Abstract: Drug-refractory pain is an indication for neurostimulation therapy, which can be either non-invasive [mainly transcutaneous electrical nerve stimulation (TENS), repetitive Transcranial Magnetic Stimulation (rTMS), and transcranial direct current stimulation (tDCS)] or invasive which requires the intervention of a surgeon to implant electrodes and a pulse generator [peripheral nerve stimulation (PNS), nerve root stimulation (NRS), spinal cord stimulation (SCS), deep brain stimulation (DBS), and motor cortex stimulation (MCS)]. In this review, the respective mechanisms of action and efficacy of TENS, rTMS, and tDCS are discussed. The advantages of TENS include non-invasiveness and ease to use, so that the technique can be operated by the patient. TENS can be indicated as a first-line treatment in patients suffering from peripheral neuropathic pain if the painful area is limited and the sensory deficit moderate. The current best indications are chronic radiculopathies, mononeuropathies, and postherpetic pain. Test sessions allow to select suitable patients and to determine the site, frequency, and optimal intensity of stimulation. Three to four 30- to 60-minute sessions per day are usually recommended. With regard to rTMS, published randomized controlled studies in chronic neuropathic and non-neuropathic pain (fibromyalgia) reached a sufficient level of evidence to recommend this technique for the indication of implanted motor cortex stimulation for the treatment of refractory neuropathic pain or as a long-term treatment for pain syndromes, in which surgery is not indicated, such as fibromyalgia. Other indications, concerning either chronic or acute pain syndromes, such as postoperative pain, should be developed in parallel with the optimization of stimulation parameters. This also includes the availability of new coils and magnetic field waveforms and progress in neuronavigation techniques, especially by the integration of functional imaging and high-resolution EEG data.
Neuropathic pain was officially defined by the International Association for the Study of Pain (IASP) in 1994 as a “pain initiated or caused by a primary lesion or dysfunction of the nervous system.” In 2008, a new definition of neuropathic pain was proposed by the NeuPSIG (”Special Interest Group on Neuropathic Pain”) (Treede et al., 2008) as follows: “pain caused by a lesion or disease of the somatosensory nervous system,” thereby excluding from the scope of neuropathic pain, dysfunctional pain, which corresponds to a dysfunction of the central inhibitory processes of pain control (Crofford et al., 2005). This last category includes a group of very common pain syndromes, such as fibromyalgia, irritable bowel syndrome, tension headaches, idiopathic orofacial pain, complex regional pain syndrome, with a marked co-morbidity between some of these pain syndromes (Kato et al., 2006). However, clinical or imaging data, as well as the efficacy, albeit limited, of drugs used in neuropathic pain (antidepressants and antiepileptics) and of neurostimulation therapies, suggest that some of these clinical conditions could actually be related to neuropathic pain (Oaklander et al., 2006). Nerve damage causing neuropathic pain can locate either in the peripheral (affecting nerve roots or trunks, sensory ganglia, or plexuses) or central nervous system (affecting the spinal cord or the brain). The most common etiologies are diffuse peripheral neuropathy, focal peripheral lesion (including trigeminal nerve lesion) of traumatic (brachial plexus avulsion, for example) or infectious origin (postherpetic neuralgia, for example), phantom limb pain, spinal cord lesion (including spine trauma and syringomyelia), and focal brain lesions (including multiple sclerosis and central post-stroke pain).
Optimal management of neuropathic pain constitutes a major challenge, in view of the frequency and severity of these syndromes and their associated direct and indirect costs: two recent studies evaluated the prevalence of predominantly neuropathic pain or pain with neuropathic characteristics to be 8% (Torrance et al., 2006) and 7% (Bouhassira et al., 2008) of the general population, respectively. Unfortunately, neuropathic pain is still underdiagnosed and poorly managed, although this type of pain has sometimes a major impact on daily living activities, quality of life, and work and social life. The prevalence of anxiety, depression, and sleep disorders is higher among patients with neuropathic pain than among patients with other types of pain (Freynhagen et al., 2006). Better training of practitioners is essential to ensure more reliable diagnosis (especially with the use of rapid and simple screening tools such as validated autoquestionnaires) and more appropriate treatment. Well conducted epidemiological studies are also essential to define the respective roles of the various etiologies, and to guide research in this field. Efficacy and usefulness of the various treatments available remain to be evaluated.
