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CC BY 4.0 · Neuropediatrics 2024; 55(05): 294-302
DOI: 10.1055/s-0044-1787103
Original Article

Potentially Life-Threatening Interaction between Opioids and Intrathecal Baclofen in Individuals with a Childhood-Onset Neurological Disorder: A Case Series and Review of the Literature

Liza M.M. van Dijk 
1   Department of Rehabilitation Medicine, Amsterdam University Medical Centers, Location Vrije Universiteit, Amsterdam, the Netherlands
2   Amsterdam Movement Sciences, Rehabilitation & Development, Amsterdam, The Netherlands
,
Annelies van Zwol
3   Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
,
Annemieke I. Buizer 
1   Department of Rehabilitation Medicine, Amsterdam University Medical Centers, Location Vrije Universiteit, Amsterdam, the Netherlands
2   Amsterdam Movement Sciences, Rehabilitation & Development, Amsterdam, The Netherlands
4   Emma Children's Hospital, Amsterdam University Medical Centers, Location University of Amsterdam, Amsterdam, The Netherlands
,
Laura A. van de Pol
5   Department of Child Neurology, Amsterdam University Medical Centers, Location Vrije Universiteit, Amsterdam, The Netherlands
,
K. Mariam Slot
6   Department of Neurosurgery, Amsterdam University Medical Centers, Location University of Amsterdam, Amsterdam, The Netherlands
7   Brain Tumor Center Amsterdam, Amsterdam University Medical Centers, Amsterdam, The Netherlands
,
Saskia N. de Wildt
8   Division of Pharmacology and Toxicology, Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands
9   Department of Neonatal and Pediatric Intensive Care, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands
,
Laura A. Bonouvrié
1   Department of Rehabilitation Medicine, Amsterdam University Medical Centers, Location Vrije Universiteit, Amsterdam, the Netherlands
2   Amsterdam Movement Sciences, Rehabilitation & Development, Amsterdam, The Netherlands
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Abstract

Background Spasticity and dystonia are movement impairments that can occur in childhood-onset neurological disorders. Severely affected individuals can be treated with intrathecal baclofen (ITB). Concomitant use of ITB and opioids has been associated with central nervous system (CNS) depression. This study aims to describe the clinical management of this interaction, based on a case series and review of literature.

Methods Four individuals with childhood-onset CNS disorders (age 8–24) and CNS-depressant overdose symptoms after the concomitant use of ITB and opioids are described. The Drug Interaction Probability Scale (DIPS) was calculated to assess the cause-relationship (doubtful <2, possible 2–4, probable 5–8, and highly probable >8) of the potential drug–drug interaction. A literature review of similar previously reported cases and the possible pharmacological mechanisms of opioid–baclofen interaction is provided.

Results After ITB and opioid co-administration, three out of four patients had decreased consciousness, and three developed respiratory depression. DIPS scores indicated a possible cause-relationship in one patient (DIPS: 4) and a probable cause-relationship in the others (DIPS: 6, 6, and 8). Discontinuation or adjusting ITB or opioid dosages resulted in clinical recovery. All patients recovered completely. In the literature, two articles describing nine unique cases were found.

Conclusion Although the opioid–ITB interaction is incompletely understood, concomitant use may enhance the risk of symptoms of CNS-depressant overdose, which are potentially life-threatening. If concomitant use is desirable, we strongly recommend to closely monitor these patients to detect interaction symptoms early. Awareness and monitoring of the potential opioid–ITB interaction is essential to reduce the risk of severe complications.

Keywords

baclofen - opioids - respiratory depression - decreased consciousness - drug interaction

Authors Contributions

L.M.vD., A.vZ., and L.A.B. designed the study. L.M.vD., A.vZ., A.I.B., S.N.dW., and L.A.B. contributed to the investigation and writing of the original draft. L.M.vD., A.vZ., A.I.B., L.A.vdP., K.M.S., S.N.dW., and L.A.B. contributed to writing, reviewing, and editing. All authors have read and agreed to the published version of the manuscript.




