Analgesics

Today we are going to learn about analgesics, or pain killers. The name "analgesic" comes from the Greek word "algos," which means pain.

Pain pathways

To understand how to treat pain, it may help to understand how pain is caused in the first place. The first step is transduction, which occurs when free nerve endings are stimulated in some way. This stage can be blocked by NSAIDs, COX-2 inhibitors and topical local anaesthetics. The next stage is conduction or transmission, when the signal is sent down the nerve to the spinal cord. This can be blocked by epidurals and regional anaesthesia. The next step is modulation, when the sensory nerve from the body synapses with one going to the brain. This can be blocked by opioids, COX-2 inhibitors, ketamine, alpha-2-delta ligands and α2 agonists. The final step is perception, when the brain notices what's going on, and this can be blocked by opioids, COX-2 inhibitors and possibly paracetamol.

Most analgesics are based on salicylates (willow bark), which mainly work by inhibiting prostaglandin synthesis in the periphery, or on opioids, which mainly work directly on the brain. Analgesics can also be classed into opioids and non-opioids. The main non-opioids used are paracetamol and NSAIDs.

Paracetamol

Paracetamol has been around for a little while (since around 1894), and is useful for its analgesic and antipyretic (anti-fever) effects. It is also pretty safe unless you take too much of it (see here for an explanation as to why this is the case). Strangely enough, we don't actually know how it works, and there are several competing theories. One of the more popular ones suggests that paracetamol may interact with the serotonin pathway or cannabinoid receptors, but this is still very unclear.

NSAIDs

There are many different NSAIDs, but they all work by inhibiting cyclooxygenase. Cyclooxygenase, as mentioned here, can break down arachidonic acid into other stuff, like prostaglandins. Prostaglandins are responsible for inflammation and pain, but they are also responsible for supporting the kidneys, stomach and platelets, which explains some of the adverse side-effects of NSAIDs. Kidney effects include renal dysfunction and renal failure, stomach problems include GI bleeding and ulcers, and platelet effects include anti-platelet activity (which leads to increased blood loss, which is a real problem if you have stomach ulcers too). Hypersensitivity reactions, such as angioedema and bronchospasm, can also result. It's not all gloom and doom, however: NSAIDs have analgesic, antipyretic and anti-inflammatory actions, which basically one-ups paracetamol.

A newer class of drugs, called the coxibs, can cut down on some of the side-effects of NSAIDs. As mentioned here, NSAIDs inhibit both COX-1 and COX-2, whereas coxibs only inhibit COX-2 (which is the isoform of cyclooxygenase associated with pain, inflammation and fever). As such, coxibs have a lower risk of GI bleeding as opposed to regular NSAIDs, though some may have a slightly higher cardiovascular risk.

Finally, a quick note on aspirin, which was one of the first NSAIDs. Unlike other NSAIDs, it blocks cyclooxygenase irreversibly, inhibiting platelets for a long time. Aspirin is also unique in regards to its toxicity: children with viral infections can be at risk of Reyes syndrome if they take aspirin, which is basically liver and brain damage. As such, aspirin is not indicated for children. Also, if you want an analgesic and anti-inflammatory medication, you'd probably be better off taking another NSAID, like ibuprofen.

Opioids

Opioids are somewhat similar in structure to endorphins and enkephalins, which you might know as the natural "feel-good" chemicals. They bind to opioid receptors (!) which are G-protein coupled receptors that come in three classes. These classes are μ, κ and δ. Most opioids, such as morphine, work on the μ class. μ opioid receptors are mainly located in the brain stem and dorsal horn of the spinal cord, though there are some in the periphery as well. Aside from causing analgesia, activation of these receptors can cause other symptoms such as miosis (not to be confused with meiosis, miosis refers to shrinkage of the pupils), euphoria, respiratory depression, nausea, vomiting and so on.

Morphine is the gold standard when it comes to opioids. Drug dealers also like it because they can modify it a bit to make heroin, which gives you a rapid (but short-lasting) high, ensuring that their customers will keep coming back to get more. Another commonly-used opioid is oxycodone, which has no active metabolites, and acts on both μ and κ receptors. Methadone is also commonly used to treat addiction, but it has to be used carefully as it has a long half-life (and thus there is the risk of accumulation). Fentanyl is also handy as it can be administered transdermally, and thus you can give someone a fentanyl patch. One opioid to avoid is pethidine, as it is very addictive.

Constipation is the most common side effect of opioids (especially with codeine, which was actually originally developed to treat diarrhoea!). This can be treated with laxatives or by changing the mode of administration of the opioid. Another common symptom is nausea, which can be treated with anti-emetics or by changing up the opioid ("opioid rotation"). Other side effects include sedation, pruritis (itching) and hallucinations.