Neuropathic pain: diagnostic and therapeutic challenges

Neuropathic pain: diagnostic and therapeutic challenges

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What is neuropathic pain?

According to current definition, neuropathic pain arises as a direct consequence of a lesion or disease affecting the somatosensory system, which is the part of the sensory system concerned with the perception of touch, pressure, pain, or temperature. The injury or disease may occur in the peripheral nervous system (the nerves leaving the spinal cord) or in the central nervous system (the brain and spinal cord). As the nerve fibres conducting painful sensations are very fine and sensitive, they can be easily damaged by several factors, listing the most common ones1:

  • Metabolic dysfunctions (e.g. diabetes mellitus)
  • Viruses (e.g. herpes, HIV)
  • Persistent mechanical effects (e.g. tumours, intervertebral discs degeneration)
  • Inflammation or autoimmune diseases (e.g. multiple sclerosis)
  • Ischaemia (e.g. stroke)
  • Nerve injuries (e.g. spinal cord injury, surgery, trauma)
  • Toxins (e.g. alcohol abuse)
  • Drugs (e.g. anti-cancer treatments)
  • Malnutrition (e.g. vitamin B12)

Neuropathic pain affects 7-10% of adult population and is more prevalent in elderly and in women2. The most common causes of peripheral neuropathic pain in humans are Herpes Zoster infection and diabetes mellitus, however neuropathic component may be present as well in other, non-neuropathic diseases such as osteoarthritis or cancer.

The risk of neuropathic pain in an individual depends on numerous factors, including genetical susceptibility, site of nerve injury, underlying disease, age, sex and probably on other, not yet fully understood factors. Fortunately, in most patient’s nerve injury or disease does not result in neuropathic pain. For example, herpes zoster infection may result in painful postherpetic neuralgia in around 4-13% patients at 6 months after acute viral infection3.

Neuropathic pain differs substantially from pain affecting the musculoskeletal system – the first one is more intense, more negatively impacts patients’ functioning, and is refractory to simple and over-the-counter analgesics.

What are the symptoms of neuropathic pain?

The mechanism of neuropathic pain is very complex. The injury of nervous system activates several mechanisms, which change the sensitivity and activity of nerves across the human body. These changes can give rise to sensory (numbness, increased sensitivity, pain), motor (weakness, muscle spasms) and autonomic (colour, temperature, sweating) symptoms.

Neuropathic pain can be suspected on clinical grounds because it has characteristic symptoms and signs. The most common symptoms and ways to describe the neuropathic pain are4:

  1. Stabbing & sharp pain (“pins & needles”)
  2. Burning
  3. Numbness & tingling
  4. Extreme cold
  5. Electric shock-like pain

Allodynia (pain arising in response to non-painful stimulus, e.g., to touch) and hyperalgesia (exaggerated response to normally painful stimulus, e.g., to pinprick) are also common and very characteristic symptoms reported by neuropathic pain patients.

How is neuropathic pain diagnosed?

In clinical practice, specific diagnosis of neuropathic pain is made by taking a history focused on relevant neurological lesion or disease, careful listening to patients’ reported pain descriptors, examining the sensory abnormalities in area of maximum pain and in some cases by arranging certain investigations, such as nerve conduction studies. Screening tools such as DN4 or Pain DETECT have been developed which allow patients and physicians to be more confident in making the diagnosis of neuropathic pain.

If a specific diagnosis is established, it may allow the disease or condition to be treated as well as the pain itself. For example, in some patients better control of diabetes would also help to improve pain from diabetic neuropathy. However, in most patients, symptomatic treatment, addressing the pain and including a combination of drug and non-drug therapies, is the only available method. Unfortunately, these recommended drugs may be not fully effective in many patients, mainly due to complex nature of neuropathic pain, inappropriate dosage, or inadequate duration of treatment.

What are the indicated treatments for neuropathic pain?

A treatment is considered successful if pain is reduced by 50%5. Thus, the main principle in pain management is to discuss treatment options with the physician, establish realistic treatment goals, consider patients’ individual preferences and limitations due to medical conditions or other circumstances, assess a patient as a whole person, not just focus on neuropathic pain. Moreover, the management should address not only pain symptoms but other possible associated problems like low mood, depression, anxiety or distress, sleep problems and functional limitations. Personalised and multidisciplinary pain management is the most effective treatment for neuropathic pain patients6.

According to current clinical guidelines, there are classes of drugs that are more likely to help neuropathic pain than the more regular painkillers. These include the recommended ‘first line’ drugs for neuropathic pain, such as antidepressants, antiepileptics and topical treatments:

a) Antidepressants – these are used for pain control, not for antidepressant effect. They work for pain at doses much lower and much faster than required for depression and work as well in patients who are not depressed.

b) Antiepileptics – these are used for pain control, not for their antiepileptic effect. They can be very helpful in ‘calming’ overactive and sensitized neurons in peripheral and central nervous system.

