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.
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
In nerve injury (eg, sciatic nerve chronic constriction injury) preclinical models, we found that theranostic (NIRF labeled) nanoemulsions loaded with celecoxib (COX-2 inhibitor) led to reduction in mechanical hypersensitivity (as a measure of pain behavior) as well as reduced macrophage infiltration at the site of injury.⁷ This apparent pain relief in a preclinical model was achieved at a very low drug dose (0.24 mg/kg) of celecoxib delivered via targeted nanoemulsions.⁶ The change coincided with an intriguing trend of decreased signal in drug-loaded nanoemulsion treated animals vs control (not shown), as measured by 19F MRI, 19F NMR and NIR fluorescence which corresponds to lowered macrophage infiltration at the site of injury and reduced neuroinflammation.⁶ Histological data further confirmed that the number of CD68 positive cells (macrophages) decreased at the site of injury, which correlates to a reduction in mechanical hypersensitivity.⁶ These compelling results provide key supporting evidence of the potential these approaches hold for further development of effective and extended pain relief with macrophage-targeted drug delivery.
Implications of macrophage-targeted nanomedicine for pain treatment and diagnosis are potentially fairly broad. As driving engines of inflammation, macrophages have been implicated in many chronic diseases that lead to chronic pain, from rheumatoid arthritis, inflammatory bowel disease to trauma.²²⁻²⁴ However, considering the promise that this technology offers as it further develops, certain questions remain. For example, it is has been shown that the immune system and nervous system show sex dimorphism. Hence, it is possible that nanomedicine may hold a key to solving the differences in therapeutic responses between males and females that have been seen in clinical and preclinical models.²⁵ Whether macrophage-targeted nanomedicine holds that specific key remains to be seen. Ongoing studies at Duquesne University are working to address these questions.
Conclusion
Overall, nanomedicine, powerfully multifaceted as it may be, needs work to streamline manufacturing, improve quality control, and reduce cost. If given adequate attention and support, it may become the solution to both the opioid crisis and the need for more effective, long-term pain management. Nanomedicine may also offer a way to directly address age and sex differences in pain medicine and to reach ultimate personalized pain treatment.