Neurobiology

Goal of the review?

In this review 1, the authors focus on recent advances in understanding the nociceptive and neuropathic components of pain, as well as treatments for skeletal pain. 

 

Why are they doing this review?

Skeletal pain neurobiology is widely prevalent and has a significant impact on an individual’s quality of life and the broader society, as it is a leading cause of work disability. For this reason, the authors argue that understanding the mechanism that drives skeletal pain is critical to the prevent and treat pain.

 

What did they find?

Primary afferent sensory nerve fibres that innervate the skeleton

Unlike the skin innervated by various sensory nerve fibres, including A-beta, A-delta, C-fibers and others, the adult skeleton (bone and joint) is predominantly innervated TfkA+ sensory nerve fibres and CGRP.

While the same nociceptive nerve fibres innervate bone and joint, the density, pattern, and morphology are very different. For example, the periosteum (tissue enveloping the bones) has the largest sensory nerve fibres with A-delta and C-sensory nerve fibres that detect injury or alteration. In contrast, the articular cartilage of the knee and temporomandibular joint lack any innervation by sensory nerve fibres or vascularization by blood vessels. Therefore, it is believed that pain from a joint injury must come from the ligaments, synovium, and muscle.

Skeletal pain is also driven by the innervation of adrenergic and cholinergic sympathetic nerve fibres. Research has shown that these regulate bone destruction, bone formation and more, and therefore may play a significant role in disease progression in cartilage, bone, and skeletal pain.

Additionally, studies have shown that following injury to the skeleton, there is an interaction between sensory and sympathetic nerve fibres that may play a role in OA and complex regional pain syndrome. 

 

Nociceptive and neuropathic components of skeletal pain

Bone fractures and injury to articular cartilage are characterized by sharp stabbing pain and a lesser dull aching pain. Following injury, A-delta and C-fibers in the synovium and subchondral bone are sensitized. Normally non-noxious loading and movement of the joint are perceived as noxious stimuli. However, as articular cartilage lacks innervation, the location of the nerves driving pain is not known. Moreover, there is no clear correlation between the extent of joint destruction and the frequency and severity of joint pain. 

Research suggests there may be a neuropathic component in different types of skeletal pain. For example, in some types of cancer pain, the tumour cells destroy the distal ends of sensory nerve fibres that innervate the skeleton, which is then accompanied by an increase in movement-based pain. Another mechanism of neurobiology pain may arise from the sprouting of sensory and sympathetic nerve fibres. In mouse models of bone cancer, the number of nerve fibres per unit increased exponentially in a way not normally seen in bone.  

 

Neurochemical and structural changes to the Central Nervous System (CNS)

Little is known about the mechanisms that drive central sensitization in skeletal pain. However, it is thought to result when chemical, electrophysiological, and pharmacological systems that transmit and modulate pain are changed in the spinal cord and higher brain centers. 

 

Potential treatments for skeletal pain

The authors point out that while analgesics are needed to control pain better, an important therapeutic approach could induce bone or cartilage formation following injury. There are currently two classes of drugs to treat age-related bone loss: antiresorptive and osteoanabolic. However, both classes of drugs have limitations. 

Recent findings have outlined several new therapeutic targets for treating bone loss. Two of these inhibitory proteins that show promise are: sclerostin and Dickkopf-1. A Phase 1 study demonstrated that a dose of anti-sclerostin antibody increased bone density in the hip and spine in healthy men and postmenopausal women.

One question the researchers raise is how much neurobiology pain should be relieved. While it is beneficial for cancer patients to have their pain eliminated, the same is not true for patients with skeletal pain due to OA, bone fracture or ageing. The elimination of all pain could lead to overuse and more deterioration. Therefore, finding a treatment that could block pain while at the same time promoting bone formation and healing is critical. 

 

Why do these findings matter?

Understanding the causes of skeletal pain will help lead to more effective and targeted treatments. 

Pain Syndromes

Goal of the Study?

In this study, 1, the authors have developed a framework to differentiate Parkinson’s Disease (PD) pain from non-PD-related pain and classify PD-related pain into 3 groups based on already validated mechanistic pain descriptors – nociceptive, neuropathic and nociplastic. 

 

Why are they doing this study?

