Learning Objectives: After participating in this continuing professional development activity, the provider should be better able to:
1. Describe the pathophysiology of the monkeypox virus.
2. Develop a plan for analgesics for the patient with monkeypox.
3. Evaluate whether a patient with monkeypox requires block therapy.
Two years after the medical world was faced with the novel coronavirus SARS-CoV-2 and global outbreak of the COVID-19 pandemic, the monkeypox virus (MPV) raised red flags when it was detected and reported by people who had traveled to Europe and North America, rather than the western and central African countries where it was endemic.
This epidemic presented the pain management community with an important challenge. Unfortunately, only limited therapy has been suggested, and without the proper input from the disciplines and practitioners who study and treat pain. There are several interventions that could be used, but patients may not be widely accessing them. This article addresses management of pain in patients with mpox, the new name of the disease that has been called monkeypox, and has recently been renamed "mpox" by the World Health Organization.1
Background on the Monkeypox Virus
MPV is 1 of the 12 known subspecies of the genus Orthopoxvirus in the family Poxviridae. Other members of this genus are the viruses that cause smallpox, cowpox, horsepox, and camelpox. MPV and mpox, the disease it causes, have been identified in humans only during the past 50 years. The first recorded patient was a 9-month-old boy who lived in the Democratic Republic of the Congo. Smallpox, which is related to mpox (monkeypox), had been eliminated in that area since 1968.2
Although the disease had remained endemic, most cases have been diagnosed in the rural and rainforest areas of the Congo. More recently, and at an increasing rate, human cases have been found in both Central Africa and West Africa, including Benin, Cameroon, the Central African Republic, the Democratic Republic of the Congo, Gabon, Cote d'Ivoire, Liberia, Nigeria, the Republic of the Congo, Sierra Leone, and South Sudan.3
Presentation of monkeypox has been variable in intensity and mortality rates. An outbreak in the Congo in 1996, while it had a high attack rate, demonstrated a lower fatality rate. The reason for this may be that there was an outbreak of chickenpox at the same time. Although chickenpox is caused by the varicella virus, which is not one of the orthopox viruses, misdiagnosis may have accounted for the lesser intensity of the disease.
In mid-November of 2017, there was an outbreak of mpox in Nigeria, with 146 suspected cases and 42 laboratory-confirmed cases from 14 states. Before that 2017 outbreak, which was caused by the West African clade but whose source was not identified, the most recent case of human monkeypox had been reported in 1978.4
Since the November 2017 outbreak in Nigeria, mpox has been identified throughout the world, no doubt spurred on by air travel. The first outbreak in the United States was confirmed in 2003, linked to contact with infected pet prairie dogs that had been kept in contact with Gambian rats and dormice brought from Africa. A total of 81 cases (41% laboratory confirmed) were reported.5,6
Mpox has also been reported in travelers coming from Nigeria to Israel in September 2018; to the United Kingdom in September 2018, December 2019, May 2021, and May 2022; to Singapore in May 2019; and to the United States in July and November 2021. In May 2022, multiple cases of mpox were identified in several nonendemic countries.7
As of December 7, 2022, cases of mpox in the United States reached 29,711 (including 20 deaths) and cases globally reached 82,517 (including 65 deaths), according to tracking by the US Centers for Disease Control and Prevention (CDC).7,8
On May 17, 2022, the Massachusetts Department of Public Health laboratory confirmed the presence of Orthopoxvirus DNA via a real-time polymerase chain reaction (PCR) from lesion swabs in a patient in Massachusetts. Subsequent PCR testing at the CDC on May 18 confirmed that the patient was infected with MPV. Since then, several thousand cases have been confirmed nationwide. It has also been documented in 28 countries, none of which had been previously identified as having endemic monkeypox. On May 17, the CDC instituted an emergency response to identify, monitor, and investigate additional mpox cases in the United States.9
MPV is an Orthopoxvirus in the Poxviridae family. MPV is an enveloped double-stranded DNA virus. There are 2 distinct genetic clades of MPV: the Central African (Congo Basin) clade and the West African clade. The Congo Basin clade has historically caused more severe disease and was thought to be more transmissible. The geographical division between the 2 clades has so far been in Cameroon, the only country where both virus clades have been found.3
Monkeypox got its name in 1958, when it was detected in several laboratory apes. It is a zoonotic viral disease, which means it can be transmitted from animals to humans. It can also pass from human to human by close contact. It is endemic to Central and Western Africa.3
The virus name is something of a misleading one. Several African rodents, including rope squirrels, tree squirrels, Gambian pouched rats, dormice, nonhuman primates, and other species, are the natural reservoirs of this virus, rather than monkeys, but the name has, unfortunately, stuck.
