Clinical Topic A-Z Clinical Speciality

Neuropathic pain - drug treatment

Neuropathic pain - drug treatment
D009437Neuralgia
Drugs and devicesNeurological
2014-02-01Last revised in February 2014

Neuropathic pain - drug treatment - Summary

Neuropathic pain is a symptom that develops as a result of damage to, or dysfunction of, the nervous system.

The pain may be constant or intermittent, and it is typically described as shooting, stabbing, burning, tingling, numb, prickling, or itching.

The causes of neuropathic pain are complex and diverse and include diabetic neuropathy, trigeminal neuralgia, stroke, spinal cord injury, and multiple sclerosis. In many cases, it is not possible to completely cure the underlying disease or lesion or to reverse the neurological changes. Consequently, neuropathic pain is usually persistent in these cases.

The general principles for prescribing drug treatment for neuropathic pain include considering:

Contraindications and potential adverse effects, especially for people with comorbid conditions.

Interactions with other medications.

Comorbid conditions that may benefit from a specific treatment, for example people with depression may benefit from treatment with an antidepressant drug.

The person's preference.

To manage neuropathic pain (except trigeminal neuralgia), amitriptyline (off-label use), duloxetine, gabapentin, or pregabalin should be offered, taking the general principles above into account.

Capsaicin 0.075% cream may be considered for people with localized neuropathic pain who wish to avoid, or cannot tolerate, oral treatments.

Advice should be offered on:

The importance of dosage titration, and the titration process. Written information should be provided if possible.

The possible adverse effects associated with each drug treatment.

An early clinical review should be arranged to assess the progress made with dose titration and the tolerability and effectiveness of the chosen treatment.

If the treatment is poorly tolerated, clinical judgement should be used to decide whether to titrate the dose more slowly upwards (especially if adverse effects improve with time following each dose increase) or to switch to one of the other three drug options.

If the treatment is still poorly tolerated, the other drugs should be tried until a treatment is found that is tolerable or all four drugs have been tried.

If the treatment is reasonably well tolerated, it should be titrated upwards until either pain is well controlled or the maximum tolerated dose has been reached and maintained for a minimum recommended period of time (which will vary for the different drugs).

If pain is poorly controlled on the maximum tolerated dose of the chosen drug, switch to one of the other three drugs until a treatment is found that is effective or all four drugs have been tried.

If pain is well controlled on the maximum tolerated dose of the chose drug, treatment should be continued. Gradual reduction of dose should be considered if any improvement is sustained.

Referral (to specialist pain services or a relevant clinical speciality) should be considered at any stage (including at initial presentation and at regular clinical reviews) if:

Pain is severe.

Pain significantly limits daily activities and quality of life.

The underlying health condition that is causing neuropathic pain has deteriorated.

Have I got the right topic?

216months3060monthsBoth

This CKS topic is based on the National Institute for Health and Care Excellence (NICE) guideline: Neuropathic pain — pharmacological management. The pharmacological management of neuropathic pain in adults in non-specialist settings [NICE, 2013].

This CKS topic covers the pharmacological treatment of adults with neuropathic pain (except trigeminal neuralgia). There is a separate CKS topic on Trigeminal neuralgia.

This CKS topic does not cover the management of adults with neuropathic pain conditions who are treated by specialist pain services, adults who have neuropathic pain in the first 3 months after trauma or orthopaedic surgical procedures, non-pharmacological treatment of neuropathic pain, or the assessment and management of the underlying condition causing neuropathic pain.

There are separate CKS topics on Diabetes - type 2 (covering painful diabetic neuropathy), Palliative cancer care - pain, Post-herpetic neuralgia, Sciatica (lumbar radiculopathy), and Shingles.

The target audience for this CKS topic is healthcare professionals working within the NHS in the UK and providing first contact or primary health care.

How up-to-date is this topic?

How up-to-date is this topic?

Changes

Last revised in February 2014

January 2014 to February 2014 — reviewed. A literature search was conducted in January 2014 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs published since the last revision of this topic. The following changes were made:

The management section has been rewritten to reflect the recommendations in the updated NICE guideline: Neuropathic pain — pharmacological management. The pharmacological management of neuropathic pain in adults in non-specialist settings [NICE, 2013].

The prescribing information section has been amended in line with the updated NICE guideline referenced above: prescribing information sections for duloxetine and capsaicin cream have been added, and prescribing information sections for drugs no longer recommended by NICE (imipramine, nortriptyline, and lidocaine plasters) have been removed.

The evidence section has been rewritten to reflect the changes in the updated NICE guideline referenced above.

Previous changes

August 2012 — minor update. Minor typographical error corrected.

May to September 2010 — topic updated. The evidence base has been reviewed in detail, and recommendations are more clearly justified and transparently linked to the supporting evidence.

January 2009 — minor update. Drug safety advice from the MHRA (Medicines and Healthcare products Regulatory Agency) that all antiepileptic drug treatment (including carbamazepine and gabapentin) is associated with a small risk of suicidal thoughts and behaviour has been added [MHRA, 2008]. Issued in February 2009.

September to December 2008 — this is a new CKS topic. The evidence base has been reviewed in detail, and recommendations are clearly justified and transparently linked to the supporting evidence.

Update

New evidence

Evidence-based guidelines

No new evidence-based guidelines since 1 January 2014.

HTAs (Health Technology Assessments)

No new HTAs since 1 January 2014.

Economic appraisals

No new economic appraisals relevant to England since 1 January 2014.

Systematic reviews and meta-analyses

No new systematic review or meta-analysis since 1 January 2014.

Primary evidence

No new randomized controlled trials published in the major journals since 1 January 2014.

New policies

No new national policies or guidelines since 1 January 2014.

New safety alerts

No new safety alerts since 1 January 2014.

Changes in product availability

No changes in product availability since 1 January 2014.

Goals and outcome measures

Goals

To support primary healthcare professionals:

To manage neuropathic pain in adults

To prescribe appropriate drugs for neuropathic pain

To refer people with neuropathic pain (if appropriate)

Background information

Definition

What is it?

Neuropathic pain is a symptom that develops as a result of damage to, or dysfunction of, the nervous system [Dworkin et al, 2007; Treede et al, 2008; NICE, 2013].

It may be caused by a wide range of conditions affecting the:

Peripheral nervous system — for example painful diabetic neuropathy, trigeminal neuralgia, post-herpetic neuralgia, radicular pain, pain after surgery, chemotherapy-induced neuropathy, neuropathy secondary to tumour infiltration, and injury to nerves (such as from trauma or electric shock).

Central nervous system — for example stroke, spinal cord injury, and multiple sclerosis.

Neuropathic pain may be constant or intermittent, and spontaneous or provoked.

The pain is typically described as shooting, stabbing, like an electric shock, burning, tingling, tight, numb, prickling, or itching.

Some people may experience:

Allodynia — pain caused by a stimulus that does not normally provoke pain (for example pain in response to light touch/pressure).

Hyperalgesia — an increased response to a stimulus that is normally painful.

[NICE, 2013]

Prevalence

How common is it?

It is not possible to quantify the overall prevalence of neuropathic pain in the general population [Dworkin et al, 2007; Freynhagen and Bennett, 2009; NICE, 2013]. The National Institute for Health and Care Excellence (NICE) highlights that estimates of population prevalence are likely to be inaccurate and inconsistent as they are based on a number of heterogeneous studies of variable validity [NICE, 2013].

Based on condition-specific studies, prevalence estimates for the following conditions are as follows [NICE, 2013]:

Painful diabetic neuropathy: 16–26% of people with diabetes.

Post-herpetic neuralgia: 8–19% of people with herpes zoster when defined as pain at 1 month after rash onset (or 8% when defined as pain at 3 months after rash onset).

Chronic pain after surgery: 10–50% for many common operations (for example 30–50% for amputation) [Shipton, 2008].

Complications

What are the complications?

When compared with people with other types of chronic pain, people with chronic neuropathic pain are more likely to report poorer physical and mental health, even after adjustment for pain intensity [Freynhagen and Bennett, 2009; NICE, 2013].

