Health Policy Advisory Committee on Technology Technology Brief

Transcription

1 Health Policy Advisory Committee on Technology Technology Brief High-frequency spinal cord stimulation and dorsal root ganglion stimulation for chronic pain July 2015

2 State of Queensland (Queensland Department of Health) 2015 This work is licensed under a Creative Commons Attribution Non-Commercial No Derivatives 3.0 Australia licence. In essence, you are free to copy and communicate the work in its current form for non-commercial purposes, as long as you attribute the authors and abide by the licence terms. You may not alter or adapt the work in any way. To view a copy of this licence, visit For further information, contact the HealthPACT Secretariat at: HealthPACT Secretariat c/o Healthcare Improvement Unit, Clinical Excellence Division Department of Health, Queensland Level 2, 15 Butterfield St HERSTON QLD 4029 Postal Address: GPO Box 48, Brisbane QLD [email protected] Telephone: For permissions beyond the scope of this licence contact: Intellectual Property Officer, Department of Health, GPO Box 48, Brisbane QLD 4001, [email protected], phone (07) Electronic copies can be obtained from: DISCLAIMER: This Brief is published with the intention of providing information of interest. It is based on information available at the time of research and cannot be expected to cover any developments arising from subsequent improvements to health technologies. This Brief is based on a limited literature search and is not a definitive statement on the safety, effectiveness or costeffectiveness of the health technology covered. The State of Queensland acting through Queensland Health ( Queensland Health ) does not guarantee the accuracy, currency or completeness of the information in this Brief. Information may contain or summarise the views of others, and not necessarily reflect the views of Queensland Health. This Brief is not intended to be used as medical advice and it is not intended to be used to diagnose, treat, cure or prevent any disease, nor should it be used for therapeutic purposes or as a substitute for a health professional's advice. It must not be relied upon without verification from authoritative sources. Queensland Health does not accept any liability, including for any injury, loss or damage, incurred by use of or reliance on the information. This Brief was commissioned by Queensland Health, in its role as the Secretariat of the Health Policy Advisory Committee on Technology (HealthPACT). The production of this Brief was overseen by HealthPACT. HealthPACT comprises representatives from health departments in all States and Territories, the Australian and New Zealand governments and MSAC. It is a sub-committee of the Australian Health Ministers Advisory Council (AHMAC), reporting to AHMAC s Hospitals Principal Committee (HPC). AHMAC supports HealthPACT through funding. This Brief was prepared by Benjamin Ellery, Jacqueline Parsons and A/Prof Tracy Merlin from Adelaide Health Technology Assessment (AHTA), School of Population Health, University of Adelaide.

3 Summary of findings Both high-frequency spinal cord stimulation (HF SCS) and dorsal root ganglion stimulation (DRGS) are examples of neuromodulatory technologies which are yet to be widely studied in comparative trials with large numbers of patients. The available evidence includes one randomised controlled trial (RCT) comparing HF10 therapy and traditional SCS, one crossover study comparing HF SCS (5 khz) and sham treatment, and six case series. Based on this evidence, HF SCS and DRGS have shown mostly consistent benefits in terms of pain reduction, (this applies particularly to HF10 therapy; less favourable results were observed for modalities delivering 5 khz stimulation). Outcomes from the RCT provide evidence that HF10 therapy is superior to traditional SCS with some caveats; in particular given the requirement for paraesthesia mapping with traditional SCS, neither patients nor study investigators were blinded to the treatment allocation. This introduces some risk of bias, and the results should be interpreted accordingly. The remaining evidence on HF10 therapy included smaller, non-comparative studies and is therefore less reliable. However, it is also true that SCS in various forms is often a last-line therapy for many patients by the time they receive it, and selecting an appropriate comparator to test the effectiveness of emerging SCS technologies is not straightforward; while use of traditional SCS as the comparator is clinically sensible, choice of this comparator may compromise methodological rigour in study design. On the other hand, comparison with sham treatment, as in the study conducted by Perruchoud and colleagues seems a likely alternative, but at this stage has only been performed in patients with prior favourable results using conventional SCS. 16 It is difficult to conclude whether or not patients who were treated firstly with HF SCS (5 khz) and then went on to receive sham stimulation experienced a benefit from sham that was independent of prior HF SCS. Future studies of HF SCS (across different frequency parameters) and DRGS with traditional SCS and sham treatment as the comparators are needed in patients naïve to any form of SCS to better establish the effectiveness of modified forms of SCS relative to traditional SCS and properly investigate any placebo effect. The included studies are not without other limitations: HF SCS parameters at 5 khz cannot be directly generalised to HF10 technology currently available in Australia which operates at 10 khz; the potential for a Hawthorne effect cannot be ruled out (particularly applicable to the smaller studies with only short-term follow-up); short follow-up times are a major limitation to conclusions about the long-term efficacy of neuromodulatory devices targeting pain. Both clinicians and industry have emphasised the importance of careful patient selection, including proper psychological assessment in the application of both traditional and newly emerging SCS techniques. Application of the technology needs to be carefully considered Spinal cord stimulation: July 2015 i

4 within the broad context of the pain care in Australia, which typically occurs in a fragmented fashion across different medical disciplines, with communication and collaboration lacking between different medical specialties, craft groups and other professional bodies. Open communication and inter-disciplinary cooperation across the broad area of pain management should be considered as key supports to achieve the best possible outcomes for patients from SCS technology in the future. HealthPACT Advice The evidence presented in this brief has demonstrated mostly consistent benefits for patients with neuropathic pain treated with high-frequency spinal cord stimulation or dorsal root ganglion stimulation. However, it is unclear from the current evidence base the possible role the placebo effect may play in terms of pain reduction. Appropriately designed studies including a sham treatment arm would clarify any placebo effect. In addition, HF SCS devices are considerably more expensive than conventional spinal cord stimulation devices. Therefore HealthPACT does not support investment in this technology in clinical practice at this time, however, HealthPACT recommends that the evidence be reviewed again in 24 months. Spinal cord stimulation: July 2015 ii

5 Technology, Company and Licensing Register ID Technology name Patient indication WP221 High-frequency spinal cord stimulation/ dorsal root ganglion stimulation for chronic pain Chronic pain including, but not limited to, intractable pain Description of the technology Spinal cord stimulation (SCS) has been used for the treatment of a variety of pain conditions for more than 40 years 1, 2, especially neuropathic pain conditions such as complex regional pain syndrome (CRPS) 3 and failed back surgery syndrome (FBSS) 4. In more recent years, high-frequency (HF) SCS 5, using stimulation in a frequency range beyond human perception (1-10 khz) 6, and dorsal root ganglion stimulation (DRGS) 7 have emerged as modified techniques that avoid some of the undesirable effects associated with traditional SCS. These techniques may also be considered for neuropathic pain conditions when patients/ physicians find the results of traditional SCS to be unsatisfactory. 8, 9 Both traditional SCS and newer variations on the technology have many features in common but also include some important differences. These are explained in detail below. Spinal cord stimulation Spinal cord stimulation (SCS) is a neuromodulatory technique that refers to the treatment of pain by epidural electrical stimulation of the dorsal columns of the spinal cord (see Appendix A, page 34, for background on spinal cord anatomy). Historically referred to as dorsal column stimulation, the technique involves the surgical placement of electrodes over the dorsal column to modulate pain generation or processing. The goal of traditional SCS (typical frequency range Hz 6 ) is to replace the sensation of pain with paraesthesia, sensations often described as tingling and buzzing. These sensations are generally considered to be acceptable to those patients for whom the treatment produces significant relief from chronic pain. Traditionally, SCS has been used for neuropathic or mixed neuropathic/ nociceptive pain. It has also been used to successfully treat ischaemic pain (see Appendix B, page 37, for descriptions of pain types). 10, 11 There are some types of pain that are suited to treatment with neuromodulatory devices and some which are not. 10 It is beyond the scope of this Brief to consider the application of pharmacological neuromodulatory agents; only information pertinent to recent developments in devices which use electrical stimulation of the SC (i.e. HF SCS) and neural structures within the spinal column (i.e. DRGS) are considered. The proposed mechanisms for the observed effects of SCS and other neuromodulatory techniques such as DRGS and HF SCS are complex and not yet fully understood. The basic premise for the concept of SCS was the gate control theory published by Melzack and Wall Spinal cord stimulation: July

6 in They proposed that pain occurs when the stimulation of small peripheral fibres (pain nerves) opens the gate in the dorsal column of the spinal cord, thereby transmitting pain sensation to the brain. This theory assumes that electrical stimulation of the spinal cord preferentially recruits large fibres and leads to closure of the gate on smaller fibres, blocking pain transmission to the brain. However, the gate control theory does not explain why neuropathic pain is selectively targeted while nociceptive pain is mostly spared. Neither does the theory inform why some patients report that pain does not return immediately after stimulation is discontinued. Zhang and colleagues provide a comprehensive discussion of gate control theory and other theoretical models which aim to explain the mechanisms underpinning SCS. 13 Generically, SCS devices consist of electrode leads, an extension cable, a pulse generator and a programmer. The leads are either percutaneous, paddle or hybrid percutaneouspaddle leads. Percutaneous and paddle leads typically have four to 16 electrodes. Percutaneous leads are introduced into the epidural space via a Tuohy needle, while placement of paddle leads requires open surgery to cut or remove part of the vertebra (laminotomy/ laminectomy) in order to access the epidural space. Table 1 Suggested lead placement for traditional SCS targeting selected body sites 6 Site of pain, condition Lead placement, relative to spinal midline and levels of vertebrae Lower extremity One lead midline and one lateral to the midline Axial back pain One lead midline and one either side of the midline Posterior occipital region C2 Upper extremity Between C2 and C5 Hand C5, C6 Chest wall, angina T1 to T4 (one lead midline, one more laterally) Thigh and knee T9 to T10 Lower leg and ankle T10 to T12 Foot Between T11 and L1 Sole of foot L5 or S1 nerve root (though difficult in practice) Note: Letters C, T, L, S refer to the sections of the vertebral column. Numbers, e.g. C1 refer to the first cervical vertebra, etc. C, cervical; T, thoracic; L, lumbar, S, sacral Spinal cord stimulation: July

