EDITORIAL For reprint orders, please contact: [email protected]
Evidence-based medicine in the management of chronic pain using noninvasive brain stimulation “EBM does not seek to replace or limit physician’s autonomy or judgment, but instead it complements individual clinical experience with the best scientific evidence to guide treatment choices and deliver the best possible care.” Gabriela Bravo1
Felipe Fregni*1,2
Evidence-based medicine (EBM), widely cited from the words of David Sackett as the “conscientious, explicit and judicious use of the best available evidence in making decisions about the care of individual patients”, dates back as early as the 18th century [1]. Thomas Beddoes (1760–1808), an English physician and philanthropist, acknowledged the need for systematic data collection that could be easily retrieved and shared with other practitioners. As more people become concerned with the quality of care provided, the practice of EBM has shifted from the moral imperative of the physician’s commitment to lifelong learning to the standard practice of medicine. There are several steps clinicians need to master and consider prior to deciding whether or not their current standard of care should be changed. Defining a clinical problem and formulating a solid question is the first step towards a successful search. Gathering available literature and assessing the quality of the studies for validity, reliability and relevance requires strong statistical literacy, as complex study designs involve
sophisticated statistical analyses that are not always easy to decode [2]. Assembling all of this information is critical to defining whether or not the research outcome is applicable to the targeted population. Over the past several years, the amount of medical literature has rapidly expanded and clinicians are presented with the daunting task of searching hundreds of journals in order to identify high-quality studies. Numerous criteria that rank different levels of evidence according to the particular study design and its inherent limitations have been developed to aid physicians in grading and labeling the strength of evidence. In general, hierarchical stratification places randomized controlled trials at the top of the evidence-based pyramid, followed by cohort or case–control studies and taking the lowest place of evidence are case reports and expert opinions [3]. The application of EBM principles to chronic pain management is critical. Chronic pain causes substantial disability, creates an economical burden and directly impacts the quality of life and productivity of those affected. Despite the wide range of
“The application of evidence-based medicine principles to chronic pain management is critical.”
Laboratory of Neuromodulation, Spaulding Rehabilitation Hospital, Harvard Medical School, 125 Nashua Street, Boston, MA 02114, USA 2 Berenson–Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA *Author for correspondence: Tel.: +1 617 573 2326; Fax: +1 617 975 5322; [email protected] 1
10.2217/PMT.12.55 © 2012 Future Medicine Ltd
Pain Manage. (2012) 2(6), 531–533
part of
ISSN 1758-1869
531
EDITORIAL Bravo & Fregni
“Despite the wide range of opiod and nonopioid analgesics available for the management of chronic pain, there is currently not enough evidence that demonstrates a clinically efficient approach for sustained pain relief.”
532
opiod and nonopioid analgesics available for the management of chronic pain, there is currently not enough evidence that demonstrates a clinically efficient approach for sustained pain relief. Instead, there is an increased trend in Phase II and Phase III pharmacological trials that fail to show superior results of the active compound over placebo in various chronic pain conditions of both neuropathic and non-neuropathic origin [4–6]. Side effects of pharmacologic therapies pose a wide range of safety issues that emphasize the need for novel nonpharmacologic and noninvasive treatments. Emerging techniques in noninvasive brain stimulation (NIBS), such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation, target plastic pain processes in the CNS with minimal to no adverse effects. Advances in the understanding of the pathophysiology of pain have demonstrated that maladaptive plastic alterations are responsible for the generation and maintenance of chronic pain. NIBS could block these mechanisms leading to central sensitization and reinstate equilibrium through ‘top-down’ modulation, by either enhancing antinociceptive properties through excitatory influence over inhibitory mechanisms or by diminishing pronociceptive properties through a decrease in excitability. Initial evidence of the use of repetitive TMS in chronic pain comes from a study by Lefaucheur