Chloroquine treatment for Coronavirus COVID-19 – why aren’t we using this? | Chloroquine | COVID-19 | Ketamine Infusion Center Alexandria Virginia for depression | Chloroquine Virginia

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By the time the government approves any vaccination, the damage by COVID-19 will be done. Why not use something we have available already? Chloroquine. It was cheap and readily available. South Korea included it’s use in their guidelines, and they had an order of magnitude fewer deaths than China!

An Effective Treatment for COVID-19

These are treatment guidelines from South Korea:

Treatment Guidelines from South Korea[7]

According to the Korea Biomedical Review, the South Korean COVID-19 Central Clinical Task Force guidelines are as follows:

1.        If patients are young, healthy, and have mild symptoms without underlying conditions, doctors can observe them without antiviral treatment;

2.        If more than 10 days have passed since the onset of the illness and the symptoms are mild, physicians do not have to start an antiviral medication;

3.        However, if patients are old or have underlying conditions with serious symptoms, physicians should consider an antiviral treatment. If they decide to use the antiviral therapy, they should start the administration as soon as possible:

… chloroquine 500mg orally per day.

4.        As chloroquine is not available in Korea, doctors could consider hydroxychloroquine 400mg orally per day (Hydroxychloroquine is an analog of chloroquine used against malaria, autoimmune disorders, etc.  It is widely available as well).

5.        The treatment is suitable for 7 – 10 days, which can be shortened or extended depending on clinical progress.

Notably, the guidelines mention other antivirals as further lines of defense, including anti-HIV drugs.

I include another paper above regarding the mechanisms by which Chloroquine may work against COVID-19 – in part by raising PH in the endosomes which open up the virus particles and by affecting ACE-2 interactions in the lung where most of the damage is done without treatment.

Here is a article from ASIA Times:

Why are Korea’s Covid-19 death rates so low?

South Korea has the dubious distinction of suffering the second-highest number of  Covid-19 infections after China – but can also boast the lowest death ratio among countries with significant numbers of cases.

According to the WHO on March 6, the crude mortality ratio for Covid-19 – that is, the number of reported deaths divided by the number of reported cases – is between 3-4%. In Korea, as of March 9, that figure was a mere 0.7%.

While, 7,478 cases were confirmed in South Korea by the Korea Center for Disease Control and Prevention (KCDC) on Monday, only 51 have died. Meanwhile, according to data from John Hopkins University, Italy has 7,375 cases and 366 deaths, while Iran has 7161 cases and 237 deaths.

Amid the outbreak, neighboring China has used a “Great Wall” strategy to cordon off entire cities. South Korea has stuck to a liberal playbook: even its most affected city, Daegu, has not been isolated. This makes Seoul’s apparent success in the struggle against Covid-19 a potential benchmark for other affected democracies.

What is behind Korea’s low fatality rate from a virus that has spooked the world? Government briefers speaking to foreign reporters in Seoul on Monday offered some pointers.

Key factors include a robust national health service; prior experience of virus outbreaks and related preparations; aggressive execution of testing, isolation and treatment protocols, fully backed by the law – and two incidences of good fortune.

Systems activated

South Korea reacted to the crisis with vigor, deploying a range of legal, medical, technological and public communication efforts.

The country could act so effectively due to a piece of rare good luck. Buttressing prior experience with SARS and MERS, the KCDC – by coincidence – conducted a table-top exercise on a coronavirus outbreak in December 2019.

As a result, officials were fully prepared when the novel coronavirus hit the nation the following month. Testing started on January 11, Kwon said; the first infection was confirmed on January 19.

Telephone consulting services, drive-through test centers and thermal cameras – which, set up in buildings and public places to detect fever, swiftly came online. South Korea has undertaken approximately 190,000 tests thus far, according to KCDC Deputy Director General Kwon Jun-wook, and has the capacity to undertake 20,000 per day. Turnaround times are six-24 hours.

Tests are highly affordable. “The test kit is about $130, and about half is covered by insurance the other half by individual,” Kwon said. Those who test positive get the test free, “So there is no reason for suspected cases to hide their symptoms,” he said.

Overseas experts approve.

