Neuropathic pain

Accurate diagnosis is key to optimal management of this challenging condition

 

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Neuropathic pain

Key points

  • Recognise that the differential diagnosis of neuropathic pain is crucial because it requires a different therapeutic approach from nociceptive pain.
  • Use a targeted history and physical examination, and consider a validated screening tool (eg DN4) to make an accurate diagnosis of neuropathic pain.
  • Consider low-dose amitriptyline as a first-line medicine for neuropathic pain and avoid prescribing pregabalin in a diagnostic capacity.
  • Optimise the benefits of neuropathic pain medicines with the lowest possible starting dosages, up-titrating gradually and an adequate trial period.
  • Recognise that medicines will often have limited efficacy for your patient and non-pharmacological strategies play a key role in coping.

 

Practice Review – Revisiting treatment options: neuropathic pain

Doctor checking statistics on a tablet

Australian GPs recently received a Practice Review on their prescribing of pregabalin and amitriptyline in practice.

  • Find more information to help you interpret and understand your data.
  • Access a sample report.
  • Reflect on your data in relation to your patients and their indications for amitriptyline and pregabalin.

Read the full details

  • Find more information to help you interpret and understand your data.
  • Access a sample report.
  • Reflect on your data in relation to your patients and their indications for amitriptyline and pregabalin.
 

Demonstration video: physical examination sensory tests 

Doctor demonstrating a physical examination sensory tests on a patient's leg

The diagnosis of neuropathic pain requires a targeted history and physical examination, which includes these 3 sensory tests:

  • light touch test
  • pinprick test
  • dynamic mechanical allodynia test.

These tests may be performed for all neuropathic pain presentations (comparing painful areas to non-painful sites/areas).

Watch a demonstration video of the tests on the resources page

  • light touch test
  • pinprick test
  • dynamic mechanical allodynia test.
 

Medicinewise News: Neuropathic pain: diagnosis and treatment today

Nerve cells

The definition of neuropathic pain has recently been updated, emphasising its association with a lesion or disease of the somatosensory nervous system. Diagnosis, through targeted history and physical examination, allows the selection of the most effective medicines and treatments for this type of chronic pain. Low-dose amitriptyline remains a first-line medicine for neuropathic pain. 

Read the full article

 
 

Why tackle neuropathic pain now? 

red and white capsules increasing from small to large left to right. 

The rise and rise of pregabalin has raised concerns about how well neuropathic pain is being diagnosed and managed.

Is pregabalin being prescribed for conditions other than neuropathic pain? Is it being used according to guidelines and the best available evidence? Are patients receiving optimal benefit from pregabalin, once prescribed?

Read the full article

 

RADAR: Pregabalin (Lyrica) for neuropathic pain

Chemical structure of pregabalin

RADAR 4 April 2013

Pregabalin is an alternative treatment for people with neuropathic pain that has not responded to other drugs. 

Read the full article

 

In my practice: Q&A

Dr Ram Prasad in his surgery

Q&A with Dr Ram Prasad, a Melbourne GP, answering questions on how he deals with diagnosis and prescribing for neuropathic pain. 

Read the full article

 

Demonstration videos of physical examination sensory tests

This video is a demonstration of 3 sensory tests – light touch, pinprick, and dynamic mechanical allodynia – on a patient with possible radicular back pain. These sensory tests may be performed for patients with all neuropathic pain presentations (comparing painful areas to non-painful sites/areas). They are easy to perform in general practice.

Viewing time: 6:05

Read video transcript

These sensory tests are part of the DN4 (Douleur Neuropathique en 4 questions), a clinician administered validated assessment tool. The DN4 is simple and easy to perform in general practice.

  • Light touch sensory test – start at 1:13 (viewing time: 0:43)
  • Pinprick sensory test – start at 1:57 (viewing time: 1:15)
  • Dynamic mechanical allodynia test – start at 3:13 (viewing time: 1:14)

Examiner: Dr Michael Vagg, Pain Specialist, Geelong, Victoria, Vice-Dean Elect, Faculty of Pain Medicine ANZCA, Clinical Senior Lecturer, Deakin University School of Medicine.

