#cerebral vasoconstriction syndrome

[kennak]

40代後半の女性で、20代の頃から時々片頭痛がありました。 夜入浴しようと浴槽につかったところ、急に激しい頭痛が出現しました。翌朝には痛みは軽くなっていたので会社へ行きましたが、夜に帰宅後も軽い頭痛は続いていました。仕事の疲れで肩がこっているせいだろうと思い、シャワーを浴びた途端、再び前日と同様の強い頭痛に襲われました。 その後痛みは後頭部から頭全体に拡がり、めまいも伴ってきたため横浜脳神経内科を受診しました。 MRA検査では、 脳底動脈（A）や中大脳動脈（B）などに、くびれて細くなった部分と、膨らんでソーセージのような形になった部分とが交互に生じています。 可逆性脳血管攣縮症候群 （RCVS: Reversible Cerebral Vasoconstriction Syndrome） で「入浴関連頭痛」と言われてきた頭痛の正体と思われます。 入浴やシャワーがきっかけとなって交感神経系（体を緊張させる神経）が過剰反応を起こし、脳動脈が収縮して強い頭痛を起こします。シャワーを浴びただけでなったり、プールに飛び込んだり潜ったりして生じる事もあります。1) 2)3)

入浴・シャワーで頭痛 | 頭痛外来 横浜脳神経内科 | 治す | 入浴関連頭痛 | 風呂 | 治る | 原因 | 悪化

[thxnews]

MHRA Updates on Pseudoephedrine Safety Review

Understanding Pseudoephedrine Risks

The Medicines and Healthcare Products Regulatory Agency (MHRA) has recently concluded a thorough review of medicines containing pseudoephedrine, a common decongestant used to relieve symptoms of nasal and sinus congestion due to colds, flu, and allergies. This review sheds light on the very rare risks of two conditions: posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS), associated with these medications. Aimed at enhancing patient safety, the MHRA's findings are pivotal for millions of UK residents who rely on these treatments.   What Are PRES and RCVS? PRES and RCVS are neurological conditions that, although very rare, pose significant risks to individuals. PRES, also known as reversible posterior leukoencephalopathy syndrome (RPLS), involves swelling in parts of the brain, leading to symptoms such as headaches, vision changes, and seizures. RCVS is characterized by a sudden onset of severe headaches due to the narrowing of blood vessels in the brain, which can also result in stroke, seizures, or brain swelling. Fortunately, most patients recover fully from both conditions.  

MHRA's Recommendations

Following the review, the MHRA has recommended updates to the Summary of Product Characteristics (SmPC) and the Patient Information Leaflet (PIL) for all pseudoephedrine-containing medicines. This update aims to provide clearer descriptions of the risks of PRES and RCVS and potential risk factors. The agency stresses that pseudoephedrine should only be used for short-term relief of congestion symptoms and not by individuals with very high or uncontrolled blood pressure, or severe kidney disease.  

Safety First: Warning Signs to Watch For

Healthcare professionals advise patients to immediately stop taking pseudoephedrine and seek urgent medical attention if they experience symptoms such as a severe headache that develops quickly, sudden nausea or vomiting, confusion, seizures, or vision changes. These could be indicators of PRES or RCVS. Healthcare professionals and patients are reminded to report any suspected side effects through the MHRA's Yellow Card scheme, a vital tool for monitoring the safety of medicines.   A Perspective on Pseudoephedrine Usage Despite the rare occurrence of these side effects, the widespread use of pseudoephedrine in the UK is undeniable, with over 4 million packets sold in 2022 alone. The MHRA has received four Yellow Card reports of suspected PRES or RCVS linked to pseudoephedrine, highlighting the importance of this safety review in the context of its widespread use.   The Role of MHRA and Healthcare Providers The MHRA, as the UK's regulatory authority for medicines and medical devices, plays a critical role in ensuring that all healthcare products are effective and safe for public use. By issuing these updated guidelines, the MHRA not only aims to protect patients but also to inform healthcare providers about these very rare risks. This collaborative effort between the MHRA, healthcare professionals, and patients is essential for maintaining the safety and efficacy of treatments available in the UK.  

Staying Informed and Vigilant

The MHRA's safety review of pseudoephedrine-containing medicines serves as a reminder of the importance of staying informed about the medications we use. Moreover, by understanding the potential risks and knowing what symptoms to look out for, patients can play an active role in their healthcare. Additionally, the MHRA's commitment to patient safety, through reviews like this, ensures that medicines in the UK remain among the safest and most effective in the world.   Sources: THX News & Medicines and Healthcare products Regulatory Agency. Read the full article

[pccmlearning]

PRES vs PRES

Cerebrovascular Dysregulation: Posterior Reversible Encephalopathy Syndrome and Reversible Cerebral Vasoconstriction Syndrome.

[mcatmemoranda]

Brain herniation can be labeled as “brain code” to connate the emergent need to timely counteract such disastrous brain processes.

The brain is encased within the skull, any rise in intracranial pressure is limited to some extent by the compensatory displacement of cerebrospinal fluid (CSF) and changes in cerebral blood volume as evident by the Monro-Kellie doctrine.*

When it overrides these compensatory mechanisms, certain parts of the brain start herniating through specific foramina formed by the falx and the tentorial incisura within the skull, thereby propagating progressive herniation syndromes.

Brain herniation is a life-threatening event and needs urgent attention. The five types of brain herniations include:

-Subfalcine involves the cingulate gyrus, which is pushed against the falx cerebri.

-Transtenorial (uncal) involves the medial temporal lobe, which is often squeezed by a mass under and across the tentorium.

-Central involves herniation of both temporal lobes through the tentorial notch.

-A tonsillar herniation is caused by an infratentorial mass, forcing the cerebellar tonsils through the foramen magnum.

-Upward herniation occurs when an infratentorial mass compressed the brainstem.

Source

I think by "upward," they meant ascending transtentorial herniation. The chart is from an Aquifer case I'm going through.

*The Monroe-Kellie hypothesis describes the relationship between the volume of the brain, CSF, and blood. Basically, if the volume of one of the components increases, then the volumes of the other two components have to decrease to maintain a normal intracranial pressure. As intracranial pressure (ICP) increases, cerebral perfusion pressure (CPP) decreases.

CPP = MAP – ICP (MAP = mean arterial pressure)

As the CPP decreases, the body responds by increasing blood pressure and dilating blood vessels. This leads to further increases in ICP.

Signs and symptoms include headache, nausea/vomiting, ocular nerve palsies, papilledema, and mental status changes. You can also look for Cushings triad: hypertension, respiratory depression, and bradycardia.

Treatment of increased ICP involves finding the cause and providing the appropriate treatment (such as evacuation of hematoma). The head of the bed should be elevated, and IV mannitol administration (to decrease cerebral edema) and hyperventilation (to cause cerebral vasoconstriction) may be necessary.

[lupine-publishers-scsoaj]

Why Vasculitis Probably can be Ameliorated with Magnesium and Antagonists of Ceramides and PlateletActivating Factor| Lupine Publishers

Journal of Surgery| Lupine Publishers  

Introduction 

Vasculitis is characterized as an inflammatory disease of the body’s small blood vessels, particularly in the lungs and kidneys [1-4]. Many other organ regions are usually affected which often induces morbidity and mortality [1-4]. Although the exact causes of vasculitis are not known, it appears to be an autoimmune disease even though physical, chemical injuries and infections can result in vasculitis [1-4]. It is classified as a rare disease in the USA because there are only about 200,000 cases. Although numerous treatments have been advocated, there is no known cure or preventative treatment. Vasculitis often leads to difficulties in breathing and renal shut -down. In addition, vasculitis leads to cardiac malfunctions, cardiac failure and strokes. Vasculitis is clearly more common in the aged [1-4]. Recently, we have found that a few patients that were diagnosed with vasculitis appear to have a magnesium deficiency (MgD), particularly in the serum ionized Mg2+fraction [unpublished findings].

Case Report 

Unlike atherosclerosis that takes decades to develop, vasculitis of small and medium sized arterial vessels, as well as microscopic arterioles. venules and capillaries, progresses rapidly, thus producing tissue ischemia via lumen-occlusive intimal hyperplasia and inflammatory syndromes [1-4]. Whether the end result is giant cell arteritis (GCA), polyarteritis nodosa (PAN), Churg- Strauss vasculitis (CSV), Wegner granulomatosis (WG), polymyalgia rheumatica (PR), Behcets disease (BD), or other vascular diseases, invasion of the arterial and microcirculatory walls by macrophages, leukocytes and CD4 T-cells seems to be pivotal [1-4]. In addition, most of these patients appear to demonstrate coagulationopathies. The degrees of luminal stenoses vary from patient to patient. Usually, degradation of the internal elastic laminae (EL) follow suit [1-3]. It has been hypothesized that the latter stenoses are due to concentric growth of the intima which seems to be related to several angiogenic growth factors, e.g., platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) [4]. What stimulates the production of these growth factors is not completely known but is thought to involve activation of nuclearfactor-KB (NF-kB) in the macrophages and leukocytes [4]. As stated, the macrophages and leukocytes clearly play key roles in the development of vasculitis. They are activated by NF-kB to produce a host of cytokines and chemokines which are needed for tissue remodeling and granuloma formation in development of vasculitis [2,4]. What activates the macrophages and leukocytes to induce production of NF-kB is not known. 

