ORIGINAL ARTICLE
Repetitive transcranial magnetic stimulation in neuropathic pain secondary to malignancy: A randomized clinical trial E.M. Khedr1, H.I. Kotb2, M.G. Mostafa3, M.F. Mohamad3, S.A. Amr3, M.A. Ahmed1, A.A. Karim4,5, S.M.M. Kamal3 1 2 3 4 5
Department of Neurology, Assiut University Hospital, Egypt Department of Anesthesiology, Assiut University Hospital, Egypt Anesthesia, Intensive Care and Pain Management, South Egypt Cancer Institute, Assiut University, Egypt Department of Prevention, Health Psychology and Neurorehabilitation, SRH University, Riedlingen, Germany Department of Psychiatry and Psychotherapy, University Clinic Tübingen, Germany
Correspondence Eman M. Khedr E-mail: [email protected] Funding sources None. Conflict of interest None declared. Accepted for publication 7 July 2014 doi:10.1002/ejp.576
Abstract Background: Significant analgesic effects of repetitive transcranial magnetic stimulation (rTMS) have been found in several studies of patients with chronic pain of various origins, but never for malignancy. The objective of this study was to assess the efficacy of 10 sessions of rTMS over the primary motor cortex (M1) in patients suffering from malignant neuropathic pain. Methods: Thirty-four patients were randomly allocated into one of two groups to receive real (20 Hz, 10 s, 10 trains with 80% intensity) or sham rTMS daily for 10 consecutive days. Patients were evaluated using a verbal descriptor scale (VDS), a visual analogue scale (VAS), Leeds assessment of neuropathic symptoms and signs (LANSS) and Hamilton rating scale for depression (HAM-D) at baseline, after the first, fifth and 10th treatment sessions, and then 15 days and 1 month after treatment. Results: There were no significant differences between real and sham groups in the duration of illness or pain rating scores at the baseline. A significant ‘Time × Group’ interaction was recorded indicating that real and sham rTMS had different effects on the VDS, VAS, LANSS and HAM-D scales. Post-hoc testing showed that the group of patients treated with real rTMS had greater improvement in all scales that persisted up to 15 days, but were not present 1 month later. Significant positive correlations between the percentage of pain reduction and HAM-D after the 10th session and 15 days later were recorded. Conclusion: The results demonstrate that 10 rTMS sessions over the M1 can induce short-term pain relief in malignant neuropathic pain.
1. Introduction Neuropathic pain (NP) in cancer patients may arise from several mechanisms. It may result from compression of the nerve or direct infiltration by the growing tumour, or secondarily from changes in the neuronal media resulting from cancer growth or from the resulting inflammatory response such as tissue pH (acidosis), release of tumour algogens, or circulating © 2014 European Pain Federation - EFICâ
chemokines and cytokines (Cleeland et al., 2003). These inflammatory events in cancer neuropathy are likely to be more common and important than in other neuropathies; in these cases, an acute tissue response subsides, leaving restricted neuropathic mechanisms within peripheral nerves and the central nervous system. Surgical interventions such as mastectomy or debulking tumours often result in deafferentation pain. Patients post-mastectomy report a Eur J Pain 19 (2015) 519--527
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What’s already known about this topic? • Some recent approaches in patients with other causes of neuropathic pain than cancer pain have successfully used transcranial methods of brain stimulation to induce plastic changes in neural circuits associated with pain. What does this study add? • The data of the present study suggest that daily sessions of transcranial brain stimulation has potential to be used as a treatment to relieve pain in patients with pain secondary to malignancy.
constellation of symptoms including pain or discomfort in the chest wall, surgical scar, upper arm and shoulder, which may be suggestive of intercostobrachial nerve damage and phantom breast sensations (Kudel et al., 2007). Finally, radiation-induced fibrosis can injure peripheral nerves (e.g. fibrosis of brachial plexus) causing chronic NP that begins months to years following treatment (Henry et al., 2008). Medications are often ineffective or cause various adverse effects (e.g. rashes, gastrointestinal upset, allergies); therefore, better approaches are needed. Significant analgesic effects of repetitive transcranial magnetic stimulation (rTMS) have been found in several studies of patients with chronic pain of various origins such as central NP [post-stroke pain (Khedr et al., 2005), spinal cord injury (Lefaucheur et al., 2004), thalamic pain (Lefaucheur et al., 2004) ] and peripheral NP [trigeminal neuralgia (Khedr et al., 2005), phantom limb pain (Irlbacher et al., 2006) and brachial plexus injury (Lefaucheur et al., 2004) ]. The frequency of transcranial magnetic stimulation (TMS) pulses influences the effects on axons. Hirayama et al. showed that relief of NP was observed only when targeting primary motor area (M1), but not other areas (Hirayama et al., 2006). Regarding the short-term effect from a single session of rTMS, most studies and meta-analyses, including the Cochrane review, demonstrated positive effects on pain relief after highfrequency stimulations (HF-rTMS) of M1, but not after low-frequency stimulations (O’Connell et al., 2010). A 2010 Cochrane Systematic Review concluded that higher stimulation frequencies (>5 Hz), greater numbers of stimuli (>500) and multiple sessions (>1) yielded better results (O’Connell et al., 2010). M1 stimulation at HF-rTMS was shown to reduce pain scores by 20–45% after active stimulation, and by less than 10% after sham stimulation (Lefaucheur et al., 2008). The therapeutic applications of rTMS in 520 Eur J Pain 19 (2015) 519--527
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pain syndromes are limited by the short duration of the induced effects, but prolonged pain relief can be obtained by repeating rTMS sessions everyday for several weeks (Lefaucheur et al., 2001). Up to our knowledge, the effect of rTMS on malignant NP has not been studied before and therefore, the present clinical trial was done to investigate whether repeated sessions of HF-rTMS over the M1 can improve pain in patients with malignant NP.
2. Patients and methods This study was conducted at the pain clinic unit of the South Egypt Cancer Institute, Assiut University and at the Department of Neuropsychiatry, Assiut University Hospital from January 2010 to May 2013. All patients were within 18–65 years with malignant lateralized NP resistant to medical treatments for at least 2 months. We excluded patients with intracranial metallic devices or with pacemakers or any other device. We also excluded those with recent myocardial ischaemia, unstable angina and those known to have a history of epilepsy. Thirty-four patients were included in the study. All of them had NP according to the Douleur Neuropathique 4 (DN4) questionnaire (Bouhassira et al., 2005). It consists of four questions with 10 items. The total score is calculated as the sum of the 10 items and the cut-off value for the diagnosis of NP is a total score of 4/10. They were randomly allocated into one of the two groups (1:1 ratio) using closed envelopes as parallel groups (real rTMS group and sham rTMS group). Fig. 1 shows the flow chart of patients through the course of the study. In the real group, the mean age of the studied patients was 47 ± 9.2 years, (1 man and 16 women), the mean duration of illness was 15.4 ± 15.9 months and the mean DN4 score was 5.6 ± 0.8 points. Two of them did not complete the study because they developed medical complications (severe gastrointestinal upset). Fourteen had lateralized post-mastectomy NP (nine had right, five had left side of chest and arm), one had soft tissue sarcoma in the right upper limb, one had giant cell glioma of right radial nerve and one had left thigh pain after femoral after femoral mass removal. Ten patients were under chemotherapy and seven were under radiotherapy. In the sham group, the mean age of the studied patients was 48 ± 9.7 years, (2 men and 15 women), the mean duration of illness was 16.8 ± 16.3 months and the mean DN4 score was 5.5 ± 0.9 points. Two patients also did not complete the study because of chemotherapy and radiotherapy complications. Fifteen patients who completed the study had lateralized post-mastectomy NP (eight had right, seven had left side of chest and arm) and two had soft tissue sarcoma in the right lower limb. Eight patients were under chemotherapy and nine were under radiotherapy. All patients were asked to not change their analgesic regimen through the course of the study. All of them were under the same regimen: tramadol hydrochloride 100 mg twice daily, pregabalin 75 mg twice daily, gabapentin 400 mg twice daily and Amitriptyline 25 mg twice daily. © 2014 European Pain Federation - EFICâ
rTMS in malignant neuropathic pain
E.M. Khedr et al.