In Parkinson’s disease (PD), about 20% of patients experience chronic pain at diagnosis. This number climbs to 80% during the course of the disease. PD pain has been divided into three categories: de novo pain related to disease onset and symptoms (PD-related); previous chronic pain aggravated by the disease or treatment (PD-indirectly-related); pain that is neither caused nor aggravated by the disease (PD-unrelated). Moreover, pain is considered PD-related when one of the following applies: when occurring along with the first motor symptoms, when occurring/aggravated during the OFF stage of the disease, when occurring at the same time with choreatic dyskinesia or when improved by dopamine treatment. However, these categories have not been validated or tested, making diagnosing and treating pain in PD. In response to this need, the authors develop a classification system to define and distinguish PD-related pain from non-PD-related pain.

 

What was done?

The authors used an international, cross-sectional, multicenter study. They recruited 159 non-demented PD patients and 37 healthy controls across 4 centers. Using the mechanistic pain descriptors (nociceptive, neuropathic and nociplastic), the authors developed a PD pain classification system (PD-PCS) by including classic pain-related situations of PD into each category. The severity of PD-related pain syndromes was scored by ratings of intensity, frequency and interference with daily living activities. Finally, they did an analysis and validation of their scale.

 

What did they find?

This study provides a unifying system for pain in PD that differentiates between PD and non-PD pain and outlines a treatment-based and mechanistic classification system for PD-related pain. Using this system, the authors found that 77% of patients experienced PD-related pain, with 15% suffering more than one syndrome at the same time. PD-related pain with nociceptive, neuropathic or nociplastic components was diagnosed in 55%, 16% and 22% of participants, respectively. Mixed pain syndromes were mostly found in nociceptive pain combined with nociplastic (12.7%) or neuropathic (9.6%). Pain unrelated to PD was found in 22% of participants, versus only 5% of controls. 

Concerning the PD-PCS, the authors found that pain severity scores significantly correlated with commonly used questionnaires such as the pains’ Brief pain Inventory and McGill Pain questionnaire. They did not find that the PD-PCS scores correlated with a motor score.

Finally, they suggest that the three pain types identified by the PD-PCS are different pain syndromes and reflect different mechanistic backgrounds and, potentially, different treatment approaches.  For example, they found that patients with higher nociceptive pain scores had worse quality of life scores, but this was not found for patients with nociplastic pain. 

 

Why do these findings matter?

Better classification of pain in PD will ensure that PD patients’ pain is treated more effectively and timely, ultimately contributing to better outcomes.

 

spinal mobility

Goal of the Study?

The goal of this study [1.Spinal mobility in radiographic axial spondyloarthritis: criterion concurrent validity of classic and novel measurements] is to evaluate spine range of motion (ROM) measured by tri-axial accelerometers compared to both current clinical tests and radiography in radiographic Axial spondyloarthritis (AxSpA) patients. 

 

Why are they doing this study?

AxSpa is a chronic and progressive form of inflammatory arthritis. To measure progression and plan treatment, there is a need to measure indicators for spinal mobility in forward and lateral bending. Currently, this is often done using a clinical tape measure. However, research has illustrated that there is poor validity using a tape measure to assess spine mobility compared to the images and RoM from radiographs. However, with the risks associated with repeated exposure to radiation for radiographs, and the lack of validity in using clinical tape measures, there is a need for better alternatives. To that end, research has illustrated the value of devices that incorporate strain gauges and/or accelerometers to measure spinal curvature.

spinal mobility

A novel measuring approach to minimize radiation exposure.

 

What was done?

This study recruited fifteen radiographic Spondyloarthritis patients. First, each participant had lateral and posterior-anterior radiographs taken standing upright. Following this, each participant completed three RoM trials in forward flexion, right lateral and left lateral bending. In total, five lumbar radiographs were taken. For each participant, three measurements were collected: tape, synchronized radiograph and accelerometer measurements at the end range of forward and bilateral lateral flexion. The researchers then used statistical software to determine reliability.

 

What did they find?

The findings of this research support using accelerometers as a replacement for sagittal spine mobility, but not lateral. The accelerometer measure of the sagittal spine had a stronger correlation to the radiographic measure than all tape measures. They argue that this approach can overcome some of the inherent challenges with tape, such as skin stretching. In lateral bending, the Lateral Spinal Flexion tape (LSFT) correlated stronger than the accelerometer method. Furthermore, an accelerometer-derived measure of frontal plane spine mobility underestimated lateral bend angles from the radiographs. It demonstrated a moderate correlation to the radiographic gold standard lower than either the LSFT or DT.

 

Why do these findings matter?

The use of accelerometers can limit patients’ exposure to ionizing radiation through repeated radiographs in the AxSpA population. Improved ability to measure spinal changes is important to evaluating and managing disease progression and treatment. 

