• complex regional pain syndrome;
  • deep brain stimulation;
  • failed back surgery syndrome;
  • motor cortex stimulation;
  • neuropathic pain;
  • neurostimulation therapy;
  • repetitive transcranial magnetic stimulation;
  • spinal cord stimulation;
  • transcutaneous electrical nerve stimulation


  1. Top of page
  2. Abstract
  3. Background and objectives
  4. Search methods
  5. Results
  6. General comments
  7. Declaration conflict of interest
  8. References
  9. Supporting Information

Pharmacological relief of neuropathic pain is often insufficient. Electrical neurostimulation is efficacious in chronic neuropathic pain and other neurological diseases. European Federation of Neurological Societies (EFNS) launched a Task Force to evaluate the evidence for these techniques and to produce relevant recommendations. We searched the literature from 1968 to 2006, looking for neurostimulation in neuropathic pain conditions, and classified the trials according to the EFNS scheme of evidence for therapeutic interventions. Spinal cord stimulation (SCS) is efficacious in failed back surgery syndrome (FBSS) and complex regional pain syndrome (CRPS) type I (level B recommendation). High-frequency transcutaneous electrical nerve stimulation (TENS) may be better than placebo (level C) although worse than electro-acupuncture (level B). One kind of repetitive transcranial magnetic stimulation (rTMS) has transient efficacy in central and peripheral neuropathic pains (level B). Motor cortex stimulation (MCS) is efficacious in central post-stroke and facial pain (level C). Deep brain stimulation (DBS) should only be performed in experienced centres. Evidence for implanted peripheral stimulations is inadequate. TENS and r-TMS are non-invasive and suitable as preliminary or add-on therapies. Further controlled trials are warranted for SCS in conditions other than failed back surgery syndrome and CRPS and for MCS and DBS in general. These chronically implanted techniques provide satisfactory pain relief in many patients, including those resistant to medication or other means.

Background and objectives

  1. Top of page
  2. Abstract
  3. Background and objectives
  4. Search methods
  5. Results
  6. General comments
  7. Declaration conflict of interest
  8. References
  9. Supporting Information

Although pharmacological research is making major efforts in the field of neuropathic pain, a considerable number of patients do not achieve sufficient pain relief with medication alone. In real life, a sufficient level of pain relief is probably one that allows the patient to have an acceptable quality of life. In evidence-based studies on pain it is customary to consider as ‘responders’ to treatment those patients that report a pain relief >50%. On that basis, it would appear from the most recent reviews and the European Federation of Neurological Societies (EFNS) guidelines that only 30–40% of the patients with chronic neuropathic pain achieve that target with pharmacotherapy [1,2]. However, the 50% rule is being increasingly argued because in many patients objective markers of satisfactory improvement may co-exist with nominal levels of scaled pain relief much <50% [3,4]. It was thereby proposed that a clinically meaningful reduction of chronic pain in placebo-controlled trials would be a two-point decrease or 30% reduction on a 0–10 numerical rating scale [5].

Ancillary treatments that are harmless, such as physical and psychological therapies, are often used. Although they may help them to cope, this is often not enough for the patients with severe pain. Amongst the alternatives, a number of previously common surgical lesions aimed at relieving neuropathic pain (such as neurotomies) have now been abandoned.

Neurostimulation therapy is increasingly being used either as a substitute for surgical lesions or in addition to the current medical therapy in several conditions, including Parkinson's disease, dystonia, obsessive-compulsive disorder and refractory pain, whilst trials are in progress in other movement and psychiatric disorders, epilepsy and migraine. The neurostimulation techniques proposed for treating pain are: transcutaneous electrical nerve stimulation (TENS), peripheral nerve stimulation (PNS), nerve root stimulation (NRS), spinal cord stimulation (SCS), deep brain stimulation (DBS), epidural motor cortex stimulation (MCS), and repetitive transcranial magnetic stimulation (rTMS). These techniques vary greatly in their degree of invasiveness, stimulated structures and rationale, but they are all adjustable and reversible.

Our Task Force aimed at providing the neurologist with evidence-based recommendations that may help to determine when a patient with neuropathic pain should try a neurostimulation procedure. To provide a better understanding, the results are preceded by a description of the procedure and its supposed rationale.

Search methods

  1. Top of page
  2. Abstract
  3. Background and objectives
  4. Search methods
  5. Results
  6. General comments
  7. Declaration conflict of interest
  8. References
  9. Supporting Information

Task Force participants were divided into subgroups and assigned the search for specific neurostimulation procedures, with two persons carrying out an independent search for each procedure. A two-stage approach to the relevant literature search was undertaken. First the MEDLINE, EMBASE and Cochrane databases were searched for systematic reviews, from inception date to May 2006. Detailed searches are listed in Appendix 1 (Supplementary Material). Recent textbooks known to the authors were also examined for relevant references. These reviews and books were used to identify the primary literature. Secondly, given the search cut off dates of previous systematic reviews, an update search for primary studies (randomized controlled trials, non-randomized controlled trials, observational comparative studies and case series) was undertaken. Studies identified by this updated search were added to the body of evidence for each neurostimulation procedure under each indication heading.

All study designs were included except case reports and very small case series (<8). In addition, we excluded those multiple-indication case series without disaggregated reported outcomes. Both reviewers undertook the study selection. For each indication, the number and type of studies was indicated and a summary of efficacy and harm findings given. Where there was more than one systematic review or primary publication on the same series of patients, we took the most comprehensive analysis. The evidence was graded and a recommendation for each indication applied according to the EFNS guidelines [6]. The full list of references of all the assessed studies can be found in Appendix 2 (Supplementary material).