Figure 3 Showed changes Hamilton rating scale for depression score in studied group of neuropathic pain patients at six points of assessment. The first was prior to commencing repetitive transcranial magnetic stimulation (rTMS) treatment (pre-stimulation). The second was after the first session (post-first session). The third was after the end of the fifth session (post-fifth session), the fourth was after the 10th session of stimulation (post-10th session), the fifth and six assessment points were 15 days and 1 month after the end of stimulation sessions. Data expressed as mean ± standard deviation. The significances between groups appeared at different points of assessment. These were seen after the fifth day of stimulation (p-value = 0.018) and after the 10th day of stimulation (p-value = 0.002), after 15 days after end of stimulation (p-value = 0.001) and at 1 month after the end of stimulation (p-value = 0.027).
Figure 2 Shows changes in the verbal descriptor scale (upper trace), the visual analogue scale (middle trace) and the Leeds assessment of neuropathic symptoms and signs (lower trace) in patients with malignant neuropathic pain at six points of assessment. The first one was prior to commencing repetitive transcranial magnetic stimulation (rTMS) treatment (pre-stimulation). The second was after first session (post-first session).The third was after the end of the fifth session (post-fifth session), the fourth was after the 10th session of stimulation (post-10th session), the fifth and sixth assessment points were at 15 days and 1 month after the end of stimulation sessions. Data expressed as mean ± standard deviation The significances between groups appeared at different points of assessment. These were seen after the 10th session and 15 days after the end of session for the three scales.
© 2014 European Pain Federation - EFICâ
Moreover, significant positive correlations between the percentage of pain reduction on VAS and of depression reduction on HAM-D were observed after the 10th session and 15 days later (r = 0.55, p = 0.002 and r = 0.52, p = 0.003, respectively). The same results were recorded with VDS/HAM-D (r = 0.679, p = 0.0001 and r = 0.648, p = 0.0001, respectively) and for LANSS/HAM-D (r = 0.408, p = 0.02 and r = 0.30, p = 0.0107, respectively). According to the percentage of pain relief in the VAS scale; the number of responders (30% or more pain relief) were: 13 (86.6%), 12(80%) and 4 (26.6%) at the three time points of assessment in the real group, which were significantly higher than the sham group: 1 (6.6%) for each time point of assessment.
4. Discussion These results suggest that rTMS at 20 Hz given every day for 10 sessions can reduce ratings of pain and depression in patients with malignant NP. The effects last at least for 2 weeks after the end of the treatment sessions, but are no longer present at a 1-month follow-up. This is very similar to previous reports of the effects of rTMS on other types of NP rather than malignant NP. Eur J Pain 19 (2015) 519--527
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(20 Hz, 10 s, 10 trains with an inter-train interval of 30 s and a total amount of pulses: 2000, intensity was 80% of the motor threshold) every day for 10 consecutive days (5 days/ week) applied through a figure-of-eight coil over the identified motor cortical area corresponding to the hand of painful side (M1) with orientation of the coil preferentially parallel to the midsagittal line, as suggested by André-Obadia et al. (2008). Sham-rTMS was applied using the same parameters, but with the coil elevated and angled away from the head to reproduce the same subjective sensation of rTMS, and yet avoid induction of current to the brain (Pascual-Leone et al., 1998; Karim et al., 2003, 2004).
2.4 Follow-up measures Measurements were done before and after the first, fifth and 10th sessions, and 15 days, and 1 month later, with all rating scales: VDS, VAS, LANSS and HAM-D. The measurements were done by a blind assessor without knowing the type of stimulation applied. During the followup, seven patients of the real group asked to decrease the dose of tramadol hydrochloride to be 50 mg twice/day after the 10th session, and eight patients of sham group asked to increase the dose of tramadol to be 150–200 mg twice/day.
2.5 Outcomes The primary outcome was pain relief on the VAS after the 10th session and 1 month later, and the secondary outcomes were pain and depression reduction on VDS, LANSS and HAM-D after the 10th session and 1 month later.
2.6 Data analysis The values of each group of patients for each scale were analysed separately by one-way analysis of variance (ANOVA) repeated measure analysis. Two-way ANOVA repeated measures of analyses were used to assess the interaction between groups (Time ‘pre, first, fifth, 10th, 15 days after stimulation and after 1 month’ × Group ‘real & sham’). Post-hoc t-tests were used to assess interaction between groups at different points of assessment. The Greenhouse– Geisser correction of degrees of freedom was used when necessary to correct for non-spherity of the data. The percentage of reduction of each scale was calculated after the 10th session of stimulation by Mann–Whitney test as a scale at the 10th day – Pre-stimulation score × 100/Pre-stimulation score. The percentage of reduction after 15 days, and 1 month after the end of stimulation, were assessed by the same calculation. We calculated the number of responders as patients showing pain relief of more than 30% on VAS compared with prerTMS baseline. Statistical correlation between the percentage of pain reduction on VAS/VDS/LANSS and of depression reduction on HAM-D after the 10th session and 15 days later were done using Spearman correlation. 522 Eur J Pain 19 (2015) 519--527
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3. Results There were no differences at baseline between the groups concerning demographic and clinical data as well as scores in the different scales of pain assessment (Table 1). No side effect could be recorded by any patient. Scores on all the rating scales changed over time, with the largest effects in the real rTMS group. For the primary outcome: two-way ANOVAs with Time (pre, after first, fifth, 10th and 15 days and 1 month later) and Group (real or sham) as main factors showed a significant Time × Group interaction for VDS [p = 0.0001, F = 0.43, degrees of freedom (df) = 2.1 (58.4) ], VAS [p = 0.001, F = 8.07, df = 2.05(57.5) ], and LANSS [p = 0.018, F = 2.83, df = 2.5(70.4) ] (Fig. 2) as well as for secondary outcome; HAM-D [p = 0.007, F = 4.85, df = 2.37(66.3) ] (Fig. 3). This indicates that the effect of treatment differed in the two groups. Follow-up one-way ANOVAs on the data from each group separately showed that there was a significant effect of time in both groups in all rating scales. Thus, both real and sham treatments tended to reduce symptoms. However, the effects were greater with real stimulation, particularly at the end of treatment and at 15 days follow-up. The results of individual t-test comparisons between groups at each time point are shown on the graphs. In general, there was no effect of real rTMS after the first treatment session. A difference with sham gradually appeared over the course of treatment, but was no longer present at 1 month. Percentages changes in ratings are shown in Table 2 for the 10th session and 1 month after the end of rTMS. There was a significant percentage reduction in all scales after the 10th session and 15 days after stimulation in both groups; however, these effects were not seen 1 month after the end of stimulation except in LANSS and HAM-D.