WHO Renames Disease Caused by Monkeypox Virus to Now Be Called Mpox
In November 2022, the World Health Organization (WHO) decided to rename "monkeypox" after hearing from concerned parties that the term could be used in ways that perpetuate racism or stigmatization of individuals, groups, or countries. The disease caused by the monkeypox virus is now called mpox. Both names will be used simultaneously for 1 year while "monkeypox" is phased out.
As of our publishing deadline December 2022, the virus had not been renamed. Although disease names are the purview of the WHO, under the International Classification of Diseases (ICD), virus naming is carried out by the International Committee on the Taxonomy of Viruses.
"WHO, in accordance with the ICD update process, held consultations to gather views from a range of experts, as well as countries and the general public, who were invited to submit suggestions for new names," according to the organization's website.
Based on these consultations, and further discussions with the WHO Director-General Dr Tedros Adhanom Ghebreyesus, the organization recommends the following:
* Adoption of the new synonym mpox in English for the disease.
* Mpox will become a preferred term, replacing monkeypox, after a transition period of 1 year. This serves to mitigate the concerns raised by experts about confusion caused by a name change in the midst of a global outbreak. It also gives time to complete the ICD update process and to update WHO publications.
* The synonym mpox will be included in the ICD-10 online in the coming days. It will be a part of the official 2023 release of the ICD-11, which is the current global standard for health data, clinical documentation, and statistical aggregation.
* The term "monkeypox" will remain a searchable term in the ICD, to match historic information.
Source: World Health Organization. WHO recommends new name for monkeypox disease. November 28, 2022. https://www.who.int/news/item/28-11-2022-who-recommends-new-name-for-monkeypox-d
This zoonotic transmission probably occurs by direct contact with infected animals (eg, bites, scratches, slaughtering, and consumption). Human-to-human transmission occurs through close contact with infected persons (eg, respiratory droplets, skin-on-skin, or sexual contact) or via fomites (eg, bedding and clothing).
The classic case in human MPV disease starts with a febrile prodrome with lymphadenopathy followed by a diffuse maculopapular transitioning to vesiculopustular skin/mucosal lesion eruptions (Figure 1). In the current 2022 outbreak, 99% of the patients are men who have sex with men, the febrile prodrome may be very brief or absent, and the skin and mucosal lesions may be isolated to the genital and anal regions. Rarely, MPV can be neuroinvasive, which has been described in animal models and previous reported case series.
Mpox is usually a self-limited disease with the symptoms lasting from 2 to 4 weeks. Although most cases of mpox will have mild disease, with supportive care being sufficient, antivirals (eg, tecovirimat and brincidofovir) and vaccinia immune globulin intravenous (VIGIV) are available as treatments. Severe cases can occur. In recent times, the case fatality ratio has been around 3% to 6%.10
Vaccines used during the smallpox eradication program also provided protection against mpox. Newer vaccines have been developed of which one has been approved for prevention of monkeypox.3
Antivirals should be administered in severe disease, immunocompromised patients such as those with preexisting and poorly controlled HIV, pediatrics, pregnant and breastfeeding women, and in any patients who are exhibiting lesions near the mouth, eyes, and genitals. An antiviral agent developed for the treatment of smallpox has also been licensed for the treatment of monkeypox.3,10
Symptoms
The presenting symptoms are fever, chills, myalgia, vesiculopustular rash (see Figure 1), swollen lymph nodes, exhaustion, respiratory symptoms, sore throat, nasal congestion, and cough.10
The invasion of the viral attack is rapid and lasts between 0 and 5 days and is characterized initially by fever, intense headache, lymphadenopathy, back pain, myalgia, and marked lack of energy and inertia. Lymphadenopathy is the most distinctive feature of monkeypox when compared with other diseases that may initially appear similar and otherwise confusing in a differential diagnosis (such as chickenpox, measles, or smallpox).10
The skin eruption begins quickly, usually within 1 to 3 days after the initial fever. The rash is concentrated more on the face and extremities rather than on the trunk, affecting the face in 95% of cases and palms of the hands and soles of the feet (75% of cases). In addition, the oral mucous membranes develop sores and pustules in 70% of cases.