Why Magnesium Deficiency is Most Likely a Key Player in Development of Vasculitis 

While we were routinely investigating the potential role of magnesium deficiency (MgD) in numerous cardiovascular- diseased patients, who presented with coronary arterial diseases, coronary vasospasm, acute myocardial infarctions (AMIs), congestive heart failure , and strokes, we noted that several of these patients had an underlying vasculitis together with significant deficits in serum ionized Mg, but not necessarily total serum Mg levels [5]. More than 50 years ago, two of us found that reduction in the concentration of extracellular free Mg ions (Mg2+ ) resulted in vasospasm of coronary, cerebral, and peripheral arterial vessels; the lower the [Mg2+ ]0, the more the intense the arterial vasospasm [6-13]. In addition, our laboratories found that microscopic blood vessels in skeletal, cutaneous, and cerebral vascular beds of intact rats, mice, rabbits, guinea- pigs, dogs, and piglets exhibited similar phenomena as dietary Mg intake was reduced over three to 12weeks [14,15]. Moreover, vascular reactivity to circulating humoral and hormonal vasoconstrictor agents (i.e., angiotensin II, norepinephrine, serotonin, numerous peptide mediators, etc.) was intensified when [Mg2+ ]0 was reduced; the lower the [Mg2+ ]0 , the greater the humoral and hormonal-induced vasoconstriction [6-10,13]. It is important to note, here, that these agents are often present at increased, circulating levels in cases of vasculitis. It is now clear that all cases of vasculitis are associated with increased levels of various cytokines and chemokines (e.g., IFN-alpha, IL-1-beta, IL-2, IL-8, IL-10, IL-4, IL-17, TNF-alpha, MCP-1, among others) which are pro-inflammatory in nature [1-4]. We have found that rats placed on MgD diets for 21days generate all of these pro-inflammatory cytokines and chemokines in the blood, cardiac tissues and arterial vessels [16,17]. Other investigators have also reported finding many of these cytokines and chemokines in MgD animals [18]. Furthermore, we have found that. These MgD animals generate growth factors similar to those found in patients presenting with various forms of vasculitis [4,5]. All of these cytokines, chemokines, and growth factors, we found in the MgD animals, were associated with microvascular wall remodeling and pathological alterations in the postcapillary venules, resulting in reduced lumen sizes, increased vascular reactivity, and adherence of leukocytes and macrophages on the endothelial cell walls [19-21], thus, in many respects, similar to what is seen in vasculitis. Last, but not least, we have found that the MgD state that we produced in the rats resulted in activation of NF-kB in cardiac, cerebral, and peripheral vascular smooth muscle cells [16-23]. In view of our findings, we believe, collectively, it is difficult to dismiss the probable role of MgD in the etiology and sustenance of a state of inflammation and vasculitis. Thus, we recommend that our hypothesis should be tested in two ways [24-26]: a) Use a Mg2+ -ion selective electrode like those we helped to pioneer [27-31], in order to carefully measure the levels of ionized free Mg; and b) Administer Mg salts, initially, intravenously, then orally, for extended periods of time. 

Low Mg2+ Induces Leukocyte and Macrophage Sticking, Increased Adhesiveness to Venular Endothelial Walls, and Increased Post-Capillary Permeability in The Microcirculation

 Approximately 40 years ago, Ross et al advanced the hypothesis that atherosclerosis is an inflammatory disease brought about by injury to the endothelial surfaces of the macro- and microcirculations [32]. The hypothesis stated that different forms of injury (e.g., ischemic events) will result in numerous dysfunctions in the homeostatic properties of the endothelium, e.g., increases in adhesiveness of macrophages and leukocytes and/or platelets, alteration in the procoagulant properties, formation/release of cytokines/chemokines and growth factors. Usually, inflammation is defined as a response of microcirculatory blood vessels and the tissues they perfuse to infections and damaged tissues which bring cells and host-defense factors/molecules directly from the circulation to all the diverse sites where they are required in order to eliminate/degrade the offending agents [33]. The mediators of the defense mechanisms include white blood cells, macrophages, phagocytic leukocytes, chemokines, antibodies, and complement proteins [33]. The inflammatory process brings these cells and molecules to the damaged or necrotic tissues. During the normal inflammatory process, macrophages, leukocytes, and monocytes migrate across the venous capillary walls through holes in between the endothelial cells due to increases in permeability and move to the site(s) of injury via chemotaxis. This sequence of events is thought to take place in all types of inflammatory events and in developing vasculitis [34]. The normal mediators for these processes to take place are adhesion molecules, cytokines, and chemokines, all of which we have found in patients with different forms of vasculitis and in MgD [5,23]. 

Probable Contributing Roles of Ceramides and Platelet Activating Factor as a Consequence of MgD to Etiology of Vasculitis

 In the late 1990’s, working with proton-nuclear magnetic resonance spectroscopy (1H-NMRS), and arterial vessels exposed to low Mg2+ levels, two of us found an increased synthesis of several sphingolipids (namely, ceramides, sphingosine, and sphingosine-1- phosphate) along with an increased formation of platelet-activating factor (PAF) [35,36]. We and others have reported that many of these sphingolipids (particularly ceramides) and PAF promote vasoconstriction and vasospasm of different types of arterial blood vessels as well as arterioles and muscular venules in the living microcirculation in situ [22-24,26,37-41]. In addition, three of us found that ceramides and PAF cause increases in postcapillary permeability, leukocyte and macrophage adhesion to the endothelial linings of the postcapillary venules, and migration of these latter cell types to the extravascular tissue spaces [41]. What we found, of particular interest, is that vascular smooth muscle cells (of different types), when exposed, in primary cell culture, to low Mg2+ caused a synthesis of both ceramides and PAF, which could be selectively inhibited using specific antagonists of ceramides and PAF [42]. More than 30 years ago, Cunningham and colleagues reported that sera from rheumatoid vasculitis patients contained platelet-releasing activity [43]. Two years later, Warren and his colleagues, using a rat model of immune complex vasculitis, found that a receptor blocker of PAF inhibited an Arthus reaction [44]. Sera taken from patients in our hospitals which had an underling vasculitis (of diverse origins), and lowered serum ionized Mg, demonstrated increased levels of both ceramides and PAF [5]. We do not believe these findings are merely coincidental. It is our contention that low Mg coupled to increased cellular and serum levels of ceramides and PAF are causal agents in many types of vasculitis.

Conclusion 

Although the exact cause(s) of vasculitis is not known, Mg depletion appears to be a presence in different types of vasculitis. When several of our cardiovascular- diseased patients were admitted to our hospitals, a number of them exhibited an underlying vasculitis coupled with an ionized Mg deficiency along with elevated serum levels of ceramides and PAF. Mg-deficient animals, in our labs, exhibited elevated serum and tissue levels of ceramides and PAF which could be reduced/inhibited with specific antagonists of ceramide and PAF synthesis. Elevated dietary levels of Mg also reduced the synthesis of both ceramides and PAF, at least in experimental animals. Experimental animals fed Mg deficient diets exhibited, in-vivo, inflammatory alterations in the microcirculation similar to those patients presenting with different forms of vasculitis (e.g., elevated cytokines, elevated chemokines, elevated adhesion molecules, elevated tissue levels of NF-kB, along with other substances). In view of these new findings from our laboratories, it is our belief that patients exhibiting vasculitis should be treated with oral Mg supplements along with inhibitors of ceramide and PAF synthesis in order to determine if our hypothesis is valid. 

Acknowledgement 

Much of our original investigations were supported, in part, by research grants from The National Heart, Lung and Blood Institute, The National Mental Health Institute, The National Institute on Drug Abuse, and The National Institute on Alcoholism and Alcohol Abuse along with unrestricted research grants from several  pharmaceutical companies. Some of our studies were initiated while two of us (BMA and BTA) were on the faculty of The Albert Einstein College of Medicine. While our original studies were underway, two of our colleagues passed away, namely Professor Lawrence M. Resnick and Anthony Carella. Both of these outstanding scientists will be sorely missed. 

#Lupine Publishers

#Lupine Publishers Group

#Journal of Surgery

#Case Studies journal

[casestudies-crimson]

Worsening of Previous Vasospasm after Sertraline Ingestion: A Reversible Cerebral Vasoconstriction Syndrome Spectrum?_Crimson Publishers

Abstract

Reversible cerebral vasoconstriction syndrome is an important vascular disease. It is characterized by diffuse segmental constriction of cerebral arteries. It has different etiologies, including medications. We present a case report of a young, previously asymptomatic patient; with a mild vasospasm secondary to a resection of a sphenoid frontotemporal meningioma that had a stroke-like episode following sertraline ingestion due to the potential worsening of a previous vasospasm. Correlating it with a possible spectrum of reversible cerebral vasoconstriction syndrome, it was successfully treated with intra-arterial and intravenous Milrinone and oral Verapamil.

Read More About this Article: https://crimsonpublishers.com/aics/fulltext/AICS.000560.php

Read More Crimson Publishers Google Scholar Articles: https://scholar.google.com/citations?view_op=view_citation&hl=en&user=ecz5dXEAAAAJ&citation_for_view=ecz5dXEAAAAJ:k_IJM867U9cC

[boorgulameherthej]

Dr Boorgula Meher Thej -  Why migraine is harmful to health

Migraine has a prevalence of about 15% of the population, with women(18%) being more affected  than men (8%). Migraine is a severe headache that can last for hours or days. They frequently affect only one side of the head, resulting in moderate to severe palpitations, tremors, or severe pain. Migraine, a fairly disabling condition, is treated with rapid and preventive medications..

Dr. Meher Thej AIIMS has treated numerous migraine patients in his career. According to him, the pain of a single migraine headache usually only lasts for a few hours or days. But it will affect your health in many ways.

