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Medicinal Chemistry

A Brief Guide to Common Painkillers

Brief Guide to Common Painkillers [2018]
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Following on from the previous post on antibiotics, it seemed logical to also take a look at the drugs we take to relieve pain. Painkilling drugs, or analgesics, come in a number of forms, but fall broadly into two main classes: non-steroid anti-inflammatory drugs (NSAIDs) and opioids. This graphic takes a look at a selection of common painkillers, their common brand names, and how they work. The mechanism of action is in many cases not fully understood, but we have a broad idea of how the two classes exert their effects.

NSAIDs

Non-steroid anti-inflammatory drugs include analgesics such as aspirin and ibuprofen, shown in the graphic, as well as naproxen. These drugs all work by inhibiting the synthesis of a class of chemical compounds called prostaglandins. Prostaglandins are produced by the body at the sites of tissue damage or infection, and, along with other chemicals produced by the body in these cases, they contribute significantly towards inflammation and pain. NSAIDs work by inhibiting the activity of two enzymes, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). These enzymes catalyse prostaglandin synthesis, so when their activity is inhibited, so is the body’s manufacture of prostaglandins. The net result is a reduction in inflammation, and subsequently a reduction in pain.

Painkillers have no innate method of reaching only the site of pain, but rather are distributed evenly through-out the body when you take them. They’re also non-discriminative in terms of their action, and will inhibit prostaglandin synthesis all over your body, not just at the site of pain. Prostaglandins don’t just have a role in pain in our bodies – they’re also found in the gut, where their role includes protection of the gut lining. As such, use of NSAIDs increases the risk of stomach ulcers and gastrointestinal irritation. For this reason, during sustained course of NSAIDs (for example, after surgery), drugs to help protect the gut lining may also be prescribed.

Opioids

The second major class of painkillers are the opioids. These are a class of drugs related to morphine, the compound found in significant concentrations in the opium poppy. The opium poppy itself has been used for its natural painkilling properties for centuries, as the opium which can be extracted from it contains around 12% morphine. The synthetic drug heroin is also obtained from a simple chemical modification of morphines structure; many of the painkilling opioids have similarly minor differences in chemical structure.

The opioids work in a different way to the NSAIDs; rather than combatting the pain at its source, they instead prevent the sensation of pain by binding to and blocking the receptors in the brain and spinal cord that are responsible for the transmission of the sensation of pain. This group of receptors are known as opioid receptors, and there are four different subtypes; the exact manner in which many of the opioids inhibit pain by binding to these receptors isn’t fully understood.

Opioids may be potent painkillers, but their overuse comes with the spectre of opioid addiction. Excessive use leads to over-stimulation of the brain’s ‘reward’ pathways; the brain also tries to compensate by reducing the number of opioid receptors, meaning progressively more of the opioid is required to achieve the same highs. No single treatment is effective for all opioid dependent patients, and oddly enough, some of the opioids drugs are used in some treatments. Methadone and buprenorphine are both commonly prescribed, as they are longer acting than, for example, heroin, and so allow for less frequent dosing. Tolerance is also slow to develop, and as such their use has been associated with a reduction in the use of other opioids in opioid dependent individuals.

Although fentanyl is the most potent opioid shown on the chart, more powerful opioids do exist. The most potent used in humans is sufentanil, considered to be approximately 500-1000 times stronger than morphine. Carfentanil, with a potency considered to be around 10,000 times that of morphine, is used as a general anaesthetic in large animals.

Paracetamol

Paracetamol is something of an oddity amongst the painkillers, in that it’s categorised separately, rather than in one of the two main groups. Part of the reason behind this is that we still don’t have a very good idea of how paracetamol exerts its painkilling effects. It’s thought that, like the NSAIDs, it works by inhibiting cyclooxygenase enzymes, but there are also suggestions that it works on the endocannabinoid system in the body, which plays a part in pain. In short, we still don’t really know how it functions – a great summary of some of the different theories is put forward in a video here by the American Chemical Society’s Reactions team.

Paracetamol also has a detraction, in that its toxic dose is relatively close to the effective dose. Excessive use or overdose can lead to damage to cells in the liver, which can in turn lead to liver failure and death. This is the reason why, when you go to the supermarket, there’s a limit on the number of boxes of paracetamol you can buy at once!

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References & Further Reading

20 replies on “A Brief Guide to Common Painkillers”

This is a great infographic. I would have loved to have it while taking medicinal chemistry classes 😛

Now,
there’s a thing I didn’t understand. You say that opioids “prevent the
sensation of pain by binding to and blocking the receptors in the
brain”. Then you say that “the brain also tries to compensate by
reducing the number of opioid
receptors, meaning progressively more of the opioid is required to
achieve the same highs.”

Tolerance and addiction are indeed huge
problems regarding opioid use, and that’s one of the reasons why people
can’t buy morphine over the counter, but I don’t really understand the
proposed mechanism for the development of tolerance.

If opioids
block the receptors the effect is the same as if the brain had *less*
receptors. Therefore, to maintain homoeostasis, the brain should
*increase* the production of the receptors. Likewise, if the number of
receptors is increased, then you would need to increase the dose of
opioids you take to ensure that the surplus of receptors your brain had
produced would also be blocked.

Is this correct or am I missing some point?