  1. Top of page
  2. Abstract
  3. Background and objectives
  4. Search methods
  5. Results
  6. General comments
  7. Declaration conflict of interest
  8. References
  9. Supporting Information

Peripheral stimulations (TENS, PNS and NRS)

Derived from folk tradition, the notion that rubbing the skin over a painful area relieves pain, found scientific support in the gate-control theory proposed by Melzack and Wall [7]. Since then, electrical stimulations for pain relief have spread worldwide. The most known technique is TENS. Surface electrodes are placed over the painful area or the nerve that innervates it and the stimulation is delivered at high frequency and low intensity (below pain threshold), to produce an intense activation of Aβ afferents and to evoke paresthesiae that cover the painful area. A completely different approach is that of using low-frequency, high-intensity stimuli that do elicit painful sensations (this technique is also called ‘acupuncture-like’ or—when delivered through needle-electrodes—’electro-acupuncture’). In both cases, stimulation sessions of very variable duration (often 20–30 min) are repeated at variable intervals. Because the pain relief is immediate but short-lasting, many patients use a portable stimulator, which can be kept on for hours or switched on during intermittent aggravations. To provide a more stable and efficient stimulation, electrodes can be percutaneously implanted to contact the nerve (usually the main limb nerves but also branches of the trigeminal or occipital nerves) and connected subcutaneously to a stimulation unit (PNS). To cover the painful areas that are not accessible from the surface, such as pelvic viscera, a lead for SCS can be implanted deeply at the root exit from the spine (NRS) or into Meckel's cave to stimulate the Gasserian ganglion.

For all these techniques, when the currents are applied at high frequency and low intensity, the accepted mechanism is that of the homotopical inhibition exerted by large-size afferents on spinothalamic pathways. Whether this inhibition is exerted mostly on pre-synaptic terminals or second-order neurons, or involves long-loops, or whether it is more efficacious on lamina I or lamina V neurons, is of no consequence from the practical point of view. It is important to know that inhibition is strictly homotopical (i.e. the large-fibre input must generate paresthesiae covering the entire painful territory) and that pain relief rapidly declines after stimulation is stopped. The less used low-frequency high-intensity stimulation (‘acupuncture-like’) is thought to activate, through a long-loop, the antinociceptive systems; because it is at least partly naloxone-reversible, the analgesic effect is thought to be also mediated by the opioid system [8,9]. Hence, in theory, it may also be effective in central pain. Importantly, the peripheral stimulation must be painful, can be heterotopic, and has long-lasting effects. Rather than the diagnosis, the main indications are derived from the therapeutic rationale. In the standard TENS, pain must be confined to a relatively small area or a territory that is innervated by an easily accessible nerve. Another important condition regards the sparing of Aβ-fibre function: patients with severe loss of such fibres (as easily assessed by the TENS-evoked sensation) are unsuitable. Finally, because transcutaneous stimulations are virtually harmless (apart from possible interferences with cardiac pacemakers), TENS is often used as an ancillary support to the drug or other physical treatments, in a large variety of conditions. In contrast, PNS/NRS have more restricted indications and are used in pharmacoresistant patients.

Evidence identified

Whereas there is plenty of controlled studies and meta-analyses in nociceptive pains, the search on neuropathic pain yielded disappointing results. We identified one systematic review on outpatient services for chronic pain [10], which analysed 38 RCTs (only two studies dealing with neuropathic pains), and came to the conclusion that clearly the pain-relieving effect of TENS increases with dose (duration of the session × frequency of sessions × total duration).

Our search on TENS in neuropathic pain (Table 1) found nine controlled trials (classes II–IV) that, although not all dealing exclusively with neuropathic pain, allowed us to extract data for about 200 patients with pain of ascertained neuropathic origin. Four studies dealt with painful diabetic neuropathy: one class-II study found very-high-frequency stimulation of the lower-limb muscles more efficacious than standard TENS [11]; the others (all class III) found low-frequency TENS or acupuncture-like more efficacious than sham stimulations [12–14]. Two class-III studies dealt with peripheral mononeuropathies: both found standard TENS better than placebo [15,16]. One small RCT in post-herpetic neuralgia (PHN) found conventional TENS to have little effect whilst electro-acupuncture was decidedly better [17]. One crossover, small-sample study (class III) in painful cervical radiculopathy found that standard TENS applied to the cervical back was better than placebo but a TENS with random frequency variation was superior (Table 1) [18]. Regarding PNS, we found six clinical trials (no RCT), in 202 patients with various kinds of peripheral neuropathy or mixed pains. These studies, none having an adequate control, reported an average success rate of 60%. Regarding NRS, we only found two class IV studies in patients with pelvic pains or interstitial cystitis (Table 1).

Table 1.   Summary of efficacy and safety of peripheral stimulations (TENS, PNS, and NRS)
Technique/conditionAvailable evidenceNo. patientsSummary of efficacySummary of harmsComparatorBlindRandomEFNS classComments
  1. TENS, transcutaneous electrical nerve stimulation; LF TENS, low-frequency, high-intensity TENS, also called acupuncture-like; PNS, peripheral nerve stimulation with implanted electrodes; NRS, nerve root stimulation with implanted electrodes; QoL, quality of life; CT, controlled trial; HF, high frequency; PENS, percutaneous electrical nerve stimulation.

TENS/chronic painOne meta-analysis [10], analysing 38 RCTs; only two on neuropathic pain: Thorsteinsson 1977 and Rutgers 1988 [16,17]There is no evidence; but it is clear that effect increases with dose (duration of the session  × frequency of sessions × total duration)Practically nothingVariousYesYesI 
TENS/NeP  Painful diabetic  neuropathyReichstein 2005 [11]25TENS compared with HF muscle: 25% success with TENS and 69% with HFPractically nothingHigh-frequency muscle s timulationYesYesIIReichstein [11] has no placebo, TENS goes far worse than HF muscle stimulation
 Diabetic  neuropathyForst 2004 [14]19LF TENS reduced VAS by 23%, significant difference from placeboPractically nothingPlaceboYesYesIII 
 Painful diabetic  neuropathyHamza 2000 [13]50Painful PENS reduced VAS by 60%, significant difference from sham, and improved QoLPractically nothingSham YesIIICrossover with an inadequate comparator (needles with no current)
 Diabetic  neuropathyKumar 1997 [12]35LF TENS with biphasic stimuli exponentially decaying was significantly better than sham in reducing neuropathic symptomsPractically nothingSham YesIIISham inadequate and report of improvement of all symptoms.
 Traumatic  neuropathyCheing 2005 [15]19Significantly better than placeboPractically nothingPlaceboYesYesII 
 RadiculopathyBloodworth 2004 [18]11Random TENS and TENS on the cervical back were significantly better than placebo, with R-TENS better than TENSPractically nothingPlacebo and Random-TENSYesYesIIIFew patients and crossover
 Mixed painsCT Tulgar 1991 (internal control)8Two did not get sufficient pain relief; one received prolonged pain relief; three went better with ‘burst’, one with high-rate and one with low-rate modulated TENSPractically nothingFour modes of TENS stimulationYesNoIVFew patients who chose which mode of TENS they preferred
 PHNRCT Rutgers 1988 [17]few Practically nothingAcupunctureSee McQuay et al. 1997 [10]   
 Peripheral  neuropathyRCT Thorsteinsson 1977 [16]24Significantly better than placeboPractically nothingPlaceboYesYesIII 
PNS/NePNo meta-analyses, no RCTs  Sometimes need for reoperationNoneNoNoClass IV not enough evidence for any recommendationVery few and old papers, this technique does not seem to be getting popular
 CRPS IIBuschmann 199952Successful in 47
 Peripheral (n)Nashold 198235Successful in 15
 Post-traumaticLaw 198022Successful in 13
 Mixed/variousPicaza 197737Successful in 18
 Mixed/variousCampbell 197633Successful in eight
 Peripheral (n) radiculopathy,  amputationPicaza 197523Successful in 20
Totals 202Successful in 121 (60%)
NRS/NePNo meta-analyses, no RCTs  Sometimes need for reoperationNoneNoNoClass IV not enough evidence for any recommendation 
 Neuropathic  pelvic painCT Everaert 200126Successful in 16
 Interstitial  cystitisWhitmore 2003, no control33Significant improvement

