A very recent systematic review 1, in the Journal of Pain, went over the neurotransmitter systems associated with the placebo and nocebo effects in healthy humans as well as those with chronic pain. It did offer a fascinating insight.

What Was the Context?

Researchers have been interested in pain for a long time. That’s why numerous studies have been conducted involving neurotransmitters. The placebo and nocebo effects associated with pain are a big part of better understanding underlying mechanisms.

However, most of the said studies feature healthy participants who are exposed to experimental pain or are experiencing acute postoperative pain.

With a continued focus on finding a way to optimize placebo effects while minimizing nocebo effects during clinical practice, it has been deemed crucial for the neurotransmitter systems (that are involved in nocebo and placebo effects) to be directly investigated in subjects with chronic pain.

According to studies, the endogenous opioid system has been observed to be involved in the placebo effects demonstrated by healthy participants. Also, placebo effects in such subjects have been reported to involve the endocannabinoid, oxytocinergic, dopaminergic, and vasopressinergic systems, too. The CCKergic or cholecystokininergic system has shown involvement in the nocebo effects in healthy subjects.

But, it’s important to note that short-duration experimental pain or acute pain (in healthy subjects) is different from subjects with chronic pain. An intact nociceptive system for modulating pain is typically present in healthy participants.

However, chronic pain is linked to various mechanisms and complex pathophysiology that might be causing the pain. Psychological components for processing pain are usually more apparent in people with chronic pain.

That’s why it makes sense to think that the mechanisms associated with placebo effects present in healthy subjects might not necessarily be the same for subjects dealing with chronic pain.

Why Conduct Such a Review?

The current systematic review is the first to go over existing evidence pertaining to the involvement of the neurotransmitter systems in healthy subjects experiencing acute postoperative or experimental pain as well as subjects with chronic pain.

The goal was to offer an answer to how placebo effects might differ in said healthy patients and those with chronic pain.

LxH Model

What Was the Methodology?

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was followed for the methodology and reporting of the current paper. The team identified placebo studies by searching several electronic databases, namely Embase, PubMed, Scopus, as well as the Cochrane Library. The nocebo studies were identified post hoc by using the same electronic databases.

The articles were all in English. Also, the range included the earliest dates available in the databases through May 23, 2019. Take note; to be added, some of the factors involved the articles featuring studies aiming to understand the placebo and nocebo mechanisms as well as displaying statistically significant effects.

What Were the Results?

The initial search presented 1133 placebo along with 147 nocebo articles. With the duplicates removed, 505 placebo and 74 nocebo articles remained. After further exclusion, the final review included 28 placebo and 2 nocebo articles.

A total of 16 studies showed the involvement of the endogenous opioid system in a healthy subject’s placebo effects. Also, 8 studies shared how naloxone can be used to fully or partially block the placebo effects. However, 2 studies revealed that such effects, in a healthy subject, can’t be blocked with naloxone.

Furthermore, 2 studies talked about the contribution of the endocannabinoid system with regards to healthy subjects and placebo effects. A total of 2 studies had mixed results when it came to the involvement of the dopaminergic system. The same held true for the oxytocinergic system. The vasopressinergic system was said to be involved by one study. Take note; no study shared the involvement of the CCKergic system.

As for the placebo effects in those with chronic pain, two studies shared how the endogenous opioid system wasn’t involved. No studies about the endocannabinoid system and patients with chronic pain were found. The same happened for the oxytocinergic, vasopressinergic, and CCKergic systems. Two studies about the dopaminergic system showed mixed results.

Furthermore, 2 studies observed how the CCKergic system might be involved in a healthy subject’s nocebo effects. However, no studies were found talking about the involvement of the other systems.

Coming to subjects with chronic pain and nocebo effects, no studies were found.

What Does It Mean?

More research is needed to collect data about the types of neurotransmitter systems involved in placebo and nocebo effects in healthy subjects and those with chronic pain. A majority of the studies have focused on healthy patients.

And according to certain findings (as an example), the endogenous opioid system might not be involved in the placebo effects in chronic pain as it is involved in the pain experienced by healthy participants.

