Correlation of Pain Reduction with fMRI BOLD Response in Osteoarthritis Patients Treated with Paracetamol: Randomized, Double-Blind, Crossover Clinical Efficacy Study

Yong Yue, Agron Collaku, Yong Yue, Agron Collaku

Abstract

Objective: To assess the relationship between the analgesic efficacy of extended-release paracetamol (ER-APAP) and brain blood oxygen level-dependent (BOLD) signal activation in response to painful stimulation measured by functional magnetic resonance imaging (fMRI) in patients with osteoarthritis of the knee.

Methods: This placebo-controlled, double-blind, crossover, randomized trial (N = 25) comprised three treatment periods in which patients received four doses of an eight-hour ER-APAP caplet (2 x 665 mg), four doses of matched placebo, and no treatment. Pain intensity of the knee was measured before and after painful stimulation at the knee with osteoarthritis and before and after fMRI.

Results: ER-APAP significantly reduced prestimulation osteoarthritis knee joint pain compared with baseline (P < 0.003) and placebo (P < 0.004). ER-APAP and placebo significantly reduced knee joint pain after stimulation (P = 0.014 and P = 0.032, respectively); however, pain reduction with ER-APAP was 35% greater than placebo. ER-APAP was associated with significant reductions in BOLD signal activation after stimulation compared with control in the sensory cortex (P = 0.002) and supramarginal gyrus (P = 0.003). Reduction in BOLD signal activation after stimulation for placebo was significantly greater than control in the subgenual prefrontal cortex (P < 0.001), frontal cortex (P < 0.001), insula (P < 0.003), and sensory cortex (P < 0.001).

Conclusions: ER-APAP had a significantly greater effect than placebo and no treatment in reducing knee pain, which was associated with reduced BOLD signal activations in pain pathways, including the sensory cortex and supramarginal gyrus. BOLD observations after placebo treatment may shed light on the role of the brain regions potentially involved in placebo response in clinical trials investigating pain therapies.

Keywords: Blood Oxygen Level–Dependent (BOLD); Brain activity; Functional Magnetic Resonance Imaging (fMRI); Osteoarthritis; Pain; Paracetamol.

© 2017 American Academy of Pain Medicine.

Figures

Figure 1
Figure 1
Subject disposition.
Figure 2
Figure 2
The blood oxygen level–dependent signal activation patterns following no treatment, placebo treatment, and extended-release paracetamol (ER-APAP) treatment, respectively, in the different levels of the whole brain after painful stimulation at the subject’s knee joint.
Figure 3
Figure 3
ER-APAP vs no treatment. A) The combined functional magnetic resonance images of BOLD activation after painful stimulation at the knee joint following treatment with ER-APAP vs no treatment. B) Left: mean change from baseline (%) in pain intensity after pressure stimulation following treatment with ER-APAP and no treatment. P = 0.014 for comparison of pretreatment pain after stimulation and post-treatment pain after stimulation prescan for ER-APAP; P = 0.99 for comparison of pain intensity after stimulation at the beginning and end of the no-treatment period prescan. Right: reduction of BOLD response after painful stimulation at the knee joint following treatment with ER-APAP and no treatment. P = 0.002, sensory cortex; P = 0.003, supramarginal gyrus. A = anterior; BOLD = blood oxygen level–dependent; ER-APAP = extended-release paracetamol; L = left side; P = posterior; R = right side; SC = sensory cortex; SE = standard error of mean; SM = supramarginal gyrus.
Figure 4
Figure 4
Placebo vs no treatment. A) The combined functional magnetic resonance images of BOLD activation after painful stimulation at the knee joint following treatment with placebo vs no treatment. B) Left: mean change from baseline (%) in pain intensity after pressure stimulation following placebo treatment and no treatment. P = 0.03 for comparison of pretreatment pain intensity after stimulation and post-treatment pain intensity after stimulation prescan for placebo treatment; P = 0.99 for comparison of pain intensity after stimulation at the beginning and end of the no-treatment period prescan. Right: reduction of BOLD response after painful stimulation at the knee joint following treatment with placebo and no treatment. P < 0.001, subgenual prefrontal cortex; P < 0.001, frontal cortex; P = 0.003, insula; P < 0.001, sensory cortex. A = anterior; BOLD = blood oxygen level–dependent; ER-APAP = extended-release paracetamol; FC = frontal cortex; IS = insula; L = left side; P = posterior; R = right side; SC = sensory cortex; SE = standard error of mean; SG = subgenual prefrontal cortex.
Figure 5
Figure 5
ER-APAP vs placebo. A) Combined functional magnetic resonance images of BOLD activation after painful stimulation at the knee joint following treatment with ER-APAP vs placebo. B) Left: mean change from baseline (%) in pain intensity after pressure stimulation following treatment with ER-APAP and placebo. P = 0.014 for comparison of pretreatment pain intensity after stimulation and post-treatment pain intensity after stimulation prescan for ER-APAP; P = 0.03 for comparison of pretreatment pain intensity after stimulation and post-treatment pain intensity after stimulation prescan for placebo. Right: reduction of BOLD response after painful stimulation at the knee joint following treatment with ER-APAP and placebo. P = 0.003, thalamus. A = anterior; BOLD = blood oxygen level–dependent; ER-APAP = extended-release paracetamol; L = left side; P = posterior; R = right side; SE = standard error of the mean; TM = thalamus.

