April 2018 FAQs

Is there a potential for misuse and abuse with gabapentin (Neurontin^®) and pregabalin (Lyrica^®)?

Introduction

Gabapentin (Neurontin^®) and pregabalin (Lyrica^®) are gabapentinoids approved for use in the United States since 1993 and 2004, respectively.^1,2  The Food and Drug Administration (FDA) approved gabapentin as an adjunctive therapy for partial onset seizures, with and without secondary generalization, in adults and children ≥ 3 years of age and as a treatment for postherpetic neuralgia in adults.¹  The approved indications for pregabalin include as an adjunctive therapy for adults with partial onset seizures and as a treatment of neuropathic pain associated with diabetic peripheral neuropathy and spinal cord injury, postherpetic neuralgia, and fibromyalgia.²  Historically, clinicians have not considered these agents problematic with regard to abuse potential even though existing package inserts discuss abuse and dependence and pregabalin was designated a Schedule V controlled substance upon approval.^1,2 More recently, the 2016 Centers for Disease Control and Prevention (CDC) guideline for prescribing opioids for chronic pain specifically promotes anticonvulsants, such as gabapentin and pregabalin, as effective nonopioid pharmacologic options for patients with certain chronic pain syndromes.³  This has led some clinicians to wonder if a potential for abuse or misuse actually exists with these agents.

Increasing Use of Gabapentin and Pregabalin

Since approval, gabapentin and pregabalin usage has expanded considerably.  In 2016, gabapentin was the 10th most commonly prescribed medication in the United States with 64 million dispensed prescriptions.⁴  This was an increase from 39 million in 2012.  Pregabalin ranked 8th in invoice drug spending in 2016, more than double its amount from 2012.  Additionally, only 3 other brand name drugs that are typically prescribed in the primary care setting had higher sales: Lantus^®, Januvia^®, and Advair^®.⁵  This prescription expansion may be explained by a variety of factors including increased off-label usage, clinicians avoiding opioid medications for treatment of pain in favor of nonopioid options, and potential abuse.

Misuse and Abuse – Scope of the Problem and Clinical Data

The prevalence of misuse, abuse, and diversion with the gabapentinoids has been more clearly defined with gabapentin than pregabalin.^6-8  Smith and colleagues published a systematic review of gabapentin misuse and diversion in 2016.⁶  Results revealed a 1% prevalence of gabapentin misuse in the general population; 40% to 65% among individuals with existing gabapentin prescriptions and 15% to 22% among individuals who abuse opioids.  In an analysis of a large commercially insured sample, gabapentin usage patterns were similar to those observed for other drugs of abuse.⁷  These patterns included utilization of a large amount of gabapentin by a small portion of users, high daily doses dispensed to patients in the top utilizing percentiles (i.e., the top 1% of users consumed and/or diverted a mean dosage of 11,274 mg/day), and elevated rates of potential abuse in patients using both gabapentin and opioid medications.  An analysis of law enforcement data from the Drug Diversion Program of the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) System confirms an increase in gabapentin diversion and misuse from 2002 to 2015.⁸  Results from this analysis revealed gabapentin diversion rates steadily climbing in conjunction with the opioid epidemic from 0 cases in the first few quarters of 2012 to a high of 0.027 cases/100,000 population in the last quarter of 2015.

Schwan and colleagues conducted an analysis of the Swedish national register of adverse drug reactions (SWEDIS) through 2009 in order to evaluate the abuse potential of pregabalin.⁹ Of the more than 82,000 reports in SWEDIS during the study period, 16 were specifically related to pregabalin abuse or addiction.  Thirteen of the 16 pregabalin-related reports involved individuals with an existing history of substance abuse.  In a separate clinical study, the presence of pregabalin in urine specimens from patients receiving outpatient therapy for opiate dependence (n=124) or those treated for other addiction disorders (n=111) was evaluated.¹⁰  Results revealed that 12.1% of all urine specimens from patients with opiate dependence were positive for pregabalin versus 2.7% of patients in the control group.  No urine-positive patient in the opiate dependence group had a medical indication for pregabalin while all positive patients in the control group received pregabalin for appropriate medical purposes.

Unfortunately, a majority of the published clinical data that describes abuse and dependence of gabapentin and pregabalin is from case reports/series and epidemiologic studies.  Table 1 summarizes data from selected case reports/series.  Most of the patients within these reports have a strong history of alcohol or illicit drug abuse or dependence issues.  Additionally, there are several case reports in the literature describing potential withdrawal effects from gabapentin.¹¹ The onset of these symptoms generally occurred within 24 to 48 hours after gabapentin discontinuation.

Table 1.  Summary of case reports/series.^12-20

Conclusion

Historically, the gabapentinoids (gabapentin and pregabalin) have been viewed as innocuous analgesics.  However, in conjunction with the widespread opioid epidemic in the United States, there have been increasing reports of potential abuse and misuse with these agents. The majority of these report have revealed particular concern for patients with a history of substance abuse.^21-23  Clinicians considering prescribing gabapentinoids should carefully evaluate a patient for a previous history of drug abuse and be able to promptly identify signs of potential abuse and misuse.

