Monash University researchers have made a breakthrough discovery that might lead to new non-opioid analgesics to treat neuropathic pain safely and effectively, without the risk of opioid addictions.
Neuropathic pain occurs when nerves are damaged or dysfunctional, and can be caused by injury, virus infection or cancer treatment, or it can be a symptom or complication of conditions such as multiple sclerosis and diabetes.
The new study, published in Nature, has shown a new mode of targeting the adenosine A1 receptor protein, which had long been a promising therapeutic target for non-opioid painkillers to treat neuropathic pain. However, development of analgesics using it had failed due to a lack of sufficient on-target selectivity, as well as undesirable adverse effects.
In the study, Monash researchers used electrophysiology and preclinical pain models to show that a particular class of molecule, called a ‘positive allosteric modulator’ (PAM), can enhance the targeting of the A1 receptor by binding to a different region of the protein.
Another breakthrough in the study was observing the high-resolution structure of the A1 receptor bound to both its natural activator, adenosine, and an analgesic PAM, which was facilitated by the application of cryo electron microscopy (cryoEM), providing the first atomic level snapshot of the drug binding location.
Chronic pain remains a widespread global health burden. A lack of treatment options has led to over-reliance on opioid painkillers, which provide only limited relief in patients with chronic (particularly neuropathic) pain, while having severe adverse effects, such as respiratory depression and addiction. In 2016, 42 000 deaths related to opioid misuse were recorded in the US, while 25 million Americans suffer from chronic pain.
This new discovery opens the door to the development of non-opioid drugs that lack such side effects.
Co-corresponding author of the study and Dean of the Faculty of Pharmacy and Pharmaceutical Sciences, Professor Arthur Christopoulos said: “The world is in the grip of a global opioid crisis and there is an urgent need for non-opioid drugs that are both safe and effective.”
A multicentre randomised trial showed that eight weeks of acupuncture sessions improved symptoms of moderate to severe chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) to a greater extent than sham therapy. Treatment effects endured over 24 weeks follow up. The findings are published in Annals of Internal Medicine.
CP/CPPS manifests as discomfort or pain in the pelvic region for at least three of the previous six months with no infection, with possible involvement of lower urinary tract symptoms, psychological issues, and sexual dysfunction. Men with CP/CPPS may have a poor quality of life associated with the disorder, such as inflammation in the prostate, anxiety and stress, and dyssynergic voiding. Standard care involves antibiotics, a-blockers, and anti-inflammatories, but their effectiveness is limited and long-term use is associated with adverse events. Though promising as an alternative treatment, acupuncture lacks high quality evidence.
A total of 440 male participants were randomised to either 8 weeks of acupuncture or sham therapy to assess the long-term efficacy of acupuncture for improving symptoms of CP/CPPS. The treatment was considered effective if participants achieved a clinically important reduction of at least 6 points from baseline on the National Institutes of Health Chronic Prostatitis Symptom Index at weeks 8 and 32. Between-group difference to be statistically significant at both time points for sustained efficacy.
More participants in the acupuncture group reported marked or moderate improvements in symptoms at all assessment points compared to the sham control group. No significant difference was found in changes in International Index of Erectile Function 5 score at all assessment time points or in peak and average urinary flow rates at week 8. No serious adverse events were reported in either group.
According to the researchers, these findings show long-term efficacy of acupuncture and provide high-quality evidence for clinical practice and guideline recommendations.
A rodent study has demonstrated the potential for transcranial focused ultrasound (tFUS) to relieve chronic pain and other symptoms.
Neuromodulation, or therapeutic stimulation of neurons with electrical energy. chemicals or potentially with acoustic waves, can amplify or dampen neuronal impulses in the brain or body to relieve symptoms such as pain or tremor.
Ultrasound is a promising non-invasive, non-surgical type of neuromodulation. It offers a temporary modulation that can be tuned for a desired effect. In this study, researchers have shown that it can be targeted at neurons with specific functions.
A team led by Bin He, PhD, professor of biomedical engineering at Carnegie Mellon University, and funded in part by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), has demonstrated the potential of a neuromodulation approach that uses low-intensity ultrasound energy, called transcranial focused ultrasound-;or tFUS. In a paper published in Nature Communications, the authors describe the use of tFUS in rodent experiments, demonstrating the non-invasive neuromodulation alternative.
