Occipital Nerve Stimulation for the Treatment of Patients With Medically Refractory Occipital Neuralgia Update

download pdf Neurosurgery

Sponsored by: Congress of Neurological Surgeons (CNS) and the Section on Pain
Endorsed by: The Congress of Neurological Surgeons (CNS), American Association of Neurological Surgeons (AANS)

Authors:

Michael D. Staudt MD MSc1,2, Salim M. Hayek MD PhD3, Joshua M. Rosenow MD4, Samer Narouze MD PhD5, Jeffrey E. Arle MD PhD6, Julie G. Pilitsis MD PhD7, Jason M. Schwalb MD8, Steven M. Falowski MD9, Jennifer A. Sweet MD10

Departmental and institutional affiliations:

¹Department of Neurosurgery, Beaumont Neuroscience Center, Royal Oak, MI

²Department of Neurosurgery, Oakland University William Beaumont School of Medicine, Rochester, MI

³Department of Anesthesiology, University Hospitals Cleveland Medical Center, Cleveland, OH

⁴Department of Neurosurgery, Northwestern University Medical School, Chicago, IL

⁵Center for Pain Medicine, Western Reserve Hospital, Cuyahoga Falls, Ohio

⁶Department of Neurosurgery, Beth Israel Deaconess Medical Center, Boston, MA, USA

⁷Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL

⁸Department of Neurosurgery, Henry Ford Hospital, Detroit, MI

⁹Advanced Surgery Center of Lancaster, Lancaster, PA, USA

¹⁰Department of Neurosurgery, University Hospitals Cleveland Medical Center, Cleveland, OH

Corresponding Author contact information:

Michael D. Staudt, MD, MSc

Department of Neurosurgery

Beaumont Neuroscience Center

3555 13 Mile Road, N220

Royal Oak, MI 48073

Phone: (248) 784-3667

Email: mikestaudt@gmail.com

No part of this article has been published or submitted for publication elsewhere.

Keywords: craniofacial pain, cervicogenic headaches, guidelines, occipital nerve stimulation, occipital neuralgia, peripheral nerve stimulation

Abbreviations: AANS, American Association of Neurological Surgeons; CNS, Congress of Neurological Surgeons; FDA, Food and Drug Administration; NRS, numerical rating scale; ON, occipital neuralgia; ONB, occipital nerve block; ONS, occipital nerve stimulation; PNS, peripheral nerve stimulation; VAS, visual analog scale

ABSTRACT 

Background: The Guidelines Task Force conducted a systematic review of the relevant literature on occipital nerve stimulation (ONS) for occipital neuralgia (ON) to update the original 2015 guidelines to ensure timeliness and accuracy for clinical practice.

Objective: To conduct a systematic review of the literature and update the evidence-based guidelines on ONS for ON.

Methods: The Guidelines Task Force conducted another systematic review of the relevant literature, using the same search terms and strategies used to search PubMed and Embase for relevant literature.  The updated search included studies published between 1966 and January 2023. The same inclusion/exclusion criteria as the original guideline were also applied. Abstracts were reviewed and relevant full text articles were retrieved and graded. Of 460 articles, 18 were retrieved for full-text review and analysis. Recommendations were updated according to new evidence yielded by this update.

Results: Nine studies were included in the original guideline, reporting the use of ONS as an effective treatment option for patients with medically refractory ON. An additional 6 studies were included in this update. All studies in the original guideline and this current update provide Class III evidence.

Conclusions: Based on the data published in the literature, the following recommendation can be made: Clinicians may use occipital nerve stimulation as a treatment option for patients with medically refractory occipital neuralgia.

 RECCOMMENDATIONS

1. Clinicians may use occipital nerve stimulation as a treatment option for patients with medically refractory occipital neuralgia (Level III)

INTRODUCTION
Goals and Rationale
In 2015, guidelines for the treatment of occipital neuralgia (ON) with occipital nerve stimulation (ONS) were established by the Congress of Neurological Surgeons.1 These guidelines were based on a literature review performed between 1966 and April 2014. The current article is an updated review of the medical literature in accordance with the standard operating procedures and methodology of the Congress of Neurological Surgeons for developing clinical practice guidelines. These guidelines are intended to evaluate and rank current evidence via multidisciplinary panel agreement, although challenges remain regarding their application and integration in neurosurgical practice.2

In the original 2015 guidelines, 9 articles were included for analysis, all which provided Class III evidence.3-11 Based on the data derived from this previous literature review, the following Level III recommendation was made: the use of ONS is a treatment option for patients with medically refractory ON.

At the time of publication of the original guidelines, the practice of ONS in the United States required the off-label use of neurostimulation devices approved by the US Food and Drug Administration (FDA). In the interim, multiple wireless peripheral nerve stimulation (PNS) systems have received FDA approval for the treatment of pain in the trunk and the extremities, with one temporary device recently receiving an expanded indication for the treatment of headache and axial neck pain. Notably, no permanent implantable device has received approval for the treatment of pain in the craniofacial region. Conversely, non-invasive devices which stimulate the occipital and trigeminal nerves have been developed, with efficacy demonstrated in the acute treatment of migraines.

 Objectives

The purpose of this update is to review the literature following publication of the original guidelines and to update the recommendations as appropriate. Based on the availability of new literature, the current article is a minor update only that does not result in modification of the prior recommendations.

 Methodology

The Guidelines Task Force initiated an update of the original systematic review of the literature and evidence-based guideline relevant to the use of ONS for the treatment of patients with ON. This guideline update was developed for educational purposes to assist practitioners in their clinical decision-making processes. Additional information about the methods utilized in this systematic review is provided via the Congress of Neurological Surgeons Methodology. 

 Literature Search 

The PubMed and Embase databases were searched using the terms: “occipital nerve stimulation” and “occipital neuralgia” or “electrical stimulation” and “occipital neuralgia” or “neuromodulation” and “occipital neuralgia” or “peripheral neurostimulation” and “occipital neuralgia” or “occipital nerve stimulation” and “cervicogenic headache” or “neuromodulation” and “cervicogenic headache”. The PubMed database was searched from April 2014 to January 2023, and the Embase database was searched without date limitation.