The principles of graduated management of neuropathic pain are schematically based on a detailed clinical and complementary diagnostic assessment (NeuPSIG guidelines, Haanpää et al., 2011) in order to recognize, localize, and identify the cause of neuropathic pain and an appropriate pharmacological treatment (Attal et al., 2010). Using the methodology of European Federation of Neurological Societies (EFNS) (Brainin et al., 2004), publications are classified in Class I, II, III, or IV. Class I: prospective study, large size (n≥25), randomized, controlled against placebo (or equivalent). Class II: prospective study, small sample size (n<25), controlled against placebo (or equivalent) or retrospective study, large size, controlled against placebo. Class III: all other types of controlled study as there are certain biases or methodological limitations. Class IV: uncontrolled study, case series, or single cases. Then, the level of evidence A, B, and C is determined. Level A: established as effective (>1 class I studies, or >2 convincing class II studies). Level B: probably effective (1 class I study or two convincing class II studies, or >2 convincing class III studies). Level C: possibly effective (1 class II study or two convincing class III studies). No recommendation: <2 studies of class III or class IV studies only. Studies from the same team are counted only once (at their best class).
First-line drugs, with level of evidence A or B for peripheral or central pain, include antiepileptics (gabapentin or pregabalin), tricyclic antidepressants, and/or lidocaïne patches (for localized allodynia). Tramadol is recommended to treat acute exacerbations of pain, especially in combination with paracetamol. For second-line treatment, selective serotonin-norepinephrine reuptake inhibitors (SNRIs), tramadol, or major opioids may be prescribed, with caution for long-term use of opioids, in view of the generally high doses required in this indication, increased risk of adverse effects, dependence/misuse, and induced hyperalgesia. If monotherapy is only partially efficacious, dual therapy can be proposed, for example, combining antiepileptic and antidepressant drugs. For central pain, especially in case of spinal cord injury or post-stroke pain, second-line treatment also includes lamotrigine (with a level of evidence B ) and cannabinoids. The non-pharmacological treatments should be proposed especially as add-on therapy, although their efficacy has not been evaluated as rigorously as that of pharmacological treatments. When this type of treatment is effective, drug intake can be limited and therefore the adverse effects of medication can be reduced. The main non-pharmacological techniques available to date include neurostimulation therapy, either non-invasive, such as transcutaneous electrical nerve stimulation (TENS), repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS), or invasive, such as peripheral nerve stimulation (PNS), nerve root stimulation (NRS), spinal cord stimulation (SCS), deep brain stimulation (DBS), and motor cortex stimulation (MCS); rehabilitation techniques, either motor, cognitive, or visuomotor (mirror techniques), especially for phantom limb pain or complex regional pain syndrome; and psychotherapy, especially cognitive and behavioral therapies, hypnosis, and relaxation, whose indications and efficacy have not yet been clearly established.
Only non-invasive stimulation therapy (TENS, rTMS, and tDCS) will be discussed in this article.
Transcutaneous Electrical Nerve Stimulation (TENS)
TENS is a simple technique of analgesic therapy, whose clinical benefit to relieve chronic pain was first reported by Wall and Sweet in 1967.
Principles, mechanisms of action, and stimulation parameters
Two types of stimulation can be distinguished based on their frequency and intensity:
1. “Standard” or “conventional” TENS uses high frequency stimulation (70-100 Hz) at low intensity, beyond pain threshold, causing paresthesia (”pins and needles,” sensation of vibration) in the painful area. The mechanism of action of conventional TENS is based on the gate-control theory, according to which stimulation of large-caliber Aβ afferent fibers inhibits the activity of small-caliber Aδ and C fiber at segmental spinal level. The stimulation electrodes are generally positioned over the nerve trunk which innervates the painful region (segmental stimulation), or on the neighboring metamere (extra-segmental), when allodynia or hyperalgesia is present.
Several points should be underlined with respect to standard or conventional TENS. First, the inhibition of pain is obtained by the stimulation of large Aβ fibers, of which function must be relatively preserved, and is strictly homotopic. Patients suffering from a major loss of these fibers (which can be evaluated clinically by the sensation generated by TENS) cannot benefit from this type of technique. Indeed, TENS produces paresthesia in the whole area of pain. The analgesic effect develops after twenty minutes to one hour in most cases, but rather quickly vanished once the stimulation is stopped (after-effects often last about thirty minutes up to several hours in some patients). The pain must be confined to a relatively restricted area and/or a region innervated by a nerve which is easily accessible to stimulation.