Prognosis

What is the prognosis?

Neuropathic pain is persistent in many cases because the causes are complex and diverse [NICE, 2013], and in many cases it is not possible to completely cure the underlying disease or lesion causing the neuropathic pain, or to reverse the neurological changes [Haanpää et al, 2009].

Response to drug treatment is often inadequate, with no more than 40–60% of people obtaining partial pain relief [Dworkin et al, 2007].

Management

Management

Scenario: Neuropathic pain - drug treatment : covers the pharmacological treatment of adults with neuropathic pain.

Scenario: Neuropathic pain - drug treatment

Scenario: Neuropathic pain - drug treatment

216months3060monthsBoth

Initial management of neuropathic pain

What is the initial management of a person with neuropathic pain?

For a person with trigeminal neuralgia, see the CKS topic on Trigeminal neuralgia.

For a person with any other neuropathic pain condition, including painful diabetic neuropathy, offer one of the following drugs: amitriptyline (off-label), duloxetine, gabapentin, or pregabalin.

When choosing a treatment, consider:

Contraindications and potential adverse effects, especially for people with comorbid conditions. See Prescribing information for information on contraindications and adverse effects of neuropathic pain drugs.

Interactions with other medications. See Prescribing information for information on drug interactions associated with neuropathic pain drugs.

Comorbid conditions that may benefit from a specific treatment, for example people with depression may benefit from treatment with an antidepressant drug.

The person's preference.

Titrate the dosage according to response and tolerability. See Prescribing information for information on suggested dose titrations of the drugs.

Do not prescribe more than one neuropathic pain drug at the same time. For example, do not prescribe amitriptyline concurrently with duloxetine, gabapentin, or pregabalin.

For a person with localized neuropathic pain who wishes to avoid, or cannot tolerate, oral treatments, consider prescribing capsaicin 0.075% cream (Axsain®).

Do not offer any other drug treatment unless advised to do so by a specialist. However, other treatments initiated by a specialist may be continued in primary care under a multidisciplinary care plan or a local shared-care agreement.

Arrange early follow up to assess the progress made with dose titration and the tolerability and effectiveness of the chosen treatment. Use clinical judgement to decide how soon to follow up the person.

Advise the person on:

The importance of dosage titration, and the titration process, providing written information if possible. Explain that the treatment does not work immediately; it commonly takes weeks to titrate up to an effective dose.

The possible adverse effects associated with each drug treatment. See Prescribing information for information on possible adverse effects of the individual neuropathic pain drugs.

Consider referring the person to a specialist pain service and/or a relevant clinical speciality (for example neurology, diabetology, or oncology) if they have severe pain; their pain significantly limits their participation in daily activities (including self care, general tasks and demands, interpersonal interactions and relationships, mobility, and sleeping); or the underlying health condition that is causing neuropathic pain has deteriorated.

For people awaiting referral after initial treatments have failed, consider prescribing a short course of tramadol for pain relief. Prescribe tramadol cautiously, bearing in mind the potential for misuse.

Basis for recommendation

Basis for recommendation

These recommendations are based largely on the National Institute for Health and Care Excellence (NICE) guideline: Neuropathic pain — pharmacological management. The pharmacological management of neuropathic pain in adults in non-specialist settings [NICE, 2013].

Offering amitriptyline, duloxetine, gabapentin, or pregabalin

NICE found consistent evidence showing that compared with placebo, amitriptyline, duloxetine, gabapentin, and pregabalin are effective at reducing neuropathic pain and are safe and cost effective.

The NICE guideline development group (GDG) was unable to recommend one drug as clearly superior to the others because of the variations between the included studies which led to considerable uncertainty about the relative efficacy of the different drugs. The NICE GDG, therefore, advises that the choice of treatment should be made on an individual basis, taking into account factors such as the underlying cause of pain, comorbidities, vulnerability to adverse effects, and personal preference [NICE, 2013].

Titrating drug treatments

Due to the risk of adverse effects associated with these drugs, the manufacturers of gabapentin, duloxetine, and pregabalin recommend starting with the lowest effective dose and titrating up to the minimum effective dose [ABPI Medicines Compendium, 2013a; ABPI Medicines Compendium, 2013b; ABPI Medicines Compendium, 2014b].

Titration of treatment is recommended when tricyclic antidepressants (TCAs) are used in the management of depression, to reduce the risk of adverse effects [Taylor et al, 2012]. CKS considers it prudent to use a similar approach when starting a TCA that is being used to manage neuropathic pain.

Capsaicin cream

The NICE GDG recommends capsaicin cream for people with localized neuropathic pain who wish to avoid, or cannot tolerate, oral treatments based on evidence that capsaicin cream is more effective than placebo and other topical treatments at reducing localized neuropathic pain [NICE, 2013].

Combination treatment

Due to the lack of evidence for the effectiveness of combining treatments, the NICE GDG does not currently recommend any combination treatments for neuropathic pain [NICE, 2013].

However, the GDG noted that combination treatment may be more practical and more effective than switching to a new treatment and may reduce adverse effects of the individual drugs due to the combination of lower doses.

Early follow up

In the expert opinion of the NICE GDG, an early clinical review is important to assess the progress made with titration and the effectiveness and tolerability of the treatment. This allows any necessary treatment adjustments to be made promptly in order to ensure optimal pain control [NICE, 2013].

CKS recommends using clinical judgement to decide how soon to follow up a person with neuropathic pain because the urgency of a follow up will depend on several factors including the cause of neuropathic pain, severity of pain, treatment prescribed, and the complexity of the titration process.

Advice

The NICE GDG recommends, based on what is considered to be good medical practice, discussing the risks and benefits of treatment to ensure the person makes an informed decision about their treatment [NICE, 2013].

Referral

NICE recommends considering referral (to specialist pain services or a condition-specific service) at any stage (including at initial presentation and at regular clinical reviews) if pain is severe, pain significantly limits daily activities and quality of life, or any underlying health condition has deteriorated, because [NICE, 2013]:

Specialist pain services provide comprehensive assessment and multi-modal management of all types of pain, including neuropathic pain.

A condition-specific service (for example oncology, neurology, or diabetology) will provide treatment for the underlying health condition that is causing neuropathic pain.

Considering tramadol whilst awaiting referral

The NICE GDG identified evidence from five small studies (n = 374) showing that tramadol is effective at reducing neuropathic pain compared with placebo. However, because of the small sample size in the included studies, the short study periods (up to 4 weeks), and the higher rates of withdrawals due to adverse effects associated with tramadol treatment, the GDG concluded that tramadol should only be considered as a rescue medication when people are awaiting referral to specialist pain services after initial treatment has failed [NICE, 2013].

NICE does not give a recommended duration of treatment with tramadol but states that it should be considered for short-term use only. CKS recommends that tramadol should be prescribed cautiously because of the potential for addiction.

In 2013, the Advisory Council on the Misuse of Drugs called for tramadol to be reclassified as a controlled drug because it found the number of tramadol-related deaths had almost doubled from 83 in 2008 to 154 in 2011. The government considered these concerns and has decided to place tramadol in Schedule 3 of the Misuse of Drugs Regulations 2001 later in 2014 [Home Office, 2014].

Treatments not recommended in primary care

The following drugs are not recommended for the treatment of neuropathic pain in primary care due to a lack of consistent evidence for their effectiveness, evidence of inferiority compared with placebo or other treatments, and/or evidence of a higher risk of adverse effects compared with other drugs [NICE, 2013]:

Carbamazepine (except for trigeminal neuralgia — see the CKS topic on Trigeminal neuralgia).

Cannabis sativa extract.

Capsaicin patch.

Imipramine.

Lacosamide.

Lamotrigine.

Levetiracetam.

Lidocaine (topical).

Morphine.

Nortriptyline.

Oxcarbazepine.

Topiramate.

Tramadol (long-term use).

Venlafaxine.

