Pain studies with untreated control groups in babies are unethical.

If you are performing a study of pain control in the newborn and you assign babies to untreated controls, you are creating unnecessary avoidable pain in the control patients. That is true for any patient who is incompetent, obviously including newborns, but also older children and adults unable to give consent for themselves. I guess you could allow competent adults to consent to be randomised to control and have painful procedures without analgesia, but good luck enrolling subjects!

There is no way this is ethical, and it should never be done, and should never be allowed by ethics review boards. (Bellieni CV, et al. Should an IRB approve a placebo-controlled randomized trial of analgesia for procedural pain in neonates? Pediatrics. 2012;130(3):550-3). There is no benefit to anyone, especially not the babies, but not to medical knowledge either. We already know that sticking needles into babies causes pain, and that there are many ways to reduce that pain. Why on earth would you perform a study comparing different methods of reducing pain for blood sampling, and include an untreated control group?

Unfortunately, it still goes on. (Bellieni CV, Johnston CC. Analgesia, nil or placebo to babies, in trials that test new analgesic treatments for procedural pain. Acta Paediatr. 2016;105(2):129-36). I was stimulated to write this post after my weekly trawl through the literature found 2 such studies. I hesitate to give them any credence by referencing them, but maybe naming and shaming is the way to go.

The first is from Stanford, of all places, by a group of people that should know better (Chang J, Filoteo L, Nasr AS. Comparing the Analgesic Effects of 4 Nonpharmacologic Interventions on Term Newborns Undergoing Heel Lance: A Randomized Controlled Trial. J Perinat Neonatal Nurs. 2020 Oct/Dec;34(4):338-345). The study design is also poor, it seems that the control group was enrolled and assigned to have pain without being randomized, but the other 4 interventions were randomized. At first the authors (and apparently the IRB) didn’t think this was research, even though they were prospectively randomizing babies to different interventions and recording responses! The study clearly satisfies every possible definition of clinical research, and, if the researchers and the IRB can’t recognize that, it bodes poorly indeed. The study was therefore started without IRB approval, which means it should never have been performed and clearly should never have been published. They recruited newborns from the postpartum wards, who they say were identified by “medical record review”, which makes no sense, presumably there were individuals screening admitted babies at some point.

It was also retrospectively registered, which means that the authors don’t understand the basics of doing clinical research.

Not surprisingly, the group of 50 babies assigned to having more pain had more pain.

I think the researchers, and the IRB, and Stanford Lucile Packard Children’s Hospital owe an apology to these infants and to their parents.

The second study (Cakirli M, Acikgoz A. A Randomized Controlled Trial: The Effect of Own Mother’s Breast Milk Odor and Another Mother’s Breast Milk Odor on Pain Level of Newborn Infants. Breastfeed Med. 2021 Jan;16(1):75-81) randomized babies into 3 groups, one of which was an untreated control group. The study is behind a paywall, and I am certainly not going to pay to get it, so I don’t know the numerical results, but the abstract notes that the group randomized to having more pain had more pain.

As I performed a quick recent literature search, what is clear is that many of recent articles of painful procedures in the newborn with untreated control groups appear in specialist pain journals, where surely the reviewers should know how unethical it is to deny analgesia to babies having planned painful procedures. Other articles I have seen recently compared skin to skin contact with control (it is already clear that skin to skin contact is effective) another using a vibrating device compared to control (why not give both groups sucrose and see if the device has additional benefit?) and another with combined sucrose, music, non-nutritive sucking and massage compared to untreated controls, (completely useless as an addition to the literature, no idea whether any of the interventions was a useful addition to the others).

Other recent articles have shown how you can do such studies without assigning babies to have more pain, for example this one (Benoit B, et al. The influence of breastfeeding on cortical and bio-behavioural indicators of procedural pain in newborns: Findings of a randomized controlled trial. Early Hum Dev. 2021;154:105308) which randomized babies to either breastfeeding or oral sucrose prior to blood sampling, so all received an effective intervention, they showed no susbtantial difference in pain scores between the gorups. Or this one (Hoarau K, et al. “Holding-Cuddling” and Sucrose for Pain Relief During Venepuncture in Newborn Infants: A Randomized, Controlled Trial (CASA). Front Pediatr. 2020;8:607900.) in which all received sucrose and non-nutritive suckling, but one group also were cuddled during the procedure. Adding a new or additional intervention to previously proven analgesic intervention is ethically acceptable, if it is not already known that the combination of interventions is substantially superior; this study showed no difference in mean pain scores, but fewer babies exceeded a pain score threshold with the combined intervention compared to sucrose alone.

These two studies are a useful addition to the literature, showing that breast-feeding or sucrose are both reasonable alternatives for blood sampling analgesia, and that cuddling a baby in addition to sucrose and NNS has some benefit at the higher end of the pain scores.

Researchers want to perform studies showing differences between groups, it is easier to get them published, which helps to advance your career. But no study with an untreated control group has any scientific value, we already know effective ways of reducing pain. Subjecting babies to painful procdures to improve your CV is unconscionable.

My plea is that if you are asked to be a reviewer for an article for publication which includes babies prospectively assigned to be untreated during a painful procedure, you reject the article with a clear note to the editor that the study was unethical.

If you sit on an IRB, please reject any study which assigns newborn infants, or any incompetent participant, to have avoidable pain.

About keithbarrington

I am a neonatologist and clinical researcher at Sainte Justine University Health Center in Montréal
This entry was posted in Neonatal Research and tagged , , , . Bookmark the permalink.

2 Responses to Pain studies with untreated control groups in babies are unethical.

  1. karel allegaert says:

    i obivously get the message, but the approach is for sure more difficult for comparative studies (eg different dosing regimens of opioids), while the practice to overdose is neither the way to go ? just as a comparison, but if none of the intented extubations in ventilated cases fails, you were likely too late with extubation in a relevant proportion of cases ? this all above a ‘fair’ balance and true equipoise, as analgesics are at the very same time effective, but not without safety issues…

    • In situations where there is no known effective analgesic, such as for endotracheal suctioning, then placebo or untreated control groups would be ethically acceptable. Efficacy is also very limited for retinopathy screening, but I do think that topical anaesthesia is appropriate anyway, and a control group of an RoP screening trial should probably get that intervention.
      The fact remains that most of the recent trials which included an untreated control group were for interventions where a simple, and very safe and effective, intervention was available, skin to skin care or sucrose.

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