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Ketamine’s Mechanism of Action
Ketamine (2-chlorophenyl)-2-(methylamino)-cyclohexanone hydrochloride), a human and veterinary anesthetic agent, has an extremely varied set of pharmacologic actions depending on the dosage used.1 A selective uncompetitive N-Methyl-D-aspartic acid (NMDA) glutamate receptor antagonist, the drug has been in legitimate clinical use since 1963.
When administered as an appropriate pharmacologic agent, ketamine has been shown to serve as a safe anesthetic agent. At sub-anesthetic doses, ketamine acts as an uncompetitive antagonist at ionotropic NMDA-type glutamate receptors, binding to a site on the receptor while it is open. Ionotropic glutamate receptors (iGluRs) mediate the majority of excitatory neurotransmission throughout the mammalian brain. Based on their pharmacology, there are three main classes of glutamate-activated channels:
- α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs)
- kainate receptors
- N-methyl-d-aspartate receptors (NMDAR).
Among ion-gated receptor subtypes (iGluRs), NMDAR are exceptional in their high unitary conductance, high Ca2+ permeability, and remarkably slow gating kinetics.
Ketamine has relatively specific effects on other glutamate subtypes. Several families of these receptors also include AMPA-type and kainate receptors, and the metabotropic family of receptors, of which many exist. NMDARs, in particular, are glutamate-gated ion channels primarily for calcium ions and are crucial for neuronal communication. NMDARs form tetrameric complexes that consist of several subunits. The subunit composition of NMDARs is subject to many changes, resulting in large numbers of receptor subtypes. Each subtype has distinct pharmacological and signaling properties.1 Interest and research is growing and abounds in defining specific functions of subtypes of the glutamate receptor system in both normal and pathological conditions in the central nervous system.
Clinical use of ketamine has led to reports of psychedelic side effects, such as hallucinations, memory defects, panic attacks, as well as nausea/vomiting, somnolence, cardiovascular stimulation and, in a minority of patients, hepatoxicity.2 In the author’s clinical experience, patients may feel a temporary sense of calm or fogginess after ketamine infusion.
Use in Migraine, Cluster Headache, and Neuropathic Pain Disorders
In more recent years, a very small number of clinicians, including the author, have used ketamine intravenously (IV), and in some cases, via intramuscular injection, to treat migraine, cluster headache, and various other chronic pain disorders, including mixed headache and neuropathic pain clinical syndromes.3-21 In the author’s clinic specifically, ketamine has been used via IV administration for more than 20 years to treat nearly 1,000 patients with various headache and pain disorders. These include: migraine and cluster headache flare-ups; headaches associated with orofacial pain disorders, such as trigeminal neuralgia (TN); atypical face pain; temporomandibular joint disorder (TMD); and neck pain.
Clinical use of ketamine has led to reports of psychedelic side effects, such as hallucinations, memory defects, panic attacks, as well as nausea/vomiting, somnolence, cardiovascular stimulation and, in a minority of patients, hepatoxicity. In the author’s clinical experience, patients may feel a temporary sense of calm or fogginess after a ketamine infusion.
The focus of this paper is to provide a summary of specific retrospective cases in which intranasal ketamine was used for the rescue of cluster headache in patients who had previously experienced a positive outcome from IV ketamine in the author’s outpatient clinic. Cluster headache was successfully eradicated in several patients [n = 17], prompting a mini anecdotal-based trial of rescue intranasal ketamine for continuing or new cluster headache flare-ups to be used by these patients at their home. Table I outlines the outpatient clinic’s treatment of various migraine and headache types. As shown, cluster headache was successfully eradicated in several patients [n = 17], prompting a mini anecdotal-based trial of rescue intranasal ketamine for continuing or new cluster headache flare-ups to be used by these patients at their home.
