In a multicentric single-blind RCT study, Fioravanti et al. (Fioravanti et al., 2007) assessed the effects of a combination of mud packs and thermal baths (with two types of mineral water) on patients with primary FS who responded poorly to pharmacological therapy. They also analysed tolerance to mud packs, since no trial using this thermal treatment has been performed in FS. Eighty patients with primary FS were randomly allocated to two groups: 40 underwent a cycle of 12 mud packs and thermal baths over a period of 2 weeks,

treatment. All participants stayed in the Dead Sea area for 10 days and continued their regular medications for FS. Physical functioning, assessed by the Fibromyalgia Impact Questionnaire (FIQ), FS-related symptoms, assessed by VAS, Functional Disability Index (FDI), Health Assessment Questionnaire (HAQ), tenderness measurements (Tender Point Count [TPC] and dolorimetry) and QoL index (Short Form-36 [SF36] and Arthritis Impact Measurement Scales [AIMS]) were recorded at basal time, at the end of treatment and 1 month and 3 months later. Physical functioning and tenderness improved moderately in both groups. With the exception of tenderness threshold, the improvement was especially evident in the treatment group and even persisted beyond 3 months. Relief in the severity of FS-related symptoms (pain, fatigue, stiffness) and reduced frequency of symptoms (headache, sleep problems and subjective joint swelling) were reported in both groups, but lasted longer in the treatment group. Significant improvement in most subscales of the SF36 was reported for both groups. Interestingly, the improvement in physical components of the QoL index usually lasted 3 months, whereas improvement in measures of psychological well-being was of shorter duration. Subjects in the balneotherapy group reported greater and longer-lasting improvement than subjects in the control group. Improvements in the control group were explained by temporary changes in lifestyle combined with the relaxed

Evcik et al. (Evcik et al., 2002) also reported significant improvements lasting up to 6 months in patients treated with balneotherapy. In this study 42 patients with FS were randomly assigned to two groups. One group (22 patients) bathed for 20 min at 36°C once a day, five times per week for 3 consecutive weeks (total 15 sessions) and the other group (20 patients) continued their regular medications without balneotherapy. Patients were evaluated by TPC, VAS for pain, Beck's Depression Index (BDI) and FIQ at basal time, after therapy and 6 months later. The balneotherapy group showed statistically significant improvements in TPC, VAS score, FIQ and BDI values at the end of therapy; at 6 months, the improvement in

A study by Donmez et al. (Donmez et al., 2005) compared the effects of a stay at a spa centre plus balneotherapy and the effects of regular care (control), recording significant improvements in major outcome measures, such as pain, TPC and FIQ with respect to control. The pain and TPC results persisted for up to one month and the FIQ results for up to 6 months. However, they could also be attributed to the effects of the spa stay (not offered

Ardiç et al. (Ardiç et al., 2007) investigated the clinical effects of balneotherapy in the treatment of FS, considering serum levels of certain inflammatory markers. One group of patients (n22) bathed 20 min per day for five days per week for three consecutive weeks and the other group (n22) (control) continued with pharmacological treatment. A statistically significant improvement in algometric score, VAS, BDI, TPC and FIQ was only

In a multicentric single-blind RCT study, Fioravanti et al. (Fioravanti et al., 2007) assessed the effects of a combination of mud packs and thermal baths (with two types of mineral water) on patients with primary FS who responded poorly to pharmacological therapy. They also analysed tolerance to mud packs, since no trial using this thermal treatment has been performed in FS. Eighty patients with primary FS were randomly allocated to two groups: 40 underwent a cycle of 12 mud packs and thermal baths over a period of 2 weeks,

to controls, who continued their habitual medical treatment and/or daily exercises).

found in the balneotherapy group at the end of the treatment cycle.

atmosphere of the Dead Sea resort.

all parameters except BDI persisted.

40 were enrolled as controls and continued their regular outpatient care routine. Because many other non-specific factors may also contribute to the effects observed after spa therapy, including changes in the environment, pleasant scenery and the absence of work duties, in order to temper these factors, all patients lived near the spa, continued working and did not modify their lifestyles. Another aspect that often amplifies the effects of spa therapy is its frequent association with physio-kinesiotherapy. These treatments were excluded from the protocol if they had not yet begun and were not already established. The following parameters were evaluated at baseline, after thermal treatment and after 16 weeks: FIQ, TPC, VAS for "minor" symptoms, AIMS1 and HAQ. Controls were assessed at the same intervals. A significant improvement in all parameters was recorded after mudpack therapy and after 16 weeks.

Figure 1 shows that the patients submitted to mud-bath therapy underwent an evident improvement of VAS score at the end of the cycle of the thermal treatment cycle (T1) and this improvement remained significant after a follow-up period of 16 weeks (T2).

**\*\*\* p<0.0001 vs basal time and vs Control (Wilcoxon Test)**

Fig. 1. VAS score (mean SD) at basal time (T0), after 2 weeks (T1) and 16 weeks (T2) in mud-bath treated patients (MBT) and in controls (C). From Fioravanti et al., Rheumatol Int 2007

Figure 2 demonstrates that TPC significantly was reduced at the end of the spa therapy cycle and remained stable after 16 weeks in comparison to baseline only in patients treated with mud-bath therapy.

The results were similar for the two types of mineral water. Regarding tolerance mud packs, no patient reported any exacerbation of symptoms and the hot applications were well tolerated by all. No drop-outs occurred during spa therapy and all patients completed the study.

A recent RCT by Özkurt et al. (Özkurt et al., 2011) of 50 woman with FS confirmed the efficacy of balneotherapy on major outcome measures such as pain, FIQ, BDI, Patient's and

Fibromyalgia Syndrome and Spa Therapy 109

Studies conducted according to rigorous methodological criteria in larger numbers of

The mechanisms by which immersion in mineral or thermal water or the application of mud alleviates suffering in FS are not fully understood. The net benefit is probably the result of a combination of factors, among which mechanical, thermal and chemical effects are most prominent (Sukenik et al., 1999; Fioravanti et al., 2011). A distinction can be made between the non-specific (hydrotherapeutic in a broad sense) mechanisms of simple bathing in hot tap water, and specific (hydromineral and crenotherapeutic) mechanisms, which depend on the chemical and physical properties of the water used. While the former are well known, the latter are difficult to identify and assess. Buoyancy, immersion, resistance and temperature all play important roles. Hot stimuli may influence muscle tone and pain intensity, helping to reduce muscle spasm and to increase the pain threshold in nerve endings. According to the "gate theory", pain relief may be due to the temperature and

Thermal stress provokes a series of neuroendocrine reactions (Kuczera & Kokot, 1996), in particular release of adrenocorticotropic hormone (ACTH), cortisol, prolactin and growth hormone (GH), although it does not alter the circadian rhythm of these hormones. The effect of thermal stress on the hypothalamus-pituitary-adrenal axis seems to be particularly important for the antiedemigenous and anti-inflammatory effects of corticosteroids. Pituitary activation could also be particularly useful in FS, where altered reactivity of the

The increase in beta-endorphin demonstrated to occur with various spa therapy techniques has an analgesic and anti-spastic effect that is particularly important in patients with FS for whom pain is the prevalent symptom. Interestingly, it has been found that application of mature thermal mud in healthy individuals brings about a rapid increase in plasma betaendorphin, which returns to pre-treatment levels within the period of the so-called thermal reaction (Cozzi et al., 1995). This increase in beta-endorphin is probably the key factor in the mechanism of individual tolerance to thermal mud baths. A recent study has shown a reduction in circulating levels of interleukin (IL)-1, prostaglandin E2 (PGE2) and leukotriene B4 (LTB4), important mediators of inflammation and pain, in FS patients undergoing a cycle of balneotherapy (Ardiç et al., 2007). It has been suggested that inflammatory process mediated by cytokines, proteases and inflammatory mediators located in soft body tissue may play a role in the pathogenesis of FS, in up to one third of FS patients (Salemi et al., 2003). This inflammatory process would stimulate subcutaneous nociceptors, resulting in a sensation of pain. The detection of IL-1, IL-6 and tumour necrosis factor-(TNF-) in skin of one-third of FS patients and elevated plasma PGE2 levels in FS supports this hypothesis (Hedenberg-Magnusson et al., 2001). The inhibitory effect of balneotherapy on the production and/or release of IL-1, PGE2 and LTB4 could explain the mechanism of clinical benefits of spa therapy in this disorder. Mineral water may also influence the oxidantantioxidant system (Eckmekcioglu et al., 2002; Bender et al., 2007), which could be beneficial, since oxidative stress disorders have been described in FS (Bagis et al., 2005). Finally, other aspects of the mechanisms of mud packs and balneotherapy in FS need to be considered; for example, the climatic and environmental conditions of spas and the fact that people relax

patients are needed to determine the potential of spa therapy for FS.

hydrostatic pressure of water on the skin (Melzack & Wall, 1965 ).

hypothalamic-pituitary axis has been observed (Gur et al., 2004).

away from their daily routines (Sukenik et al., 1999; Fioravanti et al., 2011).

**2.1 Mechanisms of action of spa therapy in FS**

Investigator's Global Assessment (PGA and IGA) scores, and SF36. The results were maintained for up to 3 months, except for BDI and investigator's global assessment score.

Fig. 2. Tender Point Count (mean SD) at basel time (T0), after 2 weeks (T1) and 16 weeks (T2) in mud-bath treated patients (MBT) and in controls (C). From Fioravanti et al. Rheumatol Int 2007

These various RCTs on spa therapy for FS suggest a positive effect on pain, other FS-related symptoms and QoL (McVeigh et al., 2008; Langhorst et al., 2009). The studies assessed the medium-long-term effect and found that the clinical efficacy of spa therapy lasted for 4-6 months. Despite low tolerance of physical treatments by FS patients, spa therapy seems to be well tolerated and to have a lower percentage of side effects, which are also less severe, than those associated with pharmacological treatments.

Some aspects of the studies on spa therapy for FS are disputable and could be a source of bias, for example the lack of double-blind experimental design due to the difficulty of creating a placebo with the same characteristics as the treatment. The methodological quality of the RCTs analysed was limited for the following reasons: 1) only two studies had a sample size of at least 25 per group, the number recognized as appropriate for detecting clinically significant differences between two active treatments (Chambless & Holton, 1998); 2) no study included intention-to-treat analysis, but analysed the completers, possibly favouring the results of spa therapy, even if the drop-out rates were low; 3) most studies did not report the method of randomization used; 4) the trials did not ensure that treatment allocation was concealed (McVeigh et al., 2008; Langhorst et al., 2009).

Comparison of the studies was difficult as the baseline characteristics of the patients were heterogeneous, the interventions differed in type, intensity and duration, the methods used for assessment of efficacy varied and patients were assessed at different times after spa therapy. In particular, the heterogeneity of "spa therapy" makes it difficult to determine which form of spa therapy is most effective and no study was designed to compare different types of spa care procedures.

Although the consistency of the results suggests that spa therapy has a therapeutic effect on FS, the methodological limitations of the studies preclude any definitive conclusions.

Investigator's Global Assessment (PGA and IGA) scores, and SF36. The results were maintained for up to 3 months, except for BDI and investigator's global assessment score.

**\*\*\***

**\*\*\***

MBT C

T0 T1 T2

Fig. 2. Tender Point Count (mean SD) at basel time (T0), after 2 weeks (T1) and 16 weeks

These various RCTs on spa therapy for FS suggest a positive effect on pain, other FS-related symptoms and QoL (McVeigh et al., 2008; Langhorst et al., 2009). The studies assessed the medium-long-term effect and found that the clinical efficacy of spa therapy lasted for 4-6 months. Despite low tolerance of physical treatments by FS patients, spa therapy seems to be well tolerated and to have a lower percentage of side effects, which are also less severe,

Some aspects of the studies on spa therapy for FS are disputable and could be a source of bias, for example the lack of double-blind experimental design due to the difficulty of creating a placebo with the same characteristics as the treatment. The methodological quality of the RCTs analysed was limited for the following reasons: 1) only two studies had a sample size of at least 25 per group, the number recognized as appropriate for detecting clinically significant differences between two active treatments (Chambless & Holton, 1998); 2) no study included intention-to-treat analysis, but analysed the completers, possibly favouring the results of spa therapy, even if the drop-out rates were low; 3) most studies did not report the method of randomization used; 4) the trials did not ensure that treatment

Comparison of the studies was difficult as the baseline characteristics of the patients were heterogeneous, the interventions differed in type, intensity and duration, the methods used for assessment of efficacy varied and patients were assessed at different times after spa therapy. In particular, the heterogeneity of "spa therapy" makes it difficult to determine which form of spa therapy is most effective and no study was designed to compare different

Although the consistency of the results suggests that spa therapy has a therapeutic effect on FS, the methodological limitations of the studies preclude any definitive conclusions.

**Time**

**\*\*\* p<0.0001 vs basal time and vs Control (Wilcoxon Test)**

(T2) in mud-bath treated patients (MBT) and in controls (C). From Fioravanti et al.

than those associated with pharmacological treatments.

allocation was concealed (McVeigh et al., 2008; Langhorst et al., 2009).

0

Rheumatol Int 2007

types of spa care procedures.

5

10

**Count**

15

20

Studies conducted according to rigorous methodological criteria in larger numbers of patients are needed to determine the potential of spa therapy for FS.

#### **2.1 Mechanisms of action of spa therapy in FS**

The mechanisms by which immersion in mineral or thermal water or the application of mud alleviates suffering in FS are not fully understood. The net benefit is probably the result of a combination of factors, among which mechanical, thermal and chemical effects are most prominent (Sukenik et al., 1999; Fioravanti et al., 2011). A distinction can be made between the non-specific (hydrotherapeutic in a broad sense) mechanisms of simple bathing in hot tap water, and specific (hydromineral and crenotherapeutic) mechanisms, which depend on the chemical and physical properties of the water used. While the former are well known, the latter are difficult to identify and assess. Buoyancy, immersion, resistance and temperature all play important roles. Hot stimuli may influence muscle tone and pain intensity, helping to reduce muscle spasm and to increase the pain threshold in nerve endings. According to the "gate theory", pain relief may be due to the temperature and hydrostatic pressure of water on the skin (Melzack & Wall, 1965 ).