Among the most painful symptoms are the eruptions on the genitalia that develop in about 30% of cases. The cornea and conjunctivae are also affected in about 20% of cases. The rash evolves from macules to papules, to vesicles, followed by pustules (lesions filled with yellowish fluid), and crusts that ultimately dry up and fall off. The number of lesions varies from a few to several thousand. In severe cases, lesions can coalesce until large sections of skin slough off.
The eruption stage lasts about 3 to 4 weeks. Usually, the disease has completely resolved in 4 to 5 weeks.
About 65 deaths have been reported worldwide, although most patients recover, albeit after a very painful course. The first death in the United States was reported in Texas by the Texas Department of State Health Services in August 2022 in a severely immune-compromised man.11
The clinical presentation of monkeypox resembles that of smallpox, a related orthopoxvirus infection that was declared eradicated worldwide in 1980 (Table 1). However, monkeypox causes lymphadenopathy, a key differentiator from smallpox. Mpox is less contagious than smallpox and causes less severe illness, but it is associated with many medical complications.3
Pain Management
Several reports have indicated a high prevalence of anorectal symptoms, including proctitis and anorectal pain with bleeding in affected patients.
In an article published in August 2022 in the New England Journal of Medicine, clinicians from 16 countries collaborated on a large case series of patients with monkeypox.12
Of the 528 cases described, 73% of patients had anogenital lesions. Among the 13% of patients who were hospitalized, the most common reason for hospitalization was for pain management of severe anorectal pain.12
Similarly, a July 2022 case series of 197 men with monkeypox, 41.6% presented with perianal lesions and 36.0% reported rectal pain.13 Additionally, a small case series of patients hospitalized with monkeypox in Berlin showed that the chief complaint in 5 of the 6 patients was intense anal pain. These individuals rated their pain level as a 9 or 10 on a 10-point numerical rating scale and described it as "unprecedented in severity ... stabbing, burning, and unbearable on defecation."
The pain can best be described as visceral when the inner muscle is involved and as neuropathic when on the external surface. Monkeypox proctitis can cause excruciating pain that is markedly exacerbated by bowel movements. It may become so severe that the patient becomes constipated due to fear of the pain, which in turn, results in a further hardening of the stool, creating a vicious cycle. Imaging is not needed to make this diagnosis, but if a CT scan is done, it will typically show thickening of the rectal wall. Patients may also have external vesiculopustular skin lesions in the perianal area that can be very painful.
CDC Pain Management Advice
The CDC published a letter to physicians about pain management for patients with mpox.14 It is not evidence-based but rather the construct of a small group of physicians at the CDC, none of whom are board-certified in pain medicine.
The CDC suggested using both topical and systemic strategies to manage pain.14
Initial conservative therapy consists of nonsteroidal anti-inflammatory drugs, acetaminophen, topical lidocaine, stool softeners, and Sitz baths. Oral lesions can be treated with saltwater gargling. Viscous lidocaine can also be used as a gargle. It is important not to use large doses of the oral spray anesthetics, such as Hurricaine spray (20% benzocaine) because excessive use can lead to methemoglobinemia.
Symptoms usually run their course over 10 to 14 days. There is no indication of a chronic pain syndrome after the acute episode resolves.
