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

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Impact

  • 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.

References

  1. 1.

    Beck, S. et al. The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity. Bull. World Health Organ. 88, 31–38 (2010).

    PubMed  Google Scholar 

  2. 2.

    Carbajal, R. et al. Epidemiology and treatment of painful procedures in neonates in intensive care units. JAMA 300, 60–70 (2008).

    CAS  PubMed  Google Scholar 

  3. 3.

    Roofthooft, D. W., Simons, S. H., Anand, K. J., Tibboel, D. & van Dijk, M. Eight years later, are we still hurting newborn infants? Neonatology 105, 218–226 (2014).

    PubMed  Google Scholar 

  4. 4.

    Carbajal, R. et al. Sedation and analgesia practices in neonatal intensive care units (EUROPAIN): results from a prospective cohort study. Lancet Respir. Med. 3, 796–812 (2015).

    PubMed  Google Scholar 

  5. 5.

    Hall, R. W. Anesthesia and analgesia in the NICU. Clin. Perinatol. 39, 239–254 (2012).

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Hartley, C. et al. Analgesic efficacy and safety of morphine in the Procedural Pain in Premature Infants (Poppi) study: randomised placebo-controlled trial. Lancet 392, 2595–2605 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Monk, V. et al. Oral morphine analgesia for preventing pain during invasive procedures in non-ventilated premature infants in hospital: the Poppi RCT. Southampton (UK): NIHR Journals Library; 2019 Aug. (Efficacy and Mechanism Evaluation, No. 6.9).

  8. 8.

    Anand, K. J. et al. Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial. Lancet 363, 1673–1682 (2004).

    CAS  PubMed  Google Scholar 

  9. 9.

    de Graaf, J. et al. Five-year follow-up of effects of neonatal intensive care and morphine infusion during mechanical ventilation on diurnal cortisol rhythm. J. Pediatr. 165, 459–463 e452 (2014).

    PubMed  Google Scholar 

  10. 10.

    de Graaf, J. et al. Long-term effects of routine morphine infusion in mechanically ventilated neonates on children’s functioning: five-year follow-up of a randomized controlled trial. Pain 152, 1391–1397 (2011).

    PubMed  Google Scholar 

  11. 11.

    Harder, H. J. & Murphy, A. Z. Early life opioid exposure and potential long-term effects. Neurobiol. Stress 10, 100156 (2019).

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    Valkenburg, A. J. et al. Long-term effects of neonatal morphine infusion on pain sensitivity: follow-up of a randomized controlled trial. J. Pain 16, 926–933 (2015).

    CAS  PubMed  Google Scholar 

  13. 13.

    Grossman, M. & Berkwitt, A. Neonatal abstinence syndrome. Semin. Perinatol. 43, 173–186 (2019).

    PubMed  Google Scholar 

  14. 14.

    Beggs, S., Currie, G., Salter, M. W., Fitzgerald, M. & Walker, S. M. Priming of adult pain responses by neonatal pain experience: maintenance by central neuroimmune activity. Brain 135, 404–417 (2012).

    PubMed  Google Scholar 

  15. 15.

    Walker, S. M. et al. Long-term impact of neonatal intensive care and surgery on somatosensory perception in children born extremely preterm. Pain 141, 79–87 (2009).

    PubMed  Google Scholar 

  16. 16.

    den Hoogen, N. J. V., Patijn, J., Tibboel, D. & Joosten, E. A. Neonatal plasticity of the nociceptive system: mechanisms, effects, and treatment of repetitive painful procedures during NICU admittance. Curr. Pharm. Des. 23, 5902–5910 (2017).

    Google Scholar 

  17. 17.

    van den Hoogen, N. J. et al. Repeated touch and needle-prick stimulation in the neonatal period increases the baseline mechanical sensitivity and postinjury hypersensitivity of adult spinal sensory neurons. Pain 159, 1166–1175 (2018).

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    van den Hoogen, N. J., Patijn, J., Tibboel, D. & Joosten, E. A. Repetitive noxious stimuli during early development affect acute and long-term mechanical sensitivity in rats. Pediatr. Res. 87, 26–31 (2019).