7 Traditional SCS targets specific areas of the body based on the placement of the electrode leads. General guidelines for placement are shown in Table 1. The final positions are adjusted from the suggested starting points based on the patient s feedback. This is referred to as paraesthesia mapping. For effective pain relief, traditional SCS requires that paraesthesia is induced in the area corresponding to the area where the patient is experiencing pain. Sedation, rather than general anaesthesia is a requirement of the procedure, as the patient is required to give feedback to the surgeon to ensure best possible placement of the leads. 6 Prior to SCS therapy, the patient with chronic pain will undergo a screening trial (usually 3 to 8 days in duration) with placement of temporary electrodes and an external pulse generator. The trial provides an indication of technical success (adequate paraesthesia coverage), clinical success (sufficient pain relief) and the patients tolerance of the treatment. 11 Paraesthesia coverage depends on which afferent nerves are stimulated. In clinical practice, the SCS electrodes are placed with several millimetres of cerebral spinal fluid and dura separating them from the pial surface (the innermost meningeal layer). This enables easy recruitment of lateral structures including the entering dorsal roots, but results in limited, focal paraesthesia coverage. Traditional SCS may also include unwanted motor recruitment and discomfort due to changing intensity of paraesthesia, particularly when patients assume 11, 14 certain positions (e.g. supine vs upright). High-frequency spinal cord stimulation A main advantage claimed for HF SCS is the provision of analgesia without the hallmark paraesthesia observed in traditional SCS. 5, 6, 15, 16 Typically, HF SCS is delivered at a frequency range (1-10 khz) at least 10-fold higher than traditional SCS ( Hz). 6 The SENZA system (Nevro Corp, Menlo Park, CA), which is now available in Australia and Europe, provides HF10 therapy at 10 khz (see Figure 1). 6 Another claimed advantage of HF SCS is that it may target axial back pain more effectively than traditional SCS. 5 The implantation of the leads/ electrodes and pulse generator for HF SCS are identical to the protocols used for traditional SCS with one exception; leads are placed using only anatomical landmarks rather than adjustments made based on patient s feedback, as paraesthesia mapping is not undertaken. Without the requirement for patient feedback, placement of HF SCS components can be done under general anaesthesia, rather than under partial sedation as is used in the implantation of traditional systems. a The two electrode leads are placed in a staggered fashion to maximise coverage. For patients experiencing back and/ or leg pain, the source of pain corresponds to the dorsal column range between T9 and T11; to target pain within this range the tip of the first electrode is placed at T8 and the second electrode tip is placed at T9. 6 a Personal communication with pain specialist, 17 March Spinal cord stimulation: July

8 Patient remote Charger Leads IPG Figure 1 The SENZA system for HF10 therapy showing implantable pulse generator (IPG) with percutaneous electrode leads attached, charger and patient remote. b Dorsal root ganglion stimulation Dorsal root ganglion stimulation (DRGS) may be targeted to primary low back pain and isolated foot pain which may be difficult to treat using traditional SCS due to limited stimulation of the deeper tracts of the spinal cord that cover the sacral dermatomes, including those of the feet. 6 The available literature also indicates that CRPS, radiculopathy, and post-surgical pain in selected areas are common targets of DRGS. 6, 17 Electrode placement for DRGS differs substantially from the placement of electrodes for SCS. In DRGS the electrodes are initially introduced the same way as in SCS but then steered laterally into the neural foramen to stimulate the DRG. 6 The proposed advantage of DRGS is the avoidance of unpleasant sensations during positional changes and a reduction in unwanted changes in paraesthesia coverage. Despite contact with Spinal Modulation, the provider of the Axium stimulator for DRGS, we did not secure express permission to include an image of the device in this Brief. c Company or developer Two distinct commercially available devices used for HF SCS and DRGS were identified. The SENZA system for HF10 therapy is manufactured by Nevro Corporation (Menlo Park, CA), and distributed in Australia by Emergo Asia Pacific Pty Ltd. Spinal Modulation Incorporated, recently acquired by St Jude Medical (Minnesota, USA), offers the Axium system for DRGS. Reason for assessment Traditional SCS is already established in Australia. New iterations of the technology such as HF SCS and DRGS are claimed to overcome a number of unwanted side effects typically associated with the traditional. Based on the burden of morbidity due to chronic pain/ back pain the cost impact of these new SCS technologies has the potential to be high. b SENZA, HF10, Nevro, and the Nevro logo are trademarks of Nevro Corp. Images of the Nevro system are reproduced with the permission of Nevro Corp. c The request was by on 28 April 2015 and a subsequent to follow up was sent on May , without success. Spinal cord stimulation: July

9 Stage of development in Australia Yet to emerge Experimental Investigational Nearly established Established Established but changed indication or modification of technique Should be taken out of use Australian Therapeutic Goods Administration approval Yes No ARTG number(s): (SENZA implantable pulse generator) (Axium implantable pulse generator) Not applicable Licensing, reimbursement and other approval The SENZA system is listed on the Australian Register of Therapeutic Goods (ARTG) and is CE marked for compliance in the European Union (EU). It has recently received approval from the US Federal Drug Administration (FDA). 18 The EU and Australia have cleared the SENZA system for compatibility with magnetic resonance imaging (MRI) at 3.0 Tesla. 19 For patients implanted with traditional SCS systems, MRI has usually been considered a contraindication as it poses a significant risk of damage to the inner circuitry of neurostimulator devices. Some SCS devices (e.g. those manufactured by Medtronic Inc) are considered compatible with 1.5T MRI under certain conditions. 20, 21 There are several ARTG listings related to the Axium system, which comprises an implantable pulse generator (IPG), electrode leads and several external components; the various configurations of leads and the other components have separate ARTG numbers. Technology type Technology use Device Therapeutic Patient Indication and Setting Disease description and associated mortality and morbidity Pain caused by back problems is very common. Back problems can be caused by injury, medical conditions such as arthritis, or general degeneration associated with ageing. Additionally, some risk factors contribute to the likelihood of experiencing back problems, such as smoking and being overweight. 22 The Australian Institute of Health and Welfare (AIHW) reports that around three million Australians have back problems, based on selfreported data. 23 Although anybody can experience back problems, they are more common in older people, evenly distributed between males and females and more common in lower Spinal cord stimulation: July

10 socioeconomic status groups. 24 Back pain is associated with considerable impact on quality of life, including inability to work or carry out daily activities. Globally, low back pain accounted for 3.2 per cent of disability adjusted life-years (DALYs) and 10.5 per cent of years of life lost due to disability in the Global Burden of Disease Study conducted in It was ranked sixth globally for burden in this study, and first in Australasia, including Australia and New Zealand. 25 In New Zealand, the Health Survey in 2013/14 found that one in five people experienced chronic pain. 26 Back disorders accounted for 2.8 per cent of DALYs in 2006 and were ranked seventh in conditions contributing to DALYs. 27 Chronic pain is such a serious issue in Australia that a National Pain Strategy has been developed and endorsed by professional and consumer groups. The strategy highlights that chronic pain is common, undertreated, and can lead to debilitating and negative effects on mental health, social and emotional wellbeing and socioeconomic circumstances. The Strategy aims to have pain recognised as a public health priority, to help individuals understand and manage their pain, to encourage evidence based practice amongst better skilled care providers and to provide better access to interdisciplinary care, alongside health service quality improvement and research. 28 Costs associated with chronic pain were found to be in excess of $34 billion in 2007, including direct and indirect costs such as lost productivity, health system and informal care costs and welfare costs. 29 AIHW reports that $1.2 billion was spent on inpatient and out of hospital costs and prescription pharmaceuticals for back pain in the financial year; the gap between these two figures indicates that costs associated with back pain are primarily borne by other parts of the health system or community, through direct and indirect costs. 30 Treatment for back pain can take many forms, including physical rehabilitation, patient education, medicinal pain management and surgery. Much of the care for back pain is undertaken in general practice and back problems are among the most commonly managed conditions in primary care, with the AIHW reporting that there were 3.7 million general practitioner consultations about back pain in In the same year, there were 104,350 hospitalisations with back pain as the principal diagnosis in Australia. 32 The Australian National Pain Strategy states that less than 10 per cent of people with noncancer chronic pain receive effective care, and estimates that over 80 per cent of people with chronic pain could be helped by existing treatments. 33 It also cautions that: current reimbursement and insurance arrangements are such that outmoded treatments with limited evidence of efficacy, including some invasive procedures, are often favoured over less invasive treatments with evidence of efficacy. Some treatments provided are not based on evidence, but funding. This risks overtreatment by Spinal cord stimulation: July

11 inappropriate methods and therefore additional costs for suboptimal outcomes. In terms of current use of implantable SCS devices, according to the Medicare Benefits Schedule (MBS) in , there were a total of 3,045 private claims related to the implantation of neurostimulators and placement of leads, 3,656 claims related to adjustment of neurostimulators and leads, and 1,333 claims related to the removal of neurostimulators and leads. 34 Current MBS items for neurostimulation are shown in Table 2. The listed fees relate to the surgical placement and not the cost of the neurostimulation system; these may be reimbursed by some health insurers, or covered by workers compensation or existing arrangements through the Department of Veteran s Affairs (DVA). If the patient is ineligible for coverage under any of these arrangements, the device cost is an out-of-pocket cost borne by the patient. d Speciality Technology setting Anaesthetics, pain relief; neurology and neurosurgery; orthopaedics; rehabilitation and disability Specialist hospitals and pain management clinics Impact Alternative and/ or complementary technology Additive and substitution: Technology can be used as a substitute in some cases, but may be used in combination with current technologies in other instances The newer neuromodulation techniques for pain relief, including HF SCS and DRGS, are predominantly intended to be used in patients for whom standard medical management has failed. They may also replace established forms of SCS, or be considered as an option where standard SCS is not effective. In other words, they are most likely to be used for patients for whom pain is considered refractory. These new technologies may also be used in patients for whom traditional SCS has been clinically effective but with side effects that are considered unacceptable (e.g. recruitment of motor fibres which prevents use of traditional SCS devices while sleeping and driving, and unpleasant sensations of electric shock and jolting which can occur during positional changes). d Personal communication with pain specialist, 17 March Spinal cord stimulation: July

