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Neuropathic Pain Relief: TCAs Outperform Opioids In Major Review

TRICYCLIC antidepressants (TCAs) and non-invasive neuromodulation techniques like repetitive transcranial magnetic stimulation (rTMS) demonstrate the highest efficacy for neuropathic pain, with TCAs achieving a number needed to treat (NNT) of 4.6, according to a comprehensive meta-analysis of 313 trials involving 48,789 participants.

Neuropathic pain remains a complex clinical challenge due to limited treatment efficacy and significant side effects. Updated recommendations from the Neuropathic Pain Special Interest Group (NeuPSIG), incorporating new pharmacological and neuromodulation evidence, aim to refine therapeutic strategies. This systematic review and meta-analysis evaluated 284 pharmacological and 29 neuromodulation trials, focusing on double-blind, placebo-controlled studies to reassess first- to third-line treatments.

The analysis revealed strong recommendations for TCAs (NNT=4.6, 95% CI 3.2–7.7), α2δ-ligands (gabapentin/pregabalin; NNT=8.9), and serotonin-norepinephrine reuptake inhibitors (SNRIs; NNT=7.4) as first-line options due to moderate certainty of efficacy and safety. Second-line weak recommendations included capsaicin 8% patches (NNT=13.2) and lidocaine 5% plasters (NNT=14.5), while third-line options featured botulinum toxin (NNT=2.7) and rTMS (NNT=4.2). Opioids, though effective (NNT=5.9), received a weak third-line recommendation due to low safety certainty (NNH=15.4). Neuromodulation techniques like rTMS showed promise but require further validation.

These findings underscore the importance of prioritising TCAs and SNRIs in clinical practice, while advocating cautious opioid use. Future research should focus on long-term efficacy trials, personalised treatment algorithms, and integrating neuromodulation into standard care pathways. Clinicians are encouraged to adopt a stratified approach, combining pharmacological and non-invasive methods to optimise outcomes in this heterogeneous patient population.

Reference

Soliman N et al. Pharmacotherapy and non-invasive neuromodulation for neuropathic pain: a systematic review and meta-analysis. The Lancet Neurology. 2025;24(5):413-28.

Best Nerve Pain Treatments Identified In Up-to-date, Global Review

Nerve or neuropathic pain has long been a tricky condition to treat effectively. However, a new study has comprehensively evaluated current drug and non-drug therapies to provide up-to-date guidelines to inform treatment options for those with the condition.

It's estimated that nerve, or neuropathic, pain affects between 6.9% and 10% of the global population. Often described as burning, electrical, or shooting, this type of pain is usually accompanied by abnormal sensations like tingling, numbness, or "pins and needles." Neuropathic pain can significantly impact quality of life.

A new study by the International Association for the Study of Pain's (IASP) Neuropathic Pain Special Interest Group (NeuPSIG) has comprehensively examined the effectiveness of current drug and non-drug therapies for neuropathic pain to compile up-to-date treatment guidelines.

"There is an unmet need for effective and safe treatments for neuropathic pain," said study co-author Michael Ferraro, a doctoral researcher at the Center for Pain IMPACT, Neuroscience Research Australia (NeuRA), and the School of Health Sciences at the University of New South Wales (UNSW). "Our research looked at the evidence for all drugs and nerve stimulation treatments, considering effectiveness, safety, cost, accessibility, and patient perspectives."

Although there are many causes of neuropathic pain, it's commonly associated with specific conditions, including diabetes (peripheral neuropathy), chemotherapy, and shingles (postherpetic neuralgia). Many people with neuropathic pain experience symptoms such as depression, anxiety, problems sleeping, and memory defects in addition to pain.

Neuropathic pain commonly occurs in the hands, legs and feet

For the present study, the researchers searched through previously published randomized controlled trials evaluating medications and nerve stimulation, or neuromodulation, treatments that had been administered for at least three weeks, or if there was at least three weeks of follow-up, and that included at least 10 participants per group. They identified 313 trials – 284 pharmacological and 29 neuromodulation studies – comprising 48,789 adult participants. The drug classes evaluated were alpha-2 delta ligands (⍺2δ-ligands), tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and opioids. The most-studied neuromodulation treatment was repetitive transcranial magnetic stimulation (rTMS).

Drugs that are ⍺2δ-ligands, such as gabapentin (Neurontin) and pregabalin (Lyrica), target specific nerve channels that help transmit pain signals. By binding to these channels, they reduce the release of chemicals that cause pain signals to be sent to the brain, resulting in decreased pain perception. TCAs, like amitriptyline (Elavil), are primarily used to treat depression but also work by increasing the levels of certain neurotransmitters like serotonin and norepinephrine in the brain and spinal cord. These neurotransmitters help block signals while exerting a calming effect on nerve cells, which can reduce pain. Likewise, SNRIs such as duloxetine (Cymbalta) and venlafaxine (Effexor) can reduce pain by increasing serotonin and norepinephrine levels in the brain and spinal cord. Opioids like tramadol, oxycodone, morphine, and buprenorphine bind to pain receptors in the brain and spinal cord to block pain signals and provide pain relief.

