During my childhood, televisions became common in middle-class American homes. Some early television shows have become classics and a few commercials, primitive by today's standards, also linger in memory. One starts with a father sitting in his easy chair reading a newspaper. His young daughter then walks over and asks, “Why is the sky blue, Daddy?” The father chuckles and puts down his newspaper. He repeats the naïve, childish question in a mocking tone, then gets about a half sentence into his explanation and hesitates. He starts again, stops again, stammers out another try and gives up, ashamed at his ignorance. The sponsor, a publisher of encyclopedias, counted upon parents' fear that their inability to answer even a simple question would hurt their children's chances for success. I do not know whether the commercial boosted sales, but I am certain that purchasers of that encyclopedia would still not be able to provide the answer. Perhaps it would contain entries on optics, diffraction, the Tyndall effect, Rayleigh scattering, the retina, and the visual cortex, but it could not explain how physical properties enter consciousness in such a way that our minds imbue objects or sensations with the quality of color. Nobody has, and even today's greatest minds still struggle with this “most daunting problem of consciousness.”1
The intriguing and long-overdue systematic review by Kissin et al.2 likewise begins with a very simple question: what happens when a local anesthetic block is performed to treat a painful neuralgia? Since the dawn of regional anesthesia, it has been recognized that “often the effects of a … nerve block will long outlast the duration of the actual sensory anesthesia.”3 Erudite explanations of this and the related phenomenon of differential nerve block4 with incremental concentrations of local anesthetics have been offered on the basis of complex neuronal effects of such agents5 as well as their distinctive pharmacology.6 But as has proven to be the case with systemic infusions of low doses of ketamine7 or local anesthetics,8 their prolonged benefit for neuropathic pain is now increasingly seen as insufficiently explained simply on a pharmacokinetic basis. Instead, pharmacodynamic explanations have been advanced whose sophistication and complexity have evolved in parallel with accumulating insights into the neurobiology of nerve injury and regional anesthesia.9 Furthermore, it has become appreciated that the mere insertion of needles during peripheral nerve blocks activates endogenous analgesia.10
It is tautological to “explain” the persistent widespread effects of local anesthetic nerve blocking as the interruption of a vicious cycle of self-sustaining pain. I myself have described to patients that a local anesthetic block for neuralgia is akin to stopping the rotation of a flywheel, knowing that this description neither explains what the procedure does, how it works, what or where the metaphorical flywheel is, nor when it may restart.
Is the everyday phenomenon of pain relief after local anesthetic block for neuralgia so obvious and well understood that further efforts to define it are a naïve waste of time and money? I do not think so, nor do some of the most insightful researchers in the field of pain. When the Arner study was first published in the journal Pain, its editor-in-chief Patrick Wall reflected,
It is a disgrace for all of us that this procedure [single local anesthetic block] has been done millions of times in the past hundred years and yet this is the first proper study of the effect. It is even more of a disgrace that there are thousands of anecdotal reports that these injections sometimes produce prolonged effects on these otherwise intractable pains and yet there has been no careful study of this potentially useful response.11
Frustrated by the lack of response to his plea to investigators, he returned to this topic in 1998 in an essay on the horizons of pain research:
One might reasonably conclude that…we were approaching full understanding [of local anesthetics] and that future developments would involve the discovery of only a few minor details. I hope to persuade the reader that this is far from the truth and that local anesthetics are in fact a powerful probe into a number of crucial unsolved questions. [Citing the Arner study he decries that] the paper appears to have sunk without a trace in spite of being written by the most distinguished group from the Karolinska. Their call for further studies seems to have fallen on deaf ears in spite of potential future consequences of their findings for practical therapeutics and the other evidence that therapeutic doses of local anesthetics were having long-term and long-range results.12
In this 1998 essay, Wall mentioned a variety of mechanisms by which local anesthetics may produce long-lasting effects, including anti-inflammatory actions, retrograde transport, and suppression of ectopic discharge in damaged nerves. In the intervening years, it has become clear that peripheral neural blockade with local anesthetics produces an immediate response in the central, cortical representation of the blocked region,13,14 which certainly has the potential to alter central processing in chronic pain. Furthermore, the spectrum of persistent anti-inflammatory effects of local anesthetics has been broadened to include inhibition of glial and astrocyte activation,15 in part mediated through central trophic factors, echoing a putative mechanism for persistent benefit from ketamine.16
The belief among world-class researchers that there remains much to be learned about the mechanisms and effects of peripheral nerve block for chronic pain remains current today. Basbaum, recently updating Wall's essay on horizons in pain research,17 stated,
I am, in fact, a very strong advocate of the view that the vast majority, if not all, of chronic pain conditions are maintained , to a great extent, by ongoing activity of peripheral afferents….Indeed, the great majority of ongoing pains (both nociceptive/inflammatory and neuropathic) can be blocked, at least transiently, by peripheral local anesthetic injection. The block will, of course, wear off, and the pain will return, but in some fortunate patients the relief significantly outlasts the anesthetic duration….One can speculate that the prolonged relief results from a transient quieting of the central sensitization that is driven by ongoing peripheral nerve activity.
Kissin et al.2 are to be congratulated for showing us with great clarity how little we know about this everyday intervention. The weakness of much of the literature on pain control18 may be looked upon as both a great misfortune and a great opportunity. As Liu et al. have done for other regional anesthetic interventions,19 it is now time to articulate the series of knowledge gaps identified in this systematic review2 and set forth a research framework to close them.
What might such a framework look like? A starting point would be the 3 general clinical impressions that introduce the present review. Conducted prospectively using placebo and comparator controls (e.g., sham and distant local anesthetic injection), these would first examine the duration of conduction blockade and pain relief in experimental and clinical pain states by assessing pain thresholds in multiple sensory modalities including dynamic tactile allodynia. Next, they would assess in individual studies of uniform models the threshold proximity, volume, and dose–response for injections distal to lesions, to produce pain relief proximally in the same nerve or branch or over the entire distribution of a proximal branch. Once the latter is characterized, one could differentiate the relative contributions of cortical reorganization versus unmasking of diffuse noxious inhibitory controls that might be tonically active in chronic neuralgic pain. Assuming that initial trials confirm long-lasting effects of local anesthetics for neuralgias, subsequent studies might examine coadministration of injected glucocorticoids or clonidine, systemic medications (mexiletene, dexmedetomidine or other α-blockers, gabapentin or pregabalin, low-dose ketamine or other N-methyl-D-aspartate blockers, …), or topical medications (lidocaine, capsaicin, …) administered singly or in combination at the time of peripheral local anesthetic injection so as to augment and prolong its benefit. If the duration of analgesia were a week or longer, one might compare efficacy, adverse effects, and costs of a series of outpatient injections versus other interventions as part of a multimodal rehabilitative program for persons with chronic neuralgic pain. Outliers identified in any of the above trials would invite more detailed pheno- and genotypic characterization, e.g., of native and newly expressed sodium or calcium channels. Care should be taken to adequately power proposed trials, because underpowering pervades the literature on regional anesthesia for chronic pain treatment.18 A group of individuals familiar with regional anesthesia, chronic pain treatment, and clinical trial design including relevant outcomes assessment might well be convened to prioritize the above and other potential issues, as has been done recently by professional organizations and federal funders addressing the problem of the evolution from acute to chronic pain.
Name: Daniel B. Carr, MD, DABPM, FFPMANZCA (Hon).
Contribution: The author wrote the manuscript.
Attestation: Daniel B. Carr approved the final manuscript.
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