We cannot draw any conclusion for PNS and NRS. Even for TENS, it is difficult to come to conclusive recommendations. The total number of patients with ascertained neuropathic pain was only some 200, with diseases, comparators, and results varying considerably from study to study. Stimulation parameters also vary considerably between the studies, using different pulse waveforms and a wide range of frequencies, not to mention number and duration of the sessions. In conclusion, standard high-frequency TENS is possibly better than placebo (level C) though probably worse than acupuncture-like or any other kind of electrical stimulation (level B).

Spinal cord stimulation

This technique consists of inserting electrodes into the posterior epidural space of the thoracic or cervical spine ipsilateral to the pain (if unilateral) and at an appropriate rostro-caudal level to evoke the topographically appropriate paraesthesiae which are a pre-requisite for (but not a guarantee of) success. Catheter or wire electrodes can be inserted percutaneously under local or general anaesthesia; plate (‘surgical’) electrode systems require an open operation but may perform better. Power is supplied by an implanted pulse generator (IPG).

The introduction of SCS followed from the gate-control theory [7] of ‘pain transmission’ but SCS does not have a simple antinociceptive action. It can modulate the spontaneous and evoked elements of neuropathic pain, including allodynia, it has an antiischaemic action, both cardiac and in the periphery, and other autonomic effects including the normalization of the autonomic manifestations of complex regional pain syndromes (CRPS). The relative contributions of local segmental actions in the spinal cord and long-loop effects have not yet been elucidated. It is known that the effect of SCS is mediated by large-myelinated Aß afferents, whose collaterals ascend in the dorsal columns. Whereas sensory loss because of distal axonopathy or peripheral nerve lesion is not an exclusion criterion, sparing of the dorsal columns is probably necessary [19].

Patient selection is mostly based on diagnosis. It is recognized that SCS may be effective against various ischaemic and specific neuropathic pain syndromes. Additional tests may be useful to confirm SCS indication, such as somatosensory evoked potentials (SEPs) [19], whereas the response to TENS does not seem to be a reliable guide. Trial stimulation via externalized leads is widely employed: it will identify the patients who do not like the sensation from SCS and those in whom appropriate stimulation cannot be achieved. However, this testing is not a guarantee of long-term success in neuropathic pain.

Evidence identified

We identified a number of systematic reviews and meta-analyses [20–22] and a few narrative but detailed reviews [23–25]. The majority of systematic reviews, as well as primary studies, to date have focused on patients with failed back surgery syndrome (FBSS) or complex regional pain syndrome (CRPS). Concerning FBSS there are two class-II RCTs, the first showing that SCS is more effective than reoperation [26] and the second that its addition is more effective than conventional medical care alone [27,28]. In these trials the responders (pain relief >50%) to SCS were 47–48% vs. 9–12% with comparator, at 6–24 months. In the pooled data from case series in 3307 FBSS patients, the proportion of responders was 62%. In CRPS type I, results and evidence level are also good, with a single class-II RCT of SCS compared with conventional care alone [29,30]. In this RCT, SCS reduced the visual analogue scale score by a mean 2.6 cm more than comparator at 6 months and by 1.7 cm at 5 years. In the pooled data from case series (n = 561) in CRPS I and II, the proportion of responders was 67%. Both RCTs and case series have also found significant improvement in functional capacity and quality of life. In a pooled safety analysis of SCS across all indications, the undesired events were mostly dysfunction in the stimulating apparatus: lead migration (13.2%), lead breakage (9.1%), and other minor hardware problems [20]. Also the medical complications were minor and never life threatening and were usually solved, like the hardware problems, by removing the device. The overall infection rate was 3.4%.

The effect of SCS has also been studied in many other conditions. We found positive case series evidence for CRPS II, peripheral nerve injury, diabetic neuropathy, PHN, brachial plexus damage, amputation (stump and phantom pains) and partial spinal cord injury, and negative evidence for central pain of brain origin, nerve root avulsion and complete spinal cord transection. However, all reports are class IV, thus preventing any firm conclusion. The efficacy and safety outcomes of SCS are detailed by indication in Table 2.

Table 2.   Summary of efficacy and safety of spinal cord stimulation (SCS)
IndicationVolume of evidence [no. trials (no. patients)]EFNS classSummary of efficacySummary of harmsEFNS gradeComments
  1. CMM, conventional medical management; ODI, Oswestry Disability Index; SIP, sickness impact profile; VAS, visual analogue scale; HRQoL, health-related quality of life; NRS, numerical rating scale; MS, multiple sclerosis.

