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14 Articles in Volume 19, Issue #1
Analgesics of the Future: NKTR-181
Antidote to CDC Guideline; Plantar Fasciitis; Patient Input
Assessing and Treating Migraine in Women and Men
Demystifying Opioid-Induced Hyperalgesia
Editorial: Have We Gone Too Far? Can We Get Back?
How to Compel Patients to Complete Home Exercises
Inflammation Targeted Nanomedicine
Intravenous Stem Cell Administration for Ileitis
Invasive Surgery: Effective in Relieving Chronic Pain?
Pain Catastrophizing: What Practitioners Need to Know
Pain Therapy Options for the Home
Regenerative Medicine
The Future of Pain Management
Whole Body Vibration: Potential Benefits in the Management of Pain and Physical Function

Inflammation Targeted Nanomedicine

A perspective on the promise and potential of biomedical technologies for pain diagnosis and management.
Pages 33-35
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As the opioid epidemic continues to weigh on healthcare providers, finding its cause and assigning blame is, in the author’s opinion, not sufficient to curb the crisis. Instead, the focus should be placed on finding and using effective non-opioid treatments. The existing timelines for drug development and approval may seem long, as they range from 5 to 10 years, depending on the approach used.1,2 As both a chronic pain patient and a researcher, I would argue that effective solutions do exist and can be made available today.

By reaching into the already established biomedical technologies toolbox, which includes targeted nanomedicine and nanoimaging, clinicians have the opportunity to repurpose existing diagnostic technological solutions that have proven successful in other areas of medicine (eg, cancer, cardiovascular diseases). This approach can help lead to new ways of assessing pain that involve assessing pathophysiology in unbiased and quantitative ways. Further, nanotechnology that has already been validated in humans for increasing the safety and efficacy of anticancer medicine may prove to reveal dramatic improvement in pain treatments. Herein are two specific opportunities for the application of nanomedicine in future pain care.

Theranostic Pain Nanomedicine

Nanomedicine is broadly defined as nanotechnology applied to disease diagnosis and treatment.3 Development of nanomedicine requires an integrated multidisciplinary approach and, as such, may provide solutions to complex problems. In the case of cancer, nano-based treatments and diagnostics have been extensively studied with diverse formulations under clinical development: these include micelle, polymeric nanoparticles, liposomes, and others. Disease-driven design has been suggested to facilitate faster clinical translation.4 This approach relies on in-depth understanding of pathophysiology and the tailoring of nanomedicine design for that pathology. I propose that this approach may be adapted to complex pathologies behind chronic pain. Further, nanomedicine, unlike traditional medicine, may offer unique advantage where diagnostics of the disease pathology and monitoring of therapeutic outcomes can be combined with delivery of treatment into one package. This approach is termed theranostic nanomedicine, and has been studied in cancer diagnosis and treatment as well as in inflammatory and cardiovascular diseases, extensively reviewed elsewhere.5

Theranostic nanomedicine has only been tested in preclinical models to date and its clinical potential is still under investigation. However, theranostic nanomedicine holds unmatched potential to provide effective, personalized, and safe pain treatment for both acute and chronic pain.

Figure 1 shows a proposed design for using inflammatory cell targeted pain nanomedicine, where non-opioid medicines and diagnostics are directly delivered to immune cells for both enhanced therapeutic efficacy and improved diagnosis. This concept of immune-system targeted pain nanomedicine was born out of my own experience with inflammatory pain. Pain and inflammation fluctuate over the course of disease progression and/or recovery. Each patient’s unique experience contributes to these changes. It is known that exercise, diet, and overall lifestyle choices can have a profound impact on inflammatory pain. The targeted theranostic nanomedicine approach may provide the means of adaptation to those changes, providing ultimate personalization for the individual person.

Figure 1. The author’s conceptual design of macrophage-targeted theranostic nanoemulsions as precision pain nanomedicines (Duquesne Univ., 2013.)

This concept has been tested in preclinical studies at Duquesne University, with researchers able to: correlate levels of monocyte-derived macrophages infiltration at the site of injury to changes in pain behavior; and dramatically reduce the overall dose of non-opioid delivered to achieve prolonged pain relief.6,7

Macrophage Targeting for Personalized Pain Relief

There is ample evidence that monocyte-derived macrophages infiltrating site of injury contribute directly to neuroinflammation and pain.8,9 It is also known that macrophages can assume varied phenotypes depending on the tissue context, timeframe following injury, and type of injury which fall between two extremes, the pro-inflammatory (M1) and anti-inflammatory/pro-healing (M2).10 M1 macrophages have been argued to be key players behind injury induced pain as they produce pro-inflammatory mediators, such as tumor necrosis factor-α (TNF-α), IL-6, IL-1β.11,12

Further, cyclooxygenase 2 (COX-2) levels are upregulated following neuronal injury,13,14 and it has been demonstrated that COX-2 is highly expressed in infiltrating macrophages. The presence of COX-2 overexpression has been correlated with the development of neuropathic pain in both animals and humans.13-16 Based on these findings, my lab team and I have argued that macrophages are attractive cellular targets for further therapeutic development in both acute and chronic pain.6

To test the hypothesis that macrophages may be targeted for pain relief, we designed proof-of-concept preclinical studies using macrophage-targeted theranostic nanoemulsions capable of both monitoring inflammation and delivery of low-dose non-opioid drugs to macrophages. Nanoemulsions are colloidal systems, where oil is dispersed in aqueous solution and stabilized by surfactants with small droplet size (50 to 200 nm). They offer useful delivery systems as they can be formulated to incorporate poorly water-soluble drugs17 and can be produced on large scale with highly controlled properties (eg, size, charge, drug loading) and high stability.18-20 Nanoemulsions can be expanded into theranostics by incorporating near-infrared fluorescent (NIRF) and fluorine magnetic resonance imaging (19F MRI) agents which, upon IV injection, allow for monitoring of macrophage infiltration at the site of injury.6,21

Last updated on: February 4, 2019
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