Retrospective Case Summaries
The dose of intranasal ketamine prescribed to patients ranged between 7.5 mg and 15 mg per 0.1 cc nasal spray (75 and 150 mg of ketamine per cc compounded in normal saline by a pharmacy). Patients were instructed to use one spray in the nostril of the affected side and wait 10 to 15 minutes to feel any effects, including side effects. They were to use the spray when they felt a cluster attack coming on. Patients were asked to use another spray of ketamine in the same nostril at 10- to 15-minute intervals until a sufficient degree of relief (at least 60 to 75%) was obtained for that cluster attack. If the attack still came on after about one hour, the instructions were for the patient to repeat the procedure. All patients were instructed not to drive after taking the medication and signed off on this agreement. Patients were also instructed to keep the nasal spray refrigerated when not in use; no efficacy loss was reported. Of the 17 patients who trialed the nasal spray, 11 elected not to have the intranasal ketamine compounded, or were lost to follow-up, leaving six case scenarios which are summarized herein.
A 38-year-old male, with a 16-year history of cluster headache, including a family history of the same, had tried a number of acute and prophylactic agents with, at best, a shortening of the cluster episode. His attacks tended to flare in the spring and lasted up to three months at a time with 4 to 6 episodes per day. The attacks prevented him from working and he came to the outpatient clinic for IV treatment with ketamine, which resulted in a complete cessation after three days, with resolution of allodynia on the right side as well. He elected to try intranasal ketamine (15 mg) at the first onset of his next cluster episode. He reported pain relief and a feeling of calm after 2 to 3 sprays, with no adverse effects. Sometimes, he had to repeat the dosing regimen the next day.
A 25-year-old woman was thrown from a horse during a competition and fractured her cervical spine, requiring surgery. The injury included syringomyelia between C3 and C7-T1 and left her with left-sided dystonia of the upper and lower body, abdomen, and chest wall, together with left-sided migraines, which she reported as new. Several times a year, she would awaken every night with left-sided cluster headache episodes, with facial allodynia, tearing, eyelid drooping, and increased dystonia and neck spasm; these occurred primarily in the winter season, with several up to six episodes in per night for a period of three to six weeks.
IV ketamine relieved most of her dystonic, cluster headache, and migraine symptoms, when complemented by IV and oral baclofen and tizanidine, as well as rescue opioids. Nasal spray ketamine was compounded, as well as buccal troches; both allowed her to continue working full-time in her hair salon. She reported no side effects while using the nasal spray ketamine. Liver function tests conducted every three to six months were unremarkable.
Cluster headache is characterized by excruciating, debilitating pain lasting from 15 to 180 minutes, or occasionally longer. The pain is typically located around or through one eye or on the temple. (Source: 123RF)
A 55-year-old woman with episodic cluster headache and migraine (3 to 4 attacks per week) also experienced chronic neck pain and had diagnosed TN on the right side. Her cluster headache attacks started at age 27, with tearing, allodynia, and facial numbness. On occasion, her migraine would evolve into a cluster episode that came on during sleep and was seasonal as well, lasting about 2 months on average. She was not a smoker and had no family history of cluster headache but did have a family history of migraine.
She was treated successfully for migraine, right TN, and neck pain with botulinum toxin-A injections (Botox) every 3 to 5 months, supplemented by prophylactic neuropathically active medications, but no opioids. The Botox did not affect her cluster headache, except when they evolved from a migraine, and only to a slight extent (15 to 20%). Multiple acute and prophylactic therapies were attempted to resolve the cluster headache episodes to no significant avail.
IV ketamine was tried on one occasion over a period of 4 days during a cluster headache episode. As a result, the attacks were reduced from 5 per day to 1 per day, and only 1 cluster attack the following week, which was resolved with additional oral oxcarbazepine (600 mg).
The patient agreed to trial nasal spray ketamine which was compounded at 10 mg per 0.1 cc spray with the suggestion that she spray the right nostril every 10 to 15 minutes upon attack to give the medicine time to absorb from the nasal mucosa and to repeat the process until at least 75% relief was obtained. She reported being happy with this approach as it gave her control of her hardest-to-treat symptom. She also reported that her cluster episodes became less frequent over about 1 year and that her migraine and TN also improved; her Botox injection intervals grew longer over time.