 

Practical tools and information

Grading system for neuropathic pain diagnosis

The International Association for the Study of Pain (IASP) published the grading system in 2016. It addresses the difficulty of making an accurate diagnosis of neuropathic pain and allows appropriate treatment decisions in the face of uncertainty.

Neuropathic pain questionnaire – DN4

The DN4 (Douleur Neuropathique en 4 questions) is a clinician-administered assessment tool.

It consists of 10 items: 7 related to patient history and 3 to physical exam.

When all items are completed, it has good sensitivity and specificity. These items can be integrated into the diagnosis usually conducted by GPs in clinical practice.

Bouhassira D, Attal N. Diagnosis and assessment of neuropathic pain: the saga of clinical tools. Pain 2011;152:S74-83.

Download a review copy of the DN4 [PDF]

Page 1 is the full version of the DN4, which includes questions about symptoms and involves conducting physical examination tests.

Page 2 is the DN4 interview, which only includes questions about symptoms.

 

Guidelines and reviews

Diagnosis and management

2011 Therapeutic Guidelines (TG) Neurology Expert Group Neuropathic Pain (subscribers only)

Recommendations are mostly for diagnosis and pharmacological management. Only very brief recommendations are made for non-pharmacological management; more detailed recommendations are in other TG guidelines for chronic pain.

Diagnosis is based on 2010 IASP (International Association for the Study of Pain) guidelines that were updated by the IASP in 2016 (see Diagnosis section below). Pharmacological management does not include updates from recently published studies and recommendations from more recent international guidelines.

The 2011 TG Neuropathic Pain is currently in review. New guidelines are expected to be released in late 2018, located in the Analgesic section.

2013 Therapeutic Guidelines (TG) Endocrinology Expert Group Diabetic Neuropathy (subscribers only)

Recommendations are for diagnosis, and pharmacological and non-pharmacological management.

Guidelines on pharmacological management differ from the 2011 TG Neuropathic Pain, including:

  • duloxetine is second-line
  • dosages vary
  • capsaicin is included.

Diagnosis

Finnerup NB, Haroutounian S, Kamerman P, et al. Neuropathic pain: an updated grading system for research and clinical practice. Pain 2016;157:1599-606

Provides details of the IASP (International Association for the Study of Pain) principles behind patient history, physical examination and confirmatory tests, and details of how they are performed in clinical practice.

Haanpää M. Chapter 18: Clinical examination of a patient with possible neuropathic pain. Pain 2014 Refresher Courses: 15th World Congress on Pain. Washington DC: International Association for the Study of Pain Press, 2014

Provides clinical practice details for diagnosis, particularly patient history, physical examination and neuroanatomically plausible distribution.

Baron R, Binder A, Wasner G. Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol 2010;9:807-19 (subscribers only)

Provides definitions of and what is done for a large number of sensory tests performed during a physical examination, and the expected pathological response for each one.

Haanpää ML, Backonja MM, Bennett MI, et al. Assessment of neuropathic pain in primary care. Am J Med 2009;122:S13-21 (subscribers only)

Provides clinical practice details for diagnosis, particularly for patient history and symptoms.

Pharmacological management

2015 IASP (International Association for the Study of Pain) Recommendations from the Special Interest Group on Neuropathic Pain (NeuPSIG) of the International Association for the Study of Pain (IASP) based on the 2015 Finnerup study

The guidelines are an update of the previous 2010 IASP guidelines.

It is a systematic review and meta-analysis of 229 randomised, double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January, 1966, and unpublished trials.

Recommendations are based on the GRADE system.

Meta-analysis and NNT and NNH data included are the most up to date that are available for specific medicines for all neuropathic conditions, which is considered best practice. This is opposed to other meta-analyses and NNT and NNH data, including Cochrane reviews, which are more recent but are either for a specific medicine and/or specific cause of neuropathic pain.