Imipramine, nortriptyline, and topical lidocaine were recommended in the previous NICE guideline on the pharmacological management of neuropathic pain [NICE, 2010]; however, due to a lack of good quality evidence to support their use, they are no longer recommended for the management of neuropathic pain [NICE, 2013]. For more information, see the updated full NICE guidance on the pharmacological management of neuropathic pain.

Follow up

How should I follow up a person being treated for neuropathic pain?

Assess the progress made with dose titration and the tolerability and effectiveness of the current treatment.

Ask about the current dose of drug and any problems they have experienced when titrating the dose upwards. Confirm understanding of the titration process.

Ask about the tolerability of any adverse effects experienced and whether they tend to improve or persist with time following each dose increase.

Assess the effectiveness of the treatment by asking about:

The degree of pain.

The impact of the pain on participation in daily activities (including self care, general tasks and demands, interpersonal interactions and relationships, mobility, and sleeping).

Their mood (in particular, whether the person is depressed or anxious).

If the treatment is poorly tolerated, use clinical judgement to decide whether to:

Titrate the dose more slowly upwards (especially if adverse effects improve with time following each dose increase), or

Switch to one of the other three drug options (for example if on amitriptyline (off-label), switch to duloxetine, gabapentin, or pregabalin). If the treatment is still poorly tolerated, consider switching again until a treatment is found that is tolerable or all four drugs have been tried.

When introducing a new drug, consider overlapping it with the old treatment to avoid deterioration in pain control. Taper the dose of the drug to be withdrawn to prevent discontinuation symptoms. See Prescribing information for more information on starting and withdrawing drug treatments.

If the treatment is reasonably well tolerated, continue titrating the dose upwards until either pain is well controlled or the maximum tolerated dose has been reached and maintained for a minimum recommended period of time. See Prescribing information for more information on recommended titration times.

If pain is poorly controlled on the maximum tolerated dose, switch to one of the other three drug options (for example if on amitriptyline (off-label), switch to duloxetine, gabapentin, or pregabalin). If pain is still poorly controlled, consider switching again until a treatment is found that is effective or all four drugs have been tried.

When introducing a new drug, consider overlapping it with the old treatment to avoid deterioration in pain control. Taper the dose of the drug to be withdrawn to prevent discontinuation symptoms. See Prescribing information for more information on starting and withdrawing drug treatments.

If pain is well controlled, continue treatment. Consider gradually reducing the dose over time if the improvement is sustained.

Consider referring the person to a specialist pain service and/or a relevant clinical speciality (for example neurology, diabetology, or oncology) if they have severe pain; their pain significantly limits their participation in daily activities (including self care, general tasks and demands, interpersonal interactions and relationships, mobility, and sleeping); or the underlying health condition that is causing neuropathic pain has deteriorated.

For people awaiting referral after initial treatments have failed, consider prescribing a short course of tramadol for pain relief. Prescribe tramadol cautiously, bearing in mind the potential for misuse.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline: Neuropathic pain — pharmacological management. The pharmacological management of neuropathic pain in adults in non-specialist settings [NICE, 2013].

Assessing progress made with dose titration and the tolerability and effectiveness of the current treatment

In the expert opinion of the NICE guideline development group (GDG), assessing progress made with dose titration as well as the tolerability and effectiveness of the current treatment is important to allow any necessary treatment adjustments to be made promptly in order to ensure optimal pain control [NICE, 2013].

Poorly tolerated treatment

CKS recommends using clinical judgement to decide on a management plan if treatment is poorly tolerated. This pragmatic advice is based on the fact that a slower upward titration may reduce the risk of intolerable adverse effects in some people whilst others may benefit from a change to one of the other drug options.

Reasonably well-tolerated treatment

CKS recommends switching to one of the other drug options if pain is poorly controlled on the maximum tolerated dose of the chosen treatment because NICE found evidence showing that compared with placebo, amitriptyline, duloxetine, gabapentin, and pregabalin are effective at reducing neuropathic pain and are safe and cost effective.

The NICE GDG was unable to recommend one drug as clearly superior to the others because of the variations between the included studies which led to considerable uncertainty about the relative efficacy of the different drugs. The NICE GDG, therefore, advises that the choice of treatment should be made on an individual basis, taking into account factors such as the underlying cause of pain, comorbidities, vulnerability to adverse effects, and personal preference [NICE, 2013].

The recommendations to continue treatment if pain is well controlled and to consider gradually reducing the dose over time if the improvement is sustained is based on the expert opinion of the NICE GDG [NICE, 2013].

Referral

NICE recommends considering referral (to specialist pain services or a condition-specific service) at any stage (including at initial presentation and at regular clinical reviews) if pain is severe, pain significantly limits daily activities and quality of life, or any underlying health condition has deteriorated, because [NICE, 2013]:

Specialist pain services provide comprehensive assessment and multi-modal management of all types of pain, including neuropathic pain.

A condition-specific service (for example oncology, neurology, or diabetology) will provide treatment for the underlying health condition that is causing neuropathic pain.

Considering tramadol whilst awaiting referral

The NICE guideline development group (GDG) identified evidence from five small studies (n = 374) showing that tramadol is effective at reducing neuropathic pain compared with placebo. However, because of the small sample size in the included studies, the short study periods (up to 4 weeks), and the higher rates of withdrawals due to adverse effects associated with tramadol treatment, the GDG concluded that tramadol should only be considered as a rescue medication when people are awaiting referral to specialist pain services after initial treatment has failed [NICE, 2013].

NICE does not give a recommended duration of treatment with tramadol but states that it should be considered for short-term use only. CKS recommends that tramadol should be prescribed cautiously because of the potential for addiction.

In 2013, the Advisory Council on the Misuse of Drugs called for tramadol to be reclassified as a controlled drug because it found the number of tramadol-related deaths had almost doubled from 83 in 2008 to 154 in 2011. The government considered these concerns and has decided to place tramadol in Schedule 3 of the Misuse of Drugs Regulations 2001 later in 2014 [Home Office, 2014].

Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically for the drugs recommended in this CKS topic. For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (eMC) (http://medicines.org.uk/emc), or the British National Formulary (BNF) (www.bnf.org).

Amitriptyline

Amitriptyline

Licensed indications

Is amitriptyline licensed for neuropathic pain?

The use of amitriptyline for the management of neuropathic pain is off-label.

However, it is widely used for this indication in current practice. This is supported by the National Institute for Health and Clinical Excellence [NICE, 2013].

Dose and titration

What dose of tricyclic antidepressants should be used and how should it be titrated?

Start with 10 mg a day (taken at night) and gradually titrate up to an effective dose or the person's maximum tolerated dose (no higher than 75 mg a day) [BNF 66, 2013].

If no improvement is seen with 75 mg a day, consider seeking specialist advice or switching to a different drug (see Follow up).

Dosages higher than 75 mg a day could be considered in consultation with a specialist pain service.

Consider trialling amitriptyline for 6–8 weeks, with at least 2 weeks at the maximum tolerated dose, before deciding it is not effective [Attal et al, 2006; Librach et al, 2006; Dworkin et al, 2007].

If amitriptyline is not effective or not tolerated, discontinue treatment gradually over a minimum of 4 weeks to prevent discontinuation symptoms (such as dizziness, nausea, paraesthesiae, anxiety, diarrhoea, flu-like symptoms, and headaches) [Haddad, 2001; Taylor et al, 2012].

Pregnancy and breastfeeding

Can tricyclic antidepressants be used during pregnancy and breastfeeding?

Amitriptyline may be used during pregnancy and breastfeeding for the management of neuropathic pain.

Pregnancy

The UK Teratology Information Service (UKTIS) states that if considered appropriate, amitriptyline may be prescribed for use in pregnancy. However, the lowest effective dose should be used [UKTIS, 2010a].

According to the UKTIS, published data do not indicate any increased risk of congenital malformations or lasting adverse fetal outcomes following prenatal amitriptyline exposure; however, data are too limited to completely rule out a risk [UKTIS, 2010a].