According to Dr. Boorgula Meher Thej, Migraine is a chronic condition characterized by episodic attacks of disabling headaches. Migraine pain is usually associated with other symptoms such as nausea, dizziness, and excessive sensitivity to light, noise, and smell. Numerous Migraine patients with chronic migraines will have additional problems that increase their tendency to headache: These covers depression, anxiety, other pain syndromes such as fibromyalgia, localized pain in the head and neck structures and conditions that cause 'metabolic' stress such as sleep apnoea or postural orthostatic tachycardia syndrome. Only about 20% of migraine sufferers experience an aura, usually before the onset of the headache (but usually not). Most aura is visual, consisting of a combination of positive visual events (floaters, flashes of light, zig-zag patterns, and so on) and negative phenomena (loss of vision blind spots). Many sufferers also experience sensory aura, often with tingling and numbness spread on one side of the body on the hands,  face, lips, and tongue. Weakness, dyspepsia and other aura symptoms are rare.

According to Boorgula Meher Tej, Thunderclap Headache and Persistent Worsening Headache are the other two common headache patterns (other than throbbing headache). Subarachnoid hemorrhage, Cerebral venous sinus thrombosis (CVST), Reversible cerebral vasoconstriction syndrome, Carotid/vertebral artery dissection, Pituitary apoplexy, Intracerebral hemorrhage/haematoma, Hypertensive encephalopathy, and Idiopathic thunderclap hemorrhage these are all causes of Thunderclap headache, and  Raised cerebrospinal fluid (CSF) pressure (tumor, abscess, CVST, idiopathic intracranial hypertension), Low CSF volume (post-lumbar puncture, spontaneous CSF leak), Meningitis (acute/chronic), Hypoxia/hypercapnia, Substance abuse/withdrawal, Systemic inflammatory conditions, including temporal arteritis, are all causes of persistent worsening headache.

How to relieve Migraine pain 

Migraine is the common cause of recurrent, severe headache. It is often difficult to identify specific triggers in patients suffering from chronic severe headaches. There are some first-line medications for migraines of mild to moderate severity. Pain relievers such as aspirin, paracetamol, ibuprofen, naproxen, diclofenac, phenazone, and tolfenamic acid can help. There are also other treatments available, such as Paradoxically it’s often the case that as chronic headaches start to boost with treatment, triggers become more obvious. Dietary regularity in relation to food, hydration, sleep, and stress is always helpful in reducing the tendency to migraine; Recognizing that this is helpful is simple, but making the expected changes in modern busy lives can be difficult. Migraine prophylaxis points to  reduce migraine frequency, severity and disability and improve quality of life.Chronic migraine patients require prophylactic therapy to reduce the frequency of migraine attacks.

According to Dr. Meher Thej AIIMS, some patients with low-frequency EM can be managed without prophylactic treatment with effective acute therapy (i.e. drugs taken during the prodrome or the migraine attack to abort it), but patients with Chronic Migraine invariably require prophylactic treatment. While acute therapy aims to abort a migraine attack, prophylactic treatment, once initiated, aims to prevent the attacks, reducing the frequency, severity, and associated disability of the headache and reliance on acute treatment, which may contribute to concurrent Medication-overuse headache(MOH).

About Dr. Boorgula Meher Thej

Dr. Boorgula Meher Thej is a neurosurgeon. He trained at AIIMS, New Delhi. He has experience in Neuro Oncology, Skull-Base Vascular Neurosurgery, Paediatric Neurosurgery, Functional-Epilepsy Surgery, Spine Surgery, and Neurotrauma. Boorgula Meher Thej's mission in life is to have a successful neurosurgical career involving all the aspects of neurosurgery, serve people, and grow himself.

[thepotterpapers]

Harry Potter and the Typical Thunderclap Headache of Reversible Cerebral Vasoconstriction Syndrome and its Various Triggers

Harry Potter and the Typical Thunderclap Headache of Reversible Cerebral Vasoconstriction Syndrome and its Various Triggers

— Potter Papers (@PotterPapers) October 24, 2018

[your-dietician]

The Overlooked Drugs to Reconsider When Prescribing for Pain

New Post has been published on https://depression-md.com/the-overlooked-drugs-to-reconsider-when-prescribing-for-pain/

The Overlooked Drugs to Reconsider When Prescribing for Pain

A review of pain medications of the past and how they may help to optimize the treatments of today.

Pain-treating clinicians are constantly searching for medications that improve patient outcomes and/or that can minimize the use of opioids. Perhaps, older treatment modalities just need to be reconsidered.

  Background

The management of pain – whether acute or chronic – is one of the most difficult medical conditions to treat and when treatment options are limited, the patient is the one left to suffer while the clinician bears the burden of trying to help the patient. The current opioid crisis in the US has significantly shifted the pendulum of opioid prescribing practices due to various restrictive guidelines, laws, regulations, and policies at both the federal and state level. Clinicians are challenged and quite possibly hesitant with managing complex pain syndromes in individuals with medical comorbidities.

Not all pharmacologic treatment options are viable for every case due to patient-specific factors, compelling medical indications and comorbidities, drug interactions, and even pharmacogenetics. Over time, some pharmacologic options are withdrawn from the market by the manufacturer, forgotten, or underutilized due to a lack of clinician knowledge or familiarity.

Here, we revisit this “land of lost analgesics” with the goal of refamiliarizing pain-treating clinicians – whether in specialty or primary care – with alternative treatment options that are worth consideration when initial first and second-line pain therapies have been optimized or are contraindicated. Potential uses, clinical considerations, and US availability are noted for each.

Not all pharmacologic treatment options are viable for every patient. Here, we revisit the “land of lost analgesics” with the goal of refamiliarizing pain-treating clinicians – whether in specialty or primary care – with alternative treatment options. (Image: iStock)

  Skeletal Muscle Relaxants

Skeletal muscle relaxants are a broad category of medications consisting of a wide spectrum of drugs with different indications and mechanisms of action. Muscle relaxants can be divided into two main categories: antispasmodic and antispasticity medications. Antispasmodics are used to reduce muscle spasms resulting from a painful condition whereas antispasticity medications are used to decrease spasticity that hinders functionality.1                   

Orphenadrine citrate

Orphenadrine citrate is classified as an antispasmodic with the mechanism of action being unclear, but is a derivative of diphenhydramine and its activity is believed to be related to its sedative effects. In four placebo-controlled trials, orphenadrine was found to be fairly effective in some musculoskeletal conditions (acute low back pain, neck pain, nocturnal leg cramps) as well as symptoms of pain intensity, stiffness, and functionality.2

However, given orphenadrine’s chemical nature, it consequently possesses anticholinergic activity and thus patients may experience dry mouth, blurry vision, constipation, urinary retention, and cognitive dysfunction.1 Orphenadrine citrate is indicated for mild to moderate pain of acute MSK disorders and as an adjunct to rest, PT, and other measures for relief of discomfort associated with acute painful MSK conditions. In 2020, FDA granted a supplemental ANDA for a combination formulation of orphenadrine citrate with aspirin and caffeine in 2020.

Brand names: Norflex, Norgesic, Orphenesic Forte

Formulations: oral, injectable

Potential targets: acute low back pain, neck pain, nocturnal leg cramps

Available in US: Yes

Tolperisone

Tolperisone is classified as an antispasmodic with the mechanism of action possessing lidocaine-like-activity by stabilizing nerve membranes of mono- and polysynaptic reflexes in the spinal cord by blocking in a dose-dependent manner.1 Tolperisone was shown to be more effective than placebo for patients with chronic low back pain and overall improvement with short term use over 21 days, but no reduction of muscle spasms or pain.1 Unlike other skeletal muscle relaxants, tolperisone has been shown to exhibit less somnolence or cognitive adverse effects when used with for up to 14 days.3 As a skeletal muscle relaxant with less CNS adverse effects than currently available in some analgesics, tolperisone may offer a more promising option for patients.

Brand names: Mydocalm

Formulation: oral

Potential targets: low back pain

Available in US: No, but the manufacturer is recruiting for Phase 3 STAR study under ClinicalTrials.gov #NCT04671082; utilized in Europe since the 1960s

Dantrolene sodium

Dantrolene is classified as an antispasmodic medication with the mechanism of action on the PNS by blocking the calcium channel of the sarcoplasmic reticulum to reduce the concentration of calcium and diminishing the potential for an actin-myosin interaction which could produce a muscle contraction.1,2 Dantrolene has shown some efficacy for use in spasticity in debilitating conditions that hinders functionality, but there is little evidence exhibiting effectiveness for musculoskeletal conditions.1 Despite dantrolene bypassing the CNS and avoiding the typical adverse effects, it is consequently associated with hepatotoxicity and muscular weakness.1

Dantrolene is still commercially available in oral and injectable formulations and FDA approved for the treatment of spasticity associated with upper motor neuron disorders such as cerebral palsy, multiple sclerosis, spinal cord injury, and stroke.

Brand names: Dantrium, Ryanodex

Formulations: Oral, injectable

Potential targets: Muscle relaxation after CNS injury

Available in US:  Yes

See also, a case report and review of dantrolene for muscle spasticity. 

