Category: Pain Management

Topical Medication Trumps Opioids for Knee Osteoarthritis Pain

Photo by Matthias Zomer from Pexels

In treating knee osteoarthritis pain, topical medication for pain relief is safer and more effective than opioids, according to a new meta-analysis.

The paper, which appears in BMJ, compared the benefits and harms of different doses of commonly prescribed treatments for hip and knee osteoarthritis, including oral non-steroidal anti-inflammatory drugs (NSAIDs), topical NSAIDs, opioids, and acetaminophen (Tylenol). The meta-analysis looked at 192 large, randomised clinical trials with a total of over 102 000 participants.

Researchers found, regardless of preparation or dose, opioids did not significantly relieve pain for osteoarthritis patients. They also found that topical Diclofenac – known to consumers as Voltaren – is effective in treating knee osteoarthritis.

The topical treatment, which can be purchased over-the-counter, is generally safer than oral NSAIDs and should be considered as first-line pharmacological treatment for knee osteoarthritis, the study authors say. Osteoarthritis affects millions of Canadians.

Study lead author, Dr. Bruno R. da Costa, Acting Director of the Applied Health Research Centre (AHRC) at the Li Ka Shing Knowledge Institute of St. Michael’s Hospital, stated that recent clinical practice guidelines recommend the lowest possible dose to minimise the risk of adverse events.

However, he said, “it is currently unclear what the lowest but still effective doses of these drugs are. Osteoarthritis affects more than 4.6 million people in Canada. Our findings allow physicians, patients, or their caregivers to have a better understanding of which of these treatments at their lowest doses would be safest while still being effective.”

“Although there is robust evidence about the harmful effects of opioids, and international concerns around the opioid epidemic, opioids remain among the most prescribed drugs for osteoarthritis pain in Canada, the United States, the United Kingdom and Australia.”

Dr da Costa said that none of the opioid interventions, regardless of dose, seemed to have a clinically relevant effect on pain or physical function. Opioids should therefore only play a secondary role in osteoarthritis treatment, when conventional treatment is exhausted.

What was most surprising was that maximum recommended daily doses of opioids do not have an effect in osteoarthritis pain that patients would consider relevant. They did not see an association between higher opioid doses and greater pain relief.

Lower doses of topical diclofenac (Voltaren) also have a similar beneficial effect to the most effective oral NSAIDs in knee osteoarthritis – an important finding as some patients with gastrointestinal complaints and other comorbidities. Adverse events of topical NSAIDs are minimal. The topical diclofenac trials had only knee osteoarthritis, and in hip osteoarthritis the depth is likely too great for any benefit.

The next step is to better understand the safety of oral NSAIDs in patients with comorbidities, and long-term use on an as-needed-basis with varying versus fixed daily doses. It would also be useful to identify if there are patients who have exhausted treatment options but could benefit from opioids or acetaminophen.

Source: Unity Health

Ultra-thin Microelectrodes to Combat Severe Pain

First author Matilda Forni with the ultra-thin microelectrodes during production (Photo: Agata Garpenlind)

In an entirely new stimulation method to combat severe pain, researchers at Lund University in Sweden have developed ultra-thin microelectrodes which are inserted into the pain centres of the brain.

This approach, which was tested in rats, provides effective and personalised analgesia, without the side effects of drugs. The findings were reported in Science Advances.

The quality of life of patients experiencing pain is greatly impacted by the lack of side-effect free treatment, and pain also impacts society in terms of reduced productivity. Side effects of pain medication can include reduced mental capacity and, in some cases, addiction. According to a recent American report, about 8% of the American population suffer from high-impact chronic pain.

To address this, professor of neurophysiology Jens Schouenborg led a research team which developed a method to combat pain via personalised stimulation using ultra-thin, tissue-friendly microelectrodes.

“The electrodes are very soft and extremely gentle on the brain. They are used to specifically activate the brain’s pain control centres without simultaneously activating the nerve cell circuits that produce side effects. The method involves implanting a cluster of the ultra-thin electrodes and then selecting a sub-group of the electrodes that provide pure pain relief, but no side effects. This procedure enables extremely precise and personalised stimulation treatment that was shown to work for every individual,” explained Prof Schouenborg.