Furthermore, the psychological mechanisms linked to placebo effects are suggested to differ in subjects with chronic pain and in those who are healthy. This might play a role in why verbal suggestions display minor results when dealing with chronic pain when compared to the pain that’s experimental or acute postoperative. Understanding such differences in varying populations and conditions could aid in creating better ways to treat and manage pain.

Core stability exercise

An interesting meta-analysis 1, published in PLoS One, decided to review the effects of core stability exercise and general exercise when dealing with people with chronic LBP or low back pain. The results showed that core stability exercise was beneficial for decreasing chronic LBP in the short term.

What Was the Context?

Along with mental illness, LBP happens to be one of the most common disabilities affecting people in Western countries. Chronic LBP is known to psychologically, physically, and financially affect global populations in an adverse manner.

Exercise therapy has been deemed to help with relieving pain as well as improve the overall functionality of people with chronic LBP. Sports medicine and rehabilitation centers have begun to use core stability training. Studies have shown that such exercises are a vital component of LBP rehabilitation.

However, it’s been a bit unclear about whether or not core stability exercise is more beneficial compared to general exercise for patients managing chronic LBP.

With a better understanding of the possible benefits, core stability exercise can be optimized for improved results and to prevent wastage of time and resources during the rehabilitation process.

What Was the Objective?

The current meta-analysis was conducted to observe the effects of administrating core stability exercise as a treatment for chronic LBP while comparing it to general exercise.

What Was the Methodology?

Randomized controlled trials or RCTs were identified from electronic databases such as China Biology Medicine disc, PubMed, Embase, and the Cochrane Library. Duplicates were removed. Also, only the RCTs which examined the effects of core stability exercise compared to general exercise for treating chronic LBP were selected.

The date range for the search was 1970 to October 2011. The selected data featured male and female subjects (all over 18 years) who had chronic LBP that was longer than three months.

Meta-analysis was done through the Review Manager Software (RevMan 5.2). The I2 statistic and the chi-squared test was used to evaluate heterogeneity among the studies.

What Were the Results?

While 229 records were identified, only 28 were potentially eligible, with the final selected articles being only 5. Data shared that for short-term relief from pain, core stability exercise was better compared to general exercise. Take note; no significant changes between the two were observed at 6 months.

Furthermore, in short-term, core stability exercise showed significant improvement in a person’s functional status when compared to general exercise.

What Was Concluded?

The overall results suggested that compared to general exercise, pain relief can be decreased and the back-specific functional status of a patient can be improved through core stability exercise. But the said difference was only observed for the short-term, with no significant differences in relief from pain in intermediate as well as long-term follow-ups.

However, the current results are supported by low-quality data. Further research can help us better understand possible intermediate and long-term benefits.

Also, with yoga, Pilates, and Tai chi being core stability exercises, more research should be conducted to see which exercise would be more beneficial for subjects with chronic LBP.


A very recent study 1 published in the ‘Journal of Biomechanics’ analyzed the dynamic interactions present between the human lumbar intervertebral motion segments during flexion and return. It wanted to help further understand the components linked to disability and pain.

What Was the Context?

Low back pain or LBP causes millions of people (around the globe) to experience physical, psychological, and economic stress. That’s why research continues to develop a more efficient means of LBP management.

Understanding of the biomechanics involved in back pain has increased due to continuous dynamic multi-segmental studies of the human lumbar motion. Such knowledge is required before attempting in vivo studies of loading during bending tasks.

However, the readings collected during bending tasks tend to be variable, and establishing normative values is challenging. That’s why, during bending tasks, there’s a need to further explore the interactions present between motion segments.

If one wants to model contemporaneous kinematics and loading for estimating relative intersegmental stresses occurring during bending motion, certain factors need to be studied. These factors include continuously measuring the proportions of the flexion as well as return motion that’s accepted by individual levels. The dynamic interactions between them, during bending, needs to be measured, too.

The current study set out to analyze the adjacent lumbar level’s motion contributions during flexion (active weight-bearing) and the return protocol while using quantitative fluoroscopy or QF.


