Integrative approach to headache

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Notes on An integrative approach to Headaches

Disclaimer:

This represents my personal approach – Dr. Remde. Please double check all therapeutics with other resources.

As with all documents on this website, does not represent medical advice. For general education only.

 

 

  • Overview
  • Tension-type and migraine headache 2nd & 3rd most prevalent disorders in the world. Migraines in 10% of population, Female: Male ratio is about 3:1. Major impact on quality of life and lost work days. 50 % Migraines under diagnosed! Directly ask if problems with headaches, because patients often don’t talk to their physicians about them.
  • Red flags/Increased surveillance:
  • First or worst
  • Abrupt new headache
  • >50 yrs.
  • Abnormal exam
  • Unstable pattern
  • Systemic illness
  • H/o cancer or immunosuppressed
  • New onset bad headache and pregnant (r/o venous thrombosis.)
    1. Secondary headaches:
      1. Subarachnoid hemorrhage (SAH) (CT misses early sentinel bleed 25 % of time – need to do LP to rule out).
      2. Meningitis (infectious on non-infectious) Fever + headache as PRIMARY complaint = R/O MENINGITIS
      3. Abnormal Intracranial pressure (ICP) (Too high or too low)
      4. Intracranial hematoma. Epidural bleed typically has a lucent interval.
      5. Tumor (rare for tumor to present SOLEY with headache with no other alarm symptoms or other physical exam  (PE) findings)
      6. Abscess
      7. Other
      8. Differential Diagnosis (Ddx) of Thunderclap headache:
        1. Aneurysmal rupture (or occasionally expansion, thrombosis, vasospasm)
        2. Cerebral sinus thrombosis (watch for in pro-thrombotic patients)
        3. Acute intracranial hypotension/CSF oligemia or leak, e.g. from dural leak (MRI w/ gadolinium will show meninges light up)
        4. Sexual headache, explosive type: indomethacin is Drug of choice (DOC).
        5. Crash migraine-(an unusual form of migraine that’s severity is maximal at onset)
      9. If eye pain is caused by eye dis, almost always eye LOOKS ABNORMAL to your naked eye. If not, it usually is neurologic cause, especially if eye signs
    2. Risk factors for secondary headache:
      1. ABNORMAL EXAM!
      2. Acute onset
      3. >55
      4. Occipital-nuchal location
    3. Neuroimaging: Any of above need imaging, e.g. MRI. Headache + blood thinner = brain imaging.
  • Migraines
      1. Overview: many often not formally diagnosed, patients often rely on Over the counter (OTC) for acute treatment.
      2. Genetic susceptibility: Migraine patient’s brains demonstrate hypersensitivity to visual, olfactory and auditory stimulation, and become more sensitive with repeated stimulation leading to allodynia, with slower than normal recovery from insults. A migraine is a genetically determined neurologic disorder of which headache is an intermittent expression. The nervous system is extra sensitive in migraine suffers – even when no headache is happening:
      3. Comorbid conditions: Depression/Anxiety, Insomnia, Irritable bowel syndrome (IBS), Fibromyalgia, Raynaud’s, Premenstrual syndrome (PMS), Essential tremor, Epilepsy, Stroke (slight increase incidence), Sensitivity to Medications!!
      4. Risk factors:
        1. F > M
        2. Obesity
        3. Low socioeconomic level
        4. Chronically exposed to stress, sleep deprivation, and poor self-care practices. 1/3 female medical students have migraines
        5. Child maltreatment strongly associated with migraines, with associated depression, anxiety, chronic illness, chronic pain IBS, chronic fatigue syndrome, and arthritis.
      5. Pathophysiology: ‘Migraine generator’ is in the serotonin-rich nuclei in the posterior midstem. Serotonin acts as a brake. The ‘engine’ is likely dopaminergic hypersensitivity which mediates prodromal migraine symptoms (as opposed to aura) including malaise, nausea, yawning, food cravings, irritability and motion sensitivity and triggers cortical spreading depression which, in turn, results in decreased cerebral blood flow. The cortical spread of slow waves from occiput is the cause of aura, which last < 60 minutes. Initial vasoconstriction is followed by vasodilation and sterile inflammation of meningeal vessels and pain. The vasoconstriction plays little, if any, role in the pathophysiology of migraine (including the increased risk of stroke).