Articles were screened via the inclusion and exclusion criteria established in the previous guidelines publication: (1) clinical series must have a minimum of 3 patients undergoing ONS for treatment of medically refractory ON, (2) clinical series must have a minimum of 2 months postoperative follow-up from ONS implantation, and (3) series that enrolled mixed patient populations were included only if they reported separate results for the target ON population.

A total of 150 and 310articles were identified through the PubMed and Embase database searches, respectively. After removal of 146 duplicate entries and 7 entries screened by the librarian, 307 articles underwent title and abstract review by 3 independent investigators (Figure 1). A total of 18 articles underwent full review and 6 met inclusion criteria. 

 Inclusion/Exclusion Criteria

Articles were retrieved and included only if they met specific inclusion/exclusion criteria. These criteria were also applied to articles provided by guideline task force members who supplemented the electronic database searches with articles from their own files. To reduce bias, these criteria were specified before conducting the literature searches.

Articles that do not meet the following criteria were, for the purposes of this evidence-based clinical practice guideline, were excluded. To be included as evidence in the guideline, an article had to be a report of a study that:

•         Investigated patients with patients with medically refractory ON;

•         Studies that enrolled mixed patient populations were included only if they reported separate results for the target ON population;

•         Have a minimum of 2 months postoperative follow-up from ONS implantation;

•         Was a full article report of a clinical study;

•         Was not a medical records review, meeting abstract, historical article, editorial, letter, or a commentary;

•         Appeared in a peer-reviewed publication or a registry report;

•         Enrolled a minimum of 3 patients;

•         Was published between April 2014 and January 2023 (PubMed search);

•         Was not a systematic review, meta-analysis, or guideline developed by others.

Systematic reviews or meta-analyses conducted by others, or guidelines developed by others were not included as evidence to support this review due to the differences in article inclusion/exclusion criteria specified compared to the criteria specified by the Guidelines Task Force. Although these articles were not included as evidence to support the review, these articles were recalled for full-text review in order for the Guidelines Task Force to conduct manual searches of the bibliographies.

Rating Quality of Evidence

The quality of evidence was rated using an evidence hierarchy for each of four different study types; therapeutic, prognostic, diagnostic, and decision modeling. These hierarchies are shown in Appendix II: Rating Evidence Quality. Additional information regarding the hierarchy classification of evidence can be located here: https://www.cns.org/guidelines/guideline-development-methodology

Revision Plans

In accordance with the Institute of Medicine’s standards for developing clinical practice guidelines and criteria specified by the National Guideline Clearinghouse, the task force will monitor related publications following the release of this document and will revise the entire document and/or specific sections “if new evidence shows that a recommended intervention causes previously unknown substantial harm; that a new intervention is significantly superior to a previously recommended intervention from an efficacy or harms perspective; or that a recommendation can be applied to new populations.”12  In addition, the task force will confirm within five years from the date of publication that the content reflects current clinical practice and the available technologies for the evaluation and treatment for patients with ON. 

 RESULTS

The literature search yielded 307 abstracts.  Task force members reviewed all abstracts yielded from the literature search and identified the literature for full text review and extraction, addressing the clinical questions, in accordance with the Literature Search Protocol (Appendix I). Task force members identified the best research evidence available to answer the targeted clinical questions. When Level I, II and or III literature was available to answer specific questions, the task force did not review Level IV studies. 

The task force selected 18 full-text articles for full text review. Of these, 12 were rejected for not meeting inclusion criteria or for being off-topic. 6 were selected for systematic review, and all 6 studies included in the updated guidelines were classified as Class III. Appendix IV outlines those studies included for consideration in the updated guidelines.

Finiels and Batifol presented a retrospective review of 111 patients with ON who had follow-up of at least 6 months.13 ONS was chosen only after the failure of radiofrequency denaturation or Botulinum toxin injections, and was performed via surgical implantation of bilateral paddle leads. Five patients were implanted, with 4 having “excellent” pain relief and total cessation of pain medications, and the other considered a treatment failure with removal of the stimulator at 19 months. No complications were noted.

Keifer et al. retrospectively reported on 20 patients with medically intractable ON, who were naïve to ONS treatment and underwent ONS implantation.14 Of note, 29 patients with ON were identified, 5 who underwent a trial and failed, and 4 patients who underwent ONS revision – these 9 patients are not discussed in detail. Twelve of these ON patients had unilateral pain and underwent unilateral implantation. There was a significant reduction in mean pain scores, from 7.4 to 2.9 on a 10-point scale, with a mean follow-up of 1 year. Complications were noted in 20% (n=4) of cases, including infection, migration, erosion and loss of efficacy, with 3 patients eventually having the system removed and one undergoing revision.

Harland et al. retrospectively reported on 22 patients with craniofacial pain who were treated with PNS, 9 of whom had medically intractable ON and were implanted with ONS.15 Four of these ON cases had bilateral percutaneous leads implanted. Mean follow-up time was 37.5 months across the entire cohort. Using 50% reduction on NRS as a marker of response, 77.7% of patients with ON were classified as responders; this is in comparison to 66.6% of patients with trigeminal neuropathic pain and 33.3% with migraine. Previous treatment with an occipital nerve block (ONB) did not differentiate responders from non-responders. Five ON patients had additional quality of life outcome metrics collected; although the results of the ON patients were not separated from other craniofacial pain diagnoses, the entire cohort demonstrated improvement on Beck’s Depression Index and components of the Pain Catastrophizing Scale and McGill Pain Questionnaire. Overall, the majority of initial and long-term responders had a primary diagnosis of ON. Three patients underwent removal due to loss of efficacy or hardware-related pain, although it is not specified if these were ON patients.

