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Methadone effectively attenuates acute and long-term consequences of neonatal repetitive procedural pain in a rat model



Painful procedures in early life cause acute pain and can alter pain processing at a spinal level lasting into adulthood. Current methods of analgesia seem unable to prevent both acute and long-term hypersensitivity associated with neonatal pain. The current study aims to prevent acute and long-term hypersensitivity associated with neonatal procedural pain using methadone analgesia in rat pups.


Sprague–Dawley rat pups received either methadone (1 mg/kg) or saline prior to repetitive needle pricks into the left hind paw from the day of birth (postnatal day (P)0) to P7. Control littermates received a tactile stimulus. Mechanical sensitivity was assessed during the neonatal period (P0–P7), from weaning to adulthood (3–7 weeks) and following surgical re-injury of the same dermatome in adulthood.


Methadone administration completely reversed acute hypersensitivity from P0 to P7. In addition, neonatal methadone analgesia prevented prolonged hypersensitivity after re-injury in adulthood, without affecting sensitivity from weaning to adulthood.


The current study shows that neonatal methadone analgesia can attenuate acute as well as long-term hypersensitivity associated with neonatal procedural pain in a rat model.


  • Methadone treatment attenuates acute and long-term hypersensitivity associated with neonatal pain in a rat model.

  • Clinical effectiveness studies are urgently warranted to assess acute and long-term analgesic effectivity of methadone.

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Fig. 1: Neonatal mechanical sensitivity during the first postnatal week.
Fig. 2: Mechanical sensitivity during 3 to 7 weeks of age.
Fig. 3: Peri-operative sensitivity in adulthood.


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Author information




N.v.d.H., J.P., D.T. and E.A.J. contributed to conception and design of the study. N.v.d.H. and T.J.d.G. collected the data. N.v.d.H. analysed the data and drafted the manuscript. N.v.d.H., T.J.d.G., J.P., D.T. and E.A.J. read and revised the manuscript, and provided final approval for publication.

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Correspondence to Nynke J. van den Hoogen.

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van den Hoogen, N.J., de Geus, T.J., Patijn, J. et al. Methadone effectively attenuates acute and long-term consequences of neonatal repetitive procedural pain in a rat model. Pediatr Res 89, 1681–1686 (2021).

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