Neuropathic Pain



National and International Guidelines

Neuropathic pain: the pharmacological management of neuropathic pain in adults in non-specialist settings.

NICE Clinical guideline, CG173 - Issued: November 2013

Cochrane Reviews

Tramadol for neuropathic pain.

Duehmke RM, Hollingshead J, Cornblath DR. Cochrane Database of Systematic Reviews2006, Issue 3.


Five randomised controlled trials involving a total of 374 participants met the inclusion criteria for this review and compared tramadol to placebo. Evidence from these trials showed that 100 to 400 mg of tramadol is an effective symptomatic treatment for peripheral neuropathic pain. One trial involving less than 40 participants compared tramadol to morphine, and one involving 21 participants compared tramadol to clomipramine. It was not possible to draw conclusions from these two trials as to which of these drugs is more effective. Treatment with tramadol may cause side effects, including constipation, nausea, sedation and a dry mouth, all of which resolve after stopping treatment. In the trials reviewed here, one person out of eight treated with tramadol left the trial because of side effects. Tramadol is also associated with a small risk of seizures (fits) and its use is contraindicated in people with a history of epilepsy.

Opioids for neuropathic pain.

Eisenberg E, McNicol ED, Carr DB. Cochrane Database of Systematic Reviews 2006, Issue 3.


Opioids, pain killers such as morphine, are effective for the treatment of long-term pain due to nerve damage. Neuropathic pain, pain caused by nerve damage, is often difficult to diagnose and treat. The use of opioids (strong pain killers such as morphine) to treat neuropathic pain is controversial owing to concerns about addiction and beliefs that this type of pain does not always respond well to opioids. The review authors looked at both short- and intermediate-term trials. They found mixed results regarding the effectiveness of short-term use of opioids. Intermediate-term trials demonstrated that opioids are effective for the subtypes of neuropathic pain tested and for the relatively short duration of published studies. Side effects such as nausea, dizziness, and drowsiness were common, but not life threatening.

Amitriptyline for neuropathic pain and fibromyalgia in adults.

Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ. CochraneDatabase of Systematic Reviews 2012, Issue 12.


Amitriptyline probably does not work in neuropathic pain associated with HIV or treatments for cancer. Amitriptyline probably does work in other types of neuropathic pain (painful diabetic neuropathy, postherpetic neuralgia, and post-stroke pain, and in fibromyalgia), though we cannot be certain of this. Our best guess is that amitriptyline provides pain relief in about 1 in 4 (25%) more people than does placebo, and about 1 in 4 (25%) more people than placebo report having at least one adverse event, probably not serious but disconcerting; we cannot trust either figure based on the information available. The most important message is that amitriptyline probably does give really good pain relief to some patients with neuropathic pain or fibromyalgia, but only a minority of them; amitriptyline will not work for most people.

Phenytoin for neuropathic pain and fibromyalgia in adults.

Birse F, Derry S, Moore RA. Cochrane Database of SystematicReviews 2012, Issue 5


We identified no good quality studies of phenytoin used in this situation. When used to treat epilepsy, phenytoin can cause potentially troublesome adverse events, affecting nervous tissue, the blood, and unborn children. Based on current evidence, phenytoin cannot be recommended for treating neuropathic pain. Other antiepileptic drugs such as pregabalin, gabapentin, and carbamazepine have been shown to be of value in neuropathic pain.

Clonazepam for neuropathic pain and fibromyalgia in adults.

Corrigan R, Derry S, Wiffen PJ, Moore RA. Cochrane Databaseof Systematic Reviews 2012, Issue 5


We identified no good quality studies of clonazepam used in this situation. Dependence and tolerance may occur with prolonged use, although it is less of a problem with clonazepam than many other drugs from the same class (benzodiazepines), and behavioural disinhibition has been reported in a few patients with psychiatric problems. Based on current evidence, clonazepam cannot be recommended for treating neuropathic pain. Other antiepileptic drugs such as pregabalin, gabapentin, and carbamazepine have been shown to be of value in neuropathic pain.

Valproic acid and sodium valproate for neuropathic pain and fibromyalgia in adults.

Gill D, Derry S, Wiffen PJ, Moore RA. Cochrane Database of Systematic Reviews 2011, Issue 10.


