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peripheral neuromodulation part 1 pain news march 2019 (1)

  • Interventional Pain Managament and Neuromodulation Practice
June 2019 Vol 17 No 2 l Pain News 97
Pain News
2019, Vol 17(2) 97 –100
© The British Pain Society 2019
Informing practice
This is part 2 of a 3-part article on the history, current
practice and future directions of peripheral neuromodulation.
In part 1, we previously covered the theory of peripheral
nerve stimulation.
In part 2, we present the role of peripheral modulation for
specific clinical indications.
Stimulation of nerve plexuses
Brachial plexus stimulation
Neuropathic pain in the upper limb is often difficult to treat
effectively.1 The upper limb is a very good target for
neuromodulation. The peripheral stimulation of the brachial
plexus is not only simpler but also seems to be more effective
compared to SCS, dorsal root ganglion (DRG) stimulation
and deep brain stimulation (DBS).
The first patient who underwent peripheral stimulation of
the brachial plexus had extremely severe neuropathic pain
(10/10) caused by brachial plexus injury; the pain co-occurred
with arm paralysis on the affected side. A preliminary, direct
stimulation of the brachial plexus with low-frequency electric
current (2 Hz) for 5 minutes relieved the pain by 95% for
7 hours.2 Subsequently, the stimulation electrode was inserted
percutaneously into the brachial plexus from posterior access.
Using the electrode in that site, stimulation with electric
current at a frequency from 2 to 10 Hz reduced the pain by
95%, which was similar to the effect of the preliminary
stimulation. Notably, after the treatment with the percutaneous
electrode, allodynia resolved within several hours after the
procedure, and a normal sense of touch returned within
several weeks. The arm function continued to improve slowly
over the next 3 months.2 Currently, insertion of stimulation
electrodes via the medial supraclavicular access under the
guidance of stimulation, ultrasonography or fluoroscopy is the
method of choice.3 This method is effective and much easier
than insertion from the posterior approach. An interesting
variant of the medial approach, which involves ultrasound
guidance, was proposed by Bouche from Nantes, who
successfully gives this treatment to patients who have not
responded to SCS.4 To date, this brachial plexus stimulation
(BPS) has been described in about 50 patients. Preliminary or
trial stimulation, for up to 2–3 weeks, can be performed in
most settings. This stimulation can be achieved with simple,
inexpensive catheters that are typically used for continuous
peripheral anaesthesia. Using brachial plexus
neuromodulation, together with a continuous block to treat
patients with upper limb ischaemia, may be a viable
therapeutic option.5 BPS may be considered as an attractive
alternative method of nerve stimulation in patients with pain of
the upper limb. However, trials to compare the effects of BPS
with those of standard treatment are required.
The following images are of BPS and majority of implants
are for severe neuropathic pain and/or CRPS (Figures 1–3).
Stimulation of the lumbar plexus/paravertebral
Stimulation of the lumbar plexus can be beneficial in patients
with intractable pain in the hip and knee joints.
It is relatively simple to insert an electrode percutaneously
into the lumbar plexus from paravertebral access at the L4 level
Peripheral neuromodulation: part 2:
somatosensory, head and facial pain
Teodor Goroszeniuk Interventional Pain Management and Neuromodulation Practice, London, UK
Andrzej Król Department of Anaesthesia and Chronic Pain Service, St George’s University Hospitals NHS Foundation Trust,
London, UK
844951PAN Peripheral Neuromodulation: part 2: somatosensory, head and facial painPeripheral Neuromodulation: part 2: somatosensory, head and facial pain
A doctor demonstrating electrotherapy on a young
woman (from the Wellcome Collection L0012521).
