2018 Pain Research Advances

Basic to Clinical

A novel analgesic compound shows promise in nonhuman primate studies.

A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates

The collaborative efforts of researchers from North Carolina, California and Japan led to the development of a new pain-killing compound, a nociceptin/mu opioid receptor agonist, with a promising analgesic efficacy and safety profile. Opioids are currently one of the most effective and widely used drugs for chronic pain treatment. Unfortunately, opioids also have some serious unwanted side effects, some of which can be life-threatening. With the current opioid crisis in the United States, the search for safer analgesics is  a priority for researchers and one of the goals of NIH HEAL Initiative.

 The team of scientists developed a new drug AT-121 that targets the nociception (NOP)/ mu opioid (MOP) receptor. In addition, it is a bifunctional NOP/MOP partial agonist. AT-121 has an analgesic profile that is approximately 100-fold more potent than morphine and simultaneously lacks reinforcing effect, producing a full antinociceptive and antiallodynic effect without affecting respiratory function, cardiovascular activity or body temperature in nonhuman primates. Moreover, tested animals did not show any sedation or motor impairment. Unlike morphine, repeated doses of AT-121 did not cause opioid-induced hyperalgesia or physical dependence. The drug is currently undergoing preclinical investigation.  If the drug has the same efficacy, safety and toxicity profile as in animals, this drug could have a significant impact on pain management for humans.

Pain Mechanisms

Availability of endogenous opioid receptor in the brain is associated with chronic pain in rats

Chronic neuropathic pain reduces opioid receptor availability with associated anhedonia in rat.

Endogenous opioids are important in the central nervous system for regulating pain, reward, and addiction. Imaging studies in humans have demonstrated that tracers are less able to bind to opioid receptors in chronic pain sufferers compared to non-chronic pain sufferers. There are a few possible reasons why tracers are less able to bind to opioid receptors in chronic pain sufferers:  1) chronic pain sufferers may have more endogenous opioids occupying opioid receptor binding sites; 2) chronic pain sufferers may have less opioid receptors in their brains (due to pain or pain treatments); or 3) chronic pain sufferers may have less neurons (particularly ones that contain opioid receptors) in their brains. Since testing these explanations requires controlled studies and invasive tissue sampling, the authors of this report used a rodent model that allowed them to extract tissues from rodents subjected to chronic pain. The authors used a common neuropathic pain model, called the spared nerve injury (SNI) model, to induce neuropathic pain in rats. The authors then used imaging techniques similar to those performed in humans to see if a tracer was less able to bind to opioid receptors in rats experiencing chronic pain. What the authors found was that, like human chronic pain sufferers, rats exposed to SNI had less tracer binding to opioid receptors in their brains. Then, using histochemical techniques, the authors found that regions of the brain where tracers were less able to bind to opioid receptors also had lower levels of opioid receptors in SNI treated rats compared to controls. The authors also found that in animals subjected to SNI, the level of opioid receptors in a brain region known as the caudate putamen (which exhibited lower opioid receptor levels and binding in SNI exposed rats) was correlated with anhedonia (inability to experience pleasure from things that are normally pleasureful). Together, these findings indicate that chronic pain sufferers may have lower levels of opioid receptors in their brain (possibly explaining their susceptibility to chronic pain) and found that lower levels of opioid receptors were associated with increased anhedonia and depression. This article provides new clues into the way pain affects the experience of pain and pleasure via the endogenous opioid system which is crucial for understanding why and how people experience chronic pain and its comorbidities. 

