Sucrose: Analgesic or placebo?

It is time for a (potentially unpopular) rant. Over the last few months, the topic of using sucrose for pain control in neonates has come up a number of times. It has been called the standard of care. It has been stated that it is unethical to run any more trials with a non-treatment arm, because we know that sucrose works.

I have a problem with that.

The idea of using sucrose to control pain has always sort of bothered me. We would never offer sucrose to an adult in pain, but in infants it is apparently a wonder drug. That seems weird. It requires us to believe that infants are fundamentally different; to really believe that children are not just small adults.

It is a minor issue, but one that has been stuck in my mind since medical school. If you were bringing a new analgesic to market, you would have to test its efficacy in a placebo controlled trial. In other words, you would test it against sugar. Sugar pills are synonymous with the placebo effect. However, as long as you are young enough to be incapable of speaking up, placebo somehow becomes treatment.

I have been unable to find a single study indicating that sucrose decreases pain in adults. I don’t know any adults whose response to pain is to grab some sugar. In patients who can communicate, sucrose does not control pain. That should probably tell us something.

If sucrose doesn’t control pain, why are there so many studies in infants that seem to conclude the opposite? (Harrison 2017; Gray 2015; Stevens 2013) I think the problem is the ‘gold standard’ being used in those studies. Neonates cannot report pain levels, so we have to rely on surrogate markers. We assess the appearance of their face or their behaviour. We ask their parents if they thought the analgesic worked. However, none of those surrogate markers tells us anything about the neonate’s actual pain.

I can always make a patient look pain free. A large dose of rocuronium will give anyone the appearance of being pain free. However, if that was my go to strategy for pain management in the emergency department, someone would rightfully have contacted the authorities. Propofol is also incredibly effective any making patients appear pain free, but we all agree that an additional analgesic is essential as part of our sedation packages.

So infants may look more comfortable after sucrose, but are they really experiencing less pain?. In two RCTs of sucrose versus placebo, Slater used electroencephalogram (EEG) to monitor brain and spinal cord nociceptive pathway activity after a painful procedure. Although the standard pain scores (based on the infant’s’ outward appearance) were decreased by sucrose, there was no difference in the neuronal activity in the nociceptive pathways. (Slater 2010; Slater 2010) The premature infant pain profile (PIPP) is one of the common pain scales used in these studies and it has been directly compared to infrared spectroscopy of the brain. Although the overall correlation isn’t bad, a significant minority of infants (10 of 33) had cortical responses to pain without a change in the PIPP. (Slater 2008) Although these are small, imperfect studies, (and all come from the same researcher), they illustrate that an infant’s outward appearance may not correlate well with pain responses in the brain.

Now EEG is clearly a disease oriented, surrogate outcome. If a patient told me she was in pain, but the EEG didn’t reveal any pain, I would trust the patient. I would much rather see a patient describe a decrease in pain than see a changing pattern on an EEG. Unfortunately, in neonates we only have surrogate outcomes. They cannot tell us about their pain. We use facial patterns and crying to make inferences about pain. In that context, I am not sure that EEG data can be so easily discounted.

Neonates can’t tell us about their pain, but young children can. The Cochrane review of sucrose in children aged 1 to 16 years found 8 trials with 808 participants. Sucrose did not reduce pain scores in toddlers or school aged children. (Harrison 2015) It strikes me as odd that sucrose stops working as soon as children are old enough to tell us that it isn’t working.

Pain is a subjective experience, and trying to assess it objectively is fraught with difficulties. In emergency medicine, we have come to a pretty wide agreement that clinicians cannot accurately judge pain in adult patients. (Mäntyselkä 2001; Guru 2000; Miner 2006; Ruben 2015; Schäfer 2016) Vital signs and patient appearance do not reflect the patient’s reported pain levels. (Marco 2006; Lord 2011) We know these techniques don’t work in adults, but we use them in infants because they are all we have.

I will admit, this is not a simple topic. There is an important distinction to be made between pain and distress. Pain is much less important that the distress it causes for the patient. Patient satisfaction has little to do with specific decreases in pain scores. (Ducharme 1995; Ward 1996; Kelly 2000) I have seen many patients who describe 6/10 pain who decline analgesics in the emergency department. They are not distressed, and I don’t argue with them. I have also seen patients with 3/10 pain asking for help. They are distressed and I do my best to help them.

Unfortunately, this distinction doesn’t help us manage the neonate. The neonate can neither report pain nor distress. We can’t ask the neonate, “would you like some more pain medication?” The neonate is at our mercy, and I think that places an increased ethical imperative on us as health care professionals.

The fact that infants cannot communicate makes them an especially vulnerable population. They can’t ask for analgesia for themselves, so we have to be much more diligent about their pain. We need to take pain control seriously. The desire to treat an infant’s pain is exactly why so many providers use sucrose. I think we should be doing the opposite. Our youngest patients cannot confront us. They cannot tell us “stop, that hurts”. Therefore, I think we have a responsibility to ensure the analgesics we use actually decrease pain. Placebo is not adequate.