Pain control is achieved by activating the brain’s pain control centres, these in turn block only the signal transfer in the pain pathways to the cerebral cortex.

“We have achieved an almost total blockade of pain without affecting any other sensory system or motor skill, which is a major breakthrough in pain research. Our results show that it is actually possible to develop powerful and side effect-free pain relief, something that has been a major challenge up to now,” explained first author and doctoral student Matilde Forni.

Over several years, the researchers developed a tissue-friendly, gelatine-based technology and surgical techniques that allowed them to precisely implant the flexible microelectrodes. According to the researchers, the new technique should work on all sorts of pain that are conveyed by the spinal cord, which is most types of pain.

“In our study we also compared our method with morphine, which was shown to deliver considerably less pain relief. In addition, of course, morphine has a powerful sedative effect as well as other cognitive effects. In the study we could also show that pain after sensitisation (hyperalgesia), which is common in chronic pain, was blocked”, said Prof Schouenborg.

The researchers plan to test the technology in humans and that within five to eight years yield an effective pain treatment, for pain from cancer or chronic pain in connection with spinal cord injuries, for which there is no currently satisfactory pain treatment..

The researchers also consider that the method could be used in a broader way to treat conditions besides pain.

“In principle, the method can be tailored to all parts of the brain, so we believe that it could also be used in the treatment of degenerative brain diseases such as Parkinson’s disease as well as in depression, epilepsy and probably stroke as well. The electrode technique also has applications in diagnostics and not least in research on how the mysterious brain works,” said Prof Schouenborg.

Source: Lund University

Electroacupuncture Spares Opioids for Knee Replacement Pain Relief

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Patients who have electroacupuncture during total knee replacement surgery report less pain and need far fewer opioids to manage their discomfort. In the study, 65% of patients who received acupuncture during surgery were able to have a low-dose or opioid-free postoperative experience, compared to 9% of patients outside of the study.

The results of the study were presented at the ANESTHESIOLOGY® 2021 annual meeting

“Total knee replacements are one of the most common operative procedures in the United States and often very painful, so there’s a great need to explore non-opioid pain relief techniques for this type of surgery,” said lead author Stephanie Cheng, MD, DABMA, assistant attending anaesthesiologist at the Hospital for Special Surgery and assistant professor of clinical anaesthesiology at Weill Cornell Medicine. “Acupuncture is extremely safe and can help reduce pain with few unwanted side effects, but it has not been well researched as part of surgical anesthesia.”

The study enrolled 41 patients who had primary total knee replacement, all of whom received the institution’s standard opioid-sparing multimodal analgesic protocol, with the addition of electroacupuncture, which is a modified form of traditional acupuncture that applies a small electric current to thin needles that are inserted at known acupuncture points on the body. The acupuncture was administered during surgery by Dr Cheng, who is board-certified in medical acupuncture, to eight specific points in the ear to provide targeted pain relief in the knee.

With the addition of acupuncture, the majority of patients had reduced postoperative opioid use, compared to historical controls, while 65% of patients either maintained a low-dose opioid regimen of 15 oxycodone pills or less (57.5%) or remained completely opioid-free (7.5%) from induction of anaesthesia to 30 days post-surgery. Historically, only 9% of patients outside of the study were able to maintain a low-dose or opioid-free regimen post-surgery. Thirty days after surgery, all patients discontinued opioid use.

“Our study shows that if a trained medical acupuncturist is available to perform acupuncture in the operating room, it can help patients with postoperative pain recovery,” said Dr Cheng. “Most studies fail to incorporate nontraditional techniques, such as acupuncture, to help decrease the dependence on opioid medications for postoperative pain control.”

Low-dose perioperative opioid consumption is key to mitigating the opioid epidemic and opioid misuse by patients. Dr Cheng pointed out that with acupuncture being commonly used outside of the hospital as an effective therapy for pain management and treatment for a range of health issues and symptoms, it’s time to consider its benefits inside the hospital as well. “Additional research is needed to further define acupuncture’s effects and encourage its use in all aspects of disease treatment.”