“There is no such thing as too much testing during an outbreak,” Dan Strickland, a retired American epidemiologist told Asia Times. “All the testing is catching false positives” – ie those who test positive but do not actually have the disease – “but is also catching mild cases.”


Dedicated centers and hospitals centralize specialized equipment and personnel, while keeping the virus out of regular hospitals. A triage system ensures only those with severe symptoms are admitted to oxygenated, low-pressure wards. Home quarantine with access to medical consulting is widely employed.

Widespread tests….

South Korea’s cases of infection had been minimal until the third week of February when cases suddenly exploded in the country’s southeast – a result of chain infections in crowded services held by the secretive Christian sect, Shincheonji.

Some 63% of Korea’s cases hail from the sect, according to government data.

While Shincheonji members are scattered nationwide, the government demanded – and received – its membership list. Contrary to widespread rumors and accusations, a senior government official said the church has cooperated.

A lot of research has been conducted based on the information delivered by their HQ, it was very comprehensive info: the number of members, their personal information and the location of their church facilities,” said Vice Minister of Health and Welfare Kim Gang-lip, who is also overall coordinator 1 of the Central Safety Countermeasures Headquarters.

“The reliability of the information was verified through an administrative investigation,” Kim said. “We went into their information systems to verify and double check; from the overall organizational perspective, they are cooperating.”

The government implemented widespread testing of the church’s 211,000 followers. Those with symptoms were triaged as priority testees; once they were cleared, tests were conducted on those who showed no symptoms to ensure they were not latent carriers.

“From the containment phase, we tried to implement case isolation and case tracking, and this was done in a very aggressive manner,” Kim Dong-hyun of the Korean Society of Epidemiology said.  

“We have legal grounds for cohort isolation,” said Kwon. “Rather than being an infringement of human rights, this was for the prevention of epidemic.” Related laws on the books date back to the MERS outbreak and further legal changes take effect in April.

Case tracking was done via CCTV data mining and credit use patterns.

…early treatment

Quarantines removed the infected from the general populace, but perhaps even more critical to the low death rate was the activation of early treatment.

“Even on followers who did not show symptoms, we conducted screening and confirmed early cases early on,” Kim said. “I think that was effective.”

The large dataset created a knowledge bank on effective measures and treatments.

“Mild and asymptomatic cases were denominated and this brings down the fatality rate,” Kim said. “I think we were able to identify almost all of the mild cases…. on that side, Korea was quite exceptional, and that allowed us to collect extensive data.”

Despite panicky headlines about a lack of specific medication for Covid-19,  advanced medical treatment offers hope even in severe cases.

“Viral pneumonia, even when complicated by bacterial pneumonia and end-organ failure, is potentially surmountable,” Ogan Gurel, a non-practicing doctor currently working as a professor in South Korea, told Asia Times. “You just need advanced medical care – and some oxygen.”

Age matters

Along with its December coronavirus drill, Korea was lucky in another respect: Its core cluster infected an age range with strong resistance to Covid-19, for Shincheonji concentrated its recruitment efforts on students and the young.

“When you look at the age and the distribution of confirmed cases in Shincheonji you see high portion of those in the 20s and 30s,” said Kim. “Therefore, the fatality rate in this cohort is low.”

“If you look at the population distribution compared to China, we have a higher portion of younger age groups,” agreed Kim Yeon-jae, an infectious disease specialist at Korea’s National Medical Center. “This has impact on the fatality rate.”

According to data supplied to journalists on Monday, there have been no fatalities in Korea among persons aged under 29.

Still, even for the aged, Korea is doing better than other affected countries, said epidemiologist Kim: the percentage of fatalities in the 70-80 age group are lower than in Japan or Italy. “I think this is thanks to early detection and early treatment,” he said.

Unanswered questions

Yet Korea is just three months into the virus. While the day-to-day increase rate appears to be slowing (see chart at bottom) it is presumptuous to declare victory.

“It too early to assess if we have been successful or not,” said Kim Dong-hyun. “We are still in a learning process….”

With Korea’s numbers having shot up just within the last three weeks, the risk of a sudden death surge, as the disease works its course through the biologies of thousands of infected, remains a possibility.

On the other hand, the low ratio of death-to-infection could continue. If so, Korea’s extensive dataset could prove Covid-19 far less lethal than many fear.