12 Table 2 MBS items related to the implantation, removal and reprogramming of neurostimulators for chronic intractable neuropathic pain or refractory pain due to angina pectoris; items include placement of components used in spinal cord stimulation and peripheral nerve stimulation 35 Category 3 - THERAPEUTIC PROCEDURES EPIDURAL LEAD, percutaneous placement of, including intraoperative test stimulation, for the management of chronic intractable neuropathic pain or pain from refractory angina pectoris, to a maximum of 4 leads Multiple Services Rule (Anaes.) Fee: $ Benefit: 75% = $ ELECTRODES, epidural or peripheral nerve, management of patient and adjustment or reprogramming of neurostimulator by a medical practitioner, for the management of chronic intractable neuropathic pain or pain from refractory angina pectoris - each day Multiple Services Rule (Anaes.) Fee: $ Benefit: 75% = $ % = $ NEUROSTIMULATOR or RECEIVER, subcutaneous placement of, including placement and connection of extension wires to epidural or peripheral nerve electrodes, for the management of chronic intractable neuropathic pain or pain from refractory angina pectoris Multiple Services Rule (Anaes.) (Assist.) Fee: $ Benefit: 75% = $ NEUROSTIMULATOR or RECEIVER, that was inserted for the management of chronic intractable neuropathic pain or pain from refractory angina pectoris, removal of, performed in the operating theatre of a hospital Multiple Services Rule (Anaes.) Fee: $ Benefit: 75% = $ % = LEAD, epidural or peripheral nerve that was inserted for the management of chronic intractable neuropathic pain or pain from refractory angina pectoris, removal of, performed in the operating theatre of a hospital Multiple Services Rule (Anaes.) Fee: $ Benefit: 75% = $ LEAD, epidural or peripheral nerve that was inserted for the management of chronic intractable neuropathic pain or pain from refractory angina pectoris, surgical repositioning to correct displacement or unsatisfactory positioning, including intraoperative test stimulation, not being a service to which item 39130, or applies Multiple Services Rule (Anaes.) Fee: $ Benefit: 75% = $ EPIDURAL LEAD, surgical placement of one or more by partial or total laminectomy, including intraoperative test stimulation, for the management of chronic intractable pain or pain from refractory angina pectoris Multiple Services Rule (Anaes.) (Assist) Fee: $ Benefit: 75% = $ Current technology The current standard of care for chronic pain relies heavily on pharmacological treatment. This includes opioids, non-steroidal anti-inflammatory drugs (NSAIDS), antidepressants, anticonvulsants/ anti-epileptics and other analgesic therapies, nerve blocks and epidural Spinal cord stimulation: July

13 corticosteroids. Also included in the current standard of care are physical and psychological rehabilitative therapies. For chronic back pain where injury or degeneration of vertebral structures has occurred, or there is a deformity, surgery may be considered appropriate and some patients seek chiropractic treatment for back problems. 4, 36, 37 In some instances, chronic pain of the back, limbs, trunk or ischaemic pain associated with angina pectoris may be targeted with established types of neurostimulation (either traditional SCS or PNS), and the surgical procedures related to these treatments have been funded on the MBS since 2004 (Table 2). International utilisation Country Level of Use Trials underway or completed Limited use Widely diffused Australia Belgium Netherlands Switzerland UK USA Diffusion of technology in Australia Traditional SCS is an established technology in Australia; HF SCS and DRGS are recent evolutions of the technology which are being clinically trialled in a number of pain centres around Australia, including the Hunter Pain Clinics (Newcastle, New South Wales) and Metro Spinal Clinics (Melbourne, Victoria). e Cost infrastructure and economic consequences In Australia, the pricing of all components used for any form of SCS is governed by the Prostheses List Advisory Committee. This includes all implantables, associated external componentry and kits comprising equipment essential for the surgical placement of leads and implantable pulse generators (IPGs). The pricing is largely uniform across companies, reflecting the intended purpose of each component. The price of leads can vary due to the number of stimulation contact points required within each system (range 1-32 contacts). SCS systems produced by several companies are listed as no-gap prostheses on the Prostheses List. 38 This means that each product is listed with a single benefit, and assuming that conditions for an insured patient are met, health insurers are legally required to pay this benefit. This is in contrast to gap-permitted prostheses which have minimum and e Details of these clinical trials are available from the Australian and New Zealand Clinical Trials Registry. Spinal cord stimulation: July

14 maximum benefits listed. For these prostheses, private health insurers are required to pay at least the minimum benefit. f Table 3 shows a breakdown of costs for the SENZA system, including two leads each with eight contact points. The full Prostheses List (Part A) 38 should be referred to for details of costings based on systems comprising leads with fewer or more contacts. Systems with more lead contacts attract a higher minimum rebate. As shown in Table 3 the supplier of the technology may discretionally supply leads for an initial trial stimulation at reduced cost, but the insurer is still required to pay the minimum benefit determined by the billing code. Where this occurs, the surplus portion of the rebate is presumably absorbed by the treating private hospital/ pain clinic. Currently MBS items do not distinguish between trial lead placement procedures and permanent lead placement procedures, in terms of the service fee. Trial leads are not reusable and so when they are removed they are replaced with permanent leads if the doctor and/ or patient considers that an acceptable level of pain reduction has been achieved. g f In cases where the treating doctor considers that a gap-permitted prosthesis is the most clinically suited option for a patient, the doctor should disclose appropriate clinical and financial information, allowing the patient to give fully informed consent prior to any procedure. Guidelines are available at guidelines.pdf g Personal communication with Spinal Modulation area director, in person meeting 28 April Spinal cord stimulation: July

15 Table 3 Cost break-down and total cost for implantables and accessory componentry used in trial and permanent implantation of the SENZA system for HF10 therapy (courtesy of Nevro Corp). h Part Description Billing Code as per Prostheses List Price Trial leads (x2) LEAD B LEAD B Blue Lead Kit, 70cm with 5mm spacing Blue Lead Kit, 70cm with 5mm spacing ER006 $995 ER006 $995 Total $1,990 Permanent leads (x2) LEAD B LEAD B Blue Lead Kit, 70cm with 5mm spacing Blue Lead Kit, 70cm with 5mm spacing ER006 $4,230 ER006 $4,230 Total $8,460 All components for permanent procedure NIPG1500 IPG Kit ER005 $22,000 LEAD B LEAD B Blue Lead Kit, 70cm with 5mm spacing Blue Lead Kit, 70cm with 5mm spacing ER006 $4,230 ER006 $4,230 ACCK1015 Insertion Needle Kit, 6 (15cm) ER037 $168 ACCK5000 Spare Lead Anchor Kit ER040 $168 PTRC1000 Patient Remote Kit ER009 $1,400 CHGR1000 Charger Kit ER008 $1,346 Total $33,542 IPG, implantable pulse generator All costings have been verified by the evaluator as consistent with Part A of the Prostheses List with the exception of lead prices displayed for trial implantation. This represents a discounted price relative to the rebate determined by the Prostheses List Billing Code. Costings do not include fees for professional services rendered by the treating doctor(s), anaesthetist or hospital fees. Prices shown are in Australian dollars. h Personal communication with Nevro representative (health economics & reimbursement), 29 April Spinal cord stimulation: July

16 The training requirements for HF SCS and DRGS are in part addressed directly by the providers of these technologies. Some of the safety issues common across the studies included in this Brief may in part be related to surgeon experience with SCS. Spinal Modulation also work with surgeons and other medical professionals in cadaver workshops, thereby enabling the development of practical skills required to implant leads for DRGS. i A representative of Nevro reported that implantation procedures for HF10 therapy are virtually identical to traditional SCS, and as such, surgeons familiar with the older technology would have no significant learning curve in adapting to working with HF technology. j Like Spinal Modulation, Nevro provide instructional material for health care professionals on the safe implantation and removal of their neurostimulation technology. In addition to manuals and printed instructional materials, Nevro have indicated k that they provide the following physician training resources: in-servicing, i.e. Nevro representatives are available in person to instruct healthcare professionals on labelling, clinical data, product kits and their contents; preceptorships in which physicians are given opportunities to observe the use of HF10 therapy at experienced centres; seminars providing ongoing professional development to discuss the latest clinical data and other educational topics on HF10 therapy; Nevro-sponsored plenary sessions at congresses on pain and neuromodulation; cadaver workshops for physicians who are new to SCS in general and wish to develop skills for implant procedures related to SCS (these are undertaken by Nevro directly or in conjunction with medical societies). Ethical, cultural, access or religious considerations Under current arrangements, SCS is primarily accessed through the private health system. The immediate outlay cost of an SCS system, including HF SCS and DRGS, would be significant for patients without private health insurance and who do not qualify for reimbursement under workers compensation or DVA arrangements. Spinal cord stimulation technologies are typically accessed through specialist pain clinics. This may present an issue for Australians living in rural and remote areas, as they may have to travel long distances in order to obtain treatment. This may be particularly relevant if adjustment of the stimulation parameters or revision of lead placement or removal is required subsequent to the implantation procedure. Some patients may seek accommodation near the pain centre during their trial period, thereby minimising the need i Personal communication with Spinal Modulation area director, in person meeting 28 April j Personal communication with Nevro representative (health economics & reimbursement), telephone conversation 2 April k Personal communication with Nevro representative (health economics & reimbursement), 17 April Spinal cord stimulation: July