So I will agree with the comment that prompted me to finally write this piece: I think it is unethical to run any more trials of sucrose for pain. I think it is unethical to treat children with placebo.

Could sucrose be an analgesic? It is possible. The science here is too weak to be sure either way. However, considering infants’ vulnerable position, I think it is essential to prove that sucrose has analgesic properties in verbal populations before exposing those who can’t communicate. Show me an RCT of sucrose reducing pain in an adult, and I will happily use in infants.

I don’t want to be misunderstood here: I am not arguing for less analgesia in infants. I think it is extremely important to treat pain. What I am arguing against is using a substance that doesn’t provide pain relief for anyone who is actually capable of reporting a pain scale.

We have better options that should be used. We have topical anesthetics, intranasal fentanyl, and all the real analgesics we use in adults. I have seen far too many infants put through an LP without lidocaine or any analgesic, because the focus was shoving a sucrose covered pacifier in their mouth to stop the crying. We wouldn’t do that with an adult; I am not sure why we allow it in infants.

I think it is fair to use sucrose in any condition that you would be willing to treat with placebo in an adult. If after controlling an adult’s pain, you offered him a candy, I am sure he would be happy. However, if you are going to do a lumbar puncture on me, please use lidocaine; don’t just shove a pacifier in my mouth and pretend like that the sugar is controlling my pain.

References

Ducharme J, Barber C. A prospective blinded study on emergency pain assessment and therapy. The Journal of emergency medicine. 1995; 13(4):571-5. [pubmed]

Fosnocht DE, Swanson ER, Bossart P. Patient expectations for pain medication delivery. The American journal of emergency medicine. 2001; 19(5):399-402. [pubmed]

Gray L, Garza E, Zageris D, Heilman KJ, Porges SW. Sucrose and warmth for analgesia in healthy newborns: an RCT. Pediatrics. 2015; 135(3):e607-14. [pubmed]

Guru V, Dubinsky I. The patient vs. caregiver perception of acute pain in the emergency department. The Journal of emergency medicine. 2000; 18(1):7-12. [pubmed]

Harrison D, Yamada J, Adams-Webber T, Ohlsson A, Beyene J, Stevens B. Sweet tasting solutions for reduction of needle-related procedural pain in children aged one to 16 years. The Cochrane database of systematic reviews. 2015; [pubmed]

Harrison D, Larocque C, Bueno M. Sweet Solutions to Reduce Procedural Pain in Neonates: A Meta-analysis. Pediatrics. 2017; 139(1):. [pubmed]

Kelly AM. Patient satisfaction with pain management does not correlate with initial or discharge VAS pain score, verbal pain rating at discharge, or change in VAS score in the Emergency Department. The Journal of emergency medicine. 2000; 19(2):113-6. [pubmed]

Lago P, Garetti E, Pirelli A. Sucrose for procedural pain control in infants: should we change our practice? Acta paediatrica (Oslo, Norway : 1992). 2014; 103(2):e88-90. [pubmed]

Lord B, Woollard M. The reliability of vital signs in estimating pain severity among adult patients treated by paramedics. Emergency medicine journal : EMJ. 2011; 28(2):147-50. [pubmed]

Mäntyselkä P, Kumpusalo E, Ahonen R, Takala J. Patients’ versus general practitioners’ assessments of pain intensity in primary care patients with non-cancer pain. The British journal of general practice : the journal of the Royal College of General Practitioners. 2001; 51(473):995-7. [pubmed]

Marco CA, Plewa MC, Buderer N, Hymel G, Cooper J. Self-reported pain scores in the emergency department: lack of association with vital signs. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 2006; 13(9):974-9. [pubmed]

Miner J, Biros MH, Trainor A, Hubbard D, Beltram M. Patient and physician perceptions as risk factors for oligoanalgesia: a prospective observational study of the relief of pain in the emergency department. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 2006; 13(2):140-6. [pubmed]

Ruben MA, van Osch M, Blanch-Hartigan D. Healthcare providers’ accuracy in assessing patients’ pain: A systematic review. Patient education and counseling. 2015; 98(10):1197-206. [pubmed]

Schäfer G, Prkachin KM, Kaseweter KA, Williams AC. Health care providers’ judgments in chronic pain: the influence of gender and trustworthiness. Pain. 2016; 157(8):1618-25. [pubmed]

Slater R, Cantarella A, Franck L, Meek J, Fitzgerald M. How well do clinical pain assessment tools reflect pain in infants? PLoS medicine. 2008; 5(6):e129. [pubmed]

Slater R, Cornelissen L, Fabrizi L. Oral sucrose as an analgesic drug for procedural pain in newborn infants: a randomised controlled trial. Lancet (London, England). 2010; 376(9748):1225-32. [pubmed]

Slater R, Worley A, Fabrizi L. Evoked potentials generated by noxious stimulation in the human infant brain. European journal of pain (London, England). 2010; 14(3):321-6. [pubmed]

Stevens B, Yamada J, Lee GY, Ohlsson A. Sucrose for analgesia in newborn infants undergoing painful procedures. The Cochrane database of systematic reviews. 2013; [pubmed]

Ward SE, Gordon DB. Patient satisfaction and pain severity as outcomes in pain management: a longitudinal view of one setting’s experience. Journal of pain and symptom management. 1996; 11(4):242-51. [pubmed]

Author: Justin Morgenstern

Community emerg doc, FOAM enthusiast, evidence junkie “One special advantage of the skeptical attitude of mind is that a man is never vexed to find that after all he has been in the wrong.” - William Osler

8 thoughts on “Sucrose: Analgesic or placebo?”