Source: American Society of Anesthesiologists

Fifth of Opioid-Naïve Patients Continue Use Post-surgery

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More than a fifth of ‘opioid-naïve’ patients continue to use opioids three months after having a procedure, underscoring the often-overlooked role surgery plays in the opioid epidemic.

In research presented at the ANESTHESIOLOGY® 2021 annual meeting, smokers and people with bipolar disorder, depression or pulmonary hypertension were found to be at highest risk.

Persistent opioid use was much higher than expected among opioid-naïve patients (those who did not have an opioid prescription filled in the previous year). Surgery is the first time many patients have used opioids, often prescribed for post-surgical pain management.

The study examined data on 13 970 opioid-naïve adults from 2013-2019. In the study, opioid-naïve patients were those who had not filled an opioid prescription 31 days to one year before surgery (patients often are prescribed opioids in advance so they are available immediately after the surgery). Researchers found that 21.2% of patients refilled their opioid prescription three months to one year after the procedure. Unless they have cancer or had chronic pain before surgery, very few patients should still need opioids three months after surgery, the researchers note.

Analysing 46 potential risk factors, researchers found many patients were still using opioids after three months. The top four risk-factors identified, which were modifiable, were: smoking, bipolar disorder, depression and pulmonary hypertension. They also found that procedures with cardiac and podiatry surgical providers and patients who had cataract surgery were at an increased risk of persistent opioid use.

“To reduce the likelihood of ongoing opioid use, physician anesthesiologists should use the preoperative assessment to identify patients at highest risk for persistent use,” said lead author Gia Pittet, AuD, PhD, visiting graduate researcher for anesthesiology and perioperative medicine at the University of California, Los Angeles. “Before they have surgery, patients who smoke should be encouraged to quit, those with pulmonary hypertension should see a doctor to help them get the condition under control and patients with bipolar disorder or depression may require a preoperative adjustment of their medications.”

Patients should also receive counseling about the safe use of opioids and be offered alternative pain management, such as limited or non-opioid multimodal treatment and be monitored frequently and closely while they are taking opioids.

Source: American Society of Anesthesiologists

A Step Closer to Effective Electrical Pain Blocking

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New research from the University of Connecticut has brought the drug-free technology of electrical anaesthesia for all chronic pain sufferers a step closer. 

Pain stimuli, or ‘nociceptive stimuli’ is picked up by nociceptors which send signals to the spinal cord, which passes it on to the brain where the perception of pain is manifested.

Bin Feng, associate professor in the Biomedical Engineering Department, led research which discovered how electrical stimulation of the dorsal root ganglia (DRG), sensory neural cell body clusters, can block nociceptive signal transmission to the spinal cord and prevent the brain from perceiving chronic pain signals. The findings are reported in PAIN.

Electrical devices to treat pain typically deliver electrical signals to the peripheral nervous system and spinal cord to block nociceptive signals from reaching the brain.

A major obstacle with these devices is that while some patients find them beneficial in relieving their chronic pain, others have little or no pain reduction. Despite incremental developments of neurostimulator technologies, there has not been much improvement in getting the devices to work for these patients.

“The trouble with this technology is that it can benefit a portion of patients very well, but for a larger portion of patients it has little benefit,” Prof Feng said.

One of the reasons is that such devices lag behind research into neural stimulation.

“We’re sitting on a huge pile of clinical data,” Prof Feng says. “But the science of neuromodulation remains understudied.”

Neurostimulators relieve pain according to a ‘gate control’ theory. Our bodies can detect both innocuous stimuli, like something brushing against the skin, and painful stimuli, through low- and high-threshold sensory neurons, respectively.

The spinal cord ‘gate’ can be shut by activating low-threshold sensory neurons, preventing painful nociceptive signals from high-threshold sensory neurons from crossing the spinal cord to the brain.

Neurostimulators reduce pain in patients by activating low-threshold sensory neurons with electrical pulses. This usually causes a non-painful tingling sensation in certain areas of the skin, or paresthaesia, masking the perception of pain.

Many patients receiving DRG stimulation treatment reported pain relief without the expected paraesthesia.

