the absence of active infection. However, serologic testing cannot identify site of infection.16

HSV PATHOPHYSIOLOGY
The prevalence of HSV-1 is 68% in the United States (age 12 years) but varies with age, gender, socioeconomic status, sexual activity, and geographic location.1,7 Primary infection with HSV-1 may present in infancy. The prevalence reaches 27% by age 4 years, and continues to increase with age.8,9 HSV causes lifelong infection in its host because of its ability to travel retrograde via sensory nerves from infected tissues to the sensory nerve root ganglia, where it remains latent.10 Primary HSV infection typically presents with malaise and myalgia, as well as pain, itching, and burning at the site of oral vesicular lesions. Young children are more likely to have asymptomatic primary infections.7,11 Reactivation occurs with triggers such as fever, trauma, fatigue, emotional stress, common cold, ultraviolet light, and pregnancy.7 Symptoms during reactivation tend to be milder with a prodrome of tingling, itching, paresthesia, and pain around the site of primary infection, but viral shedding can occur in the absence of symptoms.12,13 Although HSV-1 typically affects the oral mucosa and HSV-2 typically affects the genital mucosa, the epidemiology of HSV infection is
From the Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Accepted for publication July 27, 2010. Disclosure: The author reports no conflicts of interest. Address correspondence and reprint requests to Jeanette R. Bauchat, MD, Northwestern University Feinberg School of Medicine, 251 E. Huron St., F5-704, Chicago, IL 60611. Address e-mail to jbauchat@gmail.com. Copyright 2010 International Anesthesia Research Society
DOI: 10.1213/ANE.0b013e3181f57c30

HSV REACTIVATION AFTER NEURAXIAL MORPHINE FOR CESAREAN DELIVERY ANALGESIA

As the use of neuraxial morphine for postcesarean analgesia increased throughout the 1980s, case reports and letters to the editor suggesting a link between neuraxial morphine and reactivation of herpes labialis began appearing in the literature.1724 These reports were followed by retrospective and prospective trials that confirmed an increased rate of oral HSV reactivation among women receiving neuraxial morphine as compared with systemic morphine for postcesarean delivery analgesia. These studies are summarized in Table 1. The first prospective trial specifically addressing neuraxial morphine and HSV reactivation rates was conducted by Gieraerts et al.25 Patients receiving epidural morphine for postcesarean delivery analgesia demonstrated a higher rate of reactivation than those receiving systemic morphine. The small number of patients in the trial and low baseline prevalence of HSV infection made it difficult to assess the true risk of HSV reactivation from epidural morphine. Fuller et al.26 conducted a large, retrospective chart review of 4880 obstetric women who received epidural morphine after cesarean delivery. They reported that 3.5% of patients had a recurrence of herpes labialis. The low recurrence rate was likely in part attributable to the biases of retrospective studies such as lack of reporting or documentation. In 2 randomized controlled trials comparing epidural to systemic opioid analgesia, Crone et al.27 and Boyle28 confirmed the previous findings of increased HSV reactivation after epidural morphine. Crone et al. found a reactivation rate of 14.6% in patients receiving epidural opioids, but 0% in patients receiving systemic opioids. Boyle reported a
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Table 1. Retrospective and Prospective Trials that Conrmed an Increased Rate of Oral Herpes Simplex Virus Reactivation Among Women Receiving Neuraxial Morphine as Compared with Systemic Morphine for Postcesarean Delivery Analgesia
Study Gieraerts et al.,23 1987 Study design No. of patients Case-matched Epidural morphine, n 26 prospective trial IM morphine, n 18 Retrospective chart review Randomized controlled trial Epidural morphine, n 4880 Epidural morphine, n 96 IM opioid, n 91 Norris et al.,29 1994 Prospective cohort Epidural morphine, n 48; trial spinal morphine, n 153 Systemic opioids, n 156 Epidural morphine, n 425 Parenteral morphine, n 386 Spinal and PCIA morphine, n 50 PCIA morphine, n 48 HSV prevalence (%) Opioid dose 39.1%a Epidural morphine 3.55 mg q 12 h prn 16.7% IM morphine 10 mg to comfort then q 6 h prn Unknown Epidural morphine 25 mg 1 64.6%b 62.6% 28.9%a Epidural morphine 4 or 5 mg, 1 dose IM meperidine 50100 mg or IM morphine 7.510 mg Epidural morphine 35 mg, 1 dose; spinal morphine 0.150.25 mg, 1 dose Unspecied Unspecied Unspecied Spinal morphine 0.25 mg and IV morphine 1 mg q 6 min IV morphine 4 mg loading 1 mg q 6 min HSV reactivation rate (%) 35% 0% 3.5% 14.6%* 0% 3.5%