Table 1 Demographic and baseline assessments of both groups in the studied patients.
Age (mean ± SD) Duration of illness(months) Verbal descriptor pain scale Visual analogue scale Hamilton rating scale for depression Leeds assessment of neuropathic symptoms and signs
Real group (mean ± SD)
Sham group (mean ± SD)
p-value
47.0 ± 9.2 15.4 ± 15.9 4.7 ± 0.8 6.3 ± 0.5 13.3 ± 1.9
48.0 ± 9.7 16.8 ± 16.3 4.6 ± 0.9 6.1 ± 0.6 13.5 ± 1.5
NS NS NS NS NS
16.7 ± 2.49
16.4 ± 2.9
NS
NS, non significant; SD, standard deviation.
© 2014 European Pain Federation - EFICâ
rTMS in malignant neuropathic pain
E.M. Khedr et al.
Figure 3 Showed changes Hamilton rating scale for depression score in studied group of neuropathic pain patients at six points of assessment. The first was prior to commencing repetitive transcranial magnetic stimulation (rTMS) treatment (pre-stimulation). The second was after the first session (post-first session). The third was after the end of the fifth session (post-fifth session), the fourth was after the 10th session of stimulation (post-10th session), the fifth and six assessment points were 15 days and 1 month after the end of stimulation sessions. Data expressed as mean ± standard deviation. The significances between groups appeared at different points of assessment. These were seen after the fifth day of stimulation (p-value = 0.018) and after the 10th day of stimulation (p-value = 0.002), after 15 days after end of stimulation (p-value = 0.001) and at 1 month after the end of stimulation (p-value = 0.027).
Figure 2 Shows changes in the verbal descriptor scale (upper trace), the visual analogue scale (middle trace) and the Leeds assessment of neuropathic symptoms and signs (lower trace) in patients with malignant neuropathic pain at six points of assessment. The first one was prior to commencing repetitive transcranial magnetic stimulation (rTMS) treatment (pre-stimulation). The second was after first session (post-first session).The third was after the end of the fifth session (post-fifth session), the fourth was after the 10th session of stimulation (post-10th session), the fifth and sixth assessment points were at 15 days and 1 month after the end of stimulation sessions. Data expressed as mean ± standard deviation The significances between groups appeared at different points of assessment. These were seen after the 10th session and 15 days after the end of session for the three scales.
© 2014 European Pain Federation - EFICâ
Moreover, significant positive correlations between the percentage of pain reduction on VAS and of depression reduction on HAM-D were observed after the 10th session and 15 days later (r = 0.55, p = 0.002 and r = 0.52, p = 0.003, respectively). The same results were recorded with VDS/HAM-D (r = 0.679, p = 0.0001 and r = 0.648, p = 0.0001, respectively) and for LANSS/HAM-D (r = 0.408, p = 0.02 and r = 0.30, p = 0.0107, respectively). According to the percentage of pain relief in the VAS scale; the number of responders (30% or more pain relief) were: 13 (86.6%), 12(80%) and 4 (26.6%) at the three time points of assessment in the real group, which were significantly higher than the sham group: 1 (6.6%) for each time point of assessment.
4. Discussion These results suggest that rTMS at 20 Hz given every day for 10 sessions can reduce ratings of pain and depression in patients with malignant NP. The effects last at least for 2 weeks after the end of the treatment sessions, but are no longer present at a 1-month follow-up. This is very similar to previous reports of the effects of rTMS on other types of NP rather than malignant NP. Eur J Pain 19 (2015) 519--527
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0.038 7.9 ± 10.4 15.7 ± 9.1 0.011 7.3 ± 11.6 18.2 ± 9.9 0.182 0.105
After 10th session 15 days after the end of sessions One month after end of sessions
0.000 0.002
22.7 ± 16.3 20.8 ± 18.2
15.9 ± 10.0
0.001 0.003 10.6 ± 11.9 9.7 ± 12.3 24.4 ± 10.2 23.6 ± 10.9 0.001 0.02 7.7 ± 12.1 9.8 ± 13.1 21.9 ± 9.4 20.9 ± 11.3 0.001 0.01
30.9 ± 14.8
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36.7 ± 18.4 35.5 ± 20.8 22.8 ± 13.5 23.3 ± 13.8 49.1 ± 18.9 45.6 ± 20.7
15.9 ± 10.0 18.4 ± 11.8
p-value Sham group Real group p-value Sham group Real group Real group Sham group Real group
p-value
Visual analogue scale
Sham group
p-value
Leeds assessment of neuropathic symptoms and signs scale
E.M. Khedr et al.
Verbal descriptor scale
Table 2 Percentage of reduction of all different scales after the 10th session, 15 days and 1 month after the end of sessions in relation to baseline.
Hamilton rating scale for depression
rTMS in malignant neuropathic pain
We applied HF-rTMS since this has been generally shown to be more effective than low-frequency stimulation. For example, Lefaucheur et al. (2001) demonstrated that rTMS was able to relieve NP when administered over M1 with 10-Hz stimulation, but not with 0.5-Hz stimulation. Andre-Obadia et al. (2006) also showed that rTMS was more effective in reducing pain when applied at 20 Hz than at 1 Hz, and Saitoh et al. (2007) found that 10 Hz rTMS was more effective than 5 Hz rTMS, while 1 Hz rTMS had no significant effects. Interestingly the effects took some time to build up. There were no significant effects on VDP, VAS or LANSS scores after the first session, but these appeared after the fifth session and were greater in the real rTMS than in the sham group. A similar time course was described originally by Lefaucheur et al. (2001) who found that pain relief after a single session was optimal 2–4 days after rTMS. Pleger et al. (2004) recorded some relief of pain 30 s after rTMS, but this intensified after 45 min. Ahmed et al. (2011) also found no significant effects after the first session of rTMS. It is possible that the absence of significant pain relief after the first session could be related to the short duration of the session (10 min) as compared with 20 min used in some of the previous studies (Rollnik et al., 2002; Lefaucheur et al., 2004). The persistence of pain relief for 2 weeks or more is also similar to our previous work on other types of pain (Khedr et al., 2005). Passard et al. (2007) followed up patients for 60 days after treatment and found that the analgesic effect of rTMS continued for 15 days after end of sessions, but was not present after 30 and 60 days. Hosomi et al. (2013) also demonstrated the positive short-term analgesic effect, but no cumulative effect on 29 days follow-up. However, longer periods of pain relief were reported by Ahmed et al. (2011) who found that the analgesic effect was still present at 1- and 2-month follow-ups. In our study, the percentage reduction of VAS in the real group after the 10th session was higher compared with a small reduction in the sham group (p = 0.001). These values are close to those reported by Khedr et al. (2005) (45%) and Ahmed et al. (2011) (55%), but are slightly larger than the 12% improvement reported by Leung et al. (2009), 13.7% by O’Connell et al. (2010) and 19.7% by Hosomi et al. (2013). The observed analgesic effects could be probably prolonged by an appropriate maintenance therapy with additional weekly or monthly rTMS sessions. In the present study, we have stimulated the motor cortical area corresponding to the hand of painful side, while pain was mostly located at the chest or even in © 2014 European Pain Federation - EFICâ
rTMS in malignant neuropathic pain
E.M. Khedr et al.