Moria Bittmann, PhD, Director of the Program in Biorobotic Systems, National Institute of Biomedical Imaging and Bioengineering, said: “Transcranial focused ultrasound is a promising approach that could be used to treat forms of chronic pain, among other applications. In conditions where symptoms include debilitating pain, externally generated impulses of ultrasound at controlled frequencies and intensity could inhibit pain signals.”
The researchers designed an assembly that included an ultrasound transducer and a multi-electrode array, which records neuronal data. During experiments with anaesthetised rodents, the researchers sent acoustic pulses into the brain cortex, targeting specific neurons, while recording change in electrophysiological signals from different neuron types.
When neurons transmit signals, whether engaging the senses or controlling movement, the firing of that signal across the synapse is termed a spike. The researchers observed two types of neurons: excitatory and inhibitory neurons.
When using tFUS to emit repeated bursts of ultrasound stimulation directly at excitatory neurons, the researchers saw an elevated impulse rate, or spike. Inhibitory neurons subjected to the same tFUS energy however did not display a significant spike rate disturbance. This showed that the ultrasound signal can be transmitted through the skull to selectively activate specific neuron sub-populations, in effect targeting neurons with different functions.
“Our research addresses an unmet need to develop non-toxic, non-addictive, non-pharmacologic therapies for human use,” said Prof He. “We hope to further develop the tFUS approach with variation in ultrasound frequencies and to pursue insights into neuronal activity so that this technology has the optimal chance for benefiting brain health.”
There are many broad applications for this research. Prof He believes non-invasive tFUS neuromodulation could be used to facilitate treatment for many people suffering from pain, depression and addiction. “If we can localise and target areas of the brain using acoustic, ultrasound energy, I believe we can potentially treat a myriad of neurological and psychiatric diseases and conditions,” Prof He said.
Though muscle relaxant drugs are largely widely prescribed to treat low back pain, they are largely ineffective, suggests an analysis of the latest evidence published by The BMJ.
While the evidence shows that muscle relaxants might reduce pain in the short term, the effect is too small to be considered clinically meaningful, and there is an increased risk of side effects.
However, the researchers stressed that the certainty of evidence is low, necessitating large trials to resolve uncertainties around the use of these drugs for back pain.
Low back pain is a global public health problem and muscle relaxants (a broad class of drugs that include non-benzodiazepine antispasmodics and antispastics) are a commonly prescribed treatment. Prescriptions in England last year exceeded 1.3 million, and in the US more than 30 million. Yet clinical practice guidelines around the world provide conflicting recommendations for their use.
To cast light on the matter, researchers in Australia investigated the effectiveness, acceptability, and safety of muscle relaxants compared with placebo, usual care, or no treatment in adults with non-specific low back pain.
The team analysed 31 randomised controlled trials involving over 6500 participants. Though the trials were of varying quality, the researchers were able to assess the certainty of evidence using the recognised GRADE system.
They set a difference of at least 10 points on a 0 to 100 point scale for pain and disability to be the smallest clinically important effect, which is a threshold used in other low back pain studies.
Very low certainty evidence showed that, compared with controls, non-benzodiazepine antispasmodic drugs might reduce pain intensity at two weeks or less for patients with acute low back pain. However, the effect is less than 8 points on a 0-100 point scale, therefore not meeting common thresholds to be clinically meaningful.
Little to no effect of non-benzodiazepine antispasmodics on pain intensity was seen at 3-13 weeks or on disability. Additionally, low and very low certainty evidence also showed that non-benzodiazepine antispasmodics might increase the risk of adverse events (typically, dizziness, drowsiness, headache and nausea) and might have little to no effect on treatment discontinuation compared with controls. The effect of muscle relaxants on long term outcomes was not evaluated in any of the trials.
The researchers acknowledged some limitations of the analysis, despite its using the best available evidence, and noted that some, but not all, individuals could gain a worthwhile benefit due to the modest overall effect. The low to very low certainty of evidence does not allow any firm recommendations, they cautioned.