Demonstrate flexion using LxH Dynamic Disc Model

What Was the Methodology?

The study involved a total of 8 patients (5 males and 3 females). Each of them had chronic non-specific LBP. An obvious mechanical disruption wasn’t present in the patients. All of them went through QF during the flexion as well as return motion. The patients were matched with 8 healthy controls. The same tasks had been performed by the controls, too.

The dynamic motion sharing of segments were calculated throughout the person’s bend and return. The segments were from L2 to S1.

Furthermore, the statistical analysis included the SPSS’s Shapiro Wilk test, independent t-tests, and the Mann-Whitney U.

What Was Concluded?

The results revealed that there were no significant differences between the groups with regards to age, weight, height, or BMI. However, the asymptomatic controls did show higher ranges of intervertebral motion with the only significant reading being at the L5-S1 level. The patient population showcased a significantly less range of motion at the L2-S1 level.

In simple terms, the results revealed that the patient and control groups displayed consistent yet non-significant differences in motion sharing patterns.

According to this study, the results could offer an advantage to help identify components that have a link to disability and pain. For example, this study shared that patients and controls have significant differences in their Average Motion Share or AvMS at the L3-L4 level. Take note; the IV-RoM data was unable to reveal these differences.

The said differences could be due to involuntary muscle activity, bending strategy, or passive tissue restraint.

Hopefully, the current data could help others conduct further research while also covering the muscle’s electrical activity, oxygenation, kinematics, and loading.

cartilage damage and osteoarthritis

A very recent study 1 in the journal ‘Osteoarthritis and Cartilage’ has offered some helpful results. It focused on OA-induced pain in relation to mechanical joint loading and cartilage damage.

Why Conduct Such a Study?

Osteoarthritis or OA is defined as a degenerate joint disease that involves cartilage damage and the loss of cartilage. It tends to physically, emotionally, and economically impact numerous people around the world. And even though a lot still remains to be understood, progress has been made to look at osteoarthritis with a multifactorial lens.

Due to multiple joint tissues having identified pathologies as well as their relationship with OA, many have questioned the role pathologies play with regards to the clinical presentation of pain associated with OA.

When it comes to patients, the clinical presentation of their pain happens to be the most problematic oesteoarthritis symptom. And much remains unknown about knee pathology’s link with OA-related pain.

The current study’s primary objective was to better understand the complexities of the pain-structure relationship. The team used MJL or the mechanical joint loading model of OA for investigating knee pathology as well as nociceptive behavior.

What Was the Methodology?

The study used the MLJ model for inducing OA in the right knees of male mice. These mice were 12-weeks-old. A two-week loading regime was administered through an electronic testing machine.

A total of 36 mice had OA induced. Another batch of 36 mice (with no induced OA) acted as non-loaded controls. The team sacrificed separate groups of non-loaded and loaded mice during the one, three, and six-weeks points of post-loading for post-mortem analysis.

The study conducted behavior analysis before loading. At weeks one, three as well as six post-loading, nociception was verified (a day before the mentioned sacrifice points).

Coming to the post-mortem samples, half were used for µCT analysis, OA as well as synovitis grading. The other half ended up being used for nerve analysis.

The collected data was analyzed using the GraphPad Prism. Statistical analysis also included repeated two-way ANOVA, parametric two-way ANOVA, and Levene’s test.

Early cartilage damage

The Professional LxH Dynamic Disc Model can be used to show early cartilage damage.

What Were the Results?

According to the results, increased mechanical hypersensitivity paired with altered weight-bearing was shown by loaded mice. The initial ipsilateral cartilage lesions (that were at the one-week post-loading point) grew worse at the three and six-week points. The observed increase in lesion severity correlated with the development of mechanical hypersensitivity.

Furthermore, loaded mice also showed increased synovitis when compared to the control mice at the one-week post-loading points. However, the said increase returned to normal during the third and sixth week. Also, cortisol levels increased only during the one-week post-loading timeline.

Take note; there was no change in the subchondral bone integrity and nerve volume.

What was Concluded?