the lower limb. The observed effects may be explained by the notion that HF-rTMS (20 Hz) over the hand area could modulate some output from the nearby chest cortical representation or may be due to shift of the chest area (representation plasticity) towards the hand area in cases of postmastectomy chronic chest lesion. Supporting this notion, Lefaucheur et al. (2004) reported that better results were obtained for facial pain, after a single session of 10 Hz rTMS of 20 min, although stimulation was targeted on the hand cortical area. In patients with upper limb amputation, the former hand area of the cortex was shown to be invaded by a lateralization of the area corresponding to arm muscle proximal to the stump (Pascual-Leone et al., 1996; Schwenkreis et al., 2001) and a medialization of the face area (Pascual-Leone et al., 1996; Karl et al., 2001). Similarly, in patients with facial palsy, TMS shows an enlargement of the hand field extending in a lateral direction into the site of the face area (Rijntjes et al., 1997). However, area proximity could not explain the pain relief in the lower limb, as leg and hand representations are not adjacent, but separated by arm and trunk representations (Lefaucheur et al., 2004). It may be related to the release of endorphins as reported by Ahmed et al. (2011). They found elevation of serum beta-endorphin concentration after five sessions of 20 Hz rTMS over the hand area of motor cortex in 17 patients with chronic phantom pain. There was a significant reduction of the HAM-D in the real group after the 10th session that was greater than in the sham group p-value (0.002). These effects persisted at 1 month (p = 0.038). O’Reardon et al. (2007) reported significantly better clinical results in an active rTMS group in comparison with the sham group, as measured by the HAM-D and the Montgomery Asberg Depression Rating Scale ( (O’Reardon et al., 2007). However, Hosomi and colleagues found no effect on the Beck depression inventory (Hosomi et al., 2013). It has been suggested that the underlying pathophysiology of NP is associated with plastic changes and dysfunction of extensive neural circuits in the central nervous system, involving various structures related to pain perception, and with an affective–emotional component (Leung et al., 2009). The possible mechanisms of action of pain relief following the stimulation of M1, by rTMS, are considered to be modulation of neural activity in these structures (Lefaucheur et al., 2006). M1 itself is seen as a focal entry port point to a distributed pain system that can modulate activity in remote deep-brain structures through the subcortical © 2014 European Pain Federation - EFICâ
projections, leading to an increase in the cerebral blood flow in the ipsilateral thalamus, orbitofrontal and cingulate gyri and in the upper brain stem (García-Larrea et al., 1999; Lefaucheur et al., 2006; Goto et al., 2008). These hypotheses of cerebral modulation in the various central nervous system structures could explain how the effects of rTMS last for more than 60 min (Hosomi et al., 2013). The consequence may be to change the levels of central nervous system opioids. Maarrawi et al. reported that motor cortex stimulation may induce release of endogenous opioids in brain structures involved in the processing of acute and chronic pain (Maarrawi et al., 2007). Ahmed et al. (2011) suggested that analgesic effects of rTMS in phantom pain were delivered by increase in the endogenous betaendorphin release. Töpper et al. (2003) found that opiate antagonist naloxone abolished the rTMSinduced pain relief, which was taken as evidence that the analgesic effect of rTMS acted via the release of endorphins. Borckardt et al. (2008) found that a single session of HF-rTMS applied immediately after gastric bypass surgery at 10 Hz over the left dorsolateral prefrontal cortex for a total of 4000 pulses was associated with a 40% reduction in total morphine use during the first 2 days after surgery. This reduction corresponded to the effect of active rTMS minus that of sham stimulation (Borckardt et al., 2006, 2008). Limitations in the interpretation of our results include the small sample size of this pilot study, dropouts and variability of cause of NP (different types of malignancies) and dependence on reports by participants.
5. Conclusion Ten sessions of HF-rTMS over the M1 had beneficial reduction of pain score in malignant NP patients and the maximum effect was apparent after the end of 10 sessions. This effect was maintained for a 2-week follow-up after the end of the sessions; however, this effect was no longer present 1 month after the end of the treatment sessions.
Acknowledgements We are grateful to Dr. John Rothwell (Head of Sobell Research Department of Motor Neuroscience and Movement Disorders, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK) for revisions and comments on the manuscript. Eur J Pain 19 (2015) 519--527
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repetitive transkraniellen Magnetstimulation? Nervenarzt 77, 1196– 1203. Karim, A.A., Kammer, T., Cohen, L., Birbaumer, N. (2004). Effects of TMS and tDCS on the physiological regulation of cortical excitability in a brain–computer interface. Biomedizinische Technik 49, 55–57. Karim, A.A., Kammer, T., Lotze, M. et al. (2003). Effects of repetitive transcranial magnetic stimulation (rTMS) on slow cortical potentials (SCP). Suppl Clin Neurophysiol 56, 331–337. Karl, A., Birbaumer, N., Lutzenberger, W., Cohen, L.G., Flor, H. (2001). Reorganization of motor and somatosensory cortex in upper extremity amputees with phantom limb pain. J Neurosci 21, 3609–3618. Khedr, E.M., Kotb, H., Kamel, N.F., Ahmed, M.A., Sadek, R., Rothwell, J.C. (2005). Long-lasting antalgic effects of daily sessions of repetitive transcranial magnetic stimulation in central and peripheral neuropathic pain. J NeurolNeurosurg Psychiatry 76, 833–838. Kudel, I., Edwards, R.R., Kozachik, S., Block, B.M., Agarwal, S., Heinberg, L.J., Haythornthwaite, J., Raja, S.N. (2007). Predictors and consequences of multiple persistent postmastectomy pains. J Pain Symptom Manage 34, 619–627. Lefaucheur, J.P., Antal, A., Ahdab, R., Ciampi de Andrade, D., Fregni, F., Khedr, E.M., Nitsche, M., Paulus, W. (2008). The use of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) to relieve pain. Brain Stimul 1, 337–344. Lefaucheur, J.P., Drouot, X., Keravel, Y., Nguyen, J.P. (2001). Pain relief induced by repetitive transcranial magnetic stimulation of precentral cortex. Neuroreport 12, 2963–2965. Lefaucheur, J.P., Drouot, X., Menard-Lefaucheur, I., Zerah, F., Bendib, B., Cesaro, P., Keravel, Y., Nguyen, J.P. (2004). Neurogenic pain relief by repetitive transcranial magnetic cortical stimulation depends on the origin and the site of pain. J Neurol Neurosurg Psychiatry 75, 612– 616. Lefaucheur, J.P., Hatem, S., Nineb, A., Menard-Lefaucheur, I., Wendling, S., Keravel, Y., Nguyen, J.P. (2006). Somatotopic organization of the analgesic effects of motor cortex rTMS in neuropathic pain. Neurology 67, 1998–2004. Leung, A., Donohue, M., Xu, R., Lee, R., Lefaucheur, J.P., Khedr, E.M., Saitoh, Y., Andre-Obadia, N., Rollnik, J., Wallace, M., Chen, R. (2009). RTMS for suppressing neuropathic pain: A meta-analysis. J Pain 10, 1205–1216. Maarrawi, J., Peyron, R., Mertens, P., Costes, N., Magnin, M., Sindou, M., Laurent, B., Garcia-Larrea, L. (2007). Motor cortex stimulation for pain control induces changes in the endogenous opioid system. Neurology 69, 827–834. O’Connell, N.E., Wand, B.M., Marston, L., Spencer, S., Desouza, L.H. (2010). Non-invasive brain stimulation techniques for chronic pain. Cochrane Database Syst Rev (9), CD008208. O’Reardon, J.P., Solvason, H.B., Janicak, P.G., Sampson, S., Isenberg, K.E., Nahas, Z., McDonald, W.M., Avery, D., Fitzgerald, P.B., Loo, C., Demitrack, M.A., George, M.S., Sackeim, H.A. (2007). Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: A multisite randomized controlled trial. Biol Psychiatry 62, 1208–1216. Pascual-Leone, A., Peris, M., Tormos, J.M., Pascual, A.P., Catalá, M.D. (1996). Reorganization of human cortical motor output maps following traumatic forearm amputation. Neuroreport 7, 2068–2070. Pascual-Leone, A., Tormos, J.M., Keenan, J., Tarazona, F., Canñete, C., Catalaá, M.D. (1998). Study and modulation of human cortical excitability with transcranial magnetic stimulation. J Clin Neurophysiol 15, 333–343. Passard, A., Attal, N., Benadhira, R., Brasseur, L., Saba, G., Sichere, P., Perrot, S., Januel, D., Bouhassira, D. (2007). Effects of unilateral repetitive transcranial magnetic stimulation of the motor cortex on chronic widespread pain in fibromyalgia. Brain 130, 2661–2670. Pleger, B., Janssen, F., Schwnkreis, P., Volker, B., Maier, C., Tegenthoff, M. (2004). Repetitive transcranial magnetic stimulation of the motor cortex attenuates pain perception in complex regional syndrome type I. Neurosci Lett 356, 87–90. Portenoy, R.K., Tanner, R.M. (1996). Visual analog scale and verbal pain intensity scale. In Pain Management: Theory and Practice (Oxford: Oxford University Press, Inc.).
