The Promising Migraine Therapy you haven't Tried Yet

Migraine is a debilitating neurological disorder affecting approximately 12% of the global population, with a higher prevalence in women (Seng et al., 2021). Characterized by recurrent, throbbing headaches often accompanied by nausea, vomiting, and sensitivity to light and sound, migraines significantly impair quality of life and impose a substantial socioeconomic burden (Burch et al., 2019). While the pathophysiology of migraine is complex, involving both central and peripheral mechanisms, recent research has highlighted peripheral neurogenic inflammation—also known as peripheral sensitization—as a critical contributor to migraine initiation and persistence (Ramachandran, 2018). At our practice, we have observed that targeting this sensitization, particularly in the trigeminal system and upper cervical region, using perineural injection therapy (PIT) can offer immediate relief during active migraines and reduce their frequency and severity over time.

Understanding Migraine and Current Therapies

Migraines are classified as primary headaches, often unilateral, pulsating, and lasting 4–72 hours, as defined by the International Classification of Headache Disorders (ICHD-3) (Headache Classification Committee, 2018). Beyond headache, migraines may include aura—transient neurological symptoms such as visual disturbances—and associated symptoms like photophobia and phonophobia. The condition is multifactorial, involving genetic predisposition, environmental triggers, and neurovascular dysregulation (Goadsby et al., 2017).

Standard migraine therapies include acute and preventive approaches. Acute treatments, such as triptans (e.g., sumatriptan) and nonsteroidal anti-inflammatory drugs (NSAIDs), aim to abort attacks by targeting serotonin receptors or reducing inflammation (Marmura et al., 2015). Preventive medications, including beta-blockers, anticonvulsants (e.g., topiramate), and calcitonin gene-related peptide (CGRP) monoclonal antibodies, seek to reduce attack frequency (Silberstein et al., 2012). Non-pharmacological options, such as cognitive-behavioral therapy and lifestyle modifications, are also employed (Seng et al., 2021).

Despite these options, many patients experience suboptimal outcomes. Triptans, for instance, are ineffective in up to 40% of patients, and side effects like nausea or cardiovascular risks limit their use (Cameron et al., 2015). Preventive therapies often require months to show benefits, and adherence is low due to side effects such as fatigue or cognitive impairment (Hepp et al., 2015). Moreover, while CGRP-targeted therapies have shown promise, their high cost and variable efficacy highlight the need for alternative approaches (Charles & Pozo-Rosich, 2019). These limitations underscore the importance of exploring underrecognized mechanisms, such as peripheral sensitization, to improve migraine management.

An often-overlooked culprit of Migraine? Sensitized nerves in the face, head, and neck can trigger or worsen migraines by amplifying pain signals. This can be addressed with a relatively simple procedure, similar to cosmetic or 'Botox' injections - perineural injection therapy.

Peripheral Neurogenic Inflammation and Migraine

Peripheral neurogenic inflammation refers to the activation and sensitization of peripheral nociceptive neurons, particularly C-fibers, leading to the release of neuropeptides like CGRP, substance P, and neurokinin A (Ramachandran, 2018). In migraine, this process is prominently associated with the trigeminovascular system, which includes sensory fibers from the trigeminal nerve innervating meningeal blood vessels (Goadsby et al., 2017). Activation of these fibers, often triggered by stress, hormonal fluctuations, or cortical spreading depression, results in vasodilation, plasma extravasation, and mast cell degranulation—a sterile inflammatory response known as neurogenic inflammation (Ramachandran, 2018).

The trigeminal nerve’s ophthalmic branch (V1) and its convergence with upper cervical nerve roots (C1–C3) at the trigeminocervical complex (TCC) play a pivotal role in migraine pain (Bartsch & Goadsby, 2003). This convergence explains why migraines often involve pain referred to the occipital and neck regions. Peripheral sensitization lowers the threshold for nociceptive signaling, amplifying pain perception and contributing to allodynia—pain from non-painful stimuli like touch (Burstein et al., 2010). Studies suggest that elevated CGRP levels during migraine attacks correlate with this sensitization, reinforcing its role in headache maintenance (Raddant & Russo, 2011).