Journal information: Cashin, A.G., et al. (2021) Efficacy, acceptability, and safety of muscle relaxants for adults with non-specific low back pain: systematic review and meta-analysis. BMJ. doi.org/10.1136/bmj.n1446.
According to a new study from the University of Toronto, 63% of Canadians who suffer from migraine headaches are able to flourish, despite the painful condition.
“This research provides a very hopeful message for individuals struggling with migraines, their families and health professionals. The findings of our study have contributed to a major paradigm shift for me. There are important lessons to be learned from those who are flourishing,” said lead author Esme Fuller-Thomson, Professor at both the Factor-Inwentash Faculty of Social Work and the Department of Family & Community Medicine, University of Toronto.
Over the past decade, Prof Fuller-Thomson has published on negative mental health outcomes associated with migraines, including suicide attempts, anxiety disorders and depression.
Migraine is a complex, genetically influenced disorder characterised by episodes of moderate-to-severe headache, usually unilateral and associated with nausea and increased sensitivity to light and sound. A migraine headache is the seventh most disabling disorder in the world. However, there is little research investigating factors associated with mental health and well-being among sufferers.
The University of Toronto study investigated optimal mental health in a nationally representative sample of 2186 Canadian adults diagnosed with migraines. The data were drawn from Statistics Canada’s Canadian Community Health Survey-Mental Health. To be defined in excellent mental health, respondents had to achieve three things: 1) almost daily happiness or life satisfaction in the past month, 2) high levels of social and psychological well-being in the past month, and 3) freedom from generalised anxiety disorder and depressive disorders, suicidal thoughts and substance dependence for at least the preceding full year.
“We were so encouraged to learn that more than three in every five migraineurs were in excellent mental health and had very high levels of well-being,” said Prof Fuller-Thomson.
Those experiencing migraines who had at least one person they could confide in were four times more likely to be in excellent mental health than those without. Additionally, those using religious or spiritual beliefs to cope with everyday difficulties had 86% higher odds of excellent mental health than those who did not use spiritual coping. Poor physical health, functional limitations, and a history of depression were also found to inhibit excellent mental health among those with migraines.
“Health professionals who are treating individuals with migraines need to consider their patients’ physical health needs and possible social isolation in their treatment plans” said co-author Marta Sadkowski, a recent nursing graduate from the University of Toronto.
Journal reference: Fuller-Thomson, E & Sadkowski, M., (2021) Flourishing Despite Migraines: A Nationally Representative Portrait of Resilience and Mental Health among Canadians. Annals of Headache Medicine. doi.org/10.30756/ahmj.2021.05.02.
An implantable spinal cord stimulation device was effective at relieving diabetic neuropathy pain, according to a researcher presenting at an American Association of Clinical Endocrinology virtual meeting.
Presenting the trial results, Erika A Petersen, MD, of the University of Arkansas for Medical Sciences, said: “This is the largest randomised controlled trial evaluating spinal cord stimulation for refractory painful diabetic neuropathy.”
In total, more than 85% of patients treated with 10 kHz stimulation were considered responders to treatment — experiencing 50% or greater reduction in pain. On top of that, 60% achieved remission, defined as a pain visual analog scale (VAS) of less than 3.0 cm for 6 consecutive months.
Meanwhile, those receiving only normal medical management saw no significant pain score reduction (7.0 at baseline vs 6.9 at 6 months). More than half of those conventionally treated experienced worsening of their pain, and only about 5% were responders to this type of treatment. Overall, only 1% of patients achieved pain remission with conventional medical management.
Beyond pain improvement, those receiving high frequency spinal cord stimulation plus medical management also saw a 62% improvement in neurological examination versus 3.3% of conventional treatment-only patients (P<0.001). The neurological examination included such as lower limb motor strength, light touch sensation and a 10-point foot assessment with a pinprick and 10-g monofilament.
Patients with the stimulation device also reported a reduction in dysesthaesias or uncomfortable sensations such as itching. They also reported a 62% improvement in sleep disturbances.
Overall, 92% patients in the stimulation group said they were satisfied with their treatment, compared with 6% of those on the conventional treatment group said the same.
The trial included 216 adults with painful analgesic-resistant diabetic neuropathy of the lower limbs. Half of participants received only conventional medical management, which included pharmacotherapies.
