Migraines, Tension and Cluster Headaches

Migraines, Tension and Cluster Headaches

Definition and Pathophysiology

Primary headaches, including tension-type headaches (TTH), migraines, and cluster headaches, occur without underlying disease. Pain is mediated by peripheral mechanisms and central sensitisation is instrumental in transforming episodic into chronic and debilitating headache types.[1]

Migraines affect more women than men and involve complex brain, blood vessel, and nervous system interactions. Triggers like stress and hormonal shifts can initiate attacks, starting with cortical spreading depression (CSD) and releasing neuropeptides that cause inflammation and pain. Migraines have phases: prodrome, aura, headache, postdrome, and interictal, each with distinct symptoms.[2]

Migraine phases include prodrome (up to three days before, with symptoms like anxiety and cravings), aura (briefly before headache, lasting 4-72 hours), headache, postdrome (24-48 hours of fatigue and mood symptoms for 80% of patients), and interictal (cognitive and neuropsychiatric issues between episodes for 46% of chronic sufferers).[3,4]

Tension-type headaches (TTH) is the most prevalent neurological disorder worldwide, characterised by mid to moderate headache, but increase in severity and central sensitisation may be involved in the progression from episodic to chronic TTH. As well as myofascial mechanisms increasing band pressure, inflammation and ischaemia, vascular mechanisms, such as increased blood flow, contributes to the headache characterised by dull, steady pain without significant nausea or light sensitivity.[1] Cluster headaches are rare but extremely painful, often following a circadian rhythm. They involve the trigeminal-autonomic reflex and hypothalamus.[6]

Treatment for all primary headaches includes acute analgesia and preventative strategies to reduce attack frequency, severity, and duration. This contributes to minimising the risk of medication overuse and improving quality of life.[7]

Patient Signs and Symptoms

Migraine with or without aura (aura in 30% of cases)

  • Usually unilateral location; 4 to 72 hours.
  • Moderate/severe intensity; deep and pulsating pain.
  • Nausea or vomiting, photophobia and phonophobia symptoms with or without aura.
  • Triggered by stress, cycling female hormones and alcohol and routine physical activity

Cluster Headache

  • Strictly unilateral location; 15 to 180 minutes.
  • Severe to very severe intensity; excruciating and stabbing pain.
  • Nausea or vomiting, photophobia and phonophobia symptoms
  • Aura (in 20% of cases)

Risk Factors

Metabolic dysregulation: Events like hypoxia and hypoglycemia disturb energy metabolism, triggering migraines through oxidative stress and inflammation. Glucose and lipid metabolism can often be abnormal in the peripheral blood in migraine patients.[8]

Mitochondrial dysfunction: Reduced mitochondrial function lowers ATP production, leading to trigeminovascular mediated inflammation triggering a migraine.[9]

Sleep deprivation/disorders: Poor sleep increases headache risk and worsens pain sensitivity.[10-12]

Stress: Both emotional and physical stress elevate pain sensitivity through neuroinflammation.[13-16]

Diet: Certain foods and additives can trigger migraines by activating inflammatory processes including include alcohol, cheese, chocolate, citrus, cow's milk, wheat, eggs, coffee, tea, beef, pork, corn, tomato, rye, yeast, shellfish, food additives and nitrates.[17]

Nutritional deficiency: Lack of magnesium, vitamin D, and omega-3s can increase migraine frequency.[18-21]

Chronic inflammation: Ongoing inflammation and immune activation elevate pain sensitivity.[22,23]

Hormonal fluctuations: Changes in estrogen and progesterone levels affect pain processing. Oestrogen increases release of histamine in the brain.[24,25] This effect may be particularly prominent during perimenopause due to significant fluctuations in oestrogen levels.[26]

Hyperhomocysteinaemia/MTHFR polymorphisms: Elevated homocysteine levels and genetic factors can trigger migraines.[27-29]

Mast cell activation syndrome (MCAS): Excessive histamine release from mast cells is linked to chronic headaches and migraines.[30,31]

Red Flags [32]

Infectious symptoms/sudden onset/persistent pain: New headaches with systemic illness signs (fever, stiff neck, rash) or sudden, persistent, worsening pain may indicate serious conditions like infection, brain hemorrhage, or cancer. Refer to a GP.

Post-trauma headaches: New headaches after head trauma or manual therapies may signal subdural hematoma. Symptoms include confusion, nausea, and vision changes. Immediate referral to a GP or emergency department is necessary.

Headaches from cough/straining: These may indicate a brain mass or subarachnoid bleed. Refer to a GP.

Postural headaches: Headaches worsening upon standing may suggest low cerebrospinal fluid pressure. Refer to a GP.