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

NSAIDs are used to inhibit the enzyme cyclooxygenase (COX) which is a bifunctional membrane-bound hemoproteinthat catalyzes the reduction of arachidonicacid to cyclic endoperoxide by bis-dioxygenation for the biosynthesisof prostaglandins, prostacyclin and thromboxanes.4

There are two principle isoforms of COX enzymes which are bifunctional enzymes consisting of both cyclooxygenase and peroxidase activity: COX-1 and COX-2. COX-1 is predominantly responsible for the production of prostaglandins necessary for maintaining normal endocrine and renal function, gastric mucosal lining, and hemostasis by mediating thromboxane A2 production to cause vasoconstriction and activate platelet aggregation. COX-2 is produced in response to inflammatory and mitogenic stimuli which is important in facilitating inflammation as well as the production of prostacyclin to promote vasodilation and inhibit platelet aggregation.5

Rofecoxib

Rofecoxib is a COX-2 selective NSAID consisting of a methylsulfone moiety and a lactone ring structure that makes it >800 times more selective for COX-2 than COX-1.6 In comparison to other NSAIDs, rofecoxib is about 6 to >20 times more selective for COX-2 than celecoxib, diclofenac, indomethacin, or meloxicam. As an NSAID with significant COX-2 specificity, rofecoxib has benefits of yielding effective analgesic and anti-inflammatory activity with reduced potential for GI-related adverse effects.6 Rofecoxib was originally FDA-approved for the management of acute pain in adults, primary dysmenorrhea, and osteoarthritis.4,6        

In a Cochrane review of 26 RCTs evaluating the efficacy and safety of rofecoxib use in osteoarthritis compared to placebo, celecoxib, diclofenac, ibuprofen, naproxen, nimesulide, nabumetone, acetaminophen, and diclofenac/misoprostol combination, evidence showed that rofecoxib was more effective than placebo, but displayed no difference in efficacy when compared to the other NSAIDs at equivalent doses. From a safety standpoint, rofecoxib resulted in fewer GI-related adverse effects compared to celecoxib, ibuprofen, and naproxen with only one trial comparing rofecoxib to celecoxib reporting on the overall rates of GI-related adverse events comparing high dose rofecoxib with low dose celecoxib.7

In a similar fashion, three trials examining cardiovascular safety of rofecoxib and celecoxib used non-comparable doses with the results of those studies suggesting that rofecoxib caused more patients to experience a significant increase in systolic blood pressure and peripheral edema. However, there was no difference between rofecoxib and celecoxib in studies conducted among the general populations.7

In another Cochrane review of two RCTs evaluating the efficacy and safety of rofecoxib use in rheumatoid arthritis, one trial compared to placebo which rofecoxib exhibited a greater degree of efficacy while having a similar a safety profile.The second trial, known as the VIOXX GI Outcomes Research (VIGOR) study,was primarily designed to assess the safety of rofecoxib compared to naproxen which showed similar efficacy and lower GI-related adverse effects and bleeding, but consequently revealed a greater incidental finding of non-fatal myocardial infarctionsin the rofecoxib population.8,9

Fortunately, the overall mortality rate and rate of death from cardiovascular causes were similar in the two study groups. In another significant study, the Adenomatous Polyp Prevention on VIOXX (APPROVe) trial compared rofecoxib to placebo to evaluate its effectiveness in preventing the recurrence of colon polyps, but was unfortunately terminated prematurely due to increased incidence of myocardial infarctions and ischemic cerebrovascular eventsinitially seen following 18 months of continuous treatment.9,10

Similar to other NSAIDs with nephrotoxic adverse effects, rofecoxib causes dose-independent reductions in glomerular filtration rate and acute renal failure as well as reversible interstitial nephritis.11 Rofecoxib was subsequently voluntarily withdrawn from the market in September 2004. However, other COX-2 selective NSAIDs such as celecoxib, diclofenac, etodolac, and meloxicam are still commercially available for clinical use.

Benoxaprofen

Benoxaprofen is a arylalkanoic and proprionic acid derivative NSAID initially FDA-approved for the treatment of osteoarthritis and rheumatoid arthritis. Unlike other NSAIDs, benoxaprofen is a weak COX inhibitor, but also has an additional mechanism of action by inhibiting 5-lipoxygenase and mononuclear leukocyte migration and their chemotactic response. Benoxaprofen had a long elimination half-life 28-35 hours which allowed for once daily dosing making it convenient for clinicians to prescribe and patients to be adherent to therapy.12,13

There was strong consideration that benoxaprofen had disease-modifying effects in rheumatoid arthritis.13 A clinical trial in 2,204 patients with either active rheumatoid arthritis or symptomatic osteoarthritis treated with benoxaprofen for an average period of 14 months was shown effective for continuous antirheumatic stabilization with a single daily dose.14

Compared to other NSAIDs in rheumatoid arthritis and osteoarthritis, benoxaprofen has been shown to be more effective than aspirin or ibuprofen and more effective than ibuprofen with comparable efficacy to aspirin respectively.14 When benoxaprofen was compared to other NSAIDs such as indomethacin, naproxen, and sulindac, there was no significant difference in efficacy with rheumatoid arthritis patients.12

From an adverse effect profile, benoxaprofen is somewhat unique as it is associated with low incidences of peripheral edema and peptic ulcers, but has a high frequency of phototoxicity and onycholysis.12,14 Photosensitivity typically appears within 48 hours of treatment initiation and resolves 48 hours following discontinuation. Unfortunately, benoxaprofen was voluntarily withdrawn from manufacturer due to cholestatic jaundice with nephrotoxicity and hepatotoxicity. However, benoxaprofen is not unique with respect to its dual activity as a weak inhibitor of COX and its inhibitory effects on mononuclear leukocytes as sulindac has comparable potency and is still commercially available for clinical use.12

Choline Magnesium Trisalicylate

Choline magnesium trisalicylate (CMT) is a non-acetylated salicylate arylpropionic acid and arylacetic acid derivative NSAID that structurally contains choline salicylate and magnesium salicylate with analgesic and anti-inflammatory properties similar to aspirin. CMT does not inhibit platelet aggregation induced by two physiological aggregating agents, collagen and arachidonic acid or spontaneous platelet aggregation.15 The acetyl moiety on aspirin’s hydroxyl group facilitates it to alter factors of platelet function by irreversible acetylation of COX and thus inhibits the conversion of arachidonic acid to thromboxane A2 resulting in suppressing platelet aggregation and prolonged bleeding time. Unlike aspirin, CMT lacks an acetyl moiety and has choline and magnesium substituents on the carboxyl groups of the three salicylate molecules in its structure and as a result there is no interference with platelet aggregation or effect on bleeding.16

CMT may be an alternative NSAID for patients prescribed lithium as non-acetylated salicylates may be preferred to minimize risk for potential drug interactions and inducing lithium toxicity.17 However, CMT should still be used with caution and or avoided in patients with renal dysfunction, and compelling cardiovascular comorbidities such as congestive heart failure and coronary artery disease while prescribed other anticoagulants such as P2Y12 antagonists, phosphodiesterase-3 enzyme inhibitors, vitamin k antagonists, and direct-acting oral anticoagulants.

The most common adverse effects with CMT are similar to traditional NSAIDs with tinnitus and gastrointestinal issues (ie, gastric upset, heartburn, epigastric pain, diarrhea). CMT is FDA-approved for use in the relief of mild to moderate pain, management of acute painful shoulder, management of pyrexia, relief of sighs/symptoms of osteoarthritis, rheumatoid arthritis, and other arthritis (long-term management and acute flares), and anti-inflammatory or analgesic management (in children) of juvenile idiopathic arthritis and other appropriate conditions.

Zomepirac

Zomepirac is a pyrrole acetic acid a NSAID structurally similar to tolmetin, but is more lipophilic and may potentially have central analgesic effects. Zomepirac is nearly equivalent in potency to indomethacin and tolmetin as a COX-1 inhibitor of prostaglandin synthesis and was 2 or 3 times less active than diclofenac, but more active than aspirin, ibuprofen, or naproxen.Zomepirac is typically dosed 100 mg every 4 to 6 hours as needed, but should not be dosed greater than 400mg/day for three months or longer or exceed 600mg/day as these doses have not been studied and are not recommended.18,19

In looking at the data, zomepirac has demonstrated efficacy in relieving moderate to severe acute postoperative orthopedic, gynecologic, abdominal, and thoracic as well as dental pain.18-20 Zomepirac displayed greater efficacy over some opioids and may have been considered a viable option as an opioid sparing analgesic. In singe-dose studies in patients with acute pain, zomepirac 100mg exhibited greater efficacy compared to codeine 60 mg as well as other single agent non-opioid analgesics and other analgesic combinations. In single-dose crossover studies comprised of patients with moderate to severe postoperative pain, oral zomepirac 100 or 200mg was compared to intramuscular morphine 16mg and provided comparable analgesic effects and suggesting a “ceiling effect” of analgesic activity while also indicating that oral zomepirac was about one-sixth as potent as intramuscular morphine, but with a slower onset and longer duration of action.19

Adverse effects of zomepirac are fairly similar to other commonly prescribed NSAIDs such as gastrointestinal-related, however zomepirac exhibited a higher incidence of urogenital symptoms (ie. dysuria, cystitis, urinary frequency, hematuria, pyuria, and urinary tract infections) compared to other common NSAIDs and should be monitored more closely if used longer than six months. Following a single 200-mg dose, zomepirac sodium was shown to prolong the template bleeding time and decrease platelet retention significantly. Unlike aspirin and similar to other NSAIDs, zomepirac platelet inhibition is reversible and returns to normal function after 24 to 48 hours following discontinuation of therapy.18,20 Unfortunately, zomepirac was voluntarily withdrawn in due to various case reports of anaphylactic reactions. However, other COX-1 selective NSAIDs such as indomethacin and tolmetin with similar potency are still commercially available for use clinically applicable.

Brand names: Zomax

Formulation: oral

Potential targets: moderate to severe acute postoperative orthopedic, gynecologic, abdominal, thoracic, and dental pain

Available in US: No

  Adjuvant Analgesics

Neuropathic pain can be one of the more challenging pain syndromes as intolerable symptoms may be intermittent, constant, aggravated, or spontaneous. Adjuvant analgesics consisting of antidepressants, anticonvulsants, as well as other medications with unique properties affecting the nerve cell membrane may be used to help minimize the frequency and intensity in alleviating neuropathic pain symptoms. Some adjuvant analgesics may benefit other medical conditions as well, such as comorbid mental health disorders, potentially minimizing the need for polypharmacy and pill burden.