2. “Acupuncture-like” TENS (AL-TENS), delivered by a cutaneous electrode or “electro-acupuncture” needles, uses low frequencies (1-2 Hz) and high intensity stimulation. AL-TENS has a mechanism of action different from that of conventional TENS. It is thought to activate, through a long-loop, the anti-nociceptive systems, including descending inhibitor controls. Because it is at least partly naloxone-reversible, the analgesic effect is thought to be also mediated by the opioid system (Fukazawa et al., 2005). Therefore AL-TENS is potentially active on central pain. Peripheral vasodilatory effects have also been reported. This stimulation is somewhat uncomfortable or even painful, can be applied to heterotopic regions, and have prolonged after-effects, sometimes lasting several hours. The prolonged post-stimulation hypoalgesia provided by AL-TENS has been proved in a randomized controlled trial (RCT) study of experimental cold-induced pain in healthy volunteers (Francis et al., 2011).
Considering their excellent tolerability and ease of use (apart from possible interference with a cardiac pacemaker), TENS techniques can be proposed as an add-on therapy in many cases of localized neuropathic pain, combined with drugs or other non-pharmacological treatments.
Efficacy of TENS
Numerous RCTs and meta-analyses have been published regarding TENS efficacy. Since “sham” stimulation cannot be performed because of the induced paresthesia, these trials are only single-blind. A systematic review of 38 RCTs, including two studies of neuropathic pain, concluded that the analgesic effects of TENS increased with the “dose” of stimulation (session duration x session frequency x total time during which the technique was used) (McQuay, 1997).
The efficacy of TENS was mostly studied in non-neuropathic pain syndromes, such as acute postoperative pain, chronic low back pain, chronic headache (Figure 1), dysmenorrhea, labor pain, etc. However, these studies were rather heterogeneous, in terms of frequency or intensity of stimulation, application sites, and treatment duration. A recent RCT showed that both real and sham TENS produced similar effects over a period of 1 year, suggesting long-lasting placebo effect (Oosterhof et al., 2012).
In 2007, EFNS (Cruccu et al., 2007) emphasized the difficulty of establishing clear recommendations for the use of TENS in neuropathic pain, considering the great variability of stimulation parameters across studies. However, “conventional” TENS appears to be more effective than placebo (level of evidence C ), although probably less effective than AL-TENS or other types of neurostimulation therapy (level B).
Practical application of TENS
The main advantage of TENS is its almost total non-invasiveness and relative simplicity, so that this technique can be operated by the patient. TENS is indicated as a first-line treatment of peripheral neuropathic pain present in a limited area accompanied by a mild or moderate sensory deficit (hence TENS needs to induce paresthesia in the painful region in order to obtain an analgesic effect). The existence of mechanical allodynia requires achieving the stimulation outside the area of pain. The current best indications are chronic radiculopathies, mononeuropathies, and postherpetic pain. Test sessions are used to select the right candidates, to determine the site, frequency, and optimal intensity of stimulation which may vary across patients, and to help to train the patients to use the device. Three to four 30- to 60-minute sessions per day are usually recommended, but the patient can also use TENS for more prolonged periods with only short breaks during the day.
However, TENS effects are limited in time and for more stable efficacy over time, it has been proposed to implant percutaneously or surgically electrodes in contact with a nerve trunk and connected to a chronic stimulator (peripheral nerve stimulation). Electrodes are usually implanted around large nerve trunks majoring the limbs, but stimulation can also affect the great occipital nerve. More rarely, to cover areas that are deep or less accessible electrodes can be implanted at the emergence of a nerve root (nerve root stimulation), like the stimulation of sacral roots (S2 or S3) to treat refractory pelvic or perineal pain. For trigeminal neuralgia, electrodes can be placed in the Meckel’s cave to stimulate the Gasser ganglion. However, the EFNS guidelines (Cruccu et al., 2007) did not report any RCT for these techniques.