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Rijntjes, M., Tegenthoff, M., Liepert, J. et al. (1997). Cortical reorganization in patients with facial palsy. Ann Neurol 41, 621–630. Rollnik, J.D., Wustefeld, S., Dauper, J., Karst, M., Fink, M., Kossev, A., Dengler, R. (2002). Repetitive transcranial magnetic stimulation for the treatment of chronic pain – A pilot study. Eur Neurol 48, 6–10. Rossini, P.M., Barker, A.T., Berardelli, A., Caramia, M.D., Caruso, G., Cracco, R.Q., Dimitrijevic´, M.R., Hallett, M., Katayama, Y., Lücking, C.H., Maertens de Noordhout, A.L., Marsden, C.D., Murray, N.M.F., Rothwell, J.C., Swash, M., Tomberg, C. (1994). Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: Basic principles and procedures for routine clinical application. Report of an IFCN committee. Electroencephalogr Clin Neurophysiol 91, 79–92.
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Saitoh, Y., Hirayama, A., Kishima, H., Shimokawa, T., Oshino, S., Hirata, M., Tani, N., Kato, A., Yoshimine, T. (2007). Reduction of intractable deafferentation pain due to spinal cord or peripheral lesion by highfrequency repetitive transcranial magnetic stimulation of the primary motor cortex. J Neurosurg 107, 555–559. Schwenkreis, P., Witscher, K., Janssen, F., Pleger, B., Dertwinkel, R., Zenz, M., Malin, J.P., Tegenthoff, M. (2001). Assessment of reorganization in the sensorimotor cortex after upper limb amputation. Clin Neurophysiol 112, 627–635. Töpper, R., Foltys, H., Meister, I.G., Sparing, R., Boroojerdi, B. (2003). Repetitive transcranial magnetic stimulation of the parietal cortex transiently ameliorates phantom limb pain-like syndrome. Clin Neurophysiol 114, 1521–1530.
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Repetitive transcranial magnetic stimulation in neuropathic pain secondary to malignancy: A randomized clinical trial E.M. Khedr1, H.I. Kotb2, M.G. Mostafa3, M.F. Mohamad3, S.A. Amr3, M.A. Ahmed1, A.A. Karim4,5, S.M.M. Kamal3 1 2 3 4 5
Department of Neurology, Assiut University Hospital, Egypt Department of Anesthesiology, Assiut University Hospital, Egypt Anesthesia, Intensive Care and Pain Management, South Egypt Cancer Institute, Assiut University, Egypt Department of Prevention, Health Psychology and Neurorehabilitation, SRH University, Riedlingen, Germany Department of Psychiatry and Psychotherapy, University Clinic Tübingen, Germany
Correspondence Eman M. Khedr E-mail: [email protected] Funding sources None. Conflict of interest None declared. Accepted for publication 7 July 2014 doi:10.1002/ejp.576
Abstract Background: Significant analgesic effects of repetitive transcranial magnetic stimulation (rTMS) have been found in several studies of patients with chronic pain of various origins, but never for malignancy. The objective of this study was to assess the efficacy of 10 sessions of rTMS over the primary motor cortex (M1) in patients suffering from malignant neuropathic pain. Methods: Thirty-four patients were randomly allocated into one of two groups to receive real (20 Hz, 10 s, 10 trains with 80% intensity) or sham rTMS daily for 10 consecutive days. Patients were evaluated using a verbal descriptor scale (VDS), a visual analogue scale (VAS), Leeds assessment of neuropathic symptoms and signs (LANSS) and Hamilton rating scale for depression (HAM-D) at baseline, after the first, fifth and 10th treatment sessions, and then 15 days and 1 month after treatment. Results: There were no significant differences between real and sham groups in the duration of illness or pain rating scores at the baseline. A significant ‘Time × Group’ interaction was recorded indicating that real and sham rTMS had different effects on the VDS, VAS, LANSS and HAM-D scales. Post-hoc testing showed that the group of patients treated with real rTMS had greater improvement in all scales that persisted up to 15 days, but were not present 1 month later. Significant positive correlations between the percentage of pain reduction and HAM-D after the 10th session and 15 days later were recorded. Conclusion: The results demonstrate that 10 rTMS sessions over the M1 can induce short-term pain relief in malignant neuropathic pain.
1. Introduction Neuropathic pain (NP) in cancer patients may arise from several mechanisms. It may result from compression of the nerve or direct infiltration by the growing tumour, or secondarily from changes in the neuronal media resulting from cancer growth or from the resulting inflammatory response such as tissue pH (acidosis), release of tumour algogens, or circulating © 2014 European Pain Federation - EFICâ
chemokines and cytokines (Cleeland et al., 2003). These inflammatory events in cancer neuropathy are likely to be more common and important than in other neuropathies; in these cases, an acute tissue response subsides, leaving restricted neuropathic mechanisms within peripheral nerves and the central nervous system. Surgical interventions such as mastectomy or debulking tumours often result in deafferentation pain. Patients post-mastectomy report a Eur J Pain 19 (2015) 519--527
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What’s already known about this topic? • Some recent approaches in patients with other causes of neuropathic pain than cancer pain have successfully used transcranial methods of brain stimulation to induce plastic changes in neural circuits associated with pain. What does this study add? • The data of the present study suggest that daily sessions of transcranial brain stimulation has potential to be used as a treatment to relieve pain in patients with pain secondary to malignancy.