The study indicated that even though initial stress reaction, as well as local inflammation, was induced by loading, the said processes aren’t directly deemed responsible for the observed nociceptive phenotype.

However, allodynia induced by MJL is mainly associated with the cartilage lesions’ OA-like progression.

The team also noted that more still needs to be done to improve the understanding of how nociceptive behavior is induced by cartilage damage as well as which types of tissue pathologies could potentially play a role in pain associated with OA.

The current study’s team hopes that their current research might help others analyzing the MJL model’s pain-structure relationship.

Intervertebral disc strain

A research study 1 in the Journal of Biomechanics offered findings regarding the unique potential of DVC-MRI to help assess intervertebral disc strain in patients.

Why Conduct Such a Study?

A common cause of musculoskeletal disorders and disabilities in people is LBP or Low Back Pain. According to statistics, 70-85% of people have experienced LBP in their lifetime.

Take note; physical disruptions can play a role in degeneration and LBP. That is why it is vital to understand the mechanical behavior of IVDs or intervertebral discs further.

There is potential to create better treatment methods if internal deformities and intervertebral disc strain are quantified. Such quantification can help improve the current understanding of progressive mechanical changes in degenerate IVDs.

DVC or Digital Volume Correlation is used for assessing full-field 3D deformities as well as strains from MRIs. This method is deemed to be more sensitive than other techniques. DVC is also regarded as an efficient tool to calculate 3D strains in biological tissues.

Non-invasive strain measurements can be obtained by using DVC with MRIs. However, this combination hasn’t been appropriately used before.

The objective of this study was to quantify the deformation and strain errors associated with DVC-MRI when analyzing IVDs in humans.

What Was the Methodology?

A total of 8, fresh frozen, human cadaveric vertebral body-disc-vertebral body (VB-disc-VB) samples were collected from the L3-L4 and L4-L5 level of four male donors. A clinical MRI scanner was used to scan each sample.

A custom-made rig was designed to enable samples to be imaged within a 9.4T MRI scanner under load.

The current study used three DVC approaches. There was Direct Correlation (DC), Fast Fourier Transform (FFT), and combined FFT+DC.

The team implemented a one-way analysis of variance (ANOVA) with Tukey post hoc tests, Levene’s test, and paired-sample t-tests were used for statistical analysis.

What Did the Study Share?

The results revealed a decrease in random errors with increasing subset size for all three DVC approaches in all directions.

Compared to the DC approach, a reduced level of random errors was observed using the FFT and FFT+DC approaches.

The team designated FFT+DC as the optimal method. Also, a subset size of 56 voxels (2520 micrometers) was shown to be a good compromise between spatial resolution and errors.

It was concluded that the current method is a powerful tool to help accurately quantify the IVDs’ mechanical behavior even with certain limitations. It can also be used for assessing degenerative changes as well as to evaluate mechanical behavior-related changes after surgical procedures.

There’s a lot of potential for this method to help enhance LBP treatment options.

Lumbar intervertebral disc herniation

A controlled radiologic follow-up study 1 in the journal “Spine” decided to observe whether or not clinical symptoms changed due to changes in cord excursion with the SLR test.

What Was the Context?

Sciatica is known to have an economical, physical, and psychological impact on numerous people around the globe. It has been described as the type of pain that originates from the buttock distally in the lower limb in the sciatic nerve’s distribution.

The leading case of sciatica has been observed to be the LIDH or lumbar intervertebral disc herniation. The SLR or the straight leg raise test is a standard used around the world for diagnosing LIDH-led sciatica. However, the test is deemed insufficient in isolation.

That is why better knowledge regarding the neural biomechanics associated with SLR needs to be provided to improve test interpretation.

What Was the Objective?

Due to the nerve root excursion being impaired in people with lumbar intervertebral disc herniation during intraoperative investigations and because of this reduction being expressed in the conus medullaris (in LIDH having patients), the current research team followed up with the same patients over 1.5 years.

The objective was to investigate if there existed a relationship between the reduction of neural movement and symptomatology in patients having symptomatic radiculopathy. The study also investigated if such a relationship remained in people who have recovered.