17 to return for the permanent implantation procedure. However, for rural and remote patients with chronic pain, one or two weeks away from home, without the regular supports and services they may receive, is potentially an impediment to these patients seeking any type of SCS. Evidence and Policy Safety and effectiveness High-frequency spinal cord stimulation HF10 therapy specific Kapural et al reported on a randomised controlled trial (RCT) using the SENZA system that was conducted in ten centres in the US. 39 The RCT enrolled 241 patients with, a) chronic leg and back pain refractory to conservative therapy l for a minimum of three months; b) average back pain intensity of 5 or greater on a Visual Analogue Scale (VAS; range 0-10 where 0 is indicative of no pain and 10 indicates the worst pain); c) average leg pain of 5 or greater on VAS; d) Oswestry Disability Index (ODI) m version 2.1 score of 41 to 80 out of 100; d) assessment by study investigators indicating fitness for surgery. Subjects were excluded if they had an active disruptive psychological or psychiatric disorder or other known condition significant enough to impact perception of pain, inability to comply with the intervention, mechanical spine instability based on flexion and extension films of the lumbar spine or prior experience with SCS. Of the 241 patients enrolled, 198 were randomised to undergo either HF10 therapy (101 patients) or traditional SCS (97 patients). The study included a 14- day trial phase for both the HF10 therapy and traditional SCS groups; during the trial a nonpermanent external pulse generator was used to stimulate the spinal cord of subjects at 10kHz and standard frequencies, respectively. Patients who showed adequate treatment response during the trial phase ( 40% pain reduction on VAS) were then eligible to proceed to implantation with a permanent IPG device. Among subjects randomised to HF10 therapy and traditional SCS, 90 and 81 subjects were implanted with permanent devices, respectively. Final analyses at 12-month follow-up were reported based on these 171 permanently implanted patients. n These results are summarised in Table 4. Note that for the permanent phase of the trial, response was defined as a VAS rated pain reduction 50%, in contrast to the criterion for proceeding to permanent implantation ( 40% pain reduction). Patient satisfaction was also assessed, with 55.5 and 32.3 per cent of patients indicating that they were very satisfied with HF10 therapy and traditional SCS, respectively. l Including pain medications, physical therapy, spinal injections, pharmacological and behavioural treatments. m 0-20 = minimal disability, = moderate disability, = severe disability, = crippling back pain, = patients are either bed-bound or have an exaggeration of their symptoms. n Analyses by intention-to-treat, per protocol and permanent implant populations at three months all indicated non-inferiority of HF10 therapy compared to traditional SCS; no notable differences in treatment response were observed between these analyses according to population. As per the methods set out by the authors, the final analyses were conducted to test for superiority based on the permanent implant population only. Spinal cord stimulation: July

18 Table 4 Results for RCT comparing SENZA HF10 therapy and traditional SCS o Outcome Intervention, HF SCS n=90 Treatment arm Comparator, traditional SCS n=81 Relative ratio [95%CI] p-value (between group difference) Back pain score, mean VAS±SD Baseline 12 months 7.4± ±NR 7.8± ±NR NA NA 0.33 <0.001 Leg pain score, mean VAS±SD Baseline 12 months 7.1± ±NR 7.6± ±NR NA NA 0.34 <0.001 Back pain responders ( 50% pain reduction), % [1.2,1.9] <0.001 Leg pain responders ( 50% pain reduction), % 78.7* 51.3* 1.5 [1.2,2.0] <0.001 Back pain remitters (post-therapy pain score 2.5 on VAS), % [1.3,2.7] <0.001 Leg pain remitters (post-therapy pain score 2.5 on VAS), % [1.2,2.1] <0.001 Patients with study-related SAE, % NA 0.37 Deaths, n 0 1** NA NA Patients with study-related non-serious AE, n (%) Overall Implant site pain Uncomfortable paraesthesia Lead migration requiring surgical revision 28 (27.7) NR (11.9) - NR (3.0) 32 (33.0) NR (10.3) NR (11.3) NR (5.2) NA NA NA NA 0.44 NR NR NR 0.49 CI, confidence interval; HF, high-frequency; NA, not applicable; NR, not reported; SAE, serious adverse events; SCS, spinal cord stimulation; SD, standard deviation; VAS, Visual Analogue Scale (scale 0-10 where, 0 = no pain and 10 = worst pain imaginable) *Nevro, the trial sponsor, was contacted in order to confirm that the results for leg pain response, being identical to those for back pain response, have been reported correctly. Nevro confirmed the accuracy of these results. **Due to myocardial infarction and presumably not study-related; it is unclear whether the investigators considered the death as being study-related or not. There appears to be some disagreement in the field regarding whether lead migration requiring surgical revision is a serious adverse event or not, as indicated elsewhere in this Brief. The authors reported lead migration requiring revision specifically in the results section on non-serious adverse events. o Personal communication, Nevro Corp, 16 April Spinal cord stimulation: July

19 Kapural and colleagues reported that due to practical considerations (i.e. unlike HF10 therapy, traditional SCS produces paraesthesias which must be appropriately targeted to the correct area during surgery) neither the study subjects nor the investigators were blinded to the assigned treatment group. 39 As this introduces a risk of bias, the study results should be interpreted accordingly. Furthermore, there is some potential for confounding as the study investigators were permitted to adjust subjects pain medication use after device activation, although the study protocol did instruct the investigators not to increase pain medication above baseline levels. However, given that more patients receiving HF10 therapy reduced or eliminated opioid use compared to traditional SCS patients, it appears unlikely that differences in opioid use contributed to the finding that HF10 therapy was superior. The authors reported that their study protocol was based on best practice guidelines for comparative efficacy trial design, referencing relevant publications produced by the Group for Consolidated Standards of Reporting Trials (CONSORT) and the US Federal Drug Administration (FDA). 40, 41 In addition, three published studies reporting on the effects of HF10 therapy were identified for inclusion in this Brief. Al-Kaisy et al 42 reported on the outcomes of HF10 therapy using the SENZA system (Nevro Corp, Menlo Park, CA). A series of 83 patients (mean age 50.8±9.2 years) with chronic, intractable pain of the low back and legs were recruited from two pain centres in Belgium and the UK. Patients were only included if they had failed at least six months of conventional treatment, i.e. pharmacological, physical and radiofrequency therapy, and/ or epidural injections. After a baseline evaluation, patients underwent a trial period with lead placement via the percutaneous route for 14 to 30 days, based on each pain centre s standard practice. An external trial stimulator was used during this period to deliver a current at 10 khz. Patients then received an IPG if the trial was considered successful, defined as at least 50 per cent reduction in pain as determined by their score on VAS. Of the 82 patients enrolled, 72 were considered to have had a successful trial of the SENZA system and underwent permanent implantation. Sixty-five patients (mean age 50.6±9.1 years) out of the 72 implanted patients (90%) were included in the final analysis at 24 months of follow-up. 42 Baseline and follow-up data included VAS ratings for back and leg pain, sleep disturbance (subjective number of awakenings per night), Oswestry Disability Index (ODI) and opioid use. Patients were asked to rate their satisfaction with HF10 therapy on a 5-point Likert scale and whether they were satisfied with the treatment and would recommend the treatment to others. The results are summarised in Table 5. Spinal cord stimulation: July

20 Table 5 Effectiveness of SENZA system in patients with chronic low back and leg pain after six and 24 months treatment 42 Outcome Baseline 6-month follow-up 24-month follow-up p (difference from baseline to 24 months) Back pain VAS score, mean±sd 8.4± ± ±0.3 <0.001 Leg pain VAS score, mean±sd 5.4± ± ±0.3 <0.001 ODI score, mean±sd 55±1 NR 40±2 <0.001 No. subjective sleep disturbances per night, mean±sd 3.7±0.4 NR 1.4±0.2 <0.001 Proportion of patients taking opioids, % Dose of oral morphine equivalents per patient, mean (mg/day) 86 NR 57 < NR 27 <0.001 Proportion of patients satisfied with treatment, % NA NR 88 NA NA, not applicable; NR, not reported; ODI, Oswestry Disability Index (0-20 = minimal disability, = moderate disability, = severe disability, 61-80: crippling back pain, = patients are either bed-bound or have an exaggeration of their symptoms); SD, standard deviation; VAS, Visual Analogue Scale (scale 0-10 where, 0 = no pain and 10 = worst pain imaginable) Seventeen per cent of patients included in the analysis by Al-Kaisy et al 42 had undergone conventional SCS (failed SCS). Thus the majority of patients were naïve to SCS before the study period, meaning that the results for the majority of patients (83%) are independent of any previous experience with SCS. While the reductions in pain reported by Al-Kaisy et al 42 are statistically and clinically significant, it is unknown if these results are superior to placebo (no sham comparison performed). Table 6 summarises the occurrence of serious adverse events attributed to treatment using the SENZA system. The most common events were pocket pain and lead migration which the authors reported to be the most common adverse events associated with traditional SCS. At 24 months, no patients displayed any neurological deficit or dysfunction attributable to prolonged treatment with HF10 therapy. Spinal cord stimulation: July