The researchers used the GRADE guidelines to categorize the entire body of evidence (GRADE isn't applied to individual studies) as either high, moderate, low, or very low. From this, they were able to come up with a list of first-, second-, and third-line treatments.

"Three medication classes were recommended for first-line use," Ferraro said. "These were alpha-2 delta ligands (e.G., pregabalin, gabapentin), serotonin and norepinephrine reuptake inhibitors (e.G., duloxetine), and tricyclic antidepressants (e.G., amitriptyline). Importantly, these medicines have only modest benefits and require careful patient screening and close monitoring.

"We also established capsaicin and lidocaine patches and capsaicin cream as second-line therapies despite having small effects on pain – they are safe and tolerable, and suitable for use in older adults or patients taking multiple medications."

Capsaicin is a naturally occurring compound that gives chili peppers their 'heat.' It works by stimulating heat receptors in the skin, tricking the body into thinking it's overheating and triggering its cooling mechanisms. This can help reduce pain perception. Capsaicin is available as a supplement or in a cream. Lidocaine (Xylocaine), also known as lignocaine, is a local anesthetic that prevents pain transmission by blocking nerve signals.

NeuSPIG's last set of guidelines was published in 2015. For the first time, the researchers evaluated the effectiveness of rTMS and recommended it as an appropriate treatment for selected patients. They also found inconclusive evidence for some medications and non-pharmaceutical treatments, meaning they could neither recommend for or against these treatments, which included ketamine, lacosamide and topiramate (both are anti-seizure medications), selective serotonin reuptake inhibitors (SSRIs), transcranial direct current stimulation, and spinal cord stimulation.

Diabetic peripheral neuropathy is a common cause of neuropathic pain

There was, however, a list of medications that were not recommended for use: cannabinoids, valproate (used to treat epilepsy and bipolar disorder), levetiracetam (an anti-epileptic), and mexiletine (used to treat abnormal heart rhythms, chronic pain, and some causes of muscle stiffness). The researchers said the guidelines are designed to inform and guide treatment for people with neuropathic pain.

"Neuropathic pain affects people differently, so the guideline supports the provision of high-quality patient-centered care that considers needs, values and preferences," said Ferraro. "Treatment choices depend on potential effectiveness, safety, accessibility, comorbidities, and use of other medicines."

Ferraro hopes that future reviews will evaluate the effectiveness of other non-drug treatments.

"High-quality evidence on treatment of neuropathic pain with non-drug treatments, such as exercise, is lacking, and should be prioritized for future research," he said.

The study was published in the journal The Lancet Neurology.

Source: NeuRA

These Common Medications Could Make The Heatwave Harder On You

If you have also felt drained by the long, grey days we've experienced this year so far, you're in luck. The UK is experiencing a heatwave this week. The Met Office advises: "The warmest day of the week looks set to be Thursday, with temperatures expected to reach 29°C across parts of England."

However, before you rush out in sunnies and shorts, research has found that certain medications can have physiological effects on the body, causing the core body temperature to rise above 40°C. Other medications have been found to make people far more sensitive to heat.

The medications that can cause overheating

According to the Mental Health Foundation: "One adult in eight receives mental health treatment, with 10.4% [of those] receiving medication and 3% receiving psychological therapy.

"The overlap within the statistics is due to 1.3% of those receiving treatment reporting receiving both medication and psychological therapy."

Mental health medications fall under a number of different categories including Serotonin Reuptake Inhibitors (SSRIs), Tricyclic Antidepressants (TCAs) Antipsychotic Drugs (ACDs), and beta blockers which are often used to treat anxiety and heart conditions.

All of these medications can cause heat intolerance.

Additionally, blood pressure medications can cause heat intolerance, too. Acocrding to Centers for Disease Control: "Certain combinations of medications, such as the combined use of angiotensin converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) with a diuretic, may significantly increase risk of harm from heat exposure."

How to prevent and treat heat intolerance

To stay cool during hot weather, the NHS recommends: "Keep out of the heat if you can. If you have to go outside, stay in the shade especially between 11am and 3pm, wear sunscreen, a hat and light clothes, and avoid exercise or activity that makes you hotter.

"Cool yourself down. Have cold food and drinks, avoid alcohol, caffeine and hot drinks, and have a cool shower or put cool water on your skin or clothes."

They also advise keeping windows closed during the day and opened at night once temperatures have dipped.

For somebody potentially experiencing heat exhaustion, the health service advises the following tips:

Move them to a cool place

Remove all unnecessary clothing like a jacket or socks

Get them to drink a sports or rehydration drink, or cool water

Cool their skin – spray or sponge them with cool water and fan them. Cold packs, wrapped in a cloth and put under the armpits or on the neck are good too

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