References

1.  Neurontin [package insert].  New York, NY: Pfizer, Inc.; 2017.

2.  Lyrica [package insert].  New York, NY: Pfizer, Inc.; 2016.

3.  Dowell D, Haegerich TM, Chou R.  CDC guideline for prescribing opioids for chronic pain – United States, 2016. JAMA. 2016;315(15):1624-1645.

4.  Frellick M.  Top-selling, top-prescribed drugs for 2016.  October 2, 2017.   https://www.medscape.com/viewarticle/886404. Accessed March 23, 2018.

5.  Goodman CW, Brett AS.  Gabapentin and pregabalin for pain – is increased prescribing a cause for concern?  N Engl J Med. 2017;377(5):411-414.

6.  Smith RV, Havens JR, Walsh SL.  Gabapentin misuse, abuse, and diversion: a systematic review.  Addiction. 2016;111(7):1160-1174.

7.  Peckham AM, Fairman KA, Sclar DA.  Prevalence of gabapentin abuse: comparison with agents with known abuse potential in a commercially insured US population.  Clin Drug Investig. 2017;37(8):763-773.

8.  Buttram ME, Kurtz SP, Dart RC, Margolin ZR.  Law enforcement-derived data on gabapentin diversion and misuse, 2002-2015: diversion rates and qualitative research findings.  Pharmacoepidemiol Drug Saf. 2017;26(9):1083-1086.

9.  Schwan S, Sundstrom A, Stjernberg E, Hallberg E, Hallberg P.  A signal for an abuse liability for pregabalin – results from the Swedish spontaneous adverse drug reaction reporting system.  Eur J Clin Pharmacol. 2010;66(9):947-953.

10. Grosshans M, Lemenager T, Vollmert C, et al.  Pregabalin abuse among opiate addicted patients.  Eur J Clin Pharmacol. 2013;69(12):2021-2025.

11. Mersfelder TL, Nichols WH.  Gabapentin: abuse, dependence, and withdrawal.  Ann Pharmacother. 2016;50(3):229-233.

12. Kruszewski SP, Paczynski RP, Kahn DA.  Gabapentin-induced delirium and dependence.  J Psychiatr Pract. 2009;15(4):314-319.

13. Pittenger C, Desan PH.  Gabapentin abuse, and delirium tremens upon gabapentin withdrawal.  J Clin Psychiatry. 2007;68(3):483-484.

14. Victori-Vigneau C, Guerlals M, Jolliet P.  Abuse, dependency and withdrawal with gabapentin: a first case report.  Pharmacopsychiatry. 2007;40(1):43-44.

15. Reccoppa L, Malcolm R, Ware M.  Gabapentin abuse in inmates with prior history of cocaine dependence.  Am J Addict. 2004;13(3):321-323.

16. Markowitz JS, Finkenbine R, Myrick H, King L, Carson WH.  Gabapentin abuse in a cocaine user: implications for treatment?  J Clin Psychopharmacol. 1997;17(5):423-424.

17. Gahr M, Franke B, Freudenmann RW, Kolle MA, Schonfeldt-Lecuona C.  Concerns about pregabalin: further experience with its potential of causing addictive behaviors.  J Addict Med. 2013;7(2):147-149.

18. Carrus D, Schifano F.  Pregabalin misuse-related issues: intake of large dosages, drug-smoking allegations, and possible association with myositis.  Two case reports.  J Clin Psychopharmacol. 2012;32(6):839-840.

19. Filipetto FA, Zipp CP, Coren JS.  Potential for pregabalin abuse or diversion after past drug-seeking behavior.  J Am Ostopath Assoc. 2010;110(10):605-607.

20. Grosshans M, Mutschler J, Hermann D, et al.  Pregabalin abuse, dependence, and withdrawal: a case report.  Am J Psychiatry. 2010;167(7):869.

21. Schifano F.  Misuse and abuse of pregabalin and gabapentin: cause for concern? CNS Drugs. 2014;28(6):491-496.

22. Bastiaens L, Galus J, Mazur C.  Abuse of gabapentin is associated with opioid addiction. Psychiatr Q. 2016;87(4):763-767.

23. Schjerning O, Rosenzweig M, Pottegard A, Damkier P, Nielsen J.  Abuse potential of pregabalin.  CNS Drugs. 2016;30(1):9-25

April 2018

The information presented is current as of March 1, 2018.  This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What is the evidence behind the recent approval of the Shingrix vaccine?

Background

Shingles

Shingles is caused by the varicella-zoster virus (VZV), the same virus that causes chickenpox.¹ After an initial VZV infection, chickenpox, the virus remains dormant in the dorsal root ganglia. The reactivation of the VZV causes shingles. Shingles initially manifests as a painful unilateral rash, but can cause long-term sequelae that persist after the rash subsides. One long-term complication of shingles is severe nerve pain called post-herpetic neuralgia (PHN) in the area of the rash, which may be self-limiting, or it may persist for years. Other sequelae include ocular complications, pneumonia, hearing loss, encephalitis, or death.