Raoul et al. retrospectively reported on 60 patients with occipital headaches treated with ONS.16 This study used the terms ON and cervicogenic headache interchangeably, and also included cases with other associated headache types in addition to ON (i.e. mixed headaches). There was a clear headache etiology in 28 patients, and no clear etiology in 32 patients. Patients first underwent a TENS trial, and were considered for ONS if they reported pain improvement of 30% of greater. Paddle electrodes were implanted unilaterally or bilaterally. In all 60 patients, there was a 72.2% reduction in VAS after one year, with significant improvements in the number of headache days per month and medication use. With regards to specific etiologies, post-traumatic pain improved in 76% of cases, post-surgical in 60%, and arthritic pain in 83%. Those patients with mixed headaches improved in 76% of cases. Complications included 6 cases of lead migration or fracture, and six cases of infection. 

Magown et al. designed an open-label prospective study evaluating the efficacy of ONS in the treatment of various craniofacial pain syndromes.17 Of 13 patients included in the study, 6 were diagnosed with ON. All patients underwent blinded nerve blocks with lidocaine, bupivacaine, or saline administered in a random order at least 1 week apart, although this did not predict ONS outcome. Patients were implanted with percutaneous or paddle electrodes. Five ON cases had bilateral leads implanted. Using 50% reduction on NRS as a marker of response, 3 patients with ON were classified as responders, compared to only one other patient with migraine meeting the same threshold. Patients with ON had a greater improvement on the Headache Impact Test-6 compared to other diagnoses, although the same number of patients fulfilled the threshold for within-person minimal change, regardless of diagnosis. In the entire patient cohort, decreased NRS was correlated with improvements on the Headache Impact Test-6, Migraine Disability Assessment, Center for Epidemiologic Studies Depression Scale and SF-36. Two patients required explantation due to infection, and two patients required lead repositioning – only one of these patients had ON, who underwent revision at 3 months and explantation at 20 months for therapy failure.

Salmasi et al. described the ultrasound-guided ONS implantation in 3 patients with a primary diagnosis of ON, and a secondary diagnosis of either migraine or cervicogenic headache.18 In comparison to other studies, they utilized a dedicated PNS system with an external pulse generator. Specifically, the electrode was implanted to target the greater occipital nerve as it emerges from the C2 level between obliquus capitis inferior and semispinalis capitis. Five leads were implanted in 3 patients (2 bilateral implantations), and a mean of 55% pain relief (25–90%) was observed at mean follow-up of nine months (6–16 months). All patients underwent diagnostic ultrasound-guided greater ONB, and implant was only considered if ONB resulted in >50% pain relief. No complications were noted.

DISCUSSION 
Since the publication of the original ONS for ON guidelines in 2015, multiple new studies have been published – these are all Class III studies, and thus there is no high-level evidence to support Level I or Level II recommendations. Based on the availability of new literature, the current article is a minor update that requires no substantial change in recommendations. The verbiage of the original recommendation was updated with respect to formatting only.

The new articles included in this update demonstrate multiple similarities to the original guidelines, including comparable efficacy of ONS in the treatment of ON, with similar reported complication rates. These studies also report a variety of implantation techniques, including the use of percutaneous and paddle leads, with fluoroscopic or ultrasound guidance. Diagnostic nerve blocks continue to be common, although do not predict the response to or long-term success with ONS. No one surgical technique or nuance regarding patient selection was associated with greater pain improvement or long-term implant success. 

A key issue raised in the previous guidelines was regarding the lack of prospective, randomized, controlled trials which could support higher level recommendations. Such studies have been performed regarding the use of ONS in the treatment of intractable chronic migraines,19, 20 although none have been performed specifically for ON. Notably, the study for chronic migraine failed to meet their primary endpoint, defined as a ≥50% reduction in mean daily VAS scores between active and sham stimulation, although there was a significant reduction in the number of headache days and improvement in migraine-related disability and pain relief.20 An impressive 70% of patients experienced an adverse event in the open-label extension, with 40.7% of these events requiring additional surgery.21 As this study used conventional spinal cord stimulator electrodes, this highlights the need for dedicated PNS devices for craniofacial pain.

Future Research
The lack of high-quality data also highlights the relative rarity of ON compared to much more common headache disorders such as migraine, which can lead to challenges in designing an appropriately powered study. For example, a large Dutch population study documented the incidence of ON was 3.2 per 100,000.22 The prospective community-based Bruneck study estimated lifetime prevalence of all primary headaches and cranial neuralgias to be 51.7 and 1.6%, respectively.23 More recently, a study on the prevalence of ON in a Massachusetts community hospital-based headache clinic evaluated 800 patients with headache, and identified nearly 25% to have ON, with 15% of patients having isolated ON without a co-existing headache disorder;24 however, this study has been criticized as over-reporting the prevalence of ON due to the diagnostic criteria utilized.25

A particular challenge in evaluating patients with ON is the overlap of the diagnostic criteria with other headache disorders.25 For example, the diagnostic criteria for ON as defined by the International Headache Society include occipital pain which can be associated with allodynia, tenderness, or trigger points over the occipital nerves.26 “Occipital headaches” can thus include several headache etiologies, including ON, migraine, and cervicogenic headaches, all of which can be associated with one or more of these attributes. In particular, both ON and cervicogenic headache can present with a posterior headache, neck pain, and referred fronto-orbital pain, and they also share a common afferent pathway which involves the trigeminocervical complex.27

Given that ON, migraine, and cervicogenic headaches all may respond to ONS, it is thus important for studies to accurately document both the diagnosis and the diagnostic criteria utilized. This is highlighted in the current review, as some studies interchangeably used the terms ON and cervicogenic headaches, or reported on patients with primary ON as well as other associated headache pathologies.16, 18 In comparison, one study of ONS for cervicogenic headaches described a similar pain presentation, although explicitly excluded ON as the pain was not paroxysmal enough.28 Such descriptors can be helpful in accurately differentiating headache pathologies.