While central sensitization is well-studied in chronic migraine, peripheral mechanisms are less emphasized, yet they may initiate and sustain attacks (Pietrobon & Moskowitz, 2013). For example, animal models demonstrate that stimulating trigeminal afferents induces CGRP release and neurogenic inflammation, mimicking migraine-like pain (Williamson & Hargreaves, 2001). Human studies further show that blocking peripheral CGRP signaling reduces attack severity, suggesting that targeting peripheral sensitization could interrupt the migraine cascade early (Edvinsson et al., 2018).

Perineural Injection Therapy: A Novel Approach

At our practice, we have found perineural injection therapy (PIT) to be a valuable tool for addressing peripheral sensitization in migraine, particularly in the trigeminal and upper cervical regions. PIT involves the subcutaneous injection of low-concentration dextrose (typically 5%) or lidocaine around peripheral nerves to modulate neurogenic inflammation and restore nerve function (Lyftogt, 2007). The mechanism is thought to involve inhibition of transient receptor potential vanilloid 1 (TRPV1) channels on sensory neurons, reducing neuropeptide release and dampening inflammation (Connelly et al., 2024).

Our clinical experience aligns with emerging evidence supporting PIT for neuropathic pain conditions. In a retrospective study, patients with trigeminal neuralgia and peripheral neuropathy treated with 5% dextrose PIT reported significant pain reduction compared to lidocaine, with effects persisting weeks after treatment (Connelly et al., 2024). For migraine specifically, we observe that PIT targeting nerves such as the greater occipital, supraorbital, and auriculotemporal provides immediate relief during acute attacks, often within minutes. This rapid response may result from interrupting peripheral nociceptive signaling before it amplifies centrally.

Repeated PIT sessions, typically administered weekly over 4–6 weeks, appear to reduce migraine frequency and severity, particularly when combined with other therapies like acupuncture, stress management, and dietary optimization. We hypothesize that PIT desensitizes overactive nerves, normalizes CGRP release, and mitigates neurogenic inflammation, creating a cumulative effect. While large-scale randomized controlled trials on PIT for migraine are lacking, our observations are consistent with studies showing that peripheral nerve-targeted interventions, such as occipital nerve blocks, benefit migraineurs (Ducic et al., 2014).

Integrating PIT with Comprehensive Care

PIT is most effective as part of an integrative approach. Migraine triggers are diverse, and addressing lifestyle factors—sleep, hydration, stress, and diet—enhances outcomes (Seng et al., 2021). For instance, combining PIT with magnesium supplementation or mindfulness-based stress reduction can synergistically reduce neuronal excitability and inflammation (Burch et al., 2019). Physical therapy targeting cervical musculoskeletal dysfunction, often present in migraineurs, further complements PIT by alleviating referred pain from the upper cervical spine (Luedtke et al., 2016).

Our practice emphasizes personalized treatment plans, recognizing that each patient’s migraine profile is unique. By addressing peripheral sensitization alongside central and systemic factors, we aim to break the cycle of recurrent attacks and improve long-term outcomes.

Conclusion

Peripheral neurogenic inflammation, driven by sensitization of the trigeminal and upper cervical nerves, is a critical yet underappreciated factor in migraine pathophysiology. While conventional therapies offer relief for some, their limitations highlight the need for innovative approaches. Perineural injection therapy, based on our clinical experience, provides immediate relief during active migraines and reduces attack frequency and severity with repeated applications, especially when integrated with other therapies. As research into peripheral mechanisms advances, PIT may emerge as a valuable tool in the migraine treatment arsenal, offering hope to those seeking lasting relief.

About the Author

Dr. David George is the founder of Neuregen in Scottsdale, Arizona, where he specializes in an integrative approach to chronic pain conditions, including migraine. With over 15 years of experience in pain management, Dr. George combines cutting-edge techniques like perineural injection therapy with other modalities such as acupuncture, IV therapies, and physical rehabilitation. He is dedicated to addressing the root causes of pain, empowering patients to reclaim their quality of life through personalized, evidence-informed care.

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