In 1986, Pat Wall and Steve McMahon commented on the folly of talking about nociception as though it is pain -
‘the labelling of nociceptors as pain fibres was not an admirable simplification but an unfortunate trivialization’ and
‘…pain is an integrated package of analysed results related to meaning, significance and imperative action’ [1]
Almost 25 years have passed and still this unfortunate trivialisation dominates our language when we are discussing pain.
The bee in my bonnet was most recently stirred up by a Science news article covering a new paper from a bunch of people, with Geoffrey Woods from Cambridge at the helm and Stephen Waxman’s from Yale at the rear, published in PNAS[2]. Now, I think the PNAS article itself is really hot, with the exception of the actual numbers being absolutely impossible to extract, at least for me. I can tell you what they did: they investigated DNA of almost 600 people with arthritis and found a particular gene was associated with higher pain levels. They then tested for that gene in about 200 people with back pain and then a group with phantom limb pain. The association held. So, I think you can be very confident, on the basis of this work, in concluding that this gene is associated with higher pain levels.
The biology makes sense too – this gene encodes for a particular type of sodium channel that is important for nociceptive peripheral neurones to work properly and complete absence of this sodium channel, which happens when the culprit gene is really stuffed up (technical term = nonsensemutation), causes the stupidly labelled ‘insensitivity to pain’ – a more accurate label would be ‘insensitivity to noxious stimuli’. So, the biological rationale matches the association. I think the authors are correct in predicting that this has implications for new targets for analgesia. However, before you go and buy stocks, have a look at the size of the association. It is small. Insy winsy, teeny weeny actually. So, surprisingly enough, this large study with almost 1000 participants, reminds us that
‘…pain is an integrated package of analysed results related to meaning, significance and imperative action’
- not simply a measure of nociception. So, my take? The PNAS paper is important and might let us better address one contributor to chronic pain states. Now, back to that bee buzzing away: Quotes from the Science news article:
- “You’re more sensitive to pain.” This one attributed to Woods (gasp!);
- “the sodium influx then spurs the nerve cell to send a pain message to the brain.”;
- “can leave a person impervious to pain”;
- “allowing a stronger pain signal to be sent to the brain”;
- “stopping the pain signal sooner”.
AAAAAAAAAAAgh! I can not summarise it better than Wall & McMahon did, so I will iterate -
‘the labelling of nociceptors as pain fibres was not an admirable simplification but an unfortunate trivialization’.
Why is it important? Because our patients are always looking for Descartes, and here he is, in all his revolutionary glory.
References
[1] Wall, P., & McMahon, S. (1986). The relationship of perceived pain to afferent nerve impulses Trends in Neurosciences, 9, 254-255 DOI: 10.1016/0166-2236(86)90070-6
[2] Reimann, F., Cox, J., Belfer, I., Diatchenko, L., Zaykin, D., McHale, D., Drenth, J., Dai, F., Wheeler, J., Sanders, F., Wood, L., Wu, T., Karppinen, J., Nikolajsen, L., Mannikko, M., Max, M., Kiselycznyk, C., Poddar, M., te Morsche, R., Smith, S., Gibson, D., Kelempisioti, A., Maixner, W., Gribble, F., & Woods, C. (2010). Pain perception is altered by a nucleotide polymorphism in SCN9A Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.0913181107
Abstract
Pain perception is altered by a nucleotide polymorphism in SCN9A
The gene SCN9A is responsible for three human pain disorders. Nonsense mutations cause a complete absence of pain, whereas activating mutations cause severe episodic pain in paroxysmal extreme pain disorder and primary erythermalgia. This led us to investigate whether single nucleotide polymorphisms (SNPs) in SCN9A were associated with differing pain perception in the general population. We first genotyped….
For the full paper (Open Access) see PNAS
{ 2 comments… read them below or add one }
Interesting findings. As someone who knows diddly about genetics and its methods I would note that the 95% confidence intervals seem very wide for the significant results given the size of the populations studied. That may be completely normal for this kind of research. It is hard to know how clinically relevant it all is but if it was data from a treatment I would call it marginal.
Also this might be a moot point as I genuinely know nothing (really nothing at all) but is there any scope for blinding (or lack of) of those doing the genotyping to play a role?
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Lorimer Reply:
March 16th, 2010 at 3:54 pm
As ever, great observations Neil. I have almost no idea either. We need a genetics dude. Anyone out there?……
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Kathleen Sluka Reply:
March 17th, 2010 at 1:46 pm
Some thoughts and responses. This is an excellent paper. It shows that a relatively common mutation (SNP=single nucleotide polymorphism) in the sodium channel (NaV 1.7) gene is associated with higher pain sensitivity in several different pain conditions (OA, sciatica, phantom limb pain) and pain sensitivity in healthy controls (but not pancreatitis pain. As genetic studies go this is extremely complete and well done exmaining among several different pain conditions and healthy controls. What is really nice, is that they also examine the different SNPs on function in neurons and show that neruons with the particular SNP associated with more pain are also associated with more excitability.
To note, however, there are other genes such as COMT and serotonin transporters in the catecholamine pathways that have also been associated with more pain in some pain syndromes/conditions.
The way I interpret these types of studies is that there are several genes that might each by itself explain a portion of the pain sensitivity. There are certainly other factors, i.e. injury, personality, mental state (depression, anxiety), pain catastrophizing, fatigue, etc…. that will also explain a portion. I expect, all these variables if added together in one study would explain a greater portion of the pain sensitivity.
As stated in the article: “All such measures of pain severity (referring to self-report here) are intrinsically imprecise because they necessarily rely on subjective reporting using pain scales such as the WOMAC questionnaire or the Visual Analog Pain Scale. The consequent variability in quantifying pain is a major contributor to reducing the power of this type of study.”
The variability in pain is precisely what makes it unique to each individual. As scientists we are always trying to minimize this variability, as clinicians we try to ignore it (it is back pain, shoulder pain, osteoarthritis, etc.). However, we all need to recognize the variability if we are to find the answers to better pain management. This study begins to address a portion of the variability.
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Thanks for that insight. I agree the findings are fascinating and the study appears genuinely rigorous particularly the consistency across different patient groups. It is entirely reasonable that this SNP is just part of the genetic picture and that the combined genetic influences might be predicted to be greater. I guess how much remains to be seen.
In terms of the clinical relevance it would be really exciting to look at this and the other genetic influences in a big prospective observational study to assess the influence on incidence, natural course and prognosis of painful conditions. I guess we would be talking BIG BIG numbers research.
My concern over the size of the effect really arises from the data from observational studies in back pain. Small associations seem to produce such inconsistent results in these kinds of studies.
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