The aim of this review was to investigate the efficacy and adverse events associated with use of sodium valproate and valproic acid for the treatment of chronic neuropathic pain and fibromyalgia. We identified three relevant studies, two in diabetic neuropathy and a third in post-herpetic neuralgia. Two of the three studies report significantly greater reduction in pain for valproate than placebo, but studies were small (≤ 45 participants) and provided insufficient data for pooled analysis, and the methods of analysis used may have overestimated treatment effect. Adverse events such as nausea, sedation, drowsiness, vertigo, and abnormal liver function are more common with valproate than placebo, but these studies were unsuitable to allow for a comprehensive assessment of harm. There is insufficient evidence to support the use of valproic acid or sodium valproate as a first-line treatment for neuropathic pain.

Topical capsaicin (low concentration) for chronic neuropathic pain in adults.

Derry S, Moore RA. Cochrane Database of Systematic Reviews 2012, Issue 9.


It is unlikely that topical (rubbed on the skin), low-concentration (< 1%) capsaicin provides any useful pain relief in neuropathic pain conditions. It is known to cause local skin irritation such as burning and stinging.

Systemic administration of local anesthetic agents to relieve neuropathic pain.

Challapalli V, Tremont-Lukats IW, McNicol ED, Lau J, Carr DB. Cochrane Database of Systematic Reviews 2005, Issue 4


Intravenous lidocaine and oral derivatives relieve pain from damage to the nervous system (neuropathic pain). In early reports, intravenous lidocaine and its oral analogsmexiletine and tocainide relieved neuropathic pain, a type of pain caused by disease in the nervous system. However, the evidence was conflicting. The authors reviewed all randomized studies comparing these drugs with placebo or with other analgesics and found that: local anesthetics were superior to placebo in decreasing intensity of neuropathic pain; limited data showed no difference in efficacy or adverse effects between local anesthetics and carbamazepine, amantadine, gabapentin or morphine; local anesthetics had more adverse effects than placebo; and local anesthetics were safe.

Combination pharmacotherapy for the treatment of neuropathic pain in adults.

Chaparro LE, Wiffen PJ, Moore RA, Gilron I. Cochrane Database of Systematic Reviews 2012, Issue 7.


Despite evidence that over 45% of individuals suffering from neuropathic pain take two or more drugs for their pain, we could find only 21 high-quality studies of various different systemic and topical drug combinations. Given the wide possible variety of different drug combinations and the small number of studies, results for neuropathic pain from this review are insufficient to suggest the value of any one specific drug combination. However, the publication of multiple high-quality studies suggesting the superiority of some drug combinations, together with evidence that drug combinations are widely used in clinical practice, underline the importance of conducting more combination studies with improved methodology.

Topical Capsaicin (high concentration) for chronic neuropathic pain in adults 

Derry S, Sven-Rice A, Cole P, Tan T, Moore RA. Cochrane Database of Systematic Reviews 2013, Issue 2.


This review is about a highly concentrated preparation of capsaicin (8%) that has to be administered in carefully controlled conditions in a clinic or hospital, under local anaesthetic, because without special precautions it can cause pain and burning of the skin. The single application is designed to produce relief of pain for up to three months. In six studies with 2073 participants, we found evidence that the treatment worked in two types of neuropathic pain, pain after shingles, and nerve injury pain associated with HIV infection. About 1 person in 8 who receives the treatment will get good pain relief. Those who do not will probably not receive the treatment again, while those who do might have the treatment several times a year. In all people who have this treatment there can be short-lived localised skin problems like redness (erythema), burning, or pain, but serious problems seem to be uncommon and no more frequent in these trials with high-concentration capsaicin than with the control treatment using very low-concentration capsaicin. We do not know whether repeated treatments will give the same efficacy, or what effect they may have on the skin.

Gabapentin for chronic neuropathic pain and fibromyalgia in adults.

Moore RA,Wiffen PJ, Derry S,McQuay HJ. CochraneDatabase of Systematic Reviews 2011, Issue 3.