constellation of symptoms including pain or discomfort in the chest wall, surgical scar, upper arm and shoulder, which may be suggestive of intercostobrachial nerve damage and phantom breast sensations (Kudel et al., 2007). Finally, radiation-induced fibrosis can injure peripheral nerves (e.g. fibrosis of brachial plexus) causing chronic NP that begins months to years following treatment (Henry et al., 2008). Medications are often ineffective or cause various adverse effects (e.g. rashes, gastrointestinal upset, allergies); therefore, better approaches are needed. Significant analgesic effects of repetitive transcranial magnetic stimulation (rTMS) have been found in several studies of patients with chronic pain of various origins such as central NP [post-stroke pain (Khedr et al., 2005), spinal cord injury (Lefaucheur et al., 2004), thalamic pain (Lefaucheur et al., 2004) ] and peripheral NP [trigeminal neuralgia (Khedr et al., 2005), phantom limb pain (Irlbacher et al., 2006) and brachial plexus injury (Lefaucheur et al., 2004) ]. The frequency of transcranial magnetic stimulation (TMS) pulses influences the effects on axons. Hirayama et al. showed that relief of NP was observed only when targeting primary motor area (M1), but not other areas (Hirayama et al., 2006). Regarding the short-term effect from a single session of rTMS, most studies and meta-analyses, including the Cochrane review, demonstrated positive effects on pain relief after highfrequency stimulations (HF-rTMS) of M1, but not after low-frequency stimulations (O’Connell et al., 2010). A 2010 Cochrane Systematic Review concluded that higher stimulation frequencies (>5 Hz), greater numbers of stimuli (>500) and multiple sessions (>1) yielded better results (O’Connell et al., 2010). M1 stimulation at HF-rTMS was shown to reduce pain scores by 20–45% after active stimulation, and by less than 10% after sham stimulation (Lefaucheur et al., 2008). The therapeutic applications of rTMS in 520 Eur J Pain 19 (2015) 519--527
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pain syndromes are limited by the short duration of the induced effects, but prolonged pain relief can be obtained by repeating rTMS sessions everyday for several weeks (Lefaucheur et al., 2001). Up to our knowledge, the effect of rTMS on malignant NP has not been studied before and therefore, the present clinical trial was done to investigate whether repeated sessions of HF-rTMS over the M1 can improve pain in patients with malignant NP.
2. Patients and methods This study was conducted at the pain clinic unit of the South Egypt Cancer Institute, Assiut University and at the Department of Neuropsychiatry, Assiut University Hospital from January 2010 to May 2013. All patients were within 18–65 years with malignant lateralized NP resistant to medical treatments for at least 2 months. We excluded patients with intracranial metallic devices or with pacemakers or any other device. We also excluded those with recent myocardial ischaemia, unstable angina and those known to have a history of epilepsy. Thirty-four patients were included in the study. All of them had NP according to the Douleur Neuropathique 4 (DN4) questionnaire (Bouhassira et al., 2005). It consists of four questions with 10 items. The total score is calculated as the sum of the 10 items and the cut-off value for the diagnosis of NP is a total score of 4/10. They were randomly allocated into one of the two groups (1:1 ratio) using closed envelopes as parallel groups (real rTMS group and sham rTMS group). Fig. 1 shows the flow chart of patients through the course of the study. In the real group, the mean age of the studied patients was 47 ± 9.2 years, (1 man and 16 women), the mean duration of illness was 15.4 ± 15.9 months and the mean DN4 score was 5.6 ± 0.8 points. Two of them did not complete the study because they developed medical complications (severe gastrointestinal upset). Fourteen had lateralized post-mastectomy NP (nine had right, five had left side of chest and arm), one had soft tissue sarcoma in the right upper limb, one had giant cell glioma of right radial nerve and one had left thigh pain after femoral after femoral mass removal. Ten patients were under chemotherapy and seven were under radiotherapy. In the sham group, the mean age of the studied patients was 48 ± 9.7 years, (2 men and 15 women), the mean duration of illness was 16.8 ± 16.3 months and the mean DN4 score was 5.5 ± 0.9 points. Two patients also did not complete the study because of chemotherapy and radiotherapy complications. Fifteen patients who completed the study had lateralized post-mastectomy NP (eight had right, seven had left side of chest and arm) and two had soft tissue sarcoma in the right lower limb. Eight patients were under chemotherapy and nine were under radiotherapy. All patients were asked to not change their analgesic regimen through the course of the study. All of them were under the same regimen: tramadol hydrochloride 100 mg twice daily, pregabalin 75 mg twice daily, gabapentin 400 mg twice daily and Amitriptyline 25 mg twice daily. © 2014 European Pain Federation - EFICâ
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Figure 3 Showed changes Hamilton rating scale for depression score in studied group of neuropathic pain patients at six points of assessment. The first was prior to commencing repetitive transcranial magnetic stimulation (rTMS) treatment (pre-stimulation). The second was after the first session (post-first session). The third was after the end of the fifth session (post-fifth session), the fourth was after the 10th session of stimulation (post-10th session), the fifth and six assessment points were 15 days and 1 month after the end of stimulation sessions. Data expressed as mean ± standard deviation. The significances between groups appeared at different points of assessment. These were seen after the fifth day of stimulation (p-value = 0.018) and after the 10th day of stimulation (p-value = 0.002), after 15 days after end of stimulation (p-value = 0.001) and at 1 month after the end of stimulation (p-value = 0.027).
Figure 2 Shows changes in the verbal descriptor scale (upper trace), the visual analogue scale (middle trace) and the Leeds assessment of neuropathic symptoms and signs (lower trace) in patients with malignant neuropathic pain at six points of assessment. The first one was prior to commencing repetitive transcranial magnetic stimulation (rTMS) treatment (pre-stimulation). The second was after first session (post-first session).The third was after the end of the fifth session (post-fifth session), the fourth was after the 10th session of stimulation (post-10th session), the fifth and sixth assessment points were at 15 days and 1 month after the end of stimulation sessions. Data expressed as mean ± standard deviation The significances between groups appeared at different points of assessment. These were seen after the 10th session and 15 days after the end of session for the three scales.
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Moreover, significant positive correlations between the percentage of pain reduction on VAS and of depression reduction on HAM-D were observed after the 10th session and 15 days later (r = 0.55, p = 0.002 and r = 0.52, p = 0.003, respectively). The same results were recorded with VDS/HAM-D (r = 0.679, p = 0.0001 and r = 0.648, p = 0.0001, respectively) and for LANSS/HAM-D (r = 0.408, p = 0.02 and r = 0.30, p = 0.0107, respectively). According to the percentage of pain relief in the VAS scale; the number of responders (30% or more pain relief) were: 13 (86.6%), 12(80%) and 4 (26.6%) at the three time points of assessment in the real group, which were significantly higher than the sham group: 1 (6.6%) for each time point of assessment.
4. Discussion These results suggest that rTMS at 20 Hz given every day for 10 sessions can reduce ratings of pain and depression in patients with malignant NP. The effects last at least for 2 weeks after the end of the treatment sessions, but are no longer present at a 1-month follow-up. This is very similar to previous reports of the effects of rTMS on other types of NP rather than malignant NP. Eur J Pain 19 (2015) 519--527
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(20 Hz, 10 s, 10 trains with an inter-train interval of 30 s and a total amount of pulses: 2000, intensity was 80% of the motor threshold) every day for 10 consecutive days (5 days/ week) applied through a figure-of-eight coil over the identified motor cortical area corresponding to the hand of painful side (M1) with orientation of the coil preferentially parallel to the midsagittal line, as suggested by André-Obadia et al. (2008). Sham-rTMS was applied using the same parameters, but with the coil elevated and angled away from the head to reproduce the same subjective sensation of rTMS, and yet avoid induction of current to the brain (Pascual-Leone et al., 1998; Karim et al., 2003, 2004).