FBSSSystematic review and meta-analysis Taylor et al. 2005 [21] and Cameron 2004 [20] [1 RCT (60)] (SCS vs. reoperation) [1 cohort study (44)] [72 case series (2956)] New primary studies [1 RCT (100)] (SCS vs. CMM) ‘PROCESS’ Kumar et al. (2005, 2007) [27,28] [6 cases series (361)] Kumar et al. 2006; North et al. 2005i&ii [26]; Spincemaille et al. 2005; Van Buyten et al, 2003; May et al. 2002IIRCTs Pain relief50%: SCS 9/24 (37.5%) vs. reop. 3/26 (11.5%) (P = 0.475) at 2 years SCS 24/48 (48%) vs. CMM 4/52 (9%) P < 0.0001 at 6-months Use of opioids: SCS 3/23 vs. reop. 11/16 (P = 0.0005) at 2-years SCS 25/48 (50%) vs. CMM 31/52 (70%) (P = 0.058) at 6 months Case series Pain relief50%: 62% (95% CI: 56–72) Disability Pooled results across two case series show significant improvement in ODI following SCS with mean follow-up of 6 months Quality of life Pooled results across two case series show significant improvement in SIP following SCS with mean follow-up of 6 monthsMost common complications were: Lead migration 361/2753 (13.2%) Infection 100/2972 (3.4%) Lead breakage 250/2753 (9.1%) Hardware malfunction 80/ 2753 (2.9%) Battery failure 35/2107 (1.6%) Unwanted stimulation 65/ 2753 (2.4%) ‘Most complications were not life threatening and could usually be resolved by removing the device’. Overall 43% of patients experience one or more complicationsBPROCESS study: Trial protocol published [27] First oral presentation at EFIC Istanbul, Sept. 2006 Final results in press [28]
Failed neck surgery syndromeNo evidence found  As FBSS  
CRPSSystematic review/meta-analysis Taylor et al. 2006 and Cameron 2004 [20,21] [ 1RCT (54)] – type I CRPS Overall [25 cases series (500)] (12 case series type I, eight cases series in type II, five case series in both I and II) New primary studies 5-year follow-up on above RCT Kemler et al. 2006 [30] [2 cases series (61)] Kumar et al. 2006; Harke et al. 2005Type I: II Type II: IVRCT (at 6 and 12 months and 5-years) Change in VAS pain: SCS + physical therapy −2.4 (SD 2.5) vs. physical therapy: 0.2 (1.6) P < 0.0001 at 6-months Quality of life (EQ-5D): −2.7 (SD 2.8) vs. 0.4 (1.8) P < 0.001 at 6-months Case series Pain relief 50: 67% (95% CI: 51–74) Disability: 3/3 studies showed a significant improve in functional capacity following SCS Quality of life: 2/2 studies showed a significant improvement in HRQoL following SCS Some evidence that level of pain relief with SCS in CRPS type II patients >CRPS type IAs FBSS Overall 33% of patients experience one or more complicationsCRPS type I: B CRPS type II; D 
Peripheral nerve injuryOne retrospective 2-centre mixed case series [n = 152] Lazorthes et al. 1995IV85% good and excellent at ≥2 years.Not disaggregated. Transient paraparesis in 1/692 (whole series)DPain NRS, activity and analgesic drug intake scored
Diabetic neuropathyOne prospective case series [n = 8] Tesfaye et al. 1996; Daousi et al. 2004 One retrospective mixed case series [n = 14] Kumar et al. 2006IV IVPain relief >50% pain relief in 6/8 at 14 months (6/7: one died at 2 months) >50% relief in 5/6 at 3 years (background and peak pain) >50% relief in 4/4 at 7 years (background pain) >50% relief in 3/4 at 7 years (peak pain) Exercise tolerance Increased by 150% in 6/6 Pain relief >50% relief in 12/14 ‘long-term’Lead migration in 2/8 Superficial infection in 2/8 Skin reaction in 1/8DProspective VAS + McGill Sep. pain elements Preservation of large fibre (vibration and joint position) function essential Five outcome measures Third party assessor Follow-up unclear
Other peripheral neuropathyOne retrospective mixed case series [n = 23] Kim et al. 2001IVPain relief >50% relief in 10/23 (43.5%) at 1 yearNot disaggregatedD 
Post-herpetic neuralgiaFour retrospective case series (3 mixed) [10; 28; 8; 4 (50)] Kumar et al. 2006; Harke et al. 2002; Meglio et al. 1989; Sanchez-Ledesma et al. 1989IVPain relief Significant long-term in 38/50 (pooled) Medication stopped in 21/31 Opioids stopped in 18/19Lead fracture in one Receiver failure in one Leads replaced in three to improve coverageDSuccess varies between series due to variable deafferentation
Intercostal neuralgiaNo evidence found relating to this specific diagnosis     
Brachial plexus damage/avulsionTwo retrospective case series (2 mixed) [8; 8 (16)] Simpson et al. 2003 Hood; Siegfried 1984IVPain relief Significant relief in 8/16Nil, or not disaggregatedDDifferent scoring methods Evidence of full avulsion (cf damage) of specific relevant nerve roots not always given
Amputation pain (phantom and stump)Three retrospective case series [25; 9; 61 (95)] Lazorthes et al. 1995; Simpson 1991 Krainick + Thoden 1989; Krainick et al. 1975IVPhantom pain Significant relief in 7/14 Stump pain Significant relief in 5/9 Mixed – stump/phantom not specified Krainick's series: 56% of 61 had >50% relief (early), dropping to 43% (late). Reduced drug intake correlated Lazorthes: 60% of 25 good or excellent long-term (≥2 years)Infection 1.6% Surgical revisions 31%DPhantom and stump pains not always distinguished
Facial pain (trigeminopathic)Insufficient evidence     
Central pain of spinal cord originFive retrospective case series (4 mixed) [19; 11; 101; 9; 35 (175)] Kumar et al. 2006; Barolat et al. 1998; Lazorthes et al. 1995; Cioni et al. 1995; Meglio et al. 1989; Tasker et al. 1992IVPain relief a) cord injury: 15/62 significant long term pain relief overall incomplete: 11/33 significant relief complete: 0/11 significant relief b) MS: long-term pain relief on five outcome measures in 15/19 (Kumar) bowel/sphincter function improved in 16/28 Gait improved in 15/19 (no details) c) mixed incl trauma, tumour surgery, viral etc: 34% good/ excellent at ≥2 years (Lazorthes; n = 101). Pain relief, analgesic drug intake and activityNot stated/not disaggregated in four studies Aseptic meningitis 1/9 Superficial infection 1/9 Electrode dislodgement 1/9DCompleteness of lesion not always stated Much greater success where clinically incomplete lesion Success correlates with sensory status: the less sensory deficit the better the results
Central pain of brain originTwo retrospective case series (1 mixed) [45; 10 (55)] Katayama et al. 2001; Simpson 1991 [39]IVPain relief Significant in 6/55 >60% reduction in VAS in 3/45Not stated/not disaggregatedD 

We found level B evidence for the effectiveness of SCS in FBSS and CRPS I. The available evidence is also positive for CRPS II, peripheral nerve injury, diabetic neuropathy, PHN, brachial plexus lesion, amputation (stump and phantom pains) and partial spinal cord injury, but still requires confirmatory comparative trials before the use of SCS can be unreservedly recommended in these conditions.

