Defining Refractory Pain

Clinicians agree that refractory pain is pain that persists through normal rounds of treatment. Some say refractory pain is the same as chronic pain – that it is relentless, intractable, and persists 3 to 6 months after treatment trials – but others disagree. Adding to the complexity of defining refractory pain is that it differs in symptomology based on its underlying condition, whether that be rheumatoid arthritis, trigeminal neuralgia, degenerative disc disease, or cancer. What many do agree on is that a well-accepted definition could improve pain management.

Physiatrist Rajiv Reddy, MD, an assistant professor of anesthesiology at the University of California San Diego Health, agreed that a clearer definition is needed. “Going forward, having a more standardized definition of ‘refractory pain’ … could help ensure providers in different specialties and settings are able to communicate consistently with each other and with patients, and would be a positive step toward harmonizing consensus guidelines for its treatment in clinical practice,” he said.

“I published the fact that the CDC guidelines are, to put it nicely, very deleterious to the lives of chronic pain patients. I, for one, use opioids as a third- or fourth-line treatment, but there are cancer patients who have failed multiple treatments and who may end up truly needing opiates,” said Dr. Jay, clinical professor of neurology at the University of North Carolina, Chapel Hill.

Some clinicians are turning to the details to help determine refractory pain.

By Pathology

One UK-based report focused on refractory rheumatoid arthritis defined refractory disease as “broadly assumed to imply resistance/refractoriness of multiple agents, more than might be considered ‘normal’ or ‘reasonable’ for the specific disease.”¹

According to Sri Nalamachu, MD, medical director at Mid America PolyClinic, Overland Park, KS, “There is more awareness of pain presenting in different ways – neuropathic pain, nociceptive pain, mixed pain, acute pain, chronic pain. Some of this may be societal because we don’t like to call chronic pain with its name anymore because of some social stigma attached to it, so now we call it refractory.”

By Length of Treatment

Dr. Jay, noted, however, that the length of treatment should be considered when describing a patient’s ongoing pain as refractory. “I get many patients who I am told have failed medications and when you ask how much, it turns out they were given a small dose for a short period of time,” he said. “You need to be on a therapeutic level for an appropriate dose of pain medications, let’s say nonsteroidal, which work immediately, as do opiates, as do antibiotics. But, if you are using an anticonvulsant, for instance gabapentin, for pain, you have to wait until the patient is titrated up with an appropriate dose and give them 6 to 8 weeks after that to make sure you are giving them enough time for the medication, at the right dose, to work appropriately. Then, if they fail that, that would be one indication of a refractory problem.”

Refractory Pain and Opioid Misuse Are Pushing Pain Management Forward

Opioid Alternatives

What is clear, despite a lack of clear definition, is that the varied approaches for managing refractory pain have led to several non-opioid advances. Some examples include Nav 1.7 inhibitors, TRPV1 modulators, CGRP antagonists, nerve decompression surgery, peripheral nerve stimulation (PNS), and imaging of sigma-1 receptors (S1R). Researchers are now examining molecular mechanisms that may be linked to turning acute pain into chronic/refractory pain. One global study team found that inflammation may actually prevent pain chronification.³

The nation’s reaction to the misuse and overdosig of opioids has clearly played a role in these advances as well, according to Stephen L. Barrett, DPM, assistant professor of molecular and cellular biology at Kennesaw State University, GA. “There has been a shift from, if you want to call it, the opioid landscape… Clearly, I think what we are trying to do now, versus 10 years ago, is intervene with many things other than opioids.”

Pain-Relieving Devices

Dr. Jay called the use of CGRP antagonists over the past 5 years a “paradigm shift,” in managing migraine headache but sees great potential in nonmedical approaches as well. “I think in the future you will see more device orientation and less medication orientation, though we are never going to get rid of all medications for pain,” he said. “There are now four neuromodulatory devices that are approved by the FDA for headache. That is different from using any preventative or abortive medication for a headache. There is still a place for them.”


Dr. Barrett’s practice focuses on lower extremity peripheral nerve surgery, using a combination of nerve decompression and PNS, and he is tracking the development of SPECT imaging and PET MR technology to scan sigma-1 receptors involved in pain transmission.

“For the last 2½ to 3 years or so we have been focused on the use of peripheral nerve stimulators, especially in revision nerve cases where they have a lot of scarring,” he said. “The peripheral nerve stimulation modality in and of itself is a good adjunct to have. If you can find the cause of the symptom, that’s ideal, and these imaging modalities are exciting. The S1R imaging would be more specific for finding the pain generator, whereas as a SPECT image of the brain is going to show what is going on in the brain.”

Biopsychosocial Models

There also is a more global approach (ie, biopsychosocial) being taken to chronic and refractory pain management that examines each patient’s sleep habits, diet, and physical activity. But implementation of the biopsychosocial approach is slow-going.

Bottom Line: Refractory Pain Guidelines Still Needed

Despite the promise of those varied approaches, what clinicians would like to see is more guidance, despite the sometimes-rocky reception of CDC recommendations.

“I am hoping the guidelines will come to a stage where we will have a balance of pain management addressing the needs of the pain patients but at the same time addressing the abuse problem,” said Dr. Nalamachu. “If we have balanced guidelines, everybody is happy, so I am hoping we see that. We have come up with the guidelines that have unintended consequences and then we have to go back. The CDC has recently revised some of its guidelines, giving more freedom to the clinicians in the field. I am hoping that can lead to better patient care.”


  1. Buch, MH. Defining refractory rheumatoid arthritis. Annals Rheum Dis. 2018;77(7):966-969. doi:10.1136/annrheumdis-2017-212862
  2. Renton T. Refractory orofacial pain: Is it the patient or the pain? J Oral Facial Pain Headache. 2021;35(4):317-325. doi:10.11607/ofph.3009
  3. Parisien M, Lima LV, Dagostino C, et al. Acute inflammatory response via neutrophil activation protects against the development of chronic pain. Sci Transl Med. 2022;14(644):eabj9954. doi:10.1126/scitranslmed.abj9954