      6. Mechanism of action of pharmaceuticals:
        1. Anti-migraine medications block cortical spreading depression (CCBs, anti-convulsants) or stimulate inhibitory serotonin receptors (Triptans), reducing pro-inflammatory neuropeptides in the afferent trigeminal pathway.
        2. Menstrual migraines: falling levels of progesterone lead to dopaminergic hypersensitivity, destabilizing the trigeminovascular system and resulting in a migraine attack. Dopamine blocking drugs include anti-emetics and phenothiazines, which may reduce both the pain and the nausea of migraine.
        3. Calcitonin Gene Related Peptide (CGRP) produced by both central and peripheral neurons plays a key role in the trigeminovascular system. CGRP monoclonal antibodies improve migraine frequency and severity, sometimes with prolonged remission (Schulte, 2015 doi: 10.1016/S1474-4422(14)70295-9).
      7. Migraines & hormonal effects: ~ 60% of F migraineurs have menstrual migraines.
        1. Estrogen “withdrawal” in the late luteal phase can trigger migraine. Ovarian hormones affect inflammation, affective states, stress responses, and pain reactivity. Estrogen and progesterone have potent effects on central serotonin, norepinephrine and opioid neurons, modulating both neuronal activity and receptor density.
        2. OCPs increase RR 10X for new onset migraines. OCPs increase frequency migraines during placebo week and increase stroke risk. WHO states OCPs absolute contraindication if migraine with aura, others make relative contraindication. For women desiring OCPs who have migraine with simple visual aura and no other stroke risks (e.g., smoking) choose ethinylestradiol (EE) < 35 mcg and drospirenone (DRS) which has less migraine risk. Otherwise, use (IUD), progestin based, or barrier forms of contraception. Close follow-up to monitor the headache pattern is crucial to pick up new onset aura symptoms or changes in cardiovascular risk status. The OC should be discontinued if migraines worsen after the first few months of treatment or if she develops aura.
        3. Perimenopausal woman with migraines may benefit from non-oral route, low dose HRT if no contraindications. Transdermal estradiol patch or gel can be used during the “placebo” week or 1-2 days before the onset of menses to prevent a rapid decline in serum estradiol. The dose is typically 100 mcg estradiol patch. If contraindications to HRT, consider venlafaxine, fluoxetine, or paroxetine for control of hot flashes and migraines.
  • Children and migraines
    1. Reported as young as 18 months old. Prevalence equal pre-pubertal. Half of all migraine sufferers will have their first attack before the age of 12, leading to school absences. Migraine often goes undiagnosed in children, as the headache is generally less severe, shorter duration may be bilateral and migraine equivalents may predominate such as unexplained N/V, abdominal pain, or dizziness. Motion sickness is an early warning of predisposition to migraine.
  • Triggers:
  • Triggers are highly individualized and often multiple.
  • 97% named at least one food trigger Perceived migraine triggers: do dietary factors play a role?. Camboim Rockett F; Castro K; Rossoni de Oliveira V; da Silveira Perla A; Fagundes Chaves ML; Schweigert Perry ID. Nutricion Hospitalaria. 27(2):483-9, 2012 Mar-Apr. . Research Support, Non-U.S. Gov’t] UI: 22732972
      1. Most common: “emotional stress” (59%), “too much or little sleep” (53.5%), “odors” (46.5%), and “missing meals” (39%).
      2. “Let-down headache” after a stressful period common
      3. Caffeine withdrawal important nutritional precipitating factors of both migraine and tension type headache, and there is also evidence that missing meals and dehydration can trigger migraines. May be stress rather than alcohol per se that is the trigger. Chocolate not a trigger in controlled trials.