For further information on the use of amitriptyline during pregnancy, contact the UKTIS on 0844 892 0909.

Breastfeeding

The UK Drugs in Lactation Advisory Service advises that sedating tricyclic antidepressants (such as amitriptyline) should be used with caution during breastfeeding and only after an assessment of benefit to the mother compared with the risk, real or potential, to the infant [UK Drugs in Lactation Advisory Service, 2013].

According to the UK Drugs in Lactation Advisory Service, these drugs either have insufficient clinical data on their use in lactation to regard them as absolutely safe or they have had minor, reversible adverse effects reported in a breast-fed infant [UK Drugs in Lactation Advisory Service, 2013].

Other prescribing issues

What other prescribing issues should I be aware of when prescribing amitriptyline?

For further information on how to prescribe amitriptyline, including contraindications and cautions, adverse effects, drug interactions, and monitoring, see the Prescribing information section in the CKS topic on Depression.

Pregabalin

Pregabalin

Licensed indication

Is pregabalin licensed for neuropathic pain?

Pregabalin is licensed for the treatment of peripheral and central neuropathic pain in adults [ABPI Medicines Compendium, 2014b].

The National Institute for Health and Care Excellence recommends pregabalin as a first-line treatment option for adults with all neuropathic pain (except trigeminal neuralgia) [NICE, 2013].

Dose and titration

What dose of pregabalin should be used, and how should it be titrated?

Start pregabalin treatment at 150 mg a day (given in two to three divided doses) [BNF 66, 2013; ABPI Medicines Compendium, 2014b].

A lower starting dose may be appropriate for some people, for example people who cannot initially tolerate 150 mg a day or people with reduced renal function (see Table 1) [BNF 66, 2013; ABPI Medicines Compendium, 2014b]. Seek specialist advice and consult the manufacturer's Summary of Product Characteristics for use in people undergoing haemodialysis.

If necessary, increase the dose after 3 to 7 days to 300 mg a day (given in two to three divided doses). The dose can be increased further to a maximum dose of 600 mg a day (given in two to three divided doses) after an additional 7-day interval [BNF 66, 2013; ABPI Medicines Compendium, 2014b].

Consider trialling pregabalin for 4 weeks before deciding it is not effective.

If pregabalin is not effective or not tolerated, discontinue treatment gradually over a minimum of 1 week [ABPI Medicines Compendium, 2014b].

Table 1 . Recommended dosage adjustment for pregabalin in people with renal impairment.
Renal function (based on eGFR) Starting daily dose Maximum daily dose
Stage 3 — moderate eGFR 30–60 mL/minute/1.73 m2 75 mg a day (divided in two or three doses) 300 mg a day (divided in two or three doses)
Stage 4 — severe eGFR 15–30 mL/minute/1.73 m2 25–50 mg a day (as one daily dose or divided in two doses) 150 mg a day (as one daily dose or divided in two doses)
Stage 5 — very severe or endstage eGFR less than 15 mL/minute/1.73 m2 25 mg once a day 75 mg once a day
eGFR = estimated glomerular filtration rate. Data from: [BNF 66, 2013]

Contraindications and cautions

What are the contraindications and cautions for pregabalin?

Contraindications

Apart from hypersensitivity to pregabalin or to any of its excipients, there are no specific contraindications for pregabalin.

Prescribe pregabalin with caution if the person:

Has renal impairment — a reduced initial and maximum daily dosage is recommended (see Dose and titration).

Has diabetes — pregabalin may cause weight gain. Adjustment of anti-diabetic medication may be necessary.

Is elderly and at risk of falls — pregabalin has been associated with dizziness and somnolence, and there have been post-marketing reports of loss of consciousness, confusion, and mental impairment with pregabalin.

Has heart failure — congestive heart failure has been reported in some people on pregabalin. This is most commonly seen in elderly people with compromised cardiovascular systems. Discontinue the drug if the person develops symptoms of heart failure or worsening of heart failure.

Is at risk of suicide — there is a small increased risk of suicidal ideation and behaviour in people treated with antiepileptic drugs. The mechanism of this risk is not known, and the available data suggest that the increased risk applies to all antiepileptic drugs and is seen as early as 1 week after starting treatment [MHRA, 2008].

[ABPI Medicines Compendium, 2014b]

Pregnancy and breastfeeding

Can pregabalin be used during pregnancy and breastfeeding?

Pregabalin should not be used during pregnancy for the management of neuropathic pain.

The UK Teratology Information Service (UKTIS) states that it is not currently possible to offer an evidence-based insight into any risk pregabalin exposure may pose to a developing fetus, due to a lack of human pregnancy exposure data [UKTIS, 2013]. For further information on the use of pregabalin during pregnancy, contact the UKTIS on 0844 892 0909.

The manufacturer of pregabalin advises that pregabalin should not be used during pregnancy unless clearly necessary (that is, if the benefit to the mother clearly outweighs the potential risk to the fetus). They state that there are no adequate data for use of pregabalin in human pregnancy; studies in animals have shown reproductive toxicity, but the potential risk for humans is unknown [ABPI Medicines Compendium, 2014b].

Pregabalin is not recommended during breastfeeding for the management of neuropathic pain.

The UK Drugs in Lactation Advisory Service advises that due to the very limited published evidence of safety during breastfeeding, the use of pregabalin during breastfeeding should be done cautiously and is conditional on risk-reducing actions being taken, for example delaying breastfeeding after a maternal dose and monitoring the infant for sedation, poor feeding, adequate weight gain, and developmental milestones [UK Drugs in Lactation Advisory Service, 2012c].

An American drugs and lactation database states that the use of pregabalin is not a reason to discontinue breastfeeding; however, until more data become available, an alternate drug may be preferred, especially when nursing a newborn or preterm infant [LactMed, 2013b].

The manufacturer of pregabalin (Lyrica®) does not recommend its use during breastfeeding as it is not known if pregabalin is excreted in the breast milk of humans [ABPI Medicines Compendium, 2014b].

Adverse effects

What are the adverse effects of pregabalin, and how can they be managed?

Dizziness and somnolence are the most commonly reported adverse effects of pregabalin and are the most common causes of treatment discontinuation.

Advise people taking pregabalin not to drive, operate heavy machinery, or engage in other potentially hazardous activities until it is known whether pregabalin affects their ability to perform these activities.

Increased appetite and weight gain have also been reported.

This may be particularly undesirable for some people, for example people with diabetes mellitus as weight gain may worsen glycaemic control.

Offer lifestyle and dietary advice, if appropriate.

Suicidal thoughts and behaviour. There is a small increased risk of suicidal thoughts and behaviour associated with antiepileptic drugs (including pregabalin), which may be seen as early as 1 week after starting treatment.

Advise people taking pregabalin to be alert to any mood changes, distressing thoughts, or feelings about suicide or harming themselves at any point during treatment [MHRA, 2008].

They should seek medical advice if they develop such thoughts or behaviour, and they should be referred for appropriate treatment if necessary.

Other common adverse effects reported include:

Gastrointestinal adverse effects: vomiting, dry mouth, constipation, and flatulence.

Visual adverse effects: blurred vision and diplopia. Visual adverse effects are generally transient and may resolve or improve with discontinuation of pregabalin.

Psychiatric adverse effects: euphoria, confusion, irritability, decreased libido, disorientation, and insomnia.

Nervous system disorders: ataxia, abnormal coordination, tremor, dysarthria, memory impairment, disturbance in attention, paraesthesia, sedation, balance disorder, lethargy, and headache.

Others: abnormal gait, feeling drunk, vertigo, fatigue, erectile dysfunction, peripheral oedema, and oedema.

[ABPI Medicines Compendium, 2014b]

Drug interactions

What are the key drug interactions with pregabalin?

Pregabalin has no clinically important drug interactions.

There may be additive sedative effects when pregabalin is used with other central nervous system depressants. Pregabalin may potentiate the effects of ethanol and lorazepam.

[Dworkin et al, 2007; ABPI Medicines Compendium, 2014b]

Gabapentin

Gabapentin

Licensed indications

Is gabapentin licensed for neuropathic pain?

