Non-Botulinum Toxin Injections for Headache: Current Evidence

Nerve block (NB), a procedure in which local anesthetic is injected over the major nerves of the head, and trigger point injection (TPI), in which mechanical manipulation and injection of an anesthetic is used to relax regions of contracted myofascial tissue, are considered standard of care practice for the management of pain in people with headache. These procedures can be used as acute abortive procedures or may be scheduled at predefined intervals for preventive management of chronic pain and headache disorders.

The typical headache provider may block 1 or several cranial or cervical nerves for headache management with a sodium channel antagonist agent such as lidocaine or bupivacaine. The greater occipital nerve is the most frequent nerve targeted with this procedure. Other commonly blocked nerves include the lesser occipital, third occipital, greater auricular, auriculotemporal, zygomaticotemporal, supraorbital, supratrochlear, infratrochlear, infraorbital, and upper cervical nerves. This headache treatment can be performed as an en bloc set of procedures and is referred to as pericranial NB. The noninvasive technique of introducing viscous lidocaine or another anesthetic to the sphenopalatine ganglion (SPG) using a cotton swab or small intranasal catheter (termed SPG block) has also become a tool in the armamentarium of headache providers and can also be safely performed by patients at home.^1-3 

Despite these procedures being standard practice, little is known about the exact mechanism of action of these agents in headache management, and no large-scale randomized controlled trials (RCTs) have been carried out to measure the efficacy of NBs.

This review article presents some of the current evidence regarding the proposed mechanisms of action and the central effects of NBs and TPIs. We highlight studies supporting the efficacy of these procedures in headache management for adults and children, with specific attention to recent RCTs when available.

Mechanisms of Action

Nerve Blocks

Injection of a local anesthetic over 1 or more of the pericranial nerves initially inhibits nerve conduction through inhibition of the voltage-gated sodium channels, thus preventing the propagation of action potentials and the relay of pain signals to the brain.4 However, how this procedure provides lasting relief beyond the duration of the anesthetic’s half-life is not fully understood.^5,6

Much of our understanding of the mechanism of action underlying the therapeutic effects of NBs comes from studies focusing on greater occipital NBs (GONBs). The greater occipital nerve is the primary sensory nerve innervating the posterior scalp and derives its fibers from the dorsal roots of cervical nerves II and III. It has been proposed that GONBs decrease the afferent input from these peripheral nerve fibers to the trigeminocervical nucleus complex (TCC), modulating peripheral and central sensitization, thus producing both an acute and a persistent antinociceptive effect.^7,8 The TCC, which spans from the trigeminal nucleus caudalis to the spinal level of the C2 root, is a key center that transmits nociceptive information to higher-order brain centers thought to be involved in pain signal processing—including the hypothalamus and thalamus—which may underlie the process of central sensitization observed in chronic headache disorders. Bartsch and Goadsby⁹ showed that GONBs modulated the excitability of second-order neurons receiving input from both trigeminal and cervical afferents when either was stimulated. In a functional MRI study, GONBs with 1% lidocaine given to healthy volunteers significantly reduced TCC activation by nociceptive stimuli.¹⁰

NBs may also inhibit the release of proinflammatory neurotransmitters such as substance P, calcitonin gene-related peptide, and glutamate.¹¹ Thus, decreased afferent signaling from occipital nerve fibers to the TCC may be the primary means by which NBs exert their central effects. This mechanism is key to the relief of chronic headaches, where central sensitization and allodynia play a crucial role. NBs may modulate pain pathways and provide prompt analgesia that outlasts anesthesia providing days, weeks, or months of pain relief.¹²

Trigger Point Injections

A “trigger point” is a taut fibrous band in a muscle that transmits pain signals centrally upon physical stimulation, such as palpation.¹³ Most people with migraine have identifiable trigger points. In one study, 94% of people with migraine (n=92/98) vs 28% of controls (n=9/32) had trigger points, mostly in the temporal or suboccipital area. Mechanically triggering these points induced a migraine attack in 31% of the individuals reported in the study. This supports that peripheral sensitization is a common and clinically significant finding in people with migraine.¹⁴

