What are the risks of rhabdomyolysis when using oxycodone (OxyContin) and Tylenol (acetaminophen)?

Rhabdomyolysis Risk with Oxycodone and Acetaminophen

Opioids including oxycodone are recognized causes of rhabdomyolysis, while acetaminophen (Tylenol) in overdose has been associated with rhabdomyolysis in rare case reports, though the evidence for therapeutic doses is extremely limited.

Oxycodone and Rhabdomyolysis Risk

Direct Association

• Opioids are established causes of drug-induced rhabdomyolysis, with heroin and other opiates frequently implicated in emergency department presentations 1, 2, 3.
• The mechanism involves prolonged immobilization and muscle compression during periods of altered consciousness, rather than direct myotoxicity 2, 3.
• In a large case series of 475 hospitalized rhabdomyolysis patients, illicit drugs (including opioids), alcohol, and prescribed drugs were responsible for 46% of cases 1.

Clinical Context

• Oxycodone is recommended for restless legs syndrome in refractory cases, with acknowledged risks including fatigue, somnolence, and dizziness that could predispose to immobilization 4.
• The risk is particularly elevated when opioids are combined with benzodiazepines or other sedatives, which increase the likelihood of prolonged immobilization 2.
• Patients on prescribed polytherapy are at increased risk for rhabdomyolysis 1.

Acetaminophen and Rhabdomyolysis Risk

Evidence for Association

• Acetaminophen-associated rhabdomyolysis is extremely rare and primarily documented only in overdose situations 5, 6.
• In one case report, a patient with acetaminophen overdose developed severe rhabdomyolysis with creatine kinase levels reaching 245,595 U/L, though this was complicated by concurrent ibuprofen ingestion and multiorgan failure 6.
• Another case documented lateral pterygoid muscle rhabdomyolysis specifically attributed to acetaminophen overdose 5.

Important Caveats

• The literature does not provide a clear causal association between therapeutic-dose acetaminophen and rhabdomyolysis because most reported cases involve overdose, trauma, or multiple confounding factors 6.
• The Naranjo adverse drug reaction probability scale indicated only a "probable" (not definite) association in documented overdose cases 6.

Combined Risk Assessment

Practical Risk Stratification

• The primary rhabdomyolysis risk from oxycodone-acetaminophen combinations comes from the opioid component, not the acetaminophen at therapeutic doses 1, 2, 3.
• Risk is substantially elevated when:
  • Multiple sedating medications are used concurrently 1
  • Patients have underlying metabolic myopathies (though these account for only 10% of cases) 1
  • There is a history of substance abuse 2
  • Patients are elderly, have renal insufficiency, or are on polypharmacy 7

Monitoring Recommendations

• Monitor for early signs including muscle pain, weakness, dark urine, and altered mental status in patients on oxycodone-containing regimens 8.
• Check creatine kinase, serum creatinine, and urinalysis if rhabdomyolysis is suspected 8.
• Note that urine myoglobin by dipstick is positive in only 19% of confirmed rhabdomyolysis cases, so its absence does not exclude the diagnosis 1.

Key Clinical Pitfall

• Do not rely on urine myoglobin testing alone—serum CK elevation (>5 times upper limit of normal, or >975 IU/L) is the diagnostic standard 1.
• In 60% of rhabdomyolysis cases, multiple etiologic factors are present, so consider all potential contributors including immobilization, dehydration, and concomitant medications 1.

Management if Rhabdomyolysis Develops

• Immediately discontinue the offending agent 8.
• Initiate aggressive fluid resuscitation: 3-6L/day for moderate cases (CK 5,000-15,000 IU/L), >6L/day for severe cases (CK >15,000 IU/L) 8.
• Monitor electrolytes closely, particularly potassium, as hyperkalemia can cause life-threatening cardiac arrhythmias 8.
• With appropriate care, mortality is rare (3.4% in large case series) 1.