One expert believes Korea’s numbers are superior to the WHO’s.

“Death rates are almost always overestimates as they miss tons of people who don’t have [symptoms],” said a US-based statistical geneticist who requested anonymity. “False positive are less of an issue than untested masses.”

He added: “It is consistently in the interest of medical pros to overstate risks in order to win more funding from governments: ‘Fund me and you might not die,’ is a compelling argument!”

Culture-specific factors could be at work. In previous epidemics, some postulated that the Korean diet – heavy on such supposedly immune-boosting ingredients as garlic – might offer the populace superior in-body defenses.

Professionals are skeptical. “There is no evidence that Koreans, or other populations, have specifically strong adaptive immune systems” to the virus, said Gurel.

And big picture, Korea’s high testing/high numbers/low mortality ratios are not the only way forward: Neighbor Japan has lower overall numbers, but a higher percentage of fatalities.

“We were very strong in the early spread,” Kim said. “In Japan, there is a shortage of testing kits and they only focus on patients which show symptoms. You could say that is a strategy.”

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Many pharmacists across the world are working hard to keep up with therapeutic options for coronavirus / SARS-CoV-2 / COVID-19. This webpage was created to provide insights and resources for pharmacists helping to manage this pandemic. Take note that updates to the page will be made periodically as permitted and the content here may not be completely up-to-date as the situation is evolving quickly. Also beware that much of the data identified below is of relatively poor quality in terms of utility for determining what should be done in clinical practice.

Additionally, there are many potential COVID-19 therapies, I list several at the bottom, but do not discuss them in depth. Some of these can potentially lessen the cytokine storm associated with COVID-19 and help with managing acute respiratory distress syndrome (ARDS).

MOST IMPORTANTLY: Thus far no antiviral drug has been proven to work against COVID-19 in humans, although many randomized controlled trials are ongoing. Inclusion in this webpage is not an endorsement for use of any of these drugs for COVID-19.

If you have a resource that is helpful and reliable, but not posted here, send it to me: IDstewardship@gmail.com or @IDstewardship on Twitter.

Genereal COVID-19 Resources

Institutional & Society COVID-19 Treatment Guidelines

General Notes

Remdesivir Resources & Notes

  • Remdesivir (GS-5734, RDV) is not FDA-approved and is available for investigational use only
    • Is a nucleotide analog antiviral
    • Has activity against Ebola virus, MERS, and SARS
    • Has drug-drug interactions via the liver, so would not be expected to be given with LPV/r
      • Guidance I received from Gilead was that once remdesivir is initiated, any experimental anti-COVID-19 therapies must be ceased
    • Available intravenous only
      • Study dose in adults: RDV 200 mg loading dose on day 1 is given, followed by 100 mg iv once-daily maintenance doses for 9 days
        • Review study protocols here
  • In preparing to request investigational remdesivir, collecting the following information ahead of time may be helpful:
    • Prescriber name, address, email, and phone number associated with the treatment center
    • Professional designation (ie, MD) or qualifications of requester including medical license number
    • Institution/ hospital name, address, email, and phone number
    • Shipping information (including pharmacy hours)
    • Patient case information, including previous or current treatments and clinical status
  • There are many exclusion criteria for remdesivir
  • Remdesivir clinical trials
  • Email to contact Gilead compassionate use: compassionateaccess@gilead.com

