Botox and Complex Regional Pain Disorder

One of the many things I’m involved with online is running the London Pain Consortium twitter account, and recently someone got in touch asking about botox treatment for complex regional pain syndrome (CRPS), so I decided to write a wee post summarising what is published on the subject. Please note: I am not a doctor, or a CRPS specialist! Just a bog standard pain researcher, with experience in systematic reviews…

I found 4 publications, 2 case study format, and the other 2 involving between 14 and 37 patients. 3 of these reported that botulinum A toxin (Botox) improved symptoms when injected into trigger points and other areas affected by CRPS… sounds promising, but it’s important to also look at the quality of the study before deciding to trust what it is claiming. I have an inherent distrust in case studies – for one thing, they rarely feature qualitative outcomes measures, relying more on subjective descriptions of patient condition, and for another, they are a good example of publication bias, i.e. people prefer to share the positive rather than negative. It’d be very unusual to read a published case study describing a failed treatment – the fact is, pain is such a complex condition that many treatments will only work in very narrowly defined populations, so without good information on who was treated (age, sex, weight, medical history), how they were treated (dose, injection spot, frequency), and how any changes were assessed (pain & quality of life questionnaires, sensory testing, VAS scales), it’s difficult to say how relevant or accurate their statements are.

Looking at the 4 publications again, taking into account quality of evidence presented by the study, as well as whether they said it worked or not, shows a different picture. As I mentioned, 2 were case studies:

  • The first, published in 2009, described 4 teenage patients in good detail, but failed to mention the dose, or use objective measures in reporting changes after the treatment 
  • The second, published in 2010, described 2 adult patients, and used VAS scales to objectively measure the effect of the treatment 

The third paper, is from the authors of the second case study above, and was the only study to involve a control group, or use multiple methods of assessing pain. They looked at 14 patients, with 5 different tests, but had to call the study short due to poor tolerance of the treatment. (I imagine they planned the pilot study on the basis of the case study reported above.)

The final paper, published in 2011, was completely upfront in stating its limitations – it was done retrospectively from patient records, and had no control group, meaning it’s impossible to exclude the possibility that the reported positive results are due to the placebo effect (a well known issue in clinical trials for pain conditions), or say how it compares to another, more established drug. 

In summary, my evaluation of the literature above suggests caution – although many seem positive, the quality of the studies is low, but until someone does a high quality study, it won’t be used as a standard treatment. One of the problems in the pain field in general, and with CRPS in particular, is that clear diagnosis is often difficult, and results in patient populations which may have little in common.

I’m going to look at the evidence from the pre-clinical studies next, and do a follow-up blog to see whether that has anything to add to this discussion.

As always, questions & comments welcome :)

Articles Cited:

  1. Syndrome of fixed dystonia in adolescents-short term outcome in 4 cases. Majumdar et al., 2009
  2. Botulinum toxin A (Botox) for treatment of proximal myofascial pain in complex regional pain syndrome: two cases. Safarpour & Jabbari 2010
  3. Botulinum toxin A for treatment of allodynia of complex regional pain syndrome: a pilot study. Safarpour et al., 2010
  4. Intramuscular botulinum toxin in complex regional pain syndrome: case series and literature review. Kharkar et al., 2011

 

 

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The Science of Shotlogging

Rosie:

This is what happens when you let a scientist shot-log a film…

Originally posted on Fighting Badgers:

When I first became involved with Fighting Badgers, one of the main things I did was spreadsheets. It’s a large part of my job as a research scientist, so it seemed a natural to do as the information started piling up. Contact details, scheduling information, script breakdowns… it was all there, colour coded, formatted, and gorgeous – I can’t say how glad we were for them when it did come time to start scheduling for The Ipanema File – not having the resources to use commercial scheduling software, having it all accessible by pivot table made it a lot less terrifying!

