Peripheral analgesic agent

Central and peripheral analgesic agents from kappa-opioid agonists 95E405. 

DeHaven-Hudkins DL, Dolle RE. Peripherally restricted opioid agonists as novel analgesic agents. Curr Pharm Des. 2004 10 743-757. 

Panzer O, Moitra V, Sladen RN. Pharmacology of sedative-analgesic agents dex-medetomidine, remifentanil, ketamine, volatile anesthetics, and the role of peripheral mu antagonists. Grit Care Clin 2009 25(3) 451-69. 

Neuropathic pain is initiated or caused by a primary lesion in the peripheral or central nervous system. The causative agent may be trauma, nerve-invading cancer, herpes zoster, HIV, stroke, diabetes, alcohol or other toxic substances. Neuropathic pain is refractory to most analgesic drugs. Altered sodium channel activity is characteristics of neuropathic pain states. 

This peripheral activity may be a rational basis for the use of systemic local anaesthetics in neuropathic states since ectopic activity in damaged nerves has been shown to be highly sensitive to systemic sodium channel blockers. This too is probably part of the basis for the analgesic effects of established effective anti-convulsants that block sodium channels such as carbamazepine, although central actions are important and may even predominate. The precise actions of excitability blockers therefore remains hazy as does any clear basis for the effectiveness of antidepressants and other adrenergic agents in the treatment of neuropathic pain as both central and peripheral actions, including sympathetic effects are possible. 

Acetaminophen differs from the nonsteroidal anti-inflammatory agents described in that it is devoid of anti-inflammatory and antirheumatic properties. It was recently shown that acetaminophen, like aspirin, inhibits cyclooxygenase action in the brain and is even stronger than aspirin. On the other hand, the mechanism of analgesic action of acetaminophen is not fully clear, since it acts poorly on peripheral cyclooxygenase. 

Epibatidine s antinociceptive effect can be antagonized by pretreatment with the centrally active nAChR antagonist mecamylamine, but not with the peripheral antagonist hexamethonium, so the activation of central nAChRs is presumed to be essential for nicotinic analgesics (Sullivan et al., 1994). The high toxicity of epibatidine has been attributed to its lack of selectivity for specific neuronal nAChR subtypes and has precluded its development as a therapeutic agent. 

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