 

degenerative joint disease

Goal of the Study?

In this study 1, the authors investigate degenerative joint disease in the spine and major peripheral joints (shoulder, elbow, hip and knee) in chimpanzees, lowland gorillas and bonobos.

 

Why are they doing this study?

Degenerative joint disease is one of the most common pathological musculoskeletal conditions in human populations. It has also been observed in a variety of nonhuman animals, including nonhuman primates. Existing research has illustrated degenerative disease in chimpanzees, gorillas, orangutans, gibbons, macaques, baboons and probosci’s monkeys. Overall, prevalence has been reported as quite low in wild monkeys (with some exceptions) compared to colony-reared Old-World monkeys. 

The authors want better to understand the evolutionary basis of degenerative joint disease. 

 

What was done?

This investigation’s skeletal materials are drawn from two samples of chimpanzees, a sample of lowland gorillas and a small sample of bonobos. The samples from the chimpanzees are from Gombe National Park, Tanzania, while the other materials are from museum materials originally collected in west/central Africa. In total, 5807 sample surfaces for vertebral osteophytosis (VOP), 12,479 surfaces for spinal osteoarthritis (OA) and 1211 joints for evaluation of peripheral joint OA.

The human osteological samples are from two areas, Central California and a group of Inuit from Alaska.

The presence of VOP was based on a determination of osteophyte development. OA presence was based on hypertrophic development and changes to joint spacing. The severity of VOP and OA was scored based on slight, moderate or severe.

 

What did they find?

All apes display significantly less spinal disease compared to humans. The authors suggest that this is most likely related to movement on two legs. Among the African apes, gorillas are slightly more involved in the spine than chimpanzees with almost no spinal degeneration. Both bonobos and gorillas have significantly more involvement than chimpanzees in the cervical and thoracic regions (but the sample size for bonobos is so small that it is hard to say there is any significance).  As with previous research, the authors found that colony reared Old World monkeys, such as macaques, have higher OA levels than other free-ranging apes. The authors argue that the variation between humans and African apes in VOP and OA prevalence may be explained by human longevity.

 

Why do these findings matter?

This study can help understand basic processes in degenerative joint disease among humans and our closest relatives in a broader evolutionary context. 

 

Innervation

Goal of the Study?

In this study 1, the authors use a rat model to examine the time-course development of pathological joint changes and correlate them with pain-related behaviour in OA. 

Why are they doing this study?

There is a very high incidence of Osteoarthritis (OA) in the elderly population, and it is a leading cause of disability and pain. However, there is a lack of knowledge of OA’s pain mechanisms, particularly the role that neuropathic pain (NP) plays in OA.

OA has been described as a degenerative rather than an inflammatory disease. However, in recent years research has identified the many inflammatory processes that take place in OA.  Existing OA models have shown how this inflammation is supported by overexpression of nerve growth factors causing nociceptive fibres to grow into inflamed joints. This inflammatory process helps explain why there is a poor correlation between radiographic changes and pain levels in OA patients. Moreover, some patients continue to experience pain after a total joint replacement, suggesting that OA can result in neuropathic pain (NP). 

What was done?

The researchers used a rat monoiodoacetate (MIA) model of the ankle joint. MIA results in pathological changes and pain-like behaviour common with those observed in human OA. This model has been used extensively in research and is well validated.

They injected MIA or saline into a total of 126 male rats. For this study, they used the rat ankle joint as it receives most of its nerve supply from the sciatic nerve, which is used most commonly in NP models. From this, they assessed a variety of changes, including pain-related behaviour, hypersensitivity, reaction to cold and heat, changes to normal movement, cartilage degeneration, bone degeneration, and the effects of drug treatments.

What did they find?

 Overall, the study provided a time-course view of the development of pathological changes to the joint and the associated pain-related behaviours. 

The researchers found significant innervation increases at specific periods of time that coincided with mechanical hypersensitivity at 4 weeks and pain in response to cold at 5 weeks. X-ray findings showed significant cartilage and bone degeneration and joint space narrowing at 5 and 10 weeks. 

The study also illustrated changes in sensory and sympathetic innervation of joints in the subchondral bone and synovial membrane at 5 and 10 weeks.  This increased concentration of sensory and sympathetic fibres was associated with pain-related behaviour and similar to those observed in NP models. Furthermore, they found that pain-related behaviour and extensive joint damage were associated with the expression of activating transcription factor 3 (ATF3) in the dorsal root ganglia (DRG), as well as the microglia and astrocyte changes in the dorsal horn. Using various pharmacological treatments to inhibit or block sympathetic fibres and glial could suppress pain-related behaviour. They argue that these findings suggest that multiple factors contribute to OA pain, including inflammatory changes in the joints, supporting the theory of a neuropathic component in OA.