Both groups of drugs can cause somnolence or dizziness, so they are started at a lower dose and increased to the most effective and/or tolerated dose. Although some people may have pain relief soon after starting this anti-neuropathic pain medication, drugs often need to be taken for several weeks (2-4) at the appropriate, tolerated dose to obtain optimal pain control without significant side effects7.

c) Topical treatments – if neuropathic pain is felt in a localised area, the patients might benefit from the topical use (applied directly to and acting at the painful area) of patches containing a local anaesthetic agent. Topical treatments are much better tolerated than systemic drugs.

If neuropathic pain is not responding to the first line pain medications, changing the treatment to one of the other first line treatments, or combining two different drugs together may be considered. In patients with localized pain, 8% capsaicin patches or intradermal injections of botulinum toxin applied in specialized pain centres may be helpful56.

If the pain is severe and/or not responding to first line drugs, weak or strong opioids may be administered for a short time. The use of strong opioids to treat neuropathic pain remains controversial, however there are some clinical situations when strong opioids are recommended as first line drugs, e. g. neuropathic pain related to cancer, severe pain occurring during the titration of antiepileptics or antidepressants.

Non-drug treatments include neuromodulation techniques such as TENS (transcutaneous electrical nerve stimulation), transcranial magnetic stimulation, and spinal cord stimulation6. TENS is recommended as first line treatment for patients with localized neuropathic pain. Moreover, this method is simple, easy, relatively safe and may be applied at home.

Transcranial magnetic stimulation may be helpful in some patients, refractory to pharmacological methods and is recommended as the third-line treatment. Similarly, some types of neuropathic pain can be managed with complex implants to spinal cord. This type of invasive treatment is not common and is only considered if pain is refractory to all before mentioned drug and non-drug therapies. These non-invasive and invasive neuromodulations are only offered in specialist pain centres.

Psychological methods such as cognitive behavioural therapy, and hypnosis should be applied along with drug and non-drug treatments, as the part of multidisciplinary management6.

Despite huge progress made in neuropathic pain diagnosis and management, numerous methods available, the treatment outcomes are still unsatisfactory for both patients and physicians. Therefore, we are still looking for novel and more effective therapies, but until then multidisciplinary and patient-centred approach involving combination of drug and non-drug therapies should be applied.



1. Van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N. Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain. 2014 Apr;155(4):654-662. doi: 10.1016/j.pain.2013.11.013.

2. Torrance N, Smith BH, Bennett MI, Lee AJ. The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey. J Pain. 2006 Apr;7(4):281-9. doi: 10.1016/j.jpain.2005.11.008.

3. Reda H, Greene K, Rice FL, Rowbotham MC, Petersen KL. Natural history of herpes zoster: late follow-up of 3.9 years (n=43) and 7.7 years (n=10). Pain. 2013 Oct;154(10):2227-2233. doi: 10.1016/j.pain.2013.04.015.

4. Smith BH, Torrance N, Ferguson JA, Bennett MI, Serpell MG, Dunn KM. Towards a definition of refractory neuropathic pain for epidemiological research. An international Delphi survey of experts. BMC Neurol. 2012 May 28;12:29. doi: 10.1186/1471-2377-12-29.

5. Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, Gilron I, Haanpää M, Hansson P, Jensen TS, Kamerman PR, Lund K, Moore A, Raja SN, Rice AS, Rowbotham M, Sena E, Siddall P, Smith BH, Wallace M. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015 Feb;14(2):162-73. doi: 10.1016/S1474-4422(14)70251-0.

6. Moisset X, Bouhassira D, Avez Couturier J, Alchaar H, Conradi S, Delmotte MH, Lanteri-Minet M, Lefaucheur JP, Mick G, Piano V, Pickering G, Piquet E, Regis C, Salvat E, Attal N. Pharmacological and non-pharmacological treatments for neuropathic pain: Systematic review and French recommendations. Rev Neurol (Paris). 2020 May;176(5):325-352. doi: 10.1016/j.neurol.2020.01.361.

7. Dworkin RH, O’Connor AB, Audette J, Baron R, Gourlay GK, Haanpää ML, Kent JL, Krane EJ, Lebel AA, Levy RM, Mackey SC, Mayer J, Miaskowski C, Raja SN, Rice AS, Schmader KE, Stacey B, Stanos S, Treede RD, Turk DC, Walco GA, Wells CD. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc. 2010 Mar;85(3 Suppl):S3-14. doi: 10.4065/mcp.2009.0649.

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