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98 Pain News l June 2019 Vol 17 No 2
Peripheral neuromodulation: part 2: somatosensory, head and facial pain
Informing practice
with continuous diagnostic stimulation (2 Hz) and direct
fluoroscopy or ultrasound guidance. In a small study among
patients with knee pain, stimulation of the lumbar plexus
relieved pain in three quarters of patients, and, in two patients,
pain relief was achieved despite unsuccessful spinal cord
Paravertebral stimulation at the level of the chest can be a
promising alternative to SCS or DRG stimulation for patients
with unilateral chest pain. Paravertebral stimulation offers good
electrode stability and substantial pain relief. The paravertebral
stimulation is based on the same principle as the standard
techniques of paravertebral anaesthesia.7
Nerve stimulation for headache and facial pain
Of the 15 occipital neuralgia patients of Weiner and Reed,8
eight in fact actually suffered from chronic migraine for which it
also proved successful. It is suggested that occipital nerve
stimulation (ONS) is effective in chronic migraine because the
signals from the trigeminal nerve, dura mater and cervical spinal
nerves converge in the brainstem.9
The activation of the afferent fibres from the caudal portion of
the trigeminal nucleus, at the C2 level, can cause pain in the
trigeminal and cervical distributions. Thus, it is hypothesised
that electrical stimulation modulating the function of occipital
nerves can affect the mechanisms of pain in the areas
innervated by the cervical nerves and the trigeminal nerve.9
The great occipital nerve is a branch of the C2 spinal nerve,
and it is an easy target for stimulation-based treatments. In
patients with chronic migraine who underwent ONS, position
emission tomography (PET) showed increased blood flow in the
areas assumed to mediate pain relief, that is, the posterior
pons, anterior cingulate cortex and cuneus.10
Further series of case reports on the promising effects of
ONS in patients with chronic headaches and migraine
prompted large controlled trials assessing the effectiveness of
this treatment.10–13
A total of 66 patients with drug-resistant migraine were
enrolled in the ONSTIM study assessing the effects of bilateral
ONS. The patients were randomly allocated to receive one of
the three following treatments: variable ONS, fixed ONS and
medical treatment.11 Among the patients who received ONS,
39% responded to the variable ONS, and 6% of patients, to
Figure 2. Brachial plexus stimulation (TG copyright, with
Figure 3. Brachial plexus stimulation (TG copyright, with
Figure 1. Brachial plexus neurostimulation trial, mono-
lead. Majority of patients have implants for severe
neuropathic pain and/or CRPS. (TG copyright, with
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Peripheral neuromodulation: part 2: somatosensory, head and facial pain
Informing practice
fixed ONS. Patients who received medications did not
There may be a large placebo response as indicated in the
PRISM study, when 132 patients were randomly allocated to
undergo either nerve stimulation or sham stimulation.12 The
stimulation was given to patients for 12 weeks. The mean
reduction in the number of days with migraine was 27% in the
patients who received active stimulation, compared to 20% in
those who underwent the sham stimulation, which was not
In another study, 157 patients with refractory migraine were
randomly allocated to receive either active stimulation or sham
stimulation.13 The results showed there was a significant
difference between the groups that received either active or
sham stimulation in achieving at least a 30% (but not 50%)
reduction of headaches. This difference translated into a
reduction in the number of days with headache by 3 days
during a month and a decrease in the Migraine Disability
Assessment Scale (MIDAS) scores by 44 points.
Cluster headache – ONS
Because the hypothalamus is known to be active during cluster
headaches, it was the target of the first neuromodulation
attempts to treat patients with cluster headaches who did not
respond to medications.14 However, the hypothalamus
stimulation led to complications, and new targets for nerve
stimulation in patients with cluster headaches were tested.15,16
In patients with cluster headaches, PET showed an increased
metabolism in the hypothalamus, pons and midbrain. This
increased metabolism could be reversed by the stimulation of
the occipital nerve.17–21 A randomised, controlled trial comparing
low-frequency and high-frequency paraesthesia is ongoing.22
Cluster headache – stimulation of the
sphenopalatine ganglion
Stimulation of the sphenopalatine ganglion (SPG) is another
neuromodulation target for cluster headache. The SPG lies in
the pterygopalatine fossa, and the post-ganglionic
parasympathetic and sensory fibres originating from the
ganglion run along the blood vessels supplying the face, dura
mater and brain. Initially, blockade and radiofrequency ablation
of the SPG was used to treat patients with cluster headache
who did not improve with standard treatment.23,24 The SPG
was chosen as the target for neuromodulation because, in
animal studies, the electrical stimulation of this ganglion
reversed hypoxia and increased blood flow in the relevant
area.25 A study among 28 patients with chronic cluster
headache resistant to standard treatment tested the effects of
a neurostimulator that was implanted through the mouth, with
the tip of the electrode placed in the pterygopalatine fossa.26
This device was controlled externally via a radiofrequency
transmitter. The treatment with the SPG stimulator alleviated
cluster headaches in 67.1% of patients, and it reduced the
frequency of cluster headaches in 36% of all patients.26 This
improvement in cluster headache symptoms suggests that
stimulation of the SPG is effective during acute episodes of
cluster headache and can be also used in the prophylaxis of
these headaches. Temporary sensory disturbances in the face
were the most common adverse effects of the SPG
Facial pain
Nerve stimulation, in the treatment of patients with facial pain,
involves the stimulation of nerves located in the pain centres
and pathways transmitting pain signals such as the trigeminal
ganglion and its branches.27–29 Clinical indications include
trigeminal neuralgia, post-stroke pain, peripheral nerve injury,
and post-herpetic neuralgia. Interestingly, in a case series, Taub
etal.30 observed that stimulation of the trigeminal ganglion
successfully relieved pain in five of seven patients after stroke,
but it did not improve post-herpetic neuralgia in any patient.
