Processing pain

Understanding pain at a cellular level

A smiling nurse calls out my name, ushers me into a small side room and invites me to take a seat on a reddy-brown, vinyl covered chair -“I’m not anxious.”

As she checks my date of birth and vaccination notes, my mind starts pondering whether the blood-like chair colour is coincidental and whether or not she’ll say “small scratch coming up”. I almost smile when I hear those exact words, wince ever so slightly, and the prefilled syringe is in the sharps bin before I’ve even started to roll down my left sleeve.

One millilitre of saline containing 20 micrograms of recombinant Hepatitis B surface antigen is now diffusing into the muscle tissue in my left shoulder. In truth, it hardly hurt at all. The 23 gauge needle was very sharp, the amount of liquid was small, and I was mostly thinking about whether or not she’d say “small scratch”.

Pain is something we’re all familiar with but why does it hurt when we receive an injection, stub a toe, or hit a thumb? What is actually going on inside my thumb that allows it to recognise when it’s being burnt, stabbed, dipped in icy cold water or hit by a poorly aimed hammer? How do the cells in my thumb recognise so many noxious stimuli and how does the message get to my brain, telling me I must take my hand away from the fire, drop the ice cube or pay someone else to put up my shelves?

Cell signals

The scientific term for detecting pain at the cellular level is ‘nociception’; strictly speaking, it doesn’t become pain until a message arrives in a conscious part of my brain which I can recognise as being pain — but let’s not go there just yet. When a cell in my thumb starts to get hot, squashed or stretched then special signalling molecules on the cell’s surface pass a message to the inside of the cell saying that damage is occurring. The nature of the damage can be various. My Hep B vaccination hurt because the needle tore some cells in my shoulder apart and stretched others nearby as it was being pushed in. As the vaccine was being injected it caused more stretching and tearing of cells in the vicinity to make space for the 1ml of saline. The saline was pretty cold which upset the cells and if the injection had been formulated in water rather than saline then those cells would also receive osmotic stress.

The damaged and stressed cells pass a message to nearby nerve cells which in-turn pass the message all the way to my spine. From here the signal is sent up the spinal cord and into the lower part of my brain. It all seems fairly straightforward. However, what’s slightly counterintuitive about the nervous system is that it doesn’t pass messages along verbatim. My spinal cord actually adjusts the signals that it relays, depending on what other messages are passing up or down the line at the same time¹. This seems completely crazy in our computer enabled society where I expect the USB cable connecting my keyboard to my computer to always send a letter ‘S’ if I press the letter ‘S’. If the USB cable decided to change each ‘S’ to an ‘F’ just because the space bar was being pressed occasionally, then I’d get really piffed oss. But strangely this is exactly the sort of thing that goes on in your spinal column; it isn’t just a cable passing on messages, it’s actually doing some signal processing on the messages before they get to the main part of your brain. It’s more helpful to think of your spinal cord as an extension of your brain than simply a cable connecting your extremities.

We can demonstrate this phenomenon scientifically via a process called peripheral nerve stimulation. Imagine we prick 1,000 people with a sharp needle and ask them how much it hurt on a scale of one to ten. We then repeat the exercise with new participants, yet this time we use something like the end of a plastic hairbrush to gently press the skin around the needle prick. On the second occasion we will get a significantly lower spread of pain scores. Bizarre, but genuine². The reason it hurts less is because the nerves are sending messages about the hairbrush sensation at the same time as the message about the needle hurting. In over-simplistic terms — the pain signal is masked by all the signals about the tips of the hairbrush.

Measuring pain

This brings us onto the interesting question about how meaningful it is to measure pain. Pain scores are widely used in clinical trials, such as our example above, and they can be meaningful, but only if you have a sufficiently large population size. The problem with pain is that it’s by definition an entirely subjective sensation. Research strongly suggests that my Hepatitis B jab would have hurt more if I’d been anxious about it and if I wasn’t distracted by thinking about if the nurse would say “small scratch” or not³. Just as we can’t use the USB cable as an analogy for the nervous system, neither can we consider the brain to be like a computer processor which feels pain in direct proportion to the amount of incoming pain signals it receives. It would be far easier to understand, measure and study pain if this was the case. However pain is such an important and potentially debilitating part of our physiology that it’s safeguarded by multiple layers of processing which ensures that the transduction, transmission and interpretation of pain is finely tuned and carefully regulated.