Fuller et al.,26 1990 Crone et al.,27 1990

Boyle,28 1995 Davies et al.,30 2005

Randomized controlled trial Randomized controlled trial

36.5% 28%a 30% 66%b 77%

2.6% 5.2%* 0.5% 38%* 16.6%

HSV herpes simplex virus; PCIA patient-controlled IV analgesia; q every; prn pro re nata (as needed). a HSV prevalence obtained by patient history. b HSV prevalence obtained by serologic testing. * P 0.05.

reaction rate of 5.2% in patients receiving epidural opioids, but only 0.5% in patients receiving systemic opioids. The different reactivation rates reported in these 2 studies was likely influenced by underlying prevalence of HSV in their patient populations. However, because they used different methods of assessing underlying prevalence, it is difficult to compare the reactivation rates directly. Patients in the Crone et al.27 trial received 4 or 5 mg epidural morphine. The dose of epidural morphine used in the Boyle trial was not reported.28 In contrast to previous findings, Norris et al.29 found no increased incidence of herpes labialis in women receiving neuraxial morphine compared with systemic analgesia. However, the majority of patients in the neuraxial morphine group received spinal morphine. It was unclear whether the low rate of reactivation and lack of difference between groups was a result of intrathecal morphine use, low baseline rate of HSV infection (9%), or inadequate study power. To clarify whether intrathecal morphine specifically increased the risk of reactivation versus systemic opioids, Davies et al.30 designed a randomized controlled trial that included women with a reported history of HSV-1 scheduled for elective cesarean delivery under spinal anesthesia. This trial confirmed an increased risk of reactivation with intrathecal morphine. Unlike the previous trials, in which the risk of postpartum herpes labialis in the control group was very low (0%3%), these investigators demonstrated a 17% rate in women who received systemic analgesia, suggesting that other perioperative and peripartum factors may also influence reactivation in this at-risk population. Taken together, these trials show an increased risk of oral herpes reactivation in women receiving neuraxial morphine for postcesarean delivery analgesia compared

with systemic analgesia. There are no randomized controlled trials demonstrating whether HSV reactivation risk is increased after other neuraxial opioids. It is important to note that 72% to 86% of women with a history of herpes labialis who received neuraxial morphine did not have a recurrence. However, clinicians are understandably concerned about the risk of HSV transmission to the neonate whose mother has a recurrence.27,28,30

NEONATAL HERPES
In pregnancy, primary maternal HSV infection presents profound risks to the fetus. HSV infection is among the congenitally acquired infections that lead to severe fetal anomalies and fetal loss in utero. Neonatal herpes infections acquired peripartum are rare, with an incidence estimated from 8 to 60 cases per 100,000 live births. They can cause skin, eye, and mouth disease, encephalitis, or disseminated infection.31,32 Disseminated infection is exceedingly rare but can lead to cognitive impairment, severe neurological disease, and organ dysfunction. Mortality reaches 31% even with prompt administration of antiviral treatment to the infant.32 In the United States, 60% to 80% of acquired neonatal herpes infections result from mothers who have a primary HSV infection during the third trimester of pregnancy and shed HSV subclinically in the genital tract.16,31,33 Neonatal herpes can be transmitted postpartum from the mother, family members, or hospital personnel with active herpes labialis. However, this route of transmission accounts for only 10% of cases of neonatal herpes.34 Latent maternal HSV infection confers immunity to offspring via HSV immunoglobulin G antibodies transmitted transplacentally. The higher the neonates neutralizing antibody

