Title: A randomised patient-assessor blinded sham controlled trial of External non-invasive peripheral nerve stimulation for chronic neuropathic pain following peripheral nerve injury (EN-PENS trial).
Funder: Department of Health and Social Care

Abstract: Neuropathic pain is defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory nervous system (4). It is estimated that 8 in every 100 people in the UK have chronic neuropathic pain (5) and between 10-50% after many common operations (6). Neuropathic pain is challenging to manage because of the heterogeneity of its aetiology's and underlying mechanisms (7). Current management guidelines are heavily weighted on pharmacotherapy with modest outcomes (8-9). Invasive neuromodulation such as spinal cord stimulation (SCS) are considered next stage therapies when pharmacotherapy management is considered sub-optimal either due to intolerable side effects or insufficient pain relief (10). External non-invasive peripheral nerve stimulation (EN-PNS) is a neuromodulation technology where a ball shaped electrode is positioned over the injured nerve, and low-frequency stimulation (1-2Hz) is applied. This stimulation mode achieves long-lasting analgesia through a specific mechanism, preferential activation of superficial nociceptive A-delta fibres inducing long-term depression (LTD) of synaptic strength (11-13). Published clinical evidence for EN-PNS only exists in the form of our small prospective audit (14). Further research is needed to establish treatment efficacy. Primary aim: Establish whether EN-PNS is effective in chronic neuropathic pain following peripheral nerve injury (PPNI) in reducing pain intensity at 3 months after treatment start as compared to sham treatment. Secondary aims: Evaluate the impact of EN-PNS on quality of life and function. Exploratory Aims will assess: Cost-effectiveness of EN-PNS using health economic analysis (including impact on health care utilisation). Treatment impact on mood, self-efficacy, perceived impression of change. Whether in some cases EN-PNS might obviate the use of more complex surgical treatments and/or reduce medications. Plan of Investigation: We propose to conduct a randomised parallel patient-assessor blinded sham controlled trial, recruiting 76 patients with PPNI of &ge;12months duration with moderate-severe pain intensity of &ge;5 on an 11 point numerical rating scale (NRS) (0= no pain, 10 =worst possible pain). Patients will be computer-randomised (concealed) to either active or sham treatment. Both will deliver a perceivable electrical stimulation. Previous audit results did not allow us to confidently exclude long-lasting changes in pain character and pain intensity after treatment stop (14); therefore an alternative cross-over design was not considered feasible. Patient and public involvement has helped develop and refine the study design and outcomes. Once competent at self-administering EN-PNS/Sham, patients will independently continue treatment during a 3-month home loan period. This length of time is in keeping with consensus guidelines in respect to analgesic trials (1), and its appropriateness for this technology is also supported by long-term outcomes regarding EN-PNS use (Johnson et al in preparation). The primary outcome will be the average 24h pain intensity, recorded on an 11-point (0-10) NRS, averaged over the last 7 days of the home-loan period. Assessments will be made at both baseline and end of treatment, and pain diaries will be taken throughout the home-loan period. An optional choice between a 3-month treatment-extension, or swap to the other treatment arm will be offered at the end of the parallel phase, as a recruitment and retention aid. Summary of potential benefits to patients and the NHS: A positive trial would support inclusion of the EN-PNS technology into NHS practice. This research may deliver the evidence required to provide patients with an effective technology, which is non-invasive, convenient, and associated with few side effects. The research may provide the NHS with data allowing introduction of a technology, which is anticipated to result in cost savings if medications, and/or invasive treatments are reduced. If the trial outcome is negative this research will also benefit both patients and the NHS by providing data of non-efficacy.

Lay abstract: Eight percent of people in the UK are estimated to have persistent (chronic) neuropathic pain and for many there is no effective treatment. Medications are the most common treatment method but often have limited benefit or unwanted side effects. Surgical treatments such as spinal cord stimulation are then often considered. External non-invasive peripheral nerve stimulation (EN-PNS) is a form of electrical stimulation that involves placing a ball shaped electrode onto the skin, which can be easily self-administered by patients. We have found EN-PNS can provide significant pain relief for people with neuropathic pain, however there is currently no evidence from controlled studies, needed to support its use within the NHS. The study aims to establish whether EN-PNS is effective in reducing pain for persons with long-standing neuropathic pain following peripheral nerve injury when compared to sham treatment. Further aims are to assess: benefits to other commonly compromised areas such as quality of life, function and mood, whether treatment can help reduce medications and/or avoid surgical pain treatments This is a randomized, controlled trial of EN-PNS, versus sham treatment. Patients randomly receive either active or sham treatments (both active/sham EN-PNS machines will look the same, however the sham will deliver a non-effective stimulation). They will be trained to deliver their own treatment and then continue treatment for 3 months at home. Outcomes will be taken at the start and end of treatment. All participants will have the option to have 3 months active EN-PNS treatment at the end of the trial. Persons with neuropathic pain have helped develop the study and will also support study management. A positive study outcome will be taken forward to support the use of EN-PNS for persons with neuropathic pain within the NHS providing patients with a tool to help manage their pain independently.

Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: NEUROLOGICAL