Thermal stress provokes a series of neuroendocrine reactions (Kuczera & Kokot, 1996), in particular release of adrenocorticotropic hormone (ACTH), cortisol, prolactin and growth hormone (GH), although it does not alter the circadian rhythm of these hormones. The effect of thermal stress on the hypothalamus-pituitary-adrenal axis seems to be particularly important for the antiedemigenous and anti-inflammatory effects of corticosteroids. Pituitary activation could also be particularly useful in FS, where altered reactivity of the hypothalamic-pituitary axis has been observed (Gur et al., 2004).

The increase in beta-endorphin demonstrated to occur with various spa therapy techniques has an analgesic and anti-spastic effect that is particularly important in patients with FS for whom pain is the prevalent symptom. Interestingly, it has been found that application of mature thermal mud in healthy individuals brings about a rapid increase in plasma betaendorphin, which returns to pre-treatment levels within the period of the so-called thermal reaction (Cozzi et al., 1995). This increase in beta-endorphin is probably the key factor in the mechanism of individual tolerance to thermal mud baths. A recent study has shown a reduction in circulating levels of interleukin (IL)-1, prostaglandin E2 (PGE2) and leukotriene B4 (LTB4), important mediators of inflammation and pain, in FS patients undergoing a cycle of balneotherapy (Ardiç et al., 2007). It has been suggested that inflammatory process mediated by cytokines, proteases and inflammatory mediators located in soft body tissue may play a role in the pathogenesis of FS, in up to one third of FS patients (Salemi et al., 2003). This inflammatory process would stimulate subcutaneous nociceptors, resulting in a sensation of pain. The detection of IL-1, IL-6 and tumour necrosis factor-(TNF-) in skin of one-third of FS patients and elevated plasma PGE2 levels in FS supports this hypothesis (Hedenberg-Magnusson et al., 2001). The inhibitory effect of balneotherapy on the production and/or release of IL-1, PGE2 and LTB4 could explain the mechanism of clinical benefits of spa therapy in this disorder. Mineral water may also influence the oxidantantioxidant system (Eckmekcioglu et al., 2002; Bender et al., 2007), which could be beneficial, since oxidative stress disorders have been described in FS (Bagis et al., 2005). Finally, other aspects of the mechanisms of mud packs and balneotherapy in FS need to be considered; for example, the climatic and environmental conditions of spas and the fact that people relax away from their daily routines (Sukenik et al., 1999; Fioravanti et al., 2011).

Fibromyalgia Syndrome and Spa Therapy 111

Eckmekcioglu, C.; Strauss-Blasche, G.; Holzer, F.; Marktl, W. (2002). Effect of sulfur baths on

Evcik, D.; Kizilay, B.; Gökçen, E. (2002). The effects of balneotherapy on fibromyalgia

Fioravanti, A.; Perpignano, G.; Tirri, G.; Cardinale, G.; Gianniti, C.; Lanza, C.E.; Loi, A.; Tirri,

Goldenberg, D.L.; Burckhardt, C.; Crofford, L. (2004). Management of fibromyalgia

Gur, A.; Cevik, R.; Sarac, A.J.; Colpan, L.; Em, S. (2004). Hypothalamic-pituitary-gonadal

Hedenberg-Magnusson, B.; Ernberg, M.; Alstergren, P.; Kopp S.; (2001). Pain mediation by

Klement, A.; Hauser, W.; Bruckle, W.; Eidmann, U.; Felde, E.; Herrmann, M.; Kühn-Becker,

Kuczera, M. & Kokot, F. (1996). The influence of SPA therapy on endocrine system. Stress

Langhorst, J.; Musial, F.; Klose, P.; Häuser, W. (2009). Efficacy of hydrotherapy in

Lawrence, R.C.; Felson, D.T.; Helmick, C.G.; Arnold, L.M.; Choi, H.; Deyo, R.A.; Gabriel, S.;

Mease, P. (2005). Fibromyalgia syndrome: review of clinical presentation, pathogenesis,

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#### **3. Conclusion**

In conclusion, spa therapy seems to have a role in the treatment of FS. It cannot substitute for conventional therapy but can complement to it. The improvement reported in some clinical studies lasts over time. Actually, spa therapy can represent a useful backup to pharmacologic treatment of FS or a valid alternative for patients who do not tolerate pharmacologic treatments. Future research to clarify the mechanisms of action and the effects deriving from the application of thermal treatments are imperative. Additional RCTs with high methodological quality concerning the effectiveness of spa therapy in FS are necessary in order to obtained strong evidence on the effects of spa therapy.

#### **4. References**

In conclusion, spa therapy seems to have a role in the treatment of FS. It cannot substitute for conventional therapy but can complement to it. The improvement reported in some clinical studies lasts over time. Actually, spa therapy can represent a useful backup to pharmacologic treatment of FS or a valid alternative for patients who do not tolerate pharmacologic treatments. Future research to clarify the mechanisms of action and the effects deriving from the application of thermal treatments are imperative. Additional RCTs with high methodological quality concerning the effectiveness of spa therapy in FS are

Ardiç, F.; Őzgen, M.; Aybek, H.; Rota, S.; Cubukçu, D.; Gökgöz, A. (2007). Effects of

Bagis, S.; Tamer, L.; Sahin, G.; Bilgin, R.; Guler, H.; Ercan, B.; Erdogan, C.;(2005). Free

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Bender, T.; Bariska, J.; Vàghy, R.; Gomez, R.; Kovàcs, I. (2007). Effect of balneotherapy on the

Buskila, D.; Abu-Shakra, M.; Neumman, L.; Odes, L.; Shneider. E.; Flusser, D.; Sukenik, S.

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balneotherapy on serum IL-1, PGE2 and LTB4 levels in fibromyalgia patients. *Rheumatology International,* Vol. 27, No. 5, (March), pp. 441-6, Print ISSN: 0172-8172

radicals and antioxidants in primary fibromyalgia: an oxidative stress disorder?. *Rheumatology International,* Vol. 25, No. 3, (April), pp.188-90, Print ISSN: 0172-8172

Hydrotherapy, balneotherapy, and spa treatment in pain management. *Rheumatology International,* Vol. 25, No. 3, (April), pp. 220-224, Print ISSN: 0172-8172

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(2001). Balneotherapy for fibromyalgia at the Dead Sea. *Rheumatology International,*

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(2005). SPA therapy in fibromyalgia: a randomised controlled clinic study. *Rheumatology International,* Vol. 26, No. 2, (December), pp. 168-72, Print ISSN: 0172-

Cozzi, F.; Lazzarin, I.; Todesco, S.; Cima, L.; (1995). Hypotalamic pituary-adrenal axis

*Rheumatism,* Vol. 37, No. 8,(August), pp. 724-725, Online ISSN: 1529-0131 Dönmez, A.; Zeki Karagülle, M.; Tercan, N.; Dinler, M.; Işsever, H.; Karagülle, M.; Turan, M.

necessary in order to obtained strong evidence on the effects of spa therapy.

**3. Conclusion**

**4. References**

Online ISSN: 1437-160X

Online ISSN: 1437-160X

Online ISSN: 1437-160X

8172 Online ISSN: 1437-160X

006X

No.1, (January), pp. 86-89, ISSN: 0188-4409

**6**

*1Egypt 2,3Japan*

**Efficacy of Spinal Cord Stimulation for**

*2Department of Neurosurgery, Osaka University Graduate School of Medicine 3Department of Neuromodulation and Neurosurgery, Osaka University,Osaka*

Central post-stroke pain (CPSP) is a neuropathic-type of pain that affects about 1-8% of patients after stroke (Andersen et al., 1995; Bowsher 1993), and is characterized by pain and sensory dysfunction involving the area of the body that has been affected by the stroke (Leijon et al., 1998). Once present, CPSP rarely abates, causing a considerable long-term impact on patient's quality of life (Wider & Ahlstrom, 2002). The first line of treatment for CPSP is usually tricyclic antidepressant amitriptyline or antiepileptic gabapentine. However, these drugs are often ineffective or cause intolerable side effects; including dry mouth, urinary retention, arrhythmias, and sedation; especially in elderly stroke patients

Neuromodulatory techniques have been proposed for treatment of severe medically refractory CPSP (Kim, 2009). Deep brain stimulation (DBS) has yielded inconsistent results (Kumar et al., 1997). Motor cortex stimulation (MCS) has been the most popular technique to treat intractable CPSP. MCS involves implanting electrodes over the motor strip through a craniotomy. MCS has been reported to achieve pain relief in approximately half of patients (Katayama et al., 1998; Fontaine et al., 2009; Saitoh et al., 2007; Lazortheset al., 2006). However, a large proportion of patients remain untreated due to either failure or decline of MCS (Aly et al., 2010). One group of patients declined MCS because of the need for a craniotomy (Aly et al., 2010). Another group of patients are considered poor candidates for MCS based on their poor response to repeated transcranial Magnetic Stimulation (r TMS) (Hosomi et al., 2008; Andre-Obadia et al., 2006). Moreover, MCS needs a special neurosurgical expertise and its use is correspondingly restricted to well-established functional neurosurgical centers (Kim, 2009). In these situations, there is practically no viable option to help these patients to relive their disabling medically refractory pain (Aly et

Spinal cord stimulation (SCS) is the most widely used neurostimulation technique for chronic pain because it is minimally invasive, has a low complication rate, and is generally effective (Kumar et al., 2006; Camerons, 2004). SCS has been proven effective for various

**1. Introduction**

(Finnerup et al., 2005).

al., 2010).

**Central Post-Stroke Pain**

Mohamed Ali1 and Youichi Saitoh2,3

*1Department of Neurosurgery, Mansura University*

## **Efficacy of Spinal Cord Stimulation for Central Post-Stroke Pain**

Mohamed Ali1 and Youichi Saitoh2,3

*1Department of Neurosurgery, Mansura University 2Department of Neurosurgery, Osaka University Graduate School of Medicine 3Department of Neuromodulation and Neurosurgery, Osaka University,Osaka 1Egypt*

*2,3Japan*

#### **1. Introduction**

112 Neuropathic Pain

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*Rev* 2:CD000518

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in the management of fibromyalgia syndrome: a systematic review. *Rheumatology International,* Vol. 29, No. 2, (December), pp. 119-130, Print ISSN: 0172-8172 Online

(2001). The effect of balneotherapy at the Dead Sea on the quality of life of patients with fibromyalgia syndrome. *Clinical Rheumatology,* Vol. 20, No. 1, pp. 15-9, Print

Balneotherapy in fibromyalgia: a single blind randomized controlled clinical study. *Rheumatology International,* (in press), Print ISSN: 0172-8172 Online ISSN: 1437-160X

Detection of interleukin 1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha in skin of patient with fibromyalgia. *The Journal of Rheumatology ,* Vol. 30, No. 1,

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rheumatic diseases. *Rheumatic Diseases Clinics of North America,* Vol. 25, No. 4,

Balneotherapy for rheumatoid arthritis and osteoarthritis. *Cochrane Database Syst*

*of Rheumatology, V*ol. 10, No. 6, (December), pp. 965-968, Print ISSN: 0315-162X

Tugwell, P.; Campbell, S.M.; Abeles, M.; Clark, P. (1990). The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. *Arthritis &*

treatment of patients with primary fibromyalgia syndrome. *Physical Medicine*

Central post-stroke pain (CPSP) is a neuropathic-type of pain that affects about 1-8% of patients after stroke (Andersen et al., 1995; Bowsher 1993), and is characterized by pain and sensory dysfunction involving the area of the body that has been affected by the stroke (Leijon et al., 1998). Once present, CPSP rarely abates, causing a considerable long-term impact on patient's quality of life (Wider & Ahlstrom, 2002). The first line of treatment for CPSP is usually tricyclic antidepressant amitriptyline or antiepileptic gabapentine. However, these drugs are often ineffective or cause intolerable side effects; including dry mouth, urinary retention, arrhythmias, and sedation; especially in elderly stroke patients (Finnerup et al., 2005).

Neuromodulatory techniques have been proposed for treatment of severe medically refractory CPSP (Kim, 2009). Deep brain stimulation (DBS) has yielded inconsistent results (Kumar et al., 1997). Motor cortex stimulation (MCS) has been the most popular technique to treat intractable CPSP. MCS involves implanting electrodes over the motor strip through a craniotomy. MCS has been reported to achieve pain relief in approximately half of patients (Katayama et al., 1998; Fontaine et al., 2009; Saitoh et al., 2007; Lazortheset al., 2006). However, a large proportion of patients remain untreated due to either failure or decline of MCS (Aly et al., 2010). One group of patients declined MCS because of the need for a craniotomy (Aly et al., 2010). Another group of patients are considered poor candidates for MCS based on their poor response to repeated transcranial Magnetic Stimulation (r TMS) (Hosomi et al., 2008; Andre-Obadia et al., 2006). Moreover, MCS needs a special neurosurgical expertise and its use is correspondingly restricted to well-established functional neurosurgical centers (Kim, 2009). In these situations, there is practically no viable option to help these patients to relive their disabling medically refractory pain (Aly et al., 2010).

Spinal cord stimulation (SCS) is the most widely used neurostimulation technique for chronic pain because it is minimally invasive, has a low complication rate, and is generally effective (Kumar et al., 2006; Camerons, 2004). SCS has been proven effective for various

Efficacy of Spinal Cord Stimulation for Central Post-Stroke Pain 115

Some patients may prefer SCS over MCS because it does not need of craniotomy or general anesthesia as MCS does (Aly al., 2010). Compared to MCS, percutaneous trial SCS is much better tolerated by patients can be done under local anesthesia, and the electrodes can be removed easily if a trial fails (Aly et al., 2010). In fact, the minimal invasiveness and simplicity of SCS is one of the most appealing aspects of SCS for clinicians and

Fig. 1. Suggested algorithm for management of intractable CPSP.

