Gabriella Porter

Background: The global incidence rate of traumatic spinal cord injuries is 10.5 per 100,000 persons and approximately 768,473 new cases per year — with 48.8% requiring surgery¹. Spinal cord injuries (SCI) are largely preventable, and many cases carry a lifetime weight of co-morbidities and even mortality. Refining current treatment approaches is vital to increasing the long-term quality of life for these patients. Ultimately, approximately 70% of patients post SCI endure chronic pain². However, the use of opioids in the wake of SCI has been linked to impaired functional recovery and the development of long-term pain³. The exact mechanism for how this relationship occurs is unclear, but several pathways have been suggested to be involved.

Objective: This study sought to determine the mechanistic relationship between opioid treatment immediately post spinal cord injury and the resulting attenuated recovery, and using such results to guide the future direction of pain management post SCI.

Search Methods: The PubMed database was used to gather information from recent mechanistic and primary literature articles from the years 2017-2023. The following search terms were used: Spinal cord injury, chronic pain, attenuated recovery, opioids, opioid-induced, morphine, hyperalgesia, analgesia, cell death, and locomotor recovery.

Results: Several pathways are suggested to be involved in the opioid-induced attenuated recovery post-SCI and are likely related to an exacerbated immune response. In a study done by Rau et al., they identified that the selective activation of the Kappa Opioid Receptor (KOR) by morphine can increase the incidence of chronic pain post-SCI⁴. KOR’s are expressed on immune cells and influence the levels of TGF-alpha and IL-6, thus mediating certain aspects of acute and chronic pain. However, the Co-administration of norbinaltorphimine (KOR antagonist) with morphine post-SCI improved locomotor recovery, reduced lesion size, and reduced hyperalgesia. Alternatively, Aceves et al. suggested that such opioid-induced attenuated recovery is likely related to the activation of Toll Like Receptor 4 (TLR4)³. Opioids activating TLR4 leads to glial activation and initiation of the inflammatory response. Minocycline was then administered as an anti-inflammatory agent prior to morphine treatment post-SCI, and the results indicated reduced microglia present at the injury site and attenuated expression/maintenance of post-SCI chronic pain. Li et al. identified a similar pathway and adverse effects in orthopedic injuries⁵. In their study, they employed a TLR4 antagonist, TAK-242, prior to morphine administration post tibia fracture, and their results indicated reduced hindpaw allodynia and unweighting.

Conclusions:

Studies have found that the opioid-induced chronic pain post SCI is likely related to an exacerbated immune response through the activation of KOR and TLR4 receptors. Inhibiting such receptors proves to be beneficial in rat models and could indicate a therapeutic mechanism for clinical use. Further studies are required to compare the effects of inhibitors between different opioid types and potential side effects. Considering the occurrence of SCI and the prevalence of opioid treatment, developing a therapeutic is essential to allow for maximal recovery and increased quality of life.

Works Cited:

1. Kumar R, Lim J, Mekary RA, et al. Traumatic Spinal Injury: Global Epidemiology and Worldwide Volume. World Neurosurg. 2018;113:e345-e363. doi:10.1016/j.wneu.2018.02.033
2. Eller OC, Willits AB, Young EE, Baumbauer KM. Pharmacological and non-pharmacological therapeutic interventions for the treatment of spinal cord injury-induced pain. Front Pain Res (Lausanne). 2022;3:991736. Published 2022 Aug 24. doi:10.3389/fpain.2022.991736
3. Aceves M, Terminel MN, Okoreeh A, et al. Morphine increases macrophages at the lesion site following spinal cord injury: Protective effects of minocycline. Brain Behav Immun. 2019;79:125-138. doi:10.1016/j.bbi.2019.01.023
4. Rau J, Hemphill A, Araguz K, et al. Adverse Effects of Repeated, Intravenous Morphine on Recovery after Spinal Cord Injury in Young, Male Rats Are Blocked by a Kappa Opioid Receptor Antagonist. J Neurotrauma. 2022;39(23-24):1741-1755. doi:10.1089/neu.2022.0208
5. Li WW, Irvine KA, Sahbaie P, et al. Morphine Exacerbates Post-fracture Nociceptive Sensitization, Functional Impairment, and Microglial Activation in Mice. Anesthesiology. 2019;130(2):292-308. doi:10.1097/ALN.0000000000002495
6. Stampas A, Pedroza C, Bush JN, Ferguson AR, Kramer JLK, Hook M. The first 24 h: opioid administration in people with spinal cord injury and neurologic recovery. Spinal Cord. 2020;58(10):1080-1089. doi:10.1038/s41393-020-0483-x