    PubMed  Google Scholar 

  19. 19.

    Ren, K., Novikova, S. I., He, F., Dubner, R. & Lidow, M. S. Neonatal local noxious insult affects gene expression in the spinal dorsal horn of adult rats. Mol. Pain 1, 27 (2005).

    PubMed  PubMed Central  Google Scholar 

  20. 20.

    Walker, S. M. Long-term effects of neonatal pain. Semin. Fetal Neonatal Med. 24, 101005 (2019).

    PubMed  Google Scholar 

  21. 21.

    van den Hoogen, N. J., van Reij, R. R., Patijn, J., Tibboel, D. & Joosten, E. A. J. Adult spinal opioid receptor mu1 expression after incision is altered by early life repetitive tactile and noxious procedures in rats. Dev. Neurobiol. 78, 417–426 (2018).

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    Laprairie, J. L. & Murphy, A. Z. Neonatal injury alters adult pain sensitivity by increasing opioid tone in the periaqueductal gray. Front. Behav. Neurosci. 3, 31 (2009).

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    Schwaller, F. & Fitzgerald, M. The consequences of pain in early life: injury-induced plasticity in developing pain pathways. Eur. J. Neurosci. 39, 344–352 (2014).

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Woolf, C. J. Central sensitization: uncovering the relation between pain and plasticity. Anesthesiology 106, 864–867 (2007).

    PubMed  Google Scholar 

  25. 25.

    Mahmoud, H., Martin, N. & Hildebrand, M. E. Conserved contributions of NMDA receptor subtypes to synaptic responses in lamina II spinal neurons across early postnatal development. Mol. Brain 13, 31 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Kwok, C. H., Devonshire, I. M., Bennett, A. J. & Hathway, G. J. Postnatal maturation of endogenous opioid systems within the periaqueductal grey and spinal dorsal horn of the rat. Pain 155, 168–178 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Ebert, B., Thorkildsen, C., Andersen, S., Christrup, L. L. & Hjeds, H. Opioid analgesics as noncompetitive N-methyl-D-aspartate (NMDA) antagonists. Biochem. Pharmacol. 56, 553–559 (1998).

    CAS  PubMed  Google Scholar 

  28. 28.

    Sotgiu, M. L., Valente, M., Storchi, R., Caramenti, G. & Biella, G. E. Cooperative N-methyl-D-aspartate (NMDA) receptor antagonism and mu-opioid receptor agonism mediate the methadone inhibition of the spinal neuron pain-related hyperactivity in a rat model of neuropathic pain. Pharm. Res. 60, 284–290 (2009).

    CAS  Google Scholar 

  29. 29.

    Gorman, A. L., Elliott, K. J. & Inturrisi, C. E. The d- and l-isomers of methadone bind to the non-competitive site on the N-methyl-D-aspartate (NMDA) receptor in rat forebrain and spinal cord. Neurosci. Lett. 223, 5–8 (1997).

    CAS  PubMed  Google Scholar 

  30. 30.

    Knaepen, L. et al. Neonatal repetitive needle pricking: plasticity of the spinal nociceptive circuit and extended postoperative pain in later life. Dev. Neurobiol. 73, 85–97 (2013).

    PubMed  Google Scholar 

  31. 31.

    van den Hoogen, N. J. et al. Neonatal paracetamol treatment reduces long-term nociceptive behaviour after neonatal procedural pain in rats. Eur. J. Pain 20, 1309–1318 (2016).

    PubMed  Google Scholar 

  32. 32.

    Brennan, T. J., Vandermeulen, E. P. & Gebhart, G. F. Characterization of a rat model of incisional pain. Pain 64, 493–501 (1996).

    PubMed  Google Scholar 

  33. 33.

    Chaplan, S. R., Bach, F. W., Pogrel, J. W., Chung, J. M. & Yaksh, T. L. Quantitative assessment of tactile allodynia in the rat paw. J. Neurosci. Methods 53, 55–63 (1994).

    CAS  PubMed  Google Scholar 

  34. 34.