MCS service is generally less accessible than SCS. Because MCS needs a craniotomy and special neurosurgical expertise its use is limited to specialized neurosurgical centers (Aly et al., 2010). In contrast, the SCS technique is relatively simple, less invasive, and can be mastered not only by neurosurgeons but by many anesthesiologists and pain clinicians as

**3.3 Unavailability of MCS service**

well (Kim, 2009; Aly et al., 2010).

**3.2 Patient preference**

patients as well.

types of neuropathic pain of peripheral origin, in particular, failed back surgery syndrome (FBSS) and peripheral neuropathy (Kumar et al., 2006). In contrast, only a few reports to date have investigated the use of SCS for CPSP (Simpson, 1991; Katayama et al, 2001; Cruccu et al., 2007; Lopez al., 2009; Aly et al., 2010) . SCS is generally considered ineffective for central neuropathic pain, including CPSP in spite of the paucity of data in the literature to support this idea (Simpson, 1991; Katayama et al., 2001; Cruccu et al., 2007; Lopez et al., 2009; Aly et al., 2010). CPSP most often has a wide pain distribution and commonly occurs in a hemibody fashion (Kim, 2009). Because coverage of the entire painful area by stimulation paraesthesia is essential for success of SCS (Holsheimer, 1997), SCS was considered unsuitable for CPSP. From a pthophysiological point of view, it was argued how SCS which act on segmental spinal level would affect pain generators in CPSP which are located proximal to deafferentiation level i.e. supraspinal (Tsubokawa, et al., 1993).

In this chapter, we reviewed that literature about the use of SCS for CPSP with regard to patient selection, surgical technique, clinical outcome and, and mechanism of action.

#### **2. Presurgical evaluation**

The diagnosis of CPSP should be established based on the following criteria (Klit et al., 2009): 1) development of pain following stroke; 2) sensory disturbance correlated with the cerebrovascular lesion; 3) pain located within the territory of sensory disturbance. Other causes of nociceptive and peripheral neuropathic pain should be ruled out particularly those which are prevalent in this age group such as lumbar canal stenosis, peripheral neuropathy, and post-stroke shoulder pain (Kim, 2009; Aly et al., 2010).

Comprehensive neuropsychological assessment is essential in all patients to rule out serious psychiatric disorder or severe cognitive dysfunction (Kumar et al., 2006). To be eligible for SCS treatment, patients should have failed medical treatment for at least 6 months, including antidepressants and anticonvulsant drugs (Cruccu et al., 2007).

#### **3. Patients selection for SCS**

There is no doubt that MCS remains the primary option for treating intractable CPSP based upon the available literature (Fontaine et al., 2009; Saitoh et al., 2007; et al., 2008). The experience with MCS is larger and the outcome is more consistent. MCS hss been implanted in more than 117 patients with CPSP with approximately 50 % success rate (Fontaine et al., 2009). However, a significant proportion of patients with intractable CPSP remain untreated either due to failure, poor prediction, or refusal of MCS by patients. In a recent study, out of 87 patients presented to neurosurgery department with intractable CPSP only 13 patients eventually had underwent MCS (Aly et al., 2010).Therefore, SCS may be an alternative option in the following situations;

#### **3.1 Failure or poor predictors of MCS**

Approximately 50 % of patients who undergo MCS fail to have satisfactory pain relief (Fontaine et al., 2009; Saitoh et al., 2007; Hosomi et al., 2008). Another group of patients may be considered poor candidates for MCS based on their poor response to TMS (Saitoh et al., 2007; Hosomi et al., 2008; Aly et al., 2010). For those groups of patients SCS may be one of the few viable options.

#### **3.2 Patient preference**

114 Neuropathic Pain

types of neuropathic pain of peripheral origin, in particular, failed back surgery syndrome (FBSS) and peripheral neuropathy (Kumar et al., 2006). In contrast, only a few reports to date have investigated the use of SCS for CPSP (Simpson, 1991; Katayama et al, 2001; Cruccu et al., 2007; Lopez al., 2009; Aly et al., 2010) . SCS is generally considered ineffective for central neuropathic pain, including CPSP in spite of the paucity of data in the literature to support this idea (Simpson, 1991; Katayama et al., 2001; Cruccu et al., 2007; Lopez et al., 2009; Aly et al., 2010). CPSP most often has a wide pain distribution and commonly occurs in a hemibody fashion (Kim, 2009). Because coverage of the entire painful area by stimulation paraesthesia is essential for success of SCS (Holsheimer, 1997), SCS was considered unsuitable for CPSP. From a pthophysiological point of view, it was argued how SCS which act on segmental spinal level would affect pain generators in CPSP which are

located proximal to deafferentiation level i.e. supraspinal (Tsubokawa, et al., 1993).

patient selection, surgical technique, clinical outcome and, and mechanism of action.

and post-stroke shoulder pain (Kim, 2009; Aly et al., 2010).

including antidepressants and anticonvulsant drugs (Cruccu et al., 2007).

**2. Presurgical evaluation**

**3. Patients selection for SCS**

option in the following situations;

the few viable options.

**3.1 Failure or poor predictors of MCS**

In this chapter, we reviewed that literature about the use of SCS for CPSP with regard to

The diagnosis of CPSP should be established based on the following criteria (Klit et al., 2009): 1) development of pain following stroke; 2) sensory disturbance correlated with the cerebrovascular lesion; 3) pain located within the territory of sensory disturbance. Other causes of nociceptive and peripheral neuropathic pain should be ruled out particularly those which are prevalent in this age group such as lumbar canal stenosis, peripheral neuropathy,

Comprehensive neuropsychological assessment is essential in all patients to rule out serious psychiatric disorder or severe cognitive dysfunction (Kumar et al., 2006). To be eligible for SCS treatment, patients should have failed medical treatment for at least 6 months,

There is no doubt that MCS remains the primary option for treating intractable CPSP based upon the available literature (Fontaine et al., 2009; Saitoh et al., 2007; et al., 2008). The experience with MCS is larger and the outcome is more consistent. MCS hss been implanted in more than 117 patients with CPSP with approximately 50 % success rate (Fontaine et al., 2009). However, a significant proportion of patients with intractable CPSP remain untreated either due to failure, poor prediction, or refusal of MCS by patients. In a recent study, out of 87 patients presented to neurosurgery department with intractable CPSP only 13 patients eventually had underwent MCS (Aly et al., 2010).Therefore, SCS may be an alternative

Approximately 50 % of patients who undergo MCS fail to have satisfactory pain relief (Fontaine et al., 2009; Saitoh et al., 2007; Hosomi et al., 2008). Another group of patients may be considered poor candidates for MCS based on their poor response to TMS (Saitoh et al., 2007; Hosomi et al., 2008; Aly et al., 2010). For those groups of patients SCS may be one of Some patients may prefer SCS over MCS because it does not need of craniotomy or general anesthesia as MCS does (Aly al., 2010). Compared to MCS, percutaneous trial SCS is much better tolerated by patients can be done under local anesthesia, and the electrodes can be removed easily if a trial fails (Aly et al., 2010). In fact, the minimal invasiveness and simplicity of SCS is one of the most appealing aspects of SCS for clinicians and patients as well.

Fig. 1. Suggested algorithm for management of intractable CPSP.

#### **3.3 Unavailability of MCS service**

MCS service is generally less accessible than SCS. Because MCS needs a craniotomy and special neurosurgical expertise its use is limited to specialized neurosurgical centers (Aly et al., 2010). In contrast, the SCS technique is relatively simple, less invasive, and can be mastered not only by neurosurgeons but by many anesthesiologists and pain clinicians as well (Kim, 2009; Aly et al., 2010).

Efficacy of Spinal Cord Stimulation for Central Post-Stroke Pain 117

scheduled for implantation of a permanent SCS system (Aly et al., 2010; Stojanovic & Abdi ,

A permanent lead was implanted in a similar manner as the trial lead and was anchored subcutaneously. Finally, an implantable pulse generator (IPG; Itrel III Model 7425 or Synergy Model 7427 V, Medtronic, Inc.) is implanted under general anesthesia in the left

Pain intensity was evaluated using a visual analogue scale (VAS) ranging from 0 (no pain) to 10 (worst possible pain) at baseline, during the trial, and at follow-up visits every 6 months. In patients with wide regions of pain, the VAS was assessed independently for each region and the target area for SCS was determined based on the area with greatest pain and

In addition, the patient global impression of change (PGIC) scale was assessed at the latest follow-up visit after the permanent implant. The PGIC scale indicates overall improvement according to a seven-point categorical scale: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; and 7, very much worse. The "rank 2" and "rank 1" were considered as clinically significant improvement

During data analysis, the degree of pain relief was classified into three categories: good (≥50%), fair (30-49%), or poor (<30%) based on percent reduction of VAS (% reduction = [VAS pre-stimulation – VAS post-stimulation / VAS pre-stimulation] × 100%).13 Pain relief of "fair" or better was considered clinically significant based on a report documenting that pain reduction as low as 30 % corresponds to clinically meaningful success(Aly et al., 2010;

The most common stimulation parameters were an amplitude of 1.5-3 V (range 1.5-6 V), a pulse width of 210 μsec (range 210-350 μsec), and a frequency of 31 Hz (range 10-50 Hz)

To our knowledge, only 4 previous studies have investigated the use of SCS in CPSP (Table 1) (Simpson, 1991; Katayama, et al., 2001; Cruccu, et al., 2007; Lopez, 2009; Aly et al., 2010). All previous studied were retrospective in nature and involved a small Number of patients (6-45). Therefore, a prospective controlled study with a larger population of patients is needed to provide stronger evidence for the efficacy of SCS in CPSP. However performing such study poses certain challenges. Firstly, it is difficult to recruit a large number of CPSP patients in one center owing to the low prevalence and under-diagnosis of this condition

2002; Kumar , et al., 2006).

**4.4 Evaluation of pain relief**

disability(Aly MM, et al, 2010) (Fig. 2).

(Aly MM, et al, 2010; Farrar, J., 2001).

**4.5 Stimulation parameters**

**5. Clinical outcome**

**5.1 Previous studies design**

with a bipolar configuration (Aly et al., 2010)

Farrar,2001).

**4.3 Implantation of permanent SCS system**

lower abdomen or anterior chest (Aly et al., 2010).

#### **3.4 Pain distribution**

#### **3.4.1 Localized pain distribution**

The distribution of CPSP throughout the body may be quite variable. CPSP most often occurs in a hemibody fashion, but may be restricted to distal parts of the body, such as the hand or foot (Kim, 2009).Because coverage of the entire targeted region of pain by stimulation-induced paraesthesia is essential for success of SCS (Holsheimer, 1997), it was thought that SCS may be unsuitable for CPSP. Obviously, patients who have localized pain may be the ideal candidate for SCS. Patients with putaminal hemorrhage that affects the posterior part of the internal capsule has the propensity to cause pain that is most severe in, or confined to, the leg (Kim, 2003). This explains why that group of patients represented (40%) of cases in Ali et al study (Aly et al., 2010). Some patients have a wide pain distribution but pain is more severe in distal parts such as foot or hand which cause substantial disability due to interfering with hand movement or walking respectively (Aly et al., 2010). It was reported that targeting these distal areas which are most painful may still improve the patient pain. In this context it is helpful to measure a separate VAS rating of different areas. Finally, some patients will benefit from insertion of 2 different electrodes in cervical and dorsal spine to target a wide area (Aly et al., 2010).

#### **3.4.2 Lower extremity pain**

Patients with leg-dominant CPSP were considered more suitable candidates for SCS than upper extremity pain because thoracic electrodes are technically less demanding and less susceptible to displacement than cervical electrodes. (Kumar & Wilson, 2007 ).In addition, lower-limb pain is not considered a good indication for MCS, given the technical difficulties associated with implanting electrodes on the medial surface of the brain (Fontaine et al., 2009;Aly et al., 2010).

#### **4. Surgical procedure**

#### **4.1 Implantation of temporary electrodes**

In the prone position, a percutaneous lead with quadripolar electrodes (Pisces Quad, Model 3487A; Medtronic, Inc., MN, USA) is inserted into the epidural space through a Touhy needle under local anesthesia. The tip was advanced to the required spinal level: C4 to C7 for upper limb pain or T9 to T12 for lower limb pain. The electrodes were manipulated with fluoroscopic guidance so that the stimulation-induced paraesthesia covered the entire region affected by pain (Aly et al., 2010; Stojanovic &Abdi, 2002; Kumar et al., 2006).

#### **4.2 Trial stimulation**

Using an externalized temporary lead connected to a test stimulator (model 3625, Medtronic), trial stimulation was performed to evaluate the efficacy of pain relief before permanent implantation. During the trial period (2 to 14 days), patients were allowed to test the pain-relieving effects of several stimulation parameters and combinations of active electrodes. Thereafter, the temporary electrodes are removed and patients were discharged. After counseling the patients in outpatient clinic, those who decided to proceed were scheduled for implantation of a permanent SCS system (Aly et al., 2010; Stojanovic & Abdi , 2002; Kumar , et al., 2006).

#### **4.3 Implantation of permanent SCS system**

A permanent lead was implanted in a similar manner as the trial lead and was anchored subcutaneously. Finally, an implantable pulse generator (IPG; Itrel III Model 7425 or Synergy Model 7427 V, Medtronic, Inc.) is implanted under general anesthesia in the left lower abdomen or anterior chest (Aly et al., 2010).

