See 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: post-stroke central pain
Referral to the pain clinic for multidisciplinary pain management if there are persistent or distressing symptoms.
NICE CG173 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. 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.
Give an explanation and advice about the pain. Advise to maintain of 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 in Complex Regional Pain Syndrome to maintain function.
Some patients find this method effective. Machines are available over the counter. Patients will need to be taught how to use the TENS machine correctly, e.g. by the physiotherapy department.
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 over a period of time 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 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 need to 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
- 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
- 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
- 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, particularly the elderly, 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.
- 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.
- Patients who have gained some benefit from either amitriptyline or gabapentin but have not tolerated dose titrations may be trialled on a combination of amitriptyline plus gabapentin before considering the second-line treatment options below. The combination may allow lower doses to be used and the side-effect profile may be less.
- 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.
- See section 4.8.1 Control of the Epilepsies for MHRA Drug Safety Updates for gabapentin
2nd Line options
- 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)
- Prescribe twice daily: 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
- 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 may be combined with either tricyclic antidepressants or duloxetine
- Cost (28 days): 600mg daily (300mg 12 hourly) = £64.40
- See section 4.8.1 Control of the Epilepsies for MHRA Drug Safety Updates
- 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 sparingly three times daily
- It can be helpful in post-herpetic neuralgia
- Severe initial stinging may limit use
- Needs careful patient instruction
(Lidocaine with prilocaine 25mg + 25mg)
- May be helpful on sensitive skin
Only initiated on advice from pain clinic
Lidocaine 700mg (5% w/w) medicated plaster
- Only recommended for the treatment of post-herpetic neuralgia
- Apply to the painful area once daily for up to 12 hours, followed by a 12-hour plaster-free period; plasters may be cut to size if necessary. Up to 3 plasters may be used to cover large areas. Review after 2-4 weeks, discontinue if ineffective
- Not recommended for initiation in primary care (see national guidance from NHS England). Only for use following initiation by specialist pain team (this may include recommendation to prescribe following outpatient appointment or "advice and guidance" service)
- Pain specialists may occasionally recommend a trial of lidocaine plasters in difficult to treat cases of other forms of neuropathic pain (off-license). If successful, GPs may 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 e.g. at 3-6 months, and then 6 monthly
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