It has also been suggested that blinded trials of ONS are inherently difficult due to the production of paresthesias overlapping painful regions; however, subperception or paresthesia-free stimulation has been shown to be effective when applied to peripheral nerves,29 and could potentially provide an avenue for further study. It is also interesting to note that both percutaneous and paddle ONS leads have been reported to be equally efficacious – paddle leads may miss the occipital nerve if not directly visualized, whereas percutaneous leads provide omnidirectional stimulation. A prospective comparison of ONS lead type may also be worth investigating.

Unfortunately, ONS continues to be deemed investigational/experimental or unproven by most commercial insurance providers, thereby depriving patients with medically refractory ON of a potentially effective treatment option. This is in contrast to newer PNS devices using external generators, a number of which have been FDA-approved for the treatment of pain in the trunk and extremities. One study included in this updated review reported the use of a dedicated PNS system.18 These devices are designed specifically for peripheral nerve use, and are thus shorter and thinner than spinal cord stimulator electrodes, and do not require implantation of an implantable pulse generator. Their purported benefit, such as a lower risk of migration and infection, are attractive features for ONS, as these are some of the most common complications when using conventional electrodes

Although no implantable device has received approval for the treatment of pain in the craniofacial region, recently one temporary PNS device received an expanded indication to target the occipital nerves for the treatment of chronic head and neck pain. This approval was based off a retrospective review of real-world outcomes of patients with occipital neuralgia, migraine or cervicogenic headache, with 82% (n=32) of patients reporting 50% or greater pain relief of quality of life improvement.30 An open-label study using this device is ongoing to study PNS in the treatment of head pain (ClinicalTrials.gov NCT05491915).Another clinical trial on PNS using external power source delivery for craniofacial pain has been completed and data are currently being analyzed for potential regulatory submission (ClinicalTrials.gov NCT02729480). There are also ongoing studies regarding the long-term efficacy of non-invasive stimulation of the occipital and trigeminal nerves in the treatment of migraine, although there are no data to currently support its use in the treatment of ON.

 CONCLUSIONS
ONS may be an effective treatment option for patients with medically refractory ON. Unfortunately, the overall level of evidence remains low due to the lack of commercially available dedicated craniofacial PNS devices, of insurance coverage for many patients and of trials specifically designed to evaluate neuromodulation for craniofacial pain. 

 Conflicts of Interest

All Guideline Task Force members were required to disclose all potential COIs prior to beginning work on the guideline, using the COI disclosure form of the AANS/CNS Joint Guidelines Review Committee. The CNS Guidelines Committee and Guideline Task Force Chair reviewed the disclosures and either approved or disapproved the nomination and participation on the task force. The CNS Guidelines Committee and Guideline Task Force Chair may approve nominations of task force members with possible conflicts and restrict the writing, reviewing, and/or voting privileges of that person to topics that are unrelated to the possible COIs. See Appendix V for a complete list of disclosures.

 Disclosure of Funding  

These evidence-based clinical practice guidelines were funded exclusively by the Congress of Neurological Surgeons, which received no funding from outside commercial sources to support the development of this document.

 Disclaimer of Liability

This clinical systematic review and evidence-based guideline was developed by a physician volunteer task force as an educational tool that reflects the current state of knowledge at the time of completion. Each chapter is designed to provide an accurate review of the subject matter covered. This guideline is disseminated with the understanding that the recommendations by the authors and consultants who have collaborated in their development are not meant to replace the individualized care and treatment advice from a patient's physician(s). If medical advice or assistance is required, the services of a competent physician should be sought. The proposals contained in these guidelines may not be suitable for use in all circumstances. The choice to implement any particular recommendation contained in these guidelines must be made by a managing physician in light of the situation in each particular patient and on the basis of existing resources.

 Acknowledgments:

The guidelines task force would like to acknowledge the CNS Guidelines Committee for their contributions throughout the development of the guideline, the AANS/CNS Joint Guidelines Review Committee, as well as the contributions Trish Rehring, MPH, Associate Director for Evidence-Based Practice Initiatives for the CNS, and Janet Waters, MLS, BSN, RN, for assistance with the literature searches. Throughout the review process, the reviewers and authors were blinded from one another. At this time the guidelines task force would like to acknowledge the following individual peer reviewers for their contributions: Steve Kalkanis, MD, Koji Ebersole, MD, Andrew Carlson, MD, MS, Jamie Van Gompel, MD.