Gabapentin is licensed for the treatment of peripheral neuropathic pain such as painful diabetic neuropathy and post-herpetic neuralgia in adults [ABPI Medicines Compendium, 2013a].

The National Institute for Health and Care Excellence recommends gabapentin as a first-line treatment option for adults with all neuropathic pain (except trigeminal neuralgia) [NICE, 2013].

Dose and titration

What dose of gabapentin should be used, and how should it be titrated?

Various dose titrations may be used for gabapentin, depending on the person taking it and how well they tolerate it. The speed of titration will vary among individuals and should be tailored to the individual. For example, elderly or frail people are more likely to experience adverse effects and will require slower titration [Dworkin et al, 2007].

Adjust the dose for people with renal impairment (see Table 1). Consult the manufacturer's Summary of Product Characteristics if the person is undergoing haemodialysis.

Fast titration (usually suitable for otherwise healthy younger adults)

Start with 300 mg once a day on day 1, then 300 mg twice a day on day 2, then 300 mg three times a day on day 3.

Alternatively, start with 300 mg three times a day on day 1, then increased according to response in steps of 300 mg (in 3 divided doses) every 2–3 days up to maximum of 3600 mg a day (1200 mg three times a day).

If the person experiences adverse effects during daily titration, a slower titration may help — see below.

Slow titration (suitable if the person is elderly, frail, or has experienced adverse effects with higher doses)

Start with 100 mg at night, increasing by 100 mg a day until pain is significantly reduced, intolerable adverse effects occur, or a maximum daily dosage of 3600 mg (1200 mg three times a day) is reached [Dworkin et al, 2007].

If the person experiences adverse effects during daily titration, a slower titration (for example increasing the dose every 3–7 days) may help.

Consider trialling gabapentin for 3–8 weeks, with at least 2 weeks at the maximum tolerated dose, before deciding it is not effective [Dworkin et al, 2007].

It may take several weeks to reach an effective dosage (usually 1200 mg to 3600 mg a day). Onset of action may be seen as early as the second week of treatment with rapid titration, but the peak effect usually occurs about 2 weeks after a therapeutic dosage is achieved; therefore, an adequate trial may be 2 months or longer.

If gabapentin is not effective or not tolerated, discontinue treatment gradually over a minimum of 1 week.

[ABPI Medicines Compendium, 2013a; BNF 66, 2013]

Table 1 . Recommended dosage adjustment for gabapentin in people with renal impairment.
Renal function (based on eGFR) Starting daily dose (to be administered as three divided doses) Maximum daily dosage (to be administered as three divided doses)
eGFR 50–80 mL/minute/1.73 m2 600 mg 1800 mg a day
eGFR 30–49 mL/minute/1.73 m2 300 mg 900 mg a day
eGFR 15–29 mL/minute/1.73 m2 (stage 4, severe) 300 mg on alternate days 600 mg a day
eGFR less than 15 mL/minute/1.73 m2† (stage 5, very severe or endstage) 300 mg on alternate days 300 mg a day
eGFR = estimated glomerular filtration rate.
Data from: [BNF 66, 2013]

Contraindications and cautions

What are the contraindications and cautions for gabapentin?

Contraindications

Apart from hypersensitivity, there are no specific contraindications for gabapentin.

Prescribe gabapentin with caution if the person:

Has renal impairment — a reduced maximum daily dosage is recommended (see Dose and titration).

Is elderly (65 years or older) — the following adverse effects may be more frequent in this group: somnolence, peripheral oedema, and asthenia.

Is at risk of suicide — there is a small increased risk of suicidal ideation and behaviour in people treated with antiepileptic drugs in several indications. The mechanism of this risk is not known, and the available data suggest that the increased risk applies to all antiepileptic drugs and is seen as early as 1 week after starting treatment [MHRA, 2008].

[ABPI Medicines Compendium, 2013a]

Pregnancy and breastfeeding

Can gabapentin be used during pregnancy and breastfeeding?

Gabapentin should not be used during pregnancy for the management of neuropathic pain.

The UK Teratology Information Service (UKTIS) states that the available data does not show an increased risk of congenital malformation following gabapentin exposure. However, the data are currently too limited to state that there is no increased risk [UKTIS, 2011]. For further information on the use of gabapentin during pregnancy, contact the UKTIS on 0844 892 0909.

The manufacturer of gabapentin advises that gabapentin should not be used during pregnancy unless clearly necessary (that is, if the benefit to the mother clearly outweighs the potential risk to the fetus). They state that there are no adequate data for use of gabapentin in human pregnancy; studies in animals have shown reproductive toxicity, but the potential risk for humans is unknown [ABPI Medicines Compendium, 2013a].

Gabapentin is not recommended during breastfeeding for the management of neuropathic pain.

Limited information indicates that maternal doses of gabapentin up to 2100 mg a day produce relatively low levels in infant serum (higher doses have not been studied). The UK Drugs in Lactation Advisory Service, therefore, advises that the use of gabapentin during breastfeeding should be done cautiously and is conditional on risk-reducing actions being taken, for example monitoring the infant for adverse effects (such as sedation, poor feeding, and inadequate weight gain) and delaying breastfeeding after a maternal dose [UK Drugs in Lactation Advisory Service, 2012a].

An American drugs and lactation database advises that if gabapentin is used, the infant should be monitored for drowsiness, adequate weight gain, and developmental milestones, especially in younger, exclusively breastfed infants [LactMed, 2013a].

The manufacturer states that gabapentin should be used during breastfeeding only if the benefits clearly outweigh the risks. Gabapentin is excreted in human milk and because the effect on the breastfed infant is unknown, caution should be exercised when gabapentin is prescribed to a breastfeeding mother [ABPI Medicines Compendium, 2013a].

Adverse effects

What are the adverse effects of gabapentin, and how can they be managed?

Gabapentin is widely accepted as being well tolerated, even at high dosages (more than 2400 mg a day) [Attal et al, 2006].

Dizziness and somnolence are very common, especially at the beginning of the treatment and after a dose increase, and may be reduced by gradual dosage titration.

Advise people taking gabapentin not to drive, operate heavy machinery, or engage in other potentially hazardous activities until it is known whether gabapentin affects their ability to perform these activities.

Increased appetite and weight gain have also been reported.

This may be particularly undesirable for some people, for example people with diabetes mellitus as weight gain may worsen glycaemic control.

Offer lifestyle and dietary advice, if appropriate.

Suicidal thoughts and behaviour. There is a small increased risk of suicidal thoughts and behaviour associated with antiepileptic drugs (including gabapentin), which may be seen as early as 1 week after starting treatment.

Advise people taking gabapentin to be alert to any mood changes, distressing thoughts, or feelings about suicide or harming themselves at any point during treatment [MHRA, 2008].

They should seek medical advice if they develop such thoughts or behaviour, and they should be referred for appropriate treatment if necessary.

Other common adverse effects reported include:

Increased risk of infections and infestations: viral infection, pneumonia, otitis media, infection, urinary tract infection, and respiratory infection.

Blood and lymphatic system disorders: leucopenia.

Respiratory disorders: dyspnoea, bronchitis, pharyngitis, cough, and rhinitis.

Gastrointestinal disorders: vomiting, nausea, dental abnormalities, gingivitis, diarrhoea, abdominal pain, dyspepsia, constipation, dry mouth or throat, and flatulence.

Skin and subcutaneous tissue disorders: facial oedema, rash, pruritus, and acne.

Musculoskeletal, connective tissue and bone disorders: arthralgia, myalgia, back pain, and twitching.

Psychiatric disorders: hostility, confusion, depression, anxiety, nervousness, and abnormal thinking.

Nervous system disorders: convulsions; hyperkinesias; dysarthria; amnesia; tremor; insomnia; headache; paresthesia; hypaesthesia;abnormal coordination; nystagmus; and increased, decreased, or absent reflexes.