During the shoot, I was happy to take on the job of shotlogging – I knew from previous experience during the editing of Jagoda how vital accurate logs were, and as our editor was not present during the pre-production or shoot, I felt it was only fair to make…

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Object of the month: Shrunken Heads (real and fake)

Originally posted on Wellcome Collection blog:

As part of our development project, the tsantsa (or, shrunken head) normally on display in Medicine Man is in storage. Our replica tsantsa, however, which forms part of our cross-gallery handling collection, can still be seen. This month Charlie Morgan delves into the history and controversy of this erstwhile cultural practice.

Shrunken head, Shuar

Shrunken head, Shuar

At some point in the mid-16th century, Spanish Conquistadors entered the Amazon rainforest and came into contact with the Shuar people. In the epic colonisation of Latin America, one more indigenous group would not have made much of an impact if it had it not been for two factors: gold and tsantsas. To gain the former, the Spanish Empire tore up its initial peace agreements and subjugated the Shuar in a brutal mining system. In 1599, The Shuar – amongst other Jivaroan tribes – revolted against the Spanish, sacked their towns and –…

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Will distinguishing between exploratory and confirmatory research aid translation??

This paper makes me ranty. It’s open access – take a look, and be prepared to read it more than once to get the gist of their arguments.

Published in May 2014 in PLOS Biology (who incidentally also published the ARRIVE guidelines, which, although never mentioned by name are the clear target), it focuses on the concept that there are fundamentally two types of pre-clinical research: Exploratory and Confirmatory.

Exploratory research is described as being flexible, which sounds great until you realise what the authors mean by flexible is involving minimal pre-planning, no requirement for statement of experimental parameters which can influence outcome, and an emphasis on small samples sizes, and multi-technique or conceptual confirmation of results. These techniques, incidentally, do not need to be validated or established in any way. They argue that the use of multiple techniques negates the effect of small samples sizes, without acknowledging the fact that if the initial study is underpowered and biased, then all those that follow will be similarly afflicted. This is not the definition of robust research. Oh, and they also suggest that ‘non-informative’ data can be excluded on a whim, because, obviously you as an author know better than the readers, not to mention the fact that so-called ‘outliers’ are often worth a bit of investigation – ask why are they showing such extreme values, rather than discarding because the data is tighter without their presence.

Confirmatory studies are those which are based on robust exploratory studies, which from the above description seems somewhat contradictory. How can a study be described as robust if it is underpowered and uses unvalidated techniques? The way confirmatory research is described in this article makes it sound unimaginative and a crude approximation of how most pharmaceutical pre-clinical research is conducted.

It seems to me that instead of reducing the use of animals in research, encouraging studies with group sizes plucked out of the air will just mean more waste in attempts to replicate false positives. Seriously, why not spend a little time before starting a study working out the group sizes you will need to use inferential statistics (i.e those involving a p-value for significance)… OR simply avoid the issue and use descriptive statistics only. Makes sense, no?

There are some interesting ideas in the paper (e.g. use of multiple techniques) , but it is fundamentally flawed by its emphasis on removing so-called ‘fastidious’ methodology – be robust and respectful in your studies, or they will be worthless.

So will distinguishing between exploratory and confirmatory research aid translation? Maybe, but not the way these guys see it – true exploratory research is not that widespread (e.g. ‘trawling’ studies such as GWAS, which generate potential leads); the majority of studies are ‘confirmatory’ in some form, so really the point at which exploratory research becomes confirmatory needs to be better defined… or preferably, described differently, acknowledging the diversity of contribution to clinical understanding, not just from a drug discovery standpoint.

Official responses to this publication are in the process of being prepared, so I won’t say much more except watch this space…

I am discussing the article entitled: Distinguishing between Exploratory and Confirmatory Preclinical Research Will Improve Translation, by Kimmerman, Mogil, and Dirnagl, published by PLOS Biology in May 2014. DOI: 10.1371/journal.pbio.1001863

Adventures with Lidocaine and Amitriptyline

A few months ago, I wrote of my experiences with chronic pain and I mentioned I had started a regime of amtriptyline. Well, 6months and a referral to a pain clinic later and I feel I can report on how this is going and give a little bit of insight into how this drug, better known as an antidepressant, can help with chronic pain.

