Sublingual Administration for Pain Control: Pharmacology, Clinical Applications and Future Directions.

Sublingual (SL) drug delivery represents an important alternative route of analgesic administration, particularly in settings where rapid pain control is desired or oral and parenteral routes are limited. By enabling direct absorption through the oral mucosa, SL administration partially bypasses first-pass hepatic metabolism, potentially improving bioavailability and accelerating the onset of action for select medications. Historically, SL analgesia has been most closely associated with opioid formulations such as fentanyl, buprenorphine, and sufentanil. SL fentanyl has demonstrated efficacy in breakthrough cancer pain among opioid-tolerant patients because of its rapid absorption and potent analgesic properties, whereas buprenorphine remains widely utilized for chronic pain and opioid use disorder owing to its partial µ-opioid receptor agonism and ceiling effect on respiratory depression. More recently, SL sufentanil has gained interest for the supervised management of acute pain in perioperative and emergency settings. Beyond opioids, expanding interest in SL therapeutics has included ketamine, cannabinoids, α2-adrenergic agonists, and investigational nonsteroidal anti-inflammatory drug (NSAID) formulations. Ketamine has shown potential utility in neuropathic and refractory pain syndromes, while cannabinoids are being explored for chronic, inflammatory, neuropathic, and cancer-related pain. Clonidine and dexmedetomidine may also serve as opioid-sparing adjuncts in selected settings. This review summarizes currently available and emerging SL analgesics, emphasizing pharmacologic mechanisms, pharmacokinetics, clinical applications, safety considerations, and therapeutic limitations. Although SL delivery offers advantages, such as noninvasive administration and rapid systemic exposure, limitations including variable bioavailability, formulation challenges, adverse effects, and limited comparative clinical evidence continue to restrict broader adoption.