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titer, the lower the incidence of neonatal herpes transmission and severity of the disease.3537 Maternal HSV immunoglobulin G antibodies provide incomplete protection, however, and titers rapidly decrease in the first year of life.9 It is reassuring that neonates of mothers with a known history of herpes labialis are unlikely to acquire neonatal herpes from maternal reactivation postpartum and if they did, they would have a mild form of the disease.31,35 Currently, there are no reports in the literature of neonatal herpes contracted postpartum from maternal herpes labialis reactivation after neuraxial morphine administration. To minimize the risk of neonatal transmission, prompt treatment of maternal herpes labialis with topical antiviral creams or oral antiviral therapy should be considered to reduce the severity and length of infection. All caregivers and family members who have symptoms of herpes labialis should be educated on measures (i.e., refrain from kissing, frequent hand washing) to minimize transmission to the newborn. Given the low risk of HSV reactivation using neuraxial morphine and even smaller risk of postpartum transmission to the neonate, withholding neuraxial morphine, a highly effective analgesic technique for postcesarean delivery pain, is not supported by medical evidence.

POSTULATED MECHANISMS FOR HSV REACTIVATION WITH NEURAXIAL MORPHINE

The cellular and molecular mechanisms for HSV reactivation, independent of neuraxial morphine administration, are not clearly understood and are currently under investigation. The most frequently postulated, but unproven, mechanism for HSV reactivation is that irritation from facial scratching due to neuraxial opioid-induced pruritus (incidence ranging from 48% to 81%) leads to reactivation.2527 The mechanism for opioid-induced pruritus is also not fully elucidated, but seems to be mediated primarily via direct or indirect activation of central nervous system -opioid receptors, a high density of which are expressed in the trigeminal nerve.38,39 A doseresponse study using epidural morphine (1.55 mg) demonstrated no dose response in severity of pruritus. Thus, if reactivation rates correlate with rates or severity of pruritus, reducing the epidural morphine doses would not be expected to be of benefit.40 In contrast to epidural morphine, the severity of pruritus escalates with increasing doses of intrathecal morphine (0.025 0.5 mg) despite an analgesic ceiling effect at 0.1 mg morphine.41,42 Therefore, the lowest effective analgesic dose of intrathecal morphine should be used to reduce pruritus if for no other reason than maternal comfort.43 Although it may seem intuitive, there is no evidence that pruritus from neuraxial morphine actually has a role in HSV reactivation and this mechanism remains speculative. Boyle, after correcting for history of HSV and exposure to epidural morphine, did not demonstrate an association between pruritus and HSV reactivation.28 Both trials using intrathecal morphine for postcesarean delivery analgesia demonstrated more frequent and severe pruritus in the intrathecal group, but there was no association between pruritus and HSV reactivation after correcting for a history of herpes labialis.29,30 Given the lack of evidence that pruritus is the mechanism by which HSV is reactivated in women receiving neuraxial morphine for postcesarean analgesia, recommendations for