    Moriarty, O., Harrington, L., Beggs, S. & Walker, S. M. Opioid analgesia and the somatosensory memory of neonatal surgical injury in the adult rat. Br. J. Anaesth. 121, 314–324 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Holtman, J. R. Jr. & Wala, E. P. Characterization of the antinociceptive and pronociceptive effects of methadone in rats. Anesthesiology 106, 563–571 (2007).

    CAS  PubMed  Google Scholar 

  36. 36.

    Ling, G. S., Umans, J. G. & Inturrisi, C. E. Methadone: radioimmunoassay and pharmacokinetics in the rat. J. Pharm. Exp. Ther. 217, 147–151 (1981).

    CAS  Google Scholar 

  37. 37.

    Smith, T. H., Grider, J. R., Dewey, W. L. & Akbarali, H. I. Morphine decreases enteric neuron excitability via inhibition of sodium channels. PLoS ONE 7, e45251 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Nandi, R. et al. The functional expression of mu opioid receptors on sensory neurons is developmentally regulated; morphine analgesia is less selective in the neonate. Pain 111, 38–50 (2004).

    CAS  PubMed  Google Scholar 

  39. 39.

    Liu, X. B., Murray, K. D. & Jones, E. G. Switching of NMDA receptor 2A and 2B subunits at thalamic and cortical synapses during early postnatal development. J. Neurosci. 24, 8885–8895 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Turner, S. D. et al. Neonatal opioid withdrawal and antenatal opioid prescribing. CMAJ Open 3, E55–E61 (2015).

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Barnett, A. M. et al. The effect of intraoperative methadone during pediatric cardiac surgery on postoperative opioid requirements. Paediatr Anaesth. 30, 773–779 (2020).

    PubMed  Google Scholar 

  42. 42.

    Chana, S. K. & Anand, K. J. Can we use methadone for analgesia in neonates? Arch. Dis. Child Fetal Neonatal Ed. 85, F79–F81 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Anand, K. J. Pharmacological approaches to the management of pain in the neonatal intensive care unit. J. Perinatol. 27, S4–S11 (2007).

    CAS  PubMed  Google Scholar 

  44. 44.

    Ward, R. M. et al. The pharmacokinetics of methadone and its metabolites in neonates, infants, and children. Paediatr. Anaesth. 24, 591–601 (2014).

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Schrott, L. M., Franklin, L. & Serrano, P. A. Prenatal opiate exposure impairs radial arm maze performance and reduces levels of BDNF precursor following training. Brain Res. 1198, 132–140 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Chen, H. H. et al. Buprenorphine, methadone, and morphine treatment during pregnancy: behavioral effects on the offspring in rats. Neuropsychiatr. Dis. Treat. 11, 609–618 (2015).

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Fjelldal, M. F. et al. Opioid receptor-mediated changes in the NMDA receptor in developing rat and chicken. Int. J. Dev. Neurosci. 78, 19–27 (2019).

    CAS  PubMed  Google Scholar 

  48. 48.

    Vestal-Laborde, A. A., Eschenroeder, A. C., Bigbee, J. W., Robinson, S. E. & Sato-Bigbee, C. The opioid system and brain development: effects of methadone on the oligodendrocyte lineage and the early stages of myelination. Dev. Neurosci. 36, 409–421 (2014).

    CAS  PubMed  Google Scholar 

  49. 49.

    Duhrsen, L. et al. Effects of repetitive exposure to pain and morphine treatment on the neonatal rat brain. Neonatology 103, 35–43 (2013).

    PubMed  Google Scholar 

  50. 50.

    Stevens, B., Yamada, J., Ohlsson, A., Haliburton, S. & Shorkey, A. Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database Syst. Rev. 7, CD001069 (2016).

    PubMed  Google Scholar 

  51. 51.

    Moriarty, O. et al. Priming of adult incision response by early-life injury: neonatal microglial inhibition has persistent but sexually dimorphic effects in adult rats. J. Neurosci. 39, 3081–3093 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

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Contributions

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.

Corresponding author

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). https://doi.org/10.1038/s41390-020-01353-x

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