21 Table 6 Safety outcomes for SENZA system in patients with chronic low back and leg pain 42 Device-related serious adverse events No. events No. patients with event (%) Pocket pain 7 7 (8.4) Wound infection* 5 5 (6.0) Lead migration 4 4 (4.8) Loss of therapy effect 2 2 (2.4) Suboptimal lead placement** 1 1 (1.2) Skin erosion 1 1 (1.2) *Four infections occurred during the trial phase and one in the permanent implant phase. **Occurred in the trial phase. Al-Kaisy et al 43 also reported on the results from a UK case series (n=15 patients) using the SENZA system for refractory neuropathic pain of the upper and lower limbs. All included patients had failed conventional therapies including analgesic medications, tricyclic antidepressants, anticonvulsants, opioids, transcutaneous electrical nerve stimulation, topical treatments (lidocaine plasters, capsaicin cream), as well as rehabilitative and cognitive-behavioural therapies. This study diverted from the usual practice for implanting HF10 IPGs and leads in that paraesthesia mapping was conducted in the phase with trial lead placement, to enable traditional SCS frequency parameters to be used in the event that HF10 therapy failed. If at least 80 per cent paraesthesia coverage of the painful area was obtained in the trial phase under traditional 50 Hz stimulation, patients then went on to a trial of 10 khz SCS (n=11 patients). For the 10 patients who experienced success ( 50% pain relief) with the 10 khz trial, a permanent IPG was implanted and follow-up conducted for six months. Patients treated for lower limb pain had electrodes positioned between the T8 and T12 vertebrae; for upper limb pain, placement was between C2 and C7. Reported outcome measures were a numeric scale rating for pain, the Brief Pain Inventory, Pain Catastrophizing Scale and European Quality of Life-5 Dimensions index. The results are shown in Table 7. Spinal cord stimulation: July

22 Table 7 Effectiveness of SENZA system for refractory neuropathic pain of the upper and lower limbs after 6 months treatment 43 Outcome Baseline 1-month follow-up 3-month follow-up 6-month follow-up p (difference from baseline to 6 months) NRS pain score, mean±sd 8.2± ± ± ±1.7 <0.05 BPI score, mean±sd 57.6± ± ± ±14.5 NR PCS score, mean±sd 33±11 7±7 7±5 7±6 NR EQ-5D change, % NA NR Proportion of patients rating therapy as excellent or good, % NA NA NA 90 NA Proportion of patients who would recommend the procedure to others, % NA NA NA 90 NA BPI, Brief Pain Inventory (measures pain intensity and impact of the pain on patient s life on a scale with higher score indicating more pain and/ or larger impact); EQ-5D, European Quality of Life-5 Dimensions questionnaire (higher score indicates better quality of life); NA, not applicable; NR, not reported; NRS, numeric rating scale (0 = no pain, 10 = worst pain imaginable); PCS, Pain Catastrophizing Scale (measures catastrophic thinking related to pain; range 0-52 where increasing score indicates higher degree of catastrophic thinking related to pain) In reporting safety outcomes, the authors stated that: one patient developed an infection during the trial phase, requiring removal of the leads with reimplantation scheduled in six months; two patients required surgical revision following lead migration; three patients experienced transient pain at the site of the IPG; no neurological events occurred in relation to the SENZA system. The small number of patients included in this series precludes drawing firm conclusions about the treatment of refractory upper and lower limb pain using the SENZA system; the authors acknowledged that larger observational studies and/ or randomised controlled trials are required. Patients underwent a phase in which conventional SCS was used just prior to HF10 therapy, and therefore it cannot be excluded that the observed treatment effects are in part attributable to SCS at conventional frequency. Spinal cord stimulation: July

23 A series of patients with chronic axial back pain (n=25) recruited from five US centres reported on the efficacy and safety of an investigational 10 khz SCS device. 44 The predominant cause of the back pain was FBSS (21 patients). Tiede and colleagues followed a study protocol similar to methods described by Al-Kaisy et al, 42, 43 however, only an external trial device was used and no permanent implantation was undertaken. Patients first underwent a period of four to seven days treatment with a device that used conventional frequency parameters to determine response to SCS. Following this, patients went on to the second stage of trial treatment with an external HF10 device connected to their leads. Leads were placed between the T8 and T11 vertebrae. Twenty-four patients were included in the final analysis after a follow-up of four days. Overall pain and back pain as measured on VAS (data on back pain available for 18 patients only), adverse events, and patient preference were reported. Efficacy results are summarised in Table 8. The authors reported that five patients experienced adverse events, none of which were considered serious. Notably, in contrast to Al Kaisy et al, 42 who considered lead migration as a serious complication, Tiede and colleagues did not consider lead migration to be serious, but noted this occurrence in two patients. p The other adverse events were undesirable sensations which occurred in two patients but resolved with device reprogramming or without intervention, and muscle cramps/ spasms in one patient which also resolved uneventfully. 44 Table 8 Efficacy of investigational HF SCS in patients with axial back pain after four days follow-up 44 Outcome Baseline Follow-up* (4 days) p (difference from baseline to follow-up) Overall pain VAS score, mean±sd 8.7± ±0.8 <0.001 Back pain VAS score, mean±sd 8.1± ±0.9 <0.001 Proportion of patients who preferred HF to conventional SCS, % NA 88 NR SD, standard deviation; NA, not applicable; NR, not reported; VAS, Visual Analogue Scale (0 = no pain, 10 = worst pain imaginable) *The results of HF SCS cannot be considered to be independent of a potential residual effect of the initial trial period using conventional frequency SCS parameters. The following study limitations were noted by the authors: short trial duration; small number of patients; lack of control group and randomisation; inability to rule out the p Nevro Corp. expressed ( 11 May 2015) that lead migration does not necessarily constitute a serious adverse event, but that lead migration would be considered serious in instances requiring revision and rehospitalisation. Logically, lead migration could have an impact on the effectiveness of the therapy, but followup data to confirm or refute such a conclusion are lacking. Spinal cord stimulation: July

24 Hawthorne effectq; VAS scores rely on patient recollection and are subject to over/ underestimation; the preference for HF therapy is potentially related to the order in which treatment was received. In addition, confounding due to the utilisation of conventional frequency SCS and HF10 therapy in the same group of patients may have occurred, and a placebo effect cannot be ruled out. High-frequency spinal cord stimulation stimulation at 5 khz A randomised placebo-controlled study conducted in Switzerland by Perruchoud and colleagues reported on the efficacy of HF SCS (5 khz) r compared to sham SCS. 16 Forty patients (mean age 54.2 years) who had achieved stable pain s relief with traditional SCS were recruited, of whom 33 had data available for analysis at the end of the study period (6 weeks). Data collected under traditional stimulation parameters were used as a baseline from which to gauge response as indicated on the Patient Global Impression of Change (PGIC) score, pain intensity and quality of life. HF SCS was achieved by reprogramming previously implanted traditional neurostimulation devices provided by Medtronic (Minneapolis, MN) to deliver currents up to 5 khz. t Patients randomised to HF SCS underwent a study treatment program administered by a non-blinded study investigator in four steps: a) using a maximum of three active contacts, paraesthesia covering the widest possible area of pain was elicited with traditional SCS; b) while keeping the current amplitude below sensory threshold, the stimulation frequency was increased to 5 khz; c) the current amplitude was progressively increased to sensory threshold; d) the current amplitude was decreased again below threshold until no paraesthesia was felt regardless of the patient position. For patients randomised to sham treatment, the process was identical with the exception that the investigator switched off the stimulator after step d. A cross-over period ensued, enabling results of HF SCS and sham to be reported for all patients. The main results are summarised in Table 9. There were no statistical differences observed in terms of overall treatment effects, meaning that the two neuromodulation techniques have a similar effect. The authors did report a significant period effect as indicated by the difference in response due to the order of treatment sequences (i.e. HF SCS or sham first). For the HF first group, the response rate was 51.5 per cent compared to the sham first group which had a response rate of 21.2 per cent (mean difference 30.3%, p=0.006). The reasons for this finding are unclear but could be an artefact of confounding or of a lack of successful blinding in the first study period. q The Hawthorne effect is a phenomenon in which individuals improve in an aspect of behaviour/ experience in response to the awareness of being observed. r In contrast to HF10 therapy provided by Nevro in which stimulation is at 10 khz. s Patients with low back pain radiating to one or both legs were eligible. t The devices used, PrimeADVANCED and RestoreADVANCED, do not commercially support HF parameters. Spinal cord stimulation: July

25 Table 9 Results for pain patients treated with HF SCS at 5 khz versus sham, adjusted for baseline values reflecting conditions under treatment with traditional SCS 16 Outcome HF SCS, n=33 Sham, n=33 p Response, n (%) (based on PGIC) Pain score, mean VAS Quality of life, mean EQ-5D index 14 (42.4) 10 (30.3) NS NS NS EQ-5D, European Quality of Life-5 Dimensions questionnaire (1=perfect quality of life, 0=no quality of life); HF, high-frequency; NS, not significant; PGIC, Patient Global Impression of Change score); SCS, spinal cord stimulation; VAS, Visual Analogue Scale Reporting of safety outcomes was minimal in this RCT. One patient reported feeling malaise which was attributed to a vasovagal attack at the programming session during one of the treatment periods; the patient subsequently withdrew consent. One patient reported a modest increase in daily oral morphine use but the magnitude of the increase was not reported. 16 The study authors noted several limitations of their trial: therapy was applied at sub-threshold level by intention; the authors stated that applying stimulation above the sensory threshold posed the risk of being unpleasant, harmful and would have resulted in unblinding; results are limited to stimulation at 5 khz and cannot be generalised to other stimulation modes or patterns; due to the short study duration, it is possible that the effect of conventional SCS may have played a significant role (i.e. inadequate washout period); the trial only compared the effect of HF SCS and sham in patients with stable benefit from traditional SCS and it is unknown whether these results could be replicated in patients who are naïve to SCS or refractory to SCS. Dorsal root ganglion stimulation Three original studies which reported on the effects of DRGS were identified and are discussed here. A case series by Liem et al reported on the results of DRGS with the Axium system (Spinal Modulation, Menlo Park, CA) in 51 patients with chronic, intractable pain of the trunk, sacrum or lower limbs. Patients were recruited from several centres in Europe and Australia. The methods used in electrode lead placement and implantation of the IPG were similar to those used for standard SCS. All patients were given local anaesthesia and lightly sedated. The study physician accessed the epidural space using a 14-gauge delivery needle. The leads were then advanced anterogradely through the needle and steered into the intravertebral Spinal cord stimulation: July

