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Chronic pain remains a serious issue, affecting millions in the United States. Opioids serve as the most powerful therapeutic option but show limited efficacy in neuropathic pain and consequential side‐effects, such as tolerance, addiction, and respiratory depression. Development of novel drugs to treat pain, though, continues to stagnate. Additionally, in conditions in which opioids are required, adjuvants to reduce opioid‐induced neuroplasticity is critical. Agmatine has been shown to reduce neuropathic pain behavior and opioid tolerance, but use remains limited due to potentially reduced CNS penetration due to its hydrophilicity. Therefore, we have developed a series of agmatine‐based compounds that exhibit greater lipophilicity while exhibiting equivalent pharmacological responses (Figure 1). The goal of this study was to assess differences in pharmacokinetics and dynamics of 4 of these strategically …