What alternative muscle relaxants can be used if cyclobenzaprine (Flexeril) is not effective?

Alternative Muscle Relaxants When Cyclobenzaprine Fails

If cyclobenzaprine is not effective, switch to tizanidine as the first alternative, as it has demonstrated efficacy for acute musculoskeletal pain with a similar adverse effect profile but different mechanism of action. 1

Primary Alternative: Tizanidine

• Tizanidine is the strongest evidence-based alternative, with efficacy demonstrated in 8 trials for acute low back pain, making it the most studied alternative muscle relaxant after cyclobenzaprine 1
• Tizanidine works through alpha-2 adrenergic agonism (different mechanism than cyclobenzaprine's tricyclic structure), which may provide benefit when cyclobenzaprine fails 1
• The main adverse effect difference is that tizanidine causes more dry mouth while producing less weakness compared to other options 2

Secondary Alternatives

Carisoprodol or Orphenadrine

• Both carisoprodol and orphenadrine have fair evidence of effectiveness compared to placebo for musculoskeletal conditions, primarily acute back or neck pain 2
• These agents work through different mechanisms than cyclobenzaprine and may be effective when it fails 2
• No head-to-head trials exist comparing these agents to cyclobenzaprine, so the choice depends on tolerability and cost 3

Methocarbamol or Metaxalone

• These agents have very limited or inconsistent data regarding effectiveness compared to placebo 2
• They represent third-line options when tizanidine, carisoprodol, or orphenadrine are not tolerated or contraindicated 2

Agents to Avoid for Musculoskeletal Pain

Baclofen and Dantrolene

• Only sparse evidence (2 trials) supports baclofen and dantrolene for low back pain, as these are primarily antispasticity agents for upper motor neuron syndromes 1
• Dantrolene carries risk of rare but serious hepatotoxicity and should be avoided for simple musculoskeletal conditions 2
• Baclofen is associated with more weakness as an adverse effect compared to other options 2

Diazepam

• While diazepam showed comparable improvement to cyclobenzaprine in clinical studies, it causes more dizziness and carries risks of dependence and abuse 4
• Diazepam is particularly inappropriate for older adults due to increased risk of falls, sedation, and anticholinergic effects 5

Important Clinical Considerations

Duration of Treatment

• All muscle relaxant trials were 2 weeks or less in duration (with one 3-week exception), indicating these agents should only be used short-term 1
• There is insufficient evidence for chronic use of any muscle relaxant for musculoskeletal pain 1

Adverse Effects

• All skeletal muscle relaxants are associated with higher rates of central nervous system adverse events (RR 2.04) compared to placebo, including drowsiness and dizziness 1
• The number needed to harm is 3 for any adverse event with muscle relaxants, predominantly CNS side effects 6

Combination Therapy Caveat

• Combination therapy of cyclobenzaprine with naproxen was associated with more side effects than naproxen alone, primarily drowsiness, without clear evidence of enhanced clinical effect 4
• No well-controlled studies demonstrate that muscle relaxants enhance the effect of analgesics or vice versa 4

Clinical Algorithm

1. First switch: Tizanidine - strongest alternative evidence base 1
2. Second switch: Carisoprodol or orphenadrine - fair evidence for musculoskeletal pain 2
3. Third switch: Methocarbamol or metaxalone - limited evidence but reasonable safety profile 2
4. Avoid: Baclofen, dantrolene, and diazepam for simple musculoskeletal conditions 1, 2