  1. Fascinating read mate. I have used sucrose for a long time and never been convinced of its efficacy, but it is “the done thing”.
    Here is the trial I want to see done:
    Double blind, double dummy (excuse the pun)
    – randomise neonates requiring a needle stick to
    1. Sucrose
    2. Placebo (clearly not a sugar pill here!)

    Record video of the facial grimacing etc and audio of the crying

    Randomise expert observers (parents, nicu nurses, neonate docs) to watch the videos and guess which ones had sucrose vs. placebo

    Triple blind…. randomly label each video as neonate receiving sucrose vs. placebo (50/50 mix of true vs false labels) and show these to another panel of experts and ask them to rate the babe’s subjective distress response
    Hypothesis: experts will rate pain response lower if told they got sucrose….

    Now, off to the ethics committee…..
    Casey

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  2. Fascinating.

    To get a bit meta: what actually matters, pain or distress? If the nociceptive pathways are being triggered but the baby is not distressed by them, is that successful (and/or ethical)?

    And where does this leave us with breastfeeding as analgesia? (I don’t know many adults who find milk analgesic, but they do find a cuddle reduces distress).

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    1. I absolutely believe distress is more important than pain. However, I am not sure a lack of crying is the same as a lack of distress. (I have met many patients with sickle cell disease, for example, sitting quietly on a stretcher but complaining of 10/10 pain and desiring pain medication). The problem is that these neonates cannot effectively communicate either their pain or their distress. As an added component after real analgesics, breast feeding or sucrose are fine. It is their use as stand alones that bothers me.

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  3. Anecdotally had a 5 m.o. baby with intussusception who stopped episodic crying with sucrose pacifier while awaiting transfer (unable to do barium enema locally). N=1 but effect was impressive. Later also gave acetaminophen suppository – probably should have done both from the get-go. Thanks for the article.

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  4. The problem is that you don’t seem to grasp neurodevelopment at a very fundamental level. At very early ages, all sensory input is just noise. The idea with sucrose is to overstimulate one modality so intensely that other modalities are somewhat ignored. You will also notice that if you provide sucrose solution the infants will not respond to loud noises or light touch as they would otherwise.

    “It strikes me as odd that sucrose stops working as soon as children are old enough to tell us that it isn’t working.” This is because by the time they are children, their sensory modalities are sorted out. There is probably some critical period for this, where the infant starts to begin to orient to sound and to track faces, where their sensory modalities are being sorted. This is likely the period in which sucrose as analgesic stops being effective.

    There are a variety of interesting ways to test this, if you simply understand neurodevelopment:
    1) various concentration sucrose solutions efficacy as analgesia
    2) overstimulation via other sensory modality (loud noise? photic stimulation?) as analgesic in neonate
    3) age at which sucrose loses efficacy as analgesic (before “childhood” and after “neonate” and probably younger than we think) (map against other sensory milestones)
    4) sucrose via alternate delivery system: if sucrose itself is useful, it should be able to be administered via other mucus membranes
    5) on that same topic, alternate sweeteners: if sucrose itself is useful, the effect should be lost for fructose, steviol, saccharine, or sucralose.
    6) can you de-sensitize the child to sucrose, such that with repeated administration it stops exerting an analgesic effect?

    “I have a problem with that.” There. If you care about this topic, there’s 6-9 grants and probably 8-10 years worth of research sitting there. Enjoy.

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    1. Thank you for the comment.
      It is true that I don’t have a deep understanding of neonatal neurodevelopment, however I am not sure that changes the state of the science or current clinical practice. A theory of why sugar might work (overstimulation) doesn’t overcome the major scientific hurdle we are faced with: we simple cannot accurately measure pain in infants. It takes a leap of faith to assume that an agent that has no analgesic properties in other humans works in patients who cannot communicate. I don’t think we need to make that leap of faith when there are so many other analgesics which have been proven to work in both adults and children, and which should be our first line for painful procedures.
      The research agenda you outline is fantastic. I would be much more willing to accept sucrose as an effective treatment if it had a proven dose-response relationship and it had been demonstrated to work through multiple routes in double blind trials. However, even these mechanisms cannot distinguish between analgesic and sedative properties, and painful procedures should be addressed with analgesia not simply sedation. Until we have the research you mention, it makes a lot more sense sticking to analgesic therapies that have been proven to be effective for all humans.

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