26 foramen near the DRG under fluoroscopic guidance. Up to four leads were used at up to four DRGs to provide coverage of the painful areas, depending on feedback from the patient during paraesthesia mapping. Subjects completed baseline assessments and then underwent a trial period with external stimulation for up to 30 days. If at least a 50 per cent reduction in pain was demonstrated during the trial period, patients received a permanently implanted IPG. Thirty-two of the 51 patients received a permanent implant, and of these, seven patients had the Axium system removed and were lost to follow up: two due to lack of efficacy, three due to infection, and two due to non-compliance. After 12 months of follow-up, results for 25 patients were available for analysis. u Included outcomes were overall pain, pain specific to the back, legs, and feet (measured on VAS, BPI and McGill Pain Questionnaire); proportion of patients reporting pain improvement of at least 50 per cent (overall pain and pain specific to the back legs and feet); quality of life (European Quality of Life-5 Dimensions-3 Level version; EQ-5D-3L); Profile of Mood States (POMS); patient satisfaction on an 11-point Likert scale (0 = not satisfied, 10 = very satisfied); pain improvement based on PGIC (a 7-point Likert scale); and, adverse events. Efficacy outcomes are shown in Table 10. Similar to all but one of the studies investigating HF SCS included in this Brief, the study of DRGS by Liem et al 45 is limited by small sample size and lack of a control group. u Not all outcomes were reported for all 25 patients, in part due to differences in pain aetiology for these patients (i.e. not all patients had pain in all areas considered in the analysis). Spinal cord stimulation: July

27 Table 10 Efficacy of DRGS in patients with intractable chronic pain of the trunk, sacrum or lower limbs 45 Outcome Baseline mean±sd 12-month follow-up mean±sd % change±sd p Overall pain VAS mm scale 77.6±2.1 (n=32) 33.6±6.3 (n=25) 56.3±8.4 <0.005 Back pain VAS mm scale 74.5±5.3 (n=10) 39.7±9.6 (n=9) 41.9±14.0 <0.05 Leg pain VAS mm scale 74.6±3.3 (n=25) 28.7±7.2 (n=20) 62.4±10.8 <0.005 Foot pain VAS mm scale 81.4±2.5 (n=13) 22.0±10.7 (n=10) 79.5±12.4 <0.05 BPI score for pain severity 6.9±0.2 (n=32) 3.2±0.6 (n=25) NR <0.01 BPI score for pain interference with activities 6.5±0.4 (n=32) 3.3±0.5 (n=25) NR <0.01 McGill Pain Questionnaire score NR (n=32) NR (n=21) NR <0.001 Proportion of patients reporting pain relief 50 per cent Overall Back Leg Foot NA NA NA Patients reporting pain as a little better, better or much better as per PGIC, n (%) NA 23/25 (92) NA NA EQ-5D index score 0.30±0.24 (n=22) 0.70±0.27 (n=18) <0.001 EQ-5D VAS score 47.0±3.8 (n=32) 68.4±4.7 (n=25) 68.4 <0.005 POMS score 27.5±3.5 (n=32) 9.4±3.9 (n=25) NR <0.05 Patients rating overall satisfaction with DRGS 8/10 or higher, n(%) NA 10/25 (40) NA NA BPI, Brief Pain Inventory (measures pain intensity and impact of the pain on patient s life on a 0-10 point scale with higher score indicating more pain and/ or larger impact); DRGS, dorsal root ganglion stimulation; EQ-5D, European Quality of Life-5 Dimensions; NA, not applicable; NR, not reported; PGIC, Patient Global Impression of Change scale, 7-point Likert scale); POMS, Profile of Mood States (includes six mood domains with lower scores indicative of people with more stable mood profiles; range 0-200); SD, standard deviation; VAS, Visual Analogue Scale (100 mm pain scale where 0 = no pain, 100 mm = worst pain imaginable and VAS component of EQ-5D where 0 = worst health state imaginable and 100 = best health state imaginable) Eighty-six adverse events occurred among 29 patients, of which half were considered attributable to the device (Table 11). The most common adverse events were temporary motor stimulation (12 events), cerebrospinal fluid leak with associated headache (7 events) Spinal cord stimulation: July

28 and infection (7 events). The authors commented that the number of device-attributable adverse events was high, but that the most common events may be mitigated in the future by improvements in choosing the implant site and programming this new device, with optimisation having occurred over the course of the study period. Future studies will be required to validate this claim. Table 11 Safety outcomes for Axium DRGS for chronic pain of the trunk, sacrum or lower limbs 42 Treatment phase Adverse event Serious adverse event All adverse events Trial DRGS, n Permanent DRGS, n Total, n Events possibly, probably or definitely related to device, n (%) DRGS, dorsal root ganglion stimulation 40 (52) 3 (38) 43 (50) Schu et al reported on a case series of 29 patients treated with DRGS for chronic neuropathic groin pain in several European centres. 17 The most common aetiology of the groin pain was hernia repair; the other causes of pain were mostly related to genito-urinary surgery, abdominal surgery and the nerve damage that sometimes results from these procedures. Of the 29 patients who underwent a 30-day trial period, 25 (86.2%) were found to have greater than 50 per cent pain improvement and underwent implantation with the Axium IPG provided by Spinal Modulation (Spinal Modulation, Menlo Park, CA). Final lead placement between T12 and L4 was determined based on patient feedback during paraesthesia mapping. Data analysis was based on the results of 23 patients with a mean (±SEM v ) follow-up of 27.8 ± 4.3 weeks (range 0-68 weeks). The results of this analysis, and an analysis of the 13 patients for whom a follow-up of at least six months was achieved, are shown in Table 12. Adverse events were not reported. The authors noted that paraesthesia coverage was largely unaffected by positional changes. The study results should be interpreted with several caveats in mind, including but not limited to the small sample size, lack of comparative data, and potential bias inherent in pain as a subjective outcome measure. v Standard error of the mean. Spinal cord stimulation: July

29 Table 12 Efficacy of DRGS in patients with neuropathic groin pain 17 Outcome Baseline Follow-up % change ± SD p (difference from baseline to follow-up) Main analysis (mean follow-up ±SEM = 27.8±4.3 weeks; range 0-68 weeks); n=23 patients Overall pain VAS score, mean±sd 74.5± ± ±5.6 NR Patients with 50% pain improvement, n(%) NA 19 (82.6) NA NA Patients with 80% pain improvement, n(%) NA 11 (47.8) NA NA Analysis for patients 6 months follow-up; n=13 patients Overall pain VAS score, mean±sd 75.0± ± ±8.6 NR Patients with 50% pain improvement, n(%) NA 10 (76.9) NA NA Patients with 80% pain improvement, n(%) NA 7 (53.8) NA NA NA, not applicable; NR, not reported; SD, standard deviation; VAS, Visual Analogue Scale (100 mm pain scale where 0 = no pain, 100 mm = worst pain imaginable) Another case series by Deer and colleagues reported on the efficacy and safety of the Axium DRGS system in ten patients with chronic intractable pain of the trunk and/ or limbs. 8 The study was conducted across four centres for a period of four weeks. The study protocol and lead implantation procedures were similar to those reported by Liem et al 45 ; however, only results of trial DRGS over a period of three to seven days were reported (i.e. the study did not consider longer term effects with a permanently implanted device). Efficacy results are shown in Table 13. Seventeen adverse events occurred of which 14 were considered to be device-related; none were thought to be serious and most were technical issues related to device inactivation which were resolved without clinical consequence. One case of lead migration was reported. Spinal cord stimulation: July

30 Table 13 Efficacy of DRGS in patients with intractable chronic pain of the trunk and/ or limbs 8 Outcome Baseline 12-month follow-up % change ± SD p Overall pain VAS mm scale, mean±sd 73±10 (n=8) 59±17 (n=8) 70±32 <0.001 Back pain VAS mm scale, mean±sd NR (n=6) NR (n=5) 84±22 <0.001 Leg pain VAS mm scale, mean±sd NR (n=8) NR (n=8) 80±26 <0.001 Foot pain VAS mm scale, mean±sd NR (n=3) NR (n=3) 70±30 <0.001 Patients reporting 30% pain reduction, % NA 88 NA NA Patients reporting 50% pain reduction, % NA 75 NA NA Patients rating overall satisfaction with DRGS 7/10 or higher, % NA 78 NA NA Patients reporting reduced intake of pain medication, % NA 78 NA NA NA, not applicable; NR, not reported; SD, standard deviation; VAS, Visual Analogue Scale (100 mm pain scale where 0 = no pain, 100 mm = worst pain imaginable) Clearly, the findings of this study are of only limited use for informing clinical practice given the short-follow up, including only trial conditions rather than long term data based on experience with permanently implanted systems. Given the small study sample, improvements in pain specific to the back, legs and feet showed considerable variation. Bias in regard to the measurement of pain outcomes cannot be ruled out. Other safety information In the past, the TGA has undertaken recall actions in relation to lead breakage associated with the removal of Axium neurostimulator leads, stating that Spinal Modulation implant instructions and warnings must be followed to help prevent lead breakage. 46 In compliance with the TGA, Spinal Modulation have undertaken action w to clarify and provide additional information required to ensure the safe removal of leads subsequent to permanent implantation, and releases of the Physician Implant Manual after May 2014 incorporate this information. w Information correct as of 23 May Spinal cord stimulation: July