Shingles can occur at any age, but it is more likely to occur in older adults.¹ In the United States, approximately 1 in every 3 people will experience shingles in their lifetime. Annually, about 1% to 4% of patients are hospitalized with shingles complications, and about 96 people die from shingles.² Certain individuals are at higher risk of getting shingles, including people that are immunocompromised (eg, cancer, HIV) or taking medications that can suppress the immune system (eg, corticosteroids).¹

Shingles itself is not transmissible, but the VZV can be transmitted from a person with active shingles blisters and cause chickenpox in a person who has not had the chickenpox infection or the varicella vaccine.¹ Antiviral medications and analgesics are used to treat an active shingles infection. Acyclovir, famciclovir, and valacyclovir are indicated for the treatment of shingles. Vaccination is the only way to prevent shingles and PHN. With the approval of a new shingles vaccine, there are now two vaccines available, Zostavax and Shingrix. The Center for Disease Control and Prevention (CDC) recommends the newer vaccine, Shingrix, over Zostavax.³

Zostavax Vaccine

Zostavax was the first shingles vaccine available in the United States (see Table 1).^4,5 It is a live-attenuated virus vaccine, originally approved for the prevention of herpes zoster in patients ≥ 60 years of age.⁶ Studies in patients over 60 years showed that Zostavax reduced the incidence of shingles and PHN by 51% and 39% compared to placebo, respectively.⁴ In this age group, the efficacy after 6 years declines to less than 35%.⁵ In 2011, the Food and Drug Administration (FDA) expanded the approval of Zostavax to patients aged 50 to 59 years after the ZEST trial showed that Zostavax reduced the risk of shingles by 69.8% in that age group.⁴ However, long-term studies in this age group are lacking and because of the known rapid decline in efficacy, the CDC continues to recommend vaccination for patients ≥ 60 years.

Zostavax is administered as a single dose, subcutaneously in the deltoid.⁴ Serious risks from Zostavax are rare but include severe allergic reactions. Redness, soreness, swelling, or itching at the injection site occurs in about 1 in 3 vaccinated patients, and headache occurs in 1 out of 70 vaccinated patients.⁵ Zostavax should not be used in patients who have had a life-threatening reaction to gelatin, neomycin, or other components of the vaccine.⁷ Also, patients who are immunocompromised (eg, AIDS, immunosuppressing drugs including high-dose steroids, undergoing radiation or chemotherapy, leukemia or lymphoma) or pregnant should not receive the vaccine. Finally, patients with moderate or severe acute illness should wait until the resolution of illness before receiving the varicella vaccine.

Shingrix Vaccine

Shingrix, approved in October 2017, is a non-live recombinant vaccine.^5,8 It contains a lyophilized recombinant varicella-zoster virus glycoprotein E antigen and an adjuvant system (see Table 1). The addition of the adjuvant system was shown to elicit stronger immunogenicity in Phase II trials.^9,10 It is approved for the prevention of shingles in immunocompetent adults ≥ 50 years.⁸ Shingrix is administered intramuscularly in the deltoid as a 2-dose series at months 0 and 2 to 6. Local adverse reactions commonly experienced are pain, redness, and swelling. Patients may also experience myalgia, fatigue, headache, shivering, fever, or gastrointestinal symptoms. Shingrix is contraindicated in patients who have had a severe allergic reaction to any component of the vaccine.

Table 1. Comparison of Zostavax and Shingrix.^4,8,11

Clinical Literature Summary

Shingrix was approved based on 2 Phase III trials, ZOE-50 and ZOE-70.⁸ Additional Phase III studies in patients with a renal transplant and autologous hematopoietic cell transplant are currently underway.¹² A long-term follow-up study in older adults has also been initiated. ZOE-50 showed that in patients between the ages of 50 to 59 years, Shingrix reduced the risk of developing zoster by 97%.¹³ Furthermore, efficacy 4 years post-vaccination was 93.1% and no cases of PHN were reported.^8,13 ZOE-70 involved patients ≥ 70 years old without a history of shingles or previous vaccination against varicella or herpes zoster.¹⁴ The efficacy of Shingrix was 89.1% and efficacy against PHN was 88.8% (see Table 2).

Phase II trials demonstrated that 2 doses of the vaccine induced a stronger immune response than 1 dose.^9,10 An open-label study showed that the safety and efficacy profile of Shingrix administered at months 0 and 6 is non-inferior to administration at months 0 and 2.¹⁵ That study also showed that dosing at months 0 and 12 did not meet non-inferiority criteria due to inadequate humoral immune response. Two Phase I/IIa studies have shown that Shingrix is immunogenic and safe in patients who are immunocompromised from autologous stem-cell transplant or HIV-infection.^16,17

Table 2. Phase III Studies Evaluating Use of Shingrix.^13–15

Guideline Recommendations

Approval and Revaccination

The Advisory Committee on Immunization Practices (ACIP) is a CDC panel of medical experts who make recommendations regarding vaccines in the United States.⁷ On October 25, 2017, the ACIP determined that Shingrix is the preferred shingles vaccine and recommended vaccination with Shingrix over Zostavax. They also recommended that adults who were previously vaccinated with Zostavax be revaccinated with Shingrix. The CDC notes that Shingrix was administered at least 5 years after Zostavax in clinical studies, but there are no safety concerns regarding administering the vaccine sooner.¹⁸ Ultimately, the CDC recommends waiting at least 2 months after Zostavax vaccinate before administering Shingrix. There are no head-to-head trials comparing Zostavax and Shingrix, but the placebo-controlled clinical trials discussed above show higher efficacy of Shingrix when compared with Zostavax clinical trials.^4,13–15 Shingrix was formulated to overcome the decline in immunity that occurs with aging, observed by the decreased efficacy of the Zostavax live vaccine.¹⁹

Dosing Schedule

The CDC reinforces the recommended dosing schedule of 2 injections administered 2 to 6 months apart, but states that the vaccine series does not be restarted if more than 6 months have passed since the initial injection.²⁰ If the second injection is administered less than 1 month after the first, it is considered invalid and should be repeated in 2 months.