The other half of participants received 10-kHz SCS therapy. These participants received temporary stimulation for 5 to 7 days with percutaneous leads placed epidurally along T8 to T11. If 50% pain relief was achieved, they could have a permanent implantation of the pulse generator, usually in the low back.
In terms of safety, three infections occurred in the stimulation group, two of which required device removal.
There was no change in BMI or HbA1c in either group during the trial.
After the 6-month trial, 82% of patients on conventional treatment were eligible to crossover — meaning they had less than 50% pain relief, were dissatisfied with treatment, and the investigator agreed it was medically appropriate — and chose to receive the stimulation device.
In this extension phase, those with the stimulation device continued to experience pain relief, achieving an average VAS of 1.7 at 12 months out.
“The responder rate remained stable as well, with 86% at 12 months suggesting the attrition seen with other stimulation approaches is not a concern with 10 kHz stimulation,” said Petersen. “We will continue our follow-up to 24 months, with further evaluation of health economic data and other indicators.”
Journal information: Petersen E, et al “Neuromodulation for treatment of painful diabetic neuropathy – sustained benefits of 10kHz spinal cord stimulation in a randomized controlled trial” AACE 2021.
A team of researchers at the University of East Anglia are starting a new project to see if virtual reality, combined with an innovative brain interface could help with the treatment of chronic pain.
Almost one in five South African adults are living with chronic pain, and the team will study whether new technology delivered via a VR headset could help ease their symptoms.
One very science-fiction-like aspect of the study the use of a ‘Brain-Computer Interface’ where participants will be taught to control elements of a VR game using only their thoughts. Previous studies have shown that VR therapy was effective in reducing chronic and acute pain in children and adults.
Dr Jordan Tsigarides from UEA’s Norwich Medical School and a Rheumatology doctor at the Norfolk and Norwich University Hospital, said: “Virtual Reality is an emerging technology where the user gains a completely immersive, interactive and often transformative experience with the use of a head-mounted display.
“VR seems to flood the brain with a multitude of audiovisual signals, engaging the senses and diverting the brain’s attention from processing pain signals.”
“At present, there is evidence that VR can significantly decrease people’s acute pain. What we are looking to find out is whether this kind of technology can be used to help people suffering chronic pain as well.”
The team is working with industry partner, Orbital Innovations, and has developed an innovative VR program for patients with chronic pain conditions, such as fibromyalgia syndrome and chronic pain following a total knee replacement. It will be tested on patients recruited from the NNUH and Addenbrookes in partnership with rheumatology, orthopaedics and pain management departments.
Dr Tsigarides said: “The virtual worlds that we have created aim to transport patients to naturalistic, immersive environments whether its travelling down a cool snowy river or planting crops in a luscious warm forest. Through VR, we aim to engage patients through challenging and interactive games, with the objective of understanding more about how this technology can reboot the brain’s pain networks.
“We are working with neuroscientists at the UEA to look at the brain waves of people with chronic pain. This has the potential to allow us to see how this technology is working, as well as learn more about the brain function of people with these conditions.
“Moving things with your mind sounds like something straight from a sci-fi movie but with today’s technology, ‘Brain-Computer Interfaces’ are being used more and more in health research. We believe that this exciting new innovation when coupled with an immersive VR experience will ‘power up’ the pain relief seen with VR alone.
“Given that just under 28 million adults in the UK suffer from chronic pain, and that we are in the midst of an opioid epidemic, this treatment could be an important future intervention.”
Peter Brady, CEO of Orbital Innovations, said: “Orbital Innovations has been working towards the development of a virtual reality technology, which will offer a way of mitigating the effects of chronic pain. This innovative project collaboration with UEA, will be breaking new ground in fully exploring the exciting opportunities this technology will offer patients in the future.”
A patient in the US was awake for 13 minutes of his surgery because apparently his anaesthetic was never turned on.
In mid-2020 the patient, Matthew Caswell went into Progress West Hospital in O’Fallon, Missouri, for hernia repair and removal of a lipoma on the back of his neck.
However, he soon became aware that something was amiss.
