NICE CG173 - Neuropathic pain - pharmacological management (November 2013)
Many different types of pathology may cause neuropathic pain – this heterogeneity results in a wide variety of mechanisms and presentations of pain, for example:
- Infection: post-herpetic neuralgia;
- Metabolic: diabetic neuropathy;
- Trauma: phantom limb pain, some back pain, complex regional pain syndrome;
- Ischaemia: central post-stroke central pain
Use neuropathic pain screening questionnaires to make the diagnosis (LANNS, Pain detect, DN4).
Prior to starting treatment a pain score should be recorded in the notes. This can be a formal test such as the Brief Pain Inventory, or simple questions such as average and worst pain in last couple of weeks, and level of interference with quality of life. This information can be used to help review effectiveness of treatments at later dates.
The effectiveness of treatment should be established prior to continuing with the therapy. Some patients may be very reluctant to stop taking pregabalin as although it is not effective, it is the last drug to be tried and they are afraid to stop.
Discussion about the limited effectiveness of medication tried should be documented in the patient's notes prior to starting a trial of anti-neuropathic pain medication.
The NICE clinical guideline for neuropathic pain emphasises establishing an underlying diagnosis and initiating treatment (such as diabetes) and on tailoring pharmacological treatment to the individual.
Up to 40% of patients may be refractory to drug treatment, making a multidisciplinary approach to treatment desirable.
All anti-neuropathic pain medication should be reviewed regularly. Significant numbers of patients who find it initially helpful, will find the drug becomes less effective within a 6 month period.
If a patient is in severe pain while taking an analgesic, the effectiveness of that analgesic should be considered. The dose should be reduced and if there is no worsening of the pain, the dose reduction cycle should be repeated. Once a patient has been off the analgesic for a few weeks, it can be re-introduced to see if it is still effective. If there is worsening of pain on dose reduction, the previous dose should be prescribed, and a further review arranged in a few months.
Non-pharmacological treatments should be considered and the patient's co-morbidities taken into account when individually tailoring treatment. If diagnosis uncertain or pain is severe or has a significant impact on daily activities, consider referral to pain specialist or disease specific service if underlying condition clear.
Referral to the pain clinic for multidisciplinary pain management if there are persistent or distressing symptoms.
Give an explanation and advice about the pain. Advise to maintain normal activities and exercise. Treatment of depression or anxiety, pay attention to psychological and social factors (such as depression or joblessness) “yellow flags".
This is very important especially to maintain function. Regular aerobic exercise has been shown to be beneficial in treating pain. If patients are fearful about the safety of exercise/find it difficult to start, advice can be sought from local pain clinics.
These drugs have a ceiling effect for pain relief and side effects. Unlike conventional analgesics their side effects are often noticed by the patient before the ceiling effect for pain relief is reached. Therefore the drugs should be given slowly and titrated upwards with careful monitoring of side effects.
In neuropathic pain, prescribing should be based on a patient's symptoms and signs i.e. mechanisms of pain rather than pathophysiological diagnosis.
In choosing pharmacological agents to treat consider patient co-morbidity, patient preference, occupation and mental health. Consider the following points:
- Carbamazepine (see 4.8 Antiepileptic drugs) remains the drug of choice for the stabbing pain of trigeminal neuralgia.
- Tricyclic antidepressants and anti-epileptics remain the most useful drugs.
- Vulnerability to specific side effects (dizziness or sedation in the elderly, particularly with tricyclic drugs).
- Comorbidity and specific contra-indications (the effects of renal impairment on drug excretion; use of tricyclic drugs or SNRI drugs in patients with uncontrolled hypertension).
- Impact on driving or shift work.
- Mental health, consider drugs with antidepressant activity in patients with low mood (duloxetine). Consider pregabalin in patients with significant anxiety.
- Sleep, tricyclic drugs or pregabalin in patients with poor sleep.
Once established, frequent clinical reviews are required. Ideally 30-50% reduction in Visual Analogue Scale (VAS) pain score. However, also assess and record improvements in daily activities, patient global impression of improvement, sleep and mood. Dose should be titrated to achieve maximum benefit with minimum side effects.
1st line options
4.3 Antidepressant drugs
- Start with 10mg at 7-8 pm with upward titration to an effective dose or the person's maximum tolerated dose of no higher than 75mg as a single evening dose.
- If anticholinergic side effects are excessive but tricyclic is efficacious then consider imipramine as a secondary option. Imipramine has a similar anticholinergic profile to nortriptyline but is significantly cheaper.
- See notes above for tricyclic drugs, caution in the elderly.
- Cost (28 days): 75mg daily = £2.37
4.3 Antidepressant drugs
- Use the same regime as amitriptyline (see above). Ensure the patient takes their dose in the early evening to reduce the risk of next morning sedation.
- Imipramine can be used as a second line agent if amitriptyline is efficacious but its anticholinergic side effects limit its use. See notes above for tricyclic drugs, caution in the elderly.
- Nortriptyline remains an option as a tertiary tricyclic drug if imipramine is still not tolerable for the patient but is considerably more expensive, 75mg daily = £26.64 (28 days)
- Cost (28 days): 75mg daily = £3.03
4.8.1 Control of the epilepsies
- Start at 300mg at night, with upward titration to an effective dose or the person's maximum tolerated dose of no higher than 3600mg per day (divided into three doses. Some patients may need significantly lower doses.
