Which muscle relaxant is safe to use concomitantly with a selective serotonin reuptake inhibitor (SSRI)?

Muscle Relaxants Safe to Use with SSRIs

Tizanidine is the safest muscle relaxant to use with SSRIs because it acts as an alpha-2 adrenoceptor agonist without affecting serotonergic pathways, eliminating the risk of serotonin syndrome that exists with other muscle relaxants. 1

Primary Recommendation: Tizanidine

Tizanidine is the optimal choice when a muscle relaxant is needed in patients taking SSRIs. 1, 2

• The mechanism of action of tizanidine (alpha-2 adrenoceptor agonism) eliminates the primary concern when combining medications with SSRIs, which selectively inhibit serotonin reuptake with minimal effects on other neurotransmitter systems. 1

• There is no clinically significant pharmacokinetic or pharmacodynamic interaction between tizanidine and SSRIs, and these medications can be safely co-administered. 1

• Start with 2 mg up to three times daily, with gradual titration to achieve optimal effect while monitoring for side effects such as sedation, hypotension, and dizziness. 3

• Tizanidine has demonstrated efficacy for acute low back pain and muscle spasms, with additional benefits including gastroprotection that can improve tolerance to NSAIDs. 2

Alternative Safe Options

Methocarbamol and metaxalone are also safe alternatives with SSRIs:

• Methocarbamol is a centrally acting skeletal muscle relaxant with an unclear mechanism that does not involve serotonergic pathways. 4

• Metaxalone carries no risk of serotonin syndrome when comedicated with serotonergic drugs, unlike some other muscle relaxants. 2

Muscle Relaxants to AVOID with SSRIs

Cyclobenzaprine must be avoided or used with extreme caution:

• Cyclobenzaprine is structurally related to amitriptyline (a tricyclic antidepressant) and acts as a 5-HT2 receptor antagonist. 4

• Concomitant use of cyclobenzaprine with SSRIs may increase the potential for serotonin syndrome, though the risk is lower than with MAOIs. 4

Other muscle relaxants with concerning interactions:

• Meperidine has a high risk of serotonin syndrome in combination with SSRIs and should be avoided. 4

• Fentanyl carries risk of serotonin syndrome in combination with selective serotonin reuptake inhibitors. 4

Critical Safety Monitoring

When prescribing tizanidine with an SSRI, monitor for:

• Individual side effects of each drug separately: dose-dependent dizziness and sedation for tizanidine, and behavioral activation or agitation for the SSRI. 1

• Hypotension and bradycardia, as tizanidine can cause significant blood pressure drops. 3

• Renal function, as tizanidine requires dose adjustment in renal insufficiency based on creatinine clearance. 1

Ensure patients are not taking additional serotonergic medications that would create true interaction risks, including:

• Other SSRIs, SNRIs, or MAOIs. 1

• Tramadol, trazodone, St. John's Wort, and tricyclic antidepressants. 1

Important Drug Interactions with Tizanidine

Concomitant use with CYP1A2 inhibitors is contraindicated:

• CYP1A2 inhibitors significantly increase tizanidine levels and can cause severe hypotension. 3

• Common CYP1A2 inhibitors include ciprofloxacin and fluvoxamine (an SSRI). 3

Duration of Therapy

Skeletal muscle relaxants, including tizanidine, are recommended for short-term use only in acute conditions. 3

• Avoid abrupt discontinuation in long-term users; taper slowly to prevent withdrawal symptoms including tachycardia, hypertension, and rebound muscle spasm. 3

Special Populations

In elderly patients:

• Tizanidine is not on the 2023 American Geriatrics Society Beers Criteria for potentially inappropriate medications, unlike most other muscle relaxants (except baclofen). 2

• Older adults rarely tolerate doses greater than 30-40 mg per day. 3

In patients with hepatic or renal dysfunction:

• Use tizanidine with extreme caution or avoid entirely in hepatic dysfunction due to risk of hepatotoxicity. 3

• Reduce dose and monitor carefully in renal impairment. 3