EDITORIAL For reprint orders, please contact: [email protected]
Potential for transcutaneous vagus nerve stimulation in pain management “Combining a noninvasive character along with the potential lack of peripheral side effects, t‑VNS may open a new window for managing pain.”
Peter Eichhammer† Currently available therapeutic interven‑ tions for chronic pain disorders are less than ideal. For this reason, new interven‑ tion strategies complementing existing therapeutical approaches are urgently needed. In this context, neurostimulation methods may represent potential success‑ ful tools for managing clinical pain syn‑ dromes. Besides transcranial magnetic stimulation, vagus nerve stimulation (VNS) may open a window for a new pain‑relieving treatment method. Interestingly, the anatomy and physio logy of the vagus nerve (X cranial) is com‑ plex and until recently not well character‑ ized. The vagus nerve was traditionally considered as a purely parasympathetic efferent nerve. However, recent work dem‑ onstrates that approximately 80% of the nerve fibers in the cervical nerve are affer‑ ent fibers [1] . These afferent sensory fibers project via the nucleus tractus solitarius to a variety of distinct brain areas, thereby rep‑ resenting an avenue for providing informa‑ tion into the CNS [2] . In detail, the nucleus tractus solitarius relays information to the parabrachial nucleus, the cerebellum, the periaqueductal gray and via ascending secondary projections to limbic areas such
as the amygdalae as well as to paralimbic and cortical regions. This anatomically grounded bottom-up way of stimulation led to the successful introduction of VNS as a neurostimulation modality affecting the limbic system and thereby associated neuropsychiatric diseases such as epilepsy and treatment-resistant depression. Based on this potential to reach brain areas such as the periaqueductal gray, thalamic nuclei or limbic areas, which are closely involved in pain processing, it was hypothesized that VNS may bear antinoci‑ ceptive qualities [3] . In fact, neuroimaging studies using SPECT, PET and functional MRI techniques provided additional evi‑ dence that VNS changes cerebral activity in pain-processing cortical and subcorti‑ cal regions like the dorsal-rostral medulla, bilateral thalamus, right postcentral gyrus or the anterior cingulate cortex [4] . For this reason, most arguments favor a potential central mode of VNS antinociception, complemented by peripheral mechanisms such as a modulation of primary afferent nociceptors [5] . In this context, animal studies have demonstrated an inhibitory effect of VNS on the electric response of spinal
“Currently available therapeutic
interventions for chronic pain disorders are less than ideal. For this reason, new intervention strategies complementing existing therapeutical approaches are urgently needed.”
University of Regensburg, Department of Psychiatry, Universitaetsstrasse 84, 93053 Regensburg, Germany; [email protected] †
10.2217/PMT.11.27 © 2011 Future Medicine Ltd
Pain Manage. (2011) 1(4), 287–289
ISSN 1758-1869
287
Editorial Eichhammer
“…t‑VNS may affect cortical and subcortical brain areas closely linked to pain processing. Therefore, this neurostimulation modality may hold the potential to efficiently change pain processing and perception in humans.”
“For the first time, confounding factors linked to conventional VNS with its restriction to patients suffering from epilepsy or treatmentresistant depression can be reduced.”