Transcutaneous supraorbital nerve stimulation (tSNS) is
promising, and it may prove to be an effective treatment for
patients with migraine.12,31,32
The authors would like to acknowledge that this work is based on
their previous publication Goroszeniuk T and Król A. Peripheral
neuromodulation: An update. Ból 2017: 18(1): 15–27 (The official
journal of Polish Pain Society). T.G. is a developer of ExStim.
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19. Burns B, Watkins L, and Goadsby PJ. Treatment of medically intractable cluster
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Full-text available
Endogenous electric field is known to play important roles in the wound-healing process, mainly through its effects on protein synthesis and cell migration. Many clinical studies have demonstrated that electrical stimulation (ES) with steady direct currents is beneficial to accelerating wound-healing, even though the underlying mechanisms remain unclear. In the present study, a three-dimensional finite element wound model was built to optimize the electrode configuration in ES. Four layers of the skin, stratum corneum, epidermis, dermis, and subcutis, with defined thickness and electrical properties were modeled. The main goal was to evaluate the distributions of exogenous electric fields delivered with direct current (DC) stimulation using different electrode configurations such as sizes and positions. Based on the results, some guidelines were obtained in designing the electrode configuration for applications of clinical ES.
Full-text available
Headaches are one of the most common pain syndromes experienced by adult patients. International Classification of Headache Disorders identifies about 300 different entities. Primary headaches (migraine, tension-type headache, trigeminal autonomic cephalalgias, other primary headaches) has the common occurrence. Although effective treatment of these disorders is possible, it is inefficient or poorly tolerated in some patients. Neuromodulation methods, being element of multimodal treatment, provide an additional treatment option in pharmacotherapy-refractory patients. Both invasive and non-invasive stimulation methods are used. The non-invasive techniques is transcutaneous nerve stimulation using Cefaly® device. In this study, Cefaly® was used as prevention treatment in patients with pharmacotherapy-refractory headaches. This device is indicated for the prophylactic treatment of episodic primary headaches. A total of 91-patients (30 without and 61 with tSNS) were enrolled in the study, including 60-patients with migraine and 31-patients with other primary headaches. Ten courses of non-invasive peripheral (supraorbitral/supratrochlear) nerves stimulation were delivered to 57-patients; in the remaining 4 patients, the treatment was abandoned due to poor tolerance. Patients were observed for 30 days after stimulation treatment. Compared to the pre-treatment period, the reduction in the intensity of pain was observed in both the migraine group and patients with other types of headaches; this included the number of pain episodes being reduced by half, with simultaneous reduction in average pain intensity and duration of individual pain episodes. The subjective assessment of pain reduction was in the range of 40–47%. Based on our data we recommend tSNS as useful tool in the prophylaxis of primary headaches, including migraine.
Full-text available
Efferent activation of the cervical vagus nerve (cVN) dampens systemic inflammatory processes, potentially modulating a wide-range of inflammatory pathological conditions. In contrast, afferent cVN activation amplifies systemic inflammatory processes, leading to activation of the hypothalamic-pituitary-adrenal (HPA) axis, the sympathetic nervous system through the greater splanchnic nerve (GSN), and elevation of pro-inflammatory cytokines. Ideally, to clinically implement anti-inflammatory therapy via cervical vagus nerve stimulation (cVNS) one should selectively activate the efferent pathway. Unfortunately, current implementations, in animal and clinical investigations, activate both afferent and efferent pathways. We paired cVNS with kilohertz electrical stimulation (KES) nerve block to preferentially activate efferent pathways while blocking afferent pathways. Selective efferent cVNS enhanced the anti-inflammatory effects of cVNS. Our results demonstrate that: (i) afferent, but not efferent, cVNS synchronously activates the GSN in a dose-dependent manner; (ii) efferent cVNS enabled by complete afferent KES nerve block enhances the anti-inflammatory benefits of cVNS; and (iii) incomplete afferent KES nerve block exacerbates systemic inflammation. Overall, these data demonstrate the utility of paired efferent cVNS and afferent KES nerve block for achieving selective efferent cVNS, specifically as it relates to neuromodulation of systemic inflammation.
Full-text available
Chronic primary headaches are widespread disorders which cause significant quality of life and socioprofessional impairment. Available pharmacological treatments have often a limited efficacy and/or can generate unbearable side effects. Electrical nerve stimulation is a well-known non-destructive method of pain modulation which has been recently applied to headache management. In this review, we summarise recent advances in invasive and non-invasive neurostimulation techniques targeting pericranial structures for the treatment of chronic primary headaches, chiefly migraine and cluster headache: occipital nerve, supraorbital nerve, vagus nerve, and sphenopalatine ganglion stimulations. Invasive neurostimulation therapies have offered a new hope to drug-refractory headache sufferers but are not riskless and should be proposed only to chronic patients who failed to respond to most existing preventives. Non-invasive neurostimulation devices are user-friendly, safe and well tolerated and are thus taking an increasing place in the multidisciplinary therapeutical armamentarium of primary headaches.