Amitryptyline was first introduced in the early 60s as a treatment for depression, and is now used to treat a range of disorders including insomnia, tinnitus, ADHD, migraine and… chronic pain. So how is it able to treat such a wide range of conditions? What does it do?

It is categorized as a tricyclic antidepressant and acts primarily as a serotonin-noradrenaline reuptake inhibitor, leading to an increase in the levels of these neurotransmitters. It also has effects on a whole range of receptors and ion channels including some which have been strongly implicated in pain such as TrKA, sodium/potassium channels, and nicotinic receptors, where is it thought to suppress activity in c-fibres, nerve fibres known to be involved in transmission of pain.

Of course, the doses used vary widely between conditions – from ~100mg in depression, to the 20mg dose I take for my pain. This low dose for pain means the side effects, which can be quite an issue in depression, are less severe. I’ve spoken to a few people who’ve tried it for pain before with mixed results – the most common issue has been drowsiness, which I agree with. I take it at night, initially before I went to bed, but have recently switched to a little earlier as I think it was making mornings even more difficult… given I already need 3-4 alarms to get my ass in gear normally! However, on the pain front, its effect is pretty minor for me. The drowsiness at night is actually the main benefit, as it smooths over the stabbing pains which made it difficult to get comfortable before… I’m struggling to notice any real effect during the day on the pain levels, but it has made a noticeable difference to my quality of life, which is the main thing really. If I’ve only learnt one thing in the past 5 years in pain research, it’s that complete removal of pain is a rarely achievable goal, and most patients (myself included) massively appreciate anything that makes the experience of chronic pain easier, be it problems sleeping, difficulty concentrating, or any of the myriad other ways pain can interfere with your day to day life

…so then I finally got myself an appointment at a pain clinic, saw a doctor who actually understood what I was feeling (woo!) and immediately prescribed me lidocaine patches… and it’s no exaggeration to say these wee guys are my favourite thing at the moment! Lidocaine is a local anaesthetic, and is often found in creams to help with sunburn and itching (not to mention its other, murkier, use as a cutting agent with cocaine due to its strong numbing effects). I currently have 5% patches, which I stick on my stomach every day to help with the post-operative abdominal pain, and they are brilliant! Completely removes the pain associated with light touch that has been adding a layer of frustration to my daily life for the last year or so (ID badge? Bouncing against you while walking? Shouldn’t be painful, no?), and it seems to also act on the shooting pains (which may, or may not be neuropathic). Unfortunately, I can only keep them on for 12hrs a day, and within 10minutes of removing them, the pain tends to return, but I’ve only been using them for 3weeks so you never know.

Lidocaine patches are actually only licensed for postherpetic neuralgia associated with shingles, but have increasingly been used ‘off-label’ for conditions such as endometriosis and other pelvic pain conditions such as those associated with adhesions, as I have. Worth speaking to your GP about, although mine was very reluctant (“too expensive“) and it was only once I saw a pain specialist that I was ‘allowed’ them, so there we go.

I was also given a TENS machine, which I’ve played with a bit, but I think I need to go back and get some advice on positioning of electrodes and the best settings to use as they’re not actually advised for use in the abdominal area for reasons I can well understand – some of my experiments with positioning have caused weird sensations all down my leg or in other areas which don’t quite feel right. If anyone reading this has experience with using TENS abdominally, I would really welcome some tips on settings and positioning!!

Anyway, that’s all from me for now – as always, feel free to ask any questions or leave any comments as I’d love to hear from you!

How Can Charities Discuss Animal Research: A Guide

Rosie:

Interesting comparison of the approach to publicizing animal research between American and British charities…

Originally posted on Speaking of Research:

The Association of Medical Research Charities and Understanding Animal Research in the UK have recently jointly produced a booklet aimed at helping charities discuss the animal research they carry out or fund. So what is the guide about?