Stool softeners, such as products containing docusate (Colace, Dulcolax), are essential for reducing friction on the raw mucosal surface and are doubly important if the patient is treated with opioid medications that decrease bowel motility. Sitz baths and topical lidocaine rectally delivered can provide some relief, and some patients find ice packs helpful.
Gabapentin and Pregabalin
It is important to note that there are no analgesics specifically approved for dealing with monkeypox lesions.
Although gabapentin and pregabalin are commonly used for neuropathic pain from postherpetic neuralgia and diabetic peripheral neuropathy, their use here would be off label.
Gabapentin at doses of 1800 to 3600 mg daily can provide good levels of pain relief to some people with postherpetic neuralgia and peripheral diabetic neuropathy. Evidence for other types of neuropathic pain is very limited.
Topical Lidocaine
Lidocaine has been frequently used for management of painful wounds. The evidence supporting this approach comes from a prospective, multicenter study that examined the effects of 5% lidocaine cream on wound pain relief.15
In this prospective study conducted at 2 hospitals in Italy, the authors included 78 patients with painful wounds.15
Perception of pain was recorded according to the patients by using an 11-point numerical scale. Data about medications and pain experience were recorded daily, as were all clinical aspects and any adverse outcomes or events, over the 14-day treatment period.
The median age of the patients was 67.5 years (range 18-96 years). Two-thirds were women. Breakdown of causation of the injuries was as follows: traumatic wounds (n = 39), venous ulcers (n = 25), postsurgical wounds (n = 6), pyoderma gangrenosum (n = 6), vasculitis (n = 1), and pressure ulcer (n = 1).
The researchers demonstrated that the intensity of pain significantly decreased from baseline (mean score 6.7 to 1.90) to the end of treatment (3.0 to 2.23; P < 0.0001). Nine patients prematurely stopped the treatment, whether related to healing (n = 4), wound improvement (n = 2), or adverse events (n = 3). Of the 78 patients, 13 patients presented a total of 25 adverse events, 4 of them related to the treatment.
Conclusions drawn were that treating wounds with 5% lidocaine cream for 14 days decreased pain intensity. Generally, the management showed high safety and tolerability. No patients required rescue with lipid emulsion therapy.
Other recent studies have supported these beneficial findings of the efficacy of lidocaine.16
In contrast, EMLA cream (a mixture of lidocaine and prilocaine) is contraindicated in open wounds due to the risk of methemoglobin.
Antidepressants That Treat Neuropathic Pain
While not mentioned by the CDC letter, 2 classes of antidepressants may have a role in treating the pain of mpox. The mechanism by which antidepressants relieve neuropathic pain has been identified as their ability to inhibit the reuptake of serotonin and norepinephrine (NE), with the primary mediator being NE.17 There are 2 classes of antidepressants whose respective pharmacology profiles involve the aforementioned mechanism. Those 2 classes are tricyclic antidepressants (TCAs) and selective serotonin-NE reuptake inhibitors (SNRIs).
Common TCAs used in the treatment of neuropathic pain include amitriptyline, desipramine, doxepin, imipramine, nortriptyline, and trimipramine. Despite none having FDA-approved neuropathic pain management indications, this class of agents is among those preferred as first-line treatment by the International Association for the Study of Pain (IASP) evidence-based guidelines for pharmacological management of neuropathic pain.16
TCAs have quite an extensive history, and their role in the treatment of neuropathic pain has been highlighted by an assortment of randomized controlled trials.
SNRIs inhibit the reuptake of serotonin and NE. The drugs in this class include venlafaxine, desvenlafaxine, duloxetine, milnacipran, and levomilnacipran. The relative selectiveness in binding of these drugs to serotonin and NE reuptake transporters while avoiding the other somatosensory receptors reduces the risk of adverse events, compared with TCAs; nevertheless, SNRIs are still susceptible to their own degree of adverse reactions. Common adverse reactions include nausea, vomiting, headache, dry mouth, sweating, and an increased risk of serotonin syndrome and cardiovascular effects, such as hypertension, with minimal influence on cardiac conduction.