et al. in 2001, in which patients with intractable pain originating from either post-thalamic stroke or trigeminal neuropathy experienced a significant level of analgesia up to 8 days after active repetitive transcranial magnetic stimulation when compared with sham stimulation [7]. Furthermore, several studies in chronic pain conditions, such as fibromyalgia [8], chronic migraine [9], chronic back pain [10] and chronic visceral pain [11], have shown e ncouraging initial results. The possibility of therapeutic utility is promising; however, further support in the form of large randomized controlled trials are needed. A review by O’Connell et al., in which the primary outcome measure was change in selfreported pain scales, concluded that there was insufficient evidence to ascertain the efficacy of brain stimulation techniques in chronic pain conditions [12]. As the concept of NIBS for pain management is relatively new and consistently expanding, current evidence essentially features small, underpowered, exploratory studies that lack the statistical significance necessary to reach
Pain Manage. (2012) 2(6)
solid conclusions. Confounding results in the literature may be attributed to heterogeneity in trial design. Furthermore, there is insufficient evidence on the type of parameters needed to reach effective outcomes (e.g., location of electrodes, stimulus intensity and duration, number of treatment sessions and type of sham stimulation). Additionally, information on adverse events, subject allocation, blinding assessment and follow-up is not adequately reported. The importance of the inclusion of NIBS techniques in the scope of pain management lies in the advantages it provides over standard pharmacologic therapy. Both TMS and transcranial direct current stimulation are nonsurgical, painless procedures. Multiple studies and meta-analyses support the safety of these procedures [13]. Only a small proportion of individuals experience relatively mild side effects, such as transient headache, neck discomfort or tingling sensation on the scalp. In very rare instances, TMSinduced seizures or scalp burns from transcranial direct current stimulation have occurred [14]. Furthermore, several studies have shown that repeated stimulation sessions can prolong the analgesic effect by several weeks. Additionally, TMS can be used as both a d iagnostic and therapeutic tool. As it is not feasible to answer all questions through randomized controlled trials, clinicians should be prudent when extrapolating outcomes to avoid placing undue weight on new interventions. EBM does not seek to replace or limit physician’s autonomy or judgment, but instead it complements individual clinical experience with the best scientific evidence to guide treatment choices and deliver the best possible care. Although much progress has been made in the field of NIBS, the evidence base for its use in the management of chronic pain poses several issues that might account for the variability in therapeutic response. Large, confirmatory trials with consistent stimulatory paradigms are indispensable for asserting findings from previous smaller studies. In addition, factors such as disparate outcome measures, imputation strategies for missing data and selection of patients with individual complexities of pain conditions and symptom severity may account for the modest or lack of difference in negative trials. It is essential to understand the relationship between trial design and trial outcome. Pooling of small trials of NIBS in chronic pain research provide encouraging results; however,
future science group
Evidence-based medicine in the management of chronic pain using noninvasive brain stimulation until enough clinical trials provide a robust framework of evidence, findings will remain largely inconclusive. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a
References 1
2
3
4
5
Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence based medicine: what it is and what it isn’t. BMJ 312, 71–72 (1996). Young KD, Lewis RJ. Medical literature and evidence-based medicine. In: Rosen’s Emergency Medicine: Concepts and Clinical Practice (7th Edition). Marx JA, Hockberger RS, Wall RM (Eds). Mosby Elsevier, Philadelphia, PA, USA, 2507–2520 (2010). Miyasaki JM. Using evidence-based medicine in neurology. Neurol. Clin. 28, 489–503 (2010). Beydoun A, Shaibani A, Hopwood M, Wan Y. Oxcarbazepine in painful diabetic neuropathy: results of a dose-ranging study. Acta Neurol. Scand. 113, 395–404 (2006). Dworkin RH, Turk DC, Katz NP et al. Evidence-based clinical trial design for chronic pain pharmacotherapy: a blueprint
future science group
financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. for ACTION. Pain 152(Suppl. 3), S107–S115 (2011).