#### **4.4 Evaluation of pain relief**

116 Neuropathic Pain

The distribution of CPSP throughout the body may be quite variable. CPSP most often occurs in a hemibody fashion, but may be restricted to distal parts of the body, such as the hand or foot (Kim, 2009).Because coverage of the entire targeted region of pain by stimulation-induced paraesthesia is essential for success of SCS (Holsheimer, 1997), it was thought that SCS may be unsuitable for CPSP. Obviously, patients who have localized pain may be the ideal candidate for SCS. Patients with putaminal hemorrhage that affects the posterior part of the internal capsule has the propensity to cause pain that is most severe in, or confined to, the leg (Kim, 2003). This explains why that group of patients represented (40%) of cases in Ali et al study (Aly et al., 2010). Some patients have a wide pain distribution but pain is more severe in distal parts such as foot or hand which cause substantial disability due to interfering with hand movement or walking respectively (Aly et al., 2010). It was reported that targeting these distal areas which are most painful may still improve the patient pain. In this context it is helpful to measure a separate VAS rating of different areas. Finally, some patients will benefit from insertion of 2 different electrodes in

Patients with leg-dominant CPSP were considered more suitable candidates for SCS than upper extremity pain because thoracic electrodes are technically less demanding and less susceptible to displacement than cervical electrodes. (Kumar & Wilson, 2007 ).In addition, lower-limb pain is not considered a good indication for MCS, given the technical difficulties associated with implanting electrodes on the medial surface of the brain (Fontaine et al.,

In the prone position, a percutaneous lead with quadripolar electrodes (Pisces Quad, Model 3487A; Medtronic, Inc., MN, USA) is inserted into the epidural space through a Touhy needle under local anesthesia. The tip was advanced to the required spinal level: C4 to C7 for upper limb pain or T9 to T12 for lower limb pain. The electrodes were manipulated with fluoroscopic guidance so that the stimulation-induced paraesthesia covered the entire region

Using an externalized temporary lead connected to a test stimulator (model 3625, Medtronic), trial stimulation was performed to evaluate the efficacy of pain relief before permanent implantation. During the trial period (2 to 14 days), patients were allowed to test the pain-relieving effects of several stimulation parameters and combinations of active electrodes. Thereafter, the temporary electrodes are removed and patients were discharged. After counseling the patients in outpatient clinic, those who decided to proceed were

affected by pain (Aly et al., 2010; Stojanovic &Abdi, 2002; Kumar et al., 2006).

cervical and dorsal spine to target a wide area (Aly et al., 2010).

**3.4 Pain distribution**

**3.4.1 Localized pain distribution**

**3.4.2 Lower extremity pain**

2009;Aly et al., 2010).

**4.2 Trial stimulation**

**4. Surgical procedure**

**4.1 Implantation of temporary electrodes**

Pain intensity was evaluated using a visual analogue scale (VAS) ranging from 0 (no pain) to 10 (worst possible pain) at baseline, during the trial, and at follow-up visits every 6 months. In patients with wide regions of pain, the VAS was assessed independently for each region and the target area for SCS was determined based on the area with greatest pain and disability(Aly MM, et al, 2010) (Fig. 2).

In addition, the patient global impression of change (PGIC) scale was assessed at the latest follow-up visit after the permanent implant. The PGIC scale indicates overall improvement according to a seven-point categorical scale: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; and 7, very much worse. The "rank 2" and "rank 1" were considered as clinically significant improvement (Aly MM, et al, 2010; Farrar, J., 2001).

During data analysis, the degree of pain relief was classified into three categories: good (≥50%), fair (30-49%), or poor (<30%) based on percent reduction of VAS (% reduction = [VAS pre-stimulation – VAS post-stimulation / VAS pre-stimulation] × 100%).13 Pain relief of "fair" or better was considered clinically significant based on a report documenting that pain reduction as low as 30 % corresponds to clinically meaningful success(Aly et al., 2010; Farrar,2001).

#### **4.5 Stimulation parameters**

The most common stimulation parameters were an amplitude of 1.5-3 V (range 1.5-6 V), a pulse width of 210 μsec (range 210-350 μsec), and a frequency of 31 Hz (range 10-50 Hz) with a bipolar configuration (Aly et al., 2010)

#### **5. Clinical outcome**

#### **5.1 Previous studies design**

To our knowledge, only 4 previous studies have investigated the use of SCS in CPSP (Table 1) (Simpson, 1991; Katayama, et al., 2001; Cruccu, et al., 2007; Lopez, 2009; Aly et al., 2010).

All previous studied were retrospective in nature and involved a small Number of patients (6-45). Therefore, a prospective controlled study with a larger population of patients is needed to provide stronger evidence for the efficacy of SCS in CPSP. However performing such study poses certain challenges. Firstly, it is difficult to recruit a large number of CPSP patients in one center owing to the low prevalence and under-diagnosis of this condition

Efficacy of Spinal Cord Stimulation for Central Post-Stroke Pain 119

only 3 of 45 patients (7%). Aly et al reported about 30 patients who underwent a trial of spinal cord stimulation, 10 underwent permanent placement, and 9 were available for follow-up (Aly, et al., 2010). Good or fair pain relief was seen in 7 of 9 patients (78%) with just over a mean 2-year follow-up. Lopez et al reported about 6 patients with SCS for CPSP. Good-to-excellent results were attained in 5 on long-term follow up (Lopez, et al., 2009).

Three out of the 4 previous studies reported moderate to high success rate of SCS for CPSP (25-80 %). The fourth study reported a poor outcome from SCS with success rate of only 7 %.On interpreting the results of these studies it should be noted that these studies used different outcome measures and different inclusion criteria with regard to pain distribution (Table 1). Actually there is no consensus regarding what constitutes an optimum threshold for success in chronic pain studies. Most studies use the criterion of 50% pain relief as threshold of success. However, this criterion is increasingly challenged, because in clinical practice, patients will often be satisfied with 30% pain relief (Farrar et al., 2001; Cruccu et al., 2007). We therefore suspect that the use of > 60% VAS reduction by Katayama group might be unsuitably high threshold for success which may underestimated the clinical effect of

Generally, the reported complication rate is low. Minor, clinically insignificant migrations were seen in 2 patients in one study (Aly et al., 2010). One electrode fractured and was

Only one study analyzed the clinical factors predictive of success of SCS for CPSP (Aly et al., 2010).It was found that patients with hyperpathia tended to respond less well to trial stimulation than those without. This observation is consistent with a previous report in which SCS was less effective for control of evoked pain than spontaneous pain (Kim et al, 2001). It was also found that the effects of trial stimulation were sustained following permanent implantation in the majority of patients. SCS trial stimulation is thus advantageous for

The mechanism behind pain relieving effect of SCS is still not fully understood. Inhibition at spinal segmental level and activation of supraspinal mechanisms have been suggested as possible neurophysiologic mechanisms (Kishima et al., 2010). Positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) studies had detected brain activation during SCS (Stancák et al., 2008). Using H215O PET, we have recently observed activation not only in somatosensory areas but also in those areas concerned with emotional aspects of pain such as anterior cingulate cortex and prefrontal areas (Kishima et al., 2010). CPSP is thought to be due to abnormal processing of nociceptive information rostral to the level of deaffrentiation (Katayama et al., 2001).

predicting efficacy in a minimally invasive manner before permanent implantation.

**5.3 Interpretation of outcome of previous studies**

SCS in this study (Aly et al, 2010).

**5.5 Predictors of success of SCS**

**6. Mechanisms of action**

replaced in another study (Lopez et al., 2009).

**5.4 Complications**

(Kim, 2009).It is also difficult to conduct a placebo-controlled studies or blinded evaluations because SCS induces perceptible sensation (Camerons, 2004). Therefore, the role of placebo effect remains unresolved problem in SCS literature. Finally it is difficult to conduct casematched controls, as in surgical practice long-term follow-up care is available only for surgically treated patients (Aly et al., 2010).

Fig. 2. MRI reveals evidence of an old right putaminal hemorrhage (A). The distribution of pain in the left hemibody shows that pain was more severe in the left foot; the patient therefore underwent implantation of a lower thoracic electrode targeting the foot region (B).

#### **5.2 Success rate**

Simpson et al first reported about long-term efficacy of SCS for CPSP in 10 patients (Simpson, 1991). Three out of the 10 patients (30 %) reported clinically significant improvement. The study done by Katayama was the main study reporting poor outcome from SCS (Katayama, et al, 2001) . Katayama reported long-term pain reduction (≥60%) in

Table 1. Summery of clinical outcomes of SCS studies for CPSP

only 3 of 45 patients (7%). Aly et al reported about 30 patients who underwent a trial of spinal cord stimulation, 10 underwent permanent placement, and 9 were available for follow-up (Aly, et al., 2010). Good or fair pain relief was seen in 7 of 9 patients (78%) with just over a mean 2-year follow-up. Lopez et al reported about 6 patients with SCS for CPSP. Good-to-excellent results were attained in 5 on long-term follow up (Lopez, et al., 2009).

#### **5.3 Interpretation of outcome of previous studies**

Three out of the 4 previous studies reported moderate to high success rate of SCS for CPSP (25-80 %). The fourth study reported a poor outcome from SCS with success rate of only 7 %.On interpreting the results of these studies it should be noted that these studies used different outcome measures and different inclusion criteria with regard to pain distribution (Table 1). Actually there is no consensus regarding what constitutes an optimum threshold for success in chronic pain studies. Most studies use the criterion of 50% pain relief as threshold of success. However, this criterion is increasingly challenged, because in clinical practice, patients will often be satisfied with 30% pain relief (Farrar et al., 2001; Cruccu et al., 2007). We therefore suspect that the use of > 60% VAS reduction by Katayama group might be unsuitably high threshold for success which may underestimated the clinical effect of SCS in this study (Aly et al, 2010).

#### **5.4 Complications**

118 Neuropathic Pain

(Kim, 2009).It is also difficult to conduct a placebo-controlled studies or blinded evaluations because SCS induces perceptible sensation (Camerons, 2004). Therefore, the role of placebo effect remains unresolved problem in SCS literature. Finally it is difficult to conduct casematched controls, as in surgical practice long-term follow-up care is available only for

Fig. 2. MRI reveals evidence of an old right putaminal hemorrhage (A). The distribution of pain in the left hemibody shows that pain was more severe in the left foot; the patient therefore underwent implantation of a lower thoracic electrode targeting the foot region (B).

Simpson et al first reported about long-term efficacy of SCS for CPSP in 10 patients (Simpson, 1991). Three out of the 10 patients (30 %) reported clinically significant improvement. The study done by Katayama was the main study reporting poor outcome from SCS (Katayama, et al, 2001) . Katayama reported long-term pain reduction (≥60%) in

**measure**

Katayama, 2001 45 VAS > 60 % Not available 7

Lopez, 2009 6 VAS > 50 % Localized pain 80

**Pain**

improvement Not available 30

%,PGIC Localized pain 25

**distribution Success rate %**

**Authors No of cases Outcome**

Simpson, 1991 10 Subjective

Ali, 2010 30 VAS > 30

Table 1. Summery of clinical outcomes of SCS studies for CPSP

surgically treated patients (Aly et al., 2010).

**5.2 Success rate**

Generally, the reported complication rate is low. Minor, clinically insignificant migrations were seen in 2 patients in one study (Aly et al., 2010). One electrode fractured and was replaced in another study (Lopez et al., 2009).

#### **5.5 Predictors of success of SCS**

Only one study analyzed the clinical factors predictive of success of SCS for CPSP (Aly et al., 2010).It was found that patients with hyperpathia tended to respond less well to trial stimulation than those without. This observation is consistent with a previous report in which SCS was less effective for control of evoked pain than spontaneous pain (Kim et al, 2001). It was also found that the effects of trial stimulation were sustained following permanent implantation in the majority of patients. SCS trial stimulation is thus advantageous for predicting efficacy in a minimally invasive manner before permanent implantation.

#### **6. Mechanisms of action**

The mechanism behind pain relieving effect of SCS is still not fully understood. Inhibition at spinal segmental level and activation of supraspinal mechanisms have been suggested as possible neurophysiologic mechanisms (Kishima et al., 2010). Positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) studies had detected brain activation during SCS (Stancák et al., 2008). Using H215O PET, we have recently observed activation not only in somatosensory areas but also in those areas concerned with emotional aspects of pain such as anterior cingulate cortex and prefrontal areas (Kishima et al., 2010). CPSP is thought to be due to abnormal processing of nociceptive information rostral to the level of deaffrentiation (Katayama et al., 2001).

Efficacy of Spinal Cord Stimulation for Central Post-Stroke Pain 121

Katayama, Y., Yamamoto, T., Kobayashi, K., Kasai, M., Oshima, H., Fukaya, C. (2001). Motor

Kim, J.S. (2003). Post-stroke central pain or paraesthesia after lenticulocapsular hemorrhage.

Kim, S.H., Tasker, R.R., Oh, M.Y. (2001). Spinal cord stimulation for nonspecific limb pain

Kishima, H., Saitoh, Y., Oshino, S., Hosomi, K., Ali, M., Maruo, T., Hirata, M., Goto, T.,

Klit, H., Finnerup, N.B., and Jensen, T.S. (2009). Central post-stroke pain: clinical characteristics, pathophysiology, and management. *Lancet Neurology*. 8, 857-868. Kumar, K., Toth, C., Nath, R.K. (1997). Deep brain stimulation for intractable pain: a 15-year

Kumar, K., Hunter, G., Demeria, D. (2006). Spinal cord stimulation in treatment of chronic

Kumar, K., Wilson, J.R. (2007). Factors affecting spinal cord stimulation outcome in chronic benign pain with suggestions to improve success rate. *Acta Neurochir Suppl*, 97, 91-99. Lazorthes, Y., Sol, J.C., Fowo, S., Roux, F.E., Verdie, J.C. (2007). Motor cortex stimulation for

Leijon, G., Boivie, J., and Johansson, I. (1989). Central post-stroke pain -neurological

Lopez, J.A., Torres, L.M., Gala, F., Iglesias, I. (2009). Spinal Cord Stimulation and Thalamic Pain: Long-term Results of Eight Cases. *Neuromodulation*, 12, 240-243. Saitoh, Y., Yoshimine, T. (2007). Stimulation of primary motor cortex for intractable

Saitoh, Y., Hirayama, A., Kishima, H., Shimokawa, T., Oshino, S., Hirata, M., Tani, N., Kato,

Simpson, B.A. (1991). Spinal cord stimulation in 60 cases of intractable pain. *Journal of Neurol*

Stancák, A., Kozák, J., Vrba, I., Tintera, J., Vrána, J., Polácek, H., Stancák, M. (2008).

Tracy, Camerons. (2004). Safety and efficacy of spinal cord stimulation for the treatment of

Tsubokawa, T., Katayama, Y., Yamamoto, T., Hirayama, T., Koyama, S. (1991). Chronic

stimulation of the primary motor cortex. *J Neurosurg*, 107, 555-9.