- Review all patients after 6 months. Try slow downward dose titration to see if lower maintenance dose or stopping is possible. Always stop slowly.
- Please refer to treatment of pain in palliative care for dose titration of gabapentin for patients in renal impairment
- Cost (28 days): 3600mg daily = £14.65
- If initial first-line drug is ineffective or not tolerated consider switching to the other first-line drug.
- Pregabalin is not recommended locally for first-line treatment
- Tricyclic antidepressants (TCAs) are widely used and have a well-established evidence base, although unlicensed. They are contraindicated in recent MI or history of arrhythmias and in severe liver disease. They should not be used when there is a risk of overdose.
- Patients already on SSRI antidepressants are more usually treated with gabapentin. For full list of cautions and side effects see current edition of BNF.
- Gabapentin should be the second choice, unless amitriptyline is contraindicated or not tolerated. It is as effective as amitriptyline with fewer side effects in some patients. It is primarily excreted by the kidneys, therefore, reduce dose in renal impairment; it may also aggravate sedative effects of other drugs in such patients.
- Gabapentin may cause dizziness and sedation in the first few days of use.
2nd line options
Add in an alternative first line agent. Recent studies have shown gabapentin combined with a tricyclic has increased efficacy when compared to each agent alone.
For painful diabetic neuropathy
If the first-line treatment detailed above is ineffective, after a trial of at least one month, duloxetine should be considered. Start duloxetine at 60mg per day (a lower starting dose may be appropriate for some people), with upward titration to an effective dose or the person's maximum tolerated dose of no higher than 120mg per day. Stop duloxetine if pain is not reduced by 30% at one month and consider pregabalin.
4.8.1 Control of the epilepsies
- Start at 150mg per day (divided into two doses; a lower starting dose such as 25mg 12 hourly is often appropriate), with upward titration to an effective dose or the person's maximum tolerated dose of no higher than 600mg per day (divided into two doses).
- Public Health England: Practitioners should prescribe pregabalin and gabapentin appropriately to minimise the risks of misuse and dependence, and should be able to identify and manage problems of misuse if they arise. Most patients who are given these drugs will use their medicines appropriately without misuse. Further information see here.
- Pregabalin capsules have a flat pricing structure so it is most cost-effective to prescribe the least number of capsules to form the required dose and to prescribe twice daily instead of three times daily.
- Pregabalin may be combined with either tricyclic antidepressants or Duloxetine.
- Please refer to treatment of pain in palliative care for dose titration of pregabalin for patients in renal impairment.
- Review all patients after 6 months. To discontinue pregabalin reduce at the same rate of initial titration. Patients may experience a transient (up to 1 week) increase in anxiety on withdrawal, and need to be reassured about this.
- Cost (28 days): 600mg daily (300mg 12 hourly) = £64.40
4.3 Antidepressant drugs
- Start at 60mg per day (a lower starting dose may be appropriate for some people), with upward titration to an effective dose or the person's maximum tolerated dose of no higher than 120mg per day
- Cost (28 days): 120mg daily = £4.74
For painful diabetic neuropathy
If the first-line treatment detailed above is ineffective, after a trial of at least one month,
duloxetine should be considered. Start duloxetine at 60mg per day (a lower starting dose may be appropriate for some people), with upward titration to an effective dose or the person's maximum tolerated dose of no higher than 120mg per day. Stop duloxetine if pain is not reduced by 30% at one month and consider pregabalin.
3rd line options
If second line treatment not effective, refer to specialist pain service and/or condition specific service e.g. oncology, neurology, diabetology.
While waiting for referral consider adding in:
- Acute rescue therapy
- 50mg four times daily, with upward titration to a maximum daily dose of 400mg in four divided doses. Tramadol may be used instead of or in combination with second-line treatment but do not combine tramadol with duloxetine (risk of serotonergic syndrome)
Other drug treatments
Usually initiated on advice from pain clinic
Capsaicin 0.075% cream
- Apply very small amounts every 8 hours
- It can be helpful in post-herpetic neuralgia
- Severe initial stinging may limit use
- Needs careful patient instruction
- May be helpful on sensitive skin
Only initiated on advice from pain clinic
Lidocaine 700mg (5% w/w) medicated plasters
- Not recommended for initiation in primary care (see national guidance from NHS England)
- Only indicated for the treatment of post-herpetic neuralgia
- Pain specialists may occasionally recommend a trial of lidocaine plasters in difficult to treat cases of other forms of neuropathic pain. If successful, GPs may be asked to continue prescribing with ongoing review from pain specialists
- Lidocaine plasters can result in gradual desensitisation of the nerves, leading to improvement in symptoms; the plaster may be discontinued if this should occur. Prescribers should therefore consider a trial withdrawal of therapy to reassess ongoing need at appropriate intervals
Sodium valproate (refer to
4.8 Antiepileptic drugs), Topiramate (refer to 4.8 Antiepileptic drugs) may be used under specialist advice. Also strong opioids, morphine or oxycodone (refer to4.7 Analgesics) and combination therapy with more than one agent.
(Nabilone may be used by South Devon Healthcare NHS Foundation Trust)
The management of trigeminal neuralgia is distinct from other forms of neuropathic pain.
- Initially 100mg twice a day, increasing dose until pain is relieved.
- When pain is in remission, reduce the dose of carbamazepine and gradually withdraw drug if patient remains pain-free for one month
- Appropriate for GP prescribing
4. Central Nervous System >
Management of neuropathic pain
- First line
- Second line