Administration with Other Vaccines

Evidence shows that Shingrix can be safely administered with Fluarix Quadrivalent vaccine.²⁰ Additionally, the CDC recommends that Shingrix can be administered at the same time as both pneumococcal vaccines, although data regarding co-administration with Pneumovax23 is still pending. There is also ongoing evaluation for Shingrix administration with Boostrix and Tdap. When administering recombinant and adjuvant vaccines at the same time, it is recommended to administer the vaccines in different anatomic sites.

Adverse Effect Counseling

Grade 3 reactions were common in clinical trials for Shingrix.²¹ Grade 3 injection-site reactions and systemic reactions were reported in about 10% of patients. For that reason, the CDC recommends that healthcare providers counsel patients about the high probability of experiencing a reaction, both local and systemic. Notably, experiencing a grade 3 reaction does not preclude a patient from completing the 2-dose series.

Immunocompromised Population

ACIP has not made recommendations regarding the safety and efficacy of Shingrix in the immunocompromised population.²² The ACIP reinforces that both Zostavax and Shingrix can be used in patients taking low-dose oral steroids (< 20 mg/day of prednisone or equivalent). The vaccines can also be administered to patients using topical or inhaled steroids. Additionally, both vaccines can be administered to patients who anticipate immunosuppression in the future or who recently recovered from an immunocompromised state.

Conclusion

Shingles is a painful condition caused by reactivation of the varicella-zoster virus.¹ Until October 2017, the only vaccine available to prevent shingles was Zostavax, a live vaccine, with an efficacy between 38% to 69.8%.^4,8 Shingrix is the first non-live herpes zoster vaccine available in the United States. Clinical trials of Shingrix versus placebo have shown higher immunogenicity when compared to trials of Zostavax versus placebo, likely due to the adjuvant component.^4,9–15 Efficacy against shingles is 89% to 97%. The CDC currently recommends Shingrix over Zostavax, and that patients previously vaccinated with Zostavax be revaccinated with Shingrix.⁵ There are data to suggest that Shingrix can be safely used in certain immunocompromised populations, such as autologous stem-cell transplant and HIV-infection, but the CDC and ACIP have not yet recommended the routine administration of Shingrix to immunocompromised patients.^16,17,22

References

1.  Shingles (Herpes Zoster). Centers for Disease Control and Prevention website. https://www.cdc.gov/shingles/about/overview.html. Updated January 19, 2018. Accessed March 27, 2018.

2.  Shingles Surveillance. Centers for Disease Control and Prevention website. https://www.cdc.gov/shingles/surveillance.html. Updated February 23, 2018. Accessed March 27, 2018.

3.  Shingrix Recommendations. Centers for Disease Control and Prevention. https://www.cdc.gov/vaccines/vpd/shingles/hcp/shingrix/recommendations.html. Updated February 7, 2018. Accessed March 27, 2018.

4.  Zostavax [package insert]. Whitehouse Station, NJ: Merck; 2017.

5.  Vaccines and preventable diseases: Shingles. Centers for Disease Control and Prevention website. https://www.cdc.gov/vaccines/vpd/shingles/hcp/zostavax/about-vaccine.html Updated January 25, 2018. Accessed March 27, 2018.

6.  FDA Licenses New Vaccine to Reduce Older Americans' Risk of Shingles. Food and Drug Administration website. http://wayback.archive-it.org/7993/20170113080804/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108659.htm. Updated April 8, 2013. Accessed March 27, 2018.

7.  Vaccines and preventable diseases: Who should not get vaccinated with these vaccines? Centers for Disease Control and Prevention website. https://www.cdc.gov/vaccines/vpd/should-not-vacc.html. Updated February 12, 2018. Accessed March 27, 2018.

8.  Shingrix [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2017.

9.  Chlibek R, Smetana J, Pauksens K, et al. Safety and immunogenicity of three different formulations of an adjuvanted varicella-zoster virus subunit candidate vaccine in older adults: a phase II, randomized, controlled study. Vaccine. 2014;32(15):1745-1753.

10.  Chlibek R, Bayas JM, Collins H, et al. Safety and immunogenicity of an AS01-adjuvanted varicella-zoster virus subunit candidate vaccine against herpes zoster in adults >50 years of age. J Infect Dis. 2013;208(12):1953-1961.

11.  Immunize Against Shingles With the New Vaccine, Shingrix. Pharmacist’s Letter website. https://pharmacist.therapeuticresearch.com/Content/Articles/PL/2017/Dec/Immunize-Against-Shingles-With-the-New-Vaccine-Shingrix. Updated December 2017. Accessed December 15, 2017.

