Indefinite refractory pain pushes the pain treatment pipeline

A key step in managing a medical condition is to define it and then develop a guideline to treat it. Although this approach has improved, saved and extended the lives of millions, one condition – intractable pain – has eluded universal definition.

Clinicians agree that refractory pain is pain that persists through normal treatment cycles. Some say intractable pain is the same as chronic pain – that it’s relentless, intractable, and persists 3-6 months after treatment trials – but others disagree. The complexity of defining refractory pain is compounded by the fact that it differs in symptomatology depending on its underlying condition, whether it is rheumatoid arthritis, trigeminal neuralgia, degenerative disc disease or cancer. What many agree is that a well-accepted definition could improve pain management.

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

Neurologist Gary W. Jay, MD, however, said he had bad experiences with efforts to standardize approaches to intractable pain, particularly after the CDC released its 2016 recommendations for the use of opioids (see PPM In progress guideline update seriesexpected end of 2022).

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

Some clinicians look to the details to help determine refractory pain.

By pathology

A UK report focused on refractory defined refractory rheumatoid arthritis sickness as “widely assumed to involve resistance/refractory of multiple agents, more than might be considered ‘normal’ or ‘reasonable’ for the specific disease. »¹

A separate report from the UK recently concluded that “there is a need for a clear definition of the use of the term ‘refractory’ in orofacial pain conditions, excluding migraine and cluster headaches. Additionally, there is a need to reach consensus on the implications of using refractories when assessing and managing patients. »²

According to Sri Nalamachu, MD, Medical Director of Mid America PolyClinic, Overland Park, KS, “There is a greater awareness of pain presenting in different ways: neuropathic pain, nociceptive pain, mixed pain, acute pain, pain chronic. Some of this may be societal because we don’t like to call chronic pain by its name anymore due to a certain social stigma attached to it, so now we call it refractory.

By treatment duration

Dr. Jay noted, however, that the duration of treatment must be considered when describing a patient’s ongoing pain as refractory. “I get a lot of patients who are told the drugs failed and when you ask how many it turns out they got a small dose for a short time,” he said. “You have to be at the therapeutic level for an appropriate dose of painkillers, let’s say non-steroidal, that work immediately, like opiates, like antibiotics. But, if you are using an anticonvulsant, eg gabapentin, for pain, you should wait until the patient is titrated with an appropriate dose and give them 6-8 weeks after that to make sure you are giving them enough time for the pain. medication, at the right dose, to function appropriately. Then, if they fail, that would be an indication of a refractory problem.

In low back pain, he added, the patient may require an opiate, while treatment for headaches may lead to the use of CGRP (calcitonin gene-related peptide) antagonists. . A common denominator, Dr. Jay pointed out, is that any drug should be used in the right dose for the right amount of time.

Intractable pain and opioid abuse advance pain management

Alternatives to opioids

What is clear, despite the lack of a clear definition, is that various approaches to managing intractable 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 sigma-1 receptor (S1R) imaging. Researchers are currently investigating the molecular mechanisms that may be linked to the transformation of acute pain into chronic/refractory pain. A global study team has found that inflammation can actually prevent pain from chronifying.³

According to Stephen L. Barrett, DPM, assistant professor of molecular and cellular biology at Kennesaw State University, GA, the country’s response to opioid abuse and overdose clearly played a role in these advances. “There’s been a shift from, if you want to call it, the opioid landscape… Obviously I think what we’re trying to do now, compared to 10 years ago, is is to intervene with a lot of other things besides opioids.”

Among the painkillers in development, Dr. Nalamachu sees promise in Nav 1.7 inhibitors, which produce generative potentials that are small changes in voltage across neuronal membranes, and TRPV1 modulators, which mediate the detection harmful environmental stimuli. “There are a lot of new agents in clinical trials, targeting different pain pathways, so we’re addressing the pain at the root level rather than just treating the symptom, but we’re probably 5-10 years away from that. anything that would translate into clinical practice,” he said.

Pain relief devices

Dr. Jay has called the use of CGRP antagonists over the past 5 years a “paradigm shift” in migraine management, but also sees great potential in non-medical approaches. “I think in the future you’ll see more device focus and less drug focus, even though we’re never going to get rid of all pain medications,” he said. he declares. “There are now four neuromodulating devices that are FDA-cleared for headaches. This is different from using any preventative or abortive medicine 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 SNP, and he follows the development of SPECT imaging and PET MR technology to scan sigma-receptors. 1 involved in the transmission of pain.

“For the past 2½ to 3 years or so, we’ve focused on using peripheral nerve stimulators, especially in revision nerve cases where they have a lot of scarring,” he said. “The peripheral nerve stimulation modality 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. S1R imaging would be more specific to find the pain generator, whereas a SPECT image of the brain will show what is going on in the brain.

Biopsychosocial models

There is also a more holistic (i.e., biopsychosocial) approach to managing chronic, intractable pain that examines each patient’s sleep patterns, diet, and physical activity. But the implementation of the biopsychosocial approach is slow.

“We have strived to achieve a balance between providing appropriate care based on the available evidence. For patients with intractable pain, we are considering treatment options that are off-label and/or with less established evidence of effectiveness,” explained Dr. Reddy.

Bottom Line: Refractory Pain Guidelines Are Still Needed

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

“I hope the guidelines get to a point where we have a balance between pain management meeting the needs of patients with pain while addressing the issue of abuse,” Dr. Nalamachu said. “If we have balanced guidelines, everyone’s happy, so hopefully we’ll see that. We’ve come up with guidelines that have unintended consequences, and then we have to go back. The CDC recently revised some of its guidelines, giving more freedom to clinicians in the field. I hope this can lead to better patient care.”

  1. Bouche, MH. Definition of refractory rheumatoid arthritis. Annals Rheum Dis. 2018;77(7):966-969. doi:10.1136/annrheumdis-2017-212862
  2. Renton T. Intractable 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. The 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

About Antoine L. Cassell

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