What Methods Were Used?

In the 1.5 years follow-up, a total of 14 patients were reassessed clinically as well as radiologically using a 1.5T MRI scanner. All of the patients had significant sciatic symptoms because of a subacute single-level posterolateral LIDH.

The team quantified the conus medullaris’ displacement during SLR (bilateral and unilateral). The quantified collected data was compared to the data from the baseline.

Variables that were strongly associated with a decrease in LBP (Low Back Pain) and radicular symptoms were identified using the backward variable selection method and the multivariate regression models.

What Did the Results Show?

According to the results, the current data showed a significant increase in neural sliding (with respect to quantified maneuvers) when compared to the baseline values. Take note; the increase in neural sliding was observed to correlate significantly with a reduction in LBP and radicular symptoms.

The improvement of neural sliding was confirmed to be the primary variable associated with the improvement in a patient’s self-reported symptoms.

In conclusion, the shared data was deemed as the first noninvasive type of data that showed support regarding the relationship between the increase of neural adaptive movement and the resolution of LBP as well as radicular symptoms in in vivo and a human subject (who is structurally intact).

There seems to be some discourse when it comes to the effectiveness of pain neuroscience education (PNE) and traditional biomedical models (specifically manual therapy). A study 1 in the ‘Journal of Manual & Manipulative Therapy’ argued that PNE could be beneficial when used in a manual therapy model to address pain.

What was the Context?

It has been estimated that approximately 25.3 million adults living in the US experience daily chronic pain. Of course, these numbers are higher around the world. Chronic pain can be a continuing deterrent against a person’s psychological and physical wellbeing. That’s why proper methods to address such pain need to be developed. Due to chronic pain being challenging to treat, numerous clinicians report struggles.

Over the years, the interest in PNE has increased in the realm of physical therapy. Pain neuroscience education has been scientifically proven to help decrease disability, pain, limitations in movement, and more when treating patients. PNE focuses on handling pain from a biological and physiological perspective. It includes processes such as inhibition, neuroplasticity, central sensitization, and more.

PNE seems to in contrast to biomedical models (which focuses on biomechanics, pathoanatomy, and anatomy). Take note; biomedical models might play a role in elevating pain catastrophization and fear-avoidance.

Manual therapy uses the biomedical model a lot. Also, due to the contrasting natures, PNE is regarded as a ‘hands-off’ approach and different from manual therapy.

The current study set out to explore whether or not manual therapy and pain neuroscience education could exist together. The team also wanted to find out if PNE could be used in a manual therapy model to treat someone with an increasingly hypervigilant nervous system.

The Importance of Central Sensitization

When analyzing chronic pain, it has an association with increased levels of vigilance in the Central Nervous System. Such an occurrence is called central sensitization or CS. This type of sensitization can be simply described as an elevated response (by the CNS’s nociceptive neurons) to a normal input. This means that a typical touch is perceived as threatening and increases the amount of pain a person experiences.

In clinical terms, a hypervigilant nervous system covers hyperalgesia and allodynia. Hyperalgesia is when a normally pain-inducing stimulus gives rise to an increased level of pain. Allodynia is when pain is caused by a stimulus that isn’t supposed to normally cause pain.

As the existence of pain can lead from hyperalgesia to allodynia, even pain-free techniques during manual therapy can lead to a patient feeling pain.

Dynamic spine models educate patients about their own anatomy to reduce psychological spillover.


Helping Patients Understand Their Pain

Of course, pain tends to be more complicated than merely limiting it to CS. Pain is linked to the changes in a person’s immune system, brain functioning, and neglecting injuries. However, the importance of helping the patient understand their pain can’t be ignored.

Recent studies, involving low back pain or LBP, have shown that when manual therapists also incorporate PNE (specifically a neuroplasticity educational model) to educate patients, significantly positive results for managing pain were observed.

Educating patients during the initial phases of their injury can have a substantial impact on their recovery timeline. However, further research regarding these factors needs to be conducted to help transform manual therapy into a model that can effectively use PNE to help patients suffering from chronic pain.