2019 Pain Research Advances

Basic to Clinical

A Method to Deliver Targeted Therapeutics to Treat Chronic Pain.

A pH-responsive nanoparticle targets the neurokinin 1 receptor in endosomes to prevent chronic pain. 

While encapsulating drug molecules in nanoparticles can improve their efficacy by enhancing targeted delivery, when therapeutics must reach the cytoplasm or nucleus of a cell, the usefulness of nanoparticles is limited.

By conducting in-vitro tests and tests in mice and rats, researchers found that for an approved drug, aprepitant, which is used to treat nausea and vomiting caused by chemotherapy, encasing it in nanoparticles “induced a more complete and sustained anti-nociception in preclinical models than conventional therapies, including opioids.”

Delivering the treatment with nanoparticles minimized the dose required for pain-relieving effects, which could help limit side-effects, the authors note.

“The discovery that nanoparticle encapsulation enhances and prolongs analgesia provides opportunities for developing much-needed nonopioid therapies for pain.” For example, it may be possible to combine different treatments into the same nanoparticles.

A New Gene Target Could be Used to Improve Opioid Safety

Genetic behavioral screen identifies an orphan anti-opioid system.

Researchers developed a platform to help discover genes that influence opioid responsiveness and subsequently discovered a little-researched human gene that may help moderate the potential for opioid-induced analgesia, reward and withdrawal.

To screen for promising targets, the researchers generated a type of roundworm that expressed mammalian mu-opioid receptors throughout the nervous system. They bred a strain that were hypersensitive to certain opioids and identified a receptor that altered sensitivity to opioids at a behavioral level.

This roundworm receptor had analogues among mammalian cell surface receptors that previously had no known connection to opioid signaling. Expressing the human receptor in the roundworms significantly reversed their hypersensitivity to fentanyl, and further testing in human cells and other animal models provided more evidence of the receptor’s utility.

In human embryonic kidney cells, they showed that the receptor had inhibitory effects on mu-opioid signaling. Mice bred without the receptors were also hypersensitive to certain opioids. An experimental molecule that is meant to facilitate action by this particular receptor was tested on mice and was found to “negatively regulates a number of responses to acute opioid exposure, and potentiates withdrawal from chronic opioid administration.”

While the researchers identified a new target that could help improve the safety and efficacy of opioids, they also demonstrated the potential of a screening platform not just for opioid responsiveness, but that could be adapted for other kinds of neuronal circuitry. 

Pain Mechanisms

Using a Scorpion Toxin to Learn About Pain

A Cell-Penetrating Scorpion Toxin Enables Mode-Specific Modulation of TRPA1 and Pain.

Transient receptor potential ankyrin 1 (TRPA1) is a channel protein that is found on sensory nerves. This receptor can be activated by products such as wasabi or mustard oil to produce pain. Many of the ligands capable of activating TRPA1 are chemically reactive compounds which work by chemically modifying specific chemical features of the channel causing it to open. However, little is known about the way that non-chemically reactive TRPA1 ligands open this channel, as non-chemically reactive TRPA1 ligands tend to only weakly bind TRPA1. In this report, the authors aimed to find non-chemically reactive TRPA1 ligands that bind the channel strongly. The authors hoped to utilize this ligand to study a less understood mechanism of TRPA1 activation in hopes of informing development of novel analgesics. To accomplish this goal, the authors screened a large number of venoms to see if they can activate TRPA1. They found that the venom from the Australian Black Rock Scorpion strongly activated TRPA1 and they were able to identify the active compound within this venom – which they called Wasabi Receptor Toxin (WaTX). The authors then used sophisticated techniques to determine that this WaTX enters the cell and identified a pocket within the TRPA1 channel where WaTX can bind. The authors also found that WaTX binding caused the TRPA1 channel to open in a unique way which caused pain but did not produce neurogenic inflammation (a state can become persistent). Together, this work identified a new mechanism for TRPA1 activation and will guide future analgesic drug development aimed at modifying the TRPA1 channel in different ways. 

Mouse Study Suggests Different Pathways for Reacting to and Coping with Pain.

Identifying the pathways required for coping behaviours associated with sustained pain.

The underlying neural circuits of that drive first-line reflexive/defensive responses or second-line coping responses to pain have been poorly understood. In this study, researchers bred mice that were lacking a specific type of spinal neurons that respond to noxious stimuli (Tac1^Lbx1-ablated mice). Those mice were subjected to various tests meant to provoke reflexive/defensive responses to external threats and coping responses to painful stimuli like excessive heat, cold, pinching, itching, or burning sensations.

Compared to control mice, the mice lacking the neuron didn’t have significant differences in withdrawal thresholds or defensive reactions in response to mechanical force or noxious cold stimuli.

But in response to various tests to evoke sustained pain and stimuli meant to cause itching, coping behaviors such as licking in the Tac1^Lbx1-ablated mice were either significantly attenuated or abolished compared to control mice.