2.4 Follow-up measures Measurements were done before and after the first, fifth and 10th sessions, and 15 days, and 1 month later, with all rating scales: VDS, VAS, LANSS and HAM-D. The measurements were done by a blind assessor without knowing the type of stimulation applied. During the followup, seven patients of the real group asked to decrease the dose of tramadol hydrochloride to be 50 mg twice/day after the 10th session, and eight patients of sham group asked to increase the dose of tramadol to be 150–200 mg twice/day.
2.5 Outcomes The primary outcome was pain relief on the VAS after the 10th session and 1 month later, and the secondary outcomes were pain and depression reduction on VDS, LANSS and HAM-D after the 10th session and 1 month later.
2.6 Data analysis The values of each group of patients for each scale were analysed separately by one-way analysis of variance (ANOVA) repeated measure analysis. Two-way ANOVA repeated measures of analyses were used to assess the interaction between groups (Time ‘pre, first, fifth, 10th, 15 days after stimulation and after 1 month’ × Group ‘real & sham’). Post-hoc t-tests were used to assess interaction between groups at different points of assessment. The Greenhouse– Geisser correction of degrees of freedom was used when necessary to correct for non-spherity of the data. The percentage of reduction of each scale was calculated after the 10th session of stimulation by Mann–Whitney test as a scale at the 10th day – Pre-stimulation score × 100/Pre-stimulation score. The percentage of reduction after 15 days, and 1 month after the end of stimulation, were assessed by the same calculation. We calculated the number of responders as patients showing pain relief of more than 30% on VAS compared with prerTMS baseline. Statistical correlation between the percentage of pain reduction on VAS/VDS/LANSS and of depression reduction on HAM-D after the 10th session and 15 days later were done using Spearman correlation. 522 Eur J Pain 19 (2015) 519--527
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3. Results There were no differences at baseline between the groups concerning demographic and clinical data as well as scores in the different scales of pain assessment (Table 1). No side effect could be recorded by any patient. Scores on all the rating scales changed over time, with the largest effects in the real rTMS group. For the primary outcome: two-way ANOVAs with Time (pre, after first, fifth, 10th and 15 days and 1 month later) and Group (real or sham) as main factors showed a significant Time × Group interaction for VDS [p = 0.0001, F = 0.43, degrees of freedom (df) = 2.1 (58.4) ], VAS [p = 0.001, F = 8.07, df = 2.05(57.5) ], and LANSS [p = 0.018, F = 2.83, df = 2.5(70.4) ] (Fig. 2) as well as for secondary outcome; HAM-D [p = 0.007, F = 4.85, df = 2.37(66.3) ] (Fig. 3). This indicates that the effect of treatment differed in the two groups. Follow-up one-way ANOVAs on the data from each group separately showed that there was a significant effect of time in both groups in all rating scales. Thus, both real and sham treatments tended to reduce symptoms. However, the effects were greater with real stimulation, particularly at the end of treatment and at 15 days follow-up. The results of individual t-test comparisons between groups at each time point are shown on the graphs. In general, there was no effect of real rTMS after the first treatment session. A difference with sham gradually appeared over the course of treatment, but was no longer present at 1 month. Percentages changes in ratings are shown in Table 2 for the 10th session and 1 month after the end of rTMS. There was a significant percentage reduction in all scales after the 10th session and 15 days after stimulation in both groups; however, these effects were not seen 1 month after the end of stimulation except in LANSS and HAM-D.
Table 1 Demographic and baseline assessments of both groups in the studied patients.
Age (mean ± SD) Duration of illness(months) Verbal descriptor pain scale Visual analogue scale Hamilton rating scale for depression Leeds assessment of neuropathic symptoms and signs
Real group (mean ± SD)
Sham group (mean ± SD)
p-value
47.0 ± 9.2 15.4 ± 15.9 4.7 ± 0.8 6.3 ± 0.5 13.3 ± 1.9
48.0 ± 9.7 16.8 ± 16.3 4.6 ± 0.9 6.1 ± 0.6 13.5 ± 1.5
NS NS NS NS NS
16.7 ± 2.49
16.4 ± 2.9
NS
NS, non significant; SD, standard deviation.
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Figure 3 Showed changes Hamilton rating scale for depression score in studied group of neuropathic pain patients at six points of assessment. The first was prior to commencing repetitive transcranial magnetic stimulation (rTMS) treatment (pre-stimulation). The second was after the first session (post-first session). The third was after the end of the fifth session (post-fifth session), the fourth was after the 10th session of stimulation (post-10th session), the fifth and six assessment points were 15 days and 1 month after the end of stimulation sessions. Data expressed as mean ± standard deviation. The significances between groups appeared at different points of assessment. These were seen after the fifth day of stimulation (p-value = 0.018) and after the 10th day of stimulation (p-value = 0.002), after 15 days after end of stimulation (p-value = 0.001) and at 1 month after the end of stimulation (p-value = 0.027).
Figure 2 Shows changes in the verbal descriptor scale (upper trace), the visual analogue scale (middle trace) and the Leeds assessment of neuropathic symptoms and signs (lower trace) in patients with malignant neuropathic pain at six points of assessment. The first one was prior to commencing repetitive transcranial magnetic stimulation (rTMS) treatment (pre-stimulation). The second was after first session (post-first session).The third was after the end of the fifth session (post-fifth session), the fourth was after the 10th session of stimulation (post-10th session), the fifth and sixth assessment points were at 15 days and 1 month after the end of stimulation sessions. Data expressed as mean ± standard deviation The significances between groups appeared at different points of assessment. These were seen after the 10th session and 15 days after the end of session for the three scales.
© 2014 European Pain Federation - EFICâ
Moreover, significant positive correlations between the percentage of pain reduction on VAS and of depression reduction on HAM-D were observed after the 10th session and 15 days later (r = 0.55, p = 0.002 and r = 0.52, p = 0.003, respectively). The same results were recorded with VDS/HAM-D (r = 0.679, p = 0.0001 and r = 0.648, p = 0.0001, respectively) and for LANSS/HAM-D (r = 0.408, p = 0.02 and r = 0.30, p = 0.0107, respectively). According to the percentage of pain relief in the VAS scale; the number of responders (30% or more pain relief) were: 13 (86.6%), 12(80%) and 4 (26.6%) at the three time points of assessment in the real group, which were significantly higher than the sham group: 1 (6.6%) for each time point of assessment.
4. Discussion These results suggest that rTMS at 20 Hz given every day for 10 sessions can reduce ratings of pain and depression in patients with malignant NP. The effects last at least for 2 weeks after the end of the treatment sessions, but are no longer present at a 1-month follow-up. This is very similar to previous reports of the effects of rTMS on other types of NP rather than malignant NP. Eur J Pain 19 (2015) 519--527
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0.038 7.9 ± 10.4 15.7 ± 9.1 0.011 7.3 ± 11.6 18.2 ± 9.9 0.182 0.105
After 10th session 15 days after the end of sessions One month after end of sessions
0.000 0.002
22.7 ± 16.3 20.8 ± 18.2
15.9 ± 10.0
0.001 0.003 10.6 ± 11.9 9.7 ± 12.3 24.4 ± 10.2 23.6 ± 10.9 0.001 0.02 7.7 ± 12.1 9.8 ± 13.1 21.9 ± 9.4 20.9 ± 11.3 0.001 0.01
30.9 ± 14.8
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36.7 ± 18.4 35.5 ± 20.8 22.8 ± 13.5 23.3 ± 13.8 49.1 ± 18.9 45.6 ± 20.7
15.9 ± 10.0 18.4 ± 11.8
p-value Sham group Real group p-value Sham group Real group Real group Sham group Real group
p-value
Visual analogue scale
Sham group
p-value
Leeds assessment of neuropathic symptoms and signs scale
E.M. Khedr et al.