The mechanism of action of TPI is hypothesized to be a result of the mechanical effect of the needle as well as the chemical effect of the drug used. This results in muscle relaxation and relief of the trigger point.¹³ This relaxation allows for improved perfusion and adenosine triphosphate replenishment within the muscle fiber.¹⁵

Other suggested mechanisms are that the needle induces decreased pain transmission through 1 or more of the following mechanisms: the release of substance P and calcitonin gene-related peptide, which creates vasodilation that prevents local ischemia and hypoxia; activation of Aβ and Aδ fibers; activation of the endogenous opioid system; or relief of referred pain due to a peripheral nerve blockade effect.^4,16,17

Application in the Adult Population

Nerve Blocks

Figures 1 through 8 demonstrate the techniques for the different NBs that the headache provider can perform easily. There are burgeoning data to support these procedures.

A 2018 through 2021 meta-analysis¹⁸ of 4 RCTs involving 224 participants filled a gap in the literature because no previous systematic reviews or meta-analyses had examined GONBs for acute migraine relief. In these RCTs, GONB was administered using either .5% bupivacaine or 1% lidocaine, compared with placebo. The results showed that GONB significantly reduced pain scores at 30 minutes by 1.95 points, and at 45 to 60 minutes by 2.31 points. However, no significant effect was observed on pain scores within the first 15 minutes or after 60 minutes, and there was no change in the need for rescue medication.

In a 2023 RCT,¹⁹ participants with chronic migraine were randomized to receive either lidocaine or saline GONBs every 4 weeks for 12 weeks. The treatment group experienced a significantly greater reduction in mean headache days from baseline during weeks 9 through 12 (−7.2 vs −3.0 days, respectively; P=.018). A significant difference in the percentage of cases achieving ≥50% reduction in headache days from baseline was also observed (40.9% in the treatment group vs 9.1% in the control group; P=.024). 

GONBs also have supporting evidence demonstrating efficacy for pain management in episodic migraine. A 2022 RCT²⁰ found significant reduction in attack frequency at week 4 in participants receiving GONBs with lidocaine (−5.81 attacks per month; 95% CI, −2.52 to −9.09) or lidocaine plus triamcinolone (−5.69 attacks per month; 95% CI, −1.11 to −10.27). These participants also reported decreased headache severity and duration.

A notable RCT from 2023²¹ focused on headache treatment during pregnancy, comparing standard care (oral acetaminophen and caffeine) with GONBs. Participants were randomized to either group and then given crossover treatment at 2 hours. The GONB group had lower median visual rating scale scores at 1 hour, with more participants in the group achieving scores ≤3. In addition, after crossover, the standard care group experienced significantly lower visual rating scale scores after GONBs compared with the GONB group after switching to standard care. Pregnancy outcomes, including birthweight and mode of delivery, were similar between the groups, and the intervention was well tolerated. Thus, GONBs were deemed a viable, fast-acting option for the acute treatment of headache during pregnancy. 

Pericranial NBs are widely used. In 2024, 664 sets of injections were performed on 252 individuals (age range, 12 to 73 years; 1 to 15 procedures per individual during the year, with injections performed at least 1 week apart) at the SouthEast Center for Headaches (Sandy Spring, GA). Most patients only received 1 procedure during the year (59.5% [150/252]). The mean (median) number of procedures for the people who received >1 set of injections was 7.2 (4) per individual over the year (Dr. Khoury, personal data).

Cluster headache (CH) is another primary headache disorder with a demonstrated response to GONBs. For example, a 2020 study²² on people with CH refractory to standard oral therapy found that GONB use with lidocaine led to clinical success (defined as a >50% reduction in headache severity on the Visual Analogue Scale) in 81% of participants at 1 month, with 69% maintaining the response at 3 months and 31% at 6 months. Similarly, a retrospective study²³ showed a positive response to greater occipital nerve lidocaine/corticosteroid injections in people with medically intractable or non–medically intractable chronic CH. Clinical improvement was reported after 69% of first injections, 68% of second injections, and 82% of third injections. A 2022 observational prospective study²⁴ suggested that 3 GONB injections of 60 mg methylprednisolone on alternating days could provide a median pain-free period of 3 months in people with chronic CH. SPG blocks also have been shown to help in CH.²⁵

