Coadministration of Tramadol and Tizanidine in an Experimental Acute Pain Model in Rat

Ramírez-Marín, Pamela Monserrat; Cruz, Carlos Alberto Zúñiga; Déciga-Campos, Myrna

doi:10.1002/ddr.21229

Cited by 7 publications

(6 citation statements)

References 20 publications

(24 reference statements)

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“…Tizanidine was injected into the paw and produced a dose-dependent antinociceptive effect against formalin-induced pain. Isobolographic analyses revealed a significant antagonistic interaction in the tizanidine-tramadol combinations ( 29 ). Although tizanidine is associated with a moderate incidence of sedation when administered at effective systemic doses, it is well tolerated clinically, with a low incidence of hemodynamic side effects ( 15 ).…”

Section: Discussionmentioning

confidence: 99%

Spinal Antinociceptive Action of Amiloride and Its Interaction with Tizanidine in the Rat Formalin Test

Ouyang

Wang

Huang

et al. 2015

Pain Research and Management

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Several ionic channels, receptors and enzymes have been reported to be affected by amiloride. It is known to act on pharmacological target sites that are implicated in pain processing. Tizanidine is a centrally acting alpha2-adrenoceptor agonist used in the treatment of muscle spasms. The effectiveness of the antinociceptive interaction of amiloride and tizanidine was investigated using the rat formalin test.

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Section: Discussionmentioning

confidence: 99%

Spinal Antinociceptive Action of Amiloride and Its Interaction with Tizanidine in the Rat Formalin Test

Ouyang

Wang

Huang

et al. 2015

Pain Research and Management

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“…It also remains unclear why metaxalone's lower injury rate was observed exclusively among tramadol users and only when initiated simultaneously with tramadol. Regarding tizanidine, the lower rate vs. methocarbamol when initiated with tramadol might be attributed to the potential antagonistic interaction between these two drugs 32 . In an animal study, co‐administration of tramadol and tizanidine failed to produce an antinociceptive effect comparable to that achieved when the drugs were given separately, suggesting an antagonistic interaction between them 32 .…”

Section: Discussionmentioning

confidence: 99%

“…Regarding tizanidine, the lower rate vs. methocarbamol when initiated with tramadol might be attributed to the potential antagonistic interaction between these two drugs 32 . In an animal study, co‐administration of tramadol and tizanidine failed to produce an antinociceptive effect comparable to that achieved when the drugs were given separately, suggesting an antagonistic interaction between them 32 . However, if this were the sole explanation, one would anticipate lower injury rates among tizanidine users vs. methocarbamol users in other tramadol cohorts, which was not observed.…”

Section: Discussionmentioning

confidence: 99%

“…32 In an animal study, co-administration of tramadol and tizanidine failed to produce an antinociceptive effect comparable to that achieved when the drugs were given separately, suggesting an antagonistic interaction between them. 32 However, if this were the sole explanation, one would anticipate lower injury rates among tizanidine users vs. methocarbamol users in other tramadol cohorts, which was not observed. Therefore, additional research is needed to elucidate the mechanisms behind these findings.…”

Section: Articlementioning

confidence: 98%

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Comparative Risk of Injury with Concurrent Use of Opioids and Skeletal Muscle Relaxants