12.  Clinicaltrials.gov. U.S. National Library of Medicine website. https://clinicaltrials.gov. Accessed March 27, 2018.

13.  Lal H, Cunningham AL, Godeaux O, et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med. 2015;372(22):2087-2096.

14.  Cunningham AL, Lal H, Kovac M, et al. Efficacy of the herpes zoster subunit vaccine in adults 70 years of age or older. N Engl J Med. 2016;375(11):1019-1032.

15.  Lal H, Poder A, Campora L, et al. Immunogenicity, reactogenicity and safety of 2 doses of an adjuvanted herpes zoster subunit vaccine administered 2, 6 or 12 months apart in older adults: Results of a phase III, randomized, open-label, multicenter study [published online ahead of print November 22, 2017]. Vaccine. doi:10.1016/j.vaccine.2017.11.019.

16.  Stadtmauer EA, Sullivan KM, Marty FM, et al. A phase 1/2 study of an adjuvanted varicella-zoster virus subunit vaccine in autologous hematopoietic cell transplant recipients. Blood. 2014;124(19):2921-2929.

17.  Berkowitz EM, Moyle G, Stellbrink HJ, et al. Safety and immunogenicity of an adjuvanted herpes zoster subunit candidate vaccine in HIV-infected adults: a phase 1/2a randomized, placebo-controlled study. J Infect Dis. 2015;211(8):1279-1287.

18.  Vaccines and preventable diseases: Shingrix Recommendations. Centers for Disease Control and Prevention Website. https://www.cdc.gov/vaccines/vpd/shingles/hcp/shingrix/recommendations.html. Updated February 7, 2018. Accessed March 19, 2018.

19.  Shingrix Approved in the US for Prevention of Shingles in Adults Aged 50 and Over. GlaxoSmithKline website. https://www.gsk.com/en-gb/media/press-releases/shingrix-approved-in-the-us-for-prevention-of-shingles-in-adults-aged-50-and-over/. Updated October 23, 2017. Accessed December 15, 2017.

20.  Vaccines and preventable diseases: Administering Shingrix. Centers for Disease Control and Prevention Website. https://www.cdc.gov/vaccines/vpd/shingles/hcp/shingrix/administering-vaccine.html. Updated January 30, 2018. Accessed March 19, 2018.

21.  Vaccines and preventable diseases: About the Vaccine. Centers for Disease Control and Prevention Wesbite. https://www.cdc.gov/vaccines/vpd/shingles/hcp/shingrix/about-vaccine.html. Updated February 28, 2018. Accessed March 19, 2018.

22.  Dooling KL, Guo A, Patel M, et al. Recommendations of the advisory committee on immunization practices for use of herpes zoster vaccines. MMWR Morb Mortal Wkly Rep. 2018;67(3):103-108. 

Prepared by:

Kristina Falk, PharmD

PGY1 Pharmacy Resident

University of Illinois at Chicago

April 2018

The information presented is current as March 23, 2018. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What is the appropriate management of tetanus exposure?

Introduction

Tetanus is an acute disease caused by bacterial exotoxins: it affects the skeletal muscles, and it is often fatal if left untreated.¹ In the United States, 233 cases of tetanus were reported between 2001 and 2008, averaging about 29 cases per year. Of these cases, about 13% resulted in fatality. An acute wound was the precipitating factor for tetanus disease onset in 72% of patients, and 79% of these wounds were puncture wounds or contaminated, devitalized, or infected wounds eligible for tetanus immune globulin (TIG) prophylaxis.

Since 1947, reported cases of tetanus have declined by 95% in the United States, and cases of tetanus-related death have declined by 99%.² Almost all of the reported cases occur in individuals who have never been vaccinated or who have not received a booster within the last 10 years.¹ Although tetanus disease is rare in the United States, it is important for health care professionals to know how to manage tetanus exposures effectively in order to prevent clinical disease or treat it before it becomes fatal. Data from the Centers for Disease Control and Prevention (CDC) suggest that even when patients with tetanus exposure seek care, the majority do not receive the recommended prophylactic treatments to prevent onset of disease. The purpose of this article is to describe the pathophysiology and clinical presentation of tetanus, and summarize appropriate measures for tetanus prophylaxis and treatment.

Pathophysiology and Transmission

Tetanus is caused by Clostridium tetani, a gram-positive, spore-forming, obligate anaerobic bacterium.^3,4 C. tetani spores are ubiquitous in the environment, found in dust, soil, and manure.^1,4 These spores can enter the body when broken skin comes into contact with a contaminated object.⁴ Upon entry into anaerobic conditions, the spores germinate, and 2 toxins (tetanolysin and tetanospasmin) are produced.^1,5 These toxins disseminate through the lymphatic and vascular systems, and get taken up into the nerve terminals of motor neurons.⁶ Tetanospasmin, the toxin primarily responsible for the symptoms of tetanus, is transported through the lower motor neurons to inhibitory neurons in the spinal cord and brain stem, where it targets a protein in these neurons that is necessary for neurotransmitter release.^1,6 The blockade of inhibitor impulses from these neurons results in hyperactivity of the motor neurons, which leads to increased muscle activity presenting as rigidity and spasms.⁶

Tetanus exposure commonly occurs as a result of stepping on sharp objects (eg, nails or needles) that cause punctures in the skin.⁴ Other common mechanisms of tetanus exposure include wound contamination with dirt, feces, or saliva, burns, crush injuries, and injuries with dead tissue. Rare mechanisms of exposure include insect bites, dental infections, chronic sores, intravenous drug use, compound fractures, and clean superficial wounds. According to data from the CDC, 15% of tetanus cases where medical history was known occurred in patients with diabetes, and 15% occurred in intravenous drug users.¹ Heroin users who inject themselves subcutaneously are at high risk for tetanus, because the quinine used to dilute the heroin may support growth of C. tetani.