Deep brain stimulation

Deep brain stimulation for the treatment of medically refractory chronic pain preceded the gate theory [31]. Deep brain targets in current use include the sensory (ventral posterior) thalamus and periventricular gray matter (PVG) contralateral to the pain if unilateral, or bilaterally if indicated. Both sites have been targets of analgesic DBS for three decades [32,33]. After accurate target localization using MRI, stereotactic computerized tomography and brain atlas co-registration as appropriate, an electrode is stereotactically inserted into subcortical cerebrum under local anesthesia. The electrodes are connected to a subcutaneous IPG, placed in the chest or abdomen.

The mechanisms by which DBS relieves pain remain unclear. Animal experiments have shown that thalamic stimulation suppressed deafferentation pain, most probably via thalamo-corticofugal descending pathways. Autonomic effects of PVG stimulation are under investigation, a positive correlation between analgesic efficacy and magnitude of blood pressure reduction have been demonstrated in humans [34]. It is currently believed that stimulation of ventral PVG engages non-opioid dependent analgesia commensurate with passive coping behaviour whereas stimulation of dorsal PVG involves opioid-related ‘fight or flight’ analgesia with associated autonomic effects [34]. The effect of frequency, lower frequencies (5–50 Hz) being analgesic and higher frequencies (>70 Hz) pain-provoking, suggests a dynamic model whereby synchronous oscillations modulate pain perception.

As with any implanted technique of neurostimulation for treating pain, patient selection is a major challenge. Trial stimulation via externalized leads can identify those in whom DBS is not efficacious or poorly tolerated [35,36]. However, successful trial stimulation has not resulted in long-term success for up to half of cases. Contraindications include psychiatric illness, uncorrectable coagulopathy, and ventriculomegaly precluding direct electrode passage to the surgical target [37].

Evidence identified

We identified several reviews and one meta-analysis [37], which conclude that DBS is more effective for nociceptive pain than for neuropathic pain (63% vs. 47% long-term success). In patients with neuropathic pain, moderately higher rates of success were seen in patients with peripheral lesions (phantom limb pain, radiculopathies, plexopathies and neuropathies) [37]. We identified a number of primary studies, for 623 patients and a mean success rate of 46% at long-term (Table 3). However, most studies, were class-IV case series. Amongst these, two studies (Table 4) targeted the somatosensory thalamus or PAG/PVG, using current standards of MRI in target localization and current DBS devices: one study, in 15 patients with central post-stroke pain (CPSP), considered DBS successful (pain relief >30%) in 67% of patients at long-term [36]; the other, in 21 patients with various neuropathic pain conditions, concluded that DBS had low efficacy, with only 24% of patients maintaining long-term benefit (i.e. they were willing to keep using DBS after 5 years) none of these patients having CPSP [38]. Another study, comparing the efficacy of SCS, DBS (targeting the thalamus) and MCS in 45 patients with CPSP, reported DBS success in only 25% of patients [39]. The other studies were more than a decade old and had various targets; their results are summarized by clinical indication in Table 5 and by stimulation target in Table 6.

Table 3.   Summary of deep brain stimulation studies
StudyType of studyNumber of patients implantedNumber successful at long-term follow-up (%)Follow-up time (months); range (mean)EFNS class
Richardson & Akil (1977) [33]Prospective case series3018 (60)1–46IV
Plotkin (1980) 104036IV
Shulman et al. (1982) 2411 (46)(>24)IV
Young et al. (1985) 4835 (73)2–60 (20)IV
Hosobuchi (1986) 12294 (77)24–168IV
Levy et al. (1987) [53] 14142 (12)24–168 (80)IV
Siegfried (1987) 8938 (43)<24IV
Gybels et al. (1993) 3611 (31)48IV
Kumar et al. (1997) [12] 6842 (62)6–180 (78)IV
Katayama et al. (2001) [39] 4511 (25)N/AIII
Hamani et al. (2006) [38] 215 (24)2–108 (24)IV
Owen et al. (2006) [35] 3412 (35)1–44 (19)IV
Table 4.   Summary of efficacy and safety of deep brain stimulation by indication from recent and currently applicable studies
IndicationVolume of evidence no. trials (no. patients)EFNS class Summary of efficacy (%)Summary of safety
  1. Pain assessment used at least one of VAS (visual analogue scale); MPQ (McGill pain questionnaire); N1T (N-of-1 trial); HRQoL, health-related quality of life; NRS, numerical rating scale. Only VAS-related outcomes using a threshold of >50% improvement are shown here.

Amputation pain (phantom and stump)2 (5; 1)IV100; 100No indication specific complications: four wound infections; two DBS lead fractures; one intra-operative seizure; one post-operative burr hole site erosion
Post-stroke2 (16; 8)IV69; 0
Facial pain (trigeminopathic)2 (4; 4)IV100; 25
Cephalalgia not including trigeminopathic facial pain2 (3; 1)IV100; N/A
Central pain of spinal cord origin2 (2; 4)IV0; 25
Multiple sclerosis pain1 (2)IV50
Other and trauma2 (4; 1)IV75; 100
Table 5.   Summary of efficacy and safety of deep brain stimulation by indication from other, older studies (after Bittar et al. 2005) [37]
IndicationVolume of evidence (no. patients)Success on initial stimulationSuccess on chronic stimulationLong-term percentage success
Amputation pain (phantom and stump)97444
Post-stroke pain45241431
Peripheral nerve injury44363170
Post-herpetic neuralgia116436
Intercostal neuralgia43125
Brachial plexus damage/avulsion129650
Malignancy pain23191565
Facial pain (trigeminopathic)32211238
Central pain of spinal cord origin47282043
Table 6.   Summary of efficacy and anatomical targets from other, older studies (after Bittar et al. 2005 [5])
Anatomical site of DBSVolume of evidence no. patientsNumber successful long-termPercentage success
  1. PVG, periventricular gray matter; ST, sensory thalamus; IC, internal capsule.