Stojanovic, M., Abdi, S. (2002). Spinal Cord Stimulation. *Pain Phys.*, 5, 156-166.

chronic pain: a 20-year literature review. *J Neurosurg*, 100, 254-267.

deafferentation pain. In: Sakas, D.E., Simpson, B.A., editors. *Operative*

A., Yoshimine, T. (2007). Reduction of intractable deafferentation pain due to spinal cord or peripheral lesion by high-frequency repetitive transcranial magnetic

Functional magnetic resonance imaging of cerebral activation during spinal cord stimulation in failed back surgery syndrome patients. *Eur J Pain*, 12, 137-148.

motor cortex stimulation for the treatment of central pain. *Acta Neurochir Suppl*

stimulation. *Stereotaact Funct Neurosurg*, 77, 183-186.

Kim, J.S. (2009). Post-stroke pain. *Expert Rev Neurother*, 9, 711-721.

H215O PET study. *Neuroimage*, 49, 2564-2569.

experience. *Neurosurgery* 1997;40:736–746.

neuropathic pain. *Acta Neurochir*, 97 (Pt 2), 37–44.

symptoms and pain characteristics. *Pain*, 36, 13-25.

*neuromodulation, Vol. 2. Wein: Springer*, 51-6.

*Neurosurg Psychiatry*, 54, 196-199.

*(Wien)*, 52, 137-9.

experience. *Neurosurgery*, 58, 481-496.

Neurology, 61, 679-682.

1056-1064.

cortex stimulation for post-stroke pain: comparison of spinal cord and thalamic

versus neuropathic pain and spontaneous versus evoked pain. *Neurosurgery*, 48,

Yanagisawa, T., Sumitani, M., Osaki, Y., Hatazawa, J., Yoshimine, T. (2010). Modulation of neuronal activity after spinal cord stimulation for neuropathic pain;

benign pain: challenges in treatment planning and present status, a 22-year

Therefore, we speculate that the pain relieving effect of SCS in CPSP may be interpreted in light of its supraspinal mechanisms (Aly et al., 2010)

#### **7. Conclusion**

SCS may provide improved pain control in a group of patients with medically intractable CPSP. The efficacy of SCS in CPSP is generally modest; both in terms of success rate and degree of pain relief. However, this modest degree of efficacy is important considering the severity of pain in these patients, the refractory nature of their pain, and the paucity of alterative therapeutic options. A further prospective controlled study with larger population of patients is still needed to provide stronger evidence for the efficacy of SCS in CPSP and define patient population who are most likely to get benefit from SCS treatment. SCS should be one of the neurostimulation techniques available to treat the medically-refractory poststroke pain patient.

#### **8. References**

Therefore, we speculate that the pain relieving effect of SCS in CPSP may be interpreted

SCS may provide improved pain control in a group of patients with medically intractable CPSP. The efficacy of SCS in CPSP is generally modest; both in terms of success rate and degree of pain relief. However, this modest degree of efficacy is important considering the severity of pain in these patients, the refractory nature of their pain, and the paucity of alterative therapeutic options. A further prospective controlled study with larger population of patients is still needed to provide stronger evidence for the efficacy of SCS in CPSP and define patient population who are most likely to get benefit from SCS treatment. SCS should be one of the neurostimulation techniques available to treat the medically-refractory post-

Andersen, G., Vestergaard, K., Ingeman-Nielsen, M., Jensen, T.S. (1995). Incidence of central

Andre-Obadia, N., Peyron, R., Mertens, P., Mauguiere, F., Laurent, B., Garcia-Larrea, L.

Bowsher, D. (1993). Cerebrovascular disease: Sensory consequences of stroke. Lancet, 341, 156. Canavero, S., Bonicalzi, V. (2003). Spinal cord stimulation for central pain (Letter to Editor).

Cruccu, G., Aziz, T.Z., Garcia-Larrea, L., Hansson, P., Jensen, T.S., Lefaucheur, J.P., Simpson,

Farrar, J.T., Young, J.P., LaMoreaux, L., Werth, J.L., Poole, R.M. (2001). Clinical importance

Finnerup, N.B., Otto, M., McQuay, H.J., Jensen, T.S., Sindrup, S.H. (2005). Algorithm for neuropathic pain treatment: an evidence based proposal. *Pain*, 118, 289-305. Fontaine, D., Hamani, C., and Lozano, A. (2009). Efficacy and safety of motor cortex

Holsheimer, J. (1997). Effectiveness of spinal cord stimulation in the management of chronic pain: analysis of technical drawbacks and solutions. *Neurosurgery*, 40, 990-996. Hosomi, K., Saitoh, Y., Kishima, H., Oshino, S., Hirata, M., Tani, N., Shimokawa, T.,

efficacy. *Clin Neurophysiol*, 117, 1536-1544, ISSN 1388-2457

(2006). Transcranial magnetic stimulation for pain control. Double-blind study of different frequencies against placebo, and correlation with motor cortex stimulation

B.A., Taylor, R.S. (2007). EFNS guidelines on neurostimulation therapy for

of change in chronic pain intensity measured on an 11-point numerical pain rating

stimulation for chronic neuropathic pain: critical review of the literature. *J*

Yoshimine, T. (2008). Electrical stimulation of primary motor cortex within the central sulcus for intractable neuropathic pain. *Clin Neurophysiol*, 119, 993-1001. Katayama, Y., Fukaya, C., Yamamoto, T. (1998). Poststroke pain control by chronic motor

cortex stimulation: neurological characteristics predicting a favorable response. *J*

in light of its supraspinal mechanisms (Aly et al., 2010)

post stroke pain. *Pain*, 61, 187-194.

neuropathic pain. *Eur J Neurol*, 14, 952-970.

*Pain*, 103, 228–228.719.

scale. *Pain*, 94, 149-158.

*Neurosurg*, 110, 251-256.

*Neurosurg*, 89, 585-91.

**7. Conclusion**

stroke pain patient.

**8. References**

**7**

*Japan*

Ken-ichiro Uchida

**Radiofrequency Treatments for Neuropathic**

There are 2 types of radiofrequency treatment (RF) for neuropathic pain: thermal

Thermal RF (TRF) uses a constant high-frequency electric current (100,000-500,000 Hz) to produce tissue temperatures of 45 °C or more, resulting in neuroablative thermocoagulation. Thus, TRF is a neurolytic technique that uses heat for controlled destruction of nociceptive pathways. However, the use of TRF for the management of neuropathic pain is controversial because neuroablation can lead to lasting motor deficits, neuritis, and deafferentation pain. PRF was developed as an alternative to TRF. In PRF, the current is delivered in short pulses, and the tip temperature of the probe is adjusted so that it does not increase above 42 °C, thus avoiding lesions. PRF has been applied to treat various chronic pain conditions (Chua et al., 2011) but, the mechanisms of the analgesic action have not been studied in detail, and

the optimal electrical parameters (voltage and duration) have not been established.

We then presented our results from 2 self-controlled studies on each method.

studies. Therefore, case reports also have been excluded.

**2. TRF for neuropathic pain**

**2.1 Mechanism of action**

This chapter discusses the use of both TRF and PRF for treating neuropathic pain. We excluded treatments administered for arthropathy or discogenic pain, such as RF of the medial branch that innervates the zygapophyseal joints or that of the intervertebral disc.

The review section of this chapter critically evaluates the efficacy of TRF and PRF by discussing several randomized clinical trials (RCTs) and well-designed observational

The passage of low-energy, high-frequency alternating current (100,000–500,000 Hz) causes intense oscillations of tissue ions. This oscillation heats charged macromolecules, most notably proteins (Organ, 1976−1977). In TRF, heating during RF causes many cells to die rapidly if tissue temperatures reach 45 °C. Neuroablation is produced whether the electrode is placed inside the dorsal root ganglion (DRG) or onto a peripheral nerve. Above 55 °C, there is indiscriminate destruction of both small- and large-diameter myelinated fibers,

**1. Introduction**

(continuous) RF and pulsed RF (PRF).

**Pain: Review and New Approaches**

*Department of Anesthesiology, Kurashiki Central Hospital*

## **Radiofrequency Treatments for Neuropathic Pain: Review and New Approaches**

Ken-ichiro Uchida *Department of Anesthesiology, Kurashiki Central Hospital Japan*

#### **1. Introduction**

122 Neuropathic Pain

Tsubokawa, T., Katayama, Y., Yamamomto, T., Hirayama, T., Koyama, S. (1993). Chronic motor cortex stimulation in patients with thalamic pain. *J Neurosurg*, 78, 393–401. Wider, M., Ahlstrom, G. (2002). Disability after a stroke and the influence of long-term pain

on everyday life. *Scand J of Caring Sciences,* 16, 302-310.

There are 2 types of radiofrequency treatment (RF) for neuropathic pain: thermal (continuous) RF and pulsed RF (PRF).

Thermal RF (TRF) uses a constant high-frequency electric current (100,000-500,000 Hz) to produce tissue temperatures of 45 °C or more, resulting in neuroablative thermocoagulation. Thus, TRF is a neurolytic technique that uses heat for controlled destruction of nociceptive pathways. However, the use of TRF for the management of neuropathic pain is controversial because neuroablation can lead to lasting motor deficits, neuritis, and deafferentation pain.

PRF was developed as an alternative to TRF. In PRF, the current is delivered in short pulses, and the tip temperature of the probe is adjusted so that it does not increase above 42 °C, thus avoiding lesions. PRF has been applied to treat various chronic pain conditions (Chua et al., 2011) but, the mechanisms of the analgesic action have not been studied in detail, and the optimal electrical parameters (voltage and duration) have not been established.

This chapter discusses the use of both TRF and PRF for treating neuropathic pain. We excluded treatments administered for arthropathy or discogenic pain, such as RF of the medial branch that innervates the zygapophyseal joints or that of the intervertebral disc.

The review section of this chapter critically evaluates the efficacy of TRF and PRF by discussing several randomized clinical trials (RCTs) and well-designed observational studies. Therefore, case reports also have been excluded.

We then presented our results from 2 self-controlled studies on each method.

#### **2. TRF for neuropathic pain**

#### **2.1 Mechanism of action**

The passage of low-energy, high-frequency alternating current (100,000–500,000 Hz) causes intense oscillations of tissue ions. This oscillation heats charged macromolecules, most notably proteins (Organ, 1976−1977). In TRF, heating during RF causes many cells to die rapidly if tissue temperatures reach 45 °C. Neuroablation is produced whether the electrode is placed inside the dorsal root ganglion (DRG) or onto a peripheral nerve. Above 55 °C, there is indiscriminate destruction of both small- and large-diameter myelinated fibers,

Radiofrequency Treatments for Neuropathic Pain: Review and New Approaches 125

Three prospective controlled trials have examined TRF-DRG for treating neuropathic pain

Van Kleef et al. (van Kleef et al*.,* 1996) divided the patients with intractable chronic cervicobrachial pain into 2 treatment groups: 9 patients underwent TRF of the cervical DRG at 67 ºC, whereas 11 underwent sham treatment. Patients were evaluated before the procedure and 8 weeks after it. Eight patients in the thermal RF group (88.8%) and 2 patients (18.1%) in the sham group reported pain relief. Regarding side effects of TRF, 7 patients treated with TRF noticed a faint burning sensation in the treated dermatome that subsided

Slappendel et al. (Slappendel et al., 1997) conducted second RCT involving TRF of the cervical DRG in patients with cervicobrachial pain. They compared 32 patients who received TRF-DRG at 67 ºC with 29 patients who received TRF-DRG at 40 ºC, which could not produce neuroablative thermocoagulation. No statistically significant difference in pain scores was found between the 2 groups. Neuritis was reported in the TRF-DRG at 67 ºC group (18.8%) and TRF-DRG at 40 ºC group (17.2%) 6 weeks after TRF-DRG. Moreover, a few patients

A trial by Haspeslagh et al. (Haspeslagh et al., 2006) included 30 patients with cervicogenic headache. Patients were randomized to 2 groups. One group (n = 15) was treated by TRF of cervical facet joints, followed by TRF of the cervical DRG at 67 ºC if necessary, whereas the second group (n = 15) was treated by injections of a steroid and a local anesthetic into the greater occipital nerve, followed by transcutaneous electrical nerve stimulation (TENS) if necessary. There was no significant difference in the success rate between the 2 treatments, and the authors concluded that sequential TRF of facet joints and DRG had similar efficacy to local steroid and anesthetic injection, followed by

Stolker et al. (Stolker et al., 1994) conducted a prospective uncontrolled trial using TRF of the thoracic DRG at 67 ºC to treat 45 patients afflicted with thoracic segmental pain. They reported that 91% patients obtained > 50% pain relief at 2 months and that 78% continued to experience pain relief for 13 to 46 months. A smaller number of patients (13.3%) reported a transient burning pain in the corresponding dermatome that subsided within 3 weeks.

There is only 1 prospective controlled trial on the clinical efficacy of TRF of the lumbar DRG. A trial by Geurts et al. (Geurts et al., 2003) included 83 patients with chronic lumbosacral pain; 45 patients underwent TRF-DRG at 67 ºC, whereas 38 underwent sham treatment. After 3 months, 16% patients treated with TRF-DRG and 25% of sham-treated patients reported a decrease in lumbosacral pain (*P* = 0.43). Adverse events and complications, such as treatment-related pain, changes in sensation, or loss of motor function, did not differ between the treatment groups. They concluded that TRF was not an effective treatment for chronic lumbosacral radicular pain

Whereas the clinical efficacy of TRF was confirmed for some types of neuropathic pain, each of these studies has limitations, particularly small sample numbers and short-term follow-up. In

reported motor disturbances with a decreased pinch force 3 months after treatment.

There have been no prospective controlled trials on TRF of the thoracic DRG.

and stressed that such patients would attain little benefit from TRF-DRG.

stemming from cervical DRG.

within 3 weeks after treatment.

TENS.

accompanied by focal necrosis, hemorrhages, extensive edema, and features of Wallerian degeneration. Even with a voltage as low as 0.1 V, an electrode placed inside a DRG and heated to 67 °C results in total loss of myelinated fibers and hemorrhage (de Louw et al., 2001; Govind & Bogduk, 2010; Podhajsky et al., 2005; Smith et al., 1981).