Clinical Presentation and Diagnosis

Tetanus is characterized by painful muscular contractions.⁵ The masseter and neck muscles are generally affected first, followed by the trunk muscles. Abdominal rigidity is a common first sign of tetanus, but rigidity may also be confined to the area of the wound or injury. The average incubation period for tetanus is 10 days, but it may range from 3 to 21 days. If the site of infection is more heavily contaminated or closer to the central nervous system (CNS), the incubation period is usually shorter.^1,4 A short incubation period is usually accompanied by more severe disease and a higher risk of death. Serious complications of tetanus can include fractures, hypertension, laryngospasms, nosocomial infections, pulmonary embolism, aspiration pneumonia, and death.⁵

Tetanus is divided into 3 major types: generalized, localized, and cephalic.⁵ Neonatal tetanus, a form of generalized tetanus in newborn infants, can also occur due to infection of an unhealed umbilical stump; however, due to its rarity in the United States, it will not be further discussed in this article.^1,5 Generalized tetanus is the most common form of tetanus, encompassing over 80% of cases.⁵  The most common initial manifestation of generalized tetanus is spasm or locking of the jaw muscles, followed by stiffness of the neck.^1,5 This generally progresses to difficulty in swallowing and rigidity of the abdominal muscles.¹ Other manifestations of the disease may include painful spasms of the trunk, neck, and extremity muscles, seizure-like activity, or convulsions.⁵ The spasms associated with generalized tetanus typically continue for 3 to 4 weeks.¹ The rate of mortality with generalized tetanus is 10 to 20%.⁵ In localized tetanus, muscle spasms are confined to the area near the site of injury.¹ Localized tetanus may progress to generalized tetanus, but it is usually milder, and only 1% of cases are fatal. Cephalic tetanus is the rarest form of tetanus, and it is generally associated with injury to the head, although it may also occur with facial lesions or otitis media.^1,5 Cephalic tetanus has a short incubation period of 1 to 2 days and presents as flaccid cranial nerve palsies.⁵ It can also progress to generalized tetanus.

The diagnosis of tetanus is made based on clinical presentation and does not depend on laboratory bacterial culture confirmation.¹ C. tetani is only recovered from wound cultures in 30% of tetanus cases, and the presence of C. tetani in a culture does not necessarily indicate tetanus disease.

Management

Pre-exposure prophylaxis

Tetanus is a preventable disease, with 11 vaccinations available in the United States.⁷ The antigenic component of the vaccine is tetanus toxoid, a formaldehyde-treated version of the tetanus toxin.¹ All tetanus toxoid-containing vaccines are administered as 0.5 mL doses and should be refrigerated at temperatures between 35°F and 46°F.^1,7 Table 1 describes the different tetanus toxoid-containing vaccines, and Table 2 describes the recommended tetanus vaccination schedule according to age. The tetanus toxoid is always co-formulated with diphtheria toxoid, but it may be co-formulated with additional antigenic components as well. The tetanus toxoid/diphtheria toxoid co-formulation for adults and children aged ≥7 years is denoted as Td, while the co-formulation for pediatric patients aged <7 years is denoted as DT.⁸ When tetanus toxoid and diphtheria toxoid are additionally combined with acellular pertussis antigenic components, it is denoted as DTaP (for pediatric patients aged <7 years) or Tdap (for adults and pediatric patients aged ≥7 years). Compared to the adult Td and Tdap formulations, the pediatric DT and DTaP formulations contain similar amounts of tetanus toxoid, but 3 to 4 times more diphtheria toxoid. The tetanus toxoid is also available in combined DTaP-IPV formulations (Kinrix, Quadracel), which contain additional components for immunization against poliovirus, a combined DTaP-HepB-IPV formulation (Pediarix), which contains additional components for immunization against hepatitis B and poliovirus, and a combined DTaP-IPV/Hib formulation (Pentacel), which contains additional components for immunization against Haemophilus influenzae type b and poliovirus.