The differences within this class of medications lie in the fact that not all are FDA-approved for pain management, due to their notable varied pharmacokinetic profiles. Currently, only duloxetine and milnacipran carry this indication; however, duloxetine and venlafaxine are recommended as first-line treatment for neuropathic pain by the IASP neuropathic pain study group.
Neuroaxial Blocks, Sympathetic Block
A search of the literature found no published studies on the use of lumbar or caudal epidural blocks to treat mpox. This is probably the greatest unmet need for analgesia. It is important not to pass a needle through an infected lesion as this would spread the virus into the central nervous system, but if there is a clear area in the lumbar spine, then an epidural could be placed. A dilute local anesthetic infusion can provide ample analgesia. If an infusion is needed for more than 72 hours, then consideration should be given to tunneling the catheter.
There are no reports of ganglion impar blocks being used to treat perineal pain.
Phenazopyridine (Pyridium)
For pain about the meatus and urethra, phenazopyridine may be particularly helpful. Phenazopyridine is an azo dye first synthesized in 1914 and adopted by the US Pharmacopoeia in 1928, so there is almost 100 years of experience with this medication. Phenazopyridine is used to treat the discomfort, urgency, and frequency associated with lower urinary tract infections and can be used here to treat pain from lesions at the penile meatus. It is available over the counter and at higher dosages, with a prescription. The major drawback is that it turns the urine orange or red and can stain clothing. The usual course duration is just 2 days, though off-label use has been reported for up to 5 days.
It has also been linked to methemoglobinemia at higher doses. The drug is also known to cause hemolytic anemia, likely through a metabolite, aniline. In cases of hemolytic anemia, microscopic examination of red blood cells will reveal the presence of Heinz bodies and degmacytes (bite cells).
Vaccination
For all health care providers who will work with patients who have mpox, the CDC strongly recommends immunization.18
Two vaccines are currently available. The first is a licensed replication-deficient weakened live vaccinia virus (JYNNEOS). JYNNEOS can help protect against smallpox, mpox, and other diseases caused by orthopoxviruses, including vaccinia virus.
JYNNEOS is FDA-approved for prevention of smallpox and mpox in adults 18 and older who are at high risk of exposure to and infection from these diseases.
The CDC recommends JYNNEOS for certain laboratory workers and emergency response team members who might be exposed to the viruses that cause orthopoxvirus infections.
The CDC also recommends that people who administer ACAM2000 (another type of smallpox vaccine) or who care for patients infected with orthopoxviruses, consider getting vaccinated.18
JYNNEOS is usually administered as a series of 2 injections, 4 weeks apart, although only one dose might be needed for people who have received smallpox vaccine in the past. "Booster doses are recommended every 2 or 10 years if a person remains at continued risk for exposure to smallpox, monkeypox, or other orthopoxviruses," according to the CDC.
Any providers or patients who have been recommended to receive JYNNEOS because they were exposed to MPV should be vaccinated regardless of concurrent illnesses, pregnancy, breastfeeding, or weakened immune system, and even if they have recently received a COVID-19 vaccination.18
The second vaccine available is a live vaccine available under the FDA Expanded Access-Investigational New Drug mechanism.18
There are also 2 drugs available to treat mpox, the orthopox-targeting tecovirimat and the DNA virus antiviral brincidofovir. However, recent strains that emerged in the Congo differed from those that were susceptible to therapy.
Tecovirimat, (brand name Tpoxx, SIGA Technologies), is an antiviral medication with activity against orthopoxviruses such as smallpox and monkeypox. Tecovirimat is the first antipoxviral drug approved in the United States and is an inhibitor of the orthopoxvirus VP37 envelope wrapping protein. Recoviruses are members of a newly approved genus of caliciviruses. It remains to be seen how effective the vaccines and these treatments will be.19
Conclusion
The mpox epidemic presented the pain management community with an important challenge. Unfortunately, only limited therapy has been suggested, and without the proper input from the disciplines and practitioners who study and treat pain. There are several interventions that could be used, but patients may not be widely accessing them. Further research is needed to further explore these interventions and to find new ones.
References