“I knew I was in trouble when I felt the cold iodine hit my belly and they were scrubbing me off. At any second I was waiting to go out, but all of a sudden I just got stabbed in my stomach,” Caswell told local TV station KCTV.
Caswell’s lawyer Kenneth Vuylsteke told MedPage Today that a paralytic agent had already been given to his client, and then the mask was put on to receive sevoflurane for general anaesthesia, but the flow of the gas was never started.
Caswell able to feel pain and hear operating room conversation for 13 minutes, he told KCTV.
During this, his vital signs surged, said Vuylsteke. Records shared with MedPage Today show a baseline heart rate in the 65 to 70 range, which skyrocketed to 115 beats per minute within a few minutes of the first incision.
After the first incision, Caswell’s blood pressure also shot up, from a baseline of 113/73 mm Hg to 158/113 mm Hg — severe hypertension.
Vuylsteke noted that hat should have been ample warning that something was likely wrong with the anaesthetic.
What he gathered so far is that Caswell was brought into the operating room and given the paralytic agent. The anaesthesiologist or the nurse anesthetist put the anaesthetic mask on him, but then the surgeon requested to see the lipoma before starting.
Caswell was turned over so the surgeon could see the lipoma. He was then put onto his back again, and the mask was put back on, but the sevoflurane was never turned on, Vuylsteke said.
A “Significant Event Note” is in hospital records that acknowledges that a “review of the anesthetic record demonstrates a delay in initiating inhalational anesthetic after induction of anesthesia.”
The note indicates that Caswell and his mother were “immediately informed regarding the delay in initiating the inhaled anesthetic agent until after the start of the surgical procedure.” The hospital “provided emotional support and discussed our intention to ensure his pain and anxiety over the event were well controlled in the immediate term.” The hospital also recommended a psychology consult for which they would cover the cost.
Older people who use cannabis to relieve or treat health conditions generally don’t discuss their substance use with doctors, according to a new study.
In this study of over 17 000 people aged 50 and over in the US, some use cannabis daily and others have mental health problems. The findings were published in peer-reviewed The American Journal of Drug and Alcohol Abuse.
The research is the first to identify where older users obtain cannabis, with the majority saying obtaining it was easy. Those who use cannabis for health reasons are more likely than non-medical (recreational) users to buy it at a medical dispensary (20% vs 5%) and less likely to get it for free (25% vs 46%) or from other sources such as parties (49% vs 56%).
According to the authors, the findings have significant clinical and policy implications especially as more US states are legalising cannabis, which is leading to a rapid rise in uptake among older people. This has implications for other countries such as South Africa, which has recently decriminalised it for personal use.
They urge that doctors should be routinely screening older people for cannabis and other substance use, as well as checking cannabis users for mental health problems, and recommending treatment when necessary. They add that education on the risks of obtaining cannabis and cannabis products from unregulated sources is also vital for this group.
“Cannabis is readily available and accessible to older cannabis users for medical or non-medical purposes,” said Namkee G Choi from University of Texas.
“The findings suggest that some medical users may be self-treating without healthcare professional consultation.
“All older people who take cannabis should consult healthcare professionals about their use. As part of routine care, healthcare professionals should screen for cannabis and other substance use, and for mental health problems.
“They should also recommend services or treatment when indicated. Given the increase in THC (tetrahydrocannabinol) potency, healthcare professionals should educate older cannabis users, especially high-frequency users, on potential safety issues and adverse effects.”
THC content has increased significantly over the past decades. Since 1995, the potency of illicit cannabis plant material seized in the US has consistently increased over time, from approximately 4% in 1995 to approximately 12% in 2014. Among older US adults, cannabis has more than doubled between 2008 and 2019. Reasons include pain relief and treating health issues. However, not much is known about where they obtain cannabis and how much they discuss their use with doctors.
Data for the research was drawn responses from the 2018 and 2019 National Survey on Drug Use and Health (NSDUH), with 17 685 men and women aged 50 and older. This annual national survey measures substance use and misuse and mental illness across the US.
The researchers analysed responses including those on frequency of cannabis use, reasons for taking it, where it was obtained, and how much they utilised healthcare services.