A 70-old-male, with a 40-plus year history of right-sided cluster attacks with eyelid drooping, tearing, allodynia, neck pain, and other symptoms was treated for these symptoms for many years. Opioids provided him with partial relief, at best. He had a chronic cluster headache that typically awoke him from a sound sleep at 1 or 2 am. These episodes were especially bad in the winter and during weather changes. He had a history of facial and other traumas before the headaches started, including a car accident, but no family history of cluster headache. He also had occasional migraine, about three per month, as well as chronic neck and back pain. He was treated with IV medications, including ketamine, up to 200 mg over 5 hours, with relief of his symptoms in the clinic.
He agreed to trial a compounded nasal spray of ketamine [12.5 mg per 0.1 cc] to use at each bedtime. Two sprays were indicated before each bedtime and at the first onset of any cluster headache at night. Sprays were repeated every 10 minutes until 50 to 65% relief was achieved. He took tizanidine before bedtime for neck spasm and sleep. The patient would, on occasion, repeat one or two ketamine sprays in the morning or during the day if he felt the next cluster attack coming on. As he was on frequent IV and nasal spray ketamine, his liver functions tests were routinely monitored over the course of several years; there was no observed impact.
A 34-year-old male who worked in construction began having episodic cluster headache episodes at age 22. He had a family history of migraine and cluster headache. His attacks were season-specific, occurring mostly in the early summer of each or every other year. He described the attacks as very disabling and often awoke from a sound sleep for several weeks at a time as a result of them. He had tried several oral medications, including opioids, for suppression of symptoms without any real benefit and many side effects. When he first presented to the clinic, he trialed IV lidocaine, IV valproate sodium, and IV magnesium sulfate with only partial success in shutting down the episode.
IV ketamine was also offered at the beginning of one of his episodes, and it proved to work more effectively than other treatments. Specifically, the patient’s cluster episode duration was reduced by more than two-thirds (6 to 7 weeks to 7 to 10 days). Based on this result, he was prescribed compounded nasal spray ketamine (7.5 mg per 0.1cc spray) and instructed to use the spray once at bedtime, with additional sprays in one nostril (the affected side of the cluster headache) every 10 minutes until relief was obtained to at least 75%. The patient was also instructed to use the same approach during the day if the cluster headache returned. He used nasal spray ketamine for several years and his overall pattern became easier to treat successfully. His episodes grew further apart and he has reported only one short cluster headache episode in the past four years.
She got extinction of the cluster episode or at least 75% reductions in the cluster headache severity with up to 4-5 nasal sprays of ketamine at the dose described above, and has also noticed a shortening and diminution of the cluster headache episodes as time has gone by.
A 51-year-old male, with a family history of cluster headache began having episodic attacks at age 18 with strong occurrences in the spring. He was a smoker. He had tried a calcium channel blocker, lithium, and other medications to little or no avail over the years. He found that triptans taken early in the course of a cluster attack, at several doses, would sometimes abort or lighten the burden of that particular cluster series.
A 3-day course of IV ketamine at the onset of one of his episodes nearly eradicated the episode, and since he lived a great distance (6 hours each way) from the clinic, he wanted to try the nasal spray form of ketamine for at-home application. He reported that a daily dose of 1500 mg of Depakote-ER often softened the arrival of his next cluster headache episode, as did prescribed triptans. However, he did not experience an end to the attack until IV ketamine had been administered.
15 mg per 0.1cc of nasal spray ketamine were compounded for this patient. He reported some nasal burning with the nasal ketamine formulation, so was advised by his pharmacist to use one drop of 2% lidocaine and orange oil as part of the prescription. This addition alleviated the side effect. The patient has successfully used this approach for many years to date. He requires 5 to 6 nasal sprays of ketamine per day, and his episodic cluster headache pattern has markedly softened and shortened in the past few years. He has reduced his dosage of Depakote-ER to 1 or 2 per day as well and attempted to stop smoking several times.
Discussion and Recommendation
The specificity of the ketamine speaks to a unique mechanism of action primarily through the blockade of the NMDA-glutamate and other close-related receptors. This treatment approach may provide insight into the distinctive involvement of this receptor family in the generation and maintenance of this and perhaps other, more rare trigeminal autonomic cephalalgias, or TACs.21
Based on this anecdotal evidence, observed retrospectively in the author’s outpatient clinic over a period of 20 years, intranasal ketamine seems to offer a legitimate, safe pharmacologic treatment for cluster headache rescue. The medication adds a new dimension to managing out-of-control cluster headache and mixed headache/pain disorders in an outpatient setting with no monitoring. Double-blind, placebo-controlled studies are needed to confirm these primarily open-label observations. It should be noted that a small number of patients (5) were given sham nasal treatment and their cluster headache did not respond.
