• Use of Botulinum Toxin A as 3^rd line management for chronic localised peripheral neuropathic pain (typically elderly and frail patients)

• Consultant in Pain Medicine only decision and administration

• See&Treat Pain Management clinic (preferable) or pain interventions list

• Off-label use; written informed consent required before each treatment course

• Second injection at 12 weeks regardless of initial response; discharge from pathway if no response after two injections.

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Abbreviations

Peripheral neuropathic pain is a severe form of chronic pain, arising as a direct consequence of a lesion or disease affecting the somatosensory nervous system. In a recent UK study overall prevalence of Neuropathic Pain was found to be 9.2% (Baskozos et al., 2023). Meta-analyses of pharmacotherapy have indicated that only 30 to 40% of patients with neuropathic pain have an adequate response when compared with placebo which means that a large proportion of patients lack adequate pharmacotherapeutic efficacy (Finnerup et al., 2018).

The Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain conducted a systematic review of 229 randomised double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including unpublished trials (retrieved from clinicaltrials.gov and pharmaceutical websites) (Finnerup et al., 2015).

Safety in all RCTs was generally excellent. Hence botulinum toxin was recommended as 3rd line of treatment for neuropathic pain as follows:

• 1st line gabapentin/pregabalin/SNRIs/TCAs

• 2nd line capsaicin 8% patches/lidocaine 5% patches/tramadol

• 3rd line BTX-A***, strong opioids

. ***analgesic effect mediated principally by a direct action on nociceptive fibres and the inhibition of neurogenic inflammation through a blockade of neuro-transmitter release***

Neuropathic pain affects 9.2% of middle-aged adults in the UK, and 18.1% of those with chronic pain.

Treatment for patients with severe refractory peripheral neuropathic pain for whom 1st line and 2nd line therapy did not offer symptom relief, or it resulted in dose-limiting adverse effects. We aim to avoid the use of strong opioids known for their immunomodulatory effect and multiple side effects. Improve pain control, improve quality of life and functioning in patients with refractory neuropathic pain.

Typically, these are elderly patients that experience significant side effects to trials of oral gabapentinoids (pregabalin, gabapentin), tricyclic antidepressants (amitriptyline, nortriptyline) and serotonin noradrenaline reuptake inhibitors (duloxetine) and/or topical capsaicin cream 0.075%, doxepin cream, menthol 2% in aqueous cream.

We encounter elderly, frail patients with peripheral neuropathic pain for whom 1st or 2nd line therapy does not offer symptom relief or it results in dose-limiting adverse effects. Those patients can suffer from post-surgical neuropathic pain, chemotherapy induced peripheral neuropathy or radiation-toxicity associated pain.

• Chemotherapy induced peripheral neuropathy

• Persistent post-surgical pain

• Post-herpetic neuralgia

After trialling line 1 and 2 (>2 months titration of anti-neuropathic agents); adequate trial of at least two agents from first line and at least one from second-line pharmacotherapy, each for a minimum of 4 weeks at therapeutic dose

Douleur Neuropathique 4 score ≥ 4 (this is for screening purposes) and that clinical diagnosis should meet the NEUPsig criteria (2016) for probable/definite neuropathic pain

Aged ≥ 18 and pain on most days for > 6 months

Of note - Subcutaneous BTX-A injection risks diffusion to facial muscles (orbicularis oculi, orbicularis oris, zygomaticus, frontalis), potentially causing ptosis, asymmetric smile, difficulty with eye closure, or impaired oral competence. These are cosmetically and functionally significant. Post-herpetic neuralgia of V1 distribution: This is a well-recognised, often treatment-refractory condition. These patients may have exhausted first- and second-line options and have few alternatives beyond strong opioids.

