Drugs Used in Neuropathic Pain

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General Notes

Currently no drug exists that is singularly beneficial in all cases of neuropathic pain. When considering pharmacological management of chronic neuropathic pain prescribers should:

  • Adopt a trial and error approach with regard to determining effective treatment regimens and individualise treatment to each patient.
  • A ‘start low and go slow’ approach should be implemented with regard to dosing. This allows the minimum effective/maximum tolerated dose to be identified.
  • Patients should be made aware from the outset that medicines prescribed for the management neuropathic pain have variable efficacy and that initiation of these medicines is on a trial basis.

Drugs used in neuropathic pain are considered effective if there is at least a 30% reduction in pain score, or a significant improvement in functional ability, on the maximum tolerated dose.

Given that many patients suffering from chronic neuropathic pain will likely have or develop co-morbidities, tapering and withdrawing treatments that provide sub-optimal benefit is key to avoiding unnecessary polypharmacy and high risk drug combinations.

Optimisation of treatment that is effective prior to adding in further analgesia is equally important with regard to avoidance of polypharmacy.

Step 1 - Tricyclic Antidepressants

Preferred list (P)

AMITRIPTYLINE

  • Dose should be taken at around 8pm to optimise benefit of the sedative effect.

 

Total list (T)

IMIPRAMINE

  • Restriction: Should be reserved for use in patients who cannot tolerate the sedative effects of amitriptyline.

Prescribing Notes:

  • Amitriptyline is licensed for the treatment of neuropathic pain. Although imipramine is not licensed there is significant evidence and practice base to support the use.
  • Co-prescribing tricyclic anti-depressants with tramadol, duloxetine or selective serotonin reuptake inhibitors increases the risk of serotonin syndrome.
  • Tricyclic antidepressants have the potential to prolong the QT interval. Prescribers should be aware of the potential for interaction with other drugs associated with this effect (particularly citalopram). Where drug-drug combinations known to potentially cause QT prolongation are unavoidable, patients should be made aware of the risk and an ECG considered (this will depend on the risk of QT prolongation in individual patients). Further information can be found at Specialist Pharmacy Service - 'Identifying risk factors for developing a long QT interval'.
  • Although imipramine may be better tolerated than amitriptyline, there is no evidence that one tricyclic antidepressant is more effective than another in the treatment of neuropathic pain. Therefore, if amitriptyline is deemed to be ineffective, following a suitable trial period at an optimised dose, Step 2 treatment should be trialled next.

Step 2 - Gabapentinoids

Preferred list (P)

GABAPENTIN

 

Total list (T)

PREGABALIN

  • Restriction: Only for use where gabapentin has been ineffective or not well tolerated.

Prescribing Notes:

  • Less than 20% of patients prescribed gabapentin or pregabalin will obtain a significant reduction in pain.
  • Both gabapentin and pregabalin have the potential to be misused due to the euphoric effects they can produce when taken in high (normally supratherapeutic) doses. Prescribers should be aware of the potential for misuse. Public Health England has produced advice for prescribers on managing the risk of the misuse associated with pregabalin and gabapentin.
  • The SMC has restricted the use of pregabalin within NHS Scotland under certain circumstances. Further information can be found at SMC.

Gabapentin

Gabapentin is reserved for use within NHS Lanarkshire where tricyclic antidepressants are:

  • Contraindicated
  • Not tolerated
  • Ineffective despite dose optimisation and a suitable trial period (i.e. 4-6 weeks)
  • Unsuitable for individual patients (e.g. due to risk of QT prolongation)

It may be prescribed in combination with a tricyclic antidepressant where neuropathic pain is not adequately controlled by a tricyclic antidepressant alone, but has had a significant benefit (i.e. 30% reduction in pain score, significant improvement in functional ability or sleep pattern).

If response is sub-optimal after 8 weeks at the maximum tolerated dose then gabapentin should be gradually tapered and withdrawn.

In October 2017, the MHRA issued a Drug Safety Update for gabapentin. It highlighted that gabapentin is associated with a rare risk of severe respiratory depression and the dose may need to be adjusted in high risk patients.

Pregabalin

As with gabapentin, pregabalin may be used in conjunction with a tricyclic antidepressant - provided the tricyclic antidepressant is deemed effective.

If gabapentin is ineffective following an 8 week trial of the maximum tolerated dose, a trial of pregabalin may be initiated. Gabapentin should be gradually tapered and withdrawn before commencing pregabalin.

Once an optimised dose of pregabalin has been prescribed for 8 weeks, the patient should be reviewed and efficacy of treatment assessed. Patients experiencing a reduction in pain score less than 30% of baseline or limited improvement in functional ability should have their pregabalin dose gradually tapered and withdrawn.