The author found sub-anesthetic doses of intranasal ketamine to be very useful in the control of episodic and chronic cluster headache attacks, as well as in managing certain trigeminal neuralgia symptoms. On a 0 to 10 visual analog scale, pain scores were below 60 to 65% from initial baseline pain score after the use of the intranasal ketamine spray. Efficacy, as well as safety, and tolerability, of low dose IV ketamine were seen consistently in the outpatient clinic, without significant adverse effects. In the author’s opinion, therefore, ketamine may be considered when treating this clinically disabling condition. When used under controlled conditions, ketamine in a nasal spray form may offer a safe and more effective option to patients than emergency room visits and may also serve as a substitute for more standard IV-based rescue cluster headache medications.
About Cluster Headache:Cluster headache is characterized by excruciating, debilitating pain lasting from 15 to 180 minutes, or occasionally longer. The pain is typically located around or through one eye or on the temple. A series of cluster headaches can take place over several weeks to months, and may occur once or twice per year. Several of the following related symptoms may occur: lacrimation, nasal congestion, rhinorrhea, conjunctival injection, ptosis, miosis of the pupil, or forehead and facial sweating. Nausea, bradycardia and general perspiration may present as well. Attacks usually recur on the same side of the head. Cluster headaches afflict males more than females by a 2.5 to 1 ratio and have an overall prevalence of 0.4%. Onset of clusters is usually between ages 20 and 45. There is often no family history of cluster headache.
- Robert K, Simon C. Pharmacology and Physiology in Anesthetic Practice. 4th ed. Baltimore, MD: Lippincott, Williams & Wilkins; 2005
- Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. Br J Clin Phamacol. 2014;77(2):357–367.
- Virginia Scott-Krusz, Jeanne Belanger, RN, Jane Cagle, LVN, Krusz, JC, Effectiveness of IV therapy in the headache clinic for refractory migraine, poster at 9th EFNS meeting Athens, Greece. 2005.
- Krusz, JC. Intravenous treatment of chronic daily headaches in the outpatient headache clinic. Curr Pain Headache Rep. 2006;10(1):47-53.
- Krusz JC, Cagle J, Belanger J, Scott-Krusz, V. Effectiveness of IV therapy for pain in the clinic, Poster P183 presented at 2nd International Congress on Neuropathic Pain Berlin, Germany. 2007
- Krusz JC, Cagle J, Hall S. Efficacy of IV ketamine to treat pain disorders in the pain clinic, (poster 216). J Pain. 27th Annual Scientific. American Pain Society, 2008.
- Krusz JC, Cagle J, Hall S. Efficacy of IV ketamine in treating refractory migraines in the clinic (poster 218). J Pain. 27th Annual Scientific. American Pain Society, 2008.
- Krusz JC, Cagle J, Hall S. Intramuscular (IM) ketamine for treating headache and pain flare-ups in the clinic (poster 219). J Pain. 27th Annual Scientific. American Pain Society, 2008.
- Krusz JC. IV ketamine in the clinic to treat Cluster Headache (poster abstract). American Academy of Neurology. Neurol. 2009;72(11):A89-90.
- Krusz JC, Cagle J, Scott-Krusz VB. Ketamine for treating multiple types of headaches (poster). 14th Congress International Headache Society. Cephalalgia. 2009;29(Suppl 1)163.
- Krusz JC. Difficult Migraine Patient. Pract Pain Manage. 2011;11(4):16.
- Krusz JC, Cagle J. IV Ketamine: Rapid Treatment for All TAC Subtypes in the Clinic, Abstract Poster #72, 15th Congress of the International Headache Society, Berlin, Germany, 2011.
- Krusz JC, Cagle J. IM ketamine for intractable headaches and migraines (poster abstract). American Headache Society Annual Meeting, Los Angeles, CA, 2012.