Others: ataxia, fever, fatigue, anorexia, vertigo, visual disorders (amblyopia and diplopia), impotence, and false positive readings with some urinary protein tests.

[ABPI Medicines Compendium, 2013a]

Drug interactions

What are the key drug interactions with gabapentin?

Gabapentin has no clinically important drug interactions.

There may be additive sedative effects when gabapentin is used with other central nervous system depressants.

[ABPI Medicines Compendium, 2013a]

Duloxetine

Duloxetine

Licensed indication

Is duloxetine licensed for neuropathic pain?

Duloxetine is licensed for the treatment of diabetic peripheral neuropathic pain [ABPI Medicines Compendium, 2013b].

However, the National Institute for Health and Care Excellence recommends duloxetine as a first-line treatment option for adults with all neuropathic pain (except trigeminal neuralgia) [NICE, 2013].

Dose and titration

What dose of duloxetine should be used, and how should it be titrated?

Start duloxetine treatment at 60 mg a day. If necessary, increase the dose up to a maximum of 120 mg a day (in two divided doses). No dosage adjustment is necessary for people with mild or moderate renal dysfunction (creatinine clearance 30 to 80 mL/minute) [ABPI Medicines Compendium, 2013b; BNF 66, 2013].

Consider trialling duloxetine for up to 8 weeks before deciding it is not effective.

Additional response after 8 weeks is unlikely [ABPI Medicines Compendium, 2013b].

Reassess treatment at least every three months [ABPI Medicines Compendium, 2013b; BNF 66, 2013].

If duloxetine is not effective or not tolerated, discontinue treatment gradually over a minimum of 1 to 2 weeks in order to reduce the risk of withdrawal reactions [ABPI Medicines Compendium, 2014b].

Pregnancy and breastfeeding

Can duloxetine be used during pregnancy and breastfeeding?

Duloxetine should not be used during pregnancy for the management of neuropathic pain.

The UK Teratology Information Service states that duloxetine is not routinely recommended during pregnancy due to the very limited data available on its use in pregnancy [UKTIS, 2012]. For further information on the use of duloxetine during pregnancy, contact the UKTIS on 0844 892 0909.

The manufacturer states that duloxetine should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus [ABPI Medicines Compendium, 2013b].

Duloxetine is not recommended during breastfeeding for the management of neuropathic pain.

The UK Drugs in Lactation Advisory Service advises that due to the limited published evidence of safety during breastfeeding, the use of duloxetine during breastfeeding should be done cautiously and is conditional on risk-reducing actions being taken, for example monitoring the infant for adverse effects (such as sedation, poor feeding, and inadequate weight gain) and delaying breastfeeding after a maternal dose [UK Drugs in Lactation Advisory Service, 2012b].

The UK Medicines Information states that duloxetine is not recommended first line in breastfeeding women because limited data indicate that duloxetine passes into breast milk in small amounts [UKMI, 2011].

The manufacturer advises that the use of duloxetine during pregnancy is not recommended as its safety in infants is not known [ABPI Medicines Compendium, 2013b].

Other prescribing issues

What should I be aware of when prescribing duloxetine for neuropathic pain?

For further information on how to prescribe duloxetine, including contraindications and cautions, adverse effects, drug interactions, and monitoring, see the Prescribing information section in the CKS topic on Depression.

Capsaicin cream

Capsaicin cream

Licensed indications

Capsaicin 0.075% cream (Axsain®) is licensed for the symptomatic relief of postherpetic neuralgia after open skin lesions have healed, and for the symptomatic relief of painful diabetic neuropathy (only under the direct supervision of a hospital consultant who has access to specialist resources).

The National Institute for Health and Care Excellence recommends capsaicin cream for people with localized neuropathic pain who wish to avoid, or cannot tolerate, oral treatments [NICE, 2013].

Dosage

Advise the person to apply a small amount of cream (pea size) to the affected area 3–4 times a day (not more often than every 4 hours).

Pain relief usually begins within the first week of treatment and increases with continuing regular application for the next 2–8 weeks.

Pregnancy and breastfeeding

Capsaicin 0.075% cream (Axsain®) may be considered during pregnancy and breastfeeding for the management of neuropathic pain.

According to the manufacturer, although there have been no studies looking at the safety of capsaicin cream during pregnancy and breastfeeding, the small amount absorbed transdermally is considered unlikely to cause any adverse effects in humans.

Drug interactions

There are no known drug interactions with capsaicin cream.

Other prescribing issues

Capsaicin cream should not be used on broken or irritated skin.

Skin irritation has been reported following application of capsaicin cream, and the intense burning sensation experienced during initial treatment may limit use [BNF 66, 2013].

Advise the person to avoid taking a hot bath or shower just before or after applying capsaicin cream, as it can enhance the burning sensation.

Also advise the person:

That the cream should be gently rubbed in, and there should be no residue left on the surface of the skin.

To wash their hands immediately after applying capsaicin cream unless the hands are the treated areas, in which case they should be washed 30 minutes after application.

To avoid inhalation of vapours from the cream as transient irritation of the mucous membranes of the eyes and respiratory tract (including exacerbation of asthma) has been reported.

That capsaicin cream should not be applied near the eyes.

That tight bandages should not be applied on top of capsaicin cream.

That medical advice should be sought if the condition worsens.

[ABPI Medicines Compendium, 2011]

Tramadol

Tramadol

Prescribing issues

What should I be aware of when prescribing tramadol for neuropathic pain?

Licensed indication

Although not specifically licensed for the neuropathic pain, tramadol is licensed for the treatment of moderate to severe pain [ABPI Medicines Compendium, 2013c; ABPI Medicines Compendium, 2014a].

The National Institute for Health and Care Excellence (NICE) recommends tramadol for people with neuropathic pain (except trigeminal neuralgia), only if acute rescue therapy is needed [NICE, 2013].

Dosage

Start with a dose of 50 mg to 100 mg not more often than every 4 hours (up to a maximum of 400 mg a day) [ABPI Medicines Compendium, 2013c; ABPI Medicines Compendium, 2014a].

Pregnancy and breastfeeding

The use of tramadol during pregnancy is not recommended.

The UK Teratology Information Service (UKTIS) states that there are limited published data on the outcome of human pregnancy after tramadol exposure in the first trimester. However, the use of tramadol near term may cause neonatal respiratory depression, and long-term use may be associated with neonatal abstinence syndrome [UKTIS, 2010b]. For further information on the use of tramadol during pregnancy, contact the UKTIS on 0844 892 0909.

The manufacturers of tramadol advise that tramadol should not be used in pregnancy as there is inadequate evidence to assess its safety during pregnancy [ABPI Medicines Compendium, 2013c; ABPI Medicines Compendium, 2014a].

Tramadol may be used during breastfeeding. However the lowest effective dose should be prescribed for the shortest duration of time, and the woman should be advised to stop breastfeeding and seek medical advice if they experience any adverse effects (for example nausea, vomiting, constipation, and sedation).

The UK Drugs in Lactation Advisory Service now recommends tramadol for use during breastfeeding based on the low levels in breast milk when prescribed at the lowest effective dose for the shortest duration [UKMi, 2013].

The manufacturers are more cautious and state that tramadol should not be used during breast feeding as tramadol and its metabolites have been detected in breast milk; an infant could ingest 0.1% of the dose administered to the mother [ABPI Medicines Compendium, 2013c; ABPI Medicines Compendium, 2014a].

Other prescribing issues

For further information on how to prescribe tramadol, including contraindications and cautions, adverse effects, drug interactions, and monitoring, see the section on Scenario: Weak opioids in the CKS topic on Analgesia - mild-to-moderate pain.

Evidence

Evidence

Supporting evidence

Efficacy and safety of neuropathic pain drugs

Evidence on the efficacy and safety of neuropathic pain drugs

The National Institute for Health and Care Excellence (NICE) found consistent evidence showing that amitriptyline, duloxetine, gabapentin, pregabalin, and topical capsaicin are effective at reducing neuropathic pain compared with placebo, and are safe and cost effective. There was insufficient evidence to recommend one treatment as clearly superior to the others. NICE also found evidence that tramadol is effective at reducing neuropathic pain compared with placebo; however, there were higher rates of withdrawal due to adverse effects associated with tramadol.