Trigger Point Injections

With TPIs, hyperirritable spots in pericranial myofascial tissue are targeted to alleviate pain. A 2023 systematic review²⁶ found decreased headache frequency and orofacial pain in 83.7% of people receiving anesthetic injections, 37% receiving saline injections, and 93% receiving dry needling, underscoring the therapeutic role of intramuscular interventions. A 2025 pilot study²⁷ on ischemic compression myofascial trigger point therapy reported reduced headache intensity, frequency, and duration in people with episodic and chronic migraines. Furthermore, a 2024 study²⁸ found that concurrent administration of myofascial TPIs and occipital NBs (greater and lesser occipital nerves) significantly reduced headache severity and migraine days compared with occipital NB alone in participants with chronic migraine. TPIs were performed in the capitis, sternocleidomastoid, trapezius, and splenius muscles.

Despite promising results for migraine and CH, no RCT has specifically evaluated GONB treatment for occipital neuralgia, highlighting the need for further research. However, according to the third edition of the International Classification of Headache Disorders, the response to occipital NB is part of the diagnostic criteria.²⁹

Despite an increasing number of narrative reviews, systematic reviews, and meta-analyses, the volume of new RCTs solely assessing GONBs against placebo for various headache disorders appears to be declining. However, emerging research is exploring innovative modalities, such as ultrasound and CT guidance for GONBs, pulsed radiofrequency, and combination blocks targeting multiple pericranial nerves.

Overall, GONBs are effective for migraine—both for preventive and acute treatment—as well as for episodic, chronic, and pregnancy-related headaches. Their expanding use in CH, especially with corticosteroids, is encouraging. The procedure itself is generally well tolerated with mainly transient local adverse effects such as injection site pain and swelling,^19,30 and occasional systemic effects such as abdominal distention and paresthesia.³⁰ The local anesthetics used are also generally safe. However, if a large amount of drug is absorbed into the systemic circulation, this can result in toxicity (eg, local anesthetic systemic toxicity—a rare and potentially life-threatening complication). Bupivacaine is 1 of the most potent local anesthetics and most challenging to treat when local anesthetic systemic toxicity occurs, which may lead some providers to choose lidocaine over the longer-acting bupivacaine.³¹ Steroid use may also increase the risk of side effects like alopecia and cutaneous atrophy.²⁰

Given their ease of administration, low risk of interactions, and a favorable safety profile, NBs, TPIs, and SPG blocks are valuable tools in headache management. Yet, to fully understand their potential, more rigorous RCTs are essential to guide clinical practice, solidify insurance coverage, and optimize outcomes.

Application in the Pediatric Population

Similar to the prevalence of headache in the adult population, headache is the most common cause of neurologic disability in the pediatric age group. Approximately 10% of children have migraine, the majority of whom will have symptoms persisting into adulthood.^32,33 There has been an alarming increased burden of disease in this age group.³⁴ Compared with their headache-free peers, children and adolescents with headache miss more days of school, perform more poorly in school, and report a lower quality of life.^35,36 Despite this, there is a paucity of evidence-based treatments and a dearth of research in pediatric headache compared with adult headache medicine.³⁷ Medical management for headache in children and adolescents is often extrapolated from adult protocols. This is true of the use of NBs and TPIs. According to a survey of pediatric headache specialists,³⁸ most (80%) either perform or refer people for NBs for a variety of indications, including episodic migraine and status migrainosus, chronic migraine and chronic migraine exacerbation, posttraumatic headache, new daily persistent headache, trigeminal autonomic cephalalgias, cervicogenic headache, occipital neuralgia, or other cranial neuralgias. 

