Sometimes we ask the wrong question of simple drugs. Like when we add clonidine to a peripheral block. A post from Andrew Weatherall touching on a recent meta-analysis on this topic. 

Most places I work, people agree that volatile agents get people to sleep. They pretty much look on things ending in “-ronium” or “-curium” as substances that produce a non-depolarising motor blockade (though I’ve met a few people who think some of those “-curiums” are a bit watery to be useful). They all agree that heparin isn’t generally what we use to stop bleeding. We’re all on the same straight and narrow road.

When it comes to clonidine and peripheral nerve blocks though, the terrain becomes bumpy. Through my early training I’d mostly been encouraged to add clonidine to peripheral blocks because they “made them better”. This was mostly to do with prolonging the block but also this vague idea of “making it better”.

More recently I’ve met plenty of people who aren’t really that keen. There’s a bit more “meh” about the option.

So why the lack of belief from some? Why the “bah, humbug”?

All the Objections

I actually find the most interesting part of this discussion isn’t even about the drugs or the techniques. It’s interesting because there are a bunch of insights into the way people interpret the literature demonstrated both by those who think it’s worth it and those who don’t.

So here are the things I used to hear from those who were dubious:

1. It makes no sense, there’s no peripheral nerve α2 receptors for them

This one used to come up lots. The argument would go along the lines of “in an epidural or caudal, I get it. There are receptors. Those just aren’t there on peripheral nerves.” Hmmm … good point. Anaesthetists should never use any agent where they are still trying to understand exactly how it works. That would be absurd, like … using general anaesthetic agents I guess. Wait, that’s awkward.

There is a mechanism though. There is a particular current related to cation movement, the hyperpolarisation-activated cation current (Ih current) that plenty of people don’t know much about. It’s important in getting the hyperpolarised nerve back to its resting state ready to fire. Handily this mechanism seems to be particularly prominent in pain fibres. Clonidine blocks this current. So the nerve stays hyperpolarised and stays unresponsive to further stimulus.

So a potential mechanism is something we have.

2. It doesn’t make the block better

This one used to come up all the time. “You add clonidine but it doesn’t improve the block there are papers showing that.” Then they’ll point at papers like this one by Trifa et al. where the headline is that adding clonidine to axillary brachial plexus blocks doesn’t improve block quality.

This is where a bit of imprecision in the description doesn’t help. Take this paper as an example. They are defining the failure of quality as a failure of making the pain scores better. A working block should have quality that can’t really be improved on immediately afterwards, shouldn’t it? The only likely thing is that you could make that good quality last longer.

And all too often the details of these small studies aren’t helpful. Sticking with this study the technique for the block itself is a bit unique. Use a nerve stimulator, find any twitch (median, ulnar or radial) and put 75% of the solution there, then put the rest at the musculocutaneous. Both the groups in the clonidine and no clonidine groups had an average pain score of 4 in the hour after the operation.

So clonidine didn’t rescue a not particularly spectacular block technique. Bad clonidine. It’s pretty unreasonable to say clonidine doesn’t improve the block when the technique itself isn’t that great and you’re expecting it to do something it’s not designed to do.

(Incidentally it looked a lot like the first additional analgesic request was a couple of hours longer but they didn’t have enough subjects to be sure – just a trend.)

3. You get some action if you give it peripherally

This is an interesting point. Some of the effects of clonidine might be from absorption into the circulation and action elsewhere. Of course we accept that when we give opioids in the epidural space some might be absorbed via the vascular system. Yet it would invalidate clonidine as an option? Seems a bit unfair.

4. There’s mixed evidence in kids

This is an entirely fair criticism. There are some structured reviews and meta-analyses in adults that are enough to convince you that there is some benefit to using clonidine. In kids though there have been studies that are just that bit too small, or that don’t really show benefit and that kind of makes it hard to be convinced by those that are positive.

So there’s still enough out there for some to interpret it as a great addition and an entirely reasonable argument that there isn’t enough there to make it worthwhile.

So maybe we could do with some sort of bigger analysis. A meta-analysis.

The Gathering

Well a bunch of committed types have done exactly that. They did a literature search and found five randomised controlled trials, gathered the raw data and put the patients in groups with local anaesthetic alone vs local anaesthetic plus clonidine or dexmedetomidine. They made their focus block duration. Finally.

They end up with 141 patients in the LA alone group and 142 in the adjunct group. They suggest the time period until first supplementation was 2.6 times longer and fewer patient needed supplemental analgesics in the adjunct group. They also didn’t find evidence of significant side-effects.

Which is great. Except of course they only had five studies, the studies used different pain scores and they had to include different types of blocks to get those numbers.

What can we make of that then? Well each little bit of extra evidence adds to a picture of clonidine as a reasonable adjunct to lengthen peripheral nerve blocks. If you value duration of your block, I’d argue it’s worth including.

And we can make an even more definitive argument for the need for a lot more research. After all that time, this crew found 283 patients to talk about.

That’s a pretty quiet chat.

 

Notes: 

We remain very interested in people’s clever thoughts so comment away if you feel moved. You can also follow so you’ll know when a post pops up.

Here’s some things for more reading, which we always encourage. First up the meta-analysis:

Lundblad M, Trifa M, Kaabachi O, et al. Alpha-2 adrenoceptor agonists as adjuncts to peripheral nerve blocks in children: a meta-analysis. Pediatr Anesth. 2016;26:232-8.

Then that axillary brachial plexus block paper:

Trifa M, Khalifa SB, Jendoubi A, et al. Clonidine does not improve quality of ropivacaine axillary brachial plexus block in children. Pediatr Anesth. 2012;22:425-9.

Here’s an editorial in the same issue which goes over that mechanism stuff in more detail:

Lönnqvist P-A. Alpha-2 adrenoceptor agonists as adjuncts to Peripheral Nerve Blocks in Children – is there a mechanism of action and should we use them? Pediatr Anesth. 2012; 22:421-4.

And here’s one of the earlier papers that really pushed it all along:

Cucchiaro G, Ganesh A. The Effects of Clonidine on Postoperative Analgesia After Peripheral Nerve Blockade in Children. Anesth Analg. 2007;104:532-7.

That photo of the ring-tailed lemur was from the Creative Commons part of Flickr and was posted just like this by Christian Ramiro González Verón.