Lopinavir/ritonavir (Kaletra, LPV/r) Resources & Notes

  • Beware drug-drug interactions as ritonavir is a CYP enzyme inhibitor (will increase levels of other drugs)
  • Consider avoiding for patients with liver or cardiac disease
  • LPV/r comes in an oral solution, but it may not be available during times of high demand, so people may consider crushing the capsules
    • Pharmacokinetics of Lopinavir/Ritonavir Crushed versus Whole Tablets in Children
      • Crushing LPV/r can reduce the AUC by 50%
      • Increasing the LPV/r dose by 50% to compensate would mean a considerable amount of ritonavir, which may cause considerable drug-drug interactions
        • Cushing LPV/r has shown to reduce exposure to both lopinavir and ritonavir, so the increase in ritonavir may not be clinically relevant
    • From a colleague (paraphrased):
      • We may be able to use information from venetoclax (Venclexta), which like LPV/r has a film coated tablet
        • For venetoclax we dissolve the tablet into a slurry in a syringe to reduce the risk of losing drug in a crusher or amber vial. It can take up to 20 mins (per patient report) to get the drug to dissolve. The ICU nurses have not had issues with getting ventoclax surry down NG tubes, but floor nurses did report issues (potential it was not administered immediately?). We also did the tablet slurry in a syringe to reduce exposure to compounding staff.
        • This approach can avoid the use of preservatives
          • This briefing includes  information on making a pediatric venetoclax solution, notes avoiding preservatives and potential issues with stability
        • Stability data is lacking, consider immediate use
          • From the above referenced article: “Disruption of the extrude matrix environment may adversely impact this formulation affect. The crushing of the pill leaves part of the drug(s) on the walls of the container or crushing device, and the transfer of the crushed substance to the food or liquid for mixing may also generate loss of the active drug.”
  • The dose and duration I have seen recommended is LPV/r 400-100 mg BID x14 days
  • The University of Michigan COVID-19 guidance document recommends:
    • Adult dosing: 400 mg-100 mg PO BID
    • Pediatric dosing:
      • 14 days to 6 months old: lopinavir component 16 mg/kg PO BID
      • 6 months to 18 years:
        • 15-25 kg: 200 mg-50 mg PO BID
        • 26-35 kg: 300 mg-75 mg PO BID
        • >35 kg: 400 mg-100 mg PO BID
  • LPV/r oral solution has a high alcohol content and tastes terrible, which can be an issue for children in particular
  • Consider HIV testing prior to initiating therapy
  • Some clinicians are combing LPV/r with ribavirin
  • Epidemiologic Features and Clinical Course of Patients Infected With SARS-CoV-2 in Singapore
    • Includes 5 patients treated with LPV/r for COVID-19
    • None died
    • 3 of 5 developed abnormal liver test results
  • There are pre-SARS-CoV-2 publications supporting activity of LPV/r versus SARS
  • Kaletra Package Insert (tablet & oral solution)

Chloroquine Resources & Notes

Hydroxychloroquine (Plaquenil) Resources & Notes

Tocilizumab (Actemra) Resources & Notes

  • Tocilizumab is an inteurlukin-6 (IL-6) inhibitor that may be helpful for cytokine storm associated with severe COVID-19 disease
    • Cytokine storm may be a complicating factor for patients with severe COVID-19 disease
  • Reserve for patients with severe disease who have failed other therapies, consider dose capping and limiting the number of doses
  • Novel Coronavirus Pneumonia Diagnosis and Treatment Plan (Provisional 7th Edition) states:
    • For patients with extensive and bilateral lung disease and severely ill patients with elevated IL-6 levels, treatment with tocilizumab may be attempted
    • The initial dose should be 4-8mg/kg, with the recommended dosage being 400mg
    • Dilute with 0.9% saline to 100ml and infuse over the course of more than 1 hour
    • Repeat once after 12 hours (same dosage) if the response to the first dose was poor, mximum two cumulative doses
    • Single maximum dose is 800mg
    • Pay attention to allergic reactions
    • Prohibited in patients with active infections such as tuberculosis
  • One article (not peer reviewed) reports on 20 patients with severe or critical COVID-19 disease treated with tocilizumab and having good outcomes
  • Concern exists that the long-term effects of this drug may predispose patients to future infections
    • Some providers are looking to IL-1 inhibitors for this reason
  • This medication is very expensive
  • Tocilizumab (Actemra) Package Insert

More COVID-19 Articles

List of Other Potential Therapies

Other COVID-19 Resource Centers

More COVID-19 Webpages

Miscellaneous Things That May be Helpful

And Even More COVID-19 Literature

Coronavirus feed:

WHO website COVID-19

Scientific america COVID-19

Wikipedia COVID-19

What is the best public policy to counter the health risk from the Coronavirus, COVID-19? This is the question on everyone’s mind.

It is wise to try and learn from the current situation in China, where the rate of COVID-19 infections was extinguished as a result of a lockdown, and Italy, where hospitals are full and doctors have to make life-death decisions about patients because there are not enough beds to treat everyone in need. The mortality fraction of infected people appears to be higher by an order of magnitude when hospitals are overcrowded, so suppressing the rate of new infections serves the important purpose of allowing those in need to be treated.