Publication History

Received: 06 February 2024

Accepted: 22 April 2024

Article published online:
22 May 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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  • References

  • 1 Klein C, Münchau A. Progressive dystonia. Handb Clin Neurol 2013; 113: 1889-1897
    CrossrefPubMedGoogle Scholar
  • 2 Brett E, Lake B. Progressive neurometabolic brain diseases. Pediatric Neurology 1997; 3: 143-200
    PubMedGoogle Scholar
  • 3 Dyken P, Krawiecki N. Neurodegenerative diseases of infancy and childhood. Ann Neurol 1983; 13 (04) 351-364
    CrossrefPubMedGoogle Scholar
  • 4 Rosenbaum P, Paneth N, Leviton A. et al. A report: the definition and classification of cerebral palsy April 2006. Dev Med Child Neurol Suppl 2007; 109: 8-14
    PubMedGoogle Scholar
  • 5 Buizer AI, Martens BHM, Grandbois van Ravenhorst C, Schoonmade LJ, Becher JG, Vermeulen RJ. Effect of continuous intrathecal baclofen therapy in children: a systematic review. Dev Med Child Neurol 2019; 61 (02) 128-134
    CrossrefPubMedGoogle Scholar
  • 6 Albright AL. Intrathecal baclofen in cerebral palsy movement disorders. J Child Neurol 1996; 11 (Suppl. 01) S29-S35
    CrossrefPubMedGoogle Scholar
  • 7 Milanov IG. Mechanisms of baclofen action on spasticity. Acta Neurol Scand 1992; 85 (05) 305-310
    CrossrefPubMedGoogle Scholar
  • 8 Bonouvrié LA, Becher JG, Vles JSH, Vermeulen RJ, Buizer AI, Group IS. IDYS Study Group. The effect of intrathecal baclofen in dyskinetic cerebral palsy: the IDYS trial. Ann Neurol 2019; 86 (01) 79-90
    CrossrefPubMedGoogle Scholar
  • 9 Albright AL. Baclofen in the treatment of cerebral palsy. J Child Neurol 1996; 11 (02) 77-83
    CrossrefPubMedGoogle Scholar
  • 10 Knutsson E, Lindblom U, Mårtensson A. Plasma and cerebrospinal fluid levels of baclofen (Lioresal) at optimal therapeutic responses in spastic paresis. J Neurol Sci 1974; 23 (03) 473-484
    CrossrefPubMedGoogle Scholar
  • 11 Albright AL, Shultz BL. Plasma baclofen levels in children receiving continuous intrathecal baclofen infusion. J Child Neurol 1999; 14 (06) 408-409
    CrossrefPubMedGoogle Scholar
  • 12 Francisco GE, Saulino MF, Yablon SA, Turner M. Intrathecal baclofen therapy: an update. PM R 2009; 1 (09) 852-858
    CrossrefPubMedGoogle Scholar
  • 13 Jain A, Sullivan BT, Shah SA. et al. Caregiver perceptions and health-related quality-of-life changes in cerebral palsy patients after spinal arthrodesis. Spine 2018; 43 (15) 1052-1056
    CrossrefPubMedGoogle Scholar
  • 14 Richtlijn Postoperatieve pijn [Internet]. 2012 . Accessed May 02, 2024 at: https://www.anesthesiologie.nl/
    PubMedGoogle Scholar
  • 15 Kheder A, Nair KP. Spasticity: pathophysiology, evaluation and management. Pract Neurol 2012; 12 (05) 289-298
    CrossrefPubMedGoogle Scholar
  • 16 Yang J, Reilly BG, Davis TP, Ronaldson PT. Modulation of opioid transport at the blood-brain barrier by altered ATP-binding cassette (ABC) transporter expression and activity. Pharmaceutics 2018; 10 (04) 192
    CrossrefPubMedGoogle Scholar
  • 17 Yaksh TL, Wallace MS. Opioids, analgesia, and pain management. In Brunton L, Chabner B, Knollman B. (Eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics. Twelfth Edition. McGraw-Hill Professional; 2011: 481-526
    Google Scholar
  • 18 Li Y, Delcher C, Wei YJ. et al. Risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants: a population-based cohort study. Clin Pharmacol Ther 2020; 108 (01) 81-89
    CrossrefPubMedGoogle Scholar
  • 19 Khan NF, Bykov K, Barnett ML, Glynn RJ, Vine SM, Gagne JJ. Comparative risk of opioid overdose with concomitant use of prescription opioids and skeletal muscle relaxants. Neurology 2022; 99 (13) e1432-e1442
    PubMedGoogle Scholar
  • 20 Khan NF, Bykov K, Glynn RJ, Barnett ML, Gagne JJ. Coprescription of opioids with other medications and risk of opioid overdose. Clin Pharmacol Ther 2021; 110 (04) 1011-1017
    CrossrefPubMedGoogle Scholar