Clinical presentation & Dx: Mild tension headache is common & these people usually don’t seek medical attention, BUT severe ‘tension headache’ is almost always part of migraine continuum & rarely exists as a sole type of headache. Episodic and chronic disabling headache is usually migraine. Under diagnosed in 60% F & 70% M! Most prevalent young and middle-aged adults, declines after 50 y/o

International Headache Society (IHS) Criteria

    • : Any 2 of:
    • 1. Unilateral
    • 2. Throbbing
    • 3. Worse w activity
    • 4. Moderate or severe
    • + any 1 of following:
    • +N/V
    • +Sense – phobia
      1. Do NOT have to have GI SE’s, Unilaterality, Pulsation
      2. OFTEN triggered by weather changes.
      3. MAY have runny nose, congestion, & ‘sinus ache’ are common part of migraine.
      4. True ‘SINUS HEADACHE’ IS A RARE DX
      5. 60% prodrome & 90% during headache have neck pain!
      6. 10% have aura: slow onset, disappears usually after 15-30′, occasionally up to 60’, moves across cortex 2mm/min as cortical spreading depression.
        1. Aura’s should have:
          1. Positive component, e.g.  ‘bright lights’
          2. Negative component, e.g.  ‘blind spots
          3. Dynamic component, e.g.  ‘shrinking or expanding’
      7. Arteriovenous malformations (AVMs) are linked to migraine and a migrainous aura may be the only clinical manifestation of an AVM before it bleeds. AVMs in the occipital, parietal, and temporal lobes are most likely to present with aura-type symptoms. Late age of onset of symptoms, complicated auras, absence of typical angular, scintillating features of migraine visual aura, unusual neurologic symptoms including seizures and coma, and headache that starts before rather than after aura may all be warning signs. An epileptic aura can be difficult to differentiate but may include changes in awareness, positive motor phenomena or automatisms. Multiple discrete aura attacks occurring within a single day, even with associated migraine headache, may suggest an underlying coagulopathy.
      8. ‘PIN’: Answering ‘yes’ to 2 questions has sensitivity & specificity of ~ 75%:
        1. Photophobia: Does light bother you when you have a headache?
        2. Impairment: Has a headache limited your activities for a day or more in the last 3 months?
        3. Nausea? Are you nauseated or sick to your stomach when you have a headache?
  1. Chronic Daily headache = medication overuse headache (MOH) until proven otherwise. Can occur with ANY analgesic. 1-2% of headache sufferers. The intrinsic pain reaction system fails in the setting of chronic analgesics.
      1. Co-morbidities such as depression, anxiety, and sleep disturbances are common. It usually, but not invariably, resolves after the overuse is stopped. Migraine transformation: Episodic–> Tension–> Mixed–> Chronic daily headache (this would NOT have N/V, Photophobia, etc.)
      2. Key Point: Cutaneous allodynia strongly associated with chronic migraine and the risk for progression from episodic migraine to chronic migraine. Medications with a high risk for inducing medication overuse headache such as caffeine, butalbital and opioids should be used with extreme caution if at all.
  • Migraine tx

 