This guide is designed to help medical research charities answer the questions from the public about the use of animals in research.
[...]
People may have specific questions about research using animals: how and why the research is funded; what charities are doing to find alternatives; what conditions animals are kept in; how this research is regulated; what it helps us find out. This guide suggests some ways that charities can answer these questions and where they can direct people who want to find out more.

Broadly, the guide covers three main areas. It does this by taking examples of best practice from UK medical research charities to illustrate its key points.

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Efficiently Reading Scientific Articles

In the last few years, there has been a huge upsurge in referencing source material when writing a newspaper/magazine/blog article. As a scientist myself, I think it’s a brilliant thing – giving everyone the opportunity to see the research the story is based on and judge for themselves whether it has been discussed in a non-biased way. Of course, there are still issues of free access to studies, but here I’m going to give a quick-fire summary of how to judge a paper efficiently, once you have it on your screen (or in your hands…).

When I was at uni, I was taught a number of strategies designed to help you quickly read and extract the important information – as a student, you have to read a LOT of papers… some are a nice, manageable 3-7pg in length, others can clock in at over 20pg and take hours to read and understand, so it’s good to know some shortcuts.

 

1) Go straight to the Methods

This is the single most important part of a scientific paper- if the methods don’t make sense, no amount of beautiful prose in the abstract and conclusions will change the fact that the data is not sound.

If they don’t mention inclusion/exclusion criteria, how they decided on their sample size and whether they lost any subjects along the way, how can you trust that the data they so proudly present is actually representative of the experiment they did? Without complete transparency on what DIDN’T make it into the study, how can you trust what did?

Especially if it is a clinical trial, the protocol (i.e. how they did it, their experimental plan) must be pre-registered, stopping them from changing their minds about what they are really looking for half-way through a study because the primary outcome is rubbish – calculations of how many subjects are required are based on outcome measure, so changing the outcome measure half-way through invalidates the group sizes, so you have no way of knowing if any failure to detect a response is due to there not being any effect or because there just weren’t enough individuals tested.

It also lets you use a bit of common sense – I recently read a paper which claimed to be a double blind, randomised control trial… which used blinding codes of “MG” and “CG” on pill bottles given to patients. This was a study looking at the effects of magnesium. The chemical formula of magnesium is… Mg. Admittedly not everyone might know this, but if you are told you are enrolled on a trial looking at effects of magnesium supplements, and are handed a bottled marked “MG”, it’s not that hard to figure out which group you are in, unblinding yourself, and making the study invalid. Just as an aside, if you ever see a study involving animal which claims to be “double blinded”, chuck it. Throw it away. That statement suggests the animals were unaware of which treatment they received… and shows up the authors as not understanding the concept of blinding (or masking as it is sometimes referred to).

 

2) Abstracts & Conclusion

This is a common way of reading papers, I’m sure some of you reading this do the same… but by relying on the 2 parts of the paper which are most open to interpretive bias, you don’t see the big picture. Authors want to draw readers in with a jazzy abstract that highlights what they think is important, and skims over anything considered weird, unexpected, or plain dodgy, and then in the conclusion, they want to leave the reader feeling that their work is super-exciting, super-relevant, and going to lead to innumerable life-improving breakthroughs, so by concentrating on these areas of a paper, you are basically allowing yourself to be spoonfed with exactly what the authors project as important, and that isn’t the same as actually being important and useful.

 

3) “Moneyshot”

I was taught this while studying my PhD by another supervisor – his way of reading papers was to go straight to the last figure, the “Moneyshot” as it were. This will usually be the figure with the most impact, showing off the peak of the experimental findings – if that “looks good”, then read the rest… ok? NO. Not ok. By doing this, you are again falling in line with how the authors want their work to be seen. By all means judge the graphs and presentation of data, but don’t base your entire opinion of a paper on the pretty pictures – sometimes it just won’t add up. All sorts of dirty tricks can be used to make data look more sexy than it actually is – messing about with the axes (not starting at ‘0’ starts alarms bells immediately), showing raw data on some and ‘% response’ on others (makes me very suspicious – if the effect is there, you should be able to see it without resorting to data transformations of this type), and of course, if the error bars overlap, thre probably isn’t an effect – statistically significant doesn’t always mean biologically relevent,

 

So there we are – 3 different ways I have read papers in the past… number 1 is how I currently read papers, and although it might make you a bit angry and frustrated at first, being able to critically evaluate a scientific article will improve both your understanding, and if you work in the field, your own reporting as well.

