PET Probe Pinpoints Sites of Pain Generation to Improve Pain Management Interview with:
Sandip Biswal MD
Associate Professor of Radiology
Co-Section Chief, Musculoskeletal Imaging
Director, Musculoskeletal Imaging Fellowship
Member, Molecular Imaging Program at Stanford (MIPS) and Bio-X
Department of Radiology
Stanford University School of Medicine  What is the background for this study?
Response: Our ability to manage patients with chronic pain remains woefully inadequate. Chronic pain patients are faced with limited resources and inadequate care, and as a result, they make up the #1 disease group in the world—numbering more than heart disease, diabetes and cancer combined. Those suffering from low back pain, headache, fibromyalgia, arthritis and many other pain syndromes make up this ever-growing population. A big part of our inability to care for chronic pain patients is due to the fact that our current imaging methods for correctly identifying pain generators remain substantially inaccurate. Our ability to accurately identify the cause of a person’s pain, discomfort, inflammation or other related musculoskeletal symptom(s) using current clinical imaging approaches, such as magnetic resonance imaging (MRI), computed tomography (CT), digital radiography (x-ray) and ultrasound, is quite limited, lacks sensitivity/specificity and can even misguide treatment. As a musculoskeletal radiologist, I witness these shortcomings on a daily basis. I, for example, see firsthand how the lack of reliable diagnostic tools leads to significant misdiagnosis, mismanagement, incorrect use of opioids, unhelpful surgeries and, ultimately, therapeutic failures. We need a much better way to diagnose pain generators. 

Accordingly, our group has been developing new clinical imaging methods that pinpoint the site of pain generation using imaging probes—more specifically, positron-emission tomography (PET) tracers that specifically target “pain receptors” or “pain molecules.” These pain receptors or pain molecules are present in abundance at the site of pain generation. After injecting one of these imaging probes into a patient through the vein, we give the probe a few minutes to circulate around the body and stick to areas that have a high density of pain receptors. We can then take a picture of the patient with a special camera that will show “hot spots” on the image that signify the location of high number of pain receptors, thereby highlighting “painful” pro-inflammatory and/or pro-nociceptive tissues. With this approach, doctors and patients have information with which they can make more objective decisions about the diagnosis and treatment of one’s pain. What are the main findings?

Response: In our study, we used the probe [18F]FDG to find inflammation. We observed higher levels of focally increased amounts of [18F]FDG (a.k.a. “hot spots”) in the affected nerves and muscle in patients with pain when compared to the same structures in asymptomatic volunteers. These hot spots were identified in 58 of 65 patients at the site of pain and other areas of the body. After we reviewed the imaging findings with the referring physician, modifications in the patients’ management plans based on imaging findings were as follows: 13/65 no change, 16/65 mild modification (e.g., additional diagnostic test) and 36/65 significant modification (e.g., new invasive procedure suggested or ordered). For example, PET/MR imaging helped to direct treatment of a patient with occipital neuralgia by helping direct a surgeon to inflammation along one of the occipital nerves, leading to relief from the pain. In another patient, PET/MRI detected a previously ruptured plantaris muscle, causing foot pain that was not imaged in prior workup of the patient. This finding led to a very small surgical procedure that gave the patient near complete relief. Also, PET/MRI helped decide the location of placement of blood patches to treat cerebrospinal fluid leaks, which was more successful than previous conventional methods.

Adult male with decades of right neck pain,
discomfort and tightening following birth injury.The surgeon ultimately found a collection of small arteries wrapped around the nerve in this location. The small arteries underwent lysis by the surgeon and the patient reported tremendous relief of symptoms.

CREDIT: Cipriano, et al., Stanford University, CA What should readers take away from your report?

Response: A few things can be gleaned from this work thus far: 

First, a reader may ask how this approach is different from an MRI study. This study uses 2 cameras to create medical images: the MRI camera, which can take excellent anatomic pictures of internal structures, and the positron emission tomography (PET) camera, which offers a powerful, highly sensitive and specific way to look at pain molecules or pain receptors. For the first time ever, we are looking at pain through the lens of two cameras simultaneously, and therefore we have the ability to discover pain generators and increase our understanding of the pain process. The PET camera in particular is detecting abnormalities in areas where the MRI was normal.