Scope

The NICE guideline development group (GDG) considered the clinical and cost-effectiveness evidence on different drug treatments for adults with neuropathic pain [NICE, 2013].

To do this, the GDG categorized neuropathic pain into central neuropathic pain, peripheral neuropathic pain, and trigeminal neuralgia. In addition, the GDG conducted an overarching analysis of the evidence, described in the guideline as 'all neuropathic pain'. Undertaking the analysis in this way enabled the GDG to consider as much valid clinical and health economic evidence as possible.

This section summarizes the clinical evidence for 'all neuropathic pain', central neuropathic pain, and peripheral neuropathic pain.

For clinical evidence for trigeminal neuralgia, see the CKS topic on Trigeminal neuralgia.

For a summary of the cost-effectiveness evidence reviewed by NICE, see the section on Cost effectiveness of neuropathic pain drugs.

For a full version of the clinical and cost-effectiveness evidence reviewed by the NICE GDG, see the full NICE guidance and the full appendices (C–L).

All neuropathic pain

Study population

NICE identified 115 randomized controlled trials (RCTs; n = 18,087) and considered the clinical evidence on 43 different drug treatments for neuropathic pain.

NICE sought to investigate:

The clinical effectiveness of the 43 drug treatments as monotherapy compared with placebo.

The clinical effectiveness of individual drug treatments compared with each other.

The clinical effectiveness of combination therapy compared with monotherapy or other combination therapy.

Outcome measures

The GDG categorized the clinical outcomes as 'critical' and 'important'.

Critical outcomes were patient-reported global improvement; patient-reported improvement in daily physical and emotional functioning, including sleep; and major adverse effects (defined as leading to withdrawal from treatment).

Important outcomes were patient-reported pain relief/intensity reduction, individual adverse effects, and the use of rescue medication.

Analysis and presentation of results

Network meta-analyses (NMAs) were performed for all but one outcome, where a conventional pairwise meta-analysis was performed.

NMAs (also called a mixed/multiple treatment comparisons) allow simultaneous comparison of multiple treatments in a single meta-analysis using both direct comparisons of interventions within RCTs and indirect comparisons across trials based on a common comparator. NMAs help to reduce uncertainty where there are few head-to-head trials. However, assessment of risk of bias and the overall quality of evidence across a NMA is still a developing methodology.

Quality of the evidence

NICE graded the evidence using a prespecified grading system. See Appendix G of the full NICE guidance for more information.

Overall, the quality of most of the evidence for different outcomes was graded by NICE as low and very low because:

Most of the studies did not have sufficient follow-up periods to assess the long-term effect of different drugs, which is considered to be important for chronic conditions such as neuropathic pain.

Some of the included studies used different methods for dealing with missing data.

Not all studies performed an intention-to-treat analysis, and most of the studies that dealt with missing data used the last observation carried forward, which has been reported to produce bias in the results.

The included studies had varying allowances of concomitant medications, with some studies excluding some drugs but not others.

Evidence on different outcomes were also downgraded for:

Imprecision, if the included studies had confidence intervals that crossed the clinical decision threshold between recommending and not recommending a treatment, and if the optimal information size was not met.

Inconsistency, if the difference in results between studies looking at the same or similar interventions are very different and the wide difference in results is unaccounted for. In NMAs, the extent to which direct and indirect evidence agrees is also a criterion for consistency.

Indirectness, if there are substantial differences between the population, intervention, comparator, or outcome in relevant studies compared with those under consideration in a guideline or systematic review, and if there were no head-to-head trials between interventions of interest.

Results

Effectiveness of individual drugs compared with placebo: despite the quality of the evidence for different outcomes, the analyses appeared consistent that:

Amitriptyline, duloxetine, gabapentin, and pregabalin reduce neuropathic pain compared with placebo.

Tramadol is effective at reducing neuropathic pain compared with placebo. However, the effect estimated was imprecise because of the small sample size in the included studies, the short study periods (up to 4 weeks), and the higher rates of withdrawals due to adverse effects associated with tramadol treatment.

Capsaicin cream is more effective than placebo and other topical treatments at reducing localized neuropathic pain.

Relative efficacy of different treatments

Due to the variations between the included studies, there was considerable uncertainty in the results from the pairwise meta-analysis and the NMAs about the critical and important outcomes that should guide decision making on the best pharmacological treatment. As a result, the GDG was unable to recommend one treatment as clearly superior to the others.

Reporting on rescue medication use varied across the included studies, with some studies not reporting it at all and those that reported it measuring usage in different ways (such as proportion using rescue medications and number of tablets used). As a result, it was not possible to draw a meaningful conclusion from the results.

Adverse effects and withdrawal due to adverse effects

NMA of 97 RCTs reporting individual adverse effects (for example gait disturbance, dizziness, and vertigo) showed that some adverse effects were more frequent with particular drugs. However, it was difficult to draw conclusions on which particular drugs were best or worst for particular adverse effects.

NMA of 91 RCTs reporting withdrawal due to adverse effects at any follow up showed that most drugs cause more drop-outs due to adverse effects than placebo, but there was considerable uncertainty about which drugs were least likely to cause drop-outs due to adverse effects.

Combination therapy

There was insufficient evidence comparing the clinical effectiveness and tolerability of different drug combinations. Further research is needed.

Peripheral neuropathic pain

The GDG concluded that the clinical effectiveness for peripheral neuropathic pain was similar to that of 'all neuropathic pain', possibly because a large proportion of evidence on 'all neuropathic pain' came from studies on peripheral neuropathic pain. Of the 115 studies included for ‘all neuropathic pain’, 88 studies were on peripheral neuropathic pain; n = 16,660.

Central neuropathic pain

The GDG felt that there was insufficient evidence to support recommendations for central neuropathic pain that were different from those made for ‘all neuropathic pain’. Of the 115 studies included for 'all neuropathic pain', 11 studies were on central neuropathic pain; n = 660.

Trigeminal neuralgia

See the CKS topic on Trigeminal neuralgia.

Cost effectiveness of neuropathic pain drugs

Evidence on the cost effectiveness of neuropathic pain drugs

The National Institute for Health and Care Excellence (NICE) found consistent evidence showing that amitriptyline, duloxetine, gabapentin, pregabalin, and topical capsaicin are effective at reducing neuropathic pain compared with placebo, and are safe and cost effective. There was insufficient evidence to recommend one treatment as clearly superior to the others. NICE also found evidence that tramadol is effective at reducing neuropathic pain compared with placebo; however, there were higher rates of withdrawal due to adverse effects associated with tramadol.

Scope

The NICE guideline development group (GDG) considered the clinical and cost-effectiveness evidence on different drug treatments for adults with neuropathic pain [NICE, 2013].

To do this, the GDG categorized neuropathic pain into central neuropathic pain, peripheral neuropathic pain, and trigeminal neuralgia. In addition, the GDG conducted an overarching analysis of the evidence, described in the guideline as 'all neuropathic pain'. Undertaking the analysis in this way enabled the GDG to consider as much valid clinical and health economic evidence as possible in their decision making.

This section summarizes the cost-effectiveness evidence reviewed by NICE. For information on the clinical evidence, see the section on Clinical evidence. For a full version of the clinical and economic evidence reviewed by the NICE GDG, see the full NICE guidance and the full appendices (C–L).

All neuropathic pain

Study population

NICE performed a systematic review of 13 published cost–utility analyses for 16 neuropathic pain treatments, including placebo, amitriptyline, capsaicin cream, duloxetine, gabapentin, pregabalin, and tramadol.

The included studies were on people with peripheral neuropathic pain. No studies on central pain or trigeminal neuralgia were identified.

Outcome measures

NICE assessed the cost effectiveness of the treatments by considering several factors including the:

Efficacy and safety of treatments.

Cost of treatments.

Cost of treating adverse effects associated with treatments.