288
nociceptive neurons paralleled by a decrease in nociceptive behavior [6] . Bohotin and col‑ leagues investigated the effect of vagal stimula‑ tion on nociception in rats with a device used in the human therapy of patients suffering from epilepsy and found a reduction of nociceptive behavior along with a reduction of Fos-activated neurons in the ipsilateral trigeminal nucleus cau‑ dalis following verum, but not following sham VNS [7] . Moreover, an antinociceptive effect of VNS was observed in several preclinical studies demonstrating an inhibition of the nociceptive digastric reflex following tooth-pulp stimulation in cats or showing an increase of the tail-flick latencies following intense radiant heat in rats [8] . These animal data are confirmed by human research also suggesting a pain modulating effect of vagal stimulation. Focusing on headache syn‑ dromes, several case studies report a reduction of headache frequency or intensity following VNS in patients with seizures, who concurrently suf‑ fered from migraine [9] . An observational report on four therapy-refractory migraine and two cluster headache patients showed significant pain relief due to VNS in four out of six patients [10] . Moreover, Kirchner and colleagues investigated experimental pain perception in ten patients with seizures before and after the implantation of a VNS stimulator and found an increase of tonic pressure thresholds as well as a reduction of increasing pain associated with trains of con‑ secutive stimuli (wind-up). Based on these find‑ ings, the authors postulated an effect of VNS predominantly on central pain processing [11] . However, as a strong limitation, human work investigating pain perception was entirely restricted to epilepsy patients, frequently under a concurrent anticonvulsive medication. Previous studies could show that pain thresholds of patients with (temporal lobe) epilepsy differ significantly from those of healthy subjects. Moreover, anti‑ convulsant drugs are able to increase pain thresh‑ olds. Since both epilepsy and drug treatment deci‑ sively modulate pain perception, it is difficult to generalize these VNS effects on pain processing. Additionally, in all human studies an invasive device was used for vagal stimulation, requiring a surgical intervention for implanting the stim‑ ulator unit in the chest and to wrap the nervestimulating electrodes around the left cervical vagus nerve. This procedure is associated with a number of side effects including the risk of vagus nerve injuries. Preclinical work demonstrated that the integrity of vagal afferents is fundamental for
Pain Manage. (2011) 1(4)
drug-induced analgesic effects [6] . Therefore, a lesion of cervical vagus nerve branches due to sur‑ gical procedures may have influences on proper nociceptive sensing. By contrast, the transcutaneous VNS (t‑VNS) originally proposed by Ventureyra [12] enables a noninvasive stimulation of afferent vagus nerve fibers in the external auditory canal. The stimula‑ tion area at the inner side of the tragus was shown to be supplied by the auricular branch of the vagus nerve. Interestingly, clear vagus sensory evoked potentials could be recorded using a transcutane‑ ous stimulation in the outer acoustic meatus [13] . Moreover, based on this stimulation technique, functional MRI studies could demonstrate that t‑VNS is able to induce robust blood oxygen level-dependent signal decreases in limbic brain areas including the amygdala, the hippocampus or the superior temporal gyrus accompanied by increased activation in the insula or thalamus [14] . This activation pattern based on t‑VNS shows considerable similarity to findings in former VNS studies. Based on these data, t‑VNS may affect cortical and subcortical brain areas closely linked to pain processing. Therefore, this neu‑ rostimulation modality may hold the potential to efficiently change pain processing and per‑ ception in humans. Since t‑VNS does not imply surgery and seems to be associated with modest side effects, studies on pain perception in healthy humans or patients suffering from pain disorders may be feasible. For the first time, confounding factors linked to conventional VNS with its restriction to patients suffering from epilepsy or treatment-resistant depression can be reduced. Effective modulation of limbic areas representing part of the so-called medial pain network sug‑ gests t‑VNS for treating patients especially with chronic pain syndromes. However, up to now, randomized and controlled trials investigating pain-relieving effects of t‑VNS in healthy subjects or patients with chronic pain have not been car‑ ried out. In analogy to research on conventional VNS therapy in resistant depression, upcoming t‑VNS studies focusing on pain processing have to address the following questions: What are the stimulation parameters of t‑VNS for changing pain perception in humans? Are VNS stimula‑ tion parameters that are optimal for the treat‑ ment of epilepsy or depression also optimal for t‑VNS-based pain treatment? How long should patients be treated with t‑VNS to efficiently alter pain processing? Is there a dose–response effect with regard to pain perception? Is it possible
