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Recommended Drugs for Neuropathic Pain: A Systematic Review of Head-to-Head Trials

Published: 26/04/2024


Chronic neuropathic pain is caused by damage or compression of one or more nerves. This causes pain, which is commonly accompanied by a change in sensation. Many people describe neuropathic pain as having characteristic sensations, such as burning, electric shocks, or pins and needles.

Like all chronic pain conditions, treatment of neuropathic pain requires the input of many healthcare professionals. This may include physiotherapy and talking therapies. In addition, many patients need medications to help reduce the pain. Currently, the Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain (IASP), recommends eight different medications in the treatment of neuropathic pain.

Which Medications are Recommended for Neuropathic Pain?

First-line treatments are tricyclic antidepressants (TCAs), serotonin–noradrenaline reuptake inhibitors (SNRIs), pregabalin, and gabapentin. Second-line treatments are lidocaine patches, capsaicin high-concentration patches, and tramadol, and third-line treatments are strong opioids and botulinum toxin type A (BTX-A). At present medical cannabis does not feature on the recommendations.

The authors of a recent systematic review and meta-analysis aimed to compare the efficacy and acceptability of first-, second-, and third-line drugs for neuropathic pain through head-to-head trials.

Methods of the Study

The researchers searched electronic databases for relevant clinical trials and unpublished studies with results. They included comparative, double-blind randomised controlled trials that studied the pain relieving effects of at least two drugs for recommended neuropathic pain (a placebo treatment was not required).

Studies were also required to use participants treated for neuropathic pain (defined by the IASP as: pain caused by a lesion or disease of the somatosensory nervous system). This included but was not restricted to diabetic, chemotherapy-induced and other painful polyneuropathies, postherpetic neuralgia, postamputation pain, post-traumatic or postsurgical neuropathic pain, painful radiculopathy, central poststroke pain, spinal cord injury pain, and mixed neuropathic pain

Study Outcomes

The study compared the effectiveness of each medication by assessing the average change in pain severity between baseline and the end of treatment. They also assessed the proportion of people who reported a reduction in pain severity of 50% or more.

The authors also looked at measures such as quality of life, sleep duration and quality, emotional functioning (eg, anxiety and depression), withdrawal from the study during active treatment, number of dropouts due to adverse events, and total adverse events.

Results of the Study

Thirty publications were included in the review, comprising a total of 4,087 patients. None of the trials included persons under the age of 18.

Comparing antidepressants and gabapentinoids

The researchers identified 10 trials comparing TCAs with gabapentinoids. There was moderate-quality evidence which showed there was no substantial difference between the two drug classes in any primary or secondary outcomes.

Eight trials compared SNRIs with gabapentinoids. The researchers found that SNRIs were associated with higher pain reduction. Three studies looked at the proportion of responders in each group, however, and there was no difference. Adverse events were more common in patients prescribed SNRIs

Comparing tricyclic antidepressants and serotonin–noradrenaline reuptake inhibitors

Six studies investigated the effect of TCAs compared with SNRIs. There was no difference in the change in pain severity between either group. Interestingly, more people dropped out of the included trials because of adverse events in those prescribed SNRIs compared to TCAs

Comparing opioids and tricyclic antidepressants/gabapentin

Three studies investigated the effects of opioids compared with TCAs and one with gabapentin. There was no difference between opioids and TCAs in pain reduction. The 1 study with gabapentin and opioids showed no difference between opioids and gabapentin. Furthermore, no difference was observed in the number of treatment responders between opioids and TCAs or between opioids and gabapentin.

The studies showed that more people withdrew during opioid treatment and more people dropped out because of adverse events compared to TCAs.

Comparison of different tricyclic antidepressants

Four studies compared the treatment of two different TCA medications. Two studies compared the treatment effect of amitriptyline vs desipramine and found no difference between the 2 drugs. In one study there were more responders with desipramine than amitriptyline. One study compared amitriptyline with nortriptyline, and no difference was found between the treatments, except nortriptyline was better tolerated.

One final study found chlorimipramine resulted in improved pain relief compared to nortriptyline, with similar side effects.

Comparing gabapentin and pregabalin

One study found no difference between pregabalin and gabapentin treatment. One study compared 600mg of pregabalin to 1800mg of gabapentin. In this, pregabalin was associated with improved pain relief. A third study compared 600mg of pregabalin to 2400mg of gabapentin, finding that gabapentin was more efficacious at improving pain in this scenario. Gabapentin was also associated with fewer side effects.


The authors note several limitations in the current systematic review and meta-analysis. This included the lack of comparison with a placebo group, the use of various maximum doses, variations in the specific drugs within each drug class, the utilisation of different scales for measuring secondary outcomes and different study designs, lack of minimum criteria for pain intensity, and the absence of long-term follow-up data in the included trials.

Nonetheless, based on these findings, the authors of the present study concluded that head-to-head trials suggest similar efficacy and tolerability between all first-line treatments recommended by IASP. However, gabapentinoids and TCAs appeared to be better tolerated compared to SNRIs in this sample.


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