Second, one of our published studies showed that that while a patient may be given the diagnosis of sciatica, they may not actually have the classic manifestations of sciatica. Sciatica, by definition, is the result of a herniated disc impinging on a leg nerve of the lumbosacral spine, giving rise to leg pain and lower back pain. We have found those that have the diagnosis of sciatica may in fact have abnormalities that mimic sciatica. Abnormalities such as facet arthropathy or scar neuroma can give rise to the symptoms of sciatica. However, these other entities are managed very differently than classic sciatica. If a physician had a tool that showed exactly what was causing patient’s sciatica, then the physician could employ the appropriate therapy for the patient, remove the pain generator and help the patient achieve a more pain-free state. The PET/MRI approach described here has the potential to identify and localize pain generators more objectively and accurately than current methods.

Third, we employ a whole-body imaging approach that scans the patient from head to toe. A main reason why we do this is because we know that pain can be referred. Someone may be experiencing thigh pain, but the pain generator is actually in the spine from a herniated disc that compresses a nerve that supplies sensation to the thigh. Someone may be suffering from headaches, but they are due to a cerebrospinal fluid leak in the lower lumbar spine. If we were to image only the site of pain (e.g., the thigh or head), we might miss the true offending pathology. By scanning the entire body, we make sure we capture all possible causes. 

Fourth, while the study is still in its early stages, the referring physicians who send their patients for this clinical trial are finding it helpful and use the data to help make management decisions that have significantly helped a subset of patients thus far. We hope the trend continues and that we show convincingly that we minimize unnecessary or unhelpful surgeries, minimize hospital visits, help decide the use of systemic vs. local therapies or help develop/promote more efficacious or alternative therapies. What recommendations do you have for future research as a result of this work?

Response: Follow-up with a large cohort of patients should be conducted to establish the effectiveness of [18F]FDG PET/MRI to guide interventions for relieving pain. We will need to design studies where patients get scanned before and after a therapeutic maneuver. This will help validate our approach by demonstrating the fact that imaging findings, which initially show the pain generator, disappear or are minimized after an effective therapy. Alternatively, the imaging finding would persist on the post-therapeutic scan if the therapy were ineffective. Ultimately, we need to demonstrate that this imaging approach is able to positively affect patient outcomes and help patients obtain pain relief. Is there anything else you would like to add?

1) Pain is the most prevalent disease in the world. Despite that, and despite being a driver (at least in part) of the opioid epidemic, it is alarming to see that it goes largely ignored compared to other diseases. There is little funding available for pain research and drug development. With limited resources and tools to help with pain, it is not surprising that pain sufferers are among the most poorly treated disease population. Add to that the unfair stigma of being “crazy,” drug-seeking and malingering, and chronic pain patients are left with very few options and are marginalized not only in the medical community but also in general society. Other diseases such as cancer get substantial amount of funding compared to pain. For every $5,000 the National Institutes of Health give for cancer research, $1 goes to pain research. We need physician and patient advocacy groups, government agencies, philanthropists and venture capitalists to make a serious effort in to provide desperately needed resources in combating this disease, as it affects the lives of hundreds of millions of individuals across the globe. We need more accurate pain diagnostics and more safe and effective therapeutics.

2) We are observing abnormal imaging findings on nearly all pain patients. Sometimes we are able to act on them, and other times they are so new or unexpected that we must take time to understand what they mean before acting on them. While many patients will have a new plan of action after the study, for some the action plan is not yet entirely straightforward. There is a group of us who help evaluate and discuss the findings, so we are always trying our best to make the correct diagnoses and decisions. We always want to make sure we do what is best and safest for the patient and, most importantly, avoid additional harm.

3) If readers are interested learning more about this approach or are interested in participating in the clinical trial at Stanford, please feel free to visit

Any disclosures?

GE Healthcare provides funding for the clinical trial.
Responses reviewed and edited by Ms. Rebecca Maxey, Director of Communications at the SNMMI. 


18F-FDG PET/MRI of patients with chronic pain alters management
Abstract presented at the:
The Society of Nuclear Medicine and Molecular Imaging 2020 Virtual Annual Meeting


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Last Updated on July 31, 2020 by