Analgesia for Animals: My Lottery Theory of Multimodal Pain Treatment

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My Lottery Theory of Multimodal Animal Pain Management:

Good lab animal welfare requires effective treatment of any pain scientists cause. It is way too easy to pick a drug from the list, pick a dose, and never really know if the drugs is actually helping the animal feel better. One variation on this is to use three drugs, or multimodal analgesia treatment — going Beyond Buprenorphine (the most common single-agent treatment) to maximize pain relief

It’s been years now that I’ve been advocating combining different classes of pain medicines to treat research animal pain. I haven’t always prevailed; most notably, I consistently failed to get the vets or the animal committee on my recent job to enforce this standard on one particularly resistant monkey-user scientist.

I think a lot about evidence-based ethical treatment of animals when the evidence just isn’t there. When it comes to fine-tuning pain treatments for animals, our evidence is so very sparse. Whether it’s monkeys, mice, fish or others, how do we evaluate the level of pain they’re experiencing? How do we evaluate if pain medicines truly make them feel better? How then can we know if combining analgesics is even better (or worse) than using single drugs? What about side-effects of pain drugs? What about how either drugs or untreated pain might affect the experiments the animals are on?

We totally lack the most important info for even our most common drugs, and that is, what if our animal patients could self-medicate or somehow tell us they need another dose, or a stronger dose, of their pain meds?

Frankly, we don’t have the info we need to pronounce on the best pain management — other than the obvious, which is to first, cause no pain. And so IACUCs end up making an ethical decision, in what I call the ethics-of-uncertainty. Do they err on the side of caution, and require more aggressive pain treatment than some scientists want to provide? Or do they privilege concerns about how drugs will affect research data?

With my recommended 3-drug multimodal regimen, we combine an opioid (usually buprenorphine; an MD would rely more on morphine or codeine) with a Non-steroidal anti-inflammatory NSAID (for animals, we use carprofen or meloxicam; an MD might rely on ibuprofen) and also, a local “block” at the surgical incision (bupivacaine or lidocaine; your dentist uses a lot of lidocaine). Our doses for these drugs are not wild guesses, but neither are they very solid science either. We don’t know exactly how much to use, we don’t know when to re-dose, we don’t give mice or monkeys their own medicine chests, and we don’t have the best skills at round-the-clock pain evaluations.

Hence, the Lottery Theory: use all three and hope you’re getting at least one of them mostly right. While I’m watching the science develop and hoping we’ll get good answers on just what pain management, my short term approach is that we should buy three tickets in the analgesics lottery, and hope at least one of them is a winner. And yes, let’s scale back on doing painful things to animals in the first place

A new mouse painkiller in your medicine chest

This is what vets in animal laboratories need: a painkiller for mice (and other creatures) that is

— Fully effective for all strains, ages and sexes

— Completely safe with no unpleasant side effects for the mouse

— Will not interfere with the experiments – for neurobiologists, no drowsiness, disruption of Learning or other effects on brain and nerve function; for cancer biologists, no effects on immune function; for immunologists, no effects on inflammation or immunity.

— Long-acting, since you might get a monkey user to come in at night to re-dose the painkillers, but you will not get many mouse and rat users to do that

We do not have that, and so the search goes on.

Years ago, I did this wrong (I’ve written about that here): Meloxicam was a hot new dog-cat non-steroidal anti-inflammatory drug (NSAID), that might have advantages over Carprofen that we were current using, if only because the oral version is really tasty. Mouse doses of carprofen are about the same as for dogs and cats, so I started prescribing Meloxicam for mice at the same dose (around 0.2 to 0.3 mg/kg) that I’d use for dogs or cats. Two years and many under-treated mice later, the good vets in Newcastle did actual studies, and my mouse dose was about 3% of what would have actually helped those deserving animals.

And as we look for the magic long-acting safe effective non-interfering NSAID, we’re also hoping for an opioid that fits that bill.  Opioids are drugs like morphine, fentanyl, codeine and hydrocodone that work on different pathways than NSAIDs, and have less effect on the immune system. The best we’ve had to date is Sustained-Release Buprenorphine (SR-Bup). It’s not perfect and still in need of many more studies to best establish the right doses and dosing frequency, but it is now well-established in many laboratories. Scientists should resist quick changes in the pain medicines they use, as there can be subtle differences in experimental outcomes when they change things around.

SR-Bup has a big problem limiting its use, a regulatory rather than a biological problem. It’s classified as a compounded drug, not as an FDA-labeled medicine, which requires a vet’s prescription. By contrast, FDA-labeled drugs can be purchased by research facilities without relying on an individual vet’s narcotics license. For some vets, that’s a personal legal risk they don’t want to take, and I can see their point.

Enter Simbadol, a newer long-acting version of buprenorphine FDA-labeled for cats. It doesn’t require a vet’s narcotics license (though it is still an off-label use to use it for mice; not many drug companies are investing in the FDA labeling process to make mouse drugs).  NOTE: I have no financial stake in either version of buprenorphine, though I did publish a paper on SR-Bup’s use in mice.    

So, let’s all jump to Simbadol for our mice, shall we? I say, not so fast. Responsible veterinary care means evidence-based pain management. What we know so far is that it seems to work for cats, at a dose and dosing frequency determined in lab and in feline clinical trials. Will it work in mice, help them feel better and not worse (i.e., effective with minimal side effects)? How long can it last before it needs re-dosing? Will it change experimental outcomes compared to whatever painkillers the lab is currently using?

Well, we don’t know. I find two articles on-line (here and here), both very small studies, not independently replicated, and in rats, not mice. Neither found compelling evidence of effective pain management, and then, for only about an hour, not the 48 – 72 hour efficacy we are hoping to see. It’s possible that the assay they used (time until the rats move their foot from an obnoxiously hot light shone on the sole) is not the best approximation of surgical pain, so it’s possible the drug performs better in clinical use than in the lab. Possible, but we do not know. We know that very few drugs use the same amount and frequency in mice and cats, given their vastly different metabolic rates and possible differences in opioid processing.  

BOTTOM LINE #1: it would be poor practice to jump on Simbadol for treating mouse post-surgical pain at this point, without a lot more studies showing that it works, and for a long enough period of time

And BOTTOM LINE #2: we still need to know more about the other Buprenorphine formulation, especially as a sole agent without concurrent NSAID analgesics, and choice of painkillers is therefore much less important than finding non-surgical ways of conducting an experiment.