National Institute for Health and Care Excellence (NICE). Neuropathic pain in adults: pharmacological management in nonspecialist settings. Clinical guidance (CG) 173. UK: 2013 (updated 2014).

The guidelines are an update of NICE clinical guideline 96 (published March 2010).

Recommendations are for specific medicines for all neuropathic conditions, as opposed to more recent meta-analyses and NNT and NNH data that are for either a specific medicine or specific cause of neuropathic pain.

Research summary

Table 1: Pharmacological management

Medicines Study and notes
Amitriptyline and other tricyclic antidepressants (TCAs)

The IASP Guidelines, based on the 2015 Finnerup study1 (see also supplementary webappendix), made a strong GRADE recommendation for first-line use based on low NNT (for 30%-50% or at least moderate pain relief) and moderate quality of evidence, safety concerns for TCAs such as amitriptyline at dosages > 75 mg daily, low cost and large availability. NNT/NNH were 3.6/13.4.

The 2015 Moore study2 on amitriptyline for neuropathic pain used excessively higher, more stringent standards for supporting evidence for amitriptyline (a three-tiered approach, where the first tier included factors such as ≥ 50% pain reduction, ≥ 200 in the comparison group and reported an intention to treat (ITT) analysis), which may be considered less reflective of clinical practice compared to the 2015 Finnerup study. While the authors did not find first or second tier-evidence, only third tier-evidence, they concluded that ‘there is no supportive unbiased evidence for a beneficial effect,’ and that this ‘has to be balanced against decades of successful treatment in many people with neuropathic pain.’ NNT was 5.1.

Duloxetine and other SNRIs

The IASP Guidelines, based on the 2015 Finnerup study1 (see also supplementary webappendix), made a strong GRADE recommendation for first-line use, and found that duloxetine and other SNRIs are positive in most clinical trials and have high quality of evidence, moderate effect size and moderate tolerability and safety. NNT/NNH were 6.4/11.8.

The 2014 Lunn study3 on duloxetine for diabetic peripheral neuropathy came to similar conclusions as the 2015 Finnerup study, although fewer studies (4 versus 9) where included.

The 2015 Gallagher study4 on venlafaxine for neuropathic pain in adults came to similar conclusions as the 2015 Finnerup study, but included a much smaller number of participants in the meta-analysis.

Gabapentin

The IASP Guidelines, based on the 2015 Finnerup study1 (see also supplementary webappendix), made a strong GRADE recommendation for first-line use, and found that gabapentin was positive in most clinical trials and had high quality of evidence and moderate tolerability. NNT/NNH were 6.3/25.6.

The 2017 Wiffen study5 on gabapentin focussed on specific causes; postherpetic neuralgia and painful diabetic neuropathy. For NNT the findings are supportive of the 2015 Finnerup study findings (NNT for postherpetic neuralgia was 6.7 and painful diabetic neuropathy 5.9; NNH for all conditions combined was 30).

Pregabalin

The IASP Guidelines, based on the 2015 Finnerup study1 (see also supplementary webappendix), made a strong GRADE recommendation for first-line use, with high quality of evidence, and was positive in most clinical trials and had moderate tolerability. NNT/NNH were 7.7/13.9.

The 2013 Wiffen study6 on pregabalin for specific causes including painful diabetic neuropathy and postherpetic neuralgia. While more stringent and excessively high standards were applied compared to the 2015 Finnerup study, including ≥ 50% pain relief for the top tier, the conclusion that ‘only a minority of people achieved acceptably good pain relief’ is consistent with the 2015 Finnerup study. For example, NNT for 30% pain intensity reduction for pregabalin (600 mg) for painful diabetic neuropathy was 6.8.

Tramadol

The IASP Guidelines, based on the 2015 Finnerup study1 (see also supplementary webappendix), made a weak GRADE recommendation for second-line use based on positive trials and moderate quality of evidence, but potential safety concerns and an increase in deaths associated with its use have been reported. NNT/NNH were 4.7/12.6.