PVG and ST or IC554887
ST or IC16638

For the use of DBS there is weak positive evidence in peripheral neuropathic pain including pain after amputation and facial pain (expert opinion requiring confirmatory trials). In CPSP, DBS results are equivocal and require further comparative trials.

Motor cortex stimulation

During the past decade MCS has emerged as a promising tool for the treatment of patients with drug-resistant neuropathic pain. The technique consists in implanting epidural electrodes over the motor strip. Electrodes are most commonly introduced through a frontoparietal craniotomy (40 × 50 mm) over the central area, under general anaesthesia, or through a simple burr hole under local anaesthesia. The craniotomy technique minimizes the risk for epidural haematoma and renders easier the use of electrophysiological techniques to localize the central sulcus, usually with SEPs concomitant to MRI-guided ‘neuronavigation’. Intraoperative cortical stimulation with clinical assessment or EMG recordings can help to determine the position of the electrodes. One or two quadripolar electrodes are implanted over the motor representation of the painful area, either parallel or orthogonal to the central sulcus. The electrode is connected to a subcutaneous IPG. The stimulation parameters are optimized post-operatively, keeping the intensity below motor threshold, and the stimulation is usually set on cyclic mode (alternating ‘on’ and ‘off’ periods).

The mechanism of action of MCS remains hypothetical. Tsubokawa et al. [40] showed that MCS attenuated abnormal thalamic hyperactivity after spinothalamic transection in cats, and considered that such effect involved retrograde activation of somatosensory cortex by cortico-cortical axons [41]. However, positron-emission tomography and SEPs failed to show any significant activation of sensory-motor cortex during MCS, whilst a strong focal activation was observed in thalamus, insula, cingulate-orbitofrontal junction and brainstem [42,43], suggesting that MCS-induced pain relief may relate to (i) top-down activation of descending pain control systems going from motor cortex to thalamus, and perhaps to motor brainstem nuclei and (ii) blunting of affective reactions to pain via activation of orbitofrontal-perigenual cingulate cortex [43]. Both hypotheses have received recent support from studies in animals and in humans [44–46]. The fact that many of the regions activated by MCS contain high levels of opioid receptors suggests that long-lasting MCS effects may also involve secretion of endogenous opioids.

Eligible patients should be resistant or intolerant to main drugs used for neuropathic pain [1,2]. Some studies include pre-operative sessions of transcranial magnetic stimulation, which is regarded predictive of the MCS outcome (see Repetitive transcranial magnetic stimulation). Candidates to MCS have sometimes experienced failure of other neurosurgical procedures, such as radicellectomy (DREZ-lesion), anterolateral cordotomy, trigeminal nerve surgery or SCS.

Evidence identified

Our search disclosed no systematic review or meta-analysis, but found a relatively large number of studies (mostly case series) on CPSP and facial neuropathic pain. In CPSP, we extracted 143 non-overlapping patients from 20 case series: the average proportion of success was about 50%. Slightly better results (60% of responders, based on 60 patients from eight series) were obtained in facial neuropathic pain, central or peripheral. Most of these case series were class IV. Two studies can be classified as class III, because they had a comparator (results of other treatments, surgical or pharmacological), and outcome assessment and treatment were dissociated: Katayama et al. [39]. had a 48% success rate in patients with CPSP and Nuti et al. [4]. A 52% success rate in 31 patients with various neuropathic pain conditions, mostly CPSP. One of these papers provided follow-up results up to 4 years [4]. In phantom pain, brachial plexus or nerve trunk lesion, spinal cord lesions or CRPS, we only found case reports. Most common undesired events were related to some malfunction of the stimulating apparatus (e.g. unexpected battery depletion). Seizures, wound infection, sepsis, extradural haematoma, and pain induced by MCS have also been reported. Overall 20% of patients experience one or more complications, in general of benign nature. Details of the search with summary of benefits/harms can be found in Table 7 and 8.

Table 7.   Summary of efficacy and safety of MCS in CPSP
IndicationVolume of evidence [no. trials (no. patients)]EFNS classSummary of efficacySummary of harmsComments
  1. CPSP, central post-stroke pain; MCS, motor cortex stimulation.

CPSPSystematic review and meta-analysis None Primary studies (1991–2006) No RCT [20 cases series, with much overlap (143 non-overlapping patients)] Rasche et al. 2006, Nuti et al. 2005 [4] (+Mertens et al. 1999 +G-Larrea et al. 1999) [43] Saitoh et al. 2003 (+Saitoh et al. 2001) Fukaya et al. 2003 +Katayama et al. 2001 [39] +Katayama et al. 1998 +Yamamoto et al. 1997 Nguyen et al. 2000 +Nguyen et al. 2000 +Nguyen et al. 1999 +Nguyen et al. 1997 Nandi et al. 2002 Carroll et al. 2000 Fujii et al. 1997 Katayama et al. 1994 Tsubokawa et al. 1993 +Tsubokaw et al. 1991 Drouot et al. 2002All class IV (unless indicated otherwise) III IIICase series (8–45 cases) Satisfactory pain relief (≥50%) reported in 0–100% of cases (all series) In series with n >  20 cases satisfactory pain relief in 48–52% of patientsMost common complications: 26% (battery failure, seizures, wound infection and sepsis) Pain induced by MCS Phantom pain Extradural haematoma Seizures Hardware malfunction Overall 20% of patients experience one or more complications and in general of benign natureMany patient duplications or reinterventions making total nb of cases difficult to calculate. Reports with duplicated data were pooled Efficacy related to pre-operative response to drugs? (Yamamoto 1997, n = 28) Efficacy related to sensory symptoms? (Druot 2002, n = 11) Efficacy related to motor symptoms? (Katayama 1998, n = 31)
Table 8.   Summary of efficacy and safety of motor cortex stimulation in facial pain
IndicationVolume of evidence [no. trials (no. patients)]EFNS classSummary of efficacySummary of harmsComments
  1. MCS, motor cortex stimulation.