- Krusz JC. Traumatic Brain Injury: Treatment of Post-traumatic Headaches. Pract Pain Manage. 2013;13(5):57-68.
- Krusz JC, Cagle J, Belanger J, Scott-Krusz V. Effectiveness of IV therapy for pain in the clinic, Poster P183. European J Pain:11, Suppl 1, pS80, presented at 2nd Int’l Congress on Neuropathic Pain, Berlin, Germany. 2007.
- Krusz JC, Cagle J, Hall S. Efficacy of IV ketamine to treat pain disorders in the pain clinic, (poster 216). J Pain, 9: Suppl 2, P30, 27th Annual Scientific. American Pain Society. 2008.
- Krusz JC. Ketamine IV in an outpatient setting: effective treatment for neuropathic pain syndromes (poster #378). 32nd Annual Scientific Meeting, American Pain Society, New Orleans, 2013.
- Krusz JC. Ketamine IV – for CRPS, TN/TMD and other neuropathic pain in the outpatient clinic (poster #524). 4th International Congress on Neuropathic Pain, Toronto, Ontario, 2013.
- Krusz JC. The IV ketamine experience: treatment of migraines, headaches and TAC. JAMA Neurol. 2018
- Matharu MS, Goadsby PJ. Trigeminal Autonomic Cephalalgias: Diagnosis and Management. In: Silberstein SD, Lipton RB, Dodick DW, eds. Wolff’s Headache and Other Head Pain. 8th ed. New York, NY: Oxford Univ Press; 2008:379-430.
- Johnson JW, Glasgow NG, Povysheva NV. Recent insights into the mode of action of memantine and ketamine. Curr Opin Pharmacol. 2015 ;20:54-63.
The Path from Episodic to Chronic Migraine
Although episodic migraine and chronic migraine are common, they represent distinct types of headaches on the migraine pain spectrum.1 Factors involved in the transformation from episodic to chronic migraine include frequency of episodes, failure to optimize acute treatment, overuse of acute migraine medication, lower socioeconomic status, obesity, and being female.1,2 The most common technique for managing these headache conditions is pharmacologic, however, medication overuse is also the most common reason that episodic migraine may evolve into chronic migraine, often resulting in medicine overuse headache (MOH).
According to Lipton, et al,3 patients have reported that their acute treatment of episodic migraine was poorly managed as measured by the Migraine Treatment Optimization Questionnaire, with 6.8% of patients developing chronic migraine within one year compared to 1.9% of patients reporting optimized acute treatment. These results suggested the need for more effective acute treatment strategies to manage symptoms associated with episodic and chronic type migraine. In response, several studies have since shown a potential alternative treatment involving the sphenopalatine ganglion (SPG) to be effective in reducing episodes of chronic migraine (see Figure 1).
Figure 1. The sphenopalatine ganglion (SPG). (Image courtesy of authors).
The SPG is the largest neurological ganglion outside the brain, located within the pterygopalatine fossa at the posterior attachment of the middle turbinate. This ganglion has sensory, parasympathetic, and sympathetic components that house the trigeminal nerve, branches of the palatine nerves, and various sympathetic and parasympathetic automatic branches all of which innervate the cranial cavities (eg, nose, mouth) as well as facial areas, and the nasal and pharyngeal glands.4 Based on the SPG’s anatomy and physiology, it has become evident that many associated symptoms of chronic migraine may be managed by targeting the SPG using alternative methods that aim to decrease activity in this region.