future science group
Potential for transcutaneous vagus nerve stimulation in pain management to produce antinociceptive effects beyond the immediate t‑VNS stimulation period as has been shown in animals under VNS stimulation? Can predictors of response to t‑VNS therapy in patients with pain be identified by functional imaging or genetic studies? To what extent does t‑VNS therapy augment the behavioral and neu‑ robiological effects of currently available antino‑ ciceptive agents? Would modifications in stimu‑ lation parameters target different brain areas, thereby explaining response or nonresponse due to t‑VNS? To reduce complexity and the influence of confounding factors, first, studies in healthy humans should be conducted. Based on similar modes of action, t‑VNS studies have the advan‑ tage to learn from previous invasive VNS studies, also reducing well-known pitfalls associated with this stimulation technique. In conclusion, t‑VNS may hold the potential to be a valuable addition to existing treatments for patients with chronic pain disorders. As has been shown recently, t‑VNS may affect identi‑ cal brain areas as compared with invasive VNS,
2
3
4
5
Nemeroff CB, Mayberg HS, Krahl SE et al. VNS therapy in treatment-resistant depression: clinical evidence and putative neurobiological mechanisms. Neuropsychopharmacology 31, 1345–1355 (2006). George MS, Nahas Z, Bohning DE et al. Vagus nerve stimulation: a new form of therapeutic brain stimulation. CNS Spectr. 5(11), 43–52 (2000). Berthoud HR, Neuhuber WL. Functional and chemical anatomy of the afferent vagal system. Auton. Neurosci. 85, 1–17 (2000). Chae JH, Nahas Z, Lomarev M et al. A review of functional neuroimaging studies of vagus nerve stimulation. J. Psychiatr. Res. 37, 443–455 (2003). Thán M, Németh J, Szilvássy Z, Pintér E, Helyes Z, Szolcsányi J. Systemic antiinflammatory effect of somatostatin
future science group
Financial & competing interests disclosure
6
Randich A, Gebhart GF. Vagal afferent modulation of nociception. Brain Res. Brain Res. Rev. 17(2), 77–99 (1992).
7
Bohotin C, Scholsem M, Multon S, Martin D, Bohotin V, Schoenen J. Vagus nerve stimulation in awake rats reduces formalin-induced nociceptive behaviour and fos-immunoreactivity in trigeminal nucleus caudalis. Pain 101(1–2), 3–12 ( 2003).
8
9
“…t‑VNS may hold the potential to be a valuable addition to existing treatments for patients with chronic pain disorders.”
The author has no relevant affiliations or financial involvement with any organization or entity with a 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. released from capsaicin-sensitive vagal and sciatic sensory fibres of the rat and guinea-pig. Eur. J. Pharmacol. 399(2–3), 251–258 (2000).
Bibliography 1
thereby suggesting that t‑VNS may bear anti‑ nociceptive qualities, already proven in animal research and suggested by human studies in epi‑ lepsy patients. Combining a noninvasive char‑ acter along with the potential lack of peripheral side effects, t‑VNS may open a new window for managing pain. However, in analogy to VNS research on treatment-resistant depression, a lot of work has to be done to test and really confirm the antinoceptive potential of t‑VNS in humans. Nevertheless, based on aforementioned studies, t‑VNS seems to be a promising candidate in future pain management strategies.
Editorial
Ren K, Randich A, Gebhart GF. Vagal afferent modulation of a nociceptive reflex in rats: involvement of spinal opioid and monoamine receptors. Brain. Res. 446(2), 285–294 (1988). Sadler RM, Purdy RA, Rahey S. Vagal nerve stimulation aborts migraine in patient with intractable epilepsy. Cephalalgia 22(6), 482–484 (2002).
10
Mauskop A. Vagus nerve stimulation relieves chronic refractory migraine and cluster headaches. Cephalalgia 25(2), 82–86 (2005).
11
Kirchner A, Birklein F, Stefan H, Handwerker HO. Left vagus nerve stimulation suppresses experimentally induced pain. Neurology 55(8), 1167–1171 (2000).
12 Ventureyra EC. Transcutaneous vagus nerve
stimulation for partial onset seizure therapy. A new concept. Childs. Nerv. Syst. 16(2), 101–102 (2000). 13 Fallgatter AJ, Neuhauser B, Herrmann MJ
et al. Far field potentials from the brain stem after transcutaneous vagus nerve stimulation. J. Neural. Transm. 110(12), 1437–1443 (2003). 14
Kraus T, Hösl K, Kiess O, Schanze A, Kornhuber J, Forster C. BOLD fMRI deactivation of limbic and temporal brain structures and mood enhancing effect by transcutaneous vagus nerve stimulation. J. Neural. Transm. 114(11), 1485–1493 (2007).
www.futuremedicine.com
289
Potential for transcutaneous vagus nerve stimulation in pain management “Combining a noninvasive character along with the potential lack of peripheral side effects, t‑VNS may open a new window for managing pain.”