The mode of action of RF was initially attributed to the thermocoagulation of nerve fibers, but contradictory observations (most notably that only transient sensory loss is observed in the associated dermatome, whereas the pain relief may last much longer) suggest that temperature is not the only mechanism responsible for the decrease in pain transmission (Racz & Ruiz-Lopez, 2006).

#### **2.2 Treatment of neuropathic pain and its complications**

#### **2.2.1 Trigeminal neuralgia**

Trigeminal neuralgia is a common, idiopathic form of neuropathic pain that presents with paroxysms of pain involving 1 or more divisions of the trigeminal nerve.

TRF of the trigeminal ganglion has been used for decades to treat trigeminal neuralgia, and several large retrospective series have been conducted to evaluate the efficacy of this procedure. Taha and Tew (Taha & Tew, 1996) reevaluated the effects of TRF on trigeminal ganglion and compared the effectiveness with other surgical procedures for the treatment of trigeminal neuralgia. In this study, among the successfully completed procedures (n = 6205), complete initial pain relief was highest after TRF and microvascular decompression (MVD) (98%), whereas, glycerol rhizotomy and balloon compression relieved pain in 91% and 93% of patients, respectively. TRF had the highest success rate (98%) when considering both completion of the procedure and achievement of pain relief, whereas lowest success rates were achieved by glycerol rhizotomy (85%) and MVD (83%). The rate of pain recurrence following these percutaneous techniques was lower with TRF (20% in 9 years) than with glycerol rhizotomy (54% in 4 years) or balloon compression (21% in 2 years).

The chief disadvantages of TRF of the trigeminal ganglion was that the deliberately produces sensory loss with an unavoidable incidence of neuropathic pain in some patients (Niv & Gofeld, 2009). The most common complications and adverse effects of TRF of the trigeminal ganglion included facial numbness (98%), dysesthesia (24%), anesthesia dolorosa (1.5%), corneal anesthesia (7%), keratitis (1%), and trigeminal motor dysfunction (24%) (Rathmell, 2009). The mechanism of injury during TRF for trigeminal neuralgia may be related to injury caused during placement of the cannula or injury caused by thermal destruction during the procedure.

#### **2.2.2 DRG**

TRF of DRG (TRF-DRG) is mainly used to treat persistent radicular pain. Although uncontrolled studies reported acceptable clinical efficacy, the controlled clinical data on TRF yielded variable results that depended on the pain syndrome treated and the specific mode of TRF-DRG employed (Malik & Benzon, 2008). To date, there is limited evidence for only short-term relief of cervicobrachial pain, no conclusive evidence that TRF-DRG is an effective treatment for cervicogenic headaches, and limited evidence against its use in the treatment of lumbar radicular pain.

accompanied by focal necrosis, hemorrhages, extensive edema, and features of Wallerian degeneration. Even with a voltage as low as 0.1 V, an electrode placed inside a DRG and heated to 67 °C results in total loss of myelinated fibers and hemorrhage (de Louw et al.,

The mode of action of RF was initially attributed to the thermocoagulation of nerve fibers, but contradictory observations (most notably that only transient sensory loss is observed in the associated dermatome, whereas the pain relief may last much longer) suggest that temperature is not the only mechanism responsible for the decrease in pain transmission

Trigeminal neuralgia is a common, idiopathic form of neuropathic pain that presents with

TRF of the trigeminal ganglion has been used for decades to treat trigeminal neuralgia, and several large retrospective series have been conducted to evaluate the efficacy of this procedure. Taha and Tew (Taha & Tew, 1996) reevaluated the effects of TRF on trigeminal ganglion and compared the effectiveness with other surgical procedures for the treatment of trigeminal neuralgia. In this study, among the successfully completed procedures (n = 6205), complete initial pain relief was highest after TRF and microvascular decompression (MVD) (98%), whereas, glycerol rhizotomy and balloon compression relieved pain in 91% and 93% of patients, respectively. TRF had the highest success rate (98%) when considering both completion of the procedure and achievement of pain relief, whereas lowest success rates were achieved by glycerol rhizotomy (85%) and MVD (83%). The rate of pain recurrence following these percutaneous techniques was lower with TRF (20% in 9 years) than with

The chief disadvantages of TRF of the trigeminal ganglion was that the deliberately produces sensory loss with an unavoidable incidence of neuropathic pain in some patients (Niv & Gofeld, 2009). The most common complications and adverse effects of TRF of the trigeminal ganglion included facial numbness (98%), dysesthesia (24%), anesthesia dolorosa (1.5%), corneal anesthesia (7%), keratitis (1%), and trigeminal motor dysfunction (24%) (Rathmell, 2009). The mechanism of injury during TRF for trigeminal neuralgia may be related to injury caused during placement of the cannula or injury caused by thermal

TRF of DRG (TRF-DRG) is mainly used to treat persistent radicular pain. Although uncontrolled studies reported acceptable clinical efficacy, the controlled clinical data on TRF yielded variable results that depended on the pain syndrome treated and the specific mode of TRF-DRG employed (Malik & Benzon, 2008). To date, there is limited evidence for only short-term relief of cervicobrachial pain, no conclusive evidence that TRF-DRG is an effective treatment for cervicogenic headaches, and limited evidence against its use in the

2001; Govind & Bogduk, 2010; Podhajsky et al., 2005; Smith et al., 1981).

paroxysms of pain involving 1 or more divisions of the trigeminal nerve.

glycerol rhizotomy (54% in 4 years) or balloon compression (21% in 2 years).

**2.2 Treatment of neuropathic pain and its complications**

(Racz & Ruiz-Lopez, 2006).

**2.2.1 Trigeminal neuralgia**

destruction during the procedure.

treatment of lumbar radicular pain.

**2.2.2 DRG**

Three prospective controlled trials have examined TRF-DRG for treating neuropathic pain stemming from cervical DRG.

Van Kleef et al. (van Kleef et al*.,* 1996) divided the patients with intractable chronic cervicobrachial pain into 2 treatment groups: 9 patients underwent TRF of the cervical DRG at 67 ºC, whereas 11 underwent sham treatment. Patients were evaluated before the procedure and 8 weeks after it. Eight patients in the thermal RF group (88.8%) and 2 patients (18.1%) in the sham group reported pain relief. Regarding side effects of TRF, 7 patients treated with TRF noticed a faint burning sensation in the treated dermatome that subsided within 3 weeks after treatment.

Slappendel et al. (Slappendel et al., 1997) conducted second RCT involving TRF of the cervical DRG in patients with cervicobrachial pain. They compared 32 patients who received TRF-DRG at 67 ºC with 29 patients who received TRF-DRG at 40 ºC, which could not produce neuroablative thermocoagulation. No statistically significant difference in pain scores was found between the 2 groups. Neuritis was reported in the TRF-DRG at 67 ºC group (18.8%) and TRF-DRG at 40 ºC group (17.2%) 6 weeks after TRF-DRG. Moreover, a few patients reported motor disturbances with a decreased pinch force 3 months after treatment.

A trial by Haspeslagh et al. (Haspeslagh et al., 2006) included 30 patients with cervicogenic headache. Patients were randomized to 2 groups. One group (n = 15) was treated by TRF of cervical facet joints, followed by TRF of the cervical DRG at 67 ºC if necessary, whereas the second group (n = 15) was treated by injections of a steroid and a local anesthetic into the greater occipital nerve, followed by transcutaneous electrical nerve stimulation (TENS) if necessary. There was no significant difference in the success rate between the 2 treatments, and the authors concluded that sequential TRF of facet joints and DRG had similar efficacy to local steroid and anesthetic injection, followed by TENS.

There have been no prospective controlled trials on TRF of the thoracic DRG.

Stolker et al. (Stolker et al., 1994) conducted a prospective uncontrolled trial using TRF of the thoracic DRG at 67 ºC to treat 45 patients afflicted with thoracic segmental pain. They reported that 91% patients obtained > 50% pain relief at 2 months and that 78% continued to experience pain relief for 13 to 46 months. A smaller number of patients (13.3%) reported a transient burning pain in the corresponding dermatome that subsided within 3 weeks.

There is only 1 prospective controlled trial on the clinical efficacy of TRF of the lumbar DRG. A trial by Geurts et al. (Geurts et al., 2003) included 83 patients with chronic lumbosacral pain; 45 patients underwent TRF-DRG at 67 ºC, whereas 38 underwent sham treatment. After 3 months, 16% patients treated with TRF-DRG and 25% of sham-treated patients reported a decrease in lumbosacral pain (*P* = 0.43). Adverse events and complications, such as treatment-related pain, changes in sensation, or loss of motor function, did not differ between the treatment groups. They concluded that TRF was not an effective treatment for chronic lumbosacral radicular pain and stressed that such patients would attain little benefit from TRF-DRG.

Whereas the clinical efficacy of TRF was confirmed for some types of neuropathic pain, each of these studies has limitations, particularly small sample numbers and short-term follow-up. In

Radiofrequency Treatments for Neuropathic Pain: Review and New Approaches 127

Exclusion criteria were as follows: (1) MRI showing acute pathology; (2) history of adverse reactions to local anesthetics or glucocorticoids; or (3) coagulation disorders, or use of

After we provided complete information on the RF technique and its possible benefits, risks,

In the first part of this study, conventional nerve block (NB) was achieved using a local

The duration of pain relief was defined as the number of days after the treatment until the

The level at which conventional NB was administered was determined by the affected dermatome, the degree of tenderness under the rib using fluoroscopy with a C-arm, and the

Conventional NB was performed using a 22-gauge, 80-mm needle under real-time fluoroscopy with a C-arm by the laterodorsal approach (Uchida, 2009). We administered 1.5 ml of 2% mepivacaine as the local anesthetic and 2 mg of betamethasone (Rinderon®,

Four to eight weeks after assessment of the effect of conventional NB, TRF-TPN was administered in the same manner as the previous conventional NB. In the TRF procedure, the electrode (22-gauge 99-mm needle with 4-mm bare tip, TFW 22G × 99 mm®, Hakko, Japan) was used instead of a 22-gauge, 80-mm needle. Once the electrode was positioned, the electrode stylet was replaced with a thermocouple electrode. We tested whether the thermocouple electrode was placed in the physiologically correct location by applying 100- Hz stimulation of the needle tip. We initially set the voltage at 0 V, and then gradually increased it until the patient felt a tingling sensation. If a tingling sensation in the corresponding dermatome was reported at a voltage of < 0.5 V, the electrode was assumed to be in the correct position. After verifying that the needle was in the correct position, 1.5

Five minutes later, TRF-TPN was applied at 90 °C and duration of 90 seconds under control of a generator (Neuro Therm JK 3TM system, Croydon, Surrey, UK) with an automatic temperature control mode to avoid excessive elevation of temperature. After therapy, the number of days of pain relief and the complications resulting from TRF-TPN were recorded.

The duration of pain relief after TRF was significantly longer than that after conventional

NB (*P* < 0.0001, Kaplan–Meier analysis and the log–rank statistic) (Figure 1).

and side effects, the patients gave verbal informed consent for the procedure.

anesthetic and glucocorticoid, and the duration of pain relief was recorded.

pain intensity returned to the level experienced before treatment.

ml of 2% mepivacaine and 2 mg of betamethasone were administered.

**3.2.2 Conventional paravertebral nerve block**

Shionogi, Osaka, Japan) as the glucocorticoid.

**3.2.3 Radiofrequency procedures**

anticoagulants.

effect of the intercostal NB.

**3.3 Results**

**3.3.1 Primary outcomes**

their review, Malik and Benzon (Malik & Benzon, 2008) concluded that larger-scale, longerterm, controlled clinical trials are required to clearly establish the efficacy of TRF-DRG for different types of neuropathic pain, particularly pain originating from thoracic DRG.

#### **2.2.3 Sympathetic ganglia**

Although systematic reviews have found no tangible evidence supporting the benefit of sympathectomy for the management of neuropathic pain, TRF of the stellate, thoracic, and lumbar sympathetic ganglia has been used for treatment of neuropathic pain arising from sympathetic ganglia dysfunction such as complex regional pain syndrome. However, evidence for the therapeutic efficacy of TRF, is limited to small case series. RCTs are needed to validate the efficacy of TRF for these syndromes and to define measurable and reproducible end points for it.

#### **3. Neuropathic pain treatment by combined TRF and glucocorticoids**

#### **3.1 Background**

TRF is controversial because of its neurodestructive nature (Bogduk, 2006; de Louw et al., 2001; Podhajsky et al., 2005; Smith et al., 1981; Uematsu et al., 1974). Heat lesions produced by TRF causing neural destruction have sequelae similar to other forms of neural injury. Even with proper technique, TRF is associated with sensory loss and the onset of neuropathic pain. Although the frequency of these complications is minimized by the proper use of sensory and motor stimulation trials to isolate somatosensory and motor axons before lesion, injury to adjacent nerves can easily occur (Rathmell, 2009). Glucocorticoids have been used to treat neuropathic pain for many years, and they do effectively alleviate acute and continued postoperative pain by suppressing inflammatory mediators and glial activation, resulting in decreased nociceptive activity, sympathetic sprouting, and central neuropathic changes such as central sensitization (Romundstad & Stubhaug, 2007). We suggest that the effect of glucocorticoids could be additive to that of TRF and that glucocorticoids might avert pain associated with neuroinflammation after RF lesioning.

#### **3.2 Methods**

#### **3.2.1 Patients**

Fourteen patients (7 females, 7 males) with refractory neuropathic pain from postherpetic neuralgia were included in this study. Median age was 70.5 years (interquartile range, 69.3– 71.8 years). The median pain duration was 9.0 months (interquartile range, 7.0–13.5 months).

Patients were selected to undergo TRF of the thoracic paravertebral nerve (TRF-TPN) combined with glucocorticoid according to the following criteria: (1) the presence of radiating pain in the thoracic region following herpes zoster; (2) no response to conventional treatments such as anti-inflammatory drugs, antidepressants, anticonvulsants, opioid analgesics, and topical capsaicin; (3) at least 6 months of conventional treatment; (4) temporary positive response (100% pain relief) to TPN block using local anesthetics and glucocorticoids (conventional NB) at each painful dermatome; and (5) pain severe enough to disturb sleep.