Migraine may be related, at least in part, to a hyper-excited SPG. Stimulation of the SPG has been shown to induce a pathophysiological response seen in migraine attacks, including vasodilation of intra- and extra-cranial arteries, release of substance P and neurokinin A, as well as activation of meningeal nociceptors, which may be contributing to the pain.4
Neurological Blockage of the SPG
Alternative treatments targeting the SPG have been developed as a means of lessening the symptoms associated with migraine. One trialed approach is a neurological blockade at the SPG with bupivacaine using a nasal applicator5,6 and topical lidocaine applied with a deep nasal anesthetic applicator (DNAA).7 Cady, et al, published two studies utilizing the device to deliver bupivacaine to the mucosa of the SPG. The first, primarily a safety study, was designed to determine acute effects. The researchers reported the bupivacaine treatment group (n = 26) decreased from pre-treatment 3.18 ± 2.79 to post-treatment at 15 minutes 2.53 ± 2.61, 30 minutes 2.41 ± 2.61, and 24 hours 2.85 ± 2.74.5
The second study was designed to determine the long-term effects of bupivacaine by delivering a set of 12 treatments over a period of six weeks. Results demonstrated that the bupivacaine treatment group (n = 25) had a significant decrease in the number of headaches in a month from 23.15 ± 5.12 to 17.44 ± 9.08 compared to 24.75 ± 4.35 to 22.82 ± 5.36 in a sham group, which was administered saline. Additionally, the average pain scores reported by the subjects in the prior 24 hours decreased from pre-treatment of 4.92 ± 2.2 to 2.86 ± 2.62 at six months after the last bupivacaine treatment.6
Lee, et al, reported 59 out of 66 cases treated with 26% lidocaine applied with DNAA had an average decrease of 4.9 pain points and 4.2 points at 15 minutes and 60 minutes post-application, respectively.7 The treatment provided rapid relief of the headache pain and decreased activity of the SPG, thereby reducing the pain associated with the migraine.5-7
Similarly, an inhibitory dose of photobiomodulation (PBM) appears to have a similar efficacy in decreasing SPG activity and may reduce migraine pain and frequency by inhibiting nerve conduction of type C pain fibers.8,9
Moving away from pharmacologic methods to treating migraine. (Source: 123RF)
Adopted by the North American Association of Photobiomodulation Therapy, photobiomodulation refers to light therapy treatments that utilize non-ionizing light sources in the visible and infrared spectrum.8 PBM is a non-thermal process that involves endogenous chromophores which elicit photophysical and photochemical events. These events theoretically lead to beneficial therapeutic outcomes, including the alleviation of pain or inflammation and immunomodulation, as well as the promotion of wound healing and tissue regeneration.8 More specifically, PBM emits photons of light that penetrate the skin and stimulate endogenous light receptors, which result in a physiological response. Low doses of PBM stimulate tissue healing and increase blood flow9 while higher doses tend to have an inhibitory effect, which may be used therapeutically to decrease pain.9
For example, low doses of light that are delivered to the tissue stimulate the cytochrome C oxidase (CCO) within the mitochondria, resulting in an increase in adenosine triphosphate (ATP) and a release of nitric oxide (NO) and reactive oxygen species (ROS).9 The ATP provides an increase in energy availability within the cells. When NO is released from CCO and from blood vessels, the result is an increase in ATP production and vasodilation. When ROS is in low concentrations, it activates the transcription factors, which lead to cell proliferation and growth.9
The authors trialed PBM on three patients (ages 42, 53, and 72) with a history of chronic migraine. Each patient had suffered from two to five migraine attacks per week for at least the prior 10 years (see Table I). Each was successfully treated using a PBM protocol to the SPG.
Initial reported pain levels ranged from 8 to 10 out of a 10-point pain scale. All three patients completed daily activities with difficulties due to frequent and painful symptoms. All patients had previously attempted pharmacological methods of treatment with little to no relief, or with additional side effects from MOH that hindered daily functioning.
Each PBM treatment consisted of applying a laser puncture utility probe attached to a PBM-transducer (Multi Radiance Medical) that delivered the photons to the SPG. The probe was placed just inside each nostril pointing toward the posterior nasal cavity where the SPG is located (see Figure 2). The treatment frequency and number of overall treatments were tailored to each patient’s responsiveness.
Figure 2. Inhibitory photobiomodulation treatment to the sphenopalatine ganglion with probe (image courtesy of authors).
Each treatment lasted 180 seconds per nostril (23.9 joules, 0.0382 watts, 6.87J/chronic). The device characteristics were as follows: wavelength super pulsed laser 905 nm; infrared 875 nm; Red 670 nm; total power, 25W, SPL variable frequency: 1000 Hz and beam spot size 0.4. The patients were evaluated for migraine frequency and intensity both pre- and post-treatment, and throughout the duration of the treatment.
