Ep 15 – Morphine for the FRCA Primary Exam

Introduction and Podcast Overview

00:00-01:35

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Hello, my fellow Gas, Gas, Gas co-conspirators. My name’s James, and today we’re looking at the primary FRCA exam content you need to know for morphine. We’re talking morphine itself and the opioid receptors, exploring the mechanisms by which morphine works, its pharmacokinetics and pharmacodynamics, as well as a bit of a look at clinical use.

Now I appreciate everyone is very familiar with morphine, and this serves two issues up. One, the examiners are going to expect you to know more than the average doctor by a fair bit, given its ubiquitous use and daily use in anaesthesia. And the counter to this is that this topic might feel really boring because you’re already very familiar with this drug. So I’ve gotten carried away and I’ve been on the hunt for some cool facts about morphine just to get things started.

Fact One: Frederick Sertürner, a German pharmacist, isolated morphine from opium poppy resin after fiddling around in his lab for quite some time in 1803. He named it morphine, after the Greek god of sleep and dreams, so called Morpheus. I now realise this is why in the Matrix Morpheus is called Morpheus, because he presides over fishing people out of the Matrix-like dream state. And what you would naturally expect of a scientist trying to elucidate such things, he tested it all on himself as well.

Opioid Receptors: Location and Mechanism

01:35-04:00

Much like the structure for the last podcast, we’re going to pile straight into some questions and answers.

“Hello, Doctor, this is your pharmacology viva. Where are the opioid receptors found, and how do they exert their actions?”

Yes, opioid receptors are ubiquitous throughout most of the central nervous system, and they’re also found in the enteric nervous system. There are several subtypes of opioid receptors. These are called the mu opioid receptor (MOP), the delta opioid receptor (DOP), the kappa opioid receptor (KOP), and the nociceptin receptor (NOP).

The mechanism of action by which morphine exerts its effect is one of agonising the G-protein coupled inhibitory complex that is associated with these morphine receptor subtypes. G-proteins have seven transmembrane domains which communicate with an intracellular secondary messenger system.

Upon agonising the opioid receptor in question, these secondary messenger systems cause potassium efflux in the neuron, leading to cellular hyperpolarisation. They induce closure of voltage-gated calcium channels, making it harder for the cell to depolarise again, and inhibit adenyl cyclase activity, leading to reductions in cyclic AMP. Cyclic AMP is thought to modulate glutamate sensitivity.

The sum of all these actions is that the neuron becomes less excitable and therefore less able to transmit pain signals from peripheries to the central nervous system and cortex.

Opioid Receptor Agonists

04:00-04:34

“And what agonists are you aware of that act upon these opioid receptors?”

There are many agonists of opioid receptors. The ones that chiefly jump to mind would be morphine, fentanyl, and alfentanil, very commonly used in anaesthesia. Other drugs that have activity would include pethidine, methadone, buprenorphine, and diacetylmorphine, or diamorphine. One other drug that comes to mind that does have a degree of mu opioid receptor activity is ketamine, although its chief actions are elsewhere.

Central Nervous System Sites of Action

04:34-05:41

“There are a number of key areas within the central nervous system that opiates act. Tell me more about this, please.”

The two places that come to mind are presynaptically in the dorsal horn of the spinal cord - agonised opioid receptors here inhibit the activity of spinal A-delta and C nerve fibres from transmitting pain peripherally to centrally. The second chief area is in the periaqueductal grey matter. This is an area of the midbrain involved in nociception transmission. Morphine or other opiates here act to modulate the activity of a descending inhibitory control pathway for pain - it again modulates spinal cord transmission.

Of note here, opioid receptors are obviously also found in your GI tract - that’s why you get constipated - and in your cortex particularly, where it makes you feel great apparently, depending on who you talk to.

Fact Two: In 1874, diacetylmorphine was discovered, and it was touted as a cure for morphine addiction. Diacetylmorphine, as we all know, is heroin. And you can see the irony here. This situation sounds very familiar, because OxyContin was not meant to be addictive either.

Receptor Subtypes in Detail

05:41-06:48

So we’re going to talk a little bit more about morphine receptor subtypes. So we mentioned MOP, KOP, DOP, and NOP. These are the four that you should know about, so called for an agonist that was originally discovered that bound to them.

So MOP (mu opioid receptor), the prototypical agonist, was morphine. KOP (kappa opioid receptor) was originally found to bind to ketocyclazocine - never heard of that one before. And DOP because it was found in the vas deferens of mice, as you do. And NOP, so called because of nociceptin. This is a neurotransmitter that increases your pain sensitivity.