      1. Quality of life worse than CHF, O/A.
      2. Try average of 5 different options before find effective tx.
      3. Stratified care better:
        1. Tx matched to migraine severity/level of disability
        2. Tx early
        3. Change tx as needed
        4. Tx triggers: Smoking, fumes. Allergies – Astelin good for these acutely. Food
      4. Key is to remove fear of the next migraine
  1. Natural treatment:
      1. Pillars of health. Keep regular habits. Healthy wt. loss helps reduce migraine in the obese
      2. Mind/body modalities first line, LOE A, such as CBT, relaxation, thermal & EMG biofeedback. Help patient adapt to ‘sensitive nervous system’ and higher stress responses. Options include yoga, meditation, MBSR, hypnosis, others
      3. Acupuncture well supported for acute and prophylaxis migraines. At least as effective and possibly more effective than medication prophylaxis. Generally twice a week for at least 10 sessions. Cochrane 2009
      4. Physical modalities:
        1. Ice massage neck
      5. Supplements:
        1. Magnesium deficiency may be important in pathogenesis of migraine headaches, by promoting cortical spreading depression (CSD), alteration of neurotransmitter release, hyperaggregation of platelets and vasoconstriction (Review by Sun-Edelstein, 2009 doi: 10.1097/AJP.0b013e31819a6f65) (LOE B) ‘Strong recommendation’ by Canadian Headache Society (CHS).
          1. Dose: Magnesium glycinate or chelate e.g. 600 – 800 mg/day in divided doses or take one dose HS. Especially helpful in menstrual migraine, pediatric migraine/tension headache. Safe in pregnancy.
        2. Riboflavin – may help mitochondrial dysfunction, energy production. Deficiency can occur in pregnancy, infancy, and the elderly. Sx include light sensitivity. Powers, 2003, PMID: 22683887). Evidence mixed. (strongly recommended by CHS (Pringsheim, 2012, Canadian Headache Society guideline for migraine prophylaxis, Can J Neurol Sci. 2012 Mar;39(2 Suppl 2):S1-59), ‘B’ recommendation by American Academy of Neurology (AAN) (Holland, 2012)
          1. Dose 4 100mg. tabs/d
        3. CoQ10: may benefit if mitochondrial dysfunction. RCT of 42 patients found 100 mg TID of CoQ10 for 3 months superior to placebo; 48% of subjects had ≥ 50% reduction in attack frequency, NNT = 3 (Sandor, 2005 PMID: 15728298). In another study of 1,550 migraine patients from 3-22 years old (mean 13.3 years), low CoQ10 levels were detected in 33%. After roughly 3 months of supplementation with CoQ10 at doses of 1-3 mg/kg, headache frequency and disability were reduced and CoQ10 levels were repleted (Hershey, 2007, PMID: 17355497). CoQ10 was ‘strongly recommended’ for migraine prophylaxis by the CHS (Pringsheim, 2012), ‘possibly effective’ by AAN. (Holland, 2012, doi: 10.1212/WNL.0b013e3182535d0c.).
          1. Use q-gel or a liposomal bound product. (Reduced form, ubiquinol, is better absorbed and more effective in CHF patients with presumed intestinal edema compared to standard ubiquinone, unknown if this is relevant to migraine use (Langsjoen, 2008 PMID: 19096107)).
          2. Dose:
            1. Adults: 300 mg/d, e.g. 100 mg TID. NNT ~ 3
            2. Peds: 1-3 mg/kg
          3. Safety: CoQ10 is generally well tolerated. Testing for deficiency may help tailor which patients will likely benefit from therapy. Safe in pregnancy; may also help prevent pre-eclampsia.
        4. Folate rich foods, esp. if MTHFR C677T variant Effects of dietary folate intake on migraine disability and frequency. Menon S; Lea RA; Ingle S; Sutherland M; Wee S; Haupt LM; Palmer M; Griffiths LR. Headache. 55(2):301-9, 2015 Feb. Randomized Controlled Trial. Research Support, Non-U.S. Gov’t UI: 25598270
  1. Vitamin D. Seasonal and geographic variation in Vitamin D levels may play a role in migraine (Prakash, 2010). Statin use assoc. with lower migraines only if Vit. D > 57 nmol/L (Buettner C1 , PMID: 25424706)
  2. Omega 3 f.a. assoc. with lower migraine freq. The relationship between different fatty acids intake and frequency of migraine attacks. Sadeghi O; Maghsoudi Z; Khorvash F; Ghiasvand R; Askari G.Iranian Journal of Nursing and Midwifery Research. 20(3):334-9, 2015 May-Jun. UI: 26120333. RCT with high Omega 3/6 showed benefit. Targeted alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: a randomized trial. Ramsden CE; Faurot KR; Zamora D; Suchindran CM; Macintosh BA; Gaylord S; Ringel A; Hibbeln JR; Feldstein AE; Mori TA; Barden A; Lynch C; Coble R; Mas E; Palsson O; Barrow DA; Mann JD. Pain. 154(11):2441-51, 2013 Nov.Randomized Controlled Trial. Research Support, N.I.H., Extramural. Research Support, Non-U.S. Gov’t] UI: 23886520