Seeking to understand this, Prof Feng’s lab discovered that electrical stimulation to the DRG can block transmission to the spinal cord at frequencies as low as 20 hertz. This is in contrast to previous research indicating that blocking requires kilohertz electrical stimulation.

“The cell bodies of sensory neurons form a T-junction with the peripheral and central axons in the DRG,” Feng says. “This T-junction appears to be the region that causes transmission block when DRG is stimulated.”

More remarkably, sensory nerve fibres with different characteristics are blocked by different electrical stimulation frequency ranges at the DRG, allowing the development of new neural stimulation protocols to enhance selective transmission blocking with different sensory fibre types.

“A-fibre nociceptors with large axon diameters are generally responsible for causing acute and sharp pain,” Prof Feng explained. “It is the long-lasting and dull-type pain that bothers the chronic pain patients mostIn a chronic pain condition, C-fibre nociceptors with small axon diameter and no myelin sheath play central role in the persistence of pain. Selectively blocking C-fibres while leaving A-fibres intact can be a promising strategy to target the cause of chronic pain.”

This provides evidence to place more electrodes for devices that target the DRG and surrounding neuronal tissues, letting doctors provide more precise neuromodulation.

“The next-generation neurostimulators will be more selective with fewer off-target effects,” Prof Feng said. “They should also be more intelligent by incorporating chemical and electrical sensory capabilities and ability to communicate bidirectionally to a cloud-based server.”

Prof Feng hopes that more people will be eventually able to achieve chronic pain relief with this technology. He is now working toward conducting clinical studies with his collaborators at UConn Health to test the efficacy of this method in humans.

Source: University of Connecticut

New Migraine Prevention Drug Gets The Green Light from FDA

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Atogepant (Qulipta) has become the first oral calcitonin gene-related peptide (CGRP) receptor antagonist (gepant) specifically developed for migraine prevention to win FDA approval, manufacturer AbbVie announced on Monday.

Following on after rimegepant, which is also indicated by the FDA for acute migraine treatment, atogepant became the second gepant approved for prevention of episodic migraine in adults.

The atogepant decision “reflects a broader shift in the treatment and management paradigm for the migraine community,” noted Peter Goadsby, MD, PhD, DSc, of the University of California Los Angeles and King’s College London.

“Qulipta provides a simple oral treatment option specifically developed to prevent migraine attacks and target CGRP, which is believed to be crucially involved in migraine in many patients,” said Dr Goadsby in a statement.
Atogepant has a high affinity at the CGRP receptor, and being a small-molecule drug it can be taken orally, unlike injectable anti-CGRP monoclonal antibodies approved for migraine prevention.
An oral CGRP-receptor antagonist is easier for patients, Goadsby noted when he presented data from atogepant’s pivotal phase IIb/III trial at the 2019 American Academy of Neurology annual meeting. “It could facilitate, with time, the greater use of this mechanism in primary care,” he told MedPage Today. “Primary care doctors will more easily use a medicine that’s relatively simple to use and well-tolerated, and that means more migraine patients can get treated.”

In the phase III ADVANCE trial, 873 participants were randomised to receive a once-daily dose of oral atogepant (10mg, 30mg, or 60mg) or placebo. After 12 weeks, average days with migraine per month dropped from baseline by 3.7 days with atogepant 10mg, 3.9 days with atogepant 30mg, 4.2 days with atogepant 60mg, and 2.5 days with placebo. The most common adverse events with atogepant were constipation and nausea, along with fatigue. 
Patients should notify their healthcare provider if they have kidney problems or are on dialysis, have liver problems, are pregnant or plan to become pregnant, or are breastfeeding or plan to breastfeed, AbbVie said.

Source: MedPage Today

Breakthrough Could Lead to New Opioid Alternatives

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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.”

Source: Monash University

Acupuncture Puts a Pin in Chronic Pelvic Pain

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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.

Source: Medical Xpress

Transcranial Focused Ultrasound for Chronic Pain Relief

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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.

Source: National Institute of Biomedical Imaging and Bioengineering

Muscle Relaxants Largely Ineffective for Low Back Pain, Study Finds

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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.

Source: News-Medical.Net

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. BMJdoi.org/10.1136/bmj.n1446.