Repetitive Transcranial Magnetic Stimulation (rTMS)
A large number of studies are now available concerning the efficacy and safety of rTMS in thousands of healthy subjects or patients with various neurological or psychiatric diseases, allowing a better evaluation of the benefit/risk balance of this technique. This technique is also improving through the integration of neuroimaging and neurophysiological data to optimize indications and targeting.
At the present time, three indications present a sufficient level of evidence to formally adopt the therapeutic indication for the use of rTMS in clinical practice: chronic neuropathic pain, major depressive episodes, and auditory hallucinations. However, many studies are underway for other indications, including movement disorders, stroke rehabilitation, epilepsy, tinnitus, and various psychiatric conditions, such as obsessive-compulsive disorders, post-traumatic stress disorder, or negative symptoms of schizophrenia. Guidelines from French clinical and scientific societies concerning the safety and indications of rTMS have been recently published (Lefaucheur et al., 2011).
Principles of rTMS
The effects of TMS are based on the law of electromagnetic induction, which states that a rapidly changing magnetic field produces an electric current when passing across a conductor, such as the excitable neural network of the human cerebral cortex.
In 1985, Barker et al. reported the first clinical use of a TMS machine to stimulate the motor cortex through a magnetic coil placed over the scalp. The magnetic field delivered by the coil is only slightly attenuated by tissues such as the scalp, skull bone, meninges, and cerebrospinal fluid layer, and produces an electric current sufficient to depolarize the axons of cortical neurons. The use of a figure-of-eight coil limits the stimulated volume to several cm2.
Most available data on the effects of TMS were obtained by stimulating the primary motor cortex (M1) to generate muscle responses (motor evoked potentials, MEPs) whose amplitude depends on the number of motor neurons activated. Axons (especially those of interneurons running parallel to the cortical surface) are preferentially stimulated by motor cortex TMS compared to neuronal cell bodies. Therefore neural networks are excited by TMS and brain structures distant from the site of stimulation can be activated.
Mechanisms of action of rTMS
When applied to M1, the effects of rTMS have been evaluated on the basis of MEP size changes in healthy subjects. In 1994, Pascual-Leone showed that a series of 20 shocks delivered at a frequency >2 Hz could increase MEP amplitude. High-frequency stimulation ≥5 Hz was subsequently described as facilitating corticospinal output, while low-frequency stimulation ≤1 Hz reduced the motor output.
However, the marked inter- and intra-individual variability of rTMS must be emphasized, and the effects of rTMS also appear to depend on the level of cortical excitability at the time of the stimulation, in line with the concept of homeostatic plasticity. This accounts for the variability of the results observed for the same rTMS protocol according to whether it is performed in healthy subjects or patients, or according to the nature of ongoing drug therapy. The therapeutic value of rTMS is essentially due to the persistence of the observed effects well beyond the stimulation time. The duration of the after-effects could increase with the number of shocks delivered.
The resulting action of rTMS relates to the intrinsic properties and orientation of nerve fibers present in the cortical region stimulated, as the TMS-induced current can activate local inter-neuronal circuits, as well as circuits projecting onto distant structures. Thus, depending on the parameters of stimulation and the underlying brain, motor cortex rTMS can activate distant structures such as the dorsal premotor cortex, supplementary motor area, primary somatosensory cortex (S1), cingulate motor area, or even deep brain (basal ganglia) and cerebellar regions (Figure 2).
The analgesic effects of motor cortex rTMS appear to be fairly similar, although not strictly identical, to those obtained by implanted epidural motor cortex stimulation, with a remote action on structures involved in the sensori-discriminative and emotional aspects of pain through the activation of GABAergic or opioidergic systems (de Andrade et al., 2011).
In most rTMS protocols, the intensity of stimulation is expressed as a percentage of the motor threshold for a muscle at rest (RMT). To produce analgesic effects, motor cortex rTMS is delivered at an intensity corresponding to 80-90% of RMT for a muscle located in the painful zone. The duration of stimulation time per session is at least ten to twenty minutes to reach a total number of more than 1,000 pulses.
The possibility of delivering sham stimulation allows RCTs to be conducted double-blind. Compared to the “real” stimulation, the sham stimulation must be delivered with the same coil position on patient’s scalp, producing the same sensory sensation and the same noise, but having no biological effect in the brain.