  1. Probiotics – preliminary studies show decreases migraine, e.g. EcologicBarrier, 2.5×10(9) cfu/g. The effects of the multispecies probiotic mixture EcologicBarrier on migraine: results of an open-label pilot study. de Roos NM; Giezenaar CG; Rovers JM; Witteman BJ; Smits MG; van Hemert S.Beneficial Microbes. 6(5):641-6, 2015 Oct 15.[Journal Article] UI: 25869282
  2. IgG based elimination diet in IBS/Migraine pts. RCT shows significant improvement. IgG-based elimination diet in migraine plus irritable bowel syndrome. Aydinlar EI; Dikmen PY; Tiftikci A; Saruc M; Aksu M; Gunsoy HG; Tozun N. Headache. 53(3):514-25, 2013 Mar. Randomized Controlled Trial. Research Support, Non-U.S. Gov’t] UI: 23216231
    1. Botanicals:
      1. Petasites hybridus (Butterbur) is widely used as a treatment for allergies and migraine prophylaxis. Inhibits lipoxygenase, leukotriene & activation of mast cells, with reduced histamine. May take up to a month to work. (Monograph, 2001). (LOE A, ‘strong recommendation’ by CHS)
        1. Petadolex (PA free) root extract standardized to contain 7.5 mg petasins
          1. Adult dose: 75 mg Gelcap po BID (more effective than 50 mg BID).
          2. Child dose: Ages 10 – 17: one 50 mg Gelcap two times daily. < 10 ‘consult physician’. (don’t give 75 mg cap to children)
          3. No serious adverse events have appeared in any clinical studies to date
      2. Tenacetum parthenium (Feverfew).
        1. Original studies on fresh plant. Migraineurs reported feeling better if ate 2 fresh feverfew leaves every day. Fresh plant can give mouth sores. 10% of long term users can get withdrawal migraines – tapering off should prevent this. Trials on dried plant mixed. May be less effective than other options such as Mg, Riboflavin, and Petasites. Feverfew CO2 extract (MIG-99) B rating AAN, but not recommended by CHS.
      3. Lipigesic-M (www.lipigesic.com ) (or GelStat Migraine) are SL combos of Tenacetum & ginger, RCTs show benefit if taken early in migraine attack (age 12 – 60). Conclusion: ‘Sublingual feverfew/ginger appears safe and effective as a first-line abortive treatment for a population of migraineurs who frequently experience mild headache prior to the onset of moderate to severe headache’. Well tolerated, can use with other migraine medications. (Cady RK, et al. A double-blind placebo-controlled pilot study of sublingual feverfew and ginger (LipiGesic™ M) in the treatment of migraine. Headache. 2011 Jul-Aug;51(7):1078-86. doi: 10.1111/j.1526-4610.2011.01910.x. Epub 2011 Jun 1). Ginger alone also has some benefit.
        1. Safety: Avoid in pregnancy
      4. Gingko:
        1. Ginkgo contains flavone glycosides that are potent antioxidants with neuroprotective effects and terpene-lactones, which block platelet activating factor (PAF) that is important for mediating inflammation and the sticking of inflammatory cells to blood vessels. Ginkgolide B modulates the action of glutamate in the CNS.
        2. Combo of Ginkolide B, CoQ10 and Vit. B12 reduced migraine frequency & severity in adults and children. (Usai et al, Neurol Sci, 2010. doi: 10.1007/s10072-010-0321-6). Ginkgolide B/CoQ10/Riboflavin/Magnesium complex in small pediatric study effective for prophylaxis (Esposito, M. doi: 10.1007/s10072-010-0411-5. Epub 2010 Sep 25)
        3. The majority of research has been conducted on doses of 120-240 mg standardized extract standardized to 24-27% flavone glycosides and 6-7% triterpenes per dose, taken at once or in two divided doses. Generally well tolerated.
      5. Nervine botanicals for stress induced migraines:
        1. Milky oat seed (gentle, safe for adults and children –‘meditation in a bottle’,
        2. Kava (root only, aqueous extract, no more than 200 mg/d of kava lactones). Great if head & neck tension),
        3. Sculletaria lactiflora (Skullcap – stronger than milky oat seed – good for the hypersensitive person)
      6. Adaptogens
        1. Ashwagandha (good for stressed/burned out, busy mind)
        2. Rhodiola (stress, chronic fatigue with migraines)