Quality of included studies

NICE graded the evidence using a prespecified grading system. See Appendix G of the full NICE guidance for more information.

Overall, the quality of most of the evidence for different outcomes was graded by NICE as low and very low because:

Results for some of the treatments were inconsistent and occasionally contradictory between analyses.

None of the included studies assessed the range of comparators included in the scope of the guideline.

It was not possible to draw robust conclusions from the heterogenous evidence assembled.

For these reasons, the GDG's economic considerations were predominantly based on the de novo health economic model devised for this guideline. See Appendix F of the full NICE guidance for more information.

Results

Despite the quality of the evidence for the different outcomes, gabapentin, amitriptyline, and capsaicin cream appeared to be the most cost-effective options for treating neuropathic pain, followed by pregabalin and then duloxetine.

The mean cost-per-QALY of tramadol was greater than would normally be considered an effective use of NHS resources; however, the GDG believes opioids may fulfil an important role in temporarily managing acute pain in people who do not experience adequate pain relief with the maintenance treatment recommended in the initial treatment phase.

Search strategy

Scope of search

A full literature search was not required as this CKS topic is primarily based on the National Institute for Health and Care Excellence (NICE) guideline: Neuropathic pain — pharmacological management. The pharmacological management of neuropathic pain in adults in non-specialist settings [NICE, 2013].

Sources of guidelines

National Institute for Health and Care Excellence (NICE)

Scottish Intercollegiate Guidelines Network (SIGN)

Royal College of Physicians

Royal College of General Practitioners

Royal College of Nursing

NICE Evidence

Health Protection Agency

National Guidelines Clearinghouse

Guidelines International Network

TRIP database

GAIN

Institute for Clinical Systems Improvement

National Health and Medical Research Council (Australia)

Royal Australian College of General Practitioners

British Columbia Medical Association

Canadian Medical Association

Towards Optimal Practice

University of Michigan Medical School

Michigan Quality Improvement Consortium

Patient UK Guideline links

Driver and Vehicle Licensing Agency

Medline (with guideline filter)

Sources of systematic reviews and meta-analyses

The Cochrane Library :

Systematic reviews

Protocols

Database of Abstracts of Reviews of Effects

Medline (with systematic review filter)

EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

The Cochrane Library :

NHS Economic Evaluations

Health Technology Assessments

Canadian Agency for Drugs and Technologies in Health

International Network of Agencies for Health Technology Assessment

NIHR Health Technology Assessment programme

Sources of randomized controlled trials

The Cochrane Library :

Central Register of Controlled Trials

Medline (with randomized controlled trial filter)

EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

Department of Health

Health Management Information Consortium (HMIC)

Patient experiences

Healthtalkonline

BMJ - Patient Journeys

Patient.co.uk - Patient Support Groups

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

British National Formulary (BNF)

electronic Medicines Compendium (eMC)

European Medicines Agency (EMEA)

LactMed

Medicines and Healthcare products Regulatory Agency (MHRA)

REPROTOX

Scottish Medicines Consortium

Stockley's Drug Interactions

TERIS

TOXBASE

Micromedex

UK Medicines Information

References

ABPI Medicines Compendium (2011) Summary of product characteristics for Axsain. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

ABPI Medicines Compendium (2013a) Summary of product characteristics for Neurontin 100mg Hard Capsules. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

ABPI Medicines Compendium (2013b) Summary of product characteristics for Cymbalta 30mg hard gastro-resistant capsules, Cymbalta 60mg hard gastro-resistant capsules. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

ABPI Medicines Compendium (2013c) Summary of product characteristics for Zamadol capsules 50 mg. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

ABPI Medicines Compendium (2014a) Summary of product characteristics for Zydol 50mg capsules. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

ABPI Medicines Compendium (2014b) Summary of product characteristics for Lyrica Capsules. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

Attal, N., Cruccu, G., Haanpää, M. et al. (2006) EFNS guidelines on pharmacological treatment of neuropathic pain. European Journal of Neurology 13(11), 1153-1169. [Abstract] [Free Full-text]

BNF 66 (2013) British National Formulary. 66th edn. London: British Medical Association and Royal Pharmaceutical Society of Great Britain.

Dworkin, R.H., O'Connor, A.B., Backonja, M. et al. (2007) Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 132(3), 237-251. [Abstract]

Freynhagen, R. and Bennett, M.I. (2009) Diagnosis and management of neuropathic pain. BMJ 339(), b3002.

Haanpää, M.L., Backonja, M.M., Bennett, M.I. et al. (2009) Assessment of neuropathic pain in primary care. American Journal of Medicine 122(10 Suppl), S13-S21. [Abstract]

Haddad, P.M. (2001) Antidepressant discontinuation syndromes. Drug Safety 24(3), 183-197. [Abstract]

Home Office (2014) Summary of responses to the consultation on proposals to schedule tramadol, and remove the prescription writing exemption for temazepam, under the Misuse of Drugs Regulations 2001. Home Office. www.gov.uk [Free Full-text]

LactMed (2013a) Gabapentin. National Library of Medicine. www.toxnet.nlm.nih.gov

LactMed (2013b) Pregabalin. National Library of Medicine. www.toxnet.nlm.nih.gov

Librach, L., Lloyd, N., Jarvis, V. et al. (2006) The use of gabapentin and tricyclic antidepressants in the treatment of neuropathic pain in cancer patients: a clinical practice guideline. Cancer Care Ontario. www.cancercare.on.ca

MHRA (2008) Antiepileptics: risk of suicidal thoughts and behaviour. Drug Safety Update 2(1), 2. [Free Full-text]

NICE (2010) Neuropathic pain. The pharmacological management of neuropathic pain in adults in non-specialist settings [Replaced by CG173]. National Institute for Health and Care Excellence. www.nice.org.uk

NICE (2013) Neuropathic pain - pharmacological management. The pharmacological management of neuropathic pain in adults in non-specialist settings (Full NICE guideline). National Institute for Health and Care Excellence. www.nice.org.uk [Free Full-text]

Shipton, E. (2008) Post-surgical neuropathic pain. ANZ Journal of Surgery 78(7), 548-555. [Abstract] [Free Full-text]

Taylor, D., Paton, C. and Kapure, S. (2012) The Maudsley prescribing guidelines. 11th edn. London: Informa Healthcare.

Treede, R.D., Jensen, T.S., Campbell, J.N. et al. (2008) Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 70(18), 1630-1635. [Abstract]

UK Drugs in Lactation Advisory Service (2012a) Gabapentin. UKMiCentral. www.midlandsmedicines.nhs.uk [Free Full-text]

UK Drugs in Lactation Advisory Service (2012b) Duloxetine. UKMiCentral. www.midlandsmedicines.nhs.uk [Free Full-text]

UK Drugs in Lactation Advisory Service (2012c) Pregabalin. UKMiCentral. www.midlandsmedicines.nhs.uk [Free Full-text]

UK Drugs in Lactation Advisory Service (2013) Antidepressants. UKMiCentral. www.midlandsmedicines.nhs.uk

UKMI (2011) Management of depression in breastfeeding mothers - are reboxetine, venlafaxine, duloxetine, mirtazapine and MAOIs safe? UK Medicines Information. www.evidence.nhs.uk

UKMi (2013) Codeine and breastfeeding: Is it safe and what are the alternatives? UK Medicines Information. www.evidence.nhs.uk

UKTIS (2010a) Use of amitriptyline in pregnancy. TOXBASEUK Teratology Information Service. www.toxbase.org

UKTIS (2010b) Use of tramadol in pregnancy. TOXBASEUK Teratology Information Service. www.toxbase.org

UKTIS (2011) Use of gabapentin in pregnancy. TOXBASEUK Teratology Information Service. www.toxbase.org

UKTIS (2012) Use of duloxetine in pregnancy. TOXBASEUK Teratology Information Service. www.toxbase.org

UKTIS (2013) Use of pregabalin in pregnancy. TOXBASEUK Teratology Information Service. www.toxbase.org