Once again, congratulations for this post and for your blog, I really enjoy reading it 🙂

This is a great infographic. I would have loved to have it while taking medicinal chemistry classes 😛

Now,
there’s a thing I didn’t understand. You say that opioids “prevent the
sensation of pain by binding to and blocking the receptors in the brain”. Then you say that “the brain also tries to compensate by
reducing the number of opioid
receptors, meaning progressively more of the opioid is required to
achieve the same highs.”

Tolerance and addiction are indeed huge
problems regarding opioid use, and that’s one of the reasons why people
can’t buy morphine over the counter, but I don’t really understand the
proposed mechanism for the development of toleance.

If opioids
block the receptors the effect is the same as if the brain had *less*
receptors. Therefore, to maintain homoeostasis, the brain should
*increase* the production of the receptors. Likewise, if the number of
receptors is increased, then you would need to increase the dose of
opioids you take to ensure that the surplus of receptors your brain had
produced would also be blocked.

Is this correct or am I missing some point?

Once again, congratulations for this post and for your blog, I really enjoy reading it 🙂

Thanks, glad you’re enjoying the blog!

The opioid dependence and tolerance question is an interesting one. I’m by no means an expert when it comes to this area – so my own understanding is a little fuzzy. As I understand it, opioids bind to opioid receptors, and their action modulates pain information that reaches the CNS. Some opioids, by binding to these receptors, can also act on the brain’s reward system, increasing levels of dopamine. Reading further into the development of tolerance, internalisation of receptors is just one proposed factor. Sadly, much like the mechanisms of some of their analgesic effects, the mechanism of tolerance doesn’t seem to be fully understood – if anyone reading can provide a more precise explanation, it’d be great!

Yes, I am aware that addiction and tolerance are not simple questions to tackle, but my question is: shouldn’t the brain increase the production of receptors, instead of decreasing it (as suggested in your post)?

Great post, lots of good information! ! I would also vote for up regulation of the opioid receptors, but don’t have time to check. Also, the opioid addiction treatments are partial agonists, ie they bind to the receptor and cause some stimulation, but then block the receptor. Keep up the great work 🙂
Cheers

Thanks Matthew!

The sources I consulted for this article, including a paper on opioid receptors, definitely mentioned down-regulation of receptors as a possible mechanism for the development of tolerance (I went back and double checked!). I agree that this seems somewhat contradictory – one of the texts I consulted merely states by way of explanation that it induces tolerance by reducing the number of receptors available for drug mediated actions. They also suggest desensitisation of receptors as another possible contributor, but it goes on to emphasise that we still don’t have a clear picture of the development of tolerance.

I’ll add in a mention of desensitisation, and the uncertainty regarding tolerance development, into the article. Sadly, in the absence of someone who knows a good deal more than myself about opioid action on opioid receptors, I suspect it’s going to be difficult to track down a clear answer.

Interesting-that should lead to saturation of receptors at lower doses and a decrease in effects, but not increased tolerance-unless it is on the feedback receptors that modulate endorphin release, in which case it would result in withdrawal effects. Unfortunately its been a couple of decades since I did any pharmacology so my memory is a bit rusty and I am sure things have moved on a lot! ! Thanks for stimulating some thoughts and old learning

[…] be taken to a list of the ingredients needed to make a solution that will remove your chosen stain. A Brief Guide to Common Painkillers. Click to enlarge Following on from the previous post on antibiotics, it seemed logical to also […]

Brilliant diagrams and explanations! Both the anti-biotics page and painkillers page are going to be extremely helpful to use with A2 Applied Scientists as a way of teaching an overview of how different classes of drugs work. If you wish to discussthe classes and how analgesics or anti-virals or how anaesthetics work …. then that’s the assignment pretty much taught 😀

Brilliant, glad they’ll prove useful! I teach straight chemistry, so it’s more a point of interest for my students rather than something they need to know. Good that it’s helping those who are studying it as well though 🙂

Well that was interesting!
But you got 2 small chemistry mistakes up there :
– Missing double bond in the left aromatic ring of Oxycodone
– The tertiary amine ring of Buprenorphine goes through the right hand bicyclo[2,2,2]octane – should be on top of it.

Good spots! This is what happens when my version of ChemDraw doesn’t recognise any of the systematic names of a molecule, and I have to draw it myself 🙂 Afternoon of teaching ahead, but I’ll fix it ASAP after that.

Just bought the poster version of this for my Brother-in-law who is graduating med school this week. Seemed fitting.

I believe it was the first & third references provided. As they state, and as noted on the graphic itself, it’s to an extent an approximation, rather than hard and fast figures, however.

[…] The barbiturates are today much less frequently used as intravenous anaesthetics, because they’ve been largely superseded by another anaesthetic: propofol. Propofol is probably the most widely used intravenous anaesthetic, as it has a number of benefits over the other featured here. Firstly, awakening and recovery from anaesthesia with propofol is relatively quick, and it can also sometimes be accompanied by a mild euphoric feeling, which has obvious benefits for patients. Additionally, its use has been associated with decreased post-operation vomiting. It does come with a larger price tag than some of the other drugs used for anaesthesia, but its use is often preferable. It is often administered with opioid drugs in order to help provide an analgesic effect (we talked about opioid painkillers in another previous graphic). […]

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