6
7
EDITORIAL
Skljarevski V, Ossanna M, Liu-Seifert H et al. A double-blind, randomized trial of duloxetine versus placebo in the management of chronic low back pain. Eur. J. Neurol. 16, 1041–1048 (2009). Lefaucheur JP, Drouot X, Keravel Y, Nguyen JP. Pain relief induced by repetitive transcranial magnetic stimulation of precentral cortex. Neuroreport 12(13), 2963–2965 (2001).
8
Sampson SM, Rome JD, Rummans TA. Slow-frequency rTMS reduces fibromyalgia pain. Pain Med. 7, 115–118 (2006).
9
Brighina F, Piazza A, Vitello G et al. rTMS of the prefrontal cortex in the treatment of chronic migraine: a pilot study. J. Neurol. Sci. 227, 67–71 (2004).
10 Johnson SSJ, Pridmore S. Changes to
somatosensory detection and pain thresholds following high frequency repetitive TMS of
the motor cortex in individuals suffering from chronic pain. Pain 123, 187–192 (2006). 11 Fregni F, DaSilva D, Potvin K et al. Treatment
of chronic visceral pain with brain stimulation. Ann. Neurol. 58, 971–972 (2005). 12 O’Connell NE, Wand BM, Marston L,
Spencer S, Desouza LH. Non-invasive brain stimulation techniques for chronic pain. Cochrane Database Syst. Rev. CD008208 (2010). 13 Janicak PG, O’Reardon JP, Sampson SM
et al. Transcranial magnetic stimulation in the treatment of major depressive disorder: a comprehensive summary of safety experience from acute exposure, extended exposure, and during reintroduction treatment. J. Clin. Psychiatry 69, 222–232 (2008). 14 Haupts MR, Daum S, Ahle G, Holinka B,
Gehlen W. Transcranial magnetic stimulation as a provocation for epileptic seizures in multiple sclerosis. Mult. Scler. 10, 475–476 (2004).
www.futuremedicine.com
533
Evidence-based medicine in the management of chronic pain using noninvasive brain stimulation “EBM does not seek to replace or limit physician’s autonomy or judgment, but instead it complements individual clinical experience with the best scientific evidence to guide treatment choices and deliver the best possible care.” Gabriela Bravo1
Felipe Fregni*1,2
Evidence-based medicine (EBM), widely cited from the words of David Sackett as the “conscientious, explicit and judicious use of the best available evidence in making decisions about the care of individual patients”, dates back as early as the 18th century [1]. Thomas Beddoes (1760–1808), an English physician and philanthropist, acknowledged the need for systematic data collection that could be easily retrieved and shared with other practitioners. As more people become concerned with the quality of care provided, the practice of EBM has shifted from the moral imperative of the physician’s commitment to lifelong learning to the standard practice of medicine. There are several steps clinicians need to master and consider prior to deciding whether or not their current standard of care should be changed. Defining a clinical problem and formulating a solid question is the first step towards a successful search. Gathering available literature and assessing the quality of the studies for validity, reliability and relevance requires strong statistical literacy, as complex study designs involve
sophisticated statistical analyses that are not always easy to decode [2]. Assembling all of this information is critical to defining whether or not the research outcome is applicable to the targeted population. Over the past several years, the amount of medical literature has rapidly expanded and clinicians are presented with the daunting task of searching hundreds of journals in order to identify high-quality studies. Numerous criteria that rank different levels of evidence according to the particular study design and its inherent limitations have been developed to aid physicians in grading and labeling the strength of evidence. In general, hierarchical stratification places randomized controlled trials at the top of the evidence-based pyramid, followed by cohort or case–control studies and taking the lowest place of evidence are case reports and expert opinions [3]. The application of EBM principles to chronic pain management is critical. Chronic pain causes substantial disability, creates an economical burden and directly impacts the quality of life and productivity of those affected. Despite the wide range of
“The application of evidence-based medicine principles to chronic pain management is critical.”