Pregnancy/post-partum headaches: May indicate cerebral vein sinus thrombosis (CVST). Common in women aged 25-35, especially post-partum. Refer to a GP for neurological investigations.[33]

Vision abnormalities: Headaches with visual disturbances may indicate glaucoma or intracranial hypertension. Refer to a GP.

Neurological symptoms: Headaches with movement changes, paralysis, or sensation changes may suggest serious pathology. Refer to a GP.

Depression: Migraine sufferers are at higher risk of depression. Use assessment tools and refer to mental health professionals if needed. Seek immediate help if there’s a risk of self-harm.[34]

Medication overuse: Overuse of migraine medication can lead to chronic headaches. Assess and address overuse and provide treatment to reduce symptoms.

Screening and Investigations

Clinical Screening

Rationale

Depression Anxiety Stress Scale (DASS-21)

A self-report questionnaire designed to measure the three related negative emotional states of depression, anxiety and tension/stress.

Health Appraisal Questionnaire (HAQ)

The HAQ provides a comprehensive assessment of physical health, allowing Practitioners to evaluate overall health and wellbeing.

Mood and Stress Questionnaire

A questionnaire designed to help Practitioners establish levels of stress, anxiety and mood concerns.

MCAS Questionnaire

Identifies and calculates the likelihood of MCAS based on clinical signs, triggering factors, laboratory parameters, imaging methods, and medical history.

Migraine Buddy

An advanced migraine and headache diary and tracking application. It helps users record and identify triggers of migraines, symptoms, medication, migraine frequency and duration, pain intensity and location.

Sleep Assessment Questionnaire (SAQ)

A questionnaire designed to help Practitioner’s screen patients for sleep health

Patient Sleep Tracker

A symptom tracker to allow patients to track their response to treatment.

Patient Pain Tracker

A symptom tracker to allow patients to track their pain response to treatment.

Blood Pressure

Monitor if patient is at risk of or presenting with cardiovascular complications.

Pathology Testing

Rationale

Erythrocyte sedimentation rate (ESR)

ESR is a non-specific indicator of inflammation. Raised ESR levels in patients with headache symptoms may indicate comorbid primary causes such as cranial arteritis, a collagen disease of systemic infection.

Vitamin D

Serum vitamin D level between 50 and 100 ng/mL (i.e. 125 to 250 nmol/L) has been associated with 80% lower odds of migraine headache, compared to serum level below 20 ng/mL (i.e. <50 nmol/L).

Plasma homocysteine (Hcy)

Hyperhomocysteinemia is characterised by raised plasma concentrations of homocysteine (Hcy) [i.e. >15 µmol/L], which may contribute to migraine pathophysiology.

Methylenetetrahydrofolate reductase (MTHFR) single nucleotide polymorphisms

Genetic polymorphisms have been associated with an increased prevalence of migraine.Elevated serum levels of homocysteine have been found to be elevated in migraine sufferers.

Lipid profile, fasting insulin and blood glucose

Metabolic dysfunction indicated by dyslipidemia, insulin resistance/blood glucose and other deranged metabolic markers can be a triggering cause of headache and migraine symptomatology.

Serum thyroid stimulating hormone (TSH)

TSH concentration is the most reliable indicator of thyroid status.

Serum free thyroxine (fT4)

Considered to provide a reliable indication of true thyroid function.

Serum free triiodothyronine (fT3)

Performed as part of a more comprehensive evaluation of thyroid function.


    Treatment Recommendations

    Core Recommendations – Acute management

    Migraine and tension headache specific, but consider for all moderate to severe primary headaches


    Highly Bioavailable Palmitoylethanolamide (PEA) with Endocannabinoid Action

    Acute dose: At onset of migraine symptoms: 2 capsules at once. If unresolved at 2 hours, may repeat this dose.

    OR

    Highly Bioavailable PEA and Magnesium for Neuromuscular Support and Pain

    Acute dose: At onset of migraine symptoms 1 serve in water immediately. If unresolved at 2 hours, may repeat this dose

    Palmitoylethanolamide (PEA) (Levagen+) employs water dispersion technology to enhance absorption by 70% to therefore increase clinical efficacy in delivering pain relieving anti-inflammatory and analgesic properties.

    • A randomised double-blind placebo-controlled study involving 64 migraineurs, found that 27/33 patients who took a single 600 mg PEA Levagen+ at the first onset of symptoms, migraine resolved within 2 hours, compared with 14/31 of those taking placebo. For those patients whose symptoms were unresolved, the dose was repeated at 2 hours and were followed up for 8 hours. Those who took Levagen+ PEA dose required significantly less (almost half) rescue medication than those on placebo.[46]
    • 600 mg/d of magnesium reduced the frequency and severity of migraine attacks in adults.[64]

    Curcumin and Boswellia (Rhuleave-K™) for Rapid Pain Relief

    Dose: Adults: Take 2 capsules as required (up to six capsules per day).