Surveillance & Human Traits

The burden of High-Impact Chronic Pain in the United States

Prevalence of chronic pain and high-impact chronic pain among adults

Chronic pain is a particularly burdensome condition that has been estimated to cost the United States close to $100 billion dollars per year. For some people, chronic pain frequently prevents them from carrying out life or work activities. Individuals with chronic pain that hinders daily activities are considered to be suffering from high-impact chronic pain (HICP).  Research that investigates the prevalence of chronic and the risk factors for chronic pain is essential for designing future interventions to address chronic pain. Therefore, in 2016, one of the objectives of the National Pain Strategy was to “estimate the prevalence of chronic pain and ‘high-impact chronic pain’ in the general population and in primary care settings….” In response to this objective, Dahlhamer et al. studied the prevalence of chronic pain and HICP in U.S. adults; the results were published in the CDC Morbidity and Mortality Weekly Report. The authors of this paper used 2016 data from the National Health Interview Survey, which was a large population wide survey sampling over 33,000 U.S. adults to estimate the number of U.S. adults suffering from chronic pain in the general population. If an individual  responded that they had pain most or every day over the prior 6 months, they were categorized as having chronic pain. If they responded that chronic pain limited life or work activities most or every day over the prior 6 months they were categorized as having HICP. The authors also collected sociodemographic data so that they could assess if any of the sociodemographic factors increased the risk of having chronic pain or HICP. The authors found that in 2016 approximately 50 million (1 out of 5) U.S. adults suffered from chronic pain and approximately 20 million adults suffered from HICP. Interestingly, the authors found that chronic pain and HICP prevalence increased with age and women had higher age-adjusted prevalence of chronic pain and HICP than men. The authors also reported that several socioeconomic factors modified the risk for chronic pain (e.g., race/ethnicity, employment status). This report provides an estimate of chronic pain and HICP prevalence in U.S. adults as well as identifies factors contributing to the risk of these disorders. The details in this report will provide scientists, policymakers and care providers with valuable information for guiding their efforts to treat chronic pain.

A clinical trial to test non-pharmacological treatments for chronic pain in low-income clinics

Literacy-adapted cognitive behavioral therapy versus education for chronic pain at low-income clinics. A randomized controlled trial.

There is a great need for non-pharmacological approaches to treating chronic pain. One non-pharmacological approach that has been found to be effective at treating chronic pain is cognitive behavioral therapy (CBT), a time-limited psychotherapeutic approach that focuses on the relationships between cognitions (or thoughts), emotions (or feelings), and behaviors. Unfortunately, low-income communities do not have easy access to CBT for pain, and the efficacy of CBT in low-income communities has not been systematically tested. In this article, Thorn et al. address this gap in knowledge by performing a randomized controlled trial (RCT) to test the effectiveness of CBT for pain compared to pain education (EDU), which is cheaper than CBT and may be effective at treating chronic pain, or usual care. The study enrolled over 200 participants who were followed for up to 6 months. The authors found that patients who engaged in either CBT or EDU treatment experienced a significant reduction in their pain intensity and physical function interference more than subjects who received usual care. Moreover, in patients treated with EDU treatment gains remained 6 months after the treatment. These results indicate that CBT and EDU are effective in treating chronic pain in low-income communities and provide much needed evidence for the efficacy of these approaches through a large RCT. This is particularly important as both approaches studied here were much less expensive than surgical approaches utilized to treat chronic pain. This study will inform treatment providers about the efficacy of these non-pharmacological, cost-effective approaches to treat chronic pain.

Comparing opioid and non-opioid medications for the treatment of chronic pain

Effect of Opioid vs. Nonopioid Medications on Pain-Related Function in Patients With Chronic Back Pain or Hip or Knee Osteoarthritis Pain: The SPACE Randomized Clinical Trial.

The “opioid crisis” has been declared a public health emergency in the United States as deaths due to opioid overdose rose almost 6-fold from 1999 to 2017. Opioids are highly addictive, frequently misused, and are frequently prescribed in the United States to treat acute and chronic pain. Chronic pain is often defined as pain persisting for more than 3 months and is believed to be distinct from acute pain. Long-term opioid use to treat chronic pain has been linked to greater risk of developing opioid use disorders. Additionally, there is a lack of strong evidence that opioids are effective for relieving chronic pain. In this article, Krebs et al; performed a randomized clinical trial (RCT) to compare the effectiveness of opioid vs. non-opioid pain relievers. An RCT is considered the gold standard for evidence assessing effectiveness of drugs; therefore, this work provides crucial evidence assessing opioid effectiveness. The authors compared the effectiveness of opioids vs. non-opioid pain relievers in patients suffering from chronic back, hip or knee pain as measured by pain related interference and intensity. The authors also examined the effects of opioid vs. non-opioid pain relievers on overall health and adverse medication-related symptoms. After one year of treatment, the authors found that opioid pain relievers did not improve pain-related interference more than non-opioid pain relievers. Moreover, the authors found that, after one year of treatment, pain intensity was lower in patients treated with non-opioid pain relievers. Patients taking opioids also had more adverse medication-related symptoms than patients taking non-opioid pain relievers. In sum, this work did not support the use of opioid pain relievers to treat chronic pain. This work helps to fill crucial gaps in the knowledge base as it is a well-controlled RCT assessing the effectiveness of opioid vs. non-opioid pain relievers. This work provides a valuable reference for prescribers and patients to help understand the risks and benefits of opioid use for relieving chronic pain.

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