Laboratory of Neuromodulation, Spaulding Rehabilitation Hospital, Harvard Medical School, 125 Nashua Street, Boston, MA 02114, USA 2 Berenson–Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA *Author for correspondence: Tel.: +1 617 573 2326; Fax: +1 617 975 5322; [email protected] 1
10.2217/PMT.12.55 © 2012 Future Medicine Ltd
Pain Manage. (2012) 2(6), 531–533
part of
ISSN 1758-1869
531
EDITORIAL Bravo & Fregni
“Despite the wide range of opiod and nonopioid analgesics available for the management of chronic pain, there is currently not enough evidence that demonstrates a clinically efficient approach for sustained pain relief.”
532
opiod and nonopioid analgesics available for the management of chronic pain, there is currently not enough evidence that demonstrates a clinically efficient approach for sustained pain relief. Instead, there is an increased trend in Phase II and Phase III pharmacological trials that fail to show superior results of the active compound over placebo in various chronic pain conditions of both neuropathic and non-neuropathic origin [4–6]. Side effects of pharmacologic therapies pose a wide range of safety issues that emphasize the need for novel nonpharmacologic and noninvasive treatments. Emerging techniques in noninvasive brain stimulation (NIBS), such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation, target plastic pain processes in the CNS with minimal to no adverse effects. Advances in the understanding of the pathophysiology of pain have demonstrated that maladaptive plastic alterations are responsible for the generation and maintenance of chronic pain. NIBS could block these mechanisms leading to central sensitization and reinstate equilibrium through ‘top-down’ modulation, by either enhancing antinociceptive properties through excitatory influence over inhibitory mechanisms or by diminishing pronociceptive properties through a decrease in excitability. Initial evidence of the use of repetitive TMS in chronic pain comes from a study by Lefaucheur et al. in 2001, in which patients with intractable pain originating from either post-thalamic stroke or trigeminal neuropathy experienced a significant level of analgesia up to 8 days after active repetitive transcranial magnetic stimulation when compared with sham stimulation [7]. Furthermore, several studies in chronic pain conditions, such as fibromyalgia [8], chronic migraine [9], chronic back pain [10] and chronic visceral pain [11], have shown e ncouraging initial results. The possibility of therapeutic utility is promising; however, further support in the form of large randomized controlled trials are needed. A review by O’Connell et al., in which the primary outcome measure was change in selfreported pain scales, concluded that there was insufficient evidence to ascertain the efficacy of brain stimulation techniques in chronic pain conditions [12]. As the concept of NIBS for pain management is relatively new and consistently expanding, current evidence essentially features small, underpowered, exploratory studies that lack the statistical significance necessary to reach
Pain Manage. (2012) 2(6)
solid conclusions. Confounding results in the literature may be attributed to heterogeneity in trial design. Furthermore, there is insufficient evidence on the type of parameters needed to reach effective outcomes (e.g., location of electrodes, stimulus intensity and duration, number of treatment sessions and type of sham stimulation). Additionally, information on adverse events, subject allocation, blinding assessment and follow-up is not adequately reported. The importance of the inclusion of NIBS techniques in the scope of pain management lies in the advantages it provides over standard pharmacologic therapy. Both TMS and transcranial direct current stimulation are nonsurgical, painless procedures. Multiple studies and meta-analyses support the safety of these procedures [13]. Only a small proportion of individuals experience relatively mild side effects, such as transient headache, neck discomfort or tingling sensation on the scalp. In very rare instances, TMSinduced seizures or scalp burns from transcranial direct current stimulation have occurred [14]. Furthermore, several