Gabapentin is associated with a moderate benefit (equivalent to at least 30% pain relief) in almost one in two patients (43%), and a substantial benefit (equivalent to at least 50% pain relief) in almost one in three (31%). Over half of those taking gabapentin for neuropathic pain will not have good pain relief, in common with most chronic pain conditions. Adverse events are experienced by about two-thirds of people taking gabapentin, mainly dizziness, somnolence (sleepiness), oedema (swelling), and gait disturbance, but only about 1 in 10 (11%) have to stop the treatment because of these unpleasant side effects. Overall gabapentin provides pain relief of a high level in about a third of people who take it for painful neuropathic pain. Adverse events are frequent, but mostly tolerable. This review looked at evidence from 29 studies involving 3571 participants.

Lacosamide for neuropathic pain and fibromyalgia in adults.

Hearn L, Derry S,Moore RA. Cochrane Database of SystematicReviews 2012, Issue 2.


This review included five studies in painful diabetic neuropathy (1863 participants) and one in fibromyalgia (159 participants). In people with painful diabetic neuropathy, lacosamide had only a modest effect, with a specific effect due to its use in 1 person in 10. This is a minor effect and may be an over-estimate due to use of the last observation carried forward method for analysis. There was insufficient information in fibromyalgia to draw any conclusions about the effect of lacosamide. There was no significant difference between lacosamide and placebo for participants with any, or a serious, adverse event, but there were significantly more adverse event withdrawals with lacosamide. Regulatory authorities have not licensed lacosamide for treating pain based on evidence presently available.

Duloxetine for treating painful neuropathy or chronic pain.

Lunn MPT, Hughes RAC, Wiffen PJ. Cochrane Database ofSystematic Reviews 2009, Issue 4.


We looked at all the published scientific literature and identified six drug trials involving a total of 2220 participants that were of sufficient quality and reliability to include. Three tested the effect of duloxetine on painful diabetic neuropathy and three on the pain of fibromyalgia.

The usual dose of duloxetine is 60 mg. At this dose, there was moderately strong evidence that duloxetine reduced pain in both painful diabetic peripheral neuropathy and fibromyalgia. In diabetic peripheral neuropathic pain the relative rate of 50% improvement with duloxetine 60 mg per day was just over one and a half times more than with placebo. This equates to needing to treat 6 people with diabetic peripheral neuropathic pain with duloxetine to achieve a 50% response in one person. The effect on fibromyalgia was similar. A dose of 20 mg was not effective and a higher dose of 120 mg was no more effective than 60 mg.

Most people taking duloxetine will have at least one side effect. These are mostly minor and are commonly feeling sick, being too awake or too sleepy, developing a headache, having a dry mouth or becoming constipated or dizzy. About one in six people stop duloxetine because of side effects but serious problems caused by duloxetine are very rare.

Duloxetine may be about as good at reducing these sorts of pain as some of the other antidepressant drugs on the market but the evidence supporting this comparison is not strong.

We have concluded that duloxetine is useful for treating pain caused by fibromyalgia and diabetic neuropathy and it seems to be about as effective as other similar drugs already on the market. No direct comparison has been performed between duloxetine and any of these other drugs. As yet it is not clear whether the use of duloxetine is cost effective when compared to the other drugs already in use.

Lamotrigine for acute and chronic pain.

Wiffen PJ, Derry S,Moore RA. Cochrane Database of Systematic Reviews 2011, Issue 2.


The review identified 12 included studies which included a total of 1511 participants. Studies were only available for neuropathic pain, with no evidence that lamotrigine was effective in this type of pain. This may be because lamotrigine works in a different way to other antiepileptic medications. Lamotrigine also seems to cause more cases of skin rash, which can be serious. Based on current evidence, lamotrigine is unlikely to help with neuropathic pain. Other antiepileptic drugs such as pregabalin, gabapentin, and carbamazepine have been shown to be of value in neuropathic pain.

Carbamazepine for acute and chronic pain in adults.

Wiffen PJ, Derry S, Moore RA, McQuay HJ. Cochrane Database ofSystematic Reviews 2011, Issue 1.


Carbamazepine is effective for relieving chronic pain caused by damage to nerves, either from injury or disease, although the data available to support this is limited. About two-thirds of patients who take carbamazepine for neuropathic pain can expect to achieve good pain relief in the short term, and two thirds can expect to experience at least one adverse event.

Pregabalin for acute and chronic pain in adults.

