Category: pain

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

 

 

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!

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.

What to do when you become a subject of your own research

They say many psychiatrists choose their profession because they themselves suffer from mental illness. When I started my PhD, studying pain, I never expected to succumb to chronic pain, but things certainly seem to be going that way, so I figure it might be useful to share my insight as both a researcher, and now a sufferer of chronic pain.

My story starts in 2008, when I was diagnosed with ovarian dermoid cysts. In the years since then, I’ve undergone two further surgeries, which have left me in constant abdominal pain which varies in intensity, location, and in the way it feels. I experience two main types: a constant dull ache, similar to period pains, and intense shooting pains, which happen whenever the hell it wants – sitting, standing, walking, lying down – and generally this is most problematic. It’s often briefly excruciating, usually nothing more than annoying and distracting, but there haven’t been a day in over a year that I haven’t experienced pain that has made me catch my breath. It’s exhausting, and I’d be lying if I said it hadn’t affected my lifestyle over the last year in particular.

Despite this, I was very resistant to admitting the possibility that the pain I was experiencing was anything out of the ordinary.  Partly, I suppose, because none of the doctors I have seen suggested it could be the case. I have tried most traditional pain medications with no effect (co-codamol, paracetamol, even tramadol), and ignored the fact that any pain persisting longer than 3months is in the running for the title of “Chronic”. Part of this reluctance was fear, but not of the unknown – I knew too much. Having spent the best part of 5 years focusing my studies on the problems of diagnosing and treating chronic/neuropathic pain conditions, I know only too well how difficult it is to successfully treat pain. It’s a minefield of misdiagnosis and I’ve read more accounts than I care to remember of patients shunted from specialist to specialist with very little improvement or even reassurance. I remember one soundbite I heard in my first year of studies that 30% of the population will experience chronic and particularly neuropathic pain, of which only 30% will experience acceptable pain relief…. so you can understand why I was burying my head in the sand! My main solutions to date have been breathing, swearing,  and stopping whatever I am doing until the pain subsides. When I’m at home I take a bath and hug a hot water bottle. It helps a bit, even if as something to do.

“Neuropathic pain” was the thing that scared me the most – this is pain which is not caused my tissue damage, but by the nervous system itself. It occurs when nerves are damaged, either by ‘foreign bodies’ (drug and viral), or by physical trauma, such as surgery. This damage alters nerve sensitivity, lowering and/or raising thresholds so that what used to be a nice shower temperature becomes way way WAY too hot, a cool breeze switches from refreshing to agonising, and even the touch of clothing against the skin is unbearable. Luckily for me, my experience seems more due to spontaneous activity, which results in shooting pains and other unusual sensations. I like to think of the way nerves function in neuropathies as similar to a faulty fire alarm – over-reacting to steam, failing to detect a fire, and then just going off for no reason whatsoever. Unfortunately, this type of pain has no simple fix, no batteries to change, no refund and replace.

Researchers are still trying to pinpoint exactly what makes one person develop neuropathic pain, and another be totally fine, given the same injury. Part of the reason for this is that pain is a learning tool – it is how our body learns to protect itself from damage, and is shaped by our experiences and attitudes, making every painful moment unique to the individual. Treatment can be complex to say the least.

Of course, it turns out that the last surgery I had (abdominal hernia repair) is one of the top three known to be associated with post-operative pain issues (the other two: mastectomy and thoracotomy)… so if I hadn’t been so busy hoping it’d go away, I probably could have been seen much earlier! Additionally, having underwent three abdominal surgeries, my insides are now riddled with adhesions – these are points where scar tissue has formed along lines of incision, sticking to anything they come into contact with. I have been aware of my own adhesions for a while – for some time they were not painful, just strangely uncomfortable, a feeling of stretching and tension inside me when I moved in certain ways, although since the last surgery I have definitely been more aware of their presence – in the abdomen, they often end up affecting the bowels, and I can definitely confirm that! Eating and needing the bathroom have been noticeably more uncomfortable… further lessons in why taking advice from an ostrich is a bad idea…

So what are my options? Keep on plugging away with co-codamol which does nothing??? Try something else? The last 10 years have seen the addition of drugs established in other areas, such as gabapentin for epilepsy and duloxetine for major depressive disorder to the analgesic arsenal. These tend to be given at much lower doses in pain conditions, and work by altering neurotransmitter levels. Other approaches include TENS, acupuncture, talking therapy, and cognitive behavioural therapy, each having their benefits and drawbacks. My personal opinion is that drugs alone are not enough – the emotional side of pain is not to be underestimated… it’s draining and miserable, but it doesn’t have to be inevitable. How we feel psychologically has such a huge effect on our physical well-being – stress releases hormones which can have a knock-on effect on pain, especially visceral pain, as anyone who suffers from irritable bowel syndrome would confirm, and our attitude and lifestyle can change the course of the disease. Furthermore, there are bidirectional associations between anxiety/depression and chronic pain, and both conditions involve many of the same parts of the brain (e.g. the amygdala), which explains why antidepressants have been used so successfully to treat chronic pain.