    Rhuleave-K™ is a clinically proven blend of curcumin and Boswellia and processed with black sesame oil to rapidly relieve inflammatory pain, comparable to paracetamol.[39,40]

    • Boswellia downregulates pro-inflammatory cytokines, including TNF-α, IL-1 and IL-6, and leukotriene B4 synthesis, which plays a key role in attracting pro-inflammatory cells into tissues (e.g. neutrophils and eosinophils).[41.42]
    • Curcumin has been observed to lower cytokine levels, such as TNF-α, IL-1, IL-1β, IL-6 and IL-8.[42-44]
      • 900 mg/d of curcuminoids can reduce levels of CGRP and substance P over 8 weeks.[45]

    Herbal Support for Hyper HPA and Stress
    Dose: Take 1 tablet three times daily.

    A combination of ziziphus, passionflower, kudzu and magnolia to support a healthy stress response and enhance GABA activity in the brain, alleviating anxiety and nervous tension associated with stress, as well as reducing pain sensitivity.
    • Zizyphus has been shown to modify the GABAα receptor subunits expressional levels, contributing to its pain-desensitising effects.[51]
    • Passionflower has been found to modulate the GABA system, demonstrating an affinity for both GABAα and GABAβ receptors, increasing its inhibitory effects.[52]
      • A clinical trial involving 154 participants with prolonged nervous tension were treated with 1,020 mg/d of passionflower for 12 weeks. Passionflower significantly improved stress-associated symptoms including restlessness, sleep disturbances, exhaustion, anxiety, poor concentration, nausea, tremors, and palpitations.[53]
    • Kudzu has demonstrated β-adrenoceptor blocking activity , similar to pharmacological beta-blockers, which are used to reduce the physical effects of anxiety and stress such as palpitations, high blood pressure, tremor, and sweating.[54,55]
    • Magnolia exhibits muscle relaxing effects via GABAergic mechanisms, as well as neuroprotective properties.[57,58]

    OR

    If patients present with low mood or depression:
    BCM-95™ Turmeric & Saffron for Depression
    Dosage: Take 1 capsule twice daily with food.

    BCM-95™ Turmeric and saffron to modulate HPA axis activity and preventing stress-induced elevation of cortisol, glutamate excitotoxicity and subsequent volumetric changes within the brain, which can contribute to depression in patients who experience chronic migraines.[76]
    • A randomised, double-blind, placebo-controlled study involving 123 participants prescribed 500 mg/d of BCM-95® Turmeric combined with 30 mg/d of saffron revealed significant reductions in depression and anxiety symptoms after 12 weeks.[77]
    • Safranal and crocin, present in saffron, have been shown to reduce HPA axis activity and decrease stress-induced plasma corticosterone levels. Safranal has also been shown to have anxiolytic and sedative effects via innervation of the GABAergic pathway.[78]
    • Turmeric activates glutamate decarboxylase, which converts glutamate to GABA.[79]
    Gamma-Aminobutyric Acid (GABA)
    Dose: Take 250 mg – 500 mg twice daily.
    Supplemental GABA, the inhibitory neurotransmitter in the CNS, effectively reduces neuronal hyperexcitation that contributes to increased pain sensitivity.
    • GABA down-regulates neural excitability and pain perception. GABAergic neurons and receptors regulate sensory information processing in the spinal cord, subsequently altering pain perception in response to painful stimuli.[48]
    • GABA regulates neuronal excitability by binding to GABA receptor subunits, which are classified into three main groups (alpha, beta and gamma).[49]


    Core Recommendations – Preventive: reduce frequency and severity of attacks:


    Ongoing support to reduce the frequency, severity and duration of primary headaches, whilst reducing the risk to chronic central sensitisation.

    Highly Bioavailable PEA (Levagen+™) and Magnesium for Neuromuscular Support and Pain
    Dosage: Add 1 level scoop (5 g) to 200 mL of water twice daily, with food.

