Pediatric dosing of acetaminophen advised for SMA adults, childen
People with spinal muscular atrophy (SMA) cleared acetaminophen, a common ingredient in pain medications, slower than healthy people, but this was generally not associated with evidence of liver toxicity for most patients, a study shows.
Only one of 12 SMA patients developed elevations in markers of liver dysfunction, but these weren’t associated with symptoms and cleared up after treatment stopped.
The researchers recommended that standard pediatric dosing of acetaminophen in the general population be used for SMA adults and children, and liver enzymes be monitored over the first couple days. “We advise clinicians to be more aware when treating SMA patients with acetaminophen for [more than] 48 hours],” the researchers wrote in “Acetaminophen treatment in children and adults with spinal muscular atrophy: a lower tolerance and higher risk of hepatotoxicity,” which was published in Neuromuscular Disorders.
Acetaminophen is a common, non-opioid ingredient in over-the-counter (e.g. Tylenol) and prescription pain medicines. SMA patients who undergo surgical procedures, such as to correct scoliosis, may take acetaminophen for several days afterward to help manage pain after surgery.
While it’s considered safe and effective, high doses or long-term use are associated with liver damage. People with preexisting risk factors may be particularly susceptible to liver toxicity, even at lower doses or for shorter treatment windows.
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Acetaminophen in SMA
People with certain neuromuscular disorders, such as SMA or Duchenne muscular dystrophy, may be at a particular risk of side effects in the liver when acetaminophen is given at a standard dose for the general population, according to researchers in Denmark, who reported they saw a patient with SMA type 2 who developed fatal liver failure after abdominal surgery, with acetaminophen toxicity being the suspected cause. Those findings have not been published.
A susceptibility to liver toxicity in SMA could be related to a few different factors, including possible existing liver impairments. SMA patients also often have altered body composition, including reduced skeletal muscle mass, leading to metabolic differences that may affect how acetaminophen is broken down.
To learn more about the safety and pharmacological properties of acetaminophen in SMA, the scientists analyzed its clearance and liver biomarkers in the blood of 12 patients (six adults, six children) with SMA type 2 and 11 healthy adults given at its standard therapeutic dose in a small clinical trial. All the participants with SMA had low skeletal muscle mass and adults with SMA had significantly lower body weight than healthy adults.
Acetaminophen was administered as an oral liquid at 15 mg/kg every six hours, with a maximum of 4,000 mg per day, over three consecutive days. Blood samples were obtained every hour over a six- to eight-hour period on the first and third day of treatment.
Slower clearance in SMA adults
Adult SMA patients had significantly slower clearance of acetaminophen from their body than healthy adults. Clearance in children with SMA was also slower, but didn’t reach statistical significance. Plus, the formation and clearance of various metabolites, substances formed as the medication breaks down, was significantly lower in patients than healthy people.
“With a lower total clearance, the patient’s elimination of the drug from the body is prolonged,” the researchers said, noting this could cause acetaminophen to accumulate and more of it be metabolized through pathways that cause cellular stress.
One adult with SMA had about a ninefold increase in liver enzymes after two days of treatment, as well as an increase in miRNA 122 and miRNA 192, other proposed markers of liver dysfunction, after the first dose. The patient didn’t have clinical symptoms and liver enzymes normalized about a week after stopping treatment.
No other SMA patients or healthy controls developed markers of abnormal liver function.
The scientists also examined whether patients had certain genetic variants, called pharmacogenetic variants, previously linked to acetaminophen metabolism, but rates largely weren’t different between SMA patients and those seen in the general northwestern European population, according to the researchers.
“We therefore do not think that testing pharmacogenetic variants in SMA patients will add significant value in future clinical practice,” the researchers wrote. “Pharmacogenetics are probably adding to the risk of increased susceptibility to acetaminophen toxicity but cannot be interpreted alone.”
While people with SMA have “several risk factors that may increase their susceptibility to acetaminophen-induced hepatoxicity [liver toxicity],” the researchers recommended a standard pediatric dose, up to 4,000 mg daily, with appropriate liver enzyme monitoring. They said more research on other “patient groups with low skeletal muscle mass treated with acetaminophen are needed.”
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