Appendix I: Literature Searches
Search Strategies

 PUBMED
((((("OCCIPITAL NERVE STIMULAT*"[TITLE/ABSTRACT] OR "ELECTRIC STIMULATION THERAPY"[MESH TERMS:NOEXP] OR "ELECTRIC STIMULAT*"[TITLE/ABSTRACT] OR "IMPLANTABLE NEUROSTIMULATORS"[MESH TERMS] OR "ELECTRICAL STIMULAT*"[TITLE/ABSTRACT] OR "ELECTROSTIMULAT*"[TITLE/ABSTRACT] OR "ELECTRO STIMULAT*"[TITLE/ABSTRACT] OR "ELECTROTHERAP*"[TITLE/ABSTRACT] OR "ELECTRO THERAP*"[TITLE/ABSTRACT] OR "TRANSCUTANEOUS ELECTRIC NERVE STIMULATION"[MESH TERMS] OR "NEUROMODULAT*"[TITLE/ABSTRACT] OR "PERIPHERAL NEUROSTIMULAT*"[TITLE/ABSTRACT] OR "PERIPHERAL NERVE STIMULAT*"[TITLE/ABSTRACT]) AND (2021/09/01:2022/04/30[DATE - PUBLICATION] AND "ENGLISH"[LANGUAGE])) NOT ("ANIMAL*"[MESH TERMS] NOT ("ANIMAL*"[MESH TERMS] AND "HUMAN*"[MESH TERMS]))) NOT ("LETTER*"[PUBLICATION TYPE] OR "COMMENT*"[PUBLICATION TYPE] OR "EDITORIAL*"[PUBLICATION TYPE])) AND (((((("NEURALGIA"[MESH TERMS:NOEXP] AND "OCCIPITAL*"[TEXT WORD]) OR "OCCIPITAL NEURALGIA*"[TITLE/ABSTRACT] OR "OCCIPITAL HEADACHE*"[TITLE/ABSTRACT] OR "CERVICOGENIC HEADACHE*"[TITLE/ABSTRACT] OR "POST-TRAUMATIC HEADACHE"[MESH TERMS]) AND "ENGLISH"[LANGUAGE]) NOT ("ANIMAL*"[MESH TERMS] NOT ("ANIMAL*"[MESH TERMS] AND "HUMAN*"[MESH TERMS]))) NOT ("LETTER*"[PUBLICATION TYPE] OR "EDITORIAL*"[PUBLICATION TYPE] OR "COMMENT*"[PUBLICATION TYPE])) AND 2021/09/01:2022/04/30[DATE - PUBLICATION] AND "ENGLISH"[LANGUAGE])) OR (((((((("NEURALGIA"[MESH TERMS:NOEXP] AND "OCCIPITAL*"[TEXT WORD]) OR "OCCIPITAL NEURALGIA*"[TITLE/ABSTRACT] OR "OCCIPITAL HEADACHE*"[TITLE/ABSTRACT] OR "CERVICOGENIC HEADACHE*"[TITLE/ABSTRACT] OR "POST-TRAUMATIC HEADACHE"[MESH TERMS]) AND "ENGLISH"[LANGUAGE]) NOT ("ANIMAL*"[MESH TERMS] NOT ("ANIMAL*"[MESH TERMS] AND "HUMAN*"[MESH TERMS]))) NOT ("LETTER*"[PUBLICATION TYPE] OR "EDITORIAL*"[PUBLICATION TYPE] OR "COMMENT*"[PUBLICATION TYPE])) AND 2021/09/01:2022/04/30[DATE - PUBLICATION] AND "ENGLISH"[LANGUAGE]) OR (((("OCCIPITAL NERVE STIMULAT*"[TITLE/ABSTRACT] OR "ELECTRIC STIMULATION THERAPY"[MESH TERMS:NOEXP] OR "ELECTRIC STIMULAT*"[TITLE/ABSTRACT] OR "IMPLANTABLE NEUROSTIMULATORS"[MESH TERMS] OR "ELECTRICAL STIMULAT*"[TITLE/ABSTRACT] OR "ELECTROSTIMULAT*"[TITLE/ABSTRACT] OR "ELECTRO STIMULAT*"[TITLE/ABSTRACT] OR "ELECTROTHERAP*"[TITLE/ABSTRACT] OR "ELECTRO THERAP*"[TITLE/ABSTRACT] OR "TRANSCUTANEOUS ELECTRIC NERVE STIMULATION"[MESH TERMS] OR "NEUROMODULAT*"[TITLE/ABSTRACT] OR "PERIPHERAL NEUROSTIMULAT*"[TITLE/ABSTRACT] OR "PERIPHERAL NERVE STIMULAT*"[TITLE/ABSTRACT]) AND (2021/09/01:2022/04/30[DATE - PUBLICATION] AND "ENGLISH"[LANGUAGE])) NOT ("ANIMAL*"[MESH TERMS] NOT ("ANIMAL*"[MESH TERMS] AND "HUMAN*"[MESH TERMS]))) NOT ("LETTER*"[PUBLICATION TYPE] OR "COMMENT*"[PUBLICATION TYPE] OR "EDITORIAL*"[PUBLICATION TYPE]))) AND (((((("NERVE BLOCK"[MESH TERMS:NOEXP] OR "NERVE BLOCK*"[TITLE/ABSTRACT] OR "AUTONOMIC NERVE BLOCK"[MESH TERMS:NOEXP]) AND "OCCIPITAL*"[TEXT WORD]) NOT ("ANIMAL*"[MESH TERMS] NOT ("ANIMAL*"[MESH TERMS] AND "HUMAN*"[MESH TERMS]))) NOT ("LETTER*"[PUBLICATION TYPE] OR "COMMENT*"[PUBLICATION TYPE] OR "EDITORIAL*"[PUBLICATION TYPE])) AND (2021/09/01:2022/04/30 [DATE - PUBLICATION] AND "ENGLISH"[LANGUAGE])) OR ("OCCIPITAL NERVE INJECTION*"[TITLE/ABSTRACT] OR "GON INJECTION*"[TITLE/ABSTRACT])))