If we do nothing, the current state of affairs is likely to worsen dramatically in the coming weeks. To gauge how bad circumstances may become, let’s examine publicly available data.

Our first plot shows the reported number of infections over time. For each country, Wikipedia has a continuously updated Web site with links to the original official sources such as the World Health Organization, research institutes and health ministries. The plotted curves show the cumulative number of known infections per country as a function of date. Colored points show the current situation as of this writing on March 15. 

Credit: Andi Burkert

The data exhibit exponential growth in all countries, except for China and South Korea. Because of the rapid growth, early action is crucial in moderating the number of infections. Extrapolating the curves all the way to the edge of the box implies that the United States will reach a million infections at the beginning of April, with four million for Spain and about 0.1 million for the United Kingdom, Netherlands and Sweden, respectively. If no effective action is taken by April 10, the U.S. and the European countries could reach the 10 million mark.

The doubling times appear to evolve, as shown in our second plot. These values represent the slopes of the growth curves, averaged over a period of eight days.

Credit: Andi Burkert

But the number of reported cases must be smaller than the actual number of infections. Many countries, including the U.S., were limited until recently by the availability of COVID-19 test kits. It is possible that there are many more cases than those in public reports. We label those “invisible infections.” South Korea performed many more tests than the U.S. and succeeded in flattening its curve. The COVID-19 tests in the U.S. had a positive fraction that was three to 10 times larger than in South Korea, implying a substantial invisible population.

If the correction factor due to the “invisible population” is a factor of approximately 10 and only about 20 percent of people infected show symptoms (based on the Diamond Princess cruise ship statistics), then the actual number of people exposed to the coronavirus at this time is already five million. This implies: (i) with an approximately 2 percent mortality fraction out of the infected population, at least 100,000 people will die; and (ii) we are only about 10 doubling times away from having most of the worldwide population being infected if no social distancing is established. Given that the measured doubling time is a few days, this implies that uninhibited exponential growth will saturate within a month, leading up to some 100 million deaths. But if many countries flatten the curve, as we all hope, then saturation will take a much longer time and the number of deaths could be reduced.

What does all of this imply? The wisest policy at the moment is to “flatten the curves” and lengthen the doubling times as much as possible by suppressing social interactions. The virus does not move on its own. It is transmitted by humans and survives a few days on contaminated surfaces. To flatten the curves, all nations must engage immediately in social distancing as well as in extensive testing and comprehensive isolation of patients with COVID-19 symptoms and people who had been in contact with such patients.

Cases in USA – CDC

Coronavirus model shows individual hospitals what to expect in the coming weeks

Why ‘flattening the curve’ may be the world’s best bet to slow the coronavirus

Penn Medicine – COVID-19 Hospital Impact Model for Epidemics

For many countries staring down fast-rising coronavirus case counts, the race is on to “flatten the curve.”

The United States and other countries, experts say, are likely to be hit by tsunamis of Covid-19 cases in the coming weeks without aggressive public health responses. But by taking certain steps — canceling large public gatherings, for instance, and encouraging some people to restrict their contact with others — governments have a shot at stamping out new chains of transmission, while also trying to mitigate the damage of the spread that isn’t under control.

The epidemic curve, a statistical chart used to visualize when and at what speed new cases are reported, could be flattened, rather than being allowed to rise exponentially.

“If you look at the curves of outbreaks, they go big peaks, and then come down. What we need to do is flatten that down,” Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, told reporters Tuesday. “That would have less people infected. That would ultimately have less deaths. You do that by trying to interfere with the natural flow of the outbreak.”

The notion that the curve of this outbreak could be flattened began to gain credence after China took the extraordinary step of locking down tens of millions of people days in advance of the Lunar New Year, to prevent the virus from spreading around the country from Wuhan, the city where the outbreak appears to have started. Many experts at the time said it would have been impossible to slow a rapidly transmitting respiratory infection by effectively shutting down enormous cities — and possibly counterproductive.

But the quarantines, unprecedented in modern times, appear to have prevented explosive outbreaks from occurring in cities outside of Hubei province, where Wuhan is located.