Maprotiline

Maprotiline is a dibenzo-bicyclo-octadiene secondary amine tetracyclic antidepressant with a large lipophilic carbocyclic moiety and is distinguishable from tricyclic antidepressants by the presence of an ethylene bridge rendering its three-dimensional stereochemical configuration. Maprotiline exhibits similar activity as amitriptyline and imipramine, but has a more rapid onset of action and less anticholinergic adverse effects.21,22

Similar to imipramine, maprotiline exhibits strong norepinephrine reuptake inhibition activity across the nerve cell membrane as well as weak alpha-2 adrenergic blocking activity. Maprotiline undergoes first-pass hepatic metabolism primarily by N-demethylation, oxidative deamination, and aliphatic and aromatic hydroxylation to active formation of aromatic methoxy derivatives.21, 22 Maprotiline may initiated at 75 mg/day and can be titrated up to 225-300mg/day.22

In a double-blind cross over study with maprotiline 75mg/day compared to placebo in patients with chronic tension headache, treatment with maprotiline over a 6-week period was shown to be superior to placebo with mild side effects (drowsiness, dry mouth, increased appetite/weight gain).23 A study group consisting of patients with pain and depression were treated with maprotiline and gradually titrated to a target dose up to 300mg/day (150mg/day if 60 years or older) as tolerated resulted in 72% of patients responding with a greater than a 50% reduction in pain.24 In a randomized, double-blind, crossover trial, maprotiline was compared with amitriptyline in the treatment of postherpetic neuralgia displaying some pain relief, but was not as effective as amitriptyline unless treatment with amitriptyline had failed.25

Maprotiline has similar adverse effect profile as traditional tricyclic antidepressants given its anticholinergic activity with dizziness/faintness, blurry vision, dry mouth, constipation, orthostatic hypotension and tachycardia, but to a lesser degree as well as cutaneous rashes which are more common. Cardiovascular effects have been demonstrated with maprotiline as it can cause a decrease in standing systolic pressure, flattening of T-waves, an increase in heart rate and PR interval, prolongation of the pre-ejection period, as well as QT prolongation.22

Brand names: Ludiomil

Formulation: oral

Potential targets: depressionand anxiety

Available in US: Yes

More on the overlap between chronic pain conditions and psychiatric disorders.

  Antiarrhythmics

Mexiletine

Mexiletine is a class 1B antiarrythmic agent FDA-approved for the treatment of ventricular arrhythmias. Pharmacologically, mexiletine is a structural analogue of lidocaine and acts by blocking voltage-gated sodium channels decreasing the rate of depolarization of ventricular cardiac myocytes, but also has similar potency in local anesthetic properties.26,27

Mexiletine is a racemic mixture of R-(–)- and S-(+)-enantiomers that possess characteristic antiarrhythmic potency with the R-(–)-enantiomer exhibiting increased cardiac sodium channel binding and greater antiarrhythmic activity than the S-(+)-enantiomer, but neither of the isomers significantly changed the electrocardiographic intervals (PR, QRS, QTc) or refractory periods.26 Mexiletine has been used to treat various neuropathic pain syndromes including: alcoholic neuropathy, cancer and radiation-induced neuropathic pain, painful diabetic neuropathy, dysaesthetic pain associated with multiple sclerosis, HIV-induced neuropathy, myofascial pain, peripheral nerve disease, phantom limb pain, postherpetic neuralgia, spinal cord injury, thalamic (post-stroke) pain, and trigeminal neuralgia.28

Mexiletine has a narrow therapeutic range from 0.75 to 2 mg/L that correlates serum concentration level to both its antiarrhythmic efficacy as well as adverse effects.26 However, there are no serum mexiletine concentration levels that correlate with efficacy in relieving neuropathic pain syndromes that have been studied. Therapeutic doses of mexiletine have ranged from 300 to 675mg/day, but clinicians should be vigilant and avoid dosages that can result in serum concentrations exceeding >2 mg/L. Mexiletine is predominantly hepatically metabolized via CYP2D6 to p-Hydroxymexilitine so dosage adjustments are not necessary in patients with severe renal dysfunction or on hemodialysis.28 The consequences of genetic polymorphism to CYPD6 in patients receiving mexiletine for neuropathic pain remain unclear, but should be used with caution and monitored closely during initiation and dose titrations especially in the setting of potential clinically significant drug-drug interactions.26,28

Opioids may have a potential clinically significant drug interaction with mexiletine. Despite there being no studies designed to evaluate the effects of opioids on the pharmacokinetics of mexiletine, it has been reported that patients taking morphine have significantly lower mean concentrations of mexiletine 3 hours following the first dose. The mechanism caused by the lower mexiletine serum concentration is believed to be due to opioids inhibiting gastric emptying and in turn slowing the absorption of mexiletine.26 (More on opioids below.)

The most common adverse effects patients may experience with mexiletine are dizziness or lightheadedness, tremor, nervousness, ataxia, nausea, anorexia, and gastric irritation, but tolerability may be improved with food or reducing the dose.27 Mexiletineis still commercially available in oral formulations and FDA-approved for the management of ventricular arrhythmias, but may potentially be an alternative option as an adjunct analgesic for neuropathic pain who have failed response or cannot tolerate first line treatment options.

Brand names: Mexitil

Formulation: oral

Potential targets: neuropathic pain

Available in US: Yes

  Opioids

Opioids are not just purely mu-opioid agonists; some can be mixedmu opioid receptor agonist-antagonists, as well as agonists of the delta and or kappa opioid receptors with varying pharmacodynamic effects. Mixedmu opioid receptor agonist-antagonists are not used as often as full mu-opioid agonists due to their limited commercial availability, but as a result of their antagonist activity has less dependence and abuse potential.

Opioid analgesics may be considered as adjunctive therapy upon initiation and during optimization of non-opioid analgesics especially for severe pain, but dose and duration of therapy should be kept to a minimum where possible and consideration should be made to taper toward discontinuation as goals of therapy are met and as overall pain improves with optimization of non-opioid analgesics. If opioids are to be used, risk mitigation strategies such as obtaining an opioid treatment agreement or consent, review of prescription drug monitoring program reports, and conducting urine drug testing should be performed periodically as clinically indicated as recommended per established clinical practice guidelines as well as state regulations.

Butorphanol

Butorphanol is a synthetic phenanthrene kappa opioid receptor agonist, mixed mu opioid receptor agonist-antagonist, as well as apartial sigma receptor agonist which is responsible for psychotomimetic effects such as dysphoria, respiratory and vasomotor stimulation.29 potency of parental butorphanol ranges from 4 to 8 times more than morphine, 30 to 40 times more than meperidine, and 15 to 24 times more than pentazocine whereas oral is about 7 times more than codeine and 6 times more than pentazocine.29,30

Butorphanol’s antagonist activity is about 30 times more than pentazocine while only a fraction (1/40) of naloxone and given its high binding affinity to the mu opioid receptor, higher doses of naloxone may be necessary in order to reverse any adverse effects of butorphanol compared to pure opioid agonists such as morphine.29 The absorption of butorphanol is adequate via oral and parenteral routes, but undergoes extensive first-pass hepatic metabolism primarily by hydroxylation to the major metabolite hydroxybutorphanol and N-dealkykation to minor metabolite norbutorphanol which leaves oral bioavailability yielding about only 5 to 17%. With transnasal administration of butorphanol on the other hand, this route of administration bypasses the gastrointestinal tract, and improving bioavailability to about 48 to 70% similar to parenteral administration.30

Additionally, transnasal butorphanol absorbs rapidly while providing onset of analgesia within 15 minutes making it an ideal short-term treatment option for patients with moderate to severe acute postoperative, musculoskeletal and migraine headache pain. The bioavailability and pharmacokinetics of transnasal butorphanol may be influenced by age and sex as the median value for tmax was marginally higher in the elderly (older than 65 years) in elderly men (75%), but was significantly lower in elderly women (48%). However, the bioavailability in young men (68%) and young women (70%) the Cmax and AUC values were relatively similar.30

The most common adverse effects to be expected from butorphanol are sedation, drowsiness, dizziness, as well as nausea and/or vomiting. Unlike pure opioid agonists such as morphine which can cause respiratory depression in a dose proportional manner, butorphanol exhibits a ‘ceiling effect’ with respect to the degree of respiratory depression such as increasing doses beyond 2mg may not result in a corresponding increase in degree of respiratory depression, but the duration of respiratory depression increases with higher doses.29,30 Butorphanol has hemodynamic effects similar to pentazocine but to a lesser degree with cardiovascular effects consisting of: increased pulmonary artery and wedge pressure, increased left ventricular end diastolic pressure, increased systemic arterial pressure, increased pulmonary vascular resistance, as well as increases to cardiac index and cardiac work.29

Considering these cardiovascular effects, butorphanol should be used with caution or avoided where possible in patients with acute myocardial infarction, coronary insufficiency, or ventricular dysfunction. Butorphanol is FDA-approved for use in the relief of moderate to severe pain, as a supplement to balanced anesthesia, for the relief of postpartum pain, and as preoperative or preanesthetic medication with the ladder three indications utilizing injectable formulations only.29

Brand names: Stadol (International)

Formulation: nasal, injectable

Potential targets: moderate to severe pain, postpartum pain, perioperative

Available in US: Yes (generic); Stadol (US) was discontinued due to severe hypertension

Nalbuphine

Nalbuphine is a semi-synthetic phenanthrene kappa opioid receptor agonist and mixed mu opioid receptor agonist-antagonist structurally similar to oxymorphone and naloxone.29,31,32The potency of parental nalbuphine is equivalent to approximately 0.7 to 0.8 times that of morphine whereas oral is 3 times more than codeine.29,32