In April 2022, the MHRA issued a Drug Safety Update for pregabalin- a new study has suggested pregabalin may slightly increase the risk of major congenital malformations if used in pregnancy. Patients should continue to use effective contraception during treatment and avoid use in pregnancy unless clearly necessary.

Adjuvants

Total list (T)

TRAMADOL

  • Restriction: For short-term use in patients who have not obtained adequate benefit from Step 1 and 2 medicines whilst awaiting referral to the Pain Clinic.
  • Capsules are currently the most cost effective modified release formulation of tramadol.

Tramadol: Morphine Equivalence
(As per BNF online - conversion ratios vary and these figures are a guide only)

Preparation Total Dose Oral morphine equivalence over 24 hours
Tramadol 50mg Capsules Two capsules four times a day (400mg) 40mg morphine daily
Tramadol MR Capsules 50mg One capsule twice a day (100mg) 10mg morphine daily
Tramadol MR Capsules 100mg One capsule twice a day (200mg) 20mg morphine daily
Tramadol MR Capsules 150mg One capsule twice a day (300mg) 30mg morphine daily
Tramadol MR Capsules 200mg One capsule twice a day (400mg) 40mg morphine daily

 

Specialist initiation (S1)

DULOXETINE

  • Restriction: 60mg-120mg daily for treatment of diabetic neuropathy ONLY where treatment with Step 1 and 2 medicines has not provided adequate benefit.

MORPHINE sustained release (Zomorph®)

  • Sustained release preparations of morphine should be prescribed by brand name.

  • Zomorph® is currently the brand of choice within NHS Lanarkshire to ensure continuity between primary and secondary care settings.

    • In patients with true swallowing difficulties Zomorph® capsules can be opened and the contents mixed with semi-solid food (e.g. puree, jam, yoghurt).

    • The contents can also be suspended in water and administered via gastric or gastrostomy tubes of a diameter of more than 16 F.G. with an open distal end or lateral pores [SPC].

OXYCODONE modified release (Oxypro®)

  • Oxypro® are the preferred brand of modified-release (MR) oxycodone tablets in primary care in NHS Lanarkshire.

Oxypro® : Morphine Equivalence
(As per BNF online rounded to nearest 5mg - conversion ratios vary and these figures are a guide only)

Preparation Total Dose Oral morphine equivalence over 24 hours
Oxypro® 5mg tablets One tablet twice a day (10mg) 15mg morphine daily
Oxypro® 10mg tablets One tablet twice a day (20mg) 30mg morphine daily
Oxypro® 15mg tablets One tablet twice a day (30mg) 50mg morphine daily
Oxypro® 20mg tablets One tablet twice a day (40mg) 65mg morphine daily
Oxypro® 30mg tablets One tablet twice a day (60mg) 100mg morphine daily
Oxypro® 40mg tablets One tablet twice a day (80mg) 130mg morphine daily

Tramadol

In 2014 tramadol was reclassified as a Schedule 3 Controlled Drug following an increase in the number of deaths related to its use.

Use of tramadol is restricted to patients who fail to obtain adequate benefit from Step 1 and 2 drugs whilst awaiting referral to the Pain Clinic.

Duloxetine

Is only licensed for the treatment of diabetic peripheral neuropathic pain. Its use is further restricted within NHS Scotland (as per SMC guidance) to specialist initiation in patients with peripheral diabetic neuropathy that has not adequately responded to other treatments (i.e. Step 1 and 2 treatments at an optimised dose for an appropriate trial period).

Should be discontinued after a trial period of 2 months if response is inadequate (i.e. less than 30% reduction in pain score or insignificant improvement in functional ability). Discontinuation should be gradual to avoid occurrence of withdrawal adverse effects.

Where duloxetine is effective, this should be reviewed at least every 3 months and a trial reduction considered to assess ongoing need.

NHSL Joint Adult Formulary Key

To indicate the category of a formulary medicine, updated sections adopt the following key:

Preferred list (P): First-line formulary choices.

 

Total list (T): Alternative choices when preferred list options not effective/not tolerated, or not indicated.

 

Specialist initiation (S1): Specialist initiation, or on the advice of a Consultant or Specialist Practitioner in this therapeutic area. Continuation in primary care is acceptable.

 

Specialist use only (S2): Supply via hospital, Homecare Service or a hospital based prescription (HBP) for dispensing by community pharmacy. Not prescribed in primary care setting.

Last reviewed: 31 January 2022

Next review: 31 January 2025

Author(s): NHSL

Version: Please refer to the introduction section for an explanation of the review dates above.

Approved By: ADTC

Reviewer Name(s): KM & CM