EMBASE

SEARCH 1 ONLY

('neuralgia'/de AND occipital*:ti,ab,de OR (occipital* NEAR/2 (neuralgia* OR neuropath* OR 'nerve pain' OR neurodynia)) OR 'cervicogenic headache':ti,ab OR 'cervico genic headache':ti,ab OR 'cervicogenic headaches':ti,ab OR 'cervico genic headaches':ti,ab OR ('secondary headache'/exp AND occipital*:ti,ab,de) OR ('posttraumatic headache'/exp AND occipital*:ti,ab,de) OR (('posttraumatic headache' OR 'post traumatic headache' OR 'posttraumatic headaches' OR 'post traumatic headaches') NEAR/4 occipital*)) NOT ('animal'/exp NOT ('animal'/exp AND 'human'/exp)) NOT ('abstract report'/exp OR 'conference paper'/exp OR 'editorial'/exp OR 'book'/exp) AND [english]/lim AND [embase]/lim NOT ([embase]/lim AND [medline]/lim) AND ('electrotherapy'/de OR electrotherap*:ti,ab OR 'electro therapy':ti,ab OR 'nerve stimulation'/de OR 'nerve stimulation':ti,ab OR 'transcutaneous electrical nerve stimulation'/exp OR 'electrostimulation'/exp OR electrostimulat*:ti,ab OR 'electric stimulation':ti,ab OR 'electrical stimulation':ti,ab OR 'neuromodulation'/exp OR neuromodulat*:ti,ab OR 'neuro modulation':ti,ab OR 'neuro-modulation':ti,ab OR 'neuro-stimulation':ti,ab OR neurostimulat*:ti,ab OR 'neuro stimulation':ti,ab) NOT (('neuralgia'/de AND occipital*:ti,ab,de OR (occipital* NEAR/2 (neuralgia* OR neuropath* OR 'nerve pain' OR neurodynia)) OR 'cervicogenic headache':ti,ab OR 'cervico genic headache':ti,ab OR 'cervicogenic headaches':ti,ab OR 'cervico genic headaches':ti,ab OR ('secondary headache'/exp AND occipital*:ti,ab,de) OR ('posttraumatic headache'/exp AND occipital*:ti,ab,de) OR (('posttraumatic headache' OR 'post traumatic headache' OR 'posttraumatic headaches' OR 'post traumatic headaches') NEAR/4 occipital*)) NOT ('animal'/exp NOT ('animal'/exp AND 'human'/exp)) NOT ('abstract report'/exp OR 'conference paper'/exp OR 'editorial'/exp OR 'book'/exp) AND [english]/lim AND [embase]/lim NOT ([embase]/lim AND [medline]/lim) AND ('electrotherapy'/de OR electrotherap*:ti,ab OR 'electro therapy':ti,ab OR 'nerve stimulation'/de OR 'nerve stimulation':ti,ab OR 'transcutaneous electrical nerve stimulation'/exp OR 'electrostimulation'/exp OR electrostimulat*:ti,ab OR 'electric stimulation':ti,ab OR 'electrical stimulation':ti,ab OR 'neuromodulation'/exp OR neuromodulat*:ti,ab OR 'neuro modulation':ti,ab OR 'neuro-modulation':ti,ab OR 'neuro-stimulation':ti,ab OR neurostimulat*:ti,ab OR 'neuro stimulation':ti,ab) AND 'conference abstract'/it) AND [01-09-2021]/sd NOT [01-05-2022]/sd

SEARCH 2 ONLY

(('nerve block'/de OR 'nerve block':ti,ab OR 'nerve blocks':ti,ab OR 'nerve blockade':ti,ab OR 'nerve blockades':ti,ab OR 'nerve blocking':ti,ab OR 'autonomic blocker':ti,ab OR 'autonomic blocking':ti,ab OR 'conduction block':ti,ab OR 'nerve conduction block':ti,ab OR 'neurogenic blockade':ti,ab) AND occipital:ti,ab AND ('response'/exp OR respons*:ti,ab OR 'treatment response'/exp OR 'predictive value'/exp OR predict*:ti,ab,de OR outcome*:ti,ab,de OR 'prediction'/exp) OR (('injection'/de OR injection*:ti,ab) AND occipital*:ti,ab,de)) AND ('neuralgia'/de AND occipital*:ti,ab,de OR (occipital* NEAR/2 (neuralgia* OR neuropath* OR 'nerve pain' OR neurodynia)) OR 'cervicogenic headache':ti,ab OR 'cervico genic headache':ti,ab OR 'cervicogenic headaches':ti,ab OR 'cervico genic headaches':ti,ab OR ('secondary headache'/exp AND occipital*:ti,ab,de) OR ('posttraumatic headache'/exp AND occipital*:ti,ab,de) OR (('posttraumatic headache' OR 'post traumatic headache' OR 'posttraumatic headaches' OR 'post traumatic headaches') NEAR/4 occipital*) OR 'electrotherapy'/de OR electrotherap*:ti,ab OR 'electro therapy':ti,ab OR 'nerve stimulation'/de OR 'nerve stimulation':ti,ab OR 'transcutaneous electrical nerve stimulation'/exp OR 'electrostimulation'/exp OR electrostimulat*:ti,ab OR 'electric stimulation':ti,ab OR 'electrical stimulation':ti,ab OR 'neuromodulation'/exp OR neuromodulat*:ti,ab OR 'neuro modulation':ti,ab OR 'neuro-modulation':ti,ab OR 'neuro-stimulation':ti,ab OR neurostimulat*:ti,ab OR 'neuro stimulation':ti,ab) NOT ('animal'/exp NOT ('animal'/exp AND 'human'/exp)) NOT (('neuralgia'/de AND occipital*:ti,ab,de OR (occipital* NEAR/2 (neuralgia* OR neuropath* OR 'nerve pain' OR neurodynia)) OR 'cervicogenic headache':ti,ab OR 'cervico genic headache':ti,ab OR 'cervicogenic headaches':ti,ab OR 'cervico genic headaches':ti,ab OR ('secondary headache'/exp AND occipital*:ti,ab,de) OR ('posttraumatic headache'/exp AND occipital*:ti,ab,de) OR (('posttraumatic headache' OR 'post traumatic headache' OR 'posttraumatic headaches' OR 'post traumatic headaches') NEAR/4 occipital*) OR 'electrotherapy'/de OR electrotherap*:ti,ab OR 'electro therapy':ti,ab OR 'nerve stimulation'/de OR 'nerve stimulation':ti,ab OR 'transcutaneous electrical nerve stimulation'/exp OR 'electrostimulation'/exp OR electrostimulat*:ti,ab OR 'electric stimulation':ti,ab OR 'electrical stimulation':ti,ab OR 'neuromodulation'/exp OR neuromodulat*:ti,ab OR 'neuro modulation':ti,ab OR 'neuro-modulation':ti,ab OR 'neuro-stimulation':ti,ab OR neurostimulat*:ti,ab OR 'neuro stimulation':ti,ab) NOT ('animal'/exp NOT ('animal'/exp AND 'human'/exp)) AND 'conference abstract'/it) NOT ('letter'/exp OR 'editorial'/exp OR commentary:ti) AND [english]/lim NOT (study AND protocol:ti) AND [01-09-2021]/sd NOT [01-05-2022]/sd

Appendix II: Rating Evidence Quality

Classification of Evidence on Therapeutic Effectiveness and Levels of Recommendation

Class I Evidence Level I (or A) Recommendation	Evidence from one or more well-designed, randomized controlled clinical trial, including overviews of such trials.
Class II Evidence Level II (or B) Recommendation	Evidence from one or more well-designed comparative clinical studies, such as non-randomized cohort studies, case-control studies, and other comparable studies, including less well-designed randomized controlled trials.
Class III Evidence Level III (or C) Recommendation	Evidence from case series, comparative studies with historical controls, case reports, and expert opinion, as well as significantly flawed randomized controlled trials.