The 2017 Duehmke study7 on tramadol for neuropathic pain in adults used a more stringent standard of ≥ 50% pain relief and fewer studies compared to the 2015 Finnerup study, but found a similar NNT of 4.4.

Lidocaine (lignocaine) patches

The IASP Guidelines, based on the 2015 Finnerup study1 (see also supplementary webappendix), made a weak GRADE recommendation for second-line use for peripheral neuropathic pain use based on poor quality of evidence, but high values and preferences, and excellent balance between desirable and undesirable side effects. NNT/NNH were not available. While the lack of high quality studies resulted in no pooling of data and meta-analysis was not performed, individual studies indicated some improvement compared to placebo.

The 2014 Derry study8 on lidocaine for neuropathic pain in adults made similar conclusions to the 2015 Finnerup study.

Strong opioids (eg oxycodone and morphine)

The IASP Guidelines, based on the 2015 Finnerup study1 (see also supplementary webappendix), made a weak GRADE recommendation for third-line use due to moderate quality of evidence and demonstrated efficacy in the short term, but low values and preferences and potential safety concerns, as well as risks associated with long-term use. NNT/NNH were 4.3/11.7.

The 2016 Gaskell study9 on oxycodone for neuropathic pain in adults and 2017 Cooper study10 on morphine for chronic neuropathic pain in adults made weak findings similar to the 2015 Finnerup study.

Cannabinoids

The IASP Guidelines, based on the 2015 Finnerup study1 (see also supplementary webappendix), didn’t conduct a meta-analysis for cannabinoids, but made a weak GRADE recommendation against the use of cannabinoids due to misuse, abuse and diversion concerns.

The 2017 Nugent study11 on cannabis for adults with chronic pain concluded ‘limited evidence suggests that cannabis may alleviate neuropathic pain in some patients.’

An RACGP position statement on medical cannabis12 found very low GRADE evidence for diabetic peripheral neuropathy.

Others

For botulinum toxin A, tapentadol, capsaicin and other neuropathic pain medicines, see 2015 Finnerup study.1

For paracetamol, the 2017 Wiffen study did not find any studies that satisfied their inclusion criteria, hence it could not be assessed.13

For NSAIDs, the 2015 Moore study included two studies that found no indication of any significant pain reduction.14

Table 2: Condition management

Condition Study and notes
Low back pain

The 2017 Shanthanna study15 is a systematic review and meta-analysis of RCTs of pregabalin and gabapentin (gabapentinoids) for chronic low back pain. It found the current available evidence is limited and does not support use of pregabalin in non-specific chronic low back pain.

The ‘Discussion’ section briefly reviews evidence on pregabalin for low back neuropathic pain, and finds no clinical improvement compared to placebo.

The 2017 Mathieson study16 is an RCT on pregabalin for acute and chronic sciatica, which concluded that pregabalin was not effective for pain reduction.

The reasons for the lack of efficacy include incorrect diagnosis (only 22%–34% of patients may have had neuropathic pain (based on positive PainDetect scores), and sciatica resolves over time and is associated with different characteristics from other neuropathic pain (distinct clinical phenotype/pathogenesis).

Fibromyalgia

While fibromyalgia does not fit within the IASP definition of neuropathic pain,17,18 and pregabalin is not TGA-approved or PBS-listed for fibromyalgia (correct as of February 2018),19 the 2016 Derry study20 investigated pregabalin (450 mg) for fibromyalgia.

It found NNT of 7.2 for at least 30% pain reduction and 9.7 for at least 50% pain reduction, and NNH of 11 for withdrawals due to adverse events.

The efficacy of pregabalin may be explained by its mode of action (blocking voltage gated calcium channels, reducing synaptic release of neurotransmitters and hence neuronal excitability). This can target disease mechanisms of unrelated conditions, such as epilepsy, neuropathic pain, anxiety and also fibromyalgia, which share similar disease mechanisms.21

However, the 2017 European League Against Rheumatism (EULAR) guidelines found that there is weak evidence in support of pregabalin for fibromyalgia and, while it’s recommended for severe pain, it is only recommended second-line after exercise and other non-pharmacological therapies have been tried and found to be insufficient.22

 

References

  1. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 2015;14:162-73.
  2. Moore RA, Derry S, Aldington D, et al. Amitriptyline for neuropathic pain in adults. Cochrane Database Syst Rev 2015:CD008242.
  3. Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev 2014:CD007115.
  4. Gallagher HC, Gallagher RM, Butler M, et al. Venlafaxine for neuropathic pain in adults. Cochrane Database Syst Rev 2015:CD011091.
  5. Wiffen PJ, Derry S, Bell RF, et al. Gabapentin for chronic neuropathic pain in adults. Cochrane Database Syst Rev 2017;6:CD007938.
  6. Wiffen PJ, Derry S, Moore RA, et al. Antiepileptic drugs for neuropathic pain and fibromyalgia - an overview of Cochrane reviews. Cochrane Database Syst Rev 2013:CD010567.
  7. Duehmke RM, Derry S, Wiffen PJ, et al. Tramadol for neuropathic pain in adults. Cochrane Database Syst Rev 2017;6:CD003726.
  8. Derry S, Wiffen PJ, Moore RA, et al. Topical lidocaine for neuropathic pain in adults. Cochrane Database Syst Rev 2014:CD010958.
  9. Gaskell H, Derry S, Stannard C, et al. Oxycodone for neuropathic pain in adults. Cochrane Database Syst Rev 2016;7:CD010692.
  10. Cooper TE, Chen J, Wiffen PJ, et al. Morphine for chronic neuropathic pain in adults. Cochrane Database Syst Rev 2017;5:CD011669.
  11. Nugent SM, Morasco BJ, O'Neil ME, et al. The effects of cannabis among adults with chronic pain and an overview of general harms: A systematic review. Ann Intern Med 2017.
  12. Royal Australian College of General Practitioners. RACGP Position Statement: Medicinal use of cannabis products. Melbourne: RACGP, 2016 (accessed 5 October 2017).
  13. Wiffen PJ, Knaggs R, Derry S, et al. Paracetamol (acetaminophen) with or without codeine or dihydrocodeine for neuropathic pain in adults. Cochrane Database Syst Rev 2016;12:CD012227.
  14. Moore RA, Chi CC, Wiffen PJ, et al. Oral nonsteroidal anti-inflammatory drugs for neuropathic pain. Cochrane Database Syst Rev 2015:CD010902.
  15. Shanthanna H, Gilron I, Rajarathinam M, et al. Benefits and safety of gabapentinoids in chronic low back pain: A systematic review and meta-analysis of randomized controlled trials. PLoS Med 2017;14:e1002369.
  16. Mathieson S, Maher CG, McLachlan AJ, et al. Trial of Pregabalin for Acute and Chronic Sciatica. N Engl J Med 2017;376:1111-20.
  17. Jensen TS, Baron R, Haanp\u00e4\u00e4 M, et al. A new definition of neuropathic pain. Pain 2011;152:2204-5.
  18. Magrinelli F, Zanette G, Tamburin S. Neuropathic pain: diagnosis and treatment. Pract Neurol 2013;13:292-307.
  19. Rheumatology Expert Group. Therapeutic guidelines: Rheumatology. West Melbourne: Therapeutic Guidelines Ltd, 2017 (accessed 2 Feb 2018).
  20. Derry S, Cording M, Wiffen PJ, et al. Pregabalin for pain in fibromyalgia in adults. Cochrane Database Syst Rev 2016;9:CD011790.
  21. Kavoussi R. Pregabalin: From molecule to medicine. Eur Neuropsychopharmacol 2006;16 Suppl 2:S128-33.
  22. Macfarlane GJ, Kronisch C, Dean LE, et al. EULAR revised recommendations for the management of fibromyalgia. Ann Rheum Dis 2017;76:318-28.