Neuroinflammation and Central Sensitization in Chronic and Widespread Pain

Ru-Rong Ji, Ph.D.; Andrea Nackley, Ph.D.; Yul Huh, B.S., M.S.; Niccolò Terrando, Ph.D.; William Maixner, D.D.S., Ph.D.


Anesthesiology. 2018;129(2):343-366. 

In This Article

Clinical Trials and Translational gap

The current levels of enthusiasm and interest in the development of new treatments that specifically target neuroinflammation and glial activation may be tempered by the somewhat disappointing results of previous clinical trials. Although animal models, as reviewed in the previous sections, demonstrated promising results in the reduction of neuropathic pain, glial activation, and neuroinflammation when treated by the glial modulator propentofylline,[237,238] the same compound failed to provide beneficial reductions in neuropathic pain when administered to patients suffering from postherpetic neuralgia.[239] Despite its efficacy in reducing postoperative pain in animal models, intrathecal injection of cyclooxygenase inhibitor such as ketorolac did not improve acute or chronic pain after hip arthroplastry.[119,196] Although the clinical trial does not support a central role of cyclooxygenase/prostaglandin E2 pathway in clinical pain, cytokines and chemokines can independently regulate central sensitization via direct actions on nociceptive neurons (Figure 5). Thus, future clinical studies are still needed to test the effects of spinal inhibition of cytokines/chemokines in clinical pain. Neuropathic pain patients demonstrate tolerance to p38 inhibitors including dilmapimod and losmapimod,[240,241] but these drugs have inconsistent levels of efficacy. An exploratory trial of dilmapimod significantly inhibited nerve injury–induced neuropathic pain;[240] however, losmapimod did not demonstrate any significant analgesic effect in comparison to placebo controls.[241] Intriguingly, acute postsurgical dental pain was significantly reduced when treated with another p38 inhibitor, specifically the novel p38α mitogen-activated protein kinase inhibitor SCIO-469.[242]

The use of cytokine inhibitors and glial modulators in clinical trials has shown some encouraging results. Intractable discogenic lower back pain patients showed up to 8 weeks of pain relief when given a single intradiscal treatment of entanercept, a tumor necrosis factor inhibitor.[243] Additionally, lumbar disc herniation patients who received entanercept via transforaminal epidural injections had up to 26 weeks of pain relief after two injections in a randomized, double-blind, and placebo-controlled trial.[244] Another cytokine inhibitor, the interleukin-1 trap rilonacept, is well tolerated by patients, and in a proof-of-concept study, treatment with the drug showed pain relief for a small group of patients being treated for chronic refractory gouty arthritis.[245] By contrast, subcutaneous inhibition of interleukin-1β with anakinra has no beneficial effect on chronic fatigue syndrome.[246] Microglial activation can be blocked in vitro by low doses of naltrexone,[247] and a pilot trial also showed that treatment with the drug can help to reduce symptoms related to fibromyalgia.[248]

Certain limitations and concerns regarding the design of the mentioned trials need to be addressed. The first concern regards the lack of neuroinflammation analysis by biomarkers, because inhibition of in vivo glial responses in the propentyofylline study notably had no biomarker validation.[239] A second concern is the lack of validation regarding whether central sites, including the spinal cord, received exposure to systemically administered drugs. For instance, it was noted by the authors of the losmapimod study that the lack of response may be a result of central sites having a lack of adequate exposure to the drug.[241] In the majority of preclinical studies, inhibitors of glial cells, mitogen-activated protein kinases, cytokines, and chemokines are given via intrathecal administration, which ensures direct exposure of central sites to the drug being studied.[108] The third concern is the absence of analysis of sex-dependent effects of treatments in previous studies of p38 and glial inhibitors in light of emerging evidence of sex dimorphism in microglial and p38 signaling and T-cell signaling in inflammatory and neuropathic pain.[163,164] Fourth, the timing of administration appears to be a critical component of a treatment's efficacy. During the acute phase of pain, inhibitors of microglia, p38 mitogen-activated protein kinase, and tumor necrosis factor-α show stronger efficacy, with more partial effects in the chronic phase according to preclinical studies.[108,249] In line with this point, the effective results of the p38 inhibitor SCIO-46 trial were demonstrated in dental patients during the acute phase of postsurgical pain.[242] It should be noted, however, that the intrathecal administration of the interleukin-1 receptor antagonist anakinra at 16 weeks post–bone fracture in rodents can reduce chronic postoperative pain.[58] Finally, the mechanisms of the tested drugs need to be further elucidated. Propentofylline, although a glial modulator, also acts as a phopsphodiesterase inhibitor, as well as an adenosine uptake inhibitor. Thus, the administration of this drug may alter cAMP and adenosine levels in both glial and nonglial cells.[250]

Animal models are of exceeding importance in the understanding of the mechanisms of pain, as well as for testing newly developed therapeutics. However, animal models cannot reproduce all key clinical symptoms of pain, and thus the gap in translation between preclinical studies in rodents and clinical studies in humans is a major topic in pain research discussed in numerous review articles.[251,252] With regard to methods of measurement, in animal studies pain is measured by application of von Frey filaments to cause reflex pain with subsequent quantification of paw withdrawal thresholds, whereas most clinical studies measure pain based on the visual pain scale. Additionally, the time course of pain is very different between animals and humans, with the duration of pain in preclinical studies lasting normally from days to weeks, whereas clinical patients with chronic pain often suffer from their symptoms from months to years. Thus, developing animal models that accurately reflect the various genetic, sex-dependent, psychologic, and environmental factors and sequelae of the development and maintenance of chronic pain proves to pose a continuing challenge. Although clinically effective treatments do show efficacy in animal models thus far, increasing efforts to increase the translatability of preclinical and clinical studies will prove important, for instance measurement of spontaneous pain in animal models and quantitative sensory testing in human patients.[59,253–256]