Full-text available
Peripheral nerve stimulation (PNS) for the treatment of chronic pain has become an increasingly important field in the arena of neuromodulation, given the ongoing advances in electrical neuromodulation technology since 1999 permitting minimally invasive approaches using an percutaneous approach as opposed to implantable systems. Our review aims to provide clinicians with the recent advances and studies in the field, with specific emphasis on clinical data and indications that have been accumulated over the last several years. In addition, we aim to address key basic science studies to further emphasize the importance of translational research outcomes driving clinical management.
Full-text available
Significance Rheumatoid arthritis (RA) is a chronic, prevalent, and disabling autoimmune disease that occurs when inflammation damages joints. Recent advances in neuroscience and immunology have mapped neural circuits that regulate the onset and resolution of inflammation. In one circuit, termed “the inflammatory reflex,” action potentials transmitted in the vagus nerve inhibit the production of tumor necrosis factor (TNF), an inflammatory molecule that is a major therapeutic target in RA. Although studied in animal models of arthritis and other inflammatory diseases, whether electrical stimulation of the vagus nerve can inhibit TNF production in humans has remained unknown. The positive mechanistic results reported here extend the preclinical data to the clinic and reveal that vagus nerve stimulation inhibits TNF and attenuates disease severity in RA patients.
Objectives: We report the outcome of a consecutive series of 26 patients suffering from chronic medically-refractory neuropathic pain of the upper limb (including 16 patients with complex regional pain syndrome), topographically limited, treated by brachial plexus (BP) nerve roots or supra-scapular nerve (SSN) peripheral nerve stimulation (PNS). Materials and methods: The technique consisted in ultrasound-guided percutaneous implantation of a cylindrical lead (Pisces-Quad, Medtronic) close to the SSN or the cervical nerve roots within the BP, depending on the pain topography. All the patients underwent a positive trial stimulation before lead connection to a subcutaneous stimulator. Chronic bipolar stimulation mean parameters were: frequency 55.5 Hertz, voltage 1.17 Volts. The voltage was set below the threshold inducing muscle contractions or paresthesias. Results: Two patients were lost immediately after surgery. At last follow-up (mean 27.5 months), the 20 patients still using the stimulation experienced a mean pain relief of 67.1%. Seventeen patients were improved ≥50%, including 12 improved ≥70%. In 11 patients with a follow-up >2 years, the mean pain relief was 68%. At last follow-up, respectively, six out of the nine (67%) patients treated by SSN stimulation and 10 out of 17 patients (59%) treated by BP stimulation were improved ≥50%. At last follow-up, 12 out of 20 patients still using the stimulation were very satisfied, six were satisfied, and two were poorly satisfied. Complications were: stimulation intolerance due to shock-like sensations (three cases), superficial infection (1), lead fractures (2), and migration (1). Conclusion: In this pilot study, SSN or BP roots PNS provided a relatively safe, durable and effective option to control upper limb neuropathic pain.
Introduction: Currently available central nervous system treatment strategies are often insufficient in management of peripheral neuropathic pain, prompting a resurgence of neuromodulation focused on peripheral pain. A new peripheral nerve stimulation device was investigated in a prospective, randomized, double blind, crossover study, looking specifically at efficacy and safety, with Food and Drug Administration oversight. Methods: Prospective, multicenter, randomized, double-blind, partial crossover study to assess safety and efficacy. After IRB approval, patients were enrolled, implanted, and then followed for three months to assess efficacy and one year for safety based on Food and Drug Administration guidance. Results: One hundred forty-seven patients were consented and screened for the study. Thirty-five did not meet inclusion or exclusion criteria. Ninety-four patients were implanted and then randomized to the treatment (45) or the Control group (49). The primary efficacy endpoint, three months after randomization to treatment, demonstrated that patients receiving active stimulation achieved a statistically significantly higher response rate of 38% vs. the 10% rate found in the Control group (p = 0.0048). Improvement in pain was statistically significant between the randomized groups, with the Treatment group achieving a mean pain reduction of 27.2% from Baseline to Month 3 compared to a 2.3% reduction in the Control group (p < 0.0001). During the partial crossover period, patients again demonstrated statistically significant improvement in pain relief with active stimulation compared to baseline. Further, the Treatment group had significantly better improvement than the Control group in secondary measures including but not limited to quality of life and satisfaction. Safety, assessed throughout the trial and with follow-up to one year, demonstrated no serious adverse events related to the device. All device-related adverse events were minor and self-limiting. Conclusion: The novel peripheral nerve stimulation device is a safe and effective treatment strategy to address neuropathic pain of peripheral nerve origin.