Background & Aims

Chronic low back pain (cLBP) is a persistent and highly prevalent condition characterized by pain, discomfort, or tension in the lower back, lasting for at least three months. While the mechanisms of cLBP are poorly understood, our group has shown this condition to be associated with neuroinflammation, detected as increased levels of the 18 kDa translocator protein (TSPO)1. Minocycline is a tetracycline antibiotic drug that has been shown to reduce neuroinflammation in preclinical pain models2. Whether this drug has a similar anti-inflammatory effect on pain or brain inflammation in humans is currently unknown. In this double-blind phase II placebo-controlled clinical trial, we investigated whether minocycline reduces pain levels and brain TSPO signals in subjects with cLBP.

Methods

Forty-eight patients with cLBP were recruited and randomized to receive either Minocycline 100mg (N=25) or placebo (N=23) for two weeks. Patients underwent Positron Emission Tomography/Magnetic Resonance Imaging (PET-MRI) with [11C]PBR28, a second-generation TSPO radioligand, both before and after the treatment period. In addition, patients completed a daily survey including the Brief Pain Inventory (BPI)3 starting from one week before treatment and throughout the treatment period. TSPO signal was measured by evaluating the standard uptake value ratio (SUVR) in the thalamus (the brain region showing the most consistent TSPO signal in cLBP vs controls in our prior studies)1,4. The effect of treatment on TSPO signal and pain ratings was assessed using mixed effect longitudinal models including treatment, time, and their interaction, accounting for age, sex, and TSPO genotype (which predicts binding affinity5) as covariates.

Results

When assessing the thalamic TSPO signal, we did not observe significant effects of group, time, group*time (i.e. treatment), sex, or genotype (p=0.42 or higher). Age was significantly and negatively associated with TSPO signal (?= -0.00105; 95% Confidence Interval=-0.00198, -0.00013; p=0.027), indicating that -unexpectedly- older participants tended to have lower thalamic TSPO signal. This relationship held irrespective of the treatment group and was observed in both pre-treatment (r= -0.353, p=0.014) and post-treatment PET data (r= -0.365, p=0.011).
When assessing the effect of treatment on average pain assessed by daily BPI surveys, there was no effect of group, sex, genotype, or age (all p>0.192). Time showed a significant negative main effect (p<0.001) indicating that pain was reduced over time in both groups. However, the group*time interaction was not significant (p=0.333).

Conclusions

Our findings did not support the evidence that Minocycline is an effective drug in reducing neuroinflammation, assessed by thalamic TSPO SUVR, in patients with cLBP. In addition, we observed that the average daily pain reported by the patients was reduced over time irrespective of treatment allocation, an effect which may therefore be explained by a placebo effect. Future studies are warranted to explore the effect of the drug in specific subtypes of patients (e.g. patients with axial vs. radicular pain), within different brain regions, as well as using full radiotracer binding quantification with kinetic modeling.

References

[1] M.L. Loggia, D.B. Chonde, O. Akeju, et al., Evidence for brain glial activation in chronic pain patients, Brain 138 (Pt 3) (2015) 604–615, https://doi.org/10.1093/brain/awu377.
[2] B.W. Leblanc, M.L. Zerah, L.M. Kadasi, et al., Minocycline injection in the ventral posterolateral thalamus reverses microglial reactivity and thermal hyperalgesia secondary to sciatic neuropathy, Neurosci. Lett. 498 (2) (2011) 138–142, https://doi.org/10.1016/j.neulet.2011.04.077.
[3] G. Tan, M.P. Jensen, J.I. Thornby, et al., Validation of the brief pain inventory for chronic nonmalignant pain, J. Pain 5 (2) (2004) 133–137, https://doi.org/10.1016/j.jpain.2003.12.005.
[4] Torrado-Carvajal A, Toschi N, Albrecht DS, et al. Thalamic neuroinflammation as a reproducible and discriminating signature for chronic low back pain. Pain. 2021;162(4):1241-1249. https://doi:10.1097/j.pain.0000000000002108.
[5] D.R. Owen, A.J. Yeo, R.N. Gunn, et al., An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28, J. Cereb. Blood Flow Metabo. : Off. J. Int. Soc. Cerebral Blood Flow and Metabo. 32 (1) (2012) 1–5, https://doi.org/10.1038/jcbfm.2011.147.

Presenting Author

Ellie Minhae Kim

Poster Authors

Mehrbod Mohammadian, PhD

PhD

A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School

Lead Author

Ludovica Brusaferri

London South Bank University

Lead Author

Minhae Kim

Massachusetts General Hospital

Lead Author

Nikolaos Efthimiou

PhD

A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School

Lead Author

Jennifer P. Murphy

BS

A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School

Lead Author

Erin J. Morrissey

BA

A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School

Lead Author

Zeynab Alshelh

PhD

A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School

Lead Author

Grace Grmek

BA

A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School

Lead Author

Jack H. Schnieders

BS

A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School

Lead Author

Atreyi Saha

BA

A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School

Lead Author

Paulina C. Knight

BA

A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School

Lead Author

Angelica Sandström

PhD

A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School

Lead Author

Ciprian Catana

MD/PhD

A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School

Lead Author

Jodi M. Gilman

PhD

Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School

Lead Author

Joseph J. Locascio

PhD

Department of Neurology, Massachusetts General Hospital, Harvard Medical School

Lead Author

Robert Edwards

PhD

Brigham & Women's Hospital/Harvard Medical School

Lead Author

Vitaly Napadow

Spaulding Rehabilitation Hospital

Lead Author

Marco L. Loggia

PhD

A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School

Lead Author

Topics

  • Pain Imaging