Peter Eichhammer† Currently available therapeutic interven‑ tions for chronic pain disorders are less than ideal. For this reason, new interven‑ tion strategies complementing existing therapeutical approaches are urgently needed. In this context, neurostimulation methods may represent potential success‑ ful tools for managing clinical pain syn‑ dromes. Besides transcranial magnetic stimulation, vagus nerve stimulation (VNS) may open a window for a new pain‑relieving treatment method. Interestingly, the anatomy and physio logy of the vagus nerve (X cranial) is com‑ plex and until recently not well character‑ ized. The vagus nerve was traditionally considered as a purely parasympathetic efferent nerve. However, recent work dem‑ onstrates that approximately 80% of the nerve fibers in the cervical nerve are affer‑ ent fibers [1] . These afferent sensory fibers project via the nucleus tractus solitarius to a variety of distinct brain areas, thereby rep‑ resenting an avenue for providing informa‑ tion into the CNS [2] . In detail, the nucleus tractus solitarius relays information to the parabrachial nucleus, the cerebellum, the periaqueductal gray and via ascending secondary projections to limbic areas such
as the amygdalae as well as to paralimbic and cortical regions. This anatomically grounded bottom-up way of stimulation led to the successful introduction of VNS as a neurostimulation modality affecting the limbic system and thereby associated neuropsychiatric diseases such as epilepsy and treatment-resistant depression. Based on this potential to reach brain areas such as the periaqueductal gray, thalamic nuclei or limbic areas, which are closely involved in pain processing, it was hypothesized that VNS may bear antinoci‑ ceptive qualities [3] . In fact, neuroimaging studies using SPECT, PET and functional MRI techniques provided additional evi‑ dence that VNS changes cerebral activity in pain-processing cortical and subcorti‑ cal regions like the dorsal-rostral medulla, bilateral thalamus, right postcentral gyrus or the anterior cingulate cortex [4] . For this reason, most arguments favor a potential central mode of VNS antinociception, complemented by peripheral mechanisms such as a modulation of primary afferent nociceptors [5] . In this context, animal studies have demonstrated an inhibitory effect of VNS on the electric response of spinal
“Currently available therapeutic
interventions for chronic pain disorders are less than ideal. For this reason, new intervention strategies complementing existing therapeutical approaches are urgently needed.”
University of Regensburg, Department of Psychiatry, Universitaetsstrasse 84, 93053 Regensburg, Germany; [email protected] †
10.2217/PMT.11.27 © 2011 Future Medicine Ltd
Pain Manage. (2011) 1(4), 287–289
ISSN 1758-1869
287
Editorial Eichhammer
“…t‑VNS may affect cortical and subcortical brain areas closely linked to pain processing. Therefore, this neurostimulation modality may hold the potential to efficiently change pain processing and perception in humans.”
“For the first time, confounding factors linked to conventional VNS with its restriction to patients suffering from epilepsy or treatmentresistant depression can be reduced.”