The Problem of Medication Over-use Headaches

In common with many labs, we have a weekly journal club, and last week one of my colleagues presented some fascinating work on the under-recognised problem of medication over-use headaches. I’m not going to go into the definition of migraine, rather, I will briefly consider the problems associated with the drugs used to treat it.

Why? This is something which interests me on many levels:

*The paradox of treatments designed to help a condition actually worsening symptoms can promote a drive to further understand what the drug does and how it interacts with any underlying pathology (this is the geek in me, always wanting to know WHY)
*My boyfriend suffers from migraine/cluster headaches so there is a personal incentive to better understanding of what is going on in there
*I’m currently involved in production of a feature film, the protagonist of which who suffers from aura migraine… my perfectionist nature wants to make sure our representation is accurate

So what’s it all about then? Headaches and migraine have been treated for years using classic opioids, NSAIDs such as naproxen, and combination drugs like co-codamol (Codiene + paracetamol). Then in the early 90s, the “Migraine Wonder Drug”, Sumitriptan, was first introduced, promising targeted relief for headaches caused not by muscle tension, but by the cranial nerves and the brain itself. These drugs work by imitating the neurotransmitter serotonin (5-HT) (which incidentally is also very similar structurally to DMT) at very specific receptor subtypes (5-HT1B/D) found primarily on blood vessels within the brain. Here, the molecules act to reduce inflammation of the vessels (as opposed to increased vasodilation, as is often assumed), reducing the experience of pain.

All these types of medication work best when given BEFORE the migraine hits its peak (i.e. during the premonitory or prodrome phase), and this is where the problems start.

Sometimes you might get symptoms which never manifest as a migraine… sometimes what you think is going to be a migraine turns out to be a tension headache instead. Taking triptans unnecessarily can cause a sustained increase in neurotransmitters such as CGRP, and has been shown to result in a latent sensitisation, whereby the individual becomes more sensitive to migraine triggers than before, resulting in more frequent migraines…. and thus the cycle starts and sustains itself – triptans cause a headache which can be treated with naproxen, until it too causes a headache which can only be treated with opioids, and so it goes until there are no more options left. What was originally an episodic condition (less than 15 attacks a month) can quickly escalate under these conditions, becoming chronic and intractable.

As estimated 1-2% of the European population suffer from headaches which are caused or exacerbated by medication over-use – this figure is even higher in the USA, where opioid drugs are more freely prescribed and obtained. In a condition such as migraine, one of the most common neurological disorders, and one which can cripple, it is vital we understand why this happens, and what can be done to avoid it in future treatments. It’s not reasonable to just stop prescribing medication to these patients – for many, these drugs are all that allow them to function and interact with the world – what we need is to find out why this happens, and make sure new treatments can avoid these issues…

References:
Meng et al., 2011 (Cephalalgia) Pathophysiology of medication overuse headache: insights and hypotheses from preclinical studies.
De Felice et al., 2010 (Ann. Neurol.) Triptan-induced latent sensitization: a possible basis for medication overuse headache.

Fighting Pain with Pain: The ‘joys’ of DNIC

It might sound counter-intuitive, but there are actually many treatments for pain which already rely on this phenomenon, such as cupping and even acupuncture may involve some elements.