studies have shown that repeated stimulation sessions can prolong the analgesic effect by several weeks. Additionally, TMS can be used as both a d iagnostic and therapeutic tool. As it is not feasible to answer all questions through randomized controlled trials, clinicians should be prudent when extrapolating outcomes to avoid placing undue weight on new interventions. EBM does not seek to replace or limit physician’s autonomy or judgment, but instead it complements individual clinical experience with the best scientific evidence to guide treatment choices and deliver the best possible care. Although much progress has been made in the field of NIBS, the evidence base for its use in the management of chronic pain poses several issues that might account for the variability in therapeutic response. Large, confirmatory trials with consistent stimulatory paradigms are indispensable for asserting findings from previous smaller studies. In addition, factors such as disparate outcome measures, imputation strategies for missing data and selection of patients with individual complexities of pain conditions and symptom severity may account for the modest or lack of difference in negative trials. It is essential to understand the relationship between trial design and trial outcome. Pooling of small trials of NIBS in chronic pain research provide encouraging results; however,
future science group
Evidence-based medicine in the management of chronic pain using noninvasive brain stimulation until enough clinical trials provide a robust framework of evidence, findings will remain largely inconclusive. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a
References 1
2
3
4
5
Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence based medicine: what it is and what it isn’t. BMJ 312, 71–72 (1996). Young KD, Lewis RJ. Medical literature and evidence-based medicine. In: Rosen’s Emergency Medicine: Concepts and Clinical Practice (7th Edition). Marx JA, Hockberger RS, Wall RM (Eds). Mosby Elsevier, Philadelphia, PA, USA, 2507–2520 (2010). Miyasaki JM. Using evidence-based medicine in neurology. Neurol. Clin. 28, 489–503 (2010). Beydoun A, Shaibani A, Hopwood M, Wan Y. Oxcarbazepine in painful diabetic neuropathy: results of a dose-ranging study. Acta Neurol. Scand. 113, 395–404 (2006). Dworkin RH, Turk DC, Katz NP et al. Evidence-based clinical trial design for chronic pain pharmacotherapy: a blueprint
future science group
financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. for ACTION. Pain 152(Suppl. 3), S107–S115 (2011).
6
7
EDITORIAL
Skljarevski V, Ossanna M, Liu-Seifert H et al. A double-blind, randomized trial of duloxetine versus placebo in the management of chronic low back pain. Eur. J. Neurol. 16, 1041–1048 (2009). Lefaucheur JP, Drouot X, Keravel Y, Nguyen JP. Pain relief induced by repetitive transcranial magnetic stimulation of precentral cortex. Neuroreport 12(13), 2963–2965 (2001).
8
Sampson SM, Rome JD, Rummans TA. Slow-frequency rTMS reduces fibromyalgia pain. Pain Med. 7, 115–118 (2006).
9
Brighina F, Piazza A, Vitello G et al. rTMS of the prefrontal cortex in the treatment of chronic migraine: a pilot study. J. Neurol. Sci. 227, 67–71 (2004).
10 Johnson SSJ, Pridmore S. Changes to
somatosensory detection and pain thresholds following high frequency repetitive TMS of
the motor cortex in individuals suffering from chronic pain. Pain 123, 187–192 (2006). 11 Fregni F, DaSilva D, Potvin K et al. Treatment
of chronic visceral pain with brain stimulation. Ann. Neurol. 58, 971–972 (2005). 12 O’Connell NE, Wand BM, Marston L,
Spencer S, Desouza LH. Non-invasive brain stimulation techniques for chronic pain. Cochrane Database Syst. Rev. CD008208 (2010). 13 Janicak PG, O’Reardon JP, Sampson SM
et al. Transcranial magnetic stimulation in the treatment of major depressive disorder: a comprehensive summary of safety experience from acute exposure, extended exposure, and during reintroduction treatment. J. Clin. Psychiatry 69, 222–232 (2008). 14 Haupts MR, Daum S, Ahle G, Holinka B,
Gehlen W. Transcranial magnetic stimulation as a provocation for epileptic seizures in multiple sclerosis. Mult. Scler. 10, 475–476 (2004).
www.futuremedicine.com
533