Moore RA, StraubeS,Wiffen PJ, Derry S, McQuay HJ. Cochrane Databaseof Systematic Reviews 2009, Issue 3


With pregabalin daily doses of 300 mg to 600 mg, the patient global impression of change rating of much or very much improved was about 35% in postherpetic neuralgia, 50% in painful diabetic neuropathy, and 40% in fibromyalgia. There is no evidence that pregabalin is effective in acute conditions where pain is already established, and in chronic conditions in which nerve damage is not the prime source of the pain, such as arthritis.

Cervico-thoracic or lumbar sympathectomy for neuropathic painand complex regional pain syndrome.

Straube S, Derry S, Moore RA, McQuay HJ. Cochrane Database of Systematic Reviews 2010, Issue 7.


This systematic review found only one small study (20 participants) of good methodological quality, which reported no significant difference between surgical and chemical sympathectomy for relieving neuropathic pain. Potentially serious complications of sympathectomy are well documented in the literature, and one (neuralgia) occurred in this study.

The practice of sympathectomy for treating neuropathic pain is based on very weak evidence. Furthermore, complications of the procedure may be significant.



National and International Guidelines

AAN-EFNS guidelines on trigeminal neuralgia management. 

European Journal of Neurology 2008

Cochrane Reviews

Neuropathic analgesics: see 'General' section. 

Non-antiepileptic drugs for trigeminal neuralgia.

Yang M, Zhou M, He L, Chen N, Zakrzewska JM. Cochrane Database ofSystematic Reviews 2011, Issue 1.


Three randomized controlled trials, each with an unclear risk of bias, compared the three different non-antiepileptic drugs tizanidine, tocainide and pimozide with carbamazepine, which is the standard drug treatment. Tizanidine and tocainide did not produce significantly more benefit than with carbamazepine. Tocainide had severe side effects. Pimozode produced significantly more improvement than carbamazepine but side effects were very common. In a fourth trial with a low risk of bias proparacaine hydrochloride eye drops did not show any significant benefit. Further well designed randomized controlled trials are needed to establish whether non-antiepileptic drugs are beneficial in trigeminal neuralgia.

Neurosurgical interventions for the treatment of classical trigeminal neuralgia.

Zakrzewska JM, AkramH. Cochrane Databaseof Systematic Reviews 2011, Issue 9.


One study compared two different techniques of radiofrequency thermocoagulation, in 40 participants six months after the procedure. This technique involves heating the nerve by passing an electrical current through the tip of a special needle which has been introduced through the skin into a hole in the base of the skull and into the ganglion from which the three divisions of the trigeminal nerve branch out (Gasserian ganglion). If the radiofrequency was given as pulsed treatment (which causes the tip of the needle to heat up intermittently and not continuously) the original pain in all participants returned by three months. The continuous radiofrequency treatment then had to be applied, and these participants then achieved pain control comparable to those who had received continuous radiofrequency throughout. Changes in sensation ranging from mild to severe numbness were common in the conventional (continuous) radiofrequency treatment group.

A second trial, in 87 participants, looked at using one or two isocentres (specific points in the nerve) to deliver radiation to the trigeminal nerve just as it leaves the brainstem inside the skull. Use of medication afterwards was considered a surrogate measure for pain. Use of two isocentres increased the occurrence of sensory loss as a complication. Increased age and prior surgery were predictors for poorer pain relief. There were insufficient data given to judge the effectiveness of one procedure better than the other.

A third study compared two techniques for performing radiofrequency thermocoagulation of the Gasserian ganglion in 54 participants. The study compared two ways of introducing the needle and guiding it, using either X-rays or a special neuronavigation system. Pain relief was measured by a questionnaire at three months. Both techniques provided pain relief (which did not differ significantly between the two arms) but it was more sustained if a neuronavigation system was used and this system also decreased side effects.

All the reviewed procedures resulted in pain relief and some participants were then able to stop taking medications. However, many procedures tended to result in sensory side effects. All the studies in this review had flaws in their methods and all but two showed considerable risk of bias. There is little evidence from these trials to guide the person with trigeminal neuralgia as to the most effective surgical procedure. There is now an urgent need to evaluate the surgical interventions used in trigeminal neuralgia and to design robust studies; either randomised controlled trials or long-term prospective independently assessed cohort studies.