Exclusion criteria were as follows: (1) MRI showing acute pathology; (2) history of adverse reactions to local anesthetics or glucocorticoids; or (3) coagulation disorders, or use of anticoagulants.

After we provided complete information on the RF technique and its possible benefits, risks, and side effects, the patients gave verbal informed consent for the procedure.

#### **3.2.2 Conventional paravertebral nerve block**

126 Neuropathic Pain

their review, Malik and Benzon (Malik & Benzon, 2008) concluded that larger-scale, longerterm, controlled clinical trials are required to clearly establish the efficacy of TRF-DRG for

Although systematic reviews have found no tangible evidence supporting the benefit of sympathectomy for the management of neuropathic pain, TRF of the stellate, thoracic, and lumbar sympathetic ganglia has been used for treatment of neuropathic pain arising from sympathetic ganglia dysfunction such as complex regional pain syndrome. However, evidence for the therapeutic efficacy of TRF, is limited to small case series. RCTs are needed to validate the efficacy of TRF for these syndromes and to define measurable and

TRF is controversial because of its neurodestructive nature (Bogduk, 2006; de Louw et al., 2001; Podhajsky et al., 2005; Smith et al., 1981; Uematsu et al., 1974). Heat lesions produced by TRF causing neural destruction have sequelae similar to other forms of neural injury. Even with proper technique, TRF is associated with sensory loss and the onset of neuropathic pain. Although the frequency of these complications is minimized by the proper use of sensory and motor stimulation trials to isolate somatosensory and motor axons before lesion, injury to adjacent nerves can easily occur (Rathmell, 2009). Glucocorticoids have been used to treat neuropathic pain for many years, and they do effectively alleviate acute and continued postoperative pain by suppressing inflammatory mediators and glial activation, resulting in decreased nociceptive activity, sympathetic sprouting, and central neuropathic changes such as central sensitization (Romundstad & Stubhaug, 2007). We suggest that the effect of glucocorticoids could be additive to that of TRF and that glucocorticoids might avert pain

Fourteen patients (7 females, 7 males) with refractory neuropathic pain from postherpetic neuralgia were included in this study. Median age was 70.5 years (interquartile range, 69.3– 71.8 years). The median pain duration was 9.0 months (interquartile range, 7.0–13.5 months). Patients were selected to undergo TRF of the thoracic paravertebral nerve (TRF-TPN) combined with glucocorticoid according to the following criteria: (1) the presence of radiating pain in the thoracic region following herpes zoster; (2) no response to conventional treatments such as anti-inflammatory drugs, antidepressants, anticonvulsants, opioid analgesics, and topical capsaicin; (3) at least 6 months of conventional treatment; (4) temporary positive response (100% pain relief) to TPN block using local anesthetics and glucocorticoids (conventional NB) at each painful dermatome; and (5) pain severe enough to

different types of neuropathic pain, particularly pain originating from thoracic DRG.

**3. Neuropathic pain treatment by combined TRF and glucocorticoids**

**2.2.3 Sympathetic ganglia**

reproducible end points for it.

associated with neuroinflammation after RF lesioning.

**3.1 Background**

**3.2 Methods 3.2.1 Patients**

disturb sleep.

In the first part of this study, conventional nerve block (NB) was achieved using a local anesthetic and glucocorticoid, and the duration of pain relief was recorded.

The duration of pain relief was defined as the number of days after the treatment until the pain intensity returned to the level experienced before treatment.

The level at which conventional NB was administered was determined by the affected dermatome, the degree of tenderness under the rib using fluoroscopy with a C-arm, and the effect of the intercostal NB.

Conventional NB was performed using a 22-gauge, 80-mm needle under real-time fluoroscopy with a C-arm by the laterodorsal approach (Uchida, 2009). We administered 1.5 ml of 2% mepivacaine as the local anesthetic and 2 mg of betamethasone (Rinderon®, Shionogi, Osaka, Japan) as the glucocorticoid.

#### **3.2.3 Radiofrequency procedures**

Four to eight weeks after assessment of the effect of conventional NB, TRF-TPN was administered in the same manner as the previous conventional NB. In the TRF procedure, the electrode (22-gauge 99-mm needle with 4-mm bare tip, TFW 22G × 99 mm®, Hakko, Japan) was used instead of a 22-gauge, 80-mm needle. Once the electrode was positioned, the electrode stylet was replaced with a thermocouple electrode. We tested whether the thermocouple electrode was placed in the physiologically correct location by applying 100- Hz stimulation of the needle tip. We initially set the voltage at 0 V, and then gradually increased it until the patient felt a tingling sensation. If a tingling sensation in the corresponding dermatome was reported at a voltage of < 0.5 V, the electrode was assumed to be in the correct position. After verifying that the needle was in the correct position, 1.5 ml of 2% mepivacaine and 2 mg of betamethasone were administered.

Five minutes later, TRF-TPN was applied at 90 °C and duration of 90 seconds under control of a generator (Neuro Therm JK 3TM system, Croydon, Surrey, UK) with an automatic temperature control mode to avoid excessive elevation of temperature. After therapy, the number of days of pain relief and the complications resulting from TRF-TPN were recorded.

#### **3.3 Results**

#### **3.3.1 Primary outcomes**

The duration of pain relief after TRF was significantly longer than that after conventional NB (*P* < 0.0001, Kaplan–Meier analysis and the log–rank statistic) (Figure 1).

Radiofrequency Treatments for Neuropathic Pain: Review and New Approaches 129

Peripheral nerve destruction caused by TRF has paradoxical effects on neuropathic pain. It is believed that the therapeutic effect of TRF is achieved by a partial nerve lesion to nociceptive afferents (Bogduk, 2006). On the other hand, minor nerve injury can sometimes produce devastating pain, whereas modest or diffuse deafferentation does not (Devor et al. 2006). The cause of this effect has not been elucidated. In a clinical study, it was suggested that even long-standing central sensitization can be reversed quickly when the peripheral input is removed (Gracely et al., 1992). Therefore we believe that TRF is an acceptable

We used TRF-TPN for postherpetic neuralgia instead of TRF-DRG in this case series. TRF-TPN has an simpler surgical approach than TRF-DRG and thus a lower probability of injuring the radicular artery, an event that may induce serious neurologic complications,

We reported previously that repeated administration of TRF-TPN combined with glucocorticoid administration decreased pain and improved the quality of life in patients

Although the use of glucocorticoids for NB is also controversial, glucocorticoids are usually coadministered with a local anesthetic. Pro-inflammatory cytokines secreted at or near the site of nerve injury are involved in the development and maintenance of central

The lesions produced by the RF energy are well-demarcated areas of coagulative necrosis surrounded by inflammatory cell infiltrate and hemorrhage. This inflammatory response can lead to increased tenderness, pain, and limited movement after TRF (Dobrogowski et al., 2005). Glucocorticoids are known to suppress pro-inflammatory cytokines (such as TNFα and IL-1β) and induce the expression of anti-inflammatory cytokines (such as IL-10). Moreover, there is convincing evidence for acute analgesic and antihyperalgesic effects of glucocorticoids after surgery in humans and experimental injuries in animal models (Romundstad & Stubhaug, 2007). The duration of pain relief was significantly longer after TRF-TPN treatment than after conventional NB in this self-controlled study, and few serious side effects were reported despite the increased hypoesthesia. Van Kleef et al. (van Kleef et al., 1995) evaluated the effectiveness of TRF-DRG (67 °C, 60 s) on patients presenting with chronic thoracic pain and reported significantly better short-term and long-term pain relief. However, in their report, 14 (33%) out of 43 patients experienced a mild burning pain in the treated dermatome for some days following treatment. In our previous report, 3 patients experienced no transient burning pain after 21 successive TRF-TPN despite the high temperature and repetition (Uchida, 2009). Dobrogowski et al. (Dobrogowski et al., 2005) found that TRF with methylprednisolone administration to the lumbar medial branch tended to decrease the

Although the site and extent of treatment were different as well as the degree of the effect of glucocorticoid remains unclear, these results suggests that glucocorticoids can decrease the

with the refractory neuropathic pain of postmastectomy syndrome (Uchida, 2009).

including brain and spinal cord infarction and death (Uchida, 2009) .

sensitization and neuropathic pain (Romundstad & Stubhaug, 2007).

**4. Pulsed radiofrequency treatment for neuropathic pain**

Two theories have been proposed to explain the analgesic effects of PRF.

treatment modality for neuropathic pain.

frequency of postoperative pain.

**4.1 Mechanism of action**

pain related to neural injury after TRF.

Fig. 1. Analgesic effect of conventional NB vs. TRF of TPN.

Kaplan-Meier graphs depicting the cumulative proportions of patients who reported pain relief following conventional NB or TRF-TPN. Censored values represent patients whose pain returned to pretreatment levels. The vertical axis indicates cumulative proportion of patients reporting pain relief.

#### **3.3.2 Secondary outcome**

The mean electrical sensory stimulation threshold before TRF-TPN was 0.20 ± 0.14 V (mean ± SD) at 100 Hz and 0.20 V at 3 Hz (median, interquartile range: 0.10–0.35 V). The impedance after therapy (local anesthetic and glucocorticoid injection + TRF) was significantly lower than that measured before TRF (before TRF: 637.9 ± 182.4 Ω; after therapy: 511.6 ± 79.3 Ω; mean ± SD*, P* = 0.0045 by paired t-test).

In all cases, hypoesthesia increased in the corresponding dermatome after TRF. No major complications, such as anesthesia dolorosa and burning pain, were reported after the procedure, and no patient claimed that their pain had increased after the procedure.

#### **3.4 Discussion**

Controversy has arisen over the use of TRF for the management of nonmalignant neuropathic pain because of its potential for neurodestruction, which could lead to motor deficits, neuritis, and deafferentation pain. Van Kleef et al. (Van Kleef et al., 1995) suggested that the potential hazard of nonspecific neural destruction after treatment with TRF-DRG might actually intensify symptoms by inducing deafferentation pain. Therefore, they insisted that TRF-DRG was not suitable for neuropathic pain syndromes with sensory loss due to nerve damage, such as postthoracotomy pain, postherpetic neuralgia, and postmastectomy syndrome, and that TRF-DRG should be restricted to purely nociceptive pain syndromes.

**TRF-TPN**

**Conventional NB**

**0 200 400<PHONE_NUMBER> Duration of pain relief (Days)**

Kaplan-Meier graphs depicting the cumulative proportions of patients who reported pain relief following conventional NB or TRF-TPN. Censored values represent patients whose pain returned to pretreatment levels. The vertical axis indicates cumulative proportion of

The mean electrical sensory stimulation threshold before TRF-TPN was 0.20 ± 0.14 V (mean ± SD) at 100 Hz and 0.20 V at 3 Hz (median, interquartile range: 0.10–0.35 V). The impedance after therapy (local anesthetic and glucocorticoid injection + TRF) was significantly lower than that measured before TRF (before TRF: 637.9 ± 182.4 Ω; after

In all cases, hypoesthesia increased in the corresponding dermatome after TRF. No major complications, such as anesthesia dolorosa and burning pain, were reported after the

Controversy has arisen over the use of TRF for the management of nonmalignant neuropathic pain because of its potential for neurodestruction, which could lead to motor deficits, neuritis, and deafferentation pain. Van Kleef et al. (Van Kleef et al., 1995) suggested that the potential hazard of nonspecific neural destruction after treatment with TRF-DRG might actually intensify symptoms by inducing deafferentation pain. Therefore, they insisted that TRF-DRG was not suitable for neuropathic pain syndromes with sensory loss due to nerve damage, such as postthoracotomy pain, postherpetic neuralgia, and postmastectomy syndrome, and that

procedure, and no patient claimed that their pain had increased after the procedure.

Fig. 1. Analgesic effect of conventional NB vs. TRF of TPN.

therapy: 511.6 ± 79.3 Ω; mean ± SD*, P* = 0.0045 by paired t-test).

 It is believed that the therapeutic effect of TRF is achieved by a partial nerve lesion to nociceptive afferents (Bogduk, 2006). On the other hand, minor nerve injury can sometimes produce devastating pain, whereas modest or diffuse deafferentation does not (Devor et al. 2006). The cause of this effect has not been elucidated. In a clinical study, it was suggested that even long-standing central sensitization can be reversed quickly when the peripheral input is removed (Gracely et al., 1992). Therefore we believe that TRF is an acceptable treatment modality for neuropathic pain.

We used TRF-TPN for postherpetic neuralgia instead of TRF-DRG in this case series. TRF-TPN has an simpler surgical approach than TRF-DRG and thus a lower probability of injuring the radicular artery, an event that may induce serious neurologic complications, including brain and spinal cord infarction and death (Uchida, 2009) .

We reported previously that repeated administration of TRF-TPN combined with glucocorticoid administration decreased pain and improved the quality of life in patients with the refractory neuropathic pain of postmastectomy syndrome (Uchida, 2009).

Although the use of glucocorticoids for NB is also controversial, glucocorticoids are usually coadministered with a local anesthetic. Pro-inflammatory cytokines secreted at or near the site of nerve injury are involved in the development and maintenance of central sensitization and neuropathic pain (Romundstad & Stubhaug, 2007).

The lesions produced by the RF energy are well-demarcated areas of coagulative necrosis surrounded by inflammatory cell infiltrate and hemorrhage. This inflammatory response can lead to increased tenderness, pain, and limited movement after TRF (Dobrogowski et al., 2005). Glucocorticoids are known to suppress pro-inflammatory cytokines (such as TNFα and IL-1β) and induce the expression of anti-inflammatory cytokines (such as IL-10). Moreover, there is convincing evidence for acute analgesic and antihyperalgesic effects of glucocorticoids after surgery in humans and experimental injuries in animal models (Romundstad & Stubhaug, 2007).