These findings led the authors to conclude that separate neural pathways drive reflexive/defensive responses and sustained pain responses, respectively. They write that these findings challenge a commonly held notion that reflexive-defensive responses can be used to measure sustained pain, a belief that they say may contribute to poor translation from preclinical animal studies to humans.

Why is Pain Unpleasant?

An amygdalar neural ensemble that encodes the unpleasantness of pain.

While the process by which nerves transmit pain signals to the brain, or nociception, is understood, the way in which the brain actually translates that information into the unpleasant experience of pain has been less clear. These researchers identified a neural ensemble in the basolateral amygdala that encodes negative pain feelings. Experiments in mice found that silencing this neural ensemble alleviated pain behavior while preserving how the mice detected noxious stimuli, their withdrawal reflexes and anxiety. The researchers write that coming to an understanding of the mechanisms by which brain circuits transform the spinal processing of nociception into a negative pain precept could help point to innovative treatment strategies for chronic pain patients.

“The presence of a purely nociceptive-specific subpopulation of neurons within the larger BLA nociceptive ensemble, distinct from general aversion-encoding populations, suggests the capacity for computing and assigning an accompanying ‘pain tag’ to valence information,” they write, adding: “This finding may enable the development of chronic pain therapies that could selectively diminish pain unpleasantness, regardless of etiology, without influencing reward, and importantly, preserving reflexes and sensory-discriminative processes necessary for the detection and localization of noxious stimuli.”

Risk Factors and Causes

Reaction to Time-delayed Painful Stimuli Varies with Age

Effects of manipulating the interstimulus interval on heat-evoked temporal summation of second pain across the age span.

Age is a significant risk factor for pain and pain is a leading cause of disability in older adults. It is not clear why pain may be more prevalent in older adults, especially since older adults report higher pain thresholds. One hypothesis to explain why older adults report more chronic pain is that aging causes dysregulation in pain processing in the central nervous system (CNS - the brain and spinal cord). One measure of central pain processing function is Temporal Summation of Second Pain (TSSP) which involves repeatedly applying painful stimuli to participant at short, fixed time-intervals and asking the patient to rate the delayed, second pain (i.e. the pain experienced while the stimulus is not being applied) that results after the initial painful stimulus (i.e. between stimulations). Measuring the second pain is of particular importance because it is thought to more accurately represent chronic/persistent pain, and a higher TSSP indicates that central pain processing is more sensitive in that participant. In this report, authors measured TSSP, evoked by a series of 10 painful heat stimulations, in participants of various ages. They also tested the effect of changing the time between stimuli on TSSP to see if this CNS process is altered in older adults. The authors found that increasing the stimulus interval decreased TSSP, however, at all stimulus intervals older adults had the highest TSSP. This indicates that in older adults, CNS pain processing is more sensitive and may explain why chronic pain may be more prevalent in older adults. 

Surveillance and Human Trials

Treating Complex Regional Pain Syndrome with Sympathetic Blocks

Outcomes of Sympathetic Blocks in the Management of Complex Regional Pain Syndrome: A Retrospective Cohort Study

Complex regional pain syndrome (CRPS) is an incredibly painful condition that can occur after an injury. Besides persistent, severe pain, patients often present with clear signs of inflammation and abnormalities in the autonomic nervous system responses (such as excessive sweating, change in skin color and temperature). A common treatment for CRPS is to inject an anesthetic into nerves of the sympathetic nervous system (i.e. the fight or flight system). While these treatments, known as sympathetic nerve blocks, are commonly utilized clinically, their effectiveness has not been systematically evaluated. In this report, Cheng and colleagues used electronic health records from their institution to analyze results from all patients who had successful nerve blocks over a 7-year period. The authors wanted to evaluate the amount of pain reduction patients experienced after a nerve block and determine if there were any patient characteristics that predicted pain responses. The authors found that 58% of the patients who received a nerve block experienced successful pain reduction and in most of these patients, pain reduction lasted 1-4 weeks. Pre-procedure patient characteristics, however, did not predict pain relief. Next the authors looked to see if pain relief after sympathetic nerve block was predictive of successful pain relief after spinal stimulation, another treatment for long-term CRPS relief. However, despite the fact that spinal stimulation was successful at reducing pain in almost 90% of patients, the effect of this treatment was not impacted by whether the patient experienced pain relief after nerve block. This study provided evidence that techniques to treat CRPS were effective and highlights the need for more understanding of the factors that influence treatment effectiveness.         

Use of Services, Treatments and Interventions

Examining the Role of Opioids in Treating Cancer Pain

Balancing opioid analgesia with the risk of nonmedical opioid use in patients with cancer.

Despite popular perceptions to the contrary, there is emerging evidence that cancer patients who are prescribed opioids for pain are at risk for misuse. However, there are limited evidence-based recommendations for safe opioid prescribing for cancer pain. This review sought to summarize the evidence that is available for safe prescribing practices, screening for opioid misuse risk and non-medical use behaviors, and management of opioid misuse if it is detected. It also discusses the difficult subject of treating pain in end-of-life care, and notes that while monitoring for opioid use in this context may be seen as invasive, ensuring safe opioid use and storage remains essential to protect patients and their families.

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