Since then, spread of the virus in China has slowed to a trickle; the country reported only 19 cases on Monday. And South Korea, which has had the third largest outbreak outside of China, also appears to be beating back transmission through aggressive actions. But other places, notably Italy and Iran, are struggling.

For weeks, a debate has raged about whether the virus could be “contained” — an approach the WHO has been exhorting countries to focus on — or whether it made more sense to simply try to lessen the virus’ blow, an approach known as “mitigation.”

That argument has been counterproductive, Mike Ryan, the head of the WHO’s health emergencies program, said Monday.

“I think we’ve had this unfortunate emergence of camps around the containment camp, the mitigation camp — different groups presenting and championing their view of the world. And frankly speaking, it’s not helpful,” Ryan told reporters.

Caitlin Rivers, an assistant professor of epidemiology at the Johns Hopkins Center for Health Security, said any lessening of spread will help health systems remain functional.

“Even if we are not headed to zero transmission, any cases that we can prevent and any transmission that we can avoid are going to have enormous impact,” she said. “Not only on the individuals who end up not getting sick but all of the people that they would have ended up infecting. … And so the more that we can minimize it, the better.”

On any normal day, health systems in the United States typically run close to capacity. If a hospital is overwhelmed by Covid-19 cases, patients will have a lower chance of surviving than they would if they became ill when the hospital’s patient load was more manageable. People in car crashes, people with cancer, pregnant women who have complications during delivery — all those people risk getting a lesser caliber of care when a hospital is trying to cope with the chaos of an outbreak.

“I think the whole notion of flattening the curve is to slow things down so that this doesn’t hit us like a brick wall,” said Michael Mina, associate medical director of clinical microbiology at Boston’s Brigham and Women’s Hospital. “It’s really all borne out of the risk of our health care infrastructure pulling apart at the seams if the virus spreads too quickly and too many people start showing up at the emergency room at any given time.”

Countries and regions that have been badly hit by the virus report hospitals that are utterly swamped by the influx of sick people struggling to breathe.

Alessandro Vespignani, director of the Network Science Institute at Northeastern University, is gravely worried about what he’s hearing from contacts in Italy, where people initially played down the outbreak as “a kind of flu,” he said. Hospitals in the north of the country, which the virus first took root, are filled beyond capacity, he said, and may soon face the nightmarish dilemma of having to decide who to try to save.

“This was what was really keeping me up at night, to unfortunately see Italy approaching that point,” Vespignani said, adding that now that the country has effectively followed China’s example and put its population on lockdown, “hopefully this will work.”

Vespignani, along with colleagues, published a recent modeling study in Science that showed travel restrictions — which the United States has adopted to a degree — only slow spread when combined with public health interventions and individual behavioral change. He’s not convinced that people in the United States comprehend what’s coming.

“I think people are not yet fully understanding the scale of this outbreak and how dangerous it is to downplay,” he said.

Mina agreed: “Without a very clear signal coming from our government at the national level, it’s really just like a small trickle as people start to recognize that this is happening.”

COVID-19 infection growth rates, lagged mortality rates, and other interesting statistics

COVID Dashboard

An interactive web-based dashboard to track COVID-19 in real time

Chinese COVID infection dashboard

No longer in a low-growth world

The growth of the COVID-19 virus is staggering. From January 22nd to the time of this writing, the median daily rate of new cases is 5.6 percent. More startling is the median daily growth in deaths at 9.3 percent. That said, it’s comforting to see that the median recovery growth rate of 16.2 percent is higher than the combined new case and mortality growth rates.

Estimating the Number of Future Coronavirus Cases in the United States

Trump directs FDA to examine whether malaria drug can be used for coronavirus

ER Wait Times:

https://www.hospitalstats.org/ER-Wait-Time/

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A recent study with 50 patients demonstrated that Ketamine has a more rapid efficacy with less cognitive decline than does ECT.

What is ECT? Here is a Youtube Video demonstrating it:

electroshock probes

Although both treatmens work with similiar results of depression decrease in the end, ther eis less cognitive decline with Ketamine infusions in terms of attention, visual memory, and executive functions.