Appendix III: PRISMA Flowchart

Appendix IV. Evidence Tables

PICO  Question	Author, Year	Type of Evidence	Study Type	Description of Study	Level of Evidence	Reviewer’s Conclusions
1	Finiels and Batifol, 2016	Therapeutic	Retrospective case series	111 patients with ON. ONS was chosen following failure of radiofrequency/Botox. 5 patients were implanted with bilateral paddle leads. At least 6 months follow-up.	III	Study shows 4 patients with “excellent” pain relief and total cessation of pain medications. 1 patient considered a treatment failure with removal of the stimulator at 19 months. No reported complications.
1	Keifer et al., 2017	Therapeutic	Retrospective case series	29 patients with ON. 9 patients not reported on: 5 failed ONS trial, 4 underwent revision of previous ONS system. 20 patients were naïve to surgical treatment underwent ONS implantation with percutaneous leads. Mean follow-up of 1 year.	III	85% of patients reported >50% reduction in pain severity and frequency. Mean post-operative pain score decreased from 7.4 to 2.9. Complications in 20% (n=4) of cases, including infection, migration, erosion and loss of efficacy. 3 patients eventually underwent system removal or revision.
1	Harland et al., 2020	Therapeutic	Retrospective case series	22 patients, 9 with ON. Percutaneous leads implanted, bilateral in 4. Follow-up of 1.37-82.57 months.	III	77.7% of subjects with ON were responders (50% reduction on NRS). Patients with ONS were more likely to be responders, although this was not statistically significantly. Improvement in quality of life measures also reported, although not subdivided by pathology. PNS removed in 2 patients for loss of benefit, and in 1 patient for hardware-related pain – not specified if these were ON patients.
1	Raoul et al., 2020	Therapeutic	Retrospective case series	60 patients with “occipital headaches”. ON and cervicogenic headache were used interchangeably. Clear headache etiology in 28 patients, unknown in 32. TENS trial prior to implant with paddle leads. At least one year follow-up (range 13–72 months).	III	After one year, mean VAS decreased by 72.2%, with 76% of patients having at least 50% reduction. Post-traumatic pain improved in 76% of cases, post-surgical in 60%, and arthritic pain in 83%. Complications in 20% (n=12) of cases, including electrode displacement or fracture (10%), and infection (10%)
1	Magown et al., 2020	Therapeutic	Open-label prospective case series	13 patients, 6 with ON. All patients underwent blinded nerve blocks. Both percutaneous and paddle leads used, bilateral in 5. Follow-up of 24-48 months.	III	50% of subjects with ON were responders (50% reduction on NRS), compared to 16.7% of patients with other pain diagnoses. Headache Impact Test (HIT-6) scores decreased more for ON patients. One patient with ON was revised at 3 months and then explanted at 20 months for therapy failure. 3 non-ON patients underwent revision or explantation for migration or infection.
1	Salmasi et al., 2020	Therapeutic	Retrospective case series	3 patients with primary diagnosis of ON. Dedicated PNS system with an external pulse generator, implanted with ultrasound guidance targeting the GON as it emerges from C2. Diagnostic nerve block as trial. Five leads implanted in 3 patients. Mean follow-up of 9 months (range 6-16 months).	III	Mean pain relief of 55% (range 25–90%). No complications reported.

Appendix V. Conflicts of Interest

Author	Disclosure
Michael D. Staudt MD MSc	No Disclosures
Salim M. Hayek MD PhD
Joshua M. Rosenow MD
Samer Narouze MD PhD
Jeffrey E. Arle MD PhD
Julie G. Pilitsis, MD PhD	Dr. Pilitsis is a consultant for Boston Scientific, Nevro, Medtronic, Saluda and Abbott and receives grant support from Medtronic, Boston Scientific, Abbott, Nevro, Saluda, NIH 2R01CA166379-06 and NIH U44NS115111. She is the medical advisor for Aim Medical Robotics and has stock equity.
Jason M. Schwalb MD
Steven M. Falowski MD
Jennifer A. Sweet MD

References

1.         Sweet JA, Mitchell LS, Narouze S, et al. Occipital Nerve Stimulation for the Treatment of Patients With Medically Refractory Occipital Neuralgia: Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline. Neurosurgery. Sep 2015;77(3):332-341.

2.         Fehlings MG, Nater A. Development and implementation of guidelines in neurosurgery. Neurosurgery clinics of North America. Apr 2015;26(2):271-282, x.

3.         Weiner RL, Reed KL. Peripheral neurostimulation for control of intractable occipital neuralgia. Neuromodulation : journal of the International Neuromodulation Society. Jul 1999;2(3):217-221.

4.         Oh MY, Ortega J, Bellotte JB, Whiting DM, Alo K. Peripheral nerve stimulation for the treatment of occipital neuralgia and transformed migraine using a c1-2-3 subcutaneous paddle style electrode: a technical report. Neuromodulation : journal of the International Neuromodulation Society. Apr 2004;7(2):103-112.

5.         Kapural L, Mekhail N, Hayek SM, Stanton-Hicks M, Malak O. Occipital nerve electrical stimulation via the midline approach and subcutaneous surgical leads for treatment of severe occipital neuralgia: a pilot study. Anesthesia and analgesia. Jul 2005;101(1):171-174, table of contents.