    A combination of PEA Levagen+™ and Meta Mag® Magnesium bisglycinate with anti-inflammatory, glutamate-blocking and endocannabinoid-like actions to attenuate pain signalling.
    • PEA down-regulates mast cell activation that contributes to migraine pathophysiology. Low magnesium levels increase pain signalling.[59] Replete magnesium levels reduce pain signalling.[60]
      • In 20 migraine patients, 1,200 mg/day of PEA resulted in statistically significant pain relief after 60 days. Treatment reduced the number of migraine attacks per month (p<0.0002). Patients taking PEA were also able to reduce their intake of NSAIDs.[61]
    • 525mg – 600mg of PEA Levagen+™ demonstrated positive effects on headache and migraine.
      • 525 mg of reduced headache pain scores by at least 85%, which was comparable to ibuprofen use after two and four hours.[62]
    Support sleep:
    If presenting with chronic sleep disorders such as insomnia or sleep apnoea:
    Magnesium with Lutein and Zeaxanthin for Sleep Pattern Support
    Dosage: Add 1 scoop (5.7 g) in 200 mL of water once daily in the evening.

    Meta Mag® magnesium bisglycinate, ornithine, ashwagandha, lutein, and zeaxanthin are blended to address disrupted sleep cycle patterns.
    • Magnesium has been shown to significantly decrease serum cortisol levels within hours of sleep initiation, resulting in increased in SWS (p<0.01).[84]
      • 500 mg/d of elemental magnesium over eight weeks was shown to significantly increase sleep time and sleep efficiency, while improving sleep onset latency (p<0.03). Patient serum cortisol levels were shown to decrease with increased in melatonin (p<0.007).[85]
    • Ornithine also improves sleep quality, as well as reducing stress markers through the regulation of cortisol and dehydroepiandrosterone sulfate (DHEAS) production. L-ornithine was shown to reduce serum cortisol and improve cortisol/DHEAS ratio supporting its beneficial effects on HPA axis function.[86]
    • Withania somnifera has been shown to simultaneously improve sleep quality and moderate cortisol levels, which may counteract stress induced HPA overactivity in insomnia.[87]
    • Lutein and zeaxanthin may assist sleep regulation by enhancing ocular macular pigment optic density and support the production and release of melatonin.[88] These carotenoids have been shown to reduce the effects of excessive screen time (i.e., six hours of screen time daily for six months) and improve sleep onset and maintenance over 6 months.[89]

    Enhanced Bioavailability Ubiquinol for Energy and Cardiovascular Health
    Dosage: Take 1 capsule daily with food.

    Active ubiquinol (CoQ10) to support mitochondrial respiration and ATP production required for cellular energy and maintenance of neuronal energy reserves, which are inversely associated with headache and migraine severity.
    • CoQ10 participates in redox reactions within the electron transport chain, which occurs in the mitochondria to produce ATP.[65]
      • In a study of 45 women with headaches and migraines, significant improvement was found in patients taking 400 mg/d of CoQ10 (n=23) versus placebo (n=17), including reduced frequency, duration and severity of migraines, as well as reducing levels of inflammatory mediators, TNF-a and CGRP.[66]
      • In 80 migraine patients taking preventative drugs, 100 mg/d of CoQ10 reduced the number and severity of migraines over three months compared to prophylactic drugs alone. Migraine-related nausea, photophobia and phonophobia were also reduced in the treatment group.[67]
      • A recent meta-analysis found that 100 mg/d to 150 mg/d of CoQ10 was more effective than placebo in reducing migraine days per month and migraine duration.[68]
    High Purity, Low Reflux, Concentrated Fish Oil Liquid or Capsules
    Dose: 4.2 mL (1 tsp) daily or 2 capsules twice daily.
    Omega-3 essential fatty acids (EFAs) to reduce the production of inflammatory cytokines and neuroinflammatory cascades that cause headaches and migraines symptoms.
    • Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) modulate the production of eicosanoids, cytokines and other factors such as peroxisome proliferator-activated receptors (PPARs), which regulate the inflammatory response.[72-74]
    • In a study of 51 chronic migraine sufferers who were also on prophylactic amitriptyline (tricyclic antidepressant), 1.5 g/d of fish oil containing 800 mg EPA and 700 mg DHA, taken for 60 days, resulted in an 80% reduction in the number of headache days per month.[75]

    Additional considerations:

    If vitamin D levels are <75 nmol/L:
    Vitamin D3
    Dosage: Take 1 capsule daily with food.

    Adequate Vitamin D is associated with reduced migraine and headache frequency and severity.
    • Serum vitamin D level between 50 ng/mL and 100 ng/mL has been associated with 80% lower odds of migraine headache, compared to serum levels below 20 ng/mL.[69]
      • One clinical study showed that 60% of a group of 60 migraine sufferers were deficient in vitamin D versus 13% in a control of 30 individuals. While 43% of the control group had adequate serum levels of vitamin D compared to 6.7% of the migraine group.[70]
      • In a retrospective observational study conducted in 157 patients, 94.9% migraineurs had vitamin D insufficiency (less than or equal to 20 ng/L 25(OH)D).[71]

    If presenting with raised homocysteine levels:
    B12/Folate (5-MTHF) for Cellular Health
    Dosage: Take 1 capsule daily with food.