31 Economic evaluation None identified. Ongoing research A search of the Australian and New Zealand Clinical Trials Registry identified several clinical trials that are either ongoing, actively recruiting, or will commence recruitment soon (Table 14). Table 14 Clinical trials relevant to new types of SCS registered on anzctr.org.au Study ID Country Intervention Comparator Status ACTRN Australia Short pulse width SCS (supplied by Boston Scientific Corporation) - Recruiting ACTRN Australia SENZA HF10 therapy - Recruiting ACTRN Australia SENZA HF10 therapy - Recruiting ACTRN Australia Axium DRGS - Not yet recruiting ACTRN Australia HF SCS (device not specified) Sham treatment Not yet recruiting ACTRN Australia SENZA HF10 therapy - Recruiting ACTRN Australia SENZA HF10 therapy - Not yet recruiting HF, high-frequency; DRGS, dorsal root ganglion stimulation; SCS, spinal cord stimulation Internationally, ClinicalTrials.gov reports nine potentially relevant clinical trials of new types of SCS, including HF SCS and DRGS (Table 15). Table 15 Clinical trials relevant to new types of SCS registered on ClinicalTrials.gov Study ID Country Intervention Comparator Status NCT Netherlands HF SCS (device not specified) Low frequency SCS Not yet recruiting NCT USA PRECISION high-rate SCS (Boston Scientific Corporation) Commercial rate SCS Recruiting NCT USA Axium DRGS Conventional SCS Active; not recruiting NCT USA PRECISION Plus high-rate subperception SCS Low rate subperception SCS Recruiting NCT USA SENZA HF10 therapy Commercially available SCS Active, not recruiting NCT UK 4 different frequency settings on RestoreSensor SCS (Medtronic) - Recruiting NCT Netherlands Axium DRGS Medtronic SCS Recruiting NCT USA SENZA HF10 therapy - Not yet recruiting NCT USA PRECISION HF SCS (1000 Hz) Low frequency SCS Active, not recruiting DRGS, dorsal root ganglion stimulation; SCS, spinal cord stimulation Spinal cord stimulation: July

32 Other issues Contributing authors to all the studies included on the safety and effectiveness of HF SCS (all stimulation parameters) and DRGS reported conflicts of interest relating to corporate affiliation or financial reimbursement from Nevro, Medtronic, Spinal Modulation and several other companies. Details are shown in Table 16. Table 16 Conflicts of interest acknowledged by authors of studies included on safety and effectiveness Study Al-Kaisy et al Al-Kaisy et al Deer et al Liem et al Perruchoud et al Schu et al 17 Tiede et al Conflict of interest details Authors received travel sponsorship and speaker fees from Nevro and Medtronic Authors received travel sponsorship and speaker fees from Nevro, Medtronic and Spinal Modulation The study was funded by Spinal Modulation, Bioness, St Jude Medical, Vertos and Medtronic; several authors declared their consultancy to these companies and membership with the affiliated advisory boards; one author reported being a Spinal Modulation shareholder One author is an employee of Spinal Modulation; several others declared consultancy to Spinal Modulation Several authors declared their role as consultants and advisory board members for Medtronic; the authors have also received honoraria, consulting, speaking and travel fees from Medtronic A number of Spinal Modulation employees were involved in the writing of the manuscript and data analysis; several study authors are consultants to Spinal Modulation Authors are consultants and speakers for Nevro and have received consultant fee and/ or stock options; the study was sponsored by Nevro One pain physician located in the Netherlands expressed concerns regarding patients who require revision for the placement of leads used in DRGS. x It was his opinion that the anatomical location of the leads for DRGS increases the likelihood of the leads becoming stuck in comparison to traditional SCS. However, he also countered this statement with his personal finding that a few patients who fail traditional SCS can have acceptable results with DRGS. Based on his statement, it appears patient selection is particularly important. A comment by another pain physician based in Switzerland was provided in an addendum of the paper on the case series by Deer et al This physician expressed that the applicability of DRGS in certain patient groups, such as those with foraminal stenosis, still requires investigation. The issue of careful patient selection is also recognised by industry: one representative from Spinal Modulation explained that in addition to clinical considerations, patient selection needs to take into account prospective patient s psychological fitness. This representative commented that in the Australian private system where the vast majority of SCS procedures occur, infrastructure and working connections x Personal communication, 19 March Spinal cord stimulation: July

33 across medical and allied health disciplines are lacking, and that adequate psychological assessment of patients being considered for SCS and appropriate follow up rarely occur. y Following a neurostimulation workshop in 2014, Cambridge Consultants released a working paper, Neurostimulation 2024 that addresses the development potential of neurostimulation for the next ten years. In an interview with a representative of Cambridge Consultants, MedGadget identified the following themes: a move in neuromodulation manufacturing from a focus on implant technology (waveforms, control systems, power storage etc) to a focus on the wider therapeutic ecosystem, with a vision toward infrastructure building, including digital services linking patients to clinical stakeholders, caregivers and health system data; growing need for small start-up providers of medical devices to collaborate across the fractured clinical landscape of neuromodulation, otherwise dominated by select larger companies; finding solutions based on the successful open source models used in other industries. 47 Number of studies included All evidence included for assessment in this Technology Brief has been assessed according to the revised NHMRC levels of evidence. A document summarising these levels may be accessed via the HealthPACT web site. Total number of studies: 8 Total number of Level II studies: 2 Total number of Level IV studies: 6 Search criteria to be used (MeSH terms) MeSH terms Spinal cord stimulation; ganglion, spinal Text terms Neuromodulation; dorsal root ; dorsal root ganglion stimulation ; spinal cord stimulation ; high frequency ; high-frequency ; HF y Personal communication with Spinal Modulation area director, in person meeting 28 April Spinal cord stimulation: July

34 References 1. Shealy, C. N., Mortimer, J. T.& Reswick, J. B. (1967). 'Electrical inhibition of pain by stimulation of the dorsal columns: preliminary clinical report'. Anesthesia and analgesia, 46 (4), Shealy, C. N., Taslitz, N. et al (1967). 'Electrical inhibition of pain: experimental evaluation'. Anesthesia and analgesia, 46 (3), Kemler, M. A., Barendse, G. A. et al (2000). 'Spinal cord stimulation in patients with chronic reflex sympathetic dystrophy'. The New England journal of medicine, 343 (9), Kumar, K., Taylor, R. S. et al (2007). 'Spinal cord stimulation versus conventional medical management for neuropathic pain: a multicentre randomised controlled trial in patients with failed back surgery syndrome'. Pain, 132 (1-2), Vallejo, R. (2012). 'High-frequency spinal cord stimulation: An emerging treatment option for patients with chronic pain'. Techniques in Regional Anesthesia and Pain Management, 16 (2), Song, J. J., Popescu, A.& Bell, R. L. (2014). 'Present and potential use of spinal cord stimulation to control chronic pain'. Pain Physician, 17 (3), Krames, E. S. (2015). 'The dorsal root ganglion in chronic pain and as a target for neuromodulation: A review'. Neuromodulation, 18 (1), Deer, T. R., Grigsby, E. et al (2013). 'A prospective study of dorsal root ganglion stimulation for the relief of chronic pain'. Neuromodulation, 16 (1), Van Buyten, J. P., Al-Kaisy, A. et al (2013). 'High-frequency spinal cord stimulation for the treatment of chronic back pain patients: Results of a prospective multicenter European clinical study'. Neuromodulation, 16 (1), Deer, T. R., Mekhail, N. et al (2014). 'The appropriate use of neurostimulation of the spinal cord and peripheral nervous system for the treatment of chronic pain and ischemic diseases: The neuromodulation appropriateness consensus committee'. Neuromodulation, 17 (6), North, R. B. (2008). 'Neural interface devices: Spinal cord stimulation technology'. P Ieee, 96 (7), Melzack, R.& Wall, P. D. (1996). 'Pain mechanisms: A new theory (Reprinted from Science, vol 150, pg , 1965)'. Pain Forum, 5 (1), Zhang, T. C., Janik, J. J.& Grill, W. M. (2014). 'Mechanisms and models of spinal cord stimulation for the treatment of neuropathic pain'. Brain Res, 1569, Kramer, J., Liem, L. et al (2015). 'Lack of body positional effects on paresthesias when stimulating the dorsal root ganglion (DRG) in the treatment of chronic pain'. Neuromodulation, 18 (1), Deer, T., Pope, J. et al (2012). 'Neurostimulation for the treatment of axial back pain: A review of mechanisms, techniques, outcomes, and future advances'. Neuromodulation, 17 (S2), Perruchoud, C., Eldabe, S. et al (2013). 'Analgesic efficacy of high-frequency spinal cord stimulation: A randomized double-blind placebo-controlled study'. Neuromodulation, 16 (4), Spinal cord stimulation: July

35 17. Schu, S., Gulve, A. et al (2014). 'Spinal cord stimulation of the dorsal root ganglion for groin pain-a retrospective review'. Pain Practice. 18. FDA (2015). FDA approves spinal cord stimulation system that treats pain without tingling sensation. [Internet]. US Food and Drug Administration. Available from: m [Accessed 11 May 2015]. 19. MedGadget (2015). Nevro Senza Spinal Cord Stimulator Cleared in EU, Australia for 3T MRI Use. [Internet]. MedGadget LLC. Available from: Medgadget+%28Medgadget%29 [Accessed March 2015]. 20. Kumar, K.& Rizvi, S. (2014). 'Historical and present state of neuromodulation in chronic pain'. Current Pain and Headache Reports, 18 (1). 21. Medtronic (2015). Determining MRI Eligibility. [Internet]. Medtronic Inc. Available from: [Accessed March 2015]. 22. Australian Institute of Health and Welfare (2015). What are back problems? Available from: [Accessed 17 Mar 2015]. 23. Australian Institute of Health and Welfare (2015). Back pain and problems. Available from: [Accessed 17 Mar 2015]. 24. Australian Institute of Health and Welfare (2015). Who gets back problems? Available from: [Accessed 17 Mar 2015]. 25. Australian Institute of Health and Welfare (2015). What is the health burden of back problems? Available from: [Accessed 18 Mar 2015]. 26. Ministry of Health (2014). Annual update of key results 2013/14: New Zealand Health Survey, Ministry of Health, Wellington. NZ 27. Ministry of Health (2013). Health Loss in New Zealand: A report from the New Zealand burden of diseases, injuries and risk factors study , Ministry of Health, Wellington, NZ 28. National Pain Summit Initiative (2011). National Pain Strategy, rategy% pdf. 29. Access Economics (2007). The high price of pain: the economic impact of persistant pain in Australia, Access Economics, Australia 30. Australian Institute of Health and Welfare (2015). How much is spent on back problems? Available from: [Accessed 18 Mar 2015]. Spinal cord stimulation: July