Contraindications and precautions of rTMS
The only absolute contraindication is the presence of ferromagnetic material or an implanted neurostimulation device, in close contact with the coil. In the case of cortical stimulation (coil applied to the scalp), this contraindication essentially concerns cochlear implants and some intracranially implanted devices.
In contrast, cortical TMS can be performed in the presence of a cardiac pacemaker or vagus nerve or spinal cord stimulation, if a screen more than 10 cm thick is used to protect these devices from any unfortunate dysfunction potentially induced by the magnetic field.
rTMS is used only in clearly justified and particular indications and is not recommended in pregnant women, children, and patients with hearing disorders (rTMS is contraindicated in children under the age of 2 years).
The only risk that needs to be considered in relation to the use of rTMS is that of inducing seizures (but not an epileptic disease). Seizure prophylaxis by antiepileptic drugs (at effective doses in patients with a history of seizures, or at prophylactic doses in patients with no history of seizures) administered concomitantly to the stimulation protocol must be considered in patients with a history of poorly treated epilepsy, focal brain lesions, history of head injury, administration of drugs or substances that lower the seizure threshold, sleep deprivation, or drug withdrawal.
Efficacy of rTMS in chronic pain
Rather than an isolated therapy, rTMS should be considered as an add-on treatment, combined with drugs or physiotherapy, to increase the speed and extent of the therapeutic response. This type of combined strategy has already been evaluated in the treatment of depression and in stroke rehabilitation.
1. Neuropathic pain
The development of non-invasive, non-pharmacological treatments such as rTMS is justified by the frequency of neuropathic pain and the often partial efficacy of pharmacological treatments (only 30 to 40% of patients obtain more than 50% pain relief). In 2011, 31 studies had been published on rTMS for the treatment neuropathic pain, including 15 controlled trials on series of at least 10 patients. Stimulation for neuropathic pain is delivered to the precentral motor cortex of the cerebral hemisphere contralateral to pain location (generally in the homotopic cortical representation of the painful zone).
The conclusions of recent guidelines on the use of rTMS (Lefaucheur et al., 2011) comply with those of the three meta-analyses already published on the role of rTMS in the treatment of neuropathic pain (Cruccu et al., 2007; Leo et al., 2007; Leung et al., 2009). The main point is that high-frequency rTMS (≥5 Hz) delivered to M1 produces significant analgesic effects of more than 30% in 45-60% of patients, including a remarkable effect exceeding 50% for 30% of them. Better results in terms of intensity and especially duration can be obtained by performing repeated daily sessions of high-frequency rTMS. In contrast, low-frequency rTMS (≤1 Hz) is not superior to sham stimulation to produce analgesia, which was found in about 6% of patients.
It is noteworthy that rTMS is very well tolerated in all studies, regardless of the protocol applied. The analgesic efficacy of rTMS is predictive of that of epidural motor cortex stimulation (Lefaucheur et al., 2011). Therefore, single sessions of motor cortex rTMS can be used as a preoperative assessment tool. However, the place of repeated sessions of rTMS as a treatment option for neuropathic pain needs to be more clearly defined.
The value of new targets of rTMS, especially prefrontal targets, is currently under evaluation, according to the demonstrated efficacy of this target in the treatment of depression by rTMS and according to the close relationship between depression and chronic pain.
2. Other types of pain
The analgesic effects of rTMS have been evaluated in various non-neuropathic pain syndromes, such as fibromyalgia, migraine, complex regional pain syndrome (CRPS) type I, and visceral pain.
In fibromyalgia, five studies are available to date concerning a total of 108 patients. Pain was reduced and quality of life was improved for up to 30 days beyond a series of daily sessions of high-frequency rTMS delivered to the left motor cortex in a prospective, double-blind RCT performed in 30 fibromyalgic patients (class I study) (Passard et al., 2007). A second study published by the same team (Mhalla et al., 2011) confirmed these results and demonstrated the value of maintenance sessions to obtain a prolonged effect over several months.
In migraine, rTMS has been used in a much smaller number of patients. The frequency and intensity of migraine attacks and drug intake were reduced for up to two months after high-frequency rTMS sessions delivered to the left prefrontal cortex in a prospective, double-blind RCT performed in 11 patients with migraine (class III study) (Brighina et al., 2004).
