Analgesic Learning Materials

Analgesic   Drug used to relieve pain. Act in various ways on the peripheral and central nervous systems.   Separated into narcotics and non-narcotics. Narcotics: o Opiates (e.g. morphine). o Opioids (e.g. heroin, codeine). Non-narcotics. o NSAIDs (e.g. aspirin, ibuprofen). o Paracetamol.  Opioids/opiates  Natural opioids: o Endogenous agonistic opioids are endorphins, enkephalins and dynorphins. o Endorphins control persistent pain and provide a sense of euphoria.  Synthetic opiates: o Opium: fluid obtained from the poppy plant. o Opiate: a substance derived from opium (e.g. morphine). History of opium  Used in the orient for centuries.  Heroin was first synthesised in 1874 by the chemist, C.R. Alder Wright.  First commercial production in 1898 by the Bayer Pharmaceutical Company.  Bayer scientist Heinrich Dreser announced that heroin was ideal for treating bronchitis, emphysema, asthma, tuberculosis, and was a cure for opium and morphine dependence. Mode of action  Opiate receptors work in the brain at specific opiate receptors: o Several types of opiate receptors, but main receptor is called µ. o Belongs to the class of G-protein coupled receptors.       Opiates bind to opioid receptor, which are G-protein coupled receptors. Neurons are excited mainly in the periaqueductal grey matter (PAG) and in the nucleus reticularis paragigantocellularis (NRPG). These neurons project to the nucleus raphe magnus (NRM). The NRM contain 5-hydroxytryptamine (5-HT) and enkephalincontaining neurons that run to the substantia gelatinosa of the dorsal horn. These neurons exert an inhibitory influence on the transmission of pain. Opioids also act directly on the dorsal horn and on the peripheral terminals of the nociceptive afferent neurons. Clinical use  Opioid analgesics are commonly prescribed for relief of mild to moderate pain of acute, chronic or post-operative types.  They have also been found to be invaluable in palliative care to alleviate the severe, chronic, disabling pain of terminal conditions (e.g. cancer). Side effects  The consumption of opiates, particularly heroin, is marked by: o A euphoric rush. o A warm feeling of relaxation. o A sense of security and protection. o A dissipation of pain, fear, hunger, tension and anxiety.  The rush is intense and orgasmic. Tolerance and addiction  With regular opiate use, tolerance develops. o User must use more opiate to achieve the same intensity of effect.  As higher doses are used over time, physical dependence and addiction develop. Withdrawal  If use is stopped, withdrawal symptoms may occur.  Symptoms include: o Drug craving.  o Restlessness. o Muscle and bone pain. o Insomnia. o Diarrhoea and vomiting. o Cold flashes with goose bumps (“cold turkey”). o Kicking movements (“kicking the habit”). Major withdrawal symptoms peak between 48 – 72 hours after the last dose and subside after about a week. Summary – actions of opioids  Analgesia.  Euphoria and sedation.  Respiratory depression and suppression of cough.  Nausea and vomiting.  Pupillary constriction.  Reduced GIT motility, causing constipation.  Histamine release, causing bronchoconstriction and hypotension. Opiate antagonists  Naloxone (short-lasting) and naltrexone (long-lasting).  Competitive antagonists at mu, kappa and sigma receptor.  Displaces morphine and other opioids from receptor – reverses all actions of the opioids.  Drug is used for addiction treatment because patients receive no euphoric effect from heroin (negative reinforcement).  Naltrexone implants are used in Australia. NSAIDs    Analgesics, antipyretic and anti-inflammatory effects – reduce pain, fever and inflammation. Members include aspirin, ibuprofen and naproxen. Inhibit PG synthesis and by this mechanism lower pain levels. o PGs facilitate transduction at nociceptive afferent terminals by stimulating voltage-gated Na+ channels, therefore aiding in depolarisation of pain fibre. Paracetamol  It is not an anti-inflammatory agent and does not produce GIT damage or unwarranted cardiovascular and renal effects.  Acute overdose can cause fatal liver damage often heightened with the use of alcohol.  Main mechanism was considered to be the indirect inhibition of COX. o COX is active when it is oxidised. o Paracetamol reduces the oxidised form of the COX enzyme, preventing it from forming pro-inflammatory chemicals. o Reducing PGE2 in the CNS lowers the hypothalamic set-point in the thermoregulatory centre.  It was shown that paracetamol also modulates the endogenous cannabinoid system. o Paracetamol is metabolised to AM404, competitively and selectively inhibiting the reuptake of endogenous cannabinoid ligand, anandamide. o AM404 is thought to induce its analgesic action through its activity on the cannabinoid, COX and TRPV systems, all of which are present in pain and thermoregulatory pathways. o Thus, paracetamol is a pro-drug, the active one being a cannabinoid.