288
nociceptive neurons paralleled by a decrease in nociceptive behavior [6] . Bohotin and col‑ leagues investigated the effect of vagal stimula‑ tion on nociception in rats with a device used in the human therapy of patients suffering from epilepsy and found a reduction of nociceptive behavior along with a reduction of Fos-activated neurons in the ipsilateral trigeminal nucleus cau‑ dalis following verum, but not following sham VNS [7] . Moreover, an antinociceptive effect of VNS was observed in several preclinical studies demonstrating an inhibition of the nociceptive digastric reflex following tooth-pulp stimulation in cats or showing an increase of the tail-flick latencies following intense radiant heat in rats [8] . These animal data are confirmed by human research also suggesting a pain modulating effect of vagal stimulation. Focusing on headache syn‑ dromes, several case studies report a reduction of headache frequency or intensity following VNS in patients with seizures, who concurrently suf‑ fered from migraine [9] . An observational report on four therapy-refractory migraine and two cluster headache patients showed significant pain relief due to VNS in four out of six patients [10] . Moreover, Kirchner and colleagues investigated experimental pain perception in ten patients with seizures before and after the implantation of a VNS stimulator and found an increase of tonic pressure thresholds as well as a reduction of increasing pain associated with trains of con‑ secutive stimuli (wind-up). Based on these find‑ ings, the authors postulated an effect of VNS predominantly on central pain processing [11] . However, as a strong limitation, human work investigating pain perception was entirely restricted to epilepsy patients, frequently under a concurrent anticonvulsive medication. Previous studies could show that pain thresholds of patients with (temporal lobe) epilepsy differ significantly from those of healthy subjects. Moreover, anti‑ convulsant drugs are able to increase pain thresh‑ olds. Since both epilepsy and drug treatment deci‑ sively modulate pain perception, it is difficult to generalize these VNS effects on pain processing. Additionally, in all human studies an invasive device was used for vagal stimulation, requiring a surgical intervention for implanting the stim‑ ulator unit in the chest and to wrap the nervestimulating electrodes around the left cervical vagus nerve. This procedure is associated with a number of side effects including the risk of vagus nerve injuries. Preclinical work demonstrated that the integrity of vagal afferents is fundamental for
Pain Manage. (2011) 1(4)
drug-induced analgesic effects [6] . Therefore, a lesion of cervical vagus nerve branches due to sur‑ gical procedures may have influences on proper nociceptive sensing. By contrast, the transcutaneous VNS (t‑VNS) originally proposed by Ventureyra [12] enables a noninvasive stimulation of afferent vagus nerve fibers in the external auditory canal. The stimula‑ tion area at the inner side of the tragus was shown to be supplied by the auricular branch of the vagus nerve. Interestingly, clear vagus sensory evoked potentials could be recorded using a transcutane‑ ous stimulation in the outer acoustic meatus [13] . Moreover, based on this stimulation technique, functional MRI studies could demonstrate that t‑VNS is able to induce robust blood oxygen level-dependent signal decreases in limbic brain areas including the amygdala, the hippocampus or the superior temporal gyrus accompanied by increased activation in the insula or thalamus [14] . This activation pattern based on t‑VNS shows considerable similarity to findings in former VNS studies. Based on these data, t‑VNS may affect cortical and subcortical brain areas closely linked to pain processing. Therefore, this neu‑ rostimulation modality may hold the potential to efficiently change pain processing and per‑ ception in humans. Since t‑VNS does not imply surgery and seems to be associated with modest side effects, studies on pain perception in healthy humans or patients suffering from pain disorders may be feasible. For the first time, confounding factors linked to conventional VNS with its restriction to patients suffering from epilepsy or treatment-resistant depression can be reduced. Effective modulation of limbic areas representing part of the so-called medial pain network sug‑ gests t‑VNS for treating patients especially with chronic pain syndromes. However, up to now, randomized and controlled trials investigating pain-relieving effects of t‑VNS in healthy subjects or patients with chronic pain have not been car‑ ried out. In analogy to research on conventional VNS therapy in resistant depression, upcoming t‑VNS studies focusing on pain processing have to address the following questions: What are the stimulation parameters of t‑VNS for changing pain perception in humans? Are VNS stimula‑ tion parameters that are optimal for the treat‑ ment of epilepsy or depression also optimal for t‑VNS-based pain treatment? How long should patients be treated with t‑VNS to efficiently alter pain processing? Is there a dose–response effect with regard to pain perception? Is it possible