avoidance of facial scratching or aggressive treatment of pruritus cannot be advocated except for maternal comfort. There is more compelling evidence that HSV reactivation may be attributable to disruption of the molecular mechanisms promoting a balance between viral transcription and host immunity in the central nervous system that normally work to maintain HSV latency.44 The HSV virus causes C fibers to release the neuropeptide calcitonin gene-related peptide, which prevents immune cells in the skin from maturing and destroying the virus.10 Once inside the C fibers, the virus travels retrograde into the cell body where latencyassociated transcript RNA and immediate early (IE) gene transcripts maintain latency.10 Some IE gene transcripts inhibit the display of human leukocyte antigen class I molecules on the cell surface, effectively evading the immune system.10 CD8 T cells kill trigeminal neurons that are actively infected with virus.45 These T cells may promote HSV latency by maintaining a noncytotoxic phase in response to low levels of IE viral proteins, thus preventing reactivation but not destroying latently infected trigeminal neurons.45 Trigger factors for HSV reactivation such as pregnancy, surgery, and acute morphine administration are well known, but the cellular and molecular mechanisms by which cellular immunity and viral latency are disrupted continue to be studied.46 Catecholamines, glucocorticoids, and cytokines released during stress-related states appear to activate intracellular pathways that promote HSV viral transcription.46 Acute morphine administration can alter the immune response by suppressing interleukins and cytokines making cells more susceptible to HSV infection.45 Activated T cells express -, -, and -opioid receptors and their populations are altered by exposure to morphine.47 Altered opioid receptor expression may contribute to increased susceptibility to and reactivation of HSV-1 in mouse models after acute morphine administration.48 50 Knowledge of the molecular mechanisms controlling the balance between HSV latency and active infection and its interconnection with CD8 T cell immunity is rapidly increasing, but a thorough discussion of this topic is outside the scope of this review.

CONCLUSIONS
Herpes labialis is common in women of childbearing age. Despite this, the majority of mothers receiving neuraxial morphine for postcesarean delivery analgesia will not have an HSV reactivation. The benefits of adequate analgesia for the mother include comfort, increased mobility, and improved infant care. Withholding this clinically beneficial, cost-effective analgesic technique to reduce maternal HSV reactivation or further minimize the remote possibility of transmitting HSV to the neonate is not supported by medical evidence.
AUTHOR CONTRIBUTIONS

JRB helped write the manuscript and approved the final manuscript.
REFERENCES 1. Smith JS, Robinson NJ. Age-specific prevalence of infection with herpes simplex virus types 2 and 1: a global review. J Infect Dis 2002;186:S328 2. Hamilton BE, Martin JA, Ventura SJ. Births: preliminary data for 2007. In: Services USDoHaH, ed. Atlanta: Centers for Disease Control and Prevention, 2009:123

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www.anesthesia-analgesia.org

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Neuraxial Morphine Herpes Reactivation

