Abstract and Introduction
Preclinical pain research has applied state-of-the-art methods over the past 40 years to describe, characterize, and image molecules, cells, and circuits in rodents to understand the pathophysiology of chronic pain. Despite generating a plethora of novel analgesic targets, pharmaceuticals for chronic pain treatment remain largely limited to the same 6 drug classes as present 40 years ago. It is possible that 40 years of effort has brought us to the verge of a paradigm shift and an explosion of novel analgesic drug classes with remarkable safety, efficacy, and tolerability. We think it more likely that advances will not occur until we follow the description of exciting discoveries with hypothesis testing using clinically relevant preclinical animal models and ethologically relevant outcome measures, which better reflect the clinical characteristics of chronic pain syndromes. Furthermore, to be valuable, experiments using such models must be conducted to the highest levels of internal validity, rigor, and reproducibility. Efforts by funders, most recently the Helping End Addiction Long-Term by the National Institutes of Health, aim to address some of these challenges and enhance communication and collaboration between preclinical and clinical investigators. However, the greater problem is a culture that emphasizes novelty and number of publications over scientific rigor and robust replication leading to a high likelihood of false-positive results. A path forward is provided by the evolution of clinical research beginning 50 years ago that resulted in methods to reduce bias and enhance transparency and ethics of reporting, moving from case reports to randomized controlled trials to innovative study designs with a focus on rigor, generalizability, and reproducibility. We argue that culture changed in clinical science in part because powerful forces outside the peer review system, especially from federal regulators that approve new drugs and human studies committees that addressed ethical failures of earlier research, mandated change in studies within their purview. Whether an external force will affect change in peclinical pain research is unclear.
We need better interventions to treat acute and chronic pain. This opinion piece focuses on new pharmaceuticals, but the concepts discussed equally apply to nonpharmacologic interventions. Despite decades of basic science investigation, which includes the 2021 Nobel Prize, drugs used commonly to treat pain (local anesthetics, opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, antidepressants, and anticonvulsants) are limited by short duration, inadequate efficacy, and/or poorly tolerated adverse events. Belief in the past that opioids could treat chronic pain led to increased opioid prescribing and development of longer acting formulations, which contributed to an epidemic of opioid misuse and deaths. Better ability to visualize peripheral nerves with ultrasound imaging greatly expanded the delivery of regional analgesia, but existing local anesthetics and formulations remain limited by their short duration of action and adverse events, and there have been no new local anesthetics or selective sodium channel subtype blockers approved in 30 years. The public has responded to this situation with increasing distrust of approved analgesic drugs and medical practitioners and by embracing other therapies, such as cannabis, largely circumventing regulatory guidance, and with poor quality evidence of efficacy or safety.
For decades, basic science has rapidly advanced, often led by clinical observations and genomic research, to discover new target upon new target to treat pain. These targets have been plausibly established by a multitechnological confluence of evidence derived from studies in single cells or tissues in vitro or in vivo and in sentient animals, usually rodents. Targets have been identified, which manipulate processes ranging from genetic translation to cellular bioenergetics to complex neural interactions to crosstalk between cells of the nervous and immune systems. Despite this effort, it is noteworthy that, with few exceptions of uncommonly used drugs, clinicians and patients are essentially left with the same analgesic drug classes now as 40 years ago. The purpose of this piece is not to describe the newest targets. Rather, it is to identify possible reasons for this lack of progress and alternative pathways that might be more fruitful.
One could argue that this failure is understandable. Chronic pain, like neuropsychological disorders in general, is a highly complex biopsychosocial and individualized experience and failure to translate analgesic discovery into therapy that may reflect inadequate understanding of this complexity. Or failure may simply reflect the nature of scientific progress, which often appears saltatory, with decades-long periods of minimal change, then appearance of an idea or finding that rapidly shifts paradigms. Periods of stagnation in some cases reflect flawed thinking or hypotheses, but in others, they reflect laborious construction of new tools and concepts, which enable paradigm shifting research. For example, slow progress in fundamental understanding and generation of methods in molecular biology and immunology provided the tools that were applied to generate effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a period of weeks to months. Perhaps, the past 40 years of pain research have generated such tools and concepts that will lead to novel treatments soon.
We believe it is more likely that failure may reflect fundamental flaws in methods in rodents to identify and validate targets. Most preclinical pain research in rodents relies on behavioral responses to simple peripheral stimuli, oftentimes reflexive ones, as measures of drug efficacy. This approach works when determining pharmacologic efficacy and potency of novel compounds within drug classes of established clinical effectiveness, such as new NSAIDs, opioids, or gabapentinoids. It has been tacitly assumed that this approach would also predict human efficacy of drugs targeting novel mechanisms. Indeed, a workshop January 30–31, 2019, sponsored by the US National Institutes of Health concluded that high throughput screening of novel analgesics should be performed in rodents and that only drugs that show efficacy in such screening should move on to further testing.
The success of research in rodents to predict clinical efficacy in humans has been poor, as evidenced by failure to relieve pain despite evidence of target engagement in clinical trials of antagonists of neurokinin-1, 5-hydroxytryptamine type 3, and calcitonin gene-related peptide antagonists, although the last mentioned exhibits efficacy to treat migraine, an important and common pain state. Ziconotide is perhaps the best example of success coming from rodent research, but its clinical utility is limited by the need for continuous intrathecal infusion and its low therapeutic ratio. Other targets discovered in rodents, such as nerve growth factor or cholinergic or angiotensin II receptors,[4,5] were indeed successfully translated to humans, but their clinical development has been delayed by toxicity and adverse event factors.
More fundamental to methods are species differences. It is possible that the anatomy and neural circuitry and physiology of the peripheral and central nervous systems differ so much from rodents to humans and that the behavioral repertoire of rodents is so limited that the use of rodents in discovery science for analgesic drug development is doomed to fail. We disagree, but suggest that failures to date reflect reliance on experiments with low internal and external validity conducted in rodents. We next review some methods, which have been proposed to increase the validity of studies in rodents and optimistically hope that this will improve the chances of success.
Anesth Analg. 2022;135(6):1128-1136. © 2022 International Anesthesia Research Society