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In an effort to help patients with long COVID, family medicine clinicians can borrow from the treatment of another chronic syndrome, according to a new study published in Annals of Family Medicine.

Symptoms of the condition often resemble myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and researchers said clinicians should adopt targeted therapies like beta-blockers and low-dose naltrexone to bridge a treatment gap left by a lack of specialists who treat long COVID, also known as post-acute sequelae of COVID.

“There are high numbers of people with long COVID who either have the full criteria with ME/CFS or symptoms of it,” said Stephanie Grach, MD, MS, an internist at the Mayo Clinic in Rochester, Minnesota, who led the new study.

Both conditions are extremely similar and are marked by multiple symptoms such as extreme fatigue, cognitive dysfunction, and post-exertional malaise. Research has shown most symptoms of ME/CFS are driven by circulatory dysfunction — the same has been found of long COVID.

“In general, we have found that the treatment of those with really substantial impairment after long COVID really looks like the treatment that we used pre-pandemic for ME/CFS,” said Peter Rowe, MD, director of the ME/CFS and Related Disorders Program at the Johns Hopkins Children’s Center in Baltimore, who was not involved with the study.

Prior to the COVID pandemic, up to 2.5 million Americans had ME/CFS, a complex illness that affects multiple body systems. Since then, cases have increased 15-fold with a surge of comorbid long COVID. Researchers have estimated about half of those diagnosed with long COVID fit the diagnosis criteria for ME/CFS.

Many of the most common symptoms of the conditions, including migraine or headache and pain, can be treated by primary care clinicians, experts said. However, the new study by Grach and colleagues showed that before patients see specialists for the condition, other clinicians often did not prescribe the right medications to these patients.

They analyzed medical records from 571 adults aged 70 years or younger referred to Mayo Clinic’s ME/CFS specialty clinic between 2018 and 2022 who had an International Statistical Classification of Diseases and Related Health Problems, 10th Revision code for a condition equivalent to ME/CFS, such as chronic fatigue syndrome, post-viral fatigue, chronic fatigue, or chronic multifactorial fatigue. The diagnosis code for ME/CFS was not available until October 2022.

Grach and colleagues found many best-practice medications prescribed by ME/CFS specialists were underutilized by referring clinicians, including by primary care.

Drugs for pain, impaired sleep, and mood disorders were most prescribed to patients by the time they saw a specialist. However, medications that specialists commonly prescribe for core ME/CFS symptoms including brain fog, inflammation, and post-exertional malaise were far less commonly prescribed by referring clinicians, the study found.

Prior to being seen by a specialist, 68.3% of referred patients had had at least one medication prescribed for a symptom of ME/CFS. The most frequently prescribed drugs were antidepressants, which fail to address the hallmark symptoms of orthostatic intolerance and profound exhaustion, Grach said.

Not a Mental Health Disorder

Nearly half of referred patients were already prescribed an antidepressant, namely serotonin and norepinephrine reuptake inhibitors. But Grach noted mood dysregulation is not a primary symptom of ME/CFS — but clinicians may label symptoms of brain fog and others as psychological before an accurate diagnosis is made.

“Patients often tell us that the clinician they are working with just isn’t sure what to do and is trying to work within a wheelhouse that they know, which is anxiety, depression, and pain,” Grach said.

Patients with prior anxiety or depression often distinguish their current illness from past mental health struggles, insisting their new symptoms feel entirely different, Grach said.

“I would encourage physicians to listen to that” so patients do not receive antidepressants they do not need, she said.

Because long COVID and ME/CFS are multisystem disorders, patients often have between five and 10 symptoms, Rowe said.

“Physicians are often taught that this number of symptoms indicates a psychological origin,” Rowe said. But “brain fog, headaches, and post-exhaustion malaise often improve if you can manage their orthostatic intolerance.”

Appropriate Treatment

Clinicians can use beta-blockers, histamine 1 (H1) and histamine 2 (H2) receptor antagonists, and stimulants, such as methylphenidate and modafinil, to manage orthostatic intolerance, Rowe said.

But only 5% of patients were prescribed beta-blockers by referring clinicians, while 2.8% had received H1 or H2 blockers and 2% were on a stimulant for ME/CFS symptoms, the study found.

Gabapentin, meanwhile, was the second most prescribed drug among patients in the study, taken by 40%. But studies have shown that gabapentin fails to manage pain or improve sleep in significant portions of people with a variety of ailments, including chronic lower back pain, nerve pain, and postoperative knee pain.

“Standard modulators like gabapentin may not be as helpful as hoped” for pain, Grach said.

Instead, naltrexone — in which just 2% of medication takers in the study were prescribed — may better treat the underlying inflammation that causes pain in people with ME/CFS and long COVID, Grach said.

The drug can help alleviate brain fog and fatigue and is generally well tolerated, Grach said.

Fludrocortisone and midodrine can be prescribed to treat postural orthostatic tachycardia syndrome, whereas low-dose aripiprazole or pyridostigmine up to three times daily can treat fatigue, brain fog, and post-exertional malaise, both which are common among people with either condition.

Supplementing With Supplements

The study found that 72% of patients had taken at least one dietary supplement to manage their symptoms. Supplements are not necessarily dangerous for people with long COVID or ME/CFS, but Grach said without guidance from clinicians, patients may turn to supplements that will not help their symptoms.

The most commonly taken supplement was vitamin D. Grach and colleagues cited evidence that the supplement may improve symptoms in those with deficiency following vaccination for COVID, but that high- or intermittent-dosing is not effective for ME/CFS or long COVID.

Other vitamin intake included B₁₂ and B complex, which may be useful in improving fatigue and activity tolerance but with high doses or drop form. One small study of 38 people found high doses of vitamin B injections combined with oral folic acid supplements showed improvement in myalgia and sleep disturbances.

Clinicians should order a blood test for vitamin deficiency, particularly vitamins D and B₁₂, Rowe said.

“Those themselves can cause fatigue,” Rowe said.

Grach and colleagues found evidence to support use of red ginseng, citing an open-label study that included 188 people that showed improvements in energy levels, sleep, and mental clarity in those with chronic fatigue syndrome –– findings backed by other clinical studies, including one randomized clinical trial.

For people with headaches, Rowe is comfortable recommending people supplement with magnesium and riboflavin, which have both been shown in migraine trials to prevent migraines. The study pointed to research showing improvement in fatigue with the mineral.

Grach said clinicians should take time to discuss, review, and guide patients on medications and supplements.

Otherwise, “I worry that patients are going to continue to struggle because they are not getting the chance to improve with therapies that are right for them,” Grach said.

Rowe and Grach reported having no relevant financial disclosures.