36 31. Australian Institute of Health and Welfare (2015). What role do GPs play in treating back problems? Available from: [Accessed 18 Mar 2015]. 32. Australian Institute of Health and Welfare (2015). What role do hospitals play in treating back problems? Available from: [Accessed 18 Mar 2015]. 33. National Pain Summit Initiative (2011). National Pain Stategy. [Internet]. Pain Australia. Available from: rategy% pdf [Accessed March 2015]. 34. Medicare Item Reports [database on the Internet]2015. Available from: DoH (2015). MBS Online. [Internet]. Department of Health. Available from: [Accessed March 2015]. 36. Dworkin, R. H., O'Connor, A. B. et al (2010). 'Recommendations for the pharmacological management of neuropathic pain: an overview and literature update'. Mayo Clinic proceedings, 85 (3 Suppl), S Dworkin, R. H., O'Connor, A. B. et al (2013). 'Interventional management of neuropathic pain: NeuPSIG recommendations'. Pain, 154 (11), DoH (2015). Prostheses List. Available from: [Accessed April 2015]. 39. Kapural, L., Yu, C. et al (2015). 'Novel 10-kHz High-frequency Therapy (HF10 Therapy) Is Superior to Traditional Low-frequency Spinal Cord Stimulation for the Treatment of Chronic Back and Leg Pain: The SENZA-RCT Randomized Controlled Trial'. Anesthesiology. 40. FDA (2015). Guidance for Industry: Non-Inferiority Clinical Trials. [Internet]. US Federal Drug Administration. Available from: uidances/ucm pdf. [Accessed August 2015]. 41. Piaggio, G., Elbourne, D. R. et al (2012). 'Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010 statement'. JAMA, 308 (24), Al-Kaisy, A., Van Buyten, J. P. et al (2014). 'Sustained Effectiveness of 10kHz High- Frequency Spinal Cord Stimulation for Patients with Chronic, Low Back Pain: 24- Month Results of a Prospective Multicenter Study'. Pain Medicine (United States), 15 (3), Al-Kaisy, A., Palmisani, S. et al (2015). 'The use of 10-kilohertz spinal cord stimulation in a cohort of patients with chronic neuropathic limb pain refractory to medical management'. Neuromodulation, 18 (1), Tiede, J., Brown, L. et al (2013). 'Novel spinal cord stimulation parameters in patients with predominant back pain'. Neuromodulation, 16 (4), Spinal cord stimulation: July

37 45. Liem, L., Russo, M. et al (2014). 'One-Year Outcomes of Spinal Cord Stimulation of the Dorsal Root Ganglion in the Treatment of Chronic Neuropathic Pain'. Neuromodulation. 46. TGA (2015). Recall for Product Correction - Axium Neurostimulator Leads. [Internet]. Therapeutic Goods Administration. Available from: [Accessed April 2015]. 47. MedGadget (2014). The Next Decade of Neurostimulation: Interview with Simon Karger from Cambridge Consultants. [Internet]. MedGadget. Available from: [Accessed April 2015]. 48. UTH (2015). Neuroscience Online: An Electronic Textbook for the Neurosciences. [Internet]. Department of Neurobiology and Anatomy, The University of Texas Medical School at Houston (UTHealth) Present, All rights reserved. Available from: [Accessed March 2015]. 49. Geber, C., Baumgartner, U. et al (2009). 'Revised definition of neuropathic pain and its grading system: an open case series illustrating its use in clinical practice'. The American journal of medicine, 122 (10 Suppl), S Woolf, C. J.& Mannion, R. J. (1999). 'Neuropathic pain: aetiology, symptoms, mechanisms, and management'. Lancet, 353 (9168), Marchand, S., Bushnell, M. C. et al (1991). 'The effects of dorsal column stimulation on measures of clinical and experimental pain in man'. Pain, 45 (3), Julien, N., Goffaux, P. et al (2005). 'Widespread pain in fibromyalgia is related to a deficit of endogenous pain inhibition'. Pain, 114 (1-2), Staud, R.& Rodriguez, M. E. (2006). 'Mechanisms of disease: pain in fibromyalgia syndrome'. Nature clinical practice Rheumatology, 2 (2), Spinal cord stimulation: July

38 Appendix A. Spinal cord anatomy The spinal cord (SC) is a cylindrical structure which conveys information from the brain to the body and from the body to the brain. The entire structure is a uniform organisation of nervous tissue, comprising white and grey matter, and is classified in four distinct segments: cervical (C), thoracic (T), lumbar (L) and sacral (S)(Figure 1). Two consecutive rows of nerve roots emerge on each side of the SC. These nerve roots join distally to form 31 pairs of spinal nerves. The spinal nerves contains two types of fibres which convey information to and from all parts of the body: (a) motor fibres, which are involved in movement, and (b) sensory nerve fibres involved in a variety of processes related to external and internal sensory input. Each functional segment of the SC (C, T, L, S) innervates a dermatome (Error! Reference source not found.). 48 Figure 2 Schematic dorsal and lateral view of the spinal cord and four cross sections from cervical, thoracic, lumbar and sacral levels, respectively: Used with permission, Department of Neurobiology and Anatomy, The University of Texas Medical School at Houston (UTHealth) Present, All rights reserved. 48 A dermatome is an area of skin supplied by peripheral nerve fibres originating from a single dorsal root ganglion. If a nerve is cut, sensation is lost from the corresponding dermatome. Given that each segment of the spinal cord innervates a different region of the body, dermatomes can be precisely mapped on the body surface, and loss of sensation in a dermatome can indicate the exact level of spinal cord damage in clinical assessment of injury, though it is important to realise that a degree of overlap exists between neighbouring dermatomes. Sensory information (including pain) from the body is relayed to Spinal cord stimulation: July

39 the central nervous system (CNS) via the dorsal roots, just proximal to the dorsal root ganglia (DRG)(Figure 3). Figure 3 Innervation arising from single dorsal root ganglion supplied specific skin area (dermatome): Used with permission, Department of Neurobiology and Anatomy, The University of Texas Medical School at Houston (UTHealth) Present, All rights reserved. 48 Note: Numbers refer to the spinal segments by which each nerve is named. C, cervical; T, thoracic; L, lumbar; S, sacral spinal cord segments. The dorsal root fibres are the axons z originating from the primary sensory DRG cells. Prior to reaching the SC, each ascending dorsal root axon divides into ascending and descending branches and enters the SC several segments below and above its own segment. The ascending dorsal root fibres and the descending ventral root fibres extending to and from discrete areas of the body form the 31 pairs of spinal nerves (Figure 4). The dorsal root fibres segregate into lateral and medial divisions. The lateral division contains most of the axons carrying pain and temperature information. The medial division of dorsal root fibres consists mainly of axons conducting sensory fibres from the skin, muscles and joints. z The long, slender projections by which neurons communicate via the conduction of electrical impulses. Spinal cord stimulation: July

40 Figure 4 Spinal cord section with its ventral and dorsal root fibres and ganglia: Used with permission, Department of Neurobiology and Anatomy, The University of Texas Medical School at Houston (UTHealth) Present, All rights reserved. 48 Spinal cord stimulation: July

41 Appendix B. Taxonomy of pain Neuropathic pain Neuropathic pain refers to pain originating from nerve damage or altered nerve function. Mediated by a variety of neurotransmitters and receptors, it is frequently associated with sensations of burning, shooting, tingling or electric shock. This type of pain is not normal, unlike the type of pain which is felt in response to an external stimulus, such as in injury or exposure to extreme temperature. Neuropathic pain is often resistant to opioid drugs or requires analgesics in large doses to achieve relief, but may respond to anti-epileptics and 36, 49 antidepressants by acting on shared mechanisms of action. Neuropathic pain is predominant in a variety of disease states and syndromes. Notable examples include spinal nerve root injury, peripheral nerve injury, CRPS type I and type II, post-herpetic neuralgia, idiopathic and diabetic peripheral neuropathy, central neuropathic pain from stroke or multiple sclerosis, spinal cord injury and ischaemic nerve degeneration. 10 Nociceptive pain Nociceptive pain occurs as a result of normal mechanism of pain processing. It has a biological purpose by signalling to the body that a noxious input has occurred so that an appropriate behavioural or reflex response may occur to avoid harm. In other words, the capacity to experience nociceptive pain has a protective role, warning of imminent or sustained tissue damage and in turn eliciting conscious or reflex responses to avoid or minimise such damage. 50 Nociceptive pain is activated by mechanical, thermal or chemical irritation and may take the form of sharp, dull, aching or throbbing pain sensations. This type of pain is observed in disease states and conditions such as soft tissue trauma, various inflammatory conditions (e.g. arthritis, pancreatitis) and metastatic cancer. Experimental evidence has shown that animals can respond to SCS targeting nociceptive pain, but this response has been difficult to establish in humans. Mixed pain Many pain states cannot be exclusively regarded as either neuropathic or nociceptive. These are referred to as mixed pain. Examples of this type of pain include chronic pelvic pain, pain associated with FBSS and neural compression secondary to tumour invasion of the bony spine. 10 Dysfunctional pain For a variety of pain conditions, the underlying diagnosis/ cause is unclear; it is possible for pain to be present without any identifiable harmful stimulus, inflammation or damage to the nervous system. Examples of such conditions include fibromyalgia, interstitial cystitis 10, 51 Spinal cord stimulation: July

42 and irritable bowel syndrome. The understanding of dysfunctional pain syndromes is growing. For example, fibromyalgia is now believed to result from a deficit in endogenous pain inhibitory mechanisms, and some researchers believe this condition may be a target for SCS, although evidence for this application is yet to emerge. 10, 52, 53 Spinal cord stimulation: July