3. Wu CL, Cohen SR, Richman JM, Rowlingson AJ, Courpas GE, Cheung K, Lin EE, Liu SS. Efficacy of postoperative patientcontrolled and continuous infusion epidural analgesia versus intravenous patient-controlled analgesia with opioids: a metaanalysis. Anesthesiology 2005;103:1079 88 4. Lim Y, Jha S, Sia AT, Rawal N. Morphine for post-caesarean section analgesia: intrathecal, epidural or intravenous? Singapore Med J 2005;46:392 6 5. Lavandhomme P. Postcesarean analgesia: effective strategies and association with chronic pain. Curr Opin Anaesthesiol 2006;19:244 8 6. Gadsden J, Hart S, Santos AC. Post-cesarean delivery analgesia. Anesth Analg 2005;101:S629 7. Arduino PG, Porter SR. Herpes simplex virus type 1 infection: overview on relevant clinico-pathological features. J Oral Pathol Med 2008;37:10721 8. Taieb A, Body S, Astar I, du Pasquier P, Maleville J. Clinical epidemiology of symptomatic primary herpetic infection in children: a study of 50 cases. Acta Paediatr Scand 1987;76:12832 9. Tunback P, Bergstrom T, Claesson BA, Carlsson RM, Lowhagen GB. Early acquisition of herpes simplex virus type 1 antibodies in children: a longitudinal serological study. J Clin Virol 2007;40:26 30 10. Becker Y. Herpes simplex virus evolved to use the human defense mechanisms to establish a lifelong infection in neurons: a review and hypothesis. Virus Genes 2002;24:18796 11. Lowhagen GB, Bonde E, Eriksson B, Nordin P, Tunback P, Krantz I. Self-reported herpes labialis in a Swedish population. Scand J Infect Dis 2002;34:664 7 12. Liljeqvist JA, Tunback P, Norberg P. Asymptomatically shed recombinant herpes simplex virus type 1 strains detected in saliva. J Gen Virol 2009;90:559 66 13. Tateishi K, Toh Y, Minagawa H, Tashiro H. Detection of herpes simplex virus (HSV) in the saliva from 1,000 oral surgery outpatients by the polymerase chain reaction (PCR) and virus isolation. J Oral Pathol Med 1994;23:80 4 14. Roberts CM, Pfister JR, Spear SJ. Increasing proportion of herpes simplex virus type 1 as a cause of genital herpes infection in college students. Sex Transm Dis 2003;30:797 800 15. Wald A, Ericsson M, Krantz E, Selke S, Corey L. Oral shedding of herpes simplex virus type 2. Sex Transm Infect 2004;80:272 6 16. Gupta R, Warren T, Wald A. Genital herpes. Lancet 2007;370:212737 17. Cardan E. Herpes simplex after spinal morphine. Anaesthesia 1984;39:938 18. Acalovschi I. Herpes simplex after spinal pethidine. Anaesthesia 1986;41:12712 19. Douglas MJ, McMorland GH. Possible association of herpes simplex type I reactivation with epidural morphine administration. Can J Anaesth 1987;34:426 7 20. Crone LA, Conly JM, Clark KM, Crichlow AC, Wardell GC, Zbitnew A, Rea LM, Cronk SL, Anderson CM, Tan LK, Albritton WL. Recurrent herpes simplex virus labialis and the use of epidural morphine in obstetric patients. Anesth Analg 1988;67:318 23 21. Pennant JH, Wallace D. Intrathecal morphine and reactivation of oral herpes simplex. Anesthesiology 1991;75:167 22. Valley MA, Bourke DL, McKenzie AM. Recurrence of thoracic and labial herpes simplex virus infection in a patient receiving epidural fentanyl. Anesthesiology 1992;76:1056 7 23. Gieraerts R, Vaes L, Navalgund A, Jahr J. Recurrent HSVL and the use of epidural morphine in obstetrics. Anesth Analg 1989;68:418 24. Abouleish E. Intrathecal morphine as a cause for herpes simplex should be scratched out. Anesthesiology 1991;75:919 20 25. Gieraerts R, Navalgund A, Vaes L, Soetens M, Chang JL, Jahr J. Increased incidence of itching and herpes simplex in patients given epidural morphine after cesarean section. Anesth Analg 1987;66:1321 4 26. Fuller JG, McMorland GH, Douglas MJ, Palmer L. Epidural morphine for analgesia after caesarean section: a report of 4880 patients. Can J Anaesth 1990;37:636 40 27. Crone LA, Conly JM, Storgard C, Zbitnew A, Cronk SL, Rea LM, Greer K, Berenbaum E, Tan LK, To T. Herpes labialis in parturients receiving epidural morphine following cesarean section. Anesthesiology 1990;73:208 13