References

    1. Smith HS. Potential analgesic mechanisms of acetaminophen. Pain Physician 2009;121:269–80.
    1. Flor H, Turk DC.. Chronic Pain: An Integrated Biobehavioral Approach. Seattle, WA: IASP Press; 2011.
    1. Wanigasekera V, Mezue M, Andersson J, Kong Y, Tracey I.. Disambiguating pharmacodynamic efficacy from behavior with neuroimaging: Implications for analgesic drug development. Anesthesiology 2016;1241:159–68.
    1. Apkarian AV, Bushnell MC, Treede RD, Zubieta JK.. Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain 2005;94:463–84.
    1. Hashmi JA, Baliki MN, Huang L, et al.Shape shifting pain: Chronification of back pain shifts brain representation from nociceptive to emotional circuits. Brain 2013;136(pt 9):2751–68.
    1. Albe-Fessard D, Berkley KJ, Kruger L, Ralston HJ 3rd, Willis WD Jr.. Diencephalic mechanisms of pain sensation. Brain Res 1985;3563:217–96.
    1. Wager TD, Rilling JK, Smith EE, et al.Placebo-induced changes in FMRI in the anticipation and experience of pain. Science 2004;3035661:1162–7.
    1. Ingvar M. Pain and functional imaging. Philos Trans R Soc Lond B Biol Sci 1999;3541387:1347–58.
    1. Peyron R, Laurent B, Garcia-Larrea L.. Functional imaging of brain responses to pain. A review and meta-analysis (2000). Neurophysiol Clin 2000;305:263–88.
    1. Baliki MN, Geha PY, Jabakhanji R, et al.A preliminary fMRI study of analgesic treatment in chronic back pain and knee osteoarthritis. Mol Pain 2008;4:47..
    1. Delli Pizzi S, Mantini D, Ferretti A, et al.Pharmacological functional MRI assessment of the effect of ibuprofen-arginine in painful conditions. Int J Immunopathol Pharmacol 2010;233:927–35.
    1. Wise RG, Rogers R, Painter D, et al.Combining fMRI with a pharmacokinetic model to determine which brain areas activated by painful stimulation are specifically modulated by remifentanil. Neuroimage 2002;164:999–1014.
    1. Gear R, Becerra L, Upadhyay J, et al.Pain facilitation brain regions activated by nalbuphine are revealed by pharmacological fMRI. PLoS One 2013;81:e50169..
    1. Taylor JJ, Borckardt JJ, Canterberry M, et al.Naloxone-reversible modulation of pain circuitry by left prefrontal rTMS. Neuropsychopharmacology 2013;387:1189–97.
    1. Gimenez M, Pujol J, Ali Z, et al.Naproxen effects on brain response to painful pressure stimulation in patients with knee osteoarthritis: A double-blind, randomized, placebo-controlled, single-dose study. J Rheumatol 2014;4111:2240–8.
    1. Pickering G, Kastler A, Macian N, et al.The brain signature of paracetamol in healthy volunteers: A double-blind randomized trial. Drug Des Devel Ther 2015;9:3853–62.
    1. Woo CW, Krishnan A, Wager TD.. Cluster-extent based thresholding in fMRI analyses: Pitfalls and recommendations. Neuroimage 2014;91:412–9.
    1. Bacon TH, Hole JG, North M, Burnett I.. Analgesic efficacy of sustained release paracetamol in patients with osteoarthritis of the knee. Br J Clin Pharmacol 2002;536:629–36.
    1. Benson M, Marangou A, Russo MA, et al.Patient preference for sustained-release versus standard paracetamol (acetaminophen): A multicentre, randomized, open-label, two-way crossover study in subjects with knee osteoarthritis. J Int Med Res 2009;375:1321–35.