In comparison to pentazocine, nalbuphine is about 3 to 4 times more potent with a longer duration of action and 10 times more effective with its antagonist activity.29,31 Similar to butorphanol, nalbuphine exhibits sufficient absorption via oral and parenteral routes, but undergoes extensive first-pass hepatic metabolism with oral bioavailability yielding only about 20%.29

Much like any other opioid, the most common adverse effects exhibited with nalbuphine include sedation, drowsiness, dizziness, as well as nausea and/or vomiting.29 Comparable to butorphanol, nalbuphine also exhibits a “ceiling effect”, but to both the degree and duration of respiratory depression as escalating doses does not prolong the duration of respiratory depression beyond 3 hours regardless of dose and thus resulting in a plateau of the respiratory depression curve.29,31,32 In a study comparing nalbuphine and morphine in patients with acute myocardial infarction, nalbuphine did not cause any adverse clinical or hemodynamic effects despite decreasing heart rate and contractility, but maintained aortic pressure and hence sustaining the balance between myocardial oxygen supply and demand.29

Nalbuphine’s cardiovascular benefits with decreasing heart rate and contractility while maintaining aortic perfusion pressure may prevent further cardiac ischemia in patients with acute myocardial infarction. Nalbuphine is FDA-approved for use as an analgesic for moderate to severe pain, for preoperative analgesia, as a supplement to surgical anesthesia, and as obstetrical analgesia during labor.29

Brand names: Nubain

Formulation: injectable

Potential targets: moderate to severe pain, perioperative, labor

Available in US: Yes

Propoxyphene

Propoxyphene is a synthetic diphenyl heptane mu opioid receptor agonist, kappa opioid receptor agonist, and noncompetitive N-methyl-D-aspartate (NMDA) receptor antagoniststructurally similar to methadone that has two centers of asymmetry and exists as four stereoisomers: alpha-dextrorotatory isomer, alpha-levorotatory isomer, dextropropoxyphene, and levopropoxyphene. Dextropropoxyphene exhibits analgesic activity and levopropoxyphene has antitussive activity while the other levorotatory isomers are relatively inactive, but overall none of the isomers can be converted into methadone.Propoxyphene is about 33.33% to 50% the potency of codeine which is deemed to be less efficacious than a 650 mg dose of aspirin.Propoxyphene has rapid absorption via oral route and undergoes extensive first-pass hepatic metabolism primarily by N-demethylation to norpropoxyphene and yielding bioavailability of about only 18-25% from a 65mg dose. Propoxyphene is both a CYP450 2D6 inhibitor and substrate and consequently may be subjected to genetic polymorphisms as well as potential drug interactions.33,34

In a review written by Miller and colleagues, among 243 articles referencing propoxyphene, only 20 double-blind or triple-blind clinical studies were identified creditable for review. Fifteen studies showed that codeine at lower or equal analgesic doses produced comparable or greater analgesic efficacy than propoxyphene, but within the same parameters no study demonstrated that codeine was inferior to propoxyphene. Seven studies showed that aspirin alone or aspirin in combination with phenacetin, and caffeine (at various doses) were comparable or had greater analgesic efficacy than propoxyphene.35

Not all of the comparison studies reviewed presented propoxyphene as inferior as two separate studies showed that propoxyphene hydrochloride 65 mg was superior to codeine 32.5 mg and aspirin 325 mg alone. When compared to placebo, nine studies showed propoxyphene to be superior while seven other studies it was not.35

Common adverse effects with propoxyphene are similar to other opioids which include: dizziness, lightheadedness, visual disturbances, somnolence, drowsiness, seizures, euphoria, nausea, vomiting, abdominal pain, constipation, urinary retention. The metabolite norpropoxyphene is primarily renally eliminated and if accumulated may result in potentially fatal CNS, cardiac, and respiratory adverse events such as cardiac arrest, pulmonary edema, seizures, and even mortality.34

Norpropoxyphene has more potent direct cardiac adverse effects which include: an increase in bradycardia, decreased contractility, decreased electrical conductivity, QTc interval prolongation, as well as local anesthetic properties similar to lidocaine or quinidine which may precipitate arrhythmias. Incidents of pulmonary edema and seizures were believed to be secondary to propoxyphene and its metabolite norpropoxyphene in both high-risk patients and at high doses. Prior to removal, propoxyphene was falling out of favor by clinicians and was perceived to have no therapeutic benefit in the management of acute and/or chronic pain while having greater mortality risk due to its cardiac and neurologic toxicity profile.34

In 2009, the FDA required the drug manufacturer to conduct a multiple-ascending dose (MAD) study which was a randomized, double-blind, placebo-controlled sequential multiple-ascending dose study of propoxyphene for 11 days evaluating 600 mg and 900 mg cohorts. The results of the MAD study were submitted to the FDA by the manufacturer showing significant QTc interval prolongations observed with propoxyphene 600 mg and 900 mg dose cohorts. In 2010, the FDA concluded that the safety risks of propoxyphene outweighed the benefits and recommended against its use due to significant abnormal heart rhythm and electrical activity changes with the prolonged PR interval, widened QRS complex and prolonged QT interval at therapeutically prescribed doses.36 

Propoxyphene was withdrawn by the manufacturer promptly afterward due to the FDA’s cardiotoxicity warning. Other short-acting immediate-release opioids such as codeine, hydrocodone, and oxycodone alone or in combination with acetaminophen are still currently available for use in acute severe breakthrough pain as clinically indicated.

Brand names: Darvocet-N (propoxyphene and acetaminophen)

Formulation: oral

Potential targets: breakthrough pain

Available in US: No, but similar products are still available

Levorphanol

Levorphanol has been referred to as the “forgotten opioid” that is phenanthrene mu, delta, and kappa opioid receptor agonist and non-competitive NMDA receptor antagonist structurally similar to morphine, but without an oxygen and a 6-hydroxyl group.37-39 Similar to morphine, levorphanol has anticholinergic effects and like methadone, levorphanol inhibits the uptake of serotonin and norepinephrine.38 However, unlike methadone, levorphanol has a shorter and more predictable half-life of about 11 to 16 hours with a longer duration of action, and no CYP450 or P-gp drug interactions or associated with any QTc prolongation risk.37

Levorphanol exhibits good absorption through the intramuscular, subcutaneous, and oral routes of administration and undergoes phase II metabolism via glucuronidation to levorphanol-3-glucuronide that is renally eliminated. In some special populations such the elderly, palliative care, and SCI patients, levorphanol may be a viable option and may require a lesser need for coadministration of adjuvant analgesics.37

Common adverse effects with levorphanol are similar to other opioids such as nausea, vomiting, sedation, dizziness, constipation, pruritis, urinary retention, but a unique adverse effect is a potential increase in bile duct pressure which should be avoided in bili­ary surgery patients.39 Levorphanol is FDA-approved for management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Brand names: Levo-Dromoran

Formulation: oral

Potential targets: severe pain

Available in US: Yes

  Clinical Takeaways

Pharmacologic options of the past for treating acute, chronic, and perioperative pain may still be of clinical use. While some analgesic medications, including adjuvants, have been voluntarily withdrawn from the market by the manufacturer, others are still available and simply remain forgotten or underutilized. Pain practitioners across specialties are encouraged to refamiliarize themselves with these drugs in case they may benefit a particular patient who is refractory to or contraindicated for more widely used products.

Not all pharmacologic treatment options, however, are viable for every case; as with any prescription, risks and benefits must be weighed. Having a fuller, even if older, arsenal of potential treatment modalities for pain management can only serve to benefit the clinician and the patient. All pharmacologic treatment options old and new should be reconsidered based within patient-specific clinical parameters and trialed as potential alternative analgesics where possible.

  Miguel Escanelle, MD, and Christopher P. Emerson, MD, MS, contributed to the research of this article.

This commentary is the sole opinion of the author and does not reflect the opinion of employers, employee affiliates, and/or pharmaceutical companies mentioned or specific drugs discussed.  It was not prepared as part of official government duties for Dr. Pham.  Dr. Pham dedicates this article mentor and friend Jeffrey Fudin, PharmD.

Last updated on: September 8, 2021

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[mcatmemoranda]

Reviewing questions:

Starting at age 30, FEV1 declines. Smoking causes COPD, which increases the rate of the decline. Smoking cessation slows the rate of decline in FEV1, but the gradual decline in FEV1 won't return to the way it would've been if the pt had never started smoking in the first place.

Bronchiolitis obliterans = obstruction of small airways (bronchioles); occurs in chronic lung transplant rejection. You get fibrosis of bronchioles.

Avitaminosis A (vitamin A deficiency)-> squamous metaplasia of the epithelium of the eyes, urinary, pancreatic, and respiratory tracts to a keratinizing epithelium. This can occur in pts with cystic fibrosis because the inspissated secretions block the pancreatic ducts, so you can't release the digestive enzymes necessary to absorb fat-soluble vitamins (A, D, E, and K).

Cigarette smoke leads to inflammation, leukocyte infiltration, protease-antiprotease (i.e., elastase-alpha 1 antitrypsin) imbalance, and oxidative stress, which lead to emphysema. Specifically, the smoke triggers alveolar macrophages to release TNF, which activates CD8+ T cells. Cells that cause inflammation (neutrophils) release elastase, which breaks down the elastin in the alveoli.

Aspiration pneumonia tx = clindamycin or beta-lactam and beta lactamase inhibitor.