So this week, after chatting with some colleagues (if nothing else, my experiences have taught me to make the most of those around me), and reinvigorated with a “New Year Fresh Start Let’s Sort Stuff Out!” vibe, I went to my GP and straight out asked to be put on medication for neuropathic pain. After consulting another doctor, they agreed, and this week I will be starting on amytriptyline, another antidepressant used to treat pain. I’m bizarrely excited – the prospect of being able to go about my daily life undisturbed by pain makes me pretty hopeful. I will also start seeing someone for some talking therapy – I know myself the detrimental effect pain has on my mood, and it’d be foolish to ignore that side of things, pinning all my hopes on pharmaceuticals. These efforts might not fix me completely, and I know that, but I hope they will at least give me the tools to cope better.

I’m only too aware that my experience is very definitely at the small end of the scale when it comes to pain – I can basically function, just not in comfort most of the time – but I have been reminded that the impact of any pain condition is a result of BOTH duration AND intensity. I think most people would prefer a short sharp shock to constant dull pain, and there are studies showing that knowing pain is not going to last forever increases our tolerance as the associated anxiety is much lower.

Anyway, wish me luck, and I’ll be back in a month or so with an update on how this new approach is working…

p.s. if anyone would like references for all the above, or has any questions or points they’d like me to expand on, holla and I’ll write some more!

Gingko Biloba and Neuropathic Pain

It’s strange the way news tends to circulate, and seem to happen particularly frequently with scientific news stories.

In running the London Pain Consortium twitter feed, I keep an eye on people using the phrase “neuropathic pain” – this morning there were no fewer than a dozen tweets, all extolling the virtues of the chinese traditional medicine and health supplement, ginkgo biloba, so I had to take a closer look.

Firstly, the original article they all cite is from 2009… that’s 5 years ago guys… why bring it up again now? A quick pubmed search shows only 4 articles looking at ginkgo biloba in neuropathic pain… and none of them are clinical studies. So why the hype? Is it just hype?

So lets look at what evidence there is:

The first study looks at a model of spinal nerve ligation in rats. This is known to decrease the thresholds for detection of mechanical (i.e. touch) and thermal (i.e. cold/hot) stimuli, corresponding with increased sensitivity experienced by many neuropathic pain patients, so in theory, ginkgo should return these thresholds back up to normal levels, which a quick look at the graphs seems to confirm. However, there are some methodological issues – they only looked at rats with nerve damage, neglecting to check if gingko has an effect in healthy animals… it could very well be reducing sensation. Also, the effects are relatively short lived (2hrs on average at the highest dose), and there was a small effect at the highest dose on activity (as measured by rotorod activity), so perhaps gingko has some motor or psychotropic effects? To their credit, they did take precautions to avoid some degree of bias (blinding experimenters – obviously not literally… just ensuring they were unaware of what treatment the animal had), and mentioned exclusions, but made no reference to how many animals failed to develop neuropathic symptoms (a bugbear of mine – all animals should be included – non-responders are just as interesting, if not moreso, as those which behave as expected) and were therefore excluded, and no sample size calculations were conducted (useful to indicate whether the group sizes are large enough to detect any effect reliably).

The same group also looked at whether ginkgo is effective in a model of chemotherapy-induced neuropathic pain (i.e. vincristine), and found a very similar profile (obviously using the same tests, and making the same methodological errors as above), which is interesting, but still not making me rush out and invest in supplements.

A third study, from a different group and published only 2 years ago, looked at the effects in a model of diabetes-induced neuropathy, and is nice because it actually looks at the effects over the course of a few weeks, not just a few hours as the previous studies. They also thought a little bit more about mechanisms, and looked at levels of nitrous oxide (known to be involved in inflammation) and also at antioxidant enzyme activity. However, they also looked at both males and females mixed together, which could increase variability, and again didn’t give enough details about the animals included in the study to satisfy a strict follower of the ARRIVE guidelines such as myself! Anyway, they found much the same as the studies above, with the added bonus of showing antioxidant effects, which gives an indication of how it could be working. Which is interesting.

Sooo… 3 studies (the 4th was a rather vague review of medicinal herbs in neuropathic pain)… all showing gingko is effective in restoring normal levels of sensitivity to mechanical and cold stimuli, in rats. I don’t think that’s enough to justify being reposted all over the internets…

When reading studies like these which claim to study pain in animals, it is vital to realise most of the time, they are only looking at the sensory side – pain is so much more than a pointy stick: it is also the surprise at being poked, the anxiety over why someone jabbed you with said pointy stick, and the worry about whether it might happen again. Pain, as we know it, is generated in the brain, and is a complex amalgamation of the signals our nerves bring us about what is happening physically, and our past experiences in similar situations, our current emotional state, our environment, and countless other factors which come together to produce an experience unique to the individual. My main issue with studies like those above, is that they arguably ignore the more crucial measure of pain, which is not how much nociception they can endure, but how those sensations impacts on overall emotional and physical comfort.

What would I like to see before people get too excited is more work looking at long term effects, and effects on emotional and cognitive outcomes… perhaps some observational clinical studies looking at those who already take supplements (although most supplements have levels far lower than those used in the studies – 6000mg sounds impressive but then you notice the small print telling you the active ingredients are present at less than 25mg, below the 100mg active dose from these studies).