See the article link below :

J Psychiatr Res. 2020 Jan 16;123:1-8. doi: 10.1016/j.jpsychires.2020.01.002. [Epub ahead of print]

Antidepressant and neurocognitive effects of serial ketamine administration versus ECT in depressed patients.

Basso L1Bönke L2Aust S3Gärtner M3Heuser-Collier I3Otte C3Wingenfeld K3Bajbouj M3Grimm S4.

Author information

Abstract

BACKGROUND:

While electroconvulsive therapy (ECT) is considered the gold standard for acute treatment of patients with otherwise treatment-resistant depression, ketamine has recently emerged as a fast-acting treatment alternative for these patients. Efficacy and onset of action are currently among the main factors that influence clinical decision making, however, the effect of these treatments on cognitive functions should also be a crucial point, given that cognitive impairment in depression is strongly related to disease burden and functional recovery. ECT is known to induce transient cognitive impairment, while little is known about ketamine’s impact on cognition. This study therefore aims to compare ECT and serial ketamine administration not only with regard to their antidepressant efficacy but also to acute neurocognitive effects.

METHODS:

Fifty patients suffering from depression were treated with either serial ketamine infusions or ECT. Depression severity and cognitive functions were assessed before, during, and after treatment.

RESULTS:

ECT and ketamine administration were equally effective, however, the antidepressant effects of ketamine occurred faster. Ketamine improved neurocognitive functioning, especially attention and executive functions, whereas ECT was related to a small overall decrease in cognitive performance.

CONCLUSIONS:

Due to its pro-cognitive effects and faster antidepressant effect, serial ketamine administration might be a more favorable short-term treatment option than ECT.

LIMITATIONS:

As this research employed a naturalistic study design, patients were not systematically randomized, there was no control group and patients received concurrent and partially changing medications during treatment.

CLINICAL TRIALS REGISTRATION:

Functional and Metabolic Changes in the Course of Antidepressive Treatment, https://clinicaltrials.gov/ct2/show/NCT02099630NCT02099630.

Basso L, Bönke L, Aust S, et al. Antidepressant and neurocognitive effects of serial ketamine administration versus ECT in depressed patients. J Psychiatr Res. 2020;123:1-8.

Short Term Treatments for Depression: Ketamine vs ECT

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Weekly Ketamine Infusions Show Initial, Repeated Depression Benefits

A new study shows that weekly ketamine infusions are associated with continued and maintained reductions in depressive symptoms among patients with treatment-resistant depression.

The findings, which are considered novel among studies assessing ketamine administration for patients with treatment-resistant depression, evidence the promising role the controversial drug could play in psychiatric care.

A team of investigators, led by Jennifer L. Phillips, PhD, an associate scientist in the Mood Disorders Research Unit at The Royal’s Institute of Mental Health Research, conducted a randomized, double-blind crossover comparison of single ketamine infusion versus active placebo control midazolam. The assessment, held with 41 participants with treatment-resistant depression at single treatment center, observed patients receive 6 open-label ketamine infusions 3 times per week over 2 once patients had a relapse of depressive symptoms.

Patients who reported a decrease of at least 50% in the Montgomery-Åsberg Depression Rating Scale (MADRS) received another 4 additional infusions once weekly in a maintenance phase.

Those administered a single ketamine infusion reported significantly reduced depressive symptoms at the primary efficacy endpoint of 24 hours post-care versus those treated with midazolam. The therapy showed cumulative antidepressant effects over repeated infusions, as well a doubling of antidepressant response rate in patients, according to linear mixed models.

Investigators found that 59% of patients met the response criteria following repeated infusions, with 3 infusions serving as the median dosage required to reach achieved response. In patients receiving weekly maintenance infusions, no further improvement in MADRS scores were reported.

The first-of-its-kind findings come just 1 month following the US Food and Drug Administration (FDA) approval of esketamine nasal spray (Spravato) for the treatment of patients with treatment-resistant depression. At the time, the therapy made history as the first novel treatment indicated for depression in 30 years—and headlines as one of the first hallucinogenic drugs to reach indication for a common condition.

Dennis Charney, MD, Dean of Icahn School of Medicine at Mount Sinai and a member of the Yale University team that led pioneering antidepressant ketamine trials in the 1990s, told MD Magazine® that microdosing or implementing controversial therapies for psychiatric care require what any other trial requires: control, safety, and a carefully-assessed standard for efficacy.