Others do exist, and for interest, there’s something called ZOP or the zeta opioid receptor, depending on how you pronounce it - opioid growth factor receptor. This is stimulated by Met5-enkephalin and it regulates tissue growth and development in normal and tumorigenic, i.e. cancerous, tissues. Interesting.

Morphine: Presentation and Dosing

06:48-08:04

So now we’re going to do the exceedingly dry bit here and talk about the data for morphine and that nice blurb that you should be able to barf out if required, although more commonly, you’ll probably find yourself talking about components of what we’re going to discuss next.

So morphine is an opioid, i.e. a synthetic opiate, because they synthesise it these days instead of trying to fish it out of poppy seeds. It’s a clear, colourless liquid, and can be prepared as a tablet, an oral liquid, a patch, an IV preparation. Preservative-free intrathecal preparations can be administered intranasally.

The concentration varies considerably, but you will classically find ten milligram and fifteen milligram ampoules for IV use in theatres, and ampoules with one milligram in for intrathecal use in theatre. Its dose range is 0.1 to 0.2 milligrams per kilo, although naturally you could give more. Intrathecally, the range is from 200 to 1000 micrograms. The common dose is 200 to 300.

Its mechanism is opioid receptor agonism leading to dampened neuronal firing in pain pathways and a reduction of neuronal excitability.

Pharmacodynamics and Side Effects

08:04-10:04

If given intramuscularly, it has a thirty to sixty minute time delay for peak effect. Intravenous administration, the range is quoted as fifteen to thirty minutes - it seems to take a while. Most people just experience that dizziness and feeling a bit woozy first instead of actual pain relief. It lasts three to four hours.

It does have a relatively forgiving side effect profile. Breaking it down systematically - it’ll look good in the exam.

Cardiovascular side effects: Very stable, but in large doses may cause bradycardia, and it reduces systemic vascular resistance, which is often more demonstrable in an orthostatic hypotension variety as opposed to just a patient becomes hypotensive perspective.

The respiratory system is affected by morphine. It causes respiratory depression, reduces your sensitivity to plasma CO2, and has a potent antitussive, that is cough inhibiting, effect. There is a dose-related delayed respiratory depression effect when morphine is given intrathecally. The range of effect is 2.5 to twelve hours. Peak is at six hours. That’s useful knowledge just for daily practice there.

GI wise, it makes you feel sick, it makes you get constipated, and you reduce GI motility.

CNS wise, naturally, it causes analgesia, euphoria, and anxiolysis, so it makes people feel a bit chilled out too, and, considering their eyes, causes miosis - small pupils.

Metabolically, people can get a bit itchy, especially intrathecal morphine. This is intrathecally not modulated by histamine, but it also can trigger histamine release when given IV. Sometimes you can see a bright red tract up the patient’s arm as it tootles along. It also increases ADH secretion, i.e. your patients who are now secreting more anti-diuretic hormone hold on to water and get all dilute, and they could get a little bit of relative hyponatraemia. Oh golly, morphine times.

Fact Three: Sir William Osler’s colleague and surgical behemoth William Halsted was initially addicted to cocaine when he was at work. He went on, after several bouts at rehab, to swap this for a good old fashioned morphine addiction. Osler and Halsted were two of the four founders of Johns Hopkins University Hospital in the United States. Halsted is famous for probably inventing surgical gloves, transfusing his own blood into his postpartum haemorrhaging wife, and whipping out the gallstones from his mother at two o’clock in the morning on a kitchen table. Cool. That was your third fact.

Pharmacokinetics

10:04-12:27

Moving on to the pharmacokinetics of morphine. So absorption: it’s fifteen percent to fifty percent orally bioavailable, and there is significant hepatic first-pass metabolism. This is why Oramorph is nowhere near as potent as IV morphine.

Distribution wise, it has a pKa of 8, so it is twenty-three percent unionised at plasma pH. It’s twenty to forty percent protein bound, and has a volume of distribution of 3.3 to 4.7 litres per kilo - call it four litres per kilo.

Morphine metabolism: Phase I, there is scant N-demethylation to normorphine, but this is more or less negligible. Mostly morphine is Phase II metabolised via glucuronidation, and I’m sure you’ve heard of morphine-3 and morphine-6 glucuronide as the metabolites.

So these are almost entirely cleared renally, ninety percent - some say seventy percent renally cleared, with the rest going out through your biliary system. There is some enterohepatic recycling of that biliary bit, because glucuronidated things can get easily hydrolysed by the bugs in your GI tract, and then you can reabsorb them. Cheers, bugs.

So morphine-3 glucuronide makes you drowsy, and ninety percent of morphine is converted to that. Ten percent of morphine is converted to morphine-6 glucuronide. This is an incredibly potent analgesic, thirteen times more potent than morphine, and that’s renally cleared too.