  •  Diabetic & Other Painful Neuropathies

National and International Guidelines

Pharmacologic and nonpharmacologic treatment of painful diabetic neuropathy (PDN).

2011 American Academy of Neurology.

Cochrane Reviews

Neuropathic analgesics – see 'General' section

Enhanced glucose control for preventing and treating diabeticneuropathy.

Callaghan BC, Little AA, Feldman EL, Hughes RAC. Cochrane Database of Systematic Reviews 2012, Issue 6.


This review identified 17 randomized studies that addressed whether more aggressive attempts to lower blood glucose levels prevent people from developing neuropathy. Seven of these studies were conducted in people with type 1 diabetes, eight in type 2 diabetes, and two in both types. However, only two studies in type 1 diabetes including 1228 participants and four studies in type 2 diabetes including 6669 participants investigated our primary outcome. In type 1 diabetes, there was a significant effect of more aggressive therapies in preventing neuropathy compared with standard treatment. In type 2 diabetes, more aggressive therapy was also beneficial in preventing symptoms and signs of clinical neuropathy, but the result was not statistically significant as measured by the primary method selected for this review. However, there was a significant positive effect on the amount of nerve damage measured with electrical nerve conduction tests and a special machine to measure the threshold of detection of vibration in both types of diabetes. Overall, the evidence indicates that more aggressive treatments of sugar levels delay the onset of neuropathy in both types of diabetes. No other treatments have proven effective to date. However, the beneficial effect has to be balanced against the significantly increased risk of dangerously low blood sugar levels that can occur in both types of diabetes and which can lead to brain injury amongst other issues.

Chinese herbal medicine for diabetic peripheral neuropathy.

Chen W, Zhang Y, Liu JP. Cochrane Database of SystematicReviews 2011, Issue 6.


Based on this systematic review, there is no evidence to support the objective effectiveness and safety of Chinese herbal medicines for DPN. No well-designed, randomized placebo controlled trial with objective outcome measures has been conducted.

Decompressive surgery of lower limbs for symmetrical diabetic peripheral neuropathy.

Chaudhry V, Russell J, Belzberg A. Cochrane Database of Systematic Reviews 2008, Issue 3.


This review failed to identify a single randomized controlled trial or any other well designed prospective study controlling for the non-operated limb that showed improvements in pre defined end points after decompressive surgery.

Treatment for meralgia paraesthetica.

Khalil N, Nicotra A, Rakowicz W. Cochrane Database of Systematic Reviews 2012, Issue12.


Local injections of corticosteroid and surgical operations were found to be effective treatments in observational studies. However, a single observational study also showed that meralgiaparaesthetica improved spontaneously in the majority of cases. RCTs of treatments for meralgiaparaesthetica are needed. 


  • Postherpetic Neuralgia

No national or international guidelines available. 

Cochrane Reviews

Neuropathic analgesics – see 'General' section

Vaccination for preventing postherpetic neuralgia.

Chen N, Li Q, Zhang Y, Zhou M, Zhou D, He L. Cochrane Database of Systematic Reviews 2011, Issue 3.


We identified a single high quality trial with a total of 38,546 participants, comparing vaccination with placebo. It found a significant reduction of herpes zoster, but did not provide enough direct evidence to draw any conclusion about whether the vaccine is effective in preventing postherpetic neuralgia beyond its effect on reducing herpes zoster. Non-serious adverse events were more common among vaccine recipients than placebo recipients, but serious ones were rare. More well designed and specialised trials of vaccination for preventing postherpetic neuralgia are required.

Corticosteroids for preventing postherpetic neuralgia.

Chen N, YangM,He L, ZhangD, ZhouM, ZhuC. Cochrane Database of Systematic Reviews 2010, Issue 12.


Five trials were included in the review. There was no significant difference between the corticosteroid and control groups in the presence of postherpetic neuralgia six months after the onset of acute herpetic rash. There was also no significant difference between the treatment groups and placebo groups in the secondary outcome analyses and subgroup analyses. It can be concluded that corticosteroids are ineffective in preventing postherpetic neuralgia. No significant adverse events were noted in patients with shingles taking prednisolone. Corticosteroids used for other indications during acute zoster infection appear to be as safe as when no infection is present.

Antiviral treatment for preventing postherpetic neuralgia.