A handful of published reports and a growing number of studies presented at national meetings have assessed the use of NBs in pediatric headache.^39-44 Most published literature consists of case reports and retrospective case series where either lidocaine or bupivacaine is used in different doses, and half of these included a steroid. These are injected over different combinations of major nerves, the most common being the greater occipital nerve.^38-44 All published reports, which tend to skew toward positive findings, support using NBs in pediatric headache management, noting that the procedure is safe and can provide headache relief for most children. The most commonly reported side effects in children and adolescents include injection site soreness, temporary headache worsening, transient lightheadedness, and in one case, an allergic reaction which could have been due to the sedative used for the procedure.^39-45

There is new evidence of benefit for the use of NBs for status migrainosus in children and adolescents in the form of a well-designed blinded RCT (Occipital Nerve Blocks for Acute Treatment of Pediatric Migraine, NCT03526874), in which lidocaine injections were shown to be superior to saline for refractory headache.⁴⁶ All participants received topical lidocaine cream before injections of either lidocaine or saline. Of the 58 eligible participants (mean age, 16 ± 1.8 years), the use of topical lidocaine for 30 minutes before the procedure resulted in a mean decrease in pain score of .2 ± .9 points on a 0- to 10-point scale. After randomization, the lidocaine injection group reported a mean decrease of 2.3 ± 1.9 points in pain compared with the saline injection group, who reported a decrease of 1.1 ± 1.9 points (t test; P=.01). In the lidocaine group, 22 of 29, compared with 14 of 29 in the control group, reported a least partial relief in severity or location of pain (χ2; P=.03).⁴⁶ This is the first high-quality evidence for the use of NBs in pediatric migraine, and this peer-reviewed publication is likely to be cited often when insurance approval is questioned for this procedure in children. 

High-quality evidence in the form of single-center RCTs also supports the use of NBs in prevention of acute headache attributed to craniotomy.^47,48 For example, use of NBs during onset of surgery is associated with decreased intraoperative fentanyl use, more stable blood pressure, and decrease in objective pain scores for at least the first 24 hours after surgery. A longer time to first request for analgesic was also reported.^47,48

NBs can be performed in the outpatient or the inpatient setting. One retrospective cohort inpatient study of children with status migrainous compared treatment with dihydroergotamine vs NBs. Children treated with NBs were found to have shorter hospital stays, similar pain relief, and minimal side effects (injection site pain vs nausea/vomiting for dihydroergotamine).⁴⁹

In addition to NBs, according to the results of a survey provided to the Pediatric–Adolescent Headache Special Interest Section of the American Headache Society, approximately half of respondents also use TPIs in pediatric headache management.³⁸ However, not many studies evaluated the use of TPIs in this population. The cases reported in the literature usually relate to localized head pain such as idiopathic retroauricular pain,⁵⁰ rather than headache management.

Conclusion

Despite growing evidence supporting the use of NBs and TPIs in headache management in both adult and pediatric headache populations, there is an ongoing need for more high-quality research studies and research funding. However, there is consensus on the use of NBs and TPIs among headache providers for both pediatric and adult populations,^51,52 making NBs and TPIs part of the standard of care. 

Despite the low risk and potential benefit of NBs and TPIs in the management of headache disorders, insurance coverage can be a major barrier to their use.⁵³ In addition, high-deductible insurance plans can pose a significant financial burden, requiring individuals to pay out of pocket until their deductible is met, even when these procedures are approved by their insurance carrier.

For medical practices, obtaining prior authorization from insurance companies is often the largest hurdle.⁵³ Insurers require thorough documentation proving medical necessity before approving coverage. During follow-up visits, providers must assess and document the individual’s pain relief and its duration to justify continued approval for additional treatments. Even with sufficient documentation, including amounts of discarded medication, insurers may still deny coverage, citing a lack of long-term research evidence and classifying the procedure as experimental. When coverage is granted, it is often restricted. Some policies only cover injections targeting specific branches of the occipital nerve or limit the number of treatments allowed per year. Documentation requirements vary by insurance provider, adding further complexity. The need for prior authorization and frequent denials can place a considerable administrative and financial burden on medical offices, and limit access to treatment.⁵³ Ultimately this may lead to continued worsening of disease and inequitable care based on which people may be able to absorb out-of-pocket costs. With growing evidence for the efficacy and safety of NBs and TPIs, these procedures need to be consistently covered by insurers.