Verbal descriptor scale
Table 2 Percentage of reduction of all different scales after the 10th session, 15 days and 1 month after the end of sessions in relation to baseline.
Hamilton rating scale for depression
rTMS in malignant neuropathic pain
We applied HF-rTMS since this has been generally shown to be more effective than low-frequency stimulation. For example, Lefaucheur et al. (2001) demonstrated that rTMS was able to relieve NP when administered over M1 with 10-Hz stimulation, but not with 0.5-Hz stimulation. Andre-Obadia et al. (2006) also showed that rTMS was more effective in reducing pain when applied at 20 Hz than at 1 Hz, and Saitoh et al. (2007) found that 10 Hz rTMS was more effective than 5 Hz rTMS, while 1 Hz rTMS had no significant effects. Interestingly the effects took some time to build up. There were no significant effects on VDP, VAS or LANSS scores after the first session, but these appeared after the fifth session and were greater in the real rTMS than in the sham group. A similar time course was described originally by Lefaucheur et al. (2001) who found that pain relief after a single session was optimal 2–4 days after rTMS. Pleger et al. (2004) recorded some relief of pain 30 s after rTMS, but this intensified after 45 min. Ahmed et al. (2011) also found no significant effects after the first session of rTMS. It is possible that the absence of significant pain relief after the first session could be related to the short duration of the session (10 min) as compared with 20 min used in some of the previous studies (Rollnik et al., 2002; Lefaucheur et al., 2004). The persistence of pain relief for 2 weeks or more is also similar to our previous work on other types of pain (Khedr et al., 2005). Passard et al. (2007) followed up patients for 60 days after treatment and found that the analgesic effect of rTMS continued for 15 days after end of sessions, but was not present after 30 and 60 days. Hosomi et al. (2013) also demonstrated the positive short-term analgesic effect, but no cumulative effect on 29 days follow-up. However, longer periods of pain relief were reported by Ahmed et al. (2011) who found that the analgesic effect was still present at 1- and 2-month follow-ups. In our study, the percentage reduction of VAS in the real group after the 10th session was higher compared with a small reduction in the sham group (p = 0.001). These values are close to those reported by Khedr et al. (2005) (45%) and Ahmed et al. (2011) (55%), but are slightly larger than the 12% improvement reported by Leung et al. (2009), 13.7% by O’Connell et al. (2010) and 19.7% by Hosomi et al. (2013). The observed analgesic effects could be probably prolonged by an appropriate maintenance therapy with additional weekly or monthly rTMS sessions. In the present study, we have stimulated the motor cortical area corresponding to the hand of painful side, while pain was mostly located at the chest or even in © 2014 European Pain Federation - EFICâ
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the lower limb. The observed effects may be explained by the notion that HF-rTMS (20 Hz) over the hand area could modulate some output from the nearby chest cortical representation or may be due to shift of the chest area (representation plasticity) towards the hand area in cases of postmastectomy chronic chest lesion. Supporting this notion, Lefaucheur et al. (2004) reported that better results were obtained for facial pain, after a single session of 10 Hz rTMS of 20 min, although stimulation was targeted on the hand cortical area. In patients with upper limb amputation, the former hand area of the cortex was shown to be invaded by a lateralization of the area corresponding to arm muscle proximal to the stump (Pascual-Leone et al., 1996; Schwenkreis et al., 2001) and a medialization of the face area (Pascual-Leone et al., 1996; Karl et al., 2001). Similarly, in patients with facial palsy, TMS shows an enlargement of the hand field extending in a lateral direction into the site of the face area (Rijntjes et al., 1997). However, area proximity could not explain the pain relief in the lower limb, as leg and hand representations are not adjacent, but separated by arm and trunk representations (Lefaucheur et al., 2004). It may be related to the release of endorphins as reported by Ahmed et al. (2011). They found elevation of serum beta-endorphin concentration after five sessions of 20 Hz rTMS over the hand area of motor cortex in 17 patients with chronic phantom pain. There was a significant reduction of the HAM-D in the real group after the 10th session that was greater than in the sham group p-value (0.002). These effects persisted at 1 month (p = 0.038). O’Reardon et al. (2007) reported significantly better clinical results in an active rTMS group in comparison with the sham group, as measured by the HAM-D and the Montgomery Asberg Depression Rating Scale ( (O’Reardon et al., 2007). However, Hosomi and colleagues found no effect on the Beck depression inventory (Hosomi et al., 2013). It has been suggested that the underlying pathophysiology of NP is associated with plastic changes and dysfunction of extensive neural circuits in the central nervous system, involving various structures related to pain perception, and with an affective–emotional component (Leung et al., 2009). The possible mechanisms of action of pain relief following the stimulation of M1, by rTMS, are considered to be modulation of neural activity in these structures (Lefaucheur et al., 2006). M1 itself is seen as a focal entry port point to a distributed pain system that can modulate activity in remote deep-brain structures through the subcortical © 2014 European Pain Federation - EFICâ
projections, leading to an increase in the cerebral blood flow in the ipsilateral thalamus, orbitofrontal and cingulate gyri and in the upper brain stem (García-Larrea et al., 1999; Lefaucheur et al., 2006; Goto et al., 2008). These hypotheses of cerebral modulation in the various central nervous system structures could explain how the effects of rTMS last for more than 60 min (Hosomi et al., 2013). The consequence may be to change the levels of central nervous system opioids. Maarrawi et al. reported that motor cortex stimulation may induce release of endogenous opioids in brain structures involved in the processing of acute and chronic pain (Maarrawi et al., 2007). Ahmed et al. (2011) suggested that analgesic effects of rTMS in phantom pain were delivered by increase in the endogenous betaendorphin release. Töpper et al. (2003) found that opiate antagonist naloxone abolished the rTMSinduced pain relief, which was taken as evidence that the analgesic effect of rTMS acted via the release of endorphins. Borckardt et al. (2008) found that a single session of HF-rTMS applied immediately after gastric bypass surgery at 10 Hz over the left dorsolateral prefrontal cortex for a total of 4000 pulses was associated with a 40% reduction in total morphine use during the first 2 days after surgery. This reduction corresponded to the effect of active rTMS minus that of sham stimulation (Borckardt et al., 2006, 2008). Limitations in the interpretation of our results include the small sample size of this pilot study, dropouts and variability of cause of NP (different types of malignancies) and dependence on reports by participants.
5. Conclusion Ten sessions of HF-rTMS over the M1 had beneficial reduction of pain score in malignant NP patients and the maximum effect was apparent after the end of 10 sessions. This effect was maintained for a 2-week follow-up after the end of the sessions; however, this effect was no longer present 1 month after the end of the treatment sessions.
Acknowledgements We are grateful to Dr. John Rothwell (Head of Sobell Research Department of Motor Neuroscience and Movement Disorders, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK) for revisions and comments on the manuscript. Eur J Pain 19 (2015) 519--527
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