Facial painSystematic review and meta-analysis: None Primary studies (1991–2006) No RCT Case series (60 patients) Rasche et al. 2006 (3/50) Brown Ptiliss 2005 (10/60) Nuti et al. 2005 [4] (5/60) Drouot et al. 2002 (15) Nguyen et al. 2000a (12/83) +Nguyen et al. 2000b same +Nguyen et al. 1999 same +Nguyen et al. 1997 (7/100) Ebel et al. 1996 (7/43) Katayama et al. 1994 (3/66) Meyersonl 1993 (5/100)All class IVCase series  Satisfactory pain relief (≥50%) reported in 43–100% of cases (all series) No series with n > 20 cases Mean percent of patients with satisfactory pain relief: 66%Most common complications:  26% (battery failure, seizures, wound infection and sepsis) Pain induced by MCS Extradural haematoma Seizures Hardware malfunction Overall 20% of patients experience one or more complications, in general of benign natureMany patient duplications or reinterventions making total nb of cases difficult to calculate. Reports with duplicated data were pooled. Small series but sometimes long follow-up: 72 m

There is level C evidence (two convincing class III studies, 15–20 convergent class IV series) that MCS is useful in 50–60% of patients with CPSP and central or peripheral facial neuropathic pain, with small risk of medical complications. The evidence about any other condition remains insufficient.

Repetitive transcranial magnetic stimulation

The use of rTMS in patients with chronic pain aims at producing analgesic effects by means of a non-invasive cortical stimulation [47]. The stimulation is performed by applying on the scalp, above a targeted cortical region, the coil of a magnetic stimulator. A focal stimulation using a figure-of-eight coil is mandatory. The intensity of stimulation is expressed as a percentage of the motor threshold of a muscle at rest in the painful territory. The stimulation is performed just below motor threshold. The frequency and the total number of delivered pulses depend on the study. One single session should last at least 20 min and should include at least 1000 pulses. Daily sessions can be repeated for one or several weeks. There is no induced pain and no need for anaesthesia or for hospital stay during the treatment.

The rationale is the same as for implanted MCS. The stimulation is thought to activate some fibres that run through the motor cortex and project to remote structures involved in some aspects of neuropathic pain processing (emotional or sensori-discriminative components). The method is non-invasive and can be applied to any patient with drug-resistant, chronic neuropathic pain, who could be candidate for the implantation of a cortical stimulator. As the clinical effects are rather modest and short-lasting beyond the time of a single session of stimulation, this method cannot be considered a therapy, except if the sessions of stimulation are repeated for several days or weeks.

Evidence identified

We identified some reviews, none systematic, and 14 controlled studies that used sham stimulations in crossover or parallel groups, 280 patients with definite neuropathic pain (CPSP, spinal cord lesions, trigeminal nerve, brachial plexus, or limb nerve lesions, phantom pain and CRPS II). Efficacy, rather than varying between pain conditions, mostly depends on stimulation parameters. There is consensus from two RCTs in patients with CPSP or various peripheral nerve lesions that rTMS of the primary motor cortex, when applied at low-frequency (i.e. 1 Hz or less), is ineffective (class II) [48,49]. Focal-coil stimulations at high-rate (5–20 Hz), of long-duration (at least 1000 pulses) and possibly repeated sessions, induce pain relief (>30%) in about 50% of patients (class II/III) [50–52]. The effect begins a few days later and its duration is short, <1 week after a single session. Another important aspect is that a positive response to high-frequency rTMS is probably predictive of a positive outcome of subsequent chronic epidural MCS (class II) [49].

There is insufficient evidence for other indications or other techniques, including magnetic stimulation of the dorsolateral prefrontal cortex or the parietal cortex, as well as transcranial direct current stimulation. The efficacy and safety outcomes of transcranial magnetic stimulation are detailed in Table 9 and 10.

Table 9.   Summary of efficacy and safety of rTMS, primary motor cortex stimulation, 1 Hz or less
IndicationVolume of evidence [no. trials (no. patients)]EFNS classSummary of efficacySummary of harmsEFNS gradeComments
Stroke (n = 32), Spinal cord lesion (n = 4), Trigeminal nerve lesion (n = 1), Brachial plexus or limb nerve lesion (n = 8), Phantom limb pain (n = 14)New primary studies Three sham-controlled trials All negative (59 p.) Lefaucheur et al. 2001a André-Obadia et al. 2006 Irlbacher et al. 2006 II II IIINo efficacy Pain relief ≥30%: 5% (mean pain relief: 4%)No reported complicationsBNo significant effect compared with sham stimulation
Table 10.   Summary of efficacy and safety of rTMS, primary motor cortex stimulation, 5 Hz or more
IndicationVolume of evidence [no. trials (no. patients)EFNS classSummary of efficacySummary of harmsEFNS gradeComments
  1. rTMS, repetitive transcranial magnetic stimulation; CRPS, complex regional pain syndrome.

Stroke (n = 98), Spinal cord lesion (n = 24), Trigeminal nerve lesion (n = 60), Brachial plexus or limb nerve lesion (n = 36) CRPS (n = 10)New primary studies [11 sham-controlled trial (281 p.)] Pain relief 30%: 46% (mean pain relief: 26%)No reported complicationsBNo significant effect compared to sham stimulation in case of circular coil (Rollnik et al. 2002) or 5 Hz-rTMS (Irlbacher et al. 2006) and <1000 pulses per session (Rollnik et al. 2002; Irlbacher et al. 2006) Better pain relief in case of repeated sessions (Khedr et al. 2005) or stimulation of adjacent cortical area (Lefaucheur et al. 2006b) Pain relief duration: less than one week after a single session; about two weeks after one week of stimulation
Positive studies (228 p.) 104 responders/206 patients. Efficacy regarding indication:  idem for stroke vs.  trigeminal nerve lesion (Lefaucheur et al. 2004; Khedr et al. 2005) or brachial plexus lesion (Lefaucheur et al. 2004);  better for thalamic vs.  brainstem stroke (Lefaucheur et al. 2004)   poorer results for  spinal cord lesion (Lefaucheur et al. 2004) CRPS: no significant difference with the other causes (Pleger et al. 2004)
Lefaucheur et al. 2001aII
Lefaucheur et al. 2001bII
Lefaucheur et al. 2004aII
Pleger et al. 2004III
Khedr et al. 2005II
Hirayama et al. 2006II
Lefaucheur et al. 2006aII
Lefaucheur et al. 2006bII
Stroke (n = 20), Spinal cord lesion (n = 6), Trigeminal nerve lesion (n = 1), Brachial plexus or limb nerve lesion (n = 8) Phantom limb pain (n = 15), CRPS (n = 2), non-neuropathic  (n = 1)Negative studies (53 p.):     
Rollnik et al. 2002III    
André-Obadia et al. 2006II    
Irlbacher et al. 2006III    

There is moderate evidence that rTMS of the motor cortex, using a figure-of-eight coil and high frequency (5–20 Hz) induces significant pain relief in CPSP and several other neuropathic pain conditions (level B). However, because the effect is modest and short-lasting, rTMS should not be used as the sole treatment in chronic neuropathic pain. It may be proposed for short-lasting pains or to identify suitable candidates for an epidural implant (MCS). In contrast, in the same pain conditions, low-frequency rTMS is probably ineffective (level B).