The upshot of all this complexity is that any attempt to quantify pain with a numerical value is about as useful as trying to describe the light you see with your eyes on a scale of one to ten. Think about it … does a dull overcast day score the same as the setting sun on a clear evening? Will your score be different if you’ve just been inside a dark room for the last hour? Will your mood effect your judgement? Are green light traffic lights as bright as red ones? You get the point. Pain is a tremendously subjective and multi-layered sensation which is impacted by a host of factors such as feelings, past experiences, hormones, genetics, epigenetics, environmental factors, physiology and psychology. It is often helpful to attribute a numerical score to pain but only if you remain mindful of the deeply complex biology and neuropsychology which sits between the input and the output.

Reducing pain

OK, so we now appreciate how pain is detected, we understand that the signals are processed on their way to the brain and we recognise that the brain is a complex thing which will feel the pain in different ways depending on just about everything. But can we use any of this knowledge to reduce the pain of important parenteral therapies such as my Hep B shot? After all, we all want to improve the experience of our patients, since we’re aware it’s often linked to their compliance and outcomes.

The answer is unequivocally ‘Yes’ and in at least two ways; firstly at a cellular and secondly at a neuropsychological level.

At the cellular level, we can try to minimise the physical and chemical damage which is inflicted during injection. We can use our knowledge about the cellular damage and signal transduction processes to directly improve both formulations and delivery systems to minimise nociception. For example, we could warm the liquid, reduce osmotic shock, balance the pH, minimise trauma from the needle (during insertion, injection and retraction) and reduce the local hydrostatic pressure. These subtle improvements to the user experience haven’t received much attention from pharma R&D over the last few decades as the focus has been almost exclusively on efficacy and obtaining regulatory approval. However, as generic competition increases and consumers have greater choice we shouldn’t be surprised to see some forward-looking pharma companies considering these patient-experiential issues during the early stages of drug formulation and device development.

Secondly, we can try to positively influence the patient at a neuropsychological level. This might involve more indirect approaches to improve the patient’s mood, reduce their anxiety or to achieve effects such as peripheral nerve stimulation. There is unequivocal evidence to substantiate the validity of these type of influences on reducing perceived pain⁴. Unfortunately, this isn’t a realm which feels comfortable to most of us — we’re all much happier talking about molecules, tolerances, statistics and ISO standards. The idea of putting pictures of cute kittens on a drug vial or making a soft and fluffy needle-shield probably makes you shudder — it may well give your Head of Regulatory Affairs a nervous breakdown. However, just because it isn’t familiar doesn’t mean that it’s an area which we should ignore.

My Hep B injection did hurt me a little, as will every one of the 16 billion or so injections given this year. Whilst the pain of each injection isn’t a big deal, there’s a big opportunity to improve compliance, health and wellbeing if minor improvements can be made to reduce the pain. Even these modest changes will require intelligent decision making, foresight and open minded creativity from leaders within the pharma and device industry. The rewards, however, could be both improved health for patients and also protection of market share and differentiation in an increasingly competitive marketplace.

This article was taken from issue 8 of Insight magazine. Get your free copy of the latest issue here.

---

References
1. Handbook of Clinical Neurology (Series Editors: Aminoff, Boller and Swaab) Fernando Cervero, Troels Staehelin Jensen. 10 May 2006
2. A new method to reduce pin- prick pain of intra-muscular and subcutaneous injections.Minerva Anestesiol. 2005 Oct;71(10):609 – 15
3. Judging pain sensitivity with subcutaneous lidocaine injections. Pain Med. 2011 Apr;12(4):668 – 72
4. A novel needle for subcutaneous injection of interferon beta – 1a: effect on pain in volunteers and satisfaction in patients with multiple sclerosis. BMC Neurology 2008, 8:38 doi:10.1186/1471–2377– 8–38 Amer Jaber et al.