BOTNEP trial design involved two fixed administrations 12 weeks apart—all participants received both injections regardless of response to the first (Attal et al., 2016). This was a research protocol to assess the value of repeated administration, not a treatment algorithm for clinical practice. Almost a quarter of patients converted from non-responders to treatment responders only after two administrations

• Infection at the injection site

• Previous adverse reaction to botulinum toxin A

• Disorders of the NMJ (i.e. myasthenia gravis)

Coagulation disorders (uncontrolled bleeding diathesis) are a contraindication. Patients on stable anticoagulation (warfarin with INR in range, DOACs) may be treated with caution; increased bruising at injection sites is expected but clinically insignificant. Aspirin and other antiplatelet agents do not require cessation.

Women of childbearing age unless using effective contraception/ Pregnancy

Use of drugs acting on the NMJ (amikacin, gentamycin, neostigmine, pyridostigmine, polymixins, streptomycin, anaesthetic muscle relaxants)

Less than 3 months since last application for capsaicin and active treatment with lidocaine 5% patches

Concomitant use of peripheral nerve anaesthetic blocks/ central neuraxial anaesthesia.

Progressive motor/sensory neuropathy, undergoing further diagnosis and assessment

Active, unstable major psychiatric disorder that would preclude informed consent or compliance with follow-up.

Pain limited to the sole of the foot (? greater adverse effects)

Mean pain Numerical Rating Score on Brief Pain Inventory <4/10

Excellent safety profile (6 RCTs) - Pain at the site of injection the most frequently reported side effect (55% in BOTNEP trial). No systemic side effects (compared to all anti-neuropathic agents):

Common/very common (≥1/100 to <1/10): excessive doses may paralyse distant muscles; increased electrophysiologic jitter in some distant muscles; influenza-like symptoms; misplaced injection may paralyse nearby muscles.

Rare (≥1/10,000 to <1/1,000): antibody formation (substantial deterioration in response), arrhythmias, myocardial infarction, seizures.

Very rare (<1/10,000): aspiration; dysphonia; exaggerated muscle weakness; respiratory disorders.

- Audit/database – clinical fellow project

- Keep diary of pain/analgesic medication and function/mobility

- Nurse voicemail follow up at 4 weeks compared to baseline (1 week before the first injection) - Responder >30% reduction in pain score (average pain intensity on BPI).

- 2^nd injection trialled at 12 weeks regardless of response to first injection. Patients who achieve ≥30% reduction in average pain score (responders) may continue treatment every 12 weeks. Initial non-responders should be offered a second injection at 12 weeks, as evidence suggests approximately one quarter may convert to responders. Patients who do not achieve ≥30% pain reduction after two consecutive injections should be discharged from this treatment pathway and alternative management considered.

- If a responder – continued every 3 months if still fulfils criteria.

Consider applying EMLA cream where suitable - on the site of administration 1 hour before botulinum toxin A injection.

Botulinum toxin A must be administered subcutaneously by a Consultant in Pain Medicine.

Reconstitute each 100-unit vials with 4mLs of preservative free sodium chloride 0.9% to make up a final concentration of 25 units/mL.

After reconstitution, inject 0.2 mL (5 units) per site of botulinum toxin A across grid 1 – 1.5cm to the relevant painful area(s) using a suitable sterile needle (e.g. 27 – 30 gauge/ 0.30 – 0.40 mm).

Total dose per cycle = 50 – 100 units

Previous analgesic maintenance to be continued if well established and deemed effective.

Botulinum toxin should not be used alongside active treatment with capsaicin (must be > 3 months since last application) and lidocaine 5% patches.

Unopened vial: Do not store above 25 °C.

Reconstituted solution: Chemical and physical in-use stability have been demonstrated for 24 hours at temperatures between 2 – 8 °C.

From a microbiological point of view, the reconstituted product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

Consultant in Pain Medicine only

See&treat pain clinic (in conjunction with See&treat clinic leaflet) or pain injection list in theatre

Consultant only prescription and administration.

All patients will have completed a written consent form prior to proceeding with botulinum toxin A: off-label use, evidence quality, expected response rates [approximately 30-40% in BOTNEP], need for repeat injections, alternative options including strong opioids if BTX-A fails)

Botox-A is currently available in the trust for the management of chronic migraine; an extension of use has been approved at the Drug and Therapeutics Committee meeting on the 12^th of March 2026.