Morphine is renally cleared at a rate of 12 to 23 mils per kilo per minute, and its terminal half-life is two to four hours. Lots of information there.

Detailed Receptor Pharmacology

12:27-13:55

Lastly, we’re just going to look at these morphine receptors in a bit more detail - probably more likely to come up in the SBA than someone mercilessly quizzing you in the viva, but who knows?

So the MOP or mu opioid receptor has a natural ligand which are the endorphins mostly, with a bit of enkephalin and dynorphin also agonising it quite happily. The mu opioid receptor is mostly associated with analgesia, respiratory depression, constipation, and the cardiovascular effects. This is probably why remifentanil, which is very mu opioid receptor happy, causes that drop in heart rate and drop in cardiac output that you see, knocking about twenty percent off your cardiac output.

KOP or your kappa receptor, again, is agonised by endorphins and dynorphin mostly, quite potently, in fact. Again, KOP is associated with analgesia, but it is less of a respiratory depression offender.

Your DOP, your delta, or your vas deferens of a mouse receptor, is also good mates with the endorphins and enkephalins, and plays a role in mood and movement.

And then your NOP, this is your nociceptin receptor. The natural ligand for this one is nociceptin, but also this thing called orphanin. In low doses nociceptin causes hyperalgesia, but in high doses it causes analgesia. Cool.

Historical Context: The Opium Wars

13:55-15:11

We’re going to close out with one more opium fact, and this is a bit more geopolitical. So the opium wars, in a nutshell, as far as I understand it: The British were profiting from illegally importing opium from India into China. They were naturally profiting from that. China was not amused for two reasons perhaps. As their population was becoming rather feckless as they were all addled on opium, things weren’t going so well for them. But also, it led to a negative trade deficit, which is bad for their economy.

So China blockaded and confiscated what they could. Britain, not amused by this, initially sought to negotiate their way out of it, but eventually gave up, captured territory, destroyed the blockades, and subsequently forced concessions from China, given the British military superiority at the time. That was the first opium war. There was a second one.

Ultimately there was some obstruction from China in opium trade, and the Brits went straight, seemingly, to a military conflict. But the French joined in this time on the premise of the Chinese killing a diplomat or something the year before. The Second Opium War led to the capture of Beijing - there was a palace in Beijing that got sacked and further Chinese concessions occurred. Bad times for them.

Clinical Pearls and Take-Home Points

15:11-16:55

So hopefully you’ve learnt a bit about morphine, but also it wasn’t too disastrously boring. There are a couple of take-home points.

It is a ubiquitous drug used daily by many anaesthetists and a good understanding of its uses and clinical effects is essential. When you’re using it intrathecally, the respiratory depression tends to occur from 3.5 to twelve hours with a six hour peak. So at twelve hours, if someone’s in gibbering agony, you can feel a bit happier with giving them some parenteral morphine-like substances.

It’s important to remember that morphine-6 glucuronide, whilst there’s not much of it that’s converted from morphine to that in your liver, is thirteen times as potent and is renally cleared. So people with CKD plus morphine, sketchy combination.

Another thought here is that codeine is eventually converted to morphine and then is eventually converted to morphine-6 glucuronide. So in someone with really bad renal disease, be thoughtful with codeine too. I have had a patient opiate toxic from codeine use only.

Fentanyl is probably better than morphine. The only advantage with morphine is it lasts longer. There is a kinder side effect profile with fentanyl.

And the humdinger, last one: don’t mix up your ten milligram IV morphine with your one milligram ampoule of intrathecal morphine. It definitely happens because they look exactly the same.

Final Thoughts on Opioid Addiction

16:55-17:39

My final fact is that the likelihood of there existing a non-addicting opiate, given that the receptors are naturally liganded by endorphins, seems unlikely, but the Sackler family and Purdue Pharma did some excellent marketing and profited quite a bit from suggesting that oxycodone, OxyContin, did otherwise.

This entirely failed to go to plan on their part, and the Sackler family estate agreed to cough up six billion dollars to make all the lawsuits in America for opioid addiction go away. Clearly their antitussives didn’t work for them.

Anyway, you’ve been listening to James. This is Gas, Gas, Gas. Cheers for listening.

If you found it useful or awful, please like and subscribe and rate the show. Definitely check out the show notes for those diagrams and the detail of this content. It is a bucket of content to get to grips with. Keep working at it and you will get better, faster and stronger. It is vital to keep your interest alive for the science that we’re covering and not overcook yourself. You will be amazed by what you know come exam day. Don’t freak out, keep studying.