The study found that, overall, 9% used cannabis over the past year and of these, 19% used cannabis for a medical purpose to some extent, eg, to treat chronic pain, depression or diseases like arthritis, while the rest (81%) were recreational (non-medical) users.
The authors also found that people who reported cannabis use as being for medical reasons were over four times as likely than non-medical users to discuss their use with a healthcare professional. Nevertheless, only a minority of medical users did so, which implies that some are self-treating without consulting a doctor.
Medical users were also more likely than non-medical users to more frequently take cannabis, with 40% using it between 200 and 365 days a year.
A higher proportion of older cannabis users had mental illness, alcohol use disorder, and nicotine dependence compared with non-users of the same age, although medical users were less likely to have alcohol problems compared to recreational users.
As well as calling on doctors to do more, the study authors say the NSDUH needs updating to “reflect changing cannabis product commercialization”, such as including products available to older people like cannabidiols, topical solutions and edibles.
Limitations of the study included the relatively small number of medical users and the fact some respondents may have under-reported their cannabis and other substance use.
When timed correctly, psychological interventions can reduce the risk of chronic pain, according to a pain expert at the virtual 2021 American Academy of Pain Medicine annual meeting.
“We can look at chronic pain as occurring in a very linear process,” said Ravi Prasad, PhD, of University of California Davis, in a meeting session about multimodal ways to prevent chronic post-surgical pain.
“By definition, pain starts off as something acute,” Dr Prasad explained. The acute phase includes assessments and treatment to try to eliminate pain quickly.
“When the pain condition fails to respond to some of these initial treatments, it starts to enter the subacute category,” Dr Prasad continued. “The patient is still engaged in different medical workups to try to identify the cause of the pain and still participating in treatments, but they haven’t responded to the interventions in the manner expected, meaning the pain continues to persist.” Normally, this comes some 3 to 6 months after the acute phase.
Pain can become chronic when it has plateaued and resists medical treatment for at least 6 months.
“It’s important to recognize these time points exist,” Dr Prasad emphasised. “We can intervene at these different points — and intervene even prior to the experience of acute pain — to try to minimize the likelihood that persistent pain develops.”
There are many factors which contribute to chronic pain. These include environmental stressors, lifestyle factors, unhealthy support systems, limited care access, and patient risk factors such as substance abuse history, adverse childhood experiences, and psychiatric conditions.
Research has shown the most useful predictors of poor pain outcomes after surgery were pre-surgical somatization, depression, anxiety, and poor coping.
“All of these are things that are actually modifiable,” Prasad said. “We can actually do something about these to change the outcomes a person might have.”
Cognitive therapies and relaxation training are two interventions receiving a lot of attention, he noted. Breathing, relaxation exercises, and meditative practices can help patients learn to quiet the nervous system by working on the sympathetic-parasympathetic axis. But cognitive processes also have to be targeted, Prasad observed, and “this is where cognitive behavioral therapy can come in.”
Cognitive behavioural theory is premised on the idea that “by changing the interpretation, we can change the impact of consequences at the emotional, physical, and behavioral level,” Dr Prasad said. “The challenge with this is that our interpretations tend to be automatic.”
“Making changes in our interpretation is difficult because we have to become aware of processes that are occurring in our subconscious and make changes in something that’s been with us for a very long period of time,” he acknowledged. “These thought processes can be very resistant to change. But it’s essential we do this if we want to have sustained change in our outcomes.”
It’s not something as simple as turning negative thoughts into positive ones, Prasad added. “Rather, we look at the accuracy and the degree of helpfulness of the thoughts, and modify the thoughts into something that is more accurate and helpful.”
“We know that when people engage in cognitive behavioral therapy, their outcomes are improved. Affective stress is decreased, pain sensitivity decreases, and this can minimize opioid burden,” he continued. He added that there are many psychological-based tools backed by a strong evidence basem including biofeedback training and mindfulness-based stress reduction.
Dr Prasad emphasised however that timing of these treatments is essential.
“The way to optimize timing is to do presurgical screening to identify what’s the most appropriate intervention for the patient,” he said. Some patients may need help before surgery, others can be targeted at the acute or subacute phase. “Regardless, we want to make sure we address symptoms as early as possible and not wait for pain to be in a chronic state.
