Background/Purpose: Tizanidine, a muscle relaxant widely used for musculoskeletal pain, can lower blood pressure and is metabolized by the cytochrome P450 1A2 (CYP1A2). As a result, strong CYP1A2 inhibitors raise plasma concentrations of tizanidine 10-33 fold, thus potentially increasing the risk of tizanidine side effects. Despite this concern, there is limited information about the clinical consequences of this drug-drug interaction in routine clinical practice. We tested the hypothesis that when used in combination with strong CYP1A2 inhibitors, tizanidine is associated with higher rates of severe hypotension than the active comparator, cyclobenzaprine.

Methods: In this retrospective cohort study in the de-identified electronic health record database at Vanderbilt University Medical Center, we studied patients 18 years of age or older who had received tizanidine or cyclobenzaprine concurrently with the strong CYP1A2 inhibitors ciprofloxacin or fluvoxamine. We extracted demographic variables (including age, race, and sex) and the specific CYP1A2 inhibitor drug, and we used ICD-9 codes, which were collapsed according to the categories described in the Charlson/Deyo modified score. The primary outcome was severe hypotension, defined as systolic blood pressure (SBP) ≤70 mm Hg. To examine the association between severe hypotension and the concurrent use of tizanidine and a strong CYP1A2 inhibitor, we built two multivariate logistic regression models: (1) adjusted for age, sex, and race; (2) adjusted by a logarithmically transformed propensity score, defined as the probability of assignment to tizanidine given demographics, Charlson score, specific strong CYP1A2 inhibitor, and current use of antihypertensives (by class).

Results: The cohort was comprised of 1,626 patients prescribed tizanidine and 5,012 prescribed cyclobenzaprine concurrently with a strong CYP1A2 inhibitor. Severe hypotension occurred more often in the tizanidine group [2.03% (n=33)] than the cyclobenzaprine group [1.28% (n=64)]; OR= 1.60, p=0.029. This difference remained statistically significant after adjustment for a log-transformed propensity score (OR= 1.57, p=0.049). The highest risk for severe hypotension was among patients receiving tizanidine and a strong CYP1A2 inhibitor who had a Charlson score of 3 or more [OR=10.60 (95% C.I. 4.19-26.81)] or who received three or more concurrent anti-hypertensives [OR=5.64 (95% C.I. 2.30-13.81)].

Table: Association between concurrent prescription of tizanidine and a CYP1A2 inhibitor and severe hypotension (SBP≤70 mm Hg)

Conclusion: Strong CYP1A2 inhibition increases the risk of severe hypotensive episodes associated with the use of tizanidine. Clinicians should avoid co-prescribing tizanidine with strong CYP1A2 inhibitors, particularly in patients with higher comorbidity indices and in those who receive three or more antihypertensive agents.

« Back to 2018 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/tizanidine-a-frequently-used-muscle-relaxant-is-associated-with-severe-hypotension-role-of-cytochrome-p450-1a2-inhibition-in-routine-clinical-practice/