 

      1. Good combination proprietary products:
        1. Migra-Relief has Butterbur
        2. Ayurvedic migraine tx protocol Response to Ayurvedic therapy in the treatment of migraine without aura.Vaidya PB; Vaidya BS; Vaidya SK.International journal of Ayurveda research. 1(1):30-6, 2010 Jan. UI: 20532095
  • Pharmaceutical Management
    1. Most regimens are highly individualized. Some patients respond to certain “Triptans,” for example, and not to others. Often, several months of trial and error are required to establish adequate symptom control. Most migraineurs begin self-treatment by attempting to decrease sensory stimuli such as seeking dark, silent rooms. Sometimes, just withdrawal from light and noise, and a good sleep can relieve the symptoms of an acute migraine. Pharmacologic treatment of the pain associated with a migraine-in-process can range from over-the-counter acetaminophen to intravenous narcotics. The balance between efficacy, efficiency, and adverse effects can be a tenuous and challenging path at times.
  • Acute migraine tx:
    1. OTCs: metoclopramide (10 mg) and aspirin (1000 mg) offered effective pain relief and reduction of nausea and vomiting with minimal adverse effects (Kirthi, 2013). Can try Acetaminophen for mild migraines
    2. NSAID’s (Toradol is a good acute rescue)
    3. Narcotics/antiemetics (Compazine good choice – these work via increasing dopamine)
    4. Ergotamines, e.g. DHE can be very effective in aborting migraines.
    5. Triptans – efficacy 60% po/nasal, 80% for injectable
      1. Nasal spray works twice as fast. (Don’t sniff)
    6. 30% will have recurrence, because of short 1/2 life.
      1. Imitrex po-use 100 mg tabs stat.
      2. Amerge has nice SE profile & lasts longer.
      3. Do a ‘pre-op’ evaluation. Might do EST if high CAD risk or > 50 y/o & want to use triptan.
    7. Combo of Triptan + NSAID (e.g. Naprosyn, aspirin) superior to either alone.
    8. Adding anti-emetic often helpful & may also reduce headache
    9. Avoid Bulbalbital (high potential of dependence)- or at least limit to very sparing use.

 

 

 

  • Prophylactic tx:
    1. The decision to pursue prophylactic therapy is highly individualized, and necessitates careful discussion with the patient. There are no well-accepted “rules” for initiation of prophylactic therapy. The frequency, duration, and responsiveness to acute therapy is important, but less so than the overall impact upon the patient’s life. 
Often the patient’s medical history can dictate appropriate interventions. For example, in a patient dealing with hypertension, a beta-blocker may be suitable for both conditions, and reduce the risk of drug interactions from multiple agents. 
It is important to allow the prophylactic regimen ample time before proclaiming it ineffective. Often several months are required, depending upon the frequency of migraine flares.
    2. Treat HTN thoroughly. Good evidence that antihypertensives in general can prevent migraine headaches, although the mechanism of action is unclear. A meta-analysis of 94 studies reporting the effectiveness of various drugs (thiazides, beta-blockers, ACEI/ARBs) at controlling hypertension, analyzed the number of patients reporting headache (of any type). One third fewer people reported headache in the treated groups (8.0%) than in the placebo groups (12.4%) (Law, 2005
      1. Anti-HTN drugs:
        1. Beta blockers: e.g. Timilol, blocadren
      2. Anti-depressants:
        1. Amitriptyline works well for prophylaxis
        2. SSRI’s & SNRI’s
      3. Anti-convulsant meds (often limited by SEs):
        1. Topamax (avoid if nephrolithiasis)
        2. Gabapentin blocks sodium channels. It is used primarily in chronic neuropathic pain, blocking extracellular pain signaling. It has been shown to clearly reduce migraine frequency, and also positively impact duration, and quality of life among migraineurs. Mild adverse effect profile, with dizziness and somnolence predominating.
        3. Zonisamide is an anti-epileptic drug with multiple putative mechanisms of action that has been suggested to be effective in migraine prophylaxis in small case series and is used in clinical practice
        4. Depakote – valproate. Can produce weight gain, nausea, tremor, and alopecia
        5. Lacosamide, a newer anti-epileptic drug that may work by decreasing cortical hyper-excitability by blocking sodium channels, has been found to be useful in chronic migraine and medication overuse headache in small non-controlled case series (Krusz, 2010)
      4. NSAID, e.g. Naprosyn during menstrual migraines shown effective in studies.
      5. Placebo effect very strong in migraine. Example: rizatriptan (Maxalt) labeled as placebo was no more effective than placebo labeled as Maxalt

 

  1. How to handle analgesic rebound:
      1. If tapering off analgesics (don’t stop analgesics abruptly), consider steroids, e.g. Prednisone 100mg or Decadron 4 mg TID & taper over about 10 days, possibly with nasal Imitrex or DHE.
      2. Tramadol can be used to help rebound.
      3. Try to avoid opioids – have vasodilator effect & can lead to rebound and dependency.
      4. Anti-inflammatory meds have less chance of rebound.
      5. Caffeine has strong rebound.
      6. New evidence that overuse of analgesics may actually damage neurological center that turns off pain in CNS.”

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