  • 21 Rizzo G, Bussolin L, Genitori L. et al. The use of opioids in children receiving intrathecal baclofen therapy. Childs Nerv Syst 2019; 35 (07) 1213-1218
    CrossrefPubMedGoogle Scholar
  • 22 Horn JR, Hansten PD, Chan LN. Proposal for a new tool to evaluate drug interaction cases. Ann Pharmacother 2007; 41 (04) 674-680
    CrossrefPubMedGoogle Scholar
  • 23 Scheife RT, Hines LE, Boyce RD. et al. Consensus recommendations for systematic evaluation of drug-drug interaction evidence for clinical decision support. Drug Saf 2015; 38 (02) 197-206
    CrossrefPubMedGoogle Scholar
  • 24 Nederland Z. Farmacotherapeutisch Kompas. Accessed May 02, 2024 at: https://farmacotherapeutischkompas.nl
    PubMedGoogle Scholar
  • 25 Anderson KJ, Farmer JP, Brown K. Reversible coma in children after improper baclofen pump insertion. Paediatr Anaesth 2002; 12 (05) 454-460
    CrossrefPubMedGoogle Scholar
  • 26 Rzasa Lynn R, Galinkin JL. Naloxone dosage for opioid reversal: current evidence and clinical implications. Ther Adv Drug Saf 2018; 9 (01) 63-88
    CrossrefPubMedGoogle Scholar
  • 27 Zieglgänsberger W, Howe JR, Sutor B. The Neuropharmacology of Baclofen. Local-Spinal Therapy of Spasticity. Springer; 1988: 37-49
    Google Scholar
  • 28 Benarroch EE. GABAB receptors: structure, functions, and clinical implications. Neurology 2012; 78 (08) 578-584
    CrossrefPubMedGoogle Scholar
  • 29 Ghanavatian S, Derian A. Baclofen. 2018
    PubMedGoogle Scholar
  • 30 Zöllner C, Stein C. Opioids. Handb Exp Pharmacol 2007; (177) 31-63
    PubMedGoogle Scholar
  • 31 Watanabe JH, Yang J. Association of combination opioid, benzodiazepine, and muscle relaxant usage with emergency department visits in a nationwide cohort in the United States. Int J Clin Pharm 2021; 43 (02) 358-364
    CrossrefPubMedGoogle Scholar
  • 32 Gordon NC, Gear RW, Heller PH, Paul S, Miaskowski C, Levine JD. Enhancement of morphine analgesia by the GABAB agonist baclofen. Neuroscience 1995; 69 (02) 345-349
    CrossrefPubMedGoogle Scholar
  • 33 Pedrón VT, Varani AP, Bettler B, Balerio GN. GABAB receptors modulate morphine antinociception: pharmacological and genetic approaches. Pharmacol Biochem Behav 2019; 180: 11-21
    CrossrefPubMedGoogle Scholar
  • 34 Wilkerson JL, Felix JS, Restrepo LF, Ansari MI, Coop A, McMahon LR. The effects of morphine, baclofen, and buspirone alone and in combination on schedule-controlled responding and hot plate antinociception in rats. J Pharmacol Exp Ther 2019; 370 (03) 380-389
    CrossrefPubMedGoogle Scholar
  • 35 Fridén M, Winiwarter S, Jerndal G. et al. Structure-brain exposure relationships in rat and human using a novel data set of unbound drug concentrations in brain interstitial and cerebrospinal fluids. J Med Chem 2009; 52 (20) 6233-6243
    CrossrefPubMedGoogle Scholar
  • 36 Reichel A. Integrated approach to optimizing CNS penetration in drug discovery: from the old to the new paradigm and assessment of drug–transporter interactions. In: Hammarlund-Udenaes M, de Lange E, Thorne R. eds. Drug Delivery to the Brain. 10. New York, NY: Springer; 2014: 339-374
    Google Scholar
  • 37 Bhargava HN, Villar VM, Rahmani NH, Larsen AK. Time course of the distribution of morphine in brain regions, spinal cord and serum following intravenous injection to rats of differing ages. Pharmacology 1993; 47 (01) 13-23
    CrossrefPubMedGoogle Scholar
  • 38 Kroin JS, Ali A, York M, Penn RD. The distribution of medication along the spinal canal after chronic intrathecal administration. Neurosurgery 1993; 33 (02) 226-230 , discussion 230
    CrossrefPubMedGoogle Scholar
  • 39 Ummenhofer WC, Arends RH, Shen DD, Bernards CM. Comparative spinal distribution and clearance kinetics of intrathecally administered morphine, fentanyl, alfentanil, and sufentanil. Anesthesiology 2000; 92 (03) 739-753
    CrossrefPubMedGoogle Scholar
  • 40 Hinrichs M, Weyland A, Bantel C. [Piritramide : A critical review]. Schmerz 2017; 31 (04) 345-352
    PubMedGoogle Scholar