Chen,

Hennessy,

Brensinger

et al. 2024

Clin Pharma and Therapeutics

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Concurrent use of skeletal muscle relaxants (SMRs) and opioids has been linked to an increased risk of injury. However, it remains unclear whether the injury risks differ by specific SMR when combined with opioids. We conducted nine retrospective cohort studies within a US Medicaid population. Each cohort consisted exclusively of person‐time exposed to both an SMR and one of the three most dispensed opioids—hydrocodone, oxycodone, and tramadol. Opioid users were further divided into three cohorts based on the initiation order of SMRs and opioids—synchronically triggered, opioid‐triggered, and SMR‐triggered. Within each cohort, we used Cox proportional hazard models to compare the injury rates for different SMRs compared to methocarbamol, adjusting for covariates. We identified 349,543, 139,458, and 218,967 concurrent users of SMRs with hydrocodone, oxycodone, and tramadol, respectively. In the oxycodone‐SMR‐triggered cohort, the adjusted hazard ratios (HRs) were 1.86 (95% CI, 1.23–2.82) for carisoprodol and 1.73 (1.09–2.73) for tizanidine. In the tramadol‐synchronically triggered cohort, the adjusted HRs were 0.69 (0.49–0.97) for metaxalone and 0.62 (0.42–0.90) for tizanidine. In the tramadol‐SMR‐triggered cohort, the adjusted HRs were 1.51 (1.01–2.26) for baclofen and 1.48 (1.03–2.11) for cyclobenzaprine. All other HRs were statistically nonsignificant. In conclusion, the relative injury rate associated with different SMRs used concurrently with the three most dispensed opioids appears to vary depending on the specific opioid and the order of combination initiation. If confirmed by future studies, clinicians should consider the varying injury rates when prescribing SMRs to individuals using hydrocodone, oxycodone, and tramadol.

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“…The pharmacological profile of the combination of tramadol-tizanidine produced antagonism in an experimental acute pain model in rats (ie, no antinociceptive effect was observed after the combination treatment as compared with individual administration). 67 The underlying mechanism of this antagonistic interaction remains to be elucidated. Caution is necessary during the use of this combination in clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Tizanidine: Advances in Pharmacology & Therapeutics and Drug Formulations

Zhu,

Wang,

Zhou

2024

JPR

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Background Skeletal muscle relaxants (SMRs) are widely used in treating musculoskeletal conditions. All SMRs, with the exception of baclofen and tizanidine, are on the list of 2023 American Geriatrics Society Beers Criteria ® for potentially inappropriate medication use in older adults. In our geriatric practice, off-label use of tizanidine as preemptive analgesia drove us to find recent advances in its pharmacology and therapeutics. An update review of tizanidine was thus presented, aiming to bring the latest knowledge to clinicians and promote further research and practical exploration. Methods Relevant literature up to December 2023 was identified through searches of PubMed, Web of Science, and Embase. Results Tizanidine, a centrally acting alpha-2 adrenoceptor agonist with both antispastic and antispasmodic activity, shows efficacy in the common indications for all SMRs. From the perspective of drug safety, tizanidine has lower incidences of adverse events (injury, delirium, encephalopathy, falls, and opioid overdose) compared to baclofen, no association with risk of Alzheimer’s disease as with orphenadrine, no risk of serotonin syndrome like metaxalone when comedicated with serotonergic drugs, no significant pharmacokinetic changes in CYP2C19 poor metabolizers unlike diazepam and carisoprodol, and no physically addictive or abuse properties like carisoprodol and diazepam. From the perspective of new and potential therapeutic uses, tizanidine has additional benefits (eg, gastroprotection that can improve patient tolerance to nonsteroidal anti-inflammatory agents, anti-neuropathic pain, a key component of multimodal analgesia strategy to reduce early postoperative pain, and anti-tumor effects). New delivery systems of tizanidine are developing to improve the pharmacokinetics of oral products, including buccal patches, transdermal delivery systems, nasal spray, and in situ rectal gel. Conclusion Tizanidine is an SMR with unique features and may be an optimal initial choice for older adults. There would be more scientific studies, wider therapeutic applications, and new drug formulations in the future.

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Coadministration of Tramadol and Tizanidine in an Experimental Acute Pain Model in Rat

Cited by 7 publications

References 20 publications

Spinal Antinociceptive Action of Amiloride and Its Interaction with Tizanidine in the Rat Formalin Test

Spinal Antinociceptive Action of Amiloride and Its Interaction with Tizanidine in the Rat Formalin Test

Comparative Risk of Injury with Concurrent Use of Opioids and Skeletal Muscle Relaxants

Tizanidine: Advances in Pharmacology & Therapeutics and Drug Formulations

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