DECEMBER 16, 2024
COVID-19 has forever changed the pain management landscape. In increasing numbers, pain clinics are seeing patients with new pain complaints after COVID exposure, and experts recommend that pain clinicians be retooled with a new understanding of what treating pain in the time of COVID-19 means. Importantly, post-COVID, or long COVID pain complaints are particularly prevalent in patients who were hospitalized in the ICU.
“Chronic pain, fatigue and mental health impacts of post-COVID-19
COVID-19 has forever changed the pain management landscape. In increasing numbers, pain clinics are seeing patients with new pain complaints after COVID exposure, and experts recommend that pain clinicians be retooled with a new understanding of what treating pain in the time of COVID-19 means. Importantly, post-COVID, or long COVID pain complaints are particularly prevalent in patients who were hospitalized in the ICU.
“Chronic pain, fatigue and mental health impacts of post-COVID-19 exposure are flooding our pain clinics and resulting in challenges beyond what we already face with our chronic pain patients,” Theresa Mallick-Searle, MS, PMGT-BC, ANP-BC, a nurse practitioner at Stanford Outpatient Medical Center, in Palo Alto, Calif., told Pain Medicine News in an exclusive interview.
Defining Long COVID Pain
Creating a uniform definition of long COVID for clinical practice and research is important, Mallick-Searle noted.
According to The New England Journal of Medicine, long COVID is an infection-associated chronic condition following SARS-CoV-2 infection. It is a continuous, relapsing and remitting, or progressive disease that impacts one or more organ systems for at least three months, according to a 2024 definition from the National Academies of Sciences, Engineering, and Medicine (N Engl J Med 2024;391:1746-1753). Researchers stress that this infection-associated chronic condition can affect anyone, regardless of socioeconomic or cultural differences.
In terms of the neurologic system, long COVID–associated system dysfunction can entail cognitive difficulties, mood changes, headache, neuropathy, fatigue, dizziness, confusion, memory loss and attention deficit.
Several factors can have an effect on the prolonged pain experienced after COVID-19, Mallick-Searle explained. Immune response can lead to inflammation, resulting in body-wide discomfort. Additionally, patients often report joint and muscle pain, which although typical for viral infections, persists for a significant span of time after initial infection with COVID-19.
In a cross-sectional study based on a random sampling that included 90 COVID-19 survivors, Cypriot researchers estimated the prevalence of chronic pain was 63.3%, with the most common sites being the lower back (37.8%), joints (28.9%) and neck (12.2%) (J Clin Med 2022;11[19]:5569). The prevalence of neuropathic pain was 24.4%. Patients with chronic pain tended to be older and female. In total, 16.7% of participants reported new-onset pain following COVID-19 exposure.
Pathophysiology Explained
The underlying mechanisms of long COVID pain and other symptoms remain to be elucidated. Nevertheless, researchers have proposed various possibilities.
According to the literature, long COVID results from multiple immune system dysregulations, including T-cell depletion, innate immune cell hyperactivity, lack of naive T and B cells, and an increase in specific pro-inflammatory cytokines (Asia Pac Allergy 2023;13[1]:50-53). Patients can harbor a SARS-CoV-2 reservoir—with either negative or positive polymerase chain reaction test results for persistent low levels of the virus.
Long COVID may progress in association with mast cell activation syndrome (MCAS). Mast cells undergo abnormal granulation and release excessive cytokines. Indeed, diagnosis and antihistamine treatment of MCAS in patients with long COVID may offer symptomatic relief. Other possible approaches include the inhibition of mediators using zileuton and aspirin, the inhibition of mediator release via sodium cromoglycate, and the inhibition of degranulation of mast cells via anti–immunoglobulin E.
Long COVID pain could directly result from the following (Pain Ther 2023;12[2]:423-448):
It should be noted that ACE2 receptors are expressed on the surface of epithelial cells, gastrointestinal epithelial cells, nasal goblet cells, renal podocytes, type II alveolar cells and more; therefore, COVID-19 can cause extensive tissue damage (Eur J Clin Microbiol Infect Dis 2021;40[5]:905- 919).
Treatment Options
Following COVID-19 exposure, pain can manifest in many ways, requiring different treatment strategies.
“As there is a lack of understanding to the exact mechanisms that cause on going pain post-COVID exposure, the treatments mostly include a multidisciplinary treatment approach, similar to any chronic disease,” Mallick-Searle said. “A focus on symptom management is a top priority.”
With regard to post-COVID myalgias and fatigue, Mallick-Searle said symptoms resemble nociplastic pain, akin to fibromyalgia. Treatments could include progressive physical therapy, centrally acting neuromodulators, and behavioral counseling and therapies.
Post-COVID headache can present with symptoms similar to migraine or new daily persistent headache, according to Mallick-Searle. To treat such headache, specialists could repurpose migraine medications, such as anticonvulsants, serotonin-norepinephrine reuptake inhibitors, calcitonin gene–related peptide antagonists or triptans. Drugs of choice for post-COVID headache include the tricyclic antidepressant amitriptyline followed by venlafaxine or mirtazapine. For acute pain, analgesics like acetaminophen and nonsteroidal anti-inflammatory drugs are first-line, according to the literature (Pain Ther 2023;12[2]:423-448).
However, addressing neuropathic pain post-COVID can be challenging.
“Neuropathic pain as a complication of COVID-19 is difficult to treat,” according to researchers (Pain Ther 2023;12[2]:423-448). “The mainstay of treatment is represented by gabapentinoids, antidepressants, tramadol, and topical agents (lidocaine plasters, capsaicin patches or botulinum toxin). Strong opioids may be considered in refractory cases. Nonpharmacologic treatments include invasive or noninvasive neuro-stimulation techniques. “
The treatment of chest pain following COVID-19 is also less straightforward than normal and requires multidisciplinary strategies. Chest pain may arise secondary to myocardial injury, coronary artery disease or myocarditis. The mechanism of persistent chest pain could be coronary microvascular ischemia following COVID-19 exposure, and such patients need a cardiac referral, evaluation and possibly urgent intervention.
“With what is understood as chronic oxidative stress and inflammation possibly contributing to the mechanisms of chronic pain and fatigue, researchers and centers of treatment for post-COVID conditions are using pharmacotherapies such as low-dose naltrexone, anti-inflammatories, antihistamines, sodium cromolyn, leukotriene receptor antagonists and even [disease-modifying antirheumatic drugs],” Mallick-Searle noted.
Raising Awareness
Mallick-Searle provided insight into how awareness of post-COVID pain can be improved, such as “providing continuing education about the incidence and current research at medical conferences where clinicians who see these patients attend; public announcements to raise awareness to patients; development of patient support groups on social media; [and encouraging] engagement with research both directly to patients and to the clinicians who treat them.”
She also recommended that pain specialists utilize ClinicalTrials.gov for enrollment opportunities for their patients with long COVID.
On a final note, Mallick-Searle explained fear avoidance in long COVID patients.
“A patient may become so deconditioned over time that they develop a fear avoidance to any type of physical activity, thinking that they may further injure themselves,” she said. “We also see this type of fear avoidance in patients with post-COVID chronic pain and fatigue. Evidence has shown that combining pain psychology and graded physical therapy improves outcomes.”
—Naveed Saleh, MD, MS
Mallick-Searle reported no relevant financial disclosures.