6.         Slavin KV, Nersesyan H, Wess C. Peripheral neurostimulation for treatment of intractable occipital neuralgia. Neurosurgery. Jan 2006;58(1):112-119; discussion 112-119.

7.         Johnstone CS, Sundaraj R. Occipital nerve stimulation for the treatment of occipital neuralgia-eight case studies. Neuromodulation : journal of the International Neuromodulation Society. Jan 2006;9(1):41-47.

8.         Melvin EA, Jr., Jordan FR, Weiner RL, Primm D. Using peripheral stimulation to reduce the pain of C2-mediated occipital headaches: a preliminary report. Pain physician. May 2007;10(3):453-460.

9.         Magown P, Garcia R, Beauprie I, Mendez IM. Occipital nerve stimulation for intractable occipital neuralgia: an open surgical technique. Clinical neurosurgery. 2009;56:119-124.

10.       Abhinav K, Park ND, Prakash SK, Love-Jones S, Patel NK. Novel use of narrow paddle electrodes for occipital nerve stimulation--technical note. Neuromodulation : journal of the International Neuromodulation Society. Nov-Dec 2013;16(6):607-609.

11.       Palmisani S, Al-Kaisy A, Arcioni R, et al. A six year retrospective review of occipital nerve stimulation practice--controversies and challenges of an emerging technique for treating refractory headache syndromes. The journal of headache and pain. Aug 6 2013;14:67.

12.       Ransohoff DF, M. Pignone, and H.C. Sox, . How to decide whether a clinical practice guideline is trustworthy. . JAMA. 2013;309(2):139-140.

13.       Finiels PJ, Batifol D. The treatment of occipital neuralgia: Review of 111 cases. Neuro-Chirurgie. Oct 2016;62(5):233-240.

14.       Keifer OP, Jr., Diaz A, Campbell M, Bezchlibnyk YB, Boulis NM. Occipital Nerve Stimulation for the Treatment of Refractory Occipital Neuralgia: A Case Series. World neurosurgery. Sep 2017;105:599-604.

15.       Harland TA, Zbrzeski C, DiMarzio M, Khazen O, Staudt MD, Pilitsis JG. Craniofacial Peripheral Nerve Stimulation: Analysis of a Single Institution Series. Neuromodulation : journal of the International Neuromodulation Society. Aug 2020;23(6):805-811.

16.       Raoul S, Nguyen JM, Kuhn E, et al. Efficacy of Occipital Nerve Stimulation to Treat Refractory Occipital Headaches: A Single-Institution Study of 60 Patients. Neuromodulation : journal of the International Neuromodulation Society. Aug 2020;23(6):789-795.

17.       Magown P, Becker WJ, Kiss ZH. Outcomes of Occipital Nerve Stimulation for Craniofacial Pain Syndromes. The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques. Sep 2021;48(5):690-697.

18.       Salmasi V, Olatoye OO, Terkawi AS, Hah JM, Ottestad E, Pingree M. Peripheral Nerve Stimulation for Occipital Neuralgia. Pain Med. Aug 1 2020;21(Suppl 1):S13-S17.

19.       Saper JR, Dodick DW, Silberstein SD, McCarville S, Sun M, Goadsby PJ. Occipital nerve stimulation for the treatment of intractable chronic migraine headache: ONSTIM feasibility study. Cephalalgia : an international journal of headache. Feb 2011;31(3):271-285.

20.       Silberstein SD, Dodick DW, Saper J, et al. Safety and efficacy of peripheral nerve stimulation of the occipital nerves for the management of chronic migraine: results from a randomized, multicenter, double-blinded, controlled study. Cephalalgia : an international journal of headache. Dec 2012;32(16):1165-1179.

21.       Dodick DW, Silberstein SD, Reed KL, et al. Safety and efficacy of peripheral nerve stimulation of the occipital nerves for the management of chronic migraine: long-term results from a randomized, multicenter, double-blinded, controlled study. Cephalalgia : an international journal of headache. Apr 2015;35(4):344-358.

22.       Koopman JS, Dieleman JP, Huygen FJ, de Mos M, Martin CG, Sturkenboom MC. Incidence of facial pain in the general population. Pain. Dec 15 2009;147(1-3):122-127.

23.       Schwaiger J, Kiechl S, Seppi K, et al. Prevalence of primary headaches and cranial neuralgias in men and women aged 55-94 years (Bruneck Study). Cephalalgia : an international journal of headache. Feb 2009;29(2):179-187.

24.       Mathew PG, Najib U, Khaled S, Krel R. Prevalence of Occipital Neuralgia at a Community Hospital-based Headache Clinic. Neurology. Clinical practice. Feb 2021;11(1):6-12.

25.       Schwarz HB, Robbins MS. Are Two Head(ache)s Better Than One: Consequences of Diagnosing Migraine and Occipital Neuralgia. Neurology. Clinical practice. Feb 2021;11(1):1-2.

26.       Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia : an international journal of headache. Jan 2018;38(1):1-211.

27.       Goadsby PJ, Bartsch T. On the functional neuroanatomy of neck pain. Cephalalgia : an international journal of headache. Jul 2008;28 Suppl 1:1-7.

28.       Eghtesadi M, Leroux E, Fournier-Gosselin MP, et al. Neurostimulation for Refractory Cervicogenic Headache: A Three-Year Retrospective Study. Neuromodulation : journal of the International Neuromodulation Society. Apr 2018;21(3):302-309.

29.       Finch P, Price L, Drummond P. High-Frequency (10 kHz) Electrical Stimulation of Peripheral Nerves for Treating Chronic Pain: A Double-Blind Trial of Presence vs Absence of Stimulation. Neuromodulation : journal of the International Neuromodulation Society. Jul 2019;22(5):529-536.

30.       Sheth SJ, Kissoon NR, Pingree MJ, et al. Real-world evidence of significant pain relief following 60-day stimulation of occipital nerves for the treatment of chronic pain. Paper presented at: American Society of Regional Anesthesia and Pain Medicine2022; Orlando, Florida, USA.