Why do these findings matter?

As pain is the main reason patients seek medical help, effective pain management is critical to improving life quality. Therefore, understanding what causes pain will help in the development of pain management protocols and treatments. 

 

vacuum sign

Vacuum sign is a common radiological finding. It is also referred to as a vacuum phenomenon and often associated with degenerative spinal discs, knee joints, hip joints, and shoulder joints.  Degenerative spondylolisthesis is a spinal condition whereby one vertebra slips on another. However, it is sometimes difficult to ascertain whether this slippage is stable or not. A more than 4mm movement defines instability, but some have indicated only 2mm as clinically significant.

degenerative spondylolisthesis model

Degenerative Spondylolisthesis Dynamic Disc Model

In a research paper published in World Surgery, 1 a group of authors looked at the vacuum sign in the facet joint as an indication of degenerative instability of the spine. They wanted to investigate the relationship between the vacuum facet phenomenon and lumbar instability. Why, you may ask? More and more research is directing spine researchers to the cause of pain and disability to the imbalance of motion of the individual vertebral segments of the spine. Some have coined this motion sharing.

Each vertebral motion segment consists of two vertebrae, and a disc should have a certain stiffness level. That is, it should move similar to its adjacent segment above and below in the spinal column. For this study, they looked at L4 on L5 (which is a prevalent spinal level to degenerate with age) and used flexion/ extension X-rays in both the fully bent forward (flexion) and the fully bending backwards (extension) with degenerative spondylolisthesis. Additionally, when available, they also looked at CAT scans of these same patients. To determine the slippage degree, they used a dynamic motion index to measure the degree of slippage.

In a total of 67 patients examined, 35 patients had vacuum signs on their CAT scan, and 32 patients did not. The degree of slippage appeared to correlate with the vacuum sign as well. That is, the more the vertebrae had slipped forward, the more likelihood of the presence of the vacuum sign. With this, the authors concluded a linear correlation between the degree of slippage and the presence of vacuum sign.

Vacuum sign

Vacuum phenomenon or vacuum sign and mobility

Commentary by Jerome Fryer

Vacuum sign or vacuum phenomenon is often considered an incidental finding. However, based on the modelling research I’ve done, I believe that the vacuum sign can be a clue into joint mechanics’ stiffness. In 2017 I published an article related to the cracking event we are familiar with, and in there, I believe in having revealed the vacuum phenomenon. In the presence of cavitation, a joint will have less stiffness, and in time I hope we can collectively use these radiographic findings to help us determine which joint requires more stability in the treatment of them. JF

facet osteoarthritis, facet joint pain

Facet osteoarthritis pain is common and thought to be a significant contributor to back pain in the US. Within the United States, it costs 100 Billion dollars annually to combat this endemic problem. However, back pain can originate from many anatomical structures, and the facet joint is only one of them but thought by many as significant. Other common pain structures are the intervertebral discs in the case of disc bulges, disc extrusions, disc protrusions and frank nuclear sequestration. There are also more severe causes of back pain like aneurysm and other organ pathology, so it is crucial to have a professional look carefully at the diagnostics of each case.

In the case of mechanical lower back pain (others use the term non-specific lower back pain), the facet joint garners good attention. The word ‘facet’ comes from the French facette (12c., Old French facete), diminutive of face “face, appearance” and are two anatomical structures that reside behind the intervertebral disc.

Facet osteoarthritis

Modeling facet osteoarthritis is tricky because of the complexity of motion at the spinal level. The intervertebral disc height plays a role with respective facet compression because it resides on the front of the spinal motion segment. It is this compression thought to be contributing to back pain.

Clincally, facet osteoarthritis pain is often unilateral in nature

In a study conducted recently 1, researchers worked to induce facet joint arthritis by creating compression with a spring. Over time the researchers found the increased expression of interleukin‑1β and tumour necrosis factor‑α expression. In other words, with more compression elapsing over time, the more the expression of the molecules related to many low back pain patients.

This is an important study linking the mechanics of compression and the associated physiology of molecules, which are thought to be markers of back pain patients.

At Dynamic Disc Designs, we have developed models to help explain the associated compression of facet joints as it relates to disc height loss and gains. We are committed to bringing the best in modelling. Explore our website for more.