Patient 1: This 42-year old male developed a chronic migraine condition following a traumatic head injury, resulting in a skull fracture. His regimen encompassed three PBM treatments over a 4-week period. After the first treatment, the patient experienced no migraine for 2 weeks. His reported migraine pain decreased from 8 out of 10 to a 0 out of 10 after each treatment. After the full course, the patient reported no migraine for another 2 weeks and self-discharged from our care (follow-up was not possible).
Patient 2: A 53-year-old female was scheduled to receive a course of six PBM treatments over 21 days. The patient reported reduced frequency and intensity of migraine with aura after the first six treatments. This patient did not miss any work during the treatment period. It is worth noting that prior to starting the PBM treatments, Patient 2 had missed work due to pain intensity of her migraine and what she reported as mental dullness as a result of the medication used to control her migraine symptoms. Due to the decrease in frequency and intensity of her migraine attacks, PBM treatments were reduced to one per week for 4 weeks. Patient 2 was migraine-free at discharge after 8 weeks of total treatment. At 90-day follow-up, the patient reported that she had not experienced a post-treatment migraine.
Patient 3: A 72-year-old female underwent a course of eight PBM treatments over 4 weeks (two applications per week). Patient 3 reported that she was migraine free for 10 days after the month-long treatment was completed. She was prescribed a second round of treatments, which were then reduced to weekly for another 4 weeks. The patient reported being migraine-free during the continued treatment period. There was no 90-day follow-up for this patient.
Discussion and Steps Forward
Two of the main factors that may cause episodic migraine attacks to become chronic are medication overuse and improper care for acute attacks.1-3 As demonstrated in the three cases herein, PBM treatments to the SPG were shown to be effective in decreasing pain ratings from 8 out of 10 to 0 out of 10 after each treatment. If PBM could be used effectively to treat episodic migraine, patients may not overuse medications, which may ultimately prevent the transition of episodic to chronic migraine.
Overall, the PBM treatments described herein were deemed successful in treating chronic migraine (see Table I for details). Patient 1 started with two migraine attacks per week and decreased his episodes to zero attacks per week after a course of three treatments over 4 weeks. Patient 2 reduced her migraine frequency from two to three per week to zero after 10 treatments over 12 weeks. Patient 3, who had previously experienced three to five migraine attacks per week for 59 years, reduced her attack frequency to zero migraine attacks per week after 12 treatments over 8 weeks. None of the patients reported any side effects and tolerated the treatments well.
Similar to neurologic blocks of the sphenopalatine ganglion, the response to PBM is bi-phasic, stimulatory or inhibitory, and dose dependent.9 There has been strong evidence supporting PBM inhibition of acute, chronic, and neurological pain.10 As noted, light may reduce the formation of inflammatory proteins associated with pain including prostaglandin, cox 2 mRNA, and TNF α.10 Additionally, PBM works to inhibit nerve conduction along the AΔ and C nerve fibers, which are the main nerve fiber types that conduct pain.10
It appears that the SPG and associated nerves are hyperactive during migraine attacks, as suggested by Khan, et al.4 An inhibitory dose of PBM seems to restore the SPG and associated nerves back to their normal physiological levels. A similar occurrence was reported by Cady, et al,5-6 and Lee, et al,7 after treating migraine (with bupivacaine and lidocaine, respectively) applied to the posterior nasal cavity directed at the SPG. There is some evidence that the SPG may also be associated with refractory chronic post-traumatic headaches.10 For example, Sussman, et al, successfully treated a post-concussion headache utilizing intranasal lidocaine application to the SPG.11
In this case presentation, use of PBM treatment reduced migraine frequency to zero episodes per week in patients with a 10-year or greater history of migraine for whom medication failed to manage symptoms effectively. Due to a decrease in pain and episode occurrence, all three patients were able to improve their daily function following completion of individualized PBM treatment regimen to block the SPG. With a growing demand for non-pharmacological treatments for migraine pain, photobiomodulation may be a noninvasive therapeutic option for chronic migraine. To demonstrate the efficacy of this treatment protocol, large randomized control trials should be completed to confirm validity and long-term effects.