Li Q, Chen N, Yang J, Zhou M, Zhou D, Zhang Q, He L. Cochrane Database of Systematic Reviews 2009, Issue 2.


We identified six trials involving 1211 participants, that were suitable for inclusion in the review. There was no significant difference between the antiviral (either oral acyclovir or oral famciclovir) and placebo control groups in the presence of PHN four or six months after the rash onset. Oral acyclovir was ineffective in reducing the incidence of PHN, while insufficient evidence was found to recommend other antiviral treatments to prevent PHN. Further well-designed, randomised, controlled trials of famciclovir or other new antiviral agents with a greater number of participants are needed. Future trials should pay more attention to the severity of pain and quality of life of participants, and should be conducted among different groups of people, such as people who are immunocompromised.

Topical lidocaine for the treatment of postherpetic neuralgia.

Khaliq W, Alam S, Puri NK. Cochrane Database of Systematic Reviews 2007, Issue 2.


This review found three small studies involving 182 topical lidocaine treated participants and 132 control participants using lidocaine for patients with postherpetic neuralgia. Two studies provided data on pain relief amongst patients with postherpetic neuralgia, and they showed some improvement in pain when topical lidocaine was compared to a placebo. No comparison was made with other medications that are in current use for the treatment of postherpetic neuralgia. The side effects of topical lidocaine are very minimal, but include skin problems (such as irritation and redness). We are unable to recommend the use of topical lidocaine as a first-line treatment for postherpetic neuralgia at this stage. Further studies are needed to compare topical lidocaine to other medications in the treatment of postherpetic neuralgia.

  • Complex Regional Pain Syndrome (CRPS)

National and International Guidelines

Complex regional pain syndrome in adults: UK guidelines for diagnosis, referral and management in primary and secondary care.

Royal College of Physicians May 2012

Evidence based guidelines for complex regional pain syndrome type 1. BMC Neurology, 10 (1) DOI: 10.1186/1471-2377-10-20

Perez, R., Zollinger, P., Dijkstra, P., Thomassen-Hilgersom, I., Zuurmond, W., Rosenbrand, K., Geertzen, J., & Task force, T. (2010). 

Cochrane Reviews

Local anaesthetic sympathetic blockade for complex regional pain syndrome.

CepedaMS, CarrDB, Lau J. Cochrane Database of Systematic Reviews 2005, Issue 4.


This systematic review reveals the scarcity of published evidence to support the use of local anesthetic sympathetic blockade as the "gold standard" treatment for CRPS and raises questions as to its usefulness.


  • Phantom Limb Pain

No National or Internation guidelines available. 

Cochrane Reviews

Pharmacologic interventions for treating phantom limb pain.

Alviar MJM, Hale T, Dungca M. Cochrane Database of Systematic Reviews 2011, Issue 12.


Various medications have been tried in phantom limb pain but good treatment continues to be unsatisfactory. Whether opioids, N-methyl D-aspartate (NMDA) receptor antagonists (e.g. ketamine, memantine, dextromethorphan), anticonvulsants, antidepressants, calcitonin and anaesthetics are effective in improving outcomes that include pain, function, mood sleep, quality of life, satisfaction and safety, in the short- and long-term, remains uncertain. Morphine, gabapentin, and ketamine provided short-term pain relief but the findings were based mostly on small studies. The results for calcitonin and anaesthetics were variable. Considerable differences in the drugs, methods, designs, outcomes, outcomemeasures, follow-ups, analyses, and reporting/presenting of findings made it difficult to combine results for the interventions and outcomes. Results must be interpreted with caution as these relied on a few studies with small numbers of study participants and lacked long-term efficacy and safety data. Good quality studies with sufficient sample size, longer follow-ups and with outcomes that are important to patients are needed to make firmer recommendations to enable good advice on the best pain relief for this patient population.

Transcutaneous electrical nerve stimulation (TENS) for phantom pain and stump pain following amputation in adults.

Mulvey MR, Bagnall AM, Johnson MI, Marchant PR. Cochrane Database of Systematic Reviews 2010, Issue 5.


A search of various databases found no studies that met the eligibility criteria for inclusion in this review which prevents any judgement on the effectiveness of TENS for phantom pain and stump pain. A large multicenter randomised controlled trial is needed.