What are the potential interactions between Norflex (orphenadrine) and Flexeril (cyclobenzaprine) and naproxen with Plavix (clopidogrel) in a patient?

Drug Interactions Between Norflex, Naproxen, Flexeril and Plavix

The primary concern when combining these medications with Plavix (clopidogrel) is the significantly increased bleeding risk from naproxen, which can elevate bleeding events by at least 60%, while Norflex (orphenadrine) and Flexeril (cyclobenzaprine) have no direct pharmacokinetic interactions with clopidogrel but may increase sedation and fall risk. 1

Critical Interaction: Naproxen + Plavix

Naproxen combined with clopidogrel substantially increases bleeding risk and should be avoided unless the cardiovascular benefit clearly outweighs the gastrointestinal and bleeding risks. 1

• The combination of NSAIDs (including naproxen) with antiplatelet agents like clopidogrel increases bleeding risk by at least 60%, similar to the risk seen with vitamin K antagonists 1
• This interaction is pharmacodynamic rather than pharmacokinetic—both drugs inhibit different aspects of hemostasis, creating an additive bleeding risk 1
• Naproxen impairs healing of small developing ulcers, and when combined with clopidogrel's antiplatelet effects, the risk of serious upper GI bleeding increases substantially 1

Risk Stratification for Naproxen Use

If naproxen must be used with clopidogrel, add a proton pump inhibitor (PPI) for gastroprotection, though be aware that some PPIs may reduce clopidogrel efficacy. 1

• PPIs reduce the risk of GI bleeding by 75-85% in high-risk patients taking antiplatelet agents 1
• However, PPIs (particularly omeprazole) share the CYP2C19 metabolic pathway with clopidogrel and may theoretically reduce clopidogrel's antiplatelet effects 1, 2
• Consider pantoprazole as an alternative PPI, which has less effect on CYP2C19 2

Common pitfall: Patients routinely taking NSAIDs before acute coronary events should discontinue them during hospitalization, as their use is associated with increased mortality, reinfarction, hypertension, heart failure, and myocardial rupture 1

Norflex (Orphenadrine) + Plavix

Orphenadrine has no documented pharmacokinetic interaction with clopidogrel and can be used together, though it provides minimal additional benefit for musculoskeletal pain when combined with NSAIDs. 3

• A randomized trial of 240 patients showed that naproxen + orphenadrine provided no clinically significant improvement in functional outcomes compared to naproxen + placebo for acute low back pain 3
• The mean RMDQ improvement was 9.4 points with naproxen + orphenadrine versus 10.9 points with naproxen + placebo, with overlapping confidence intervals 3
• Orphenadrine is primarily metabolized through different pathways and does not interfere with clopidogrel's CYP2C19-mediated activation 4

Practical Considerations for Orphenadrine

• Orphenadrine has anticholinergic properties that may cause drowsiness, dry mouth, and dizziness 3
• In elderly patients on clopidogrel (often for cardiovascular disease), anticholinergic medications should be used cautiously due to increased fall risk 1
• Adverse events occurred in 9% of patients taking orphenadrine in clinical trials 3

Flexeril (Cyclobenzaprine) + Plavix

Cyclobenzaprine has no pharmacokinetic interaction with clopidogrel, but clinical trials show no meaningful benefit when added to NSAIDs for acute musculoskeletal pain, and it increases sedation-related adverse effects. 4, 5

• The FDA label explicitly states: "No significant effect on plasma levels or bioavailability of cyclobenzaprine or aspirin was noted when administered concomitantly" 4
• Concomitant administration of cyclobenzaprine and naproxen was well tolerated, but combination therapy was associated with more side effects than naproxen alone, primarily drowsiness 4
• Cyclobenzaprine is metabolized by CYP3A4, 1A2, and 2D6—not by CYP2C19, which is the critical enzyme for clopidogrel activation 4

Evidence Against Routine Cyclobenzaprine Use

A high-quality 2015 randomized trial demonstrated that adding cyclobenzaprine to naproxen provided no functional benefit over naproxen alone for acute low back pain. 5

• Among 323 patients, the mean RMDQ improvement at 1 week was 10.1 with naproxen + cyclobenzaprine versus 9.8 with naproxen + placebo (difference 0.3,98.3% CI: -2.6 to 3.2, P = 0.77) 5
• This finding contradicts an older 1990 open-label trial that suggested benefit, but the 2015 study was double-blind and better designed 5, 6

Special Considerations in Elderly Patients

In elderly patients taking clopidogrel, cyclobenzaprine plasma levels are approximately 1.7-fold higher than in younger adults, necessitating a starting dose of 5 mg rather than 10 mg. 4

• Elderly males showed the highest increase (2.4-fold), while elderly females had a 1.2-fold increase 4
• The effective half-life of cyclobenzaprine is 18 hours (range 8-37 hours), leading to accumulation with repeated dosing 4
• Drowsiness is the most frequent adverse reaction and may increase fall risk in elderly patients with cardiovascular disease 4, 1

Clinical Algorithm for Decision-Making

For patients on clopidogrel requiring musculoskeletal pain management:

1. First-line: Use acetaminophen (up to 3g/day) as it has no interaction with clopidogrel and no bleeding risk 1

2. If NSAIDs are necessary:

   • Assess cardiovascular indication for clopidogrel (recent ACS, coronary stent) 1
   • If within 12 months of acute coronary syndrome or stent placement, avoid NSAIDs entirely 1
   • If chronic stable CAD without recent events, consider short-term naproxen (lowest effective dose) with mandatory PPI co-prescription 1
   • Choose pantoprazole over omeprazole to minimize CYP2C19 interaction 2

3. Muscle relaxants (orphenadrine or cyclobenzaprine):

   • Do not add routinely, as evidence shows no functional benefit over NSAIDs alone 5, 3
   • If severe muscle spasm is present and non-pharmacologic measures fail, consider short-term use (≤7 days) 3
   • In elderly patients, start cyclobenzaprine at 5 mg and monitor for sedation and fall risk 4, 1
   • Avoid combining multiple CNS-active agents (muscle relaxants + opioids + benzodiazepines) due to increased fall risk 1

Critical warning: The combination of three or more CNS agents (including muscle relaxants) significantly increases fall risk in older adults, which is particularly dangerous in patients on antiplatelet therapy due to bleeding risk from falls 1