Table 1. Available tetanus vaccines products.^7-16

Table 2. Recommended vaccination schedule.^1,17,18

In some cases, administration of tetanus vaccines may not be appropriate.  Patients should not receive these vaccines if they have a history of anaphylaxis to previous doses of tetanus toxoid or anaphylaxis to any component of the specific vaccine being given.¹ Tetanus vaccines may be administered to patients with a history of exaggerated local Arthus-like reactions to tetanus toxoid or diphtheria toxoid-containing vaccines.  However, patients with a history of these reactions should not receive tetanus vaccines more frequently than every 10 years. Pertussis-containing tetanus vaccines (DTaP and Tdap) are additionally contraindicated in patients who have developed encephalopathy without an identifiable alternative etiology within 7 days after a prior dose of a pertussis-containing vaccine.¹⁹

Precautions to further vaccination with DTaP include temperature ≥105°F within 48 hours post-DTaP vaccination, collapse or shock-like state within 48 hours of DTaP vaccination, seizure within 3 days of DTaP vaccination, or persistent, inconsolable crying lasting ≥3 hours within 48 hours of DTaP vaccination.¹⁹ However, experiencing these problems with DTaP is not a contraindication or precaution to receiving doses of Tdap once the patient reaches adolescence or adulthood.  Precautions to Tdap vaccination include progressive, unstable neurologic disorder or history of Guillain-Barre syndrome within 6 weeks after a prior dose of tetanus toxoid-containing vaccine.

Post-Exposure Prophylaxis

If a patient is wounded, they should be evaluated for risk of tetanus exposure and given post-exposure prophylaxis when indicated to prevent the development of clinical disease.⁵ For all patients, tetanus vaccination history should be determined and appropriate wound care should be performed. All wounds should be cleaned so that any dirt or foreign material is removed. Wounds that are unclean (ie, wounds contaminated with dirt, soil, feces, or saliva, penetrating/puncture wounds, necrotic/gangrenous wounds, frostbite, avulsion injuries, burns) have a higher risk for tetanus. If the wound has necrotic or gangrenous tissue, it should be debrided. Based on the type/severity of the wound and the vaccination history of the patient, the patient may qualify for tetanus vaccination and/or human TIG administration (Table 3).

Tetanus immune globulin is a preparation of immunoglobulins prepared from the plasma of adults who have been hyperimmunized with tetanus toxoid.⁸ It provides passive immunity to tetanus toxin by supplying tetanus antibodies that neutralize unbound toxins.²⁰ It does not influence any tetanus toxin that is already bound to nerve endings. Tetanus immune globulin is recommended for all patients with wounds that are not clean and minor who have an unclear tetanus vaccination history.⁵ It is also indicated for patients with contaminated wounds and human immunodeficiency virus (HIV) or severe immunodeficiency, regardless of tetanus immunization status. For tetanus post-exposure prophylaxis, the dosing of TIG in individuals aged ≥7 years is 250 units intramuscularly (IM), given as a single dose at the same time as the tetanus toxoid-containing vaccine (administered with a different syringe in a separate extremity).⁸ For children aged <7 years, the dosing is 4 units/kg IM once, or a single dose of 250 units regardless of size. Unvaccinated individuals and individuals with an unknown or uncertain vaccination history should start and complete the primary tetanus vaccination series with an age-appropriate tetanus toxoid-containing vaccine (Table 4).⁵ For children aged <7 years, DTaP is recommended. For patients aged ≥11 years, Tdap is preferred to Td if no dose of Tdap has previously been received. Patients aged ≥7 years who are not fully immunized should receive one dose of Tdap for wound management and as part of the catch-up series.

Table 3. Post-exposure prophylaxis recommendations by age, vaccination history, and wound type.^5,21

Table 4. Primary tetanus vaccination series for persons aged ≥7 years who have not been fully immunized.¹

Treatment

Tetanus disease is considered a medical emergency; hospitalization and immediate treatment are required once a patient has been diagnosed.⁵ Upon initial presentation, the patient’s airway and ventilation should be assessed, with intubation and supportive care being provided as necessary.²² Intravenous benzodiazepines are recommended to control muscle spasms and decrease rigidity, and magnesium sulfate or morphine can be utilized for control of autonomic dysfunction.^22,23 Immediate administration of TIG is recommended for the treatment of individuals with tetanus.¹ The optimal dose of TIG in tetanus treatment has not yet been established; however, the CDC recommends a single dose of 500 units IM for children and adults.⁵ Higher doses of 3,000 to 6,000 units IM have been used for tetanus treatment, but the 500 unit IM dose appears to be equally effective and causes less discomfort.^5,24 It is usually recommended that a portion of the dose be administered via local infiltration around the wound, but the efficacy of this approach has not been proven.⁵ If TIG is unavailable, intravenous immunoglobulin (IVIG) can be used off-label for the treatment of tetanus, as it contains anti-tetanus antibodies; however, since the tetanus antibody content varies from lot to lot, it is not recommended as a treatment of choice. Dosing for IVIG in tetanus treatment is generally 200 to 400 mg/kg. Patients should undergo aggressive wound care and all wounds should be appropriately cleaned and/or debrided.²³ Although the role of antibiotic therapy is still debated, metronidazole 500 mg every 6 hours by mouth may also be recommended to potentially slow progression of the disease.^3,22,23 Tetanus disease does not lead to tetanus immunity due to the high potency of the toxin.¹ Thus, patients should start or continue active immunization with a tetanus toxoid-containing vaccine once they are clinically stabilized.