28. Boyle RK. Herpes simplex labialis after epidural or parenteral morphine: a randomized prospective trial in an Australian obstetric population. Anaesth Intensive Care 1995;23:4337 29. Norris MC, Weiss J, Carney M, Leighton BL. The incidence of herpes simplex virus labialis after cesarean delivery. Int J Obstet Anesth 1994;3:12731 30. Davies PW, Vallejo MC, Shannon KT, Amortegui AJ, Ramanathan S. Oral herpes simplex reactivation after intrathecal morphine: a prospective randomized trial in an obstetric population. Anesth Analg 2005;100:1472 6 31. Corey L, Wald A. Maternal and neonatal herpes simplex virus infections. N Engl J Med 2009;361:1376 85 32. Handsfield HH, Waldo AB, Brown ZA, Corey L, Drucker JL, Ebel CW, Leone PA, Stanberry LR, Whitley RJ. Neonatal herpes should be a reportable disease. Sex Transm Dis 2005;32:5215 33. Baker DA. Consequences of herpes simplex virus in pregnancy and their prevention. Curr Opin Infect Dis 2007;20:73 6 34. Kimberlin DW. Herpes simplex virus infections of the newborn. Semin Perinatol 2007;31:19 25 35. Kimberlin DW. Herpes simplex virus infections in neonates and early childhood. Semin Pediatr Infect Dis 2005;16:271 81 36. Kohl S, West MS, Prober CG, Sullender WM, Loo LS, Arvin AM. Neonatal antibody-dependent cellular cytotoxic antibody levels are associated with the clinical presentation of neonatal herpes simplex virus infection. J Infect Dis 1989;160:770 6 37. Sullender WM, Miller JL, Yasukawa LL, Bradley JS, Black SB, Yeager AS, Arvin AM. Humoral and cell-mediated immunity in neonates with herpes simplex virus infection. J Infect Dis 1987;155:28 37 38. Ganesh A, Maxwell LG. Pathophysiology and management of opioid-induced pruritus. Drugs 2007;67:232333 39. Scott PV, Fischer HB. Spinal opiate analgesia and facial pruritus: a neural theory. Postgrad Med J 1982;58:5315 40. Palmer CM, Nogami WM, Van Maren G, Alves DM. Postcesarean epidural morphine: a dose-response study. Anesth Analg 2000;90:88791 41. Palmer CM, Emerson S, Volgoropolous D, Alves D. Doseresponse relationship of intrathecal morphine for postcesarean analgesia. Anesthesiology 1999;90:437 44 42. Girgin NK, Gurbet A, Turker G, Aksu H, Gulhan N. Intrathecal morphine in anesthesia for cesarean delivery: dose-response relationship for combinations of low-dose intrathecal morphine and spinal bupivacaine. J Clin Anesth 2008;20:180 5 43. Gehling M, Tryba M. Risks and side-effects of intrathecal morphine combined with spinal anaesthesia: a meta-analysis. Anaesthesia 2009;64:64351 44. Boyle RK. A review of anatomical and immunological links between epidural morphine and herpes simplex labialis in obstetric patients. Anaesth Intensive Care 1995;23:42532 45. Divito S, Cherpes TL, Hendricks RL. A triple entente: virus, neurons, and CD8 T cells maintain HSV-1 latency. Immunol Res 2006;36:119 26 46. Sainz B, Loutsch JM, Marquart ME, Hill JM. Stress-associated immunomodulation and herpes simplex virus infections. Med Hypotheses 2001;56:348 56 47. McCarthy L, Wetzel M, Sliker JK, Eisenstein TK, Rogers TJ. Opioids, opioid receptors, and the immune response. Drug Alcohol Depend 2001;62:11123 48. Lioy DT, Sheridan PA, Hurley SD, Walton JR, Martin AM, Olschowka JA, Moynihan JA. Acute morphine exposure potentiates the development of HSV-1-induced encephalitis. J Neuroimmunol 2006;172:9 17 49. Mojadadi S, Jamali A, Khansarinejad B, Soleimanjahi H, Bamdad T. Acute morphine administration reduces cell-mediated immunity and induces reactivation of latent herpes simplex virus type 1 in BALB/c mice. Cell Mol Immunol 2009;6:111 6 50. Sheridan PA, Moynihan JA. Modulation of the innate immune response to HSV-1 following acute administration of morphine: role of hypothalamo-pituitary-adrenal axis. J Neuroimmunol 2005;158:14552

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