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5 Articles in this Series
A Worldwide Take on Opioid Prescribing and Access
Evolution of the Neuropathic State and Evidence-Based Treatment
Incidence and Causes of Persistent Chronic Pain After Major Surgeries
Notable Industry Surveys
Putting a Stop to Guideline Warfare: Lower Back Pain

Evolution of the Neuropathic State and Evidence-Based Treatment

With presentations by Tony Yaksh, PhD, and James Rathmell, MD

The neuropathic pain panel at the 2018 World Congress on Regional Anesthesia and Pain Medicine was kicked off by Tony Yaksh, PhD, of the University of California San Diego’s Anesthesiology Department. He provided a background on the neuropathic pain phenotype and discussed changes mediated by innate and adaptive immune processes that occur with nerve injury.1

The Mechanism of Neuropathy

Using trauma to a peripheral nerve as an example, Dr. Yaksh noted how a physician may block the neuroma and dorsal root ganglia (DRG) and still see spontaneous pain effect activity post-treatment. The mechanisms of post-injury ectopy include altered DRG protein expression driven by the original injury and trophic factors. A nerve injury can then lead to tactile allodynia, he explained. According to rodent studies, for instance, he said that while there are no changes in GABA/glycine receptors, loss of spinal glycine/GABA may occur, he explained. Loss of dorsal horn inhibition becomes a contributing factor as well, making GABA/glycerine excitatory rather than inhibitory.

Dr. Yaksh also discussed toll receptors (specifically, toll receptor 4, or TLR4) and their relation to innate immune signaling and persistent pain states via the DRG neuron (not just the macrophage), again, using rodent studies as examples. Morphine can react with TLR4 as a ligand, with one study showing significance of morphine doing harm post-operatively, he said. In the Q&A session, Dr. Yaksh clarified that morphine does not up-regulate TLR4, but rather, has potential to activate TLR4, which then activates inflammasome signaling, which ultimately leads to the prolonged pain state. Whether this postsurgical data has implications for the clinical setting has yet to be determined.

Regarding the relation between acute inflammation and tissue injury and evolution of the neuropathic state, Dr. Yaksh shared with the audience how allodynia can last well after injury-induced inflammation is resolved. The phenomena of “burnout neuropathic pain states” are the common result of this effect. Chronic arthritis, for example, that causes early phase inflammation may evolve to late phase neuropathic pain. NSAIDs may be used to block the early phase pain but not the late phase, while gabapentin, for instance, continues to act in the late phase. He concluded that spinal TLR4 signaling could mediate transition to a persistent pain state, and possibly make the patient more sensitive to a future injury.

Current Clinical Approaches

The second panelist in the neuropathic session, James Rathmell, MD, of Brigham and Women’s Health Care, shared clinical treatment updates via a review of the current literature.2

As pain practitioners know, most patients presenting with neuropathic pain have an underlying etiology(ies) that may need to be addressed first for the best outcome. So the first step in clinical approach should be to assess for other comorbidities so that these can be part of the treatment plan.

With regard to evidence-based neuropathic treatments, he noted that diabetic neuropathy and post-herpetic neuralgia are the most widely studied when trying to identify front-line treatments, such as pregabalin, gabapentin, and venlafaxine, and therefore are often applied to other neuropathic conditions. Tramadol, topical lidocaine, and certain opioid agonists have been less studied, he noted. After reviewing the literature, Dr. Rathmell pointed out that first-line recommendations between 2007 and 2017 “are exactly the same.” While some indications have been extended to other disease states, there are few prospective randomized high-quality trials to support new first-line therapies in neuropathy, he said. It has been a fairly static landscape despite accumulating mountains of evidence with opioids, in particular, he said.

In interventional therapy for neuropathic pain, Dr. Rathmell said the literature shows weak conclusions (largely due to short follow-up periods) regarding long-term effects of epidurals, radiofrequency denervation, and spinal cord stimulation. Most existing interventional studies have targeted back pain syndromes such as radiculopathy. Support for transcranial magnetic stimulation, however, may be growing in this area, and for other pain conditions, he noted (see below).

Intrathecal therapy for cancer pain using opioids as well as ziconotide, on the other hand, seems to have larger industry support and trial evidence in treating intractable pain, especially toward the end of life, and as a first-line approach before neuromodulation. Intrathecal therapy in non-cancer pain patients has yielded a lower recommendation but is still advised by experts, he noted.

Emerging therapies for neuropathic pain include repeated ketamine infusion. Dr. Rathmell pointed to what he called the best review on this topic by Zhao J, published in February 2018 . The caveat is that while short-term benefit is sometimes sustained over weeks or months, a long-term trajectory has not been demonstrated. Dosing regimen is also not standardized yet. Another review by Maher DP  showed that higher doses of ketamine for longer periods of infusion may result in longer pain relief. More efficient studies are still needed, said Dr. Rathmell, but anecdotal experience seems to be driving more use of ketamine in neuropathic pain management.

Repetitive transcranial magnetic stimulation (rTMS) is also emerging in evidence-based pain trials. By stimulating the motor cortex, an analgesic effect is produced, especially in spinal cord injury, but consensus on treatment regimen is undetermined.

Overall, Dr. Rathmell said he advocates for evidence-based approaches to treating patients with neuropathic pain and sees promise in ketamine infusion and transcranial magnetic stimulation.


Sympathetic Blocks

In the Q&A following the panel, sympathetic nerve blocks were discussed as having little research support for neuropathic pain, as only short-term analgesic effects are known. Dr. Rathmell noted that this type of block may be desired if it facilitates the patient’s functional restoration, such as for enabling them to better participate in physical therapy, but in the long run, it is not likely to help, even if performed often and early after the injury. Local anesthetic interruption certainly has benefits, he explained, but the blockade wears off, and the pain returns.

Sympathetic blocks have worked in acute states of complex regional pain syndrome (CPRS), noted the panel moderator Honorio Benzon, MD, who said he has practiced pain therapy for 42 years. Added Dr. Rathmell, sympathetic blocks have been used widely by psychiatrists in the treatment of depression and since they are FDA-approved, seem to be paving the way for more application in pain practice.



1 Yaksh T. Basic Science, Neuronal and Immunological Mechanisms. Presented at the World Congress on Regional Anesthesia and Pain Medicine, April 19-21, New York City

2 Rathmell J. Clincal Treatment Updates. Presented at the World Congress on Regional Anesthesia and Pain Medicine, April 19-21, New York City

Next summary: Incidence and Causes of Persistent Chronic Pain After Major Surgeries
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