Sarcoidosis = bilateral hilar lymphadenopathy; cough, night sweats. I remember learning in a lecture a long time ago that if the hilar LAD is not B/L, then you should be more worried about cancer. I thought this question was giving me B symptoms (weight loss, fever, night sweats), which are seen in B cell lymphoma (Hodgkin lymphoma) and it also mentioned supraclavicular nodes, which made me think cancer. The question also menitioned that the pt worked as a respiratory therapist, so I thought TB. Whatever. The answer was sarcoidosis. Non-caseating granulmonas are seen in sarcoidosis. It wasn't B cell lymphoma because B cell lymphoma would show Reed-Sternberg cells on biopsy, not granulomas.

In response to mycobacterium tuberculosis, Th1 cells relase interferon-gamma, which activates macrophages. Activated macrophages can then kill mycobacterium in phagolysosomes and become epithelioid and Langhans giant cells, which wall off the bacteria, forming granulomas.

Macrophages infected with M. tuberculosis present antigen to CD4+ Th0 cells. Macrophages also release IL-12 to Th0 cells. This triggers Th0 cells to become Th1 cells, which release interferon-gamma, which activates macrophages to kill M. tuberculosis intracellularly and to transform into epitheliod and Langhans giant cells to wall off the tuberculosis, creating granulomas. I've gotten questions on this several times now, so I better not forget it! Th1 cells also release TNF-alpha, which leads to more macrophages being recruited. You have to know what the epitheliod histiocytes and multinucleated giant cells look like on histology too.

Most cystic fibrosis pts die from cor pulmonale, bronchiectasis, or pneumonia. Makes sense since the inspissated secretions prevent proper alveolar ventilation-> pulmonary vasoconstriction-> pulmonary HTN.

The tendency of the lungs to collapse and the tendency of the chest wall to expand is balanced at functional residual capacity, which generates the negative intrapleural pressure that makes the chest wall and lung move together. A pneumothorax gets rid of the negative intrapleural pressure, and as a result, the chest wall expands to a new point of equilibrium. The hemithorax has a larger volume at the new equilibrium. The lung will collapse to the new equilibrium. Ok, I think I get it. The lungs want to collapse at all lung volumes. The chest wall wants to expand until large lung volumes. A PTX eliminates the intrapleural pressure that keeps the lungs and chest wall moving together, so then the chest wall expands. Compliance is change in volume/change in pressure. The pressure volume curve slope represents compliance; steep slop = high compliance. Hysteresis = lung compliance differs with inspiration and expiration because of alveolar surface tension. I remember one of the lecturers going over the pressure volume curves and he made a mistake or got confused trying to explain it. I think I get it.

Eosinophils have bi-lobed nuclei and granules that contain major basic protein. They attack parasites. Major basic protein can damage endo- and epithelial cells-> lung damage-> asthma.

If it's not strep pneumo, it's haemophilus influenzae or moraxella catarrhalis causing pneumonia. Infection with one of these bugs triggers COPD exacerbation (increased sputum production, dyspnea, cough, change in color of sputum). If it's viral, the most common cause is rhinovirus.

Sudden onset dyspnea = pulmonary embolism-> hypoxemia and hyperventilation. Hyperventilation causes respiratory alkalosis.

Small cell carcinoma is a neuroendocrine tumor (markers are Nueral Cell Adhesion Molecule [NCAM], neuron-specific enolase, chromagranin, and synaptophysin). Paraneoplastic syndromes are SIADH, Lambert-Eaton syndrome, and Cushing's syndrome. SIADH-> hypnatremia-> neuro symptoms. Histology shows sheets of small blue cells with little cytoplasm.

Once again, pulmonary arterial hypertension can be treated with endothelin receptor antagonists like bosentan. This prevents vasoconstriction and proliferation of vascular smooth muscle. In PAH, small arteries have proliferation of smooth muscle (hypertrophy of the tunica media) and fibrosis of the tunica intima (onion skinning). You also get capillary tufts, which are plexus-like lesions. The lumen of arteries decreases-> increased resistance-> pulmonary HTN. If it's familial PAH, it's due to inactivating mutations of BMPR2-> increased endothelin. The definitive treatment is lung transplant.

Intravenous drug abusers can get tricuspid valve endocarditis (using IV drugs-> introduction of staph aureus). The vegetations on the tricuspid valve can embolize and cause pulmonary infarcts, which are hemorrhagic. Specifically, these are septic pulmonary emboli, which cause wedge-shaped hemorrhagic infarcts in the lungs.

High altitude sickness can cause pulmonary edema (HAPE = High Altitude Pulmonary Edema) a few days after being at high altitude. Since there is less oxygen in the air at high altitudes, the less ventilated areas of lung have vasoconstriction, which is what the lungs do to divert blood flow to better ventilated areas of the lungs. But if enough of the lung vasoconstricts, then you get increased resistance to flow from the right heart to the pulmonary vasculature, so fluid backs up and can go into the lungs due to increased intravascular hydrostatic pressure. Pts present with dyspnea, cough, patchy alveolar infiltrates, crackles. They improve with supplemental oxygen. High altitude sickness doesn't just present as pulmonary edema. It can also cause acute mountain sickness (fatigue, nausea, HA) and cerebral edema (because decreased PaO2 causes increased cerebral flow; pts will be confused, lethargic, and have gait disturbance).

In COPD, FEV1 decreases more so than FVC, so the FEV1/FVC will be decreased. Reduced FEV1/FVC = obstructive lung disease.

A complication of pneumonia is an abscess, which occurs due to the release of granules by neutrophils. The granules kill bacteria, but also cause liquefactive necrosis of the lung tissue.

Electrical stimulation of the hypoglossal nerve (CN XII) can help improve obstructive sleep apnea, which I didn't know. But I guessed and got the question right. Stimulation of CN XII increases diameter of the oropharyngeal airway. Oh yeah, when I was listening to OnlineMedEd, Dustyn mentioned muscular weakness causing sleep apnea, like MS or something like that. So neuromuscular weakness can contribute to sleep apnea. The muscles relax when you sleep, so the airway can become obstructed.

When standing upright, ventilation is lowest at the apex of the lungs because gravity pulls the alveoli open, so when you inhale, the alveoli at the apex don't expand as much as the alveoli at the base of the lung. Basically, the alveoli at the apex already have the weight of the rest of the lung pulling the alveoli open, so they are already almost as expanded as they can get. The alveoli at the base of the lung don't have additional lung weight to pull them open, so they have more potential space to open. Thus, ventilation is greater at the base than the apex. When you inhale, since the alveoli at the base of the lung are not as expanded from the start of inhalation, they can expand more than the alveoli at the apex, thus they are better ventilated. I guess that's what this explanation was saying. But I remember learning that the apex is better ventilated whereas the base is better perfused. Idk. The base of the upright lung has better perfusion than the apex of the lung. The V/Q ratio is low at the base of the lung and high at the apex of the lung.

Theophylline is a bronchodilator that works like beta 2 agonists--it caueses increased cAMP-> smooth muscle relaxation. It is metabolized by the CYP450 system, so CYP450 inhibitors increase theophylline concentration-> theophylline toxicity (tremor, agitation, seizures, GI sxs, tachycardia, cardiac arrhythmias). Theophylline has a narrow therapeutic index and is not used much anymore. But it can be used for COPD or asthma. It's an adenosine receptor antagonist (similar to caffeine) and phosphodiesterase inhibitor. Infection with a fever can also cause theophylline toxicity.

Mucicarmine staining of BAL will show cryptococcus neoformans. The polysaccharide capsule of cryptococcus looks red with mucicarmine stain. India ink also shows the capsule. From Wikipedia: Mucicarmine stain is a staining procedure used for different purposes. In microbiology the stain aids in the identification of a variety of microorganisms based on whether or not the cell wall stains intensely red. Generally this is limited to microorganisms with a cell wall that is composed, at least in part, of a polysaccharide component. One of the organisms that is identified using this staining technique is Cryptococcus neoformans.

[siglerprescriptiondrugcards]

Ephedra

Scientific Names: Ephedra sinica Other Common Names: Ma huang, Indian jointfir Overall Safety: 🙁  

Therapeutic Efficacy and Considerations:

Weight Loss: 🙁 Ephedra alone has never been examined for efficacy with weight loss. Most of the “clinical evidence” touted by manufacturers used pharmaceutical ephedrine and caffeine combinations. Three published trials have compared combination products containing ephedra and herbal caffeine sources against placebo for weight loss. Although all did find a greater effect than placebo, the extent was small; most ephedra combination groups only averaged 1-2 kilograms more weight lost than the placebo groups. The safety concerns, as well as the current legal standing, of ephedra vastly outweigh the definite but small benefit of use.

Athletic Performance: 🙁 Ephedra alone, or ephedra with herbal caffeine sources, has never been studied for increasing athletic performance. Trials performed with pharmaceutical ephedrine and caffeine had inconsistent results – some found small increases in performance or time to exhaustions, while others hound no benefit. All noted significant adverse events. The evidence does not support use.

Even though ephedra is now banned in the US, these products will still be obtainable via mail and internet sources. Patients should be strongly discouraged from buying and using ephedra products for any indications and should be counseled that the use of combination products that contain caffeine or other stimulants further increases the risk of serious adverse events.

Chemistry/Pharmacology: Ephedra is a natural source of ephedrine alkaloids. Although ephedrine is the primary alkaloid discussed, the plant also contains pseudoephedrine, norephedrine, norpseudoephedrine, phenylpropanolamine, methylephedrine, and many others in varying amounts. The percentage of alkaloid content varies among the different species with Ephedra sinica having the highest content, up to 2.5%. The ephedrine alkaloids are sympathomimetics and cause vasoconstriction and bronchodilation and increases in blood pressure and heart rate. Other effects noted are variable actions on blood glucose and uterine stimulation and possibly increased platelet aggregation. Ephedra can worsen urinary retention, although it does seem to have mild diuretic action. Ephedra is often used in combination products along with caffeine, which increase stimulatory effects and increases the risk of adverse events.