    1. Altman RD, Zinsenheim JR, Temple AR, Schweinle JE.. Three-month efficacy and safety of acetaminophen extended-release for osteoarthritis pain of the hip or knee: A randomized, double-blind, placebo-controlled study. Osteoarthritis Cartilage 2007;154:454–61.
    1. Gazzaniga MS. The Cognitive Neurosciences, 4th edition Cambridge, MA: MIT Press; 2009.
    1. Wager TD, Atlas LY, Lindquist MA, et fMRI-based neurologic signature of physical pain. N Engl J Med 2013;36815:1388–97.
    1. Lamm C, Nusbaum HC, Meltzoff AN, Decety J.. What are you feeling? Using functional magnetic resonance imaging to assess the modulation of sensory and affective responses during empathy for pain. PLoS One 2007;212:e1292..
    1. Carlson NR. Structure of the nervous system In: Carlson NR, ed. Physiology of Behavior, 11 edition.New York, NY: Pearson; 2013:66–98.
    1. Reed CL, Caselli RJ.. The nature of tactile agnosia: A case study. Neuropsychologia 1994;325:527–39.
    1. Yen CT, Lu PL.. Thalamus and pain. Acta Anaesthesiol Taiwan 2013;512:73–80.
    1. Sprenger C, Finsterbusch J, Buchel C.. Spinal cord-midbrain functional connectivity is related to perceived pain intensity: A combined spino-cortical FMRI study. J Neurosci 2015;3510:4248–57.
    1. Jensen KB, Kaptchuk TJ, Chen X, et al.A neural mechanism for nonconscious activation of conditioned placebo and nocebo responses. Cereb Cortex 2015;2510:3903–10.
    1. Melzack R, Wall PD.. Pain mechanisms: A new theory. Science 1965;1503699:971–9.
    1. Geuter S, Eippert F, Hindi Attar C, Buchel C.. Cortical and subcortical responses to high and low effective placebo treatments. Neuroimage 2013;67:227–36.
    1. Price DD, Craggs J, Verne GN, Perlstein WM, Robinson ME.. Placebo analgesia is accompanied by large reductions in pain-related brain activity in irritable bowel syndrome patients. Pain 2007;127(1–2):63–72.
    1. Sevel LS, O'Shea AM, Letzen JE, et al.Effective connectivity predicts future placebo analgesic response: A dynamic causal modeling study of pain processing in healthy controls. Neuroimage 2015;110:87–94.
    1. Kaptchuk TJ, Friedlander E, Kelley JM, et al.Placebos without deception: A randomized controlled trial in irritable bowel syndrome. PLoS One 2010;512:e15591..
    1. Oken BS. Placebo effects: Clinical aspects and neurobiology. Brain 2008;131(pt 11):2812–23.
    1. Scott DJ, Stohler CS, Egnatuk CM, et al.Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses. Arch Gen Psychiatry 2008;652:220–31.
    1. Lidstone SC, Stoessl AJ.. Understanding the placebo effect: Contributions from neuroimaging. Mol Imaging Biol 2007;94:176–85.
    1. Craggs JG, Price DD, Verne GN, Perlstein WM, Robinson MM.. Functional brain interactions that serve cognitive-affective processing during pain and placebo analgesia. Neuroimage 2007;384:720–9.
    1. Goffaux P, Redmond WJ, Rainville P, Marchand S.. Descending analgesia—when the spine echoes what the brain expects. Pain 2007;130(1–2):137–43.
    1. Eklund A, Nichols TE, Knutsson H.. Cluster failure: Why fMRI inferences for spatial extent have inflated false-positive rates. Proc Natl Acad Sci USA 2016;11328:7900–5.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera