Neuropathic pain is caused by damage to- or dysfunction of- the peripheral and central nervous system, rather than stimulation of pain receptors. It can involve any level of the nervous system including the sympathetic nervous system (sympathetically-maintained pain). Neuropathic pain does not occur in all patients and it is unclear what mechanisms predispose to the development of neuropathic pain in individual patients. In neuropathic pain the nerve fibres may be damaged, dysfunctional or injured. The impact of injury includes a change in nerve function both at the site of injury and areas around the injury. This leads to incorrect signals being sent to the brain. The brain perceives that these signals are coming from pain receptors in the skin or organs where in fact this is not the case. Phantom pain following limb amputation is a good example of this. Certain conditions or factors are implicated in the development of neuropathic pain, including: diabetes, chemotherapy, shingles, surgery, alcoholism and HIV infection.
Neuropathic pain may be puzzling to those who do not understand the mechanisms underpinning this pain, including the sufferer. Patients commonly use abnormal adjectives to describe painful and non-painful sensations such as ‘shooting’, ‘burning’, ‘tingling’ and ‘numbness’. Lack of knowledge in health care professionals who are unaware of the pathophysiology may cause them to label patients as having psychosomatic pain. In patients with neuropathic pain, there are three types of changes that can occur: painful symptoms, visible skin changes and loss of sensation.
Neuropathic pain commonly results in ‘spontaneous’ pains. Some of these sensations appear to have a ‘life of their own’ and are bizarre. Sensations include abnormally painful responses to an ordinary physical stimulus (evoked pain); and spontaneous pain – which occurs in the absence of a stimulus. There are two types of spontaneous pain: continuous and paroxysmal.
- Continuous pain– is a steady, ongoing sensation which is often felt in the skin. It is sometimes described as burning, cutting, pricking, tingling, “pins and needles” and stabbing. If it is felt in the deep tissues, it is usually described as cramping, throbbing, crushing or aching.
- Paroxysmal pain – this is an intermittent pain that usually is not associated with any precursor and described as shooting, lancinating, jabbing or stabbing in nature.
Evoked pains are usually exaggerated responses to innocuous events that do not cause pain in people with ‘normal’ pain pathways:
- Allodynia - pain that comes on from simple contact that is not normally painful. This is divided into mechanical allodynia (e.g. clothes touching the skin) and thermal allodynia (e.g. cool breeze against the skin).
- Paraesthesia anddysaesthesia – absence or impairment of the senses especially touch
- Hyperpathia - a prolonged duration of pain following a painful event.
- Hyperalgesia - hypersensitivity to mildly painful events – knocks, for instance.
Other sensations can include physical contact in one area of the skin resulting in painful sensations in another (trigger zone pain), or pain that radiates down a whole leg or arm (referred pain).
In patients with neuropathic pain, there may be visible changes in the skin in the area that overlies the painful area. Mechanisms underlying these changes that may accompany neuropathic pain are not well understood and are complex. The expected changes include the skin being pinker or redder than other areas; or more blue, mottled and dusky-looking. The changes that occur are largely due to alterations in blood flow. As well as colour changes; the skin can look waxy, dry, puffy or swollen with a reduction in hair and nail growth. The affected area not only appears different; but patients sometimes also ‘divorce’ themselves from the area, especially if it is an affected limb.
Loss of sensations
Areas affected by neuropathic pain can be numb to touch. Nerve damage from injury or disease processes can lead to loss of normal sensation. The nerves that are the most prone to damage (from diseases like diabetes) are those carrying temperature sensations; and hence the assessment involves testing for sensation, pain and temperature. The loss of normal input from the anaesthetic area may cause a failure of the normal gating process and promote central sensitisation in an effort to gain information from the affected area. Such amplification may result in the paroxysmal presentation of pain in a non-sensate area. This is a confusing and distressing condition for the patient, often compounded by a lack of belief by health care professionals that a numb area can be painful. The analogy of phantom pain can be a helpful teaching metaphor for patients and health care professionals.
Neuropathic Pain Types
There are a variety of different pain types under the ‘umbrella’ of neuropathic pain but whether these have an impact from a treatment perspective is still up for debate. There is currently no agreed taxonomy of neuropathic pain. Specific syndromes include:
- Post herpetic neuralgia
- Nerve root avulsions (such as traumatic brachial plexus avulsion)
- Painful traumatic or infective mononeuropathy (eg in HIV)
- Painful polyneuropathy (particularly in diabetes)
- Trigeminal neuralgia
Postsurgical pain syndromes
- Painful scars
- Post-nephrectomy/ mastectomy pain
- Post stroke
- Spinal cord injury
- Multiple sclerosis
Complex regional pain symdrome
- Type 1 (previously referred to as reflex sympathetic dystrophy
- Type 2 (previously referred to as the causalgias)
- Neuropathic pain secondary to toxins (chemotherapy, heavy metal poisoning)
There are problems with dividing neuropathic pain into distinct groups as there may be great overlap in mechanisms and in response to treatment regimens.
Making the diagnosis
A high suspicion of neuropathic pain is raised by the patient’s use of abnormal language in their symptom reporting. A diagnosis is usually made using a combination of the patient’s report, a clinical examination and sensory nerve testing. Often, quantitative sensory testing is performed. Although these tests might highlight areas of abnormal sensation, the tests themselves cannot prove or disprove that a patient is suffering with pain caused by the nerve damage.
Cruccu et al (2004) reported on the work of a committee formed to produce guidelines on neuropathic pain assessment. The task force was set up under the auspices of the European Federation of Neurological Societies and aimed to evaluate the existing evidence about methods of assessing neuropathic pain and its treatments. A guideline resulted:
- In the clinical setting, a neurological examination that includes an accurate sensory examination is often sufficient to reach a diagnosis.
- Nerve conduction studies and somatosensory-evoked potentials, which do not assess small fibre function, may demonstrate and localize a peripheral or central nervous lesion.
- A quantitative assessment of the nociceptive pathways is provided by quantitative sensory testing and laser-evoked potentials.
- The simplest psychometric scales and quality of life measures are probably the best methods to evaluate treatment efficacy in a patient; and in controlled trials.
The full text article can be freely downloaded from PubMed (Eur J Neurol 11(3):153-62). It may be useful for your clinical practice.
Another interesting article is that by Shy et al (2003), who assessed the clinical utility, efficacy and safety of quantitative sensory testing. The authors found no adequately powered level 1 studies demonstrating the effectiveness of QST in evaluating any particular disorder. There were a number of level 2 and 3 studies using QST with patients with diabetic neuropathy, small fibre neuropathies, uraemic neuropathies and demyelinating neuropathy.They concluded that QST is a potentially useful tool for measuring sensory impairment for clinical and research studies but it should not be used as the sole criteria to diagnose pathology (Neurology2003 60: 898-904)
There are also a number of pain scales that have been developed for measuring and assessing neuropathic pain. However, caution should be exercised as many scales are developed for a specific group and the applicability of the scale to a novel study group; or the use the scale for multiple observations over time must be validated. A description of these with references, to the key research publications can be found on http://www.plosmedicine.org/article/info:doi%2F10.1371%2Fjournal.pmed.1000045 (PloS Medicine).
Managing neuropathic pain
Before considering what is available in terms of managing this type of pain, it is important to stress that any underlying condition that may be implicated should be assessed and managed. For instance, mechanical pressure (e.g. by spinal discs on spinal roots) causing the neuropathic symptoms may require surgery. Improvements in diabetic control can improve symptom progression in diabetic neuropathy but cannot reverse damage.
It may be useful to consider two approaches to managing pain of neuropathic origin:
Non-pharmacological measures(these will be discussed in the presentation) Non-pharmacological Treatment of Neuropathic Pain)
- Physical methods- desensitisation, mirror-box therapy, rehabilitative physiotherapy
- Psychological techniques such as Mindfulness, ACT, CBT
- Patient education
- Non-opioid analgesics and NSAIDs
- Topical preparations
- IV management (lidocaine, ketamine)
- Complex, multimodal treatment approaches e.g. residential intense pain managemnet programs
- Invasive techniques – nerve blocks, deinnervation, etc
The following may be useful in identifying what should be considered in managing patients with neuropathic pain:
- Challapalli, V. et al. 2005. Systemic administration of local anesthetic agents to relieve neuropathic pain. Cochrane Database of Systematic Reviews (4), p. CD003345.
- Dworkin, R. et al. 2007. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 132(3), pp. 237-251.
- Eisenberg, E. et al. 2006. Opioids for neuropathic pain. Cochrane Database of Systematic Reviews 3, p. CD006146.
- Eisenberg E, et al. 2006. Efficacy of mu-opioids agonists in the treatment of evoked neuropathic pain: systematic review of randomised controlled trials. Europ J Pain10: 667-76.
- Finnerup NB, et al. 2005. Algorithm of neuropathic pain treatment: an evidence based proposal. Pain 118 289-305.
- Finnerup, N. and Jensen, T. 2007. Clinical use of pregabalin in the management of central neuropathic pain. Neuropsychiatr Dis Treat 3(6), pp. 885-891.
- Finnerup, N. et al. 2007. Chronic neuropathic pain: mechanisms, drug targets and measurement. Fundam Clin Pharmacol 21(2), pp. 129-136.
- Furlan, A. D. et al. 2001. Chemical sympathectomy for neuropathic pain: does it work? Case report and systematic literature review. Clinical Journal of Pain 17(4), pp. 327-336.
- Hocking, G. and Cousins, M. J. 2003a. Ketamine in chronic pain management: an evidence-based review. Anesthesia & Analgesia 97(6), pp. 1730-1739.
- Hollingshead, J. et al. 2006. Tramadol for neuropathic pain.[update of Cochrane Database Syst Rev. 2004;(2):CD003726; PMID: 15106216]. Cochrane Database of Systematic Reviews 3, p. CD003726.
- Katz, J. et al. 2008. Clinical trial outcome in neuropathic pain: relationship to study characteristics. Neurology 70(4), pp. 263-272.
- Mailis, A. and Furlan, A. 2003a. Sympathectomy for neuropathic pain. Cochrane Database of Systematic Reviews (2), p. CD002918.
- Mailis-Gagnon, A. et al. 2004. Spinal cord stimulation for chronic pain. Cochrane Database of Systematic Reviews (3), p. CD003783.
- Mason L. Moore RA, Derry S, et al. 2004. Systematic review of topical capsaicin for the treatment of chronic pain. BMJ 328: 991-6.
- Saarto, T. and Wiffen, P. J. 2007. Antidepressants for neuropathic pain.[update of Cochrane Database Syst Rev. 2005;(3):CD005454; PMID: 16034979]. Cochrane Database of Systematic Reviews (4), p. CD005454.
- Wiffen, P. et al. 2005. Anticonvulsant drugs for acute and chronic pain.[update of Cochrane Database Syst Rev. 2000;(3):CD001133; PMID: 10908487]. Cochrane Database of Systematic Reviews (3), p. CD001133.
- Wiffen, P. J. et al. 2005. Gabapentin for acute and chronic pain. Cochrane Database of Systematic Reviews (3), p. CD005452.
- Wiffen, P. J. et al. 2005. Carbamazepine for acute and chronic pain. Cochrane Database of Systematic Reviews (3), p. CD005451.
- Wiffen, P. J. and Rees, J. 2007. Lamotrigine for acute and chronic pain. Cochrane Database of Systematic Reviews (2), p. CD006044.
The following provides information about certain neuropathic conditions:
- Adriaensen, H. et al. 2005. Critical review of oral drug treatments for diabetic neuropathic pain-clinical outcomes based on efficacy and safety data from placebo-controlled and direct comparative studies. Diabetes/Metabolism Research Reviews 21(3), pp. 231-240.
- Alper, B. S. and Lewis, P. R. 2002. Treatment of postherpetic neuralgia: a systematic review of the literature. Journal of Family Practice 51(2), pp. 121-128.
- Carroll, D. G. et al. 2004. Role of topiramate for the treatment of painful diabetic peripheral neuropathy. Pharmacotherapy 24(9), pp. 1186-1193.
- Cepeda, M. S. et al. 2005. Local anesthetic sympathetic blockade for complex regional pain syndrome. Cochrane Database of Systematic Reviews (4), p. CD004598.
- Collins, S. L. et al. 2000. Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia: a quantitative systematic review. Journal of Pain & Symptom Management 20(6), pp. 449-458.
- Finnerup NB. 2008. A review of central neuropathic pain states. Curr Opin Anaesthesiol 21: 586-9.
- Forouzanfar, T. et al. 2002. Treatment of complex regional pain syndrome type I. European Journal of Pain: Ejp 6(2), pp. 105-122.
- Grabow, T. S. et al. 2003. Spinal cord stimulation for complex regional pain syndrome: an evidence-based medicine review of the literature. Clinical Journal of Pain 19(6), pp. 371-383.
- Halbert, J. et al. 2002. Evidence for the optimal management of acute and chronic phantom pain: a systematic review. Clinical Journal of Pain 18(2), pp. 84-92.
- He, L. et al. 2006. Non-antiepileptic drugs for trigeminal neuralgia. Cochrane Database of Systematic Reviews 3, p. CD004029.
- He, L. et al. 2008. Corticosteroids for preventing postherpetic neuralgia. Cochrane Database of Systematic Reviews (1), p. CD005582.
- Hempenstall, K. et al. 2005. Analgesic therapy in postherpetic neuralgia: a quantitative systematic review. PLoS Medicine / Public Library of Science 2(7), p. e164.
- Jensen, T. S. et al. 2006. New perspectives on the management of diabetic peripheral neuropathic pain. Diabetes & Vascular Disease Research 3(2), pp. 108-119.
- Khaliq, W. et al. 2007a. Topical lidocaine for the treatment of postherpetic neuralgia. Cochrane Database of Systematic Reviews (2), p. CD004846.
- Kumar, V. et al. 2004. Neuraxial and sympathetic blocks in herpes zoster and postherpetic neuralgia: an appraisal of current evidence. Regional Anesthesia & Pain Medicine 29(5), pp. 454-461.
- Lopez, B. C. et al. 2004. Systematic review of ablative neurosurgical techniques for the treatment of trigeminal neuralgia. Neurosurgery 54(4), pp. 973-982; discussion 982-973.
- Smith, T. and Nicholson, R. A. 2007. Review of duloxetine in the management of diabetic peripheral neuropathic pain. Vascular Health & Risk Management 3(6), pp. 833-844.
- Tatli, M. et al. 2008. Various surgical modalities for trigeminal neuralgia: literature study of respective long-term outcomes. Acta Neurochirurgica 150(3), pp. 243-255.
- Taylor, R. S. et al. 2006. Spinal cord stimulation for complex regional pain syndrome: a systematic review of the clinical and cost-effectiveness literature and assessment of prognostic factors. European Journal of Pain: Ejp 10(2), pp. 91-101.
- Turner, J. A. et al. 2004. Spinal cord stimulation for patients with failed back surgery syndrome or complex regional pain syndrome: a systematic review of effectiveness and complications. Pain 108(1-2), pp. 137-147.
- Barrett AM, Lucero MA, LeTrong MPH, et al. 2007. Epidemiology, public health burden, and treatment of diabetic peripheral neuropathic pain: A review. Pain Med 9: S50-62.
- Forouzanfar T, Koke AJA, van Kleef M, Weber WEJ. 2002. Treatment of complex regional pain syndrome type 1. Europ J Pain 6: 105-22.
As the pathophysiology underlying neuropathic pain becomes clearer, a taxonomy of neuropathic pain states, and a more targeted approach to therapy may be possible. Continuing education for health care staff involved in the treatment of neuropathic pain is vital, as this is a fast-developing field.
Clinically, it is important to stress that neuropathic pain is a difficult problem, often resistant to multiple therapies; and requires patience and understanding by both the patient and health care professional. Treament is best with a collaborative approach to therapy; and ideally, there should be frequent reassesment of treatment response, disease progression and careful evaluation of quality of life indicators. Support groups for patients, and community-based management classes (such as the Expert Patient Program) offer additional sources of support; encourage and empower patients to self-manage and lessen dependence on health resources.