Drug Interactions: May interact with CNS stimulants, MAOIs, BETA-BLOCKERS (increases sympathomimetic effects because alpha agonist effects are not opposed), ERGOT alkaloids, ANTIARRHYTHMICS, ANTIHYPERTENSIVES, and PHENOTHIAZINES (causes tachycardia and hypotension due to blocking of alpha-adrenergic effects). May potentiate the actions of thyroid supplements. May decrease the action of hypoglycemic agents. May increase the risk of psychosis when used with alcohol.

Contraindications/Precautions: Ephedra has been banned due to its association with deaths from stroke and myocardial infarction. Its use is still permitted by Traditional Oriental Medicine practitioners for the treatment of asthma and bronchial conditions. Ephedra is contraindicated in pregnancy, in children, and in patients with heart disease or hypertension, psychiatric disorders, glaucoma, BPH, urinary retention, or kidney disease.

Adverse Effects: Adverse effects that are serious and can be fatal include stroke, myocardial infarction, cerebral vasculitis, myocarditis, seizure, psychosis, mania, rhabdomyolysis, eosinophilia myalgia syndrome, and nephrolithiasis. Other adverse effects include insomnia, increased heart rate and palpitations, nausea, vomiting, diarrhea, urinary retention, anxiety, and fever. Note: A review of reports from Poison Control Centers found that ephedra-containing products, 0.82% of all herbal product sales, were responsible for 64% of adverse reactions associated with herbs.

[drshaileshjain-blog]

Best neurologist in shalimar bagh - Why migraine is harmful to health

Migraines have a lifespan in about 15% of the population, affecting women (18%) compared to men (8%). Migraines are acute, recurring headaches that can last for hours or days. They often affect one side of the head, causing moderate to severe palpitations, tremors, or severe pain. Migraine, a fairly disabling condition, is treated with acute and preventive medications.

Dr. Shailesh Jain handled many cases of migraines in his 15+ years of career. He said, the pain of a single migraine headache usually only lasts for a few hours or days. But this will affect your health in many ways.

According to Dr. Shailesh Jain AIIMS Neurosurgeon, migraine is a chronic condition characterized by episodic attacks of disabling headaches. Migraine pain usually lacks other characteristics such as nausea, dizziness, excessive sensitivity to light, noise, and smell. Hunger, disturbances of bowel function, etc. Numerous Migraine patients with chronic migraines will have additional problems that increase their tendency to headache: These covers depression, anxiety, other pain syndromes such as fibromyalgia, localized pain in the head and neck structures and conditions that cause 'metabolic' stress such as sleep apnoea or postural orthostatic tachycardia syndrome. Only about 20% of migraine sufferers experience a headache, usually before the onset of the headache (but usually not). Most aura is visual, consisting of a combination of positive visual events (floaters, flashes of light, zig-zag patterns, and so on) and negative phenomena (loss of vision blind spots). Many sufferers also experience sensory aura, often with tingling and numbness spread on one side of the body on the hands,  face, lips, and tongue. Weakness, dyspepsia and other aura symptoms are rare.

There are two typical patterns of headache such as Thunderclap headache and persistent worsening headache. Thunderclap headache causes Subarachnoid haemorrhage, Cerebral venous sinus thrombosis (CVST), Reversible cerebral vasoconstriction syndrome, Carotid/vertebral artery dissection, Pituitary apoplexy, Intracerebral haemorrhage/haematoma, Hypertensive encephalopathy, Hypertensive encephalopathy, and Idiopathic thunderclap haemorrhage (Call–Fleming syndrome). Persistent worsening headache causes Raised cerebrospinal fluid (CSF) pressure (tumour, abscess, CVST, idiopathic intracranial hypertension), Low CSF volume (post-lumbar puncture, spontaneous CSF leak), Meningitis (acute/chronic), Hypoxia/hypercapnia, Substance abuse/withdrawal, Systemic inflammatory conditions, including temporal arteritis.

How to relieve Migraine pain 

Migraine is the usual source of recurrent, severe headache. When patients have chronic severe headaches, it is often  difficult to acknowledge specific triggers. There are some drugs of first choice for migraines of mild or moderate severity. Aspirin, paracetamol, ibuprofen, naproxen, diclofenac, phenazone and tolfenamic acid can help to ease your pain. Also there are other treatments as well, such as,  Paradoxically it’s often the case that as chronic headaches start to boost with treatment, triggers become more obvious. Dietary regularity in relation to food, hydration, sleep, and stress is always helpful in reducing the tendency to migraine; Recognizing that this is helpful is straightforward, but it can actually be more difficult to make the expected changes in modern busy lives. Migraine prophylaxis points to turn down migraine frequency, severity and disability and improve quality of life. Chronic migraine patients require prophylactic therapy to lessen the frequency of migraine attacks, but presently available evidence-based prophylactic treatment options for chronic migraine are topiramate and onabotulinumtoxinA.

Some patients with low-frequency EM can be managed with effective acute therapy(i.e. drugs taken during the prodrome or the migraine attack to abort it) without prophylactic treatment, but patients with Chronic Migraine invariably require prophylactic treatment. While acute therapy aims to prevent a migraine attack, once initiated, the goal of prophylactic treatment is to stop the attacks, reducing the frequency, severity, and associated disability of the headache and reliance on acute treatment, Which may contribute to concurrent MOH(Medication-overuse headache). 

About Dr. shailesh jain 

Dr. Shailesh Jain is the Best neurologist in shalimar bagh. He is a principal consultant neurosurgeon and stroke interventionist at Max Hospital Shalimar Bagh and runs his own Arihant Neurospine clinic in Rohini and Pitampura. 

You can Book an appointment for any kind of spinal cord Treatment as well as Brain Treatment.

[kflemhealth]

Herbal remedies for improving dilation of blood vessels in the brain

(Natural News) Reversible cerebral vasoconstriction syndrome (RCVS) is a rare condition caused by the sudden tightening of blood vessels that supply oxygen to the brain. It is characterized by severe ‘thunderclap’ headaches – with or without neurological symptoms – and in some cases, occasional seizures. RCVS can also lead to ischemic or hemorrhagic stroke. Traditionally, two...

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嗯嗯用力就雷擊頭痛　新磁振造影揪病灶 【健康醫療網／記者蔡岳宏報導】雷擊頭痛痛到要人命，磁振造影新方法現曙光！雷擊頭痛是近10年才被命名的疾病，讓許多患者頭痛到影響生活。榮陽頭痛團隊開發磁振造影新方法，有別於過去侵入性的血管攝影，研究發現腦部病變白點可視為疾病指標，且臨床醫師可輕易判讀。 雷擊頭痛要人命　增腦中風風險 可逆性腦血管收縮症候群（Reversible cerebral vasoconstriction syndrome, RCVS）是最嚴重且最危險的頭痛疾患之一，其主要臨床表現為反覆發作如爆炸般的劇烈頭痛（又稱為雷擊頭痛），合併血管收縮。頭痛常因一些日常生活的活動如上大號用力、洗澡淋浴、性行為高潮或情緒激動所誘發，這些一瞬間爆炸般的劇烈頭痛，讓病患嚴重失能、反覆至急診就診、甚至害怕從事這些日常活動。 此外，此症候群病患，有相當高的機會產生缺血性中風、腦出血或腦水腫等併發症，造成病患及醫療體系相當大的負擔。 可逆性腦血管收縮症候群是近十年才被正式命名的疾病，絕大多數的醫師（包括非治療頭痛專長的神經科醫師）及民眾對此疾病仍相當陌生，此病的病生理機轉，學術界的認知也相當有限。陽榮團隊過去在可逆性腦血管收縮症候群/雷擊頭痛的研究居於國際領先地位，迄今因診治了全世界最多此類的病患，不論是在病人臨床表現、病生理機轉及治療，都有相當大的貢獻。 腦部磁振造影　揪出不正常病灶 過去大規模研究顯示，在正常人腦部磁振造影影像上，若有少量小白點（即白質高亮度病變），將會顯著增加未來中風、失智症及死亡的風險。團隊利用新的磁振造影序列及開發了新的影像分析技術，證實RCVS病患腦部白點體積，在疾病發作期遠高於正常人10倍以上，而且這些小白點具有特殊的空間分布及時序演變，也可作為疾病嚴重程度的腦指標。 過去研究判斷疾病嚴重性，需透過侵入性的血管攝影，且需要有經驗醫師判讀；該研究所採用的新技術，讓一般的臨床醫師也可輕易判讀。研究團隊長期追蹤下，發現這些白質病變在血管收縮恢復正常時也會部分消失，可提供臨床醫師及病患重要的參考資訊。 白質病變與病情有關　有助開發進一步療法 此外，團隊利用血流動力學的分析，推論此白質病變與腦部缺血及自律神經功能異常，所造成的過強腦血流脈衝有明顯相關的病生理機轉，對後續開發進一步療法有幫助。 榮陽頭痛團隊包括陳世彬副教授、周坤賢副研究員及王署君主任，該論文已於2018年9月1日刊載於國際著名期刊《美國醫學會期刊:神經學》(JAMA Neurology)上。現正進行包括血液、尿液、腦脊髓液及基因相關的研究，尋找此病可能的生物標誌，希望能早日釐清此病病生理機轉，找出新的治療與預防之道，以嘉惠病患。 【延伸閱讀】SGLT2抑制劑控三高　二型糖尿病找回『腎力』 資料來源：健康醫療網 游勝鈞;游胜钧;指動傳播科技;指动传播科技;指傳媒;指传媒;華民通訊社;华民通讯社;民生新聞網;民生新闻网,健康醫療網,資料來源：健康醫療網新聞