General comments

  1. Top of page
  2. Abstract
  3. Background and objectives
  4. Search methods
  5. Results
  6. General comments
  7. Declaration conflict of interest
  8. References
  9. Supporting Information

Most trials on neurostimulation for pain relief did not comply with the requirements of evidence-based medicine (EBM), often because of the difficulty in using an adequate comparator for these stimulations. Level-B recommendations could however be drawn for some procedures in some pain conditions. Naturally, some neurostimulation procedures are relatively new, thus the available evidence is still sparse and it would be pre-mature to draw negative conclusions (Fig. 1).


Figure 1.  Schematic representation of different neurostimulation procedures, e.g. for a patient with pain in the left hand because of peripheral nerve injury.

Download figure to PowerPoint

Peripheral stimulations have been used very little in neuropathic pain. Acupuncture-like stimulations are probably more efficacious than high-frequency TENS, but we do not have strong evidence. Unlike some other neurostimulation procedures, TENS is extremely easy to apply and devoid of any risk. This is why TENS is so widely used in acute and chronic pain patients, with little concern whether the improvements are because of a placebo effect or not. This may also hold true for neuropathic pain patients. SCS has class II RCT evidence. Its efficacy has been so far demonstrated in two conditions, which are not ‘definitely neuropathic’: FBSS and CRPS type I. Pain in FBSS is usually mixed and it is difficult to extract the neuropathic component, and CRPS I is still a ‘putative neuropathic’ pain.

Spinal cord stimulation, DBS and MCS are typically used when all other treatments have failed. This context should be taken into account when making recommendations. We analysed only published evidence. Thousands of stimulators are implanted every year and only a tiny minority appears in published studies. Absence of evidence is not evidence of absence of effect, and low-level evidence (i.e. case series) should be given some credence. For some indications, there was a considerable body of ‘positive’ case series findings, sometimes over long periods of time. Furthermore, the whole field has been largely characterized by a heavy dependence on the outcome measure ‘50% pain relief’ as a threshold indicator of success, after both trial and definitive stimulation, which may distort the true picture. Others have found a 30% pain relief to correspond to a clinically meaningful success [5], and factors beyond changes in pain intensity are also relevant.

Although not a new therapy, DBS has metamorphosed considerably over the last decade, concomitantly with advances in both stimulator technology and neuroimaging techniques, leading to improved efficacy and reduced complications. DBS should be performed in experienced, specialist centres, using established outcome measures and willing to publish their results. Whereas its efficacy in CPSP is controversial, DBS appears more promising for phantom limb pain and trigeminal neuropathic pains.

Motor cortex stimulation is useful in CPSP and in central or peripheral facial pain. Interestingly, the proportion of good and excellent results increases consistently in patients with facial pain relative to all other classes. The reason is not yet established. Candidates for MCS have neuropathic pain that has been resistant to drugs and often to other interventions. In view of the potential development of this method, it is of the utmost importance that placebo-controlled, double-blind studies are produced to increase the level of evidence, particularly because of MCS, not being perceived by the patient, allows a perfect placebo.

As with TENS, the efficacy of rTMS seems to increase with dose: higher frequency, longer duration of the session, and more sessions tend to yield better results. Because the clinical effects are rather modest and short-lasting, rTMS cannot be considered as a therapeutic method for the long term, except if the sessions of stimulation are repeated for several days or weeks. Currently, rTMS can be proposed as a non-invasive pre-operative therapeutic test for patients with drug-resistant chronic pain who are candidates for surgically-implanted chronic MCS.

Concerning harms (detailed in the Tables), TENS and rTMS are virtually harmless. SCS, DBS and MCS do entail adverse events in a large proportion of patients (up to 20% with MCS and 40% with SCS experience one or more complications). However, most of these are simple lead migration or battery depletion that do not produce physical harm and can usually be solved. Real harms are few, usually wound infection (3.4% with SCS, 7.3% with DBS and 2.2% with MCS) and very rare cases—often single cases—of aseptic meningitis, transient paraparesis, epidural haematoma, epileptic seizures and skin reactions, none being life-threatening. Our search disclosed one case only of pre-operative death 20 years ago [53]. Indeed, one of the reasons for the use of neurostimulation therapy is that the application of low-intensity electrical currents is not associated with any of the side effects entailed by drugs.

Finally, we feel that neurostimulation therapy will prove to be useful for a broader indication than is suggested by our search. We hope that future trials are designed bearing in mind the EBM requirements. Although it is admittedly difficult to find a credible placebo for neurostimulation therapy, the investigators may compare their procedure to other treatments. Furthermore, we recommend that investigators pay attention to definition of diagnosis, inclusion criteria, blind assessment of the outcomes, and impact on patient-related variables such as quality of life and daily living activities.

Declaration conflict of interest

  1. Top of page
  2. Abstract
  3. Background and objectives
  4. Search methods
  5. Results
  6. General comments
  7. Declaration conflict of interest
  8. References
  9. Supporting Information

RST has a consultant contract with Medtronic, as an expert in Health Care Policy and Clinical Trial Design. PH, LGL, JPL and BS received honorarium from Medtronic for lectures or advisory boards. The other authors have nothing to declare.


  1. Top of page
  2. Abstract
  3. Background and objectives
  4. Search methods
  5. Results
  6. General comments
  7. Declaration conflict of interest
  8. References
  9. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Background and objectives
  4. Search methods
  5. Results
  6. General comments
  7. Declaration conflict of interest
  8. References
  9. Supporting Information

Appendix 2. Full list of studies.

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