As an integral part of the medical management of patients experiencing pain, we medical imagers desperately need to do better to help those who suffer. Individuals with musculoskeletal pain and inflammation are among the largest populations seeking medical attention worldwide. Yet our ability to pinpoint pain generators accurately remains elusive, and our current imaging approaches can be misleading. For example, current imaging used to diagnose the cause of pain in an individual can generate false positives leading to unnecessary surgeries, especially in an aging population where age-related degenerative changes abound. Alternatively, our current imaging is not sensitive enough, so much so that imaging can indirectly facilitate the rampant use of opioids as caregivers are unable to identify the source of the pain.

We hope that the emerging discipline of molecular imaging will offer answers to these diagnostic conundrums in pain diagnosis. These methods seek to display specific aberrant cellular, molecular, and physiologic phenomena connected to these disorders noninvasively. For instance, molecular imaging can identify a specific “pain receptor” or “pain molecule” that is locally elaborated at the site of pain generation or track the presence and movement of cell population(s) that are specifically recruited in enhanced nociceptive conditions.

Intriguing developments in imaging technology, engineering, chemistry, molecular biology, and genetics that have come together in multidisciplinary and multimodality endeavors are confirmed by relatively recent molecular and cellular imaging procedures. In this issue, we review some of the latest imaging efforts that specifically exploit molecular and physiologic changes elaborated in tissues that participate in nociceptive signaling and are associated with the nociceptive phenotype. It is these relatively unique mechanistic pathways in pain generation and pain-related inflammation that are exploited using molecular and functional imaging paradigms. In this light, positron emission tomography (PET) and specialized approaches in magnetic resonance imaging (MRI) have led the effort to better identify peripheral pain generators, and many of those efforts are described here.

For example, Shen et al discuss how a highly specific PET radioligand for the sigma-1 receptor, FTC-146, is used with a dedicated PET/MRI scanner in the imaging of patients with chronic pain. This endeavor is already leading to improvements in patient outcomes in individuals who had been suffering with chronic pain for years before their diagnosis with this new imaging approach. The article also offers a practical discussion and insights on the typical workflow of imaging patients with chronic pain.

Mostert et al describe varying clinical molecular and functional imaging protocols directed toward understanding certain biological processes in knee pain, including perfusion MRI, fluoride ion PET, and diffusion MRI. Chaudhari et al review the major advantages of looking at the entire body with PET in a single imaging session using the uEXPLORER system in systemic inflammatory disorders such as rheumatoid arthritis. His group uses total-body PET to look at the entire inflammatory disease burden in individual patients. This technology will no doubt be an important tool in staging disease and monitoring therapy. Yoon and Lutz explain the latest developments in how diffusion tensor imaging can be used to assess peripheral nerves and therefore serve as a readout of the physical integrity of neural pathways. This technology is already helping peripheral nerve surgeons plan their approach to remove areas of mechanical constriction and impingement. Kim and Lee provide interesting new insights into the value of edema-like marrow signal intensity in the understanding of knee pain.

Emerging preclinical methods are also discussed and will certainly bring tremendous excitement to the pain imaging world. Hascalovici et al, for example, discuss the intriguing developments of using radiocaine, a radiofluorinated version of lidocaine. His group is currently looking at this PET tracer to localize pain-generating pathology in human subjects. Van der Heijden and Biswal also discuss other important preclinical developments that could more accurately image painful pathology, covering topics such as microglial/macrophage cell imaging and efforts to image voltage-gated sodium channels, to name a few.

The discussions that follow aim to foster a greater understanding of how such methods could assist in resolving musculoskeletal problems and help in the development of more effective analgesics and anti-inflammatory methodologies in the present and future. It is the goal of these efforts to define and localize pain-generating pathology, so more efficacious, individualized pain management approaches can be tailored to bring about much needed pain relief and significant improvements in outcomes for all pain sufferers more precisely.