future science group
Potential for transcutaneous vagus nerve stimulation in pain management to produce antinociceptive effects beyond the immediate t‑VNS stimulation period as has been shown in animals under VNS stimulation? Can predictors of response to t‑VNS therapy in patients with pain be identified by functional imaging or genetic studies? To what extent does t‑VNS therapy augment the behavioral and neu‑ robiological effects of currently available antino‑ ciceptive agents? Would modifications in stimu‑ lation parameters target different brain areas, thereby explaining response or nonresponse due to t‑VNS? To reduce complexity and the influence of confounding factors, first, studies in healthy humans should be conducted. Based on similar modes of action, t‑VNS studies have the advan‑ tage to learn from previous invasive VNS studies, also reducing well-known pitfalls associated with this stimulation technique. In conclusion, t‑VNS may hold the potential to be a valuable addition to existing treatments for patients with chronic pain disorders. As has been shown recently, t‑VNS may affect identi‑ cal brain areas as compared with invasive VNS,
2
3
4
5
Nemeroff CB, Mayberg HS, Krahl SE et al. VNS therapy in treatment-resistant depression: clinical evidence and putative neurobiological mechanisms. Neuropsychopharmacology 31, 1345–1355 (2006). George MS, Nahas Z, Bohning DE et al. Vagus nerve stimulation: a new form of therapeutic brain stimulation. CNS Spectr. 5(11), 43–52 (2000). Berthoud HR, Neuhuber WL. Functional and chemical anatomy of the afferent vagal system. Auton. Neurosci. 85, 1–17 (2000). Chae JH, Nahas Z, Lomarev M et al. A review of functional neuroimaging studies of vagus nerve stimulation. J. Psychiatr. Res. 37, 443–455 (2003). Thán M, Németh J, Szilvássy Z, Pintér E, Helyes Z, Szolcsányi J. Systemic antiinflammatory effect of somatostatin
future science group
Financial & competing interests disclosure
6
Randich A, Gebhart GF. Vagal afferent modulation of nociception. Brain Res. Brain Res. Rev. 17(2), 77–99 (1992).
7
Bohotin C, Scholsem M, Multon S, Martin D, Bohotin V, Schoenen J. Vagus nerve stimulation in awake rats reduces formalin-induced nociceptive behaviour and fos-immunoreactivity in trigeminal nucleus caudalis. Pain 101(1–2), 3–12 ( 2003).
8
9
“…t‑VNS may hold the potential to be a valuable addition to existing treatments for patients with chronic pain disorders.”
The author has no relevant affiliations or financial involvement with any organization or entity with a 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. released from capsaicin-sensitive vagal and sciatic sensory fibres of the rat and guinea-pig. Eur. J. Pharmacol. 399(2–3), 251–258 (2000).
Bibliography 1
thereby suggesting that t‑VNS may bear anti‑ nociceptive qualities, already proven in animal research and suggested by human studies in epi‑ lepsy patients. Combining a noninvasive char‑ acter along with the potential lack of peripheral side effects, t‑VNS may open a new window for managing pain. However, in analogy to VNS research on treatment-resistant depression, a lot of work has to be done to test and really confirm the antinoceptive potential of t‑VNS in humans. Nevertheless, based on aforementioned studies, t‑VNS seems to be a promising candidate in future pain management strategies.
Editorial
Ren K, Randich A, Gebhart GF. Vagal afferent modulation of a nociceptive reflex in rats: involvement of spinal opioid and monoamine receptors. Brain. Res. 446(2), 285–294 (1988). Sadler RM, Purdy RA, Rahey S. Vagal nerve stimulation aborts migraine in patient with intractable epilepsy. Cephalalgia 22(6), 482–484 (2002).
10
Mauskop A. Vagus nerve stimulation relieves chronic refractory migraine and cluster headaches. Cephalalgia 25(2), 82–86 (2005).
11
Kirchner A, Birklein F, Stefan H, Handwerker HO. Left vagus nerve stimulation suppresses experimentally induced pain. Neurology 55(8), 1167–1171 (2000).
12 Ventureyra EC. Transcutaneous vagus nerve
stimulation for partial onset seizure therapy. A new concept. Childs. Nerv. Syst. 16(2), 101–102 (2000). 13 Fallgatter AJ, Neuhauser B, Herrmann MJ
et al. Far field potentials from the brain stem after transcutaneous vagus nerve stimulation. J. Neural. Transm. 110(12), 1437–1443 (2003). 14
Kraus T, Hösl K, Kiess O, Schanze A, Kornhuber J, Forster C. BOLD fMRI deactivation of limbic and temporal brain structures and mood enhancing effect by transcutaneous vagus nerve stimulation. J. Neural. Transm. 114(11), 1485–1493 (2007).
www.futuremedicine.com
289