Diffuse Noxious Inhibitory Control (DNIC) is our innate ability to modulate pain signals coming from spatially discrete areas, and broadly speaking explains why pain from one area can cancel out pain from another. A person’s capacity for this is highly variable, and some researchers are investigating whether they can use Conditioned Pain Modulation (a clinical measure of DNIC) to measure how DNIC system function is linked to individual susceptibility for developing a chronic pain condition.

I recently had some personal experience of this when I partially severed the tendon in my thumb while washing up (stealth crack in a plate – seriously, throw away any cracked crockery before it does you damage!!). As some of you who read this may know, I have been suffering from chronic post-operative pain for almost a year now, which manifests both as sudden and unpredictable shooting pains in my lower abdomen, a constant pulsing/stinging/heavy sensation which can sometimes last a few hours, and a general sensitivity to things as innocuous as my ID badge bouncing against me as I walk. Now, when I hurt my thumb, it bloody hurt. It was SERIOUSLY painful. I’ve had capscaicin (chilli pepper extract) injected into my hand (helping out a colleague by volunteering for their study – I’m not a total masochist!)… this was comparable – insanely sharp and nauseating for quite a few hours after I did it. Luckily for me, I not only work in a hospital with a world renowned hand surgery unit, but also one of my colleagues is married to a hand surgeon! It still required 8 stitches and surgery under general anaesthetic (which I was glad – would have no doubt watched them as they worked and ended up passing out or something silly…), and my mobility is pretty limited (again, luckily another colleague is a hand physio specialist so have been ‘treated’ to some one-on-one thumb-bending sessions), but then again, at least I still have a thumb, even if it does have a rather frankenstein scar wrapped around it!

In the weeks following the surgery on my hand, I hardly noticed the pain from my previous surgery… my mind was almost completely taken over by the new sensations coming from my thumb, hand, and arm. When you damage a nerve, lots of funny things happen as it works to repair itself* – most of the outer edge of my thumb is completely numb, I experience strange tingling small electric shocks whenever I moved my hand or rubbed my arm, a painful feeling of stretching inside my thumb whenever I lift my arm above my head, increased sensitivity to heat (showers OK, baths NOT OK), and particularly sensitivity to cold, with even a light breeze feeling like a biting north wind. I know these are all normal experiences when a nerve is healing, so as annoying as it is, I don’t worry about these things… especially once I noticed how they were over-riding any other pain my body may have been experiencing.

All good things must come to an end, and as the pain in my thumb subsides, the other has resurfaced with a vengeance. Swings and roundabouts, eh? Still, it was a beautiful demonstration for me, as a neuroscientist working to understand pain, of the power of the body to cope with stress and prioritise events in a hierarchical fashion (e.g. pain from recent tissue damage trumps ongoing chronic pain with no obvious/easily fixable cause). Pretty brilliant, but I don’t think it’s worth injuring myself again over!

*not all damaged nerves can repair themselves, but if the soma and some of the neurolemma (outer covering of nerve fibres) is intact, regeneration is usually possible, if slow

References:
Stability of conditioned pain modulation in patients with chronic pain: Implications for pain assessment & treatment
Yarnitsky 2010 (Curr Opin Anaesthesiol.) Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): its relevance for acute and chronic pain states.

Scientists, their pets and research…

Rosie:

Really great post!

Originally posted on unlikelyactivist:

Some presumably animal rights-leaning visitor to my blog dropped a GOTCHA! question on me this morning. This is a question she expected I would answer in a way that would poke holes in my arguments in support of humane animal research

“Well, if animal research is so important,” she says, “would you give your dogs to me so that I can use them to conduct a research project on addiction?”

This is my youngest dog, Oliver. He is, quite possibly, my favorite living being on this planet.

This is my youngest dog, Oliver. He is, quite possibly, my favorite living being on this planet.

GOTCHA, she thinks! She believes that I will either say “No, I’d never give my dogs to research”, and all my arguments that animal research is justifiable because of the benefits to human and animal welfare will fall apart. Or possibly, I’ll say “Yes”, and she’ll claim I am cruel and heartless. Either way, she wins. GOTCHA!

Here’s the thing; my answer to…

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