Aspirin is a nonsteroidal anti-inflammatory drug. Aspirin is unique in this class of drugs because it irreversibly inhibits both COX-1 and COX-2 activity by acetylating a serine residue (Ser529 and Ser516, respectively) positioned in the arachidonic acid-binding channel, thus inhibiting the synthesis of prostaglandins and reducing the inflammatory response. The drug is used either alone or in combination with other compounds for the treatment of pain, headache, as well as for reducing the risk of stroke and heart attacks in patients with brain ischemia and cardiovascular diseases.

Ecadotril or sinorphan is the S-enantiomer of racemic acetorphan (racecadotril). It inhibits enkephalinase activity. Ecadotril was studied for the treatment of hypertension and heart failure, however, its development was discontinued.

Metacetamol (3-hydroxyacetanilide) is a structural isomer of the widely used drug paracetamol and is being considered as a promising alternative to the latter because of its lower toxicity. 3-hydroxyacetanilide, the positional isomer of paracetamol, does not cause depletion of GSH in vivo or hepatotoxicity even though the extent of covalent binding of the reactive metabolite (in vivo or in vitro) is comparable to that for an equimolar dose of paracetamol. Metacetamol should prove to be a useful tool to aid in the discrimination of hepatic acetaminophen protein adducts that may be critical or noncritical to survival of hepatocytes

WS-12 is a cooling agent and potent TRPM8 agonist. It activates TRPM8 but not related TRP channels like TRPM3 and TRPV6. WS-12 seems to activate TRPM8 mediated cation currents by shifting the voltage dependence of the activation curves to the left toward more physiological membrane potentials. Highly selective TRPM8 activators may be useful for prostate cancer imaging and/or therapy and for therapy in chronic neuropathic pain states.

PF-06273340 is a brain penetrant, orally available and potent tropomyosin-related kinase (Trk) inhibitor. PF-06273340 has a low metabolic turnover in Human liver microsomes and hepatocytes is a good substrate for efflux transporters P-glycoprotein and Breast cancer resistance protein (BCRP) and have moderate passive permeability. PF-06273340 was investigated in Phase I clinical trials for the treatment acute and chronic pain. However clinical development has been discontinued.

URB-597 (KDS-4103) is a highly potent and selective inhibitor of the enzyme fatty acid amide hydrolase (FAAH), which catalyzes the intracellular hydrolysis of the endocannabinoid anandamide. URB597 is one the best studied carbamate-based inhibitors. Early studies showed that the compound did not inhibit or bind related biological targets. Administration of URB597 to rats and subsequent in vivo evaluation of brain FAAH activity showed the compound elevated endogenous anandamide levels. Importantly, the compound did not produce catalepsy, hypothermia, or hyperphagia, three of the typical effects of exogenous cannabinoids. The compound did produce antinociceptive effects in the mouse hot-plate test, which were reversed by the CB1 antagonist rimonabant. These findings again support the expectation that inhibition of FAAH produces pharmacology distinct from an exogenous CB1 agonist. A more detailed study was published later showing time-course data in mice demonstrating elevation of anandamide, oleamide, and N-palmitoyl ethanolamine for 2–6 h after administration of URB597. In vivo administration of URB597 showed almost complete inhibition of FAAH by the compound, and the FAAH inhibition was still approximately 70% after 16 h. Complete recovery of CNS FAAH activity was observed 24 h after administration of URB597. In vivo administration of URB597 or the cannabinoid receptor agonist HU210 reduced both mechanical allodynia and thermal hyperalgesia in the CFA model of inflammatory pain. Effects in the inflammatory model were partially reversed by CB1 and CB2 antagonists. In a related study, the compound produced analgesic effects in the mouse CCI model (neuropathic) when administered orally. These effects were also reversed by both CB1 and CB2 antagonists.

(R)-Norfluoxetine is a pharmacologically active metabolite of Fluoxetine that is a selective serotonin reuptake inhibitor. (R)-Norfluoxetine was being investigated by Eli Lilly and Company for treatment pain and drug abuse, but future development was discontinued.

Oliceridine (TRV-130) is a potent μ-opioid receptor agonist. In cell-based assays, TRV130 elicits robust G protein signaling, with potency and efficacy similar to morphine, but with far less β-arrestin recruitment and receptor internalization. In rodents, TRV130 is potently analgesic while causing less gastrointestinal dysfunction and respiratory suppression than morphine at equianalgesic doses. Oliceridine is being developed by Trevena for the first-line treatment of moderate-to-severe acute postoperative pain. Phase III development is underway for the treatment of postoperative pain in the US. Phase II development is underway for the treatment of acute pain in the US.

Parafluorofentanyl is a selective mu-opioid agonist, an analog of fentanyl, developed by Janssen. The drug was not developed for human use but is produced and abused illegally.

Cizolirtine is a potent analgesic in mice and rats, with an efficacy superior to that of aspirin and other nonsteroid anti-inflammatory drugs. Recent studies have shown that the analgesic effect of cizolirtine could be related, at least partially, to an inhibition of spinal substance P and calcitonin gene-related peptide release. Cizolirtine has been in clinical trials for the treatment of pain and overactive bladder. Reported adverse events are: dry mouth, dizziness, nausea, vomiting, blurred vision.