The duration of pain relief was significantly longer after TRF-TPN treatment than after conventional NB in this self-controlled study, and few serious side effects were reported despite the increased hypoesthesia. Van Kleef et al. (van Kleef et al., 1995) evaluated the effectiveness of TRF-DRG (67 °C, 60 s) on patients presenting with chronic thoracic pain and reported significantly better short-term and long-term pain relief. However, in their report, 14 (33%) out of 43 patients experienced a mild burning pain in the treated dermatome for some days following treatment. In our previous report, 3 patients experienced no transient burning pain after 21 successive TRF-TPN despite the high temperature and repetition (Uchida, 2009). Dobrogowski et al. (Dobrogowski et al., 2005) found that TRF with methylprednisolone administration to the lumbar medial branch tended to decrease the frequency of postoperative pain.

Although the site and extent of treatment were different as well as the degree of the effect of glucocorticoid remains unclear, these results suggests that glucocorticoids can decrease the pain related to neural injury after TRF.

#### **4. Pulsed radiofrequency treatment for neuropathic pain**

#### **4.1 Mechanism of action**

Two theories have been proposed to explain the analgesic effects of PRF.

Radiofrequency Treatments for Neuropathic Pain: Review and New Approaches 131

However, Sluijter (Sluijter, 2001) divided the postoperative observational period after PRF procedure into four phases and found that the second phase was associated with the highest

The clinical effects of PRF have been examined for various regions and pain conditions using voltage outputs of 20–45 V. There are no standardized criteria for the voltage output of PRF, except that voltage should not be sufficient to increase temperature above 42 °C. However, rapid temperature spikes above 42 °C were observed during PRF bursts of 45 V, occasionally reaching the lethal temperature range of 45–50 °C or more (Cosman & Cosman, 2005). These rapid temperature spikes might induce microscopic tissue damage, leading to a

To avoid rapid temperature spikes, we used low-voltage PRF (L-PRF) where the voltage output is only 5 V. This section will describe the first reported effects of L-PRF for radicular

This study was approved by the institutional review board of the institution where our study was performed, and patients provided written informed consent for participation. The basic demographic and clinical characteristics of the patients are listed in Table 1. Patients were subgrouped according to treatment sites as cervical (C), thoracic (T), and lumbar (L).

**C** 49 (49-55) 10/2 14 (10-21) Cervicobrachialgia **T** 70 (68-72) 3/7 6 (5-6) Postherpetic neuralgia **L** 70 (65-79) 5/3 74 (14-80) Degenerative spondylosis

Patients were selected for this study according to the following criteria: (1) chronic unilateral radicular pain of at least 3 months' duration that could not be adequately controlled with oral medications; (2) average pain intensity higher than 30 mm as measured on a 100 mm VAS; (3) temporary positive response (100% reduction of pain) more than twice to C, T, or L DRG block with local anesthetics and glucocorticoids under fluoroscopy; and (4) return of

Exclusion criteria were as follows: (1) MRI showing acute pathology; (2) history of adverse reactions to local anesthetics or glucocorticoids; or (3) history of cancer, myelopathy,

pain intensity to baseline after temporary relief resulting from C, T, or L DRG block.

(months)\* Etiology

post-procedure discomfort, which lasted up to 3 weeks.

**5.1 Background**

**5. Low-voltage PRF treatment for radicular neuropathic pain**

period of discomfort after PRF, and induce antinociceptive action.

(years)\* Female/Male Duration of Pain

neuropathic pain using a self-controlled design.

**5.2 Materials and methods**

Age

\*Median (Interquartile range)

Table 1. Characteristics of the Subjects

**5.2.1 Patients**

One is that pain relief depends on the rapidly changing electric fields (Sluijter, 1998); the other is that PRF produces brief heat bursts at temperatures in the range associated with destructive heat lesions (Cosman & Cosman, 2005). It is not known, however, if these transient heat bursts do have an ablative effect (Chua et al., 2011).

 These studies reported increased c-Fos expression in the dorsal horn (Higuchi et al., 2002; Van Zundert et al., 2005), increased expression of activating transcription factor 3 (Hamann et al., 2006), and morphological changes in the DRG or the peripheral nerve (Erdine et al., 2009; Erdine et al., 2005; Podhajsky et al., 2005; Protasoni et al., 2009; Tun et al., 2009).

#### **4.2 Treatment of neuropathic pain and treatment complications**

#### **4.2.1 Trigeminal neuralgia**

For trigeminal neuralgia, the therapeutic efficacy of PRF has neither surpassed nor equaled TRF. Erdine et al. (Erdine et al., 2007) compared the efficacy of TRF with PRF of the trigeminal ganglion in patients with idiopathic trigeminal neuralgia. Significant pain reductions were reported in all patients treated with TRF (n = 20), whereas only 2 of 20 patients in the PRF treatment group reported pain reduction. Five of the 20 TRF patients and 3 of 20 PRF patients reported moderate headache for 24 h. There was mild hypoesthesia and paresthesia in all patients from the TRF group. Anesthesia dolorosa occurred in 1 patient from the TRF group and medical treatment was given. They concluded that PRF, unlike TRF, was not an effective treatment method for idiopathic trigeminal neuralgia.

#### **4.2.2 DRG**

Two RCTs have examined PRF of DRG for neuropathic pain (Simopoulos *et al.*, 2008; Van Zundert *et al.*, 2007). These studies presented limited evidence that PRF of the cervical DRG could produce short-term relief of cervical radicular pain; however, there is limited evidence against its use existed in treatment of lumbar radicular pain (Malik & Benzon, 2008).

Van Zundert et al. (Van Zundert et al., 2007) compared PRF of the cervical DRG to sham treatment at 3 months after treatment; PRF of the cervical DRG showed significantly better outcome on both the global perceived effect (> 50% improvement) index and visual analog scale (20-point pain reduction).

Simopoulos et al. (Simopoulos et al., 2008) randomly divided patients with lumbosacral radicular pain into 2 groups; 1 group was treated with PRF only, whereas the second group was treated first with PRF and then with TRF at the maximum tolerated temperature. There was no significant difference in the response rate or in the average decline in VAS between the 2 groups. Survival curves showed that for both treatment groups experienced a steep loss in the analgesic effect between 2 and 4 months after the procedure. By the 8th month, the vast majority of patients relapsed to baseline pain intensity.

Malik and Benzon (Malik & Benzon, 2008) reviewed published articles on PRF-DRG and concluded that none of the studies reported any significant side effects or complications. However, Sluijter (Sluijter, 2001) divided the postoperative observational period after PRF procedure into four phases and found that the second phase was associated with the highest post-procedure discomfort, which lasted up to 3 weeks.

### **5. Low-voltage PRF treatment for radicular neuropathic pain**

#### **5.1 Background**

130 Neuropathic Pain

One is that pain relief depends on the rapidly changing electric fields (Sluijter, 1998); the other is that PRF produces brief heat bursts at temperatures in the range associated with destructive heat lesions (Cosman & Cosman, 2005). It is not known, however, if these

Secondary effects on the nervous system after PRF application have been studied in animal models (Erdine et al., 2009; Erdine et al., 2005; Hamann et al., 2006; Higuchi et al., 2002; Podhajsky et al., 2005; Protasoni et al., 2009; Tun et al., 2009; Van Zundert et al., 2005). These studies reported increased c-Fos expression in the dorsal horn (Higuchi et al., 2002; Van Zundert et al., 2005), increased expression of activating transcription factor 3 (Hamann et al., 2006), and morphological changes in the DRG or the peripheral nerve (Erdine et al., 2009;

For trigeminal neuralgia, the therapeutic efficacy of PRF has neither surpassed nor equaled TRF. Erdine et al. (Erdine et al., 2007) compared the efficacy of TRF with PRF of the trigeminal ganglion in patients with idiopathic trigeminal neuralgia. Significant pain reductions were reported in all patients treated with TRF (n = 20), whereas only 2 of 20 patients in the PRF treatment group reported pain reduction. Five of the 20 TRF patients and 3 of 20 PRF patients reported moderate headache for 24 h. There was mild hypoesthesia and paresthesia in all patients from the TRF group. Anesthesia dolorosa occurred in 1 patient from the TRF group and medical treatment was given. They concluded that PRF, unlike

Two RCTs have examined PRF of DRG for neuropathic pain (Simopoulos *et al.*, 2008; Van Zundert *et al.*, 2007). These studies presented limited evidence that PRF of the cervical DRG could produce short-term relief of cervical radicular pain; however, there is limited evidence

Van Zundert et al. (Van Zundert et al., 2007) compared PRF of the cervical DRG to sham treatment at 3 months after treatment; PRF of the cervical DRG showed significantly better outcome on both the global perceived effect (> 50% improvement) index and visual analog

Simopoulos et al. (Simopoulos et al., 2008) randomly divided patients with lumbosacral radicular pain into 2 groups; 1 group was treated with PRF only, whereas the second group was treated first with PRF and then with TRF at the maximum tolerated temperature. There was no significant difference in the response rate or in the average decline in VAS between the 2 groups. Survival curves showed that for both treatment groups experienced a steep loss in the analgesic effect between 2 and 4 months after the procedure. By the 8th month, the

Malik and Benzon (Malik & Benzon, 2008) reviewed published articles on PRF-DRG and concluded that none of the studies reported any significant side effects or complications.

against its use existed in treatment of lumbar radicular pain (Malik & Benzon, 2008).

transient heat bursts do have an ablative effect (Chua et al., 2011).

Erdine et al., 2005; Podhajsky et al., 2005; Protasoni et al., 2009; Tun et al., 2009).

TRF, was not an effective treatment method for idiopathic trigeminal neuralgia.

**4.2 Treatment of neuropathic pain and treatment complications**

**4.2.1 Trigeminal neuralgia**

scale (20-point pain reduction).

vast majority of patients relapsed to baseline pain intensity.

**4.2.2 DRG**

The clinical effects of PRF have been examined for various regions and pain conditions using voltage outputs of 20–45 V. There are no standardized criteria for the voltage output of PRF, except that voltage should not be sufficient to increase temperature above 42 °C. However, rapid temperature spikes above 42 °C were observed during PRF bursts of 45 V, occasionally reaching the lethal temperature range of 45–50 °C or more (Cosman & Cosman, 2005). These rapid temperature spikes might induce microscopic tissue damage, leading to a period of discomfort after PRF, and induce antinociceptive action.

To avoid rapid temperature spikes, we used low-voltage PRF (L-PRF) where the voltage output is only 5 V. This section will describe the first reported effects of L-PRF for radicular neuropathic pain using a self-controlled design.

#### **5.2 Materials and methods**

#### **5.2.1 Patients**

This study was approved by the institutional review board of the institution where our study was performed, and patients provided written informed consent for participation. The basic demographic and clinical characteristics of the patients are listed in Table 1. Patients were subgrouped according to treatment sites as cervical (C), thoracic (T), and lumbar (L).

\*Median (Interquartile range)

Table 1. Characteristics of the Subjects

Patients were selected for this study according to the following criteria: (1) chronic unilateral radicular pain of at least 3 months' duration that could not be adequately controlled with oral medications; (2) average pain intensity higher than 30 mm as measured on a 100 mm VAS; (3) temporary positive response (100% reduction of pain) more than twice to C, T, or L DRG block with local anesthetics and glucocorticoids under fluoroscopy; and (4) return of pain intensity to baseline after temporary relief resulting from C, T, or L DRG block.

Exclusion criteria were as follows: (1) MRI showing acute pathology; (2) history of adverse reactions to local anesthetics or glucocorticoids; or (3) history of cancer, myelopathy,

Radiofrequency Treatments for Neuropathic Pain: Review and New Approaches 133

The duration of pain relief after L-PRF was significantly longer than that after conventional NB for treating all target sites (C, T, and L DRG) (*P* < 0.05, Kaplan-Meier analysis and the

**C DRG**

**L-PRF**

**Conventional NB**

**0 100 200 300 400 500 600 700 Duration of pain relief (Days)**

**T DRG**

**L-PRF**

**Conventional NB**

**0 50 100 150 200 250 Duration of pain relief (Days)**

Fig. 2. Analgesic effect of conventional NB vs. L-PRF of C DRG

Fig. 3. Analgesic effect of conventional NB vs. L-PRF of T DRG

**5.3 Results**

**5.3.1 Primary outcomes**

**0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1**

**0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1**

log rank statistic) (Figure 2, 3, and 4).

diabetes mellitus, psychotherapeutic management, coagulation disorders, or use of anticoagulants.

#### **5.2.2 Conventional NB procedures**

Conventional NB and L-PRF of C, T, and L- DRG were performed using a 22-gauge needle under real-time fluoroscopy with a C-arm as described by Gauci (Gauci, 2004).

After fluoroscopy confirmed that the needle tip was positioned correctly, 0.2 ml of iohexol (Omnipaque 240®; Daiichi-Sankyo, Tokyo, Japan) was injected to guard against venous uptake and false-negative responses. If the contrast dye was washed out by blood flow, the needle was removed and reintroduced. Thereafter, 0.5 ml of 2% mepivacaine as the local anesthetic and 0.5 ml of 0.4% betamethasone (Rinderon®; Shionogi, Osaka, Japan) were administered.

Four to eight weeks after assessment of the effect of conventional NB, patients were treated by L-PRF.

#### **5.2.3 L-PRF procedure**

L-PRF was performed under fluoroscopy with a C-arm in the same manner as conventional NB. For L-PRF, an RF needle (22-gauge 99-mm needle with 4-mm bare tip, TFW 22G × 99 mm®, Hakko, Japan) was used instead of the 22-gauge injection needle used for conventional NB. After optimizing the position of the needle, we tested whether the thermocouple electrode was placed in the physiologically correct location by applying 100- Hz stimulation to the needle tip using a generator (Neuro Therm JK 3TM system; Neuro Therm, Croydon, Surrey, United Kingdom). If a tingling sensation was obtained at a voltage of < 0.5 V at 100-Hz stimulation, the electrode was assumed to be in the correct position. Each threshold was measured twice and the average was obtained. After the 100-Hz stimulation threshold was determined, we measured the stimulation threshold at 3 Hz that was required to induce throbbing and touch-like sensations in a similar manner and impedance.