In CRPS type I, two controlled studies concerning a total of 33 patients showed a significant reduction of pain intensity over a short follow-up period after sessions of high-frequency rTMS delivered to M1 (Pleger et al., 2004, Picarelli et al., 2010).
Practical modalities of rTMS (Figures 3 and 4)
rTMS is an outpatient technique not requiring hospitalization. However, the first session can be performed during a day admission in view of the multidisciplinary assessment that must be performed prior to the rTMS protocol. The following sessions can be performed in the context of outpatient visits, each session lasting less than 30 minutes.
Two types of protocols must be distinguished:
1. The use of preoperative rTMS sessions in the context of planned implanted motor cortex stimulation for the treatment of refractory neuropathic pain. The clinical response to rTMS is positively correlated with a good outcome of epidural MCS, and thus, appears to be an important criterion for selecting good candidates for implantation (André-Obadia et al., 2006; Hosomi et al., 2008; Lefaucheur et al., 2011). In practice, two to four sessions of high-frequency rTMS delivered to M1 representation of the painful zone are needed, separated by at least two weeks. The first session should be a sham session, to be not influenced by the effect produced by a previous session of real stimulation. The 2nd session should be a real one. A third and a fourth session may be performed to reproduce the results of the 2nd session or to test other targets within the precentral cortex, contralateral to pain side.
2. The use of rTMS for therapy, outside the indication of implanted motor cortex stimulation, particularly for the treatment of fibromyalgia, glossodynia, migraine, and CRPS. Ten sessions on ten consecutive weekdays can be performed, followed by monthly maintenance sessions.
Summary of the recommendations
According to the recently published French guidelines (Lefaucheur et al., 2011), there is a sufficient level of evidence to conclude that there is a significant analgesic efficacy of high-frequency stimulation delivered to the motor cortex in patients with neuropathic pain (several convincing class I and II RCTs leading to a level A of evidence). This effect persisted during the week following a single session, and the magnitude of the analgesic effect and its duration appeared to increase with the repetition of daily sessions. In non-neuropathic pain, a possible analgesic effect was observed in fibromyalgia or CRPS, with a level B/C of evidence.
The main perspectives for technical development of rTMS are based on the availability of new coils and magnetic waveforms, and on the progress of neuronavigation techniques, especially by integrating functional imaging and high-resolution EEG data to optimize targeting.
The major limitation of this technique is the relatively short duration of the induced clinical effects, which can be partly compensated by the repetition of daily sessions and the use of maintenance sessions.
Transcranial Direct Current Stimulation (tDCS)
Few tDCS studies have been published to date in the context of pain treatment and they are very heterogeneous in terms of stimulation parameters, repetition of sessions and indications (fibromyalgia, trigeminal neuralgia, chronic low back pain, and prophylactic treatment of migraines by cathodal tDCS of the visual cortex). The level of evidence is currently lower than that for rTMS. A recent Cochrane review concluded that there is absence of formal evidence of tDCS efficacy in pain domain, leaving room for controlled studies on a larger number of patients (O’Connell et al., 2010). The intensity of stimulation is usually set at 1 or 2 mA. The polarity of the electodes is generally anodal. Each session lasts ten to twenty minutes. Like rTMS, these sessions must be repeated on five to ten consecutive days.
However, this technique could be further developed in the future if the encouraging preliminary results are confirmed, especially for the treatment of various chronic pain syndromes, similar to those previously mentioned as rTMS indications. The main advantages of this technique are its ease of use and programming, even operated by the patient, its small size, and its low cost (about €5,000 for a tDCS machine versus €50,000 for an rTMS machine).
Despite their limitations, various non-invasive stimulation techniques can be used to treat pain syndromes. TENS, an easy and harmless method, can be used as an add-on treatment to medication in patients with chronic pain, especially of peripheral origin and limited anatomical distribution. rTMS and tDCS, because of their safety and their relatively low cost in view of the economic burden of chronic pain, will probably extensively developed in the coming years for the treatment of various types of neuropathic and non-neuropathic pain syndromes.
The authors report no conflicts of interest.
Julien Nizard, M.D., Ph.D., Centre d’Evaluation et de Traitement de la Douleur, Centre Fédératif Douleur-Soins de Support-Ethique clinique, Centre Hospitalier Universitaire Laënnec, 44093 Nantes, France.
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