I rarely discuss animal research in this blog, but occasionally something striking stimulates a new post.
I have discussed sucrose not that long ago, in particular I emphasized the over-interpretation of a secondary analysis of a non-randomized comparison of very early follow up data from an RCT of the use of sucrose as an analgesic. I will quote myself as I think I am worth quoting:
I am taking this long excursion into the results of an older study because it has been quoted many times as perhaps showing an adverse effect of sucrose on what is often referred to as “neurodevelopmental outcome”. So lets be completely clear, on secondary analysis of a small RCT, data from 2/3 of the preterm babies enrolled showed a statistically significant correlation between the number of sucrose doses given and one item of the 7 items of the NAPI at 40 weeks PMA.
I emphasize that the randomized comparison in that trial showed no difference on any of those items.
Sucrose is an effective analgesic, with no known toxicities. Long term outcome effects are “uncertain” according to the latest Cochrane review. It is difficult to believe that recurrent use of tiny quantities of sucrose would be harmful in the long term, but I guess we need to be cautious with preterm babies.
We can be a lot less cautious with rats.
In this study rats were divided at birth to receive either chronic pain, with a needle stuck into a foot paw 4 times a day for 8 weeks (sounds like being in the NICU), or they got sucrose 4 times a day, or they got the foot pricks but they were preceded by sucrose, or they got a dose of paracetamol then the foot pricks (there was also a non-foot prick no analgesia control group). The sucrose was given on the rats’ tongues so they experienced the sweetness, just like our babies.
The rats that got the foot pricks without analgesia had impaired short term memory when they were tested as adults. Sucrose prevented the decline associated with repeated pain.
Sucrose had no effect on its own, without the pain. The sucrose groups had higher endorphins in the blood. The authors also dissected out the hippocampus on the rats and measured some neurotrophic factors including brain-derived neurotrophic factor BDNF.
…results of the current study showed a significant decrease in BDNF levels in the hippocampus of chronic pain exposed animals. Sucrose treatment, on the other hand, normalized this decline in BDNF levels.
Which gives some idea of possible mechanisms, the endorphin link has been seen before, I believe, but I am new to the BDNF stuff, it sounds like this is a novel finding, but it seems to link up with other research that the authors quote. It certainly looks like BDNF is important for developing learning and memory formation.
There has never been any evidence that sucrose adversely effects human long term outcomes, on the other hand there is substantial evidence that pain does. Although this is a rat study, it does suggest that there is a chance that effective analgesia, using sucrose, will decrease those adverse effects. Even with 4 doses a day for 8 weeks.
Thanks for the information about the link between sucrose and endorphin. It is important to realize that pain has different effects on a developing brain. Were these rats newborns?
The biggest modulating effect of sucrose is still on the behavioural aspects- in the newly borns, it probably suppresses the CVS and Respiratory response mostly by its effect on the brain stem. What about its function on the cortical and subcortical areas, where chronic & recurrent pain has shown to produce adverse effects?
Thank you for bringing to research to the public and explaining it very nicely. As the PI, I would like people to know about studies like these because unfortunately hospitals and clinics do not employ this simple and non-pharmacological method to relief pain in neonates and young children.
To answer Arun Nair MD FRACP FRCPCH, yes these were neonatal rats. Treatment started post-natal day one. This research shows that neuro-chemical do change in the hippocampus as evident in the changes in BDNF, ENK, beta-END.
Dr. Barrington, since you wrote this there is what looks to me like an important new paper on sucrose: Tremblay et al: Repeated exposure to sucrose for procedural pain in mouse pups leads to long-term widespread brain alterations. Pain 158(2017 ) 1586-1598. It’s written by good people in a good journal, and to a non-scientist like me it looks worrying. I am a neonatal nurse and a passionate believer in sucrose. I’d love to know what you think of this paper.
It is certainly very interesting, the first author was one of the fellows in our program, is now a neonatologist here, but did this during a post-doc in Vancouver. The relevance of any animal model is always an issue. although the scurose doses were similar per kg body weight, to preterm babies, they are very different per g of brain tissue as mice have much tinier brains, which grow and reach full development over a much shorter time interval. So 10 doses per day, over a period which is equivalent to many months of brain development in a human might not be comparable.
The other problem of course is that we give sucrose to babies having painful procedures, so higher sucrose intake in babies relates to more pain. In this study I don’t fully undestand the analysis, so I can’t tell if the adverse effects are mostly seen in the no pain groups, or if the pain group (with and without sucrose) was different to the non-pain groups. I am trying to re-read the methods and results, and might write a comment, fortunately I can also ask Dr Sophie Tremblay directly!
Another issue is that the study was not randomized or blinded. This is a common problem in animal research, I don’t think that animal researchers are any less biased than clinical researchers. I performed most of my animal studies radnomized, and often blinded, I am sure it makes just as much of a difference in animal research (or other basic science research) as in clinical research!
Thank you so much! I find the effects of sucrose to be fairly dramatic – the baby cries much less as soon as you give the dose. People say that sucrose is more sedative than analgesic, but something that stops a baby crying must surely be doing something or other to its brain, and surely that’s beneficial in some way, even if it isn’t totally neuroprotective etc etc. I was delighted to read Dr. Nuseir’s paper. But see, I want sucrose to work – I’m biased in favour of sucrose!
There is another paper, accepted for publication in Pain but I got it ahead of print: Schneider, Duerden et al: Procedural pain and oral glucose in preterm neonates: brain development and sex specific effects. DOI:10.1097/j.pain. This seems to be uncomplimentary about sucrose too, but I haven’t read it properly yet.
I’m really grateful for your reply.
I am glad that people in the clinical world are paying attention to these types of research. True animal research is not free from bias, but perhaps more controlled, as we can control many parameters as well as the environment. What drew me to neonatal pain engagement was the recognition of the amount of pain and suffering these helpless humans endure, we need to lobby on their behalf. How pain affects the brain is still an ongoing research and weather it is beneficial or detrimental or probably a mix of both remains to be determined. Meanwhile it is my hope that doctors and nurses as well as all those involved in neonatal health pay attention and continue to try to find ways to decrease or even eliminate neonatal pain.