Conclusion

Tetanus is a preventable disease that can become fatal if a patient is not appropriately treated.¹ Although it is rare in the United States due to routine vaccination practices, it is important for health care professionals to be aware of risk factors for tetanus and understand how to recognize and manage exposures. In patients with contaminated wounds, post-exposure prophylaxis with a tetanus toxoid-containing vaccine and/or TIG may be necessary to prevent the development of tetanus disease. In patients with non-clean, non-minor wounds and incomplete or unknown tetanus vaccination status, TIG is indicated in addition to the completion of a primary tetanus vaccine series.⁵ Treatment of tetanus disease requires immediate administration of TIG, as well as aggressive wound management, symptomatic treatment (ie, benzodiazepines for muscle spasms), and other supportive care.^5,22

References

1. Epidemiology and prevention of vaccine-preventable diseases: tetanus. Centers for Disease Control and Prevention website. https://www.cdc.gov/vaccines/pubs/pinkbook/tetanus.html. Updated November 15, 2016. Accessed February 23, 2018.
2. Tetanus surveillance. Centers for Disease Control and Prevention website. https://www.cdc.gov/tetanus/surveillance.html. Updated November 15, 2016. Accessed February 23, 2018.
3. Bae C, Bourget D. Tetanus. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2017. https://www.ncbi.nlm.nih.gov. Accessed February 28, 2018.
4. Tetanus causes and transmission. Centers for Disease Control and Prevention website. https://www.cdc.gov/tetanus/about/causes-transmission.html. Updated January 10, 2017. Accessed February 24, 2018.
5. Tetanus for clinicians. Centers for Disease Control and Prevention website. https://www.cdc.gov/tetanus/clinicians.html. Updated January 13, 2017. Accessed February 24, 2018.
6. Hassel B. Tetanus: pathophysiology, treatment, and the possibility of using botulinum toxin against tetanus-induced rigidity and spasms. Toxins. 2013;5(1):73-83.
7. About diphtheria, tetanus, and pertussis vaccines. Centers for Disease Control and Prevention website. https://www.cdc.gov/vaccines/vpd/dtap-tdap-td/hcp/about-vaccine.html. Updated November 22, 2016. Accessed March 12, 2018.
8. Clinical Pharmacology [database online]. Atlanta, GA: Elsevier Inc; 2018. https://www.clinicalkey.com/pharmacology. Accessed February 25, 2018.
9. Kinrix [package insert]. Research Triangle Park, NC: GlaxoSmithKline Biologicals; 2016.
10. Quadracel [package insert]. Swiftwater, PA: Sanofi Pasteur Limited; 2015.
11. Pediarix [package insert]. Research Triangle Park, NC: GlaxoSmithKline Biologicals; 2016.
12. Diphtheria and tetanus toxoids adsorbed [package insert]. Swiftwater, PA: Sanofi Pasteur Limited; 2013.
13. Tenivac [package insert]. Swiftwater, PA: Sanofi Pasteur Limited; 2016.
14. Daptacel [package insert]. Swiftwater, PA: Sanofi Pasteur Limited; 2016.
15. Infanrix [package insert]. Research Triangle Park, NC: GlaxoSmithKline Biologicals; 2016.
16. Pentacel [package insert]. Swiftwater, PA: Sanofi Pasteur Limited; 2013.
17. Recommended immunization schedule for children and adolescents aged 18 years or younger, United States. Centers for Disease Control and Prevention website. https://www.cdc.gov/vaccines/schedules/downloads/child/0-18yrs-child-combined-schedule.pdf. Updated January 1, 2018. Accessed February 28, 2018.
18. Recommended immunization schedule for adults aged 19 years or older, United States. Centers for Disease Control and Prevention website. https://www.cdc.gov/vaccines/schedules/downloads/adult/adult-combined-schedule.pdf. Updated January 1, 2018. Accessed March 12, 2018.
19. Epidemiology and prevention of vaccine-preventable diseases: pertussis. Centers for Disease Control and Prevention website. https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/pert.pdf. Updated August 10, 2017. Accessed March 12, 2018.
20. Lexicomp Online [database online]. St. Louis, MO: Wolters Kluwer Clinical Drug Information, Inc; 2018. http://online.lexi.com. Accessed February 23, 2018.
21. Tetanus prevention after a disaster. Centers for Disease Control and Prevention website. https://www.cdc.gov/disasters/disease/tetanus.html. Updated August 25, 2015. Accessed February 28, 2018.
22. Hadowanec A, Bleck TP. Tetanus (Clostridium tetani). In: Bennett JE, Dolin R, Blaser M eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Disease. 8th ed. Philadelphia, PA: Elsevier; 2018. https://www.clinicalkey.com/#!/browse/book/3-s2.0-C20150008796. Accessed February 28, 2018.
23. Current recommendations for treatment of tetanus during humanitarian emergencies. World Health Organization website. http://www.who.int/diseasecontrol_emergencies/who_hse_gar_dce_2010_en.pdf  Updated January 2010. Accessed February 23, 2018.
24. Blake PA, Feldman RA, Buchanan TM, et al. Serologic therapy of tetanus in the United States. JAMA. 1976;236:42-44.

Prepared by:

Alisha Patel, PharmD

PGY1 Pharmacy Resident

University of Illinois at Chicago

April 2018

The information presented is current as of March 2, 2018. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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