    Provides methylation cofactors including folate, vitamin B12, serine and vitamin B2 to support healthy Hcy metabolism, which is associated with enhanced patient outcomes for chronic headaches and migraines.

    • Genetic polymorphisms have been associated with an increased prevalence of migraine, including MTHFR enzyme.[80]
      • In 70 migraineurs, serum vitamin B12 levels were significantly lower in migraineurs. The highest B12 quartile had 80% less odds of having migraines.[81]
      • A 2020 review concluded that supplementation of vitamins B6, B12 and folate had a prophylactic effect in patients with migraine with aura.[82]
      • Six months of daily supplementation with 2 mg folic acid, 25 mg vitamin B6 and 400 µg B12 in 52 migraineurs with aura reduced homocysteine levels, migraine frequency and subjective pain severity, with a greater response in those with C677T genotype.[83]


    Supportive Programs
    The Metagenics Reducing Allergy and Reactivity Program is designed to address the core drivers of allergy and reactivity. The program outlines key evidence-based strategies to minimise symptom severity in addition to outlining specialised dietary approaches. Full instructions are available in the free download.

    The Metagenics Stress Less Program offers patient-centred solutions to relieve the frequency and duration of stress symptoms, restore an appropriate response and rebuild resilience with lifestyle modifications and/or referring for psychological support.


    Diet and Lifestyle Recommendations

    Diet:

    • Hydration: Drink at least 2 litres of water daily, plus an extra litre per hour of exercise.
    • Dietary triggers: Limit cheese, chocolate, MSG, artificial sweeteners, citrus, and wine. Reduce histamine-rich foods like fish, cheese, cured meats, pickled vegetables, and alcohol.[90]
    • Dietary elimination: Trial elimination diets to identify and avoid food triggers.[91]
    • Weight management: Support weight loss with ketogenic diets to improve metabolic function and reduce migraine frequency.[92]
    • Nutritional focus: Minimize refined starches, sugar, saturated fats, and trans fats to reduce inflammation.[93]


    Lifestyle:

    • Acute relief: Use cold compresses, minimize light/noise, apply heat packs, and inhale lavender essential oil.[94]
    • Sleep hygiene: 1) schedule consistent bedtime allowing 8 hours in bed, 2) eliminate screens, reading and music in bed, 3) use visualisation techniques to shorten sleep onset, 4) consume last meal >4h before bedtime and limit fluids within 2h of bedtime, and 5) discontinue daytime naps.
    • Physical activity: Engage in regular exercise to improve health and reduce stress.[95]
    • Manual therapies: Use massage and manual therapies to relieve neck and shoulder tension.
    • Yoga: Incorporate yoga to reduce headache frequency and intensity.[96]
    • Acupuncture: Consider acupuncture to reduce migraine symptoms.[97]
    • Remote Electrical Neuromodulation (REN): Use REN for non-pharmacological migraine relief.[98]


    Pharmaceutical Treatments:

    New headache medications are continuing to be released. Contact Metagenics Clinical Support to ensure product recommendations are suitable for use in conjunction with pharmaceutical medications.

    For acute relief:[99]

    • Non-steroidal anti inflammatories (NSAIDs): Provide effective relief of migraine symptoms, however these are not considered effective for the treatment of chronic headache.
    • Triptans: Oral triptan medications are effective in the treatment of migraine. Subcutaneous sumatriptan/intranasal sumatriptan or zolmitriptan are effective for the management of chronic headache.
    • Inhalatory oxygen: Oxygen therapy shown to be effective for acute migraine relief in 46% patients, as well as effective in approximately 66% ofchronic headache patients.
    • Intranasal lidocaine: Considered effective for the acute treatment of chronic headache.


    Preventative medications:

    • Calcium channel blockers (Verapamil): Used prevent chronic headache and migraines.
    • Lithium: Considered effective forchronic headache.
    • Corticosteroids: >40 mg/d of steroids are effective for treatingchronic headache. Steroids may help reduce recurrence of migraine attacks that results in presentation to emergency departments.
    • Antiepileptic drugs: Indicated for migraine prevention. Uncontrolled studies have indicated some efficacy for the prevention of chronic headache.
    • Greater occipital nerve block: Used in the treatment of migraine and chronic headache.
    • Melatonin: Doses of 3 mg/d of melatonin may be effective for the prevention of migraine; 10 mg/d is considered effective for the treatment of chronic headache.


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