“No matter what treatment is being assessed, you have to follow those scientific approaches,” Charney said. “For conditions that don’t have effective treatments available, there should be an open mind.”

For the majority of individuals that benefit from it, it will be essentially buying them time for other treatments—be them pharmacotherapies or device-based treatment, or psychotherapies, because those are beginning to work much more slower than ketamine does,” he said.

Whatever its marketed use entails, Phillips and colleagues concluded positively that ketamine showed both initial and repeated benefits for antidepressant effects as a once-weekly infusion.

“These findings provide novel data on efficacious administration strategies for ketamine in patients with treatment-resistant depression,” they wrote. “Future studies should further expand on optimizing administration to better translate the use of ketamine into clinical settings.”

The study, “Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial,” was published online in The American Journal of Psychiatry.

703-844-0184 | Fairfax Ketamine Infusion Center | NORTHERN VIRGINIA KETAMINE CENTER FOR DEPRESSION | NOVA HEALTH RECOVERY | ESKETAMINE VIRGINIA | Natural Sleep aids | SPRAVATO CENTER OF FAIRFAX | INTRANSAL KETAMINE CENTER | 22304 22306 | FAIRFAX, VA | RESTON VIRGINIA KETAMINE INFUSION CENTER | KETAMINE DOCTOR NEAR ME | LOUDOUN COUNTY KETAMINE| 22201 | ARLINGTON KETAMINE CENTER | Loudoun County Ketamine Infusion Center

NOVA Health Recovery | Alexandria, Va 22306 | Call for esketamine and nasal ketamine as well as IV Ketamine for depression, PTSD, anxiety  703-844-0184 < Link

Calming magnesium, amino acids and herbs. Sleep Relief contains magnesium, a gentler muscle relaxer. The amino acids L-Tryptophan, L-Theanine, glycine and GABA and herbs such as Hops (Humulus lupulus) and Skullcap (Scutellaria lateriflora) all contribute to the calming effects of Sleep Relief by targeting different neurological and biochemical pathways.

  • L-Tryptophan is converted to serotonin and melatonin. Serotonin is a mood-elevating hormone and melatonin is a circadian modulator that helps regulate your body’s day and night cycle. 
  • L-Theanine promotes alpha wave brain activity, which is associated with alert relaxation.
  • Glycine and GABA are nutrients that acts as naturally calming neurotransmitters that promote relaxation.
  • Hops and Skullcap are ancient plants that have long histories of use in traditional healing systems. Native Americans relied on them for a wide variety of medicinal purposes, and extensive research has validated many of their traditional applications, including promoting healthy sleep.   

Adaptogenic herbs like Ashwagandha (Withania somnifera) and Jujube (Ziziphus jujuba). Adaptogens are a unique class of healing plants. They help balance, restore and protect the body. Ashwagandha and Jujube are ancient plants that have been used in traditional Asian medicine for thousands of years and can promote a healthy stress response.

Nutritional Biochemistry, Inc. (NBI) formulates and manufactures products that give results. Started by John Neustadt, ND, in 2006 when he couldn’t find formulas he needed to help his patients and family, NBI products solve 2 problems he was having. Existing products didn’t contain the dose or combination of nutrients used in clinical trials and actually shown to work. Equally frustrating, other companies would cite studies on their websites, but then use lower amounts of nutrients than what was used in the study, or use entirely different nutrients that weren’t supported by the research.

Neustadt’s latest creation is Sleep Relief [3]. NBI’s Sleep Relief is a breakthrough in sleep technology. Its bi-phasic, time-release technology delivers NBI’s proprietary formula with clinically validated nutrients in two stages—a quick-release first stage and a slow-release second stage to help you gently fall asleep, stay asleep and wake refreshed and ready for your day. NBI’s Osteo-K [5] delivers the clinical dose of nutrients shown in more than 25 clinical trials to grow stronger bones and reduce fractures more than 80%.

NBI is and always has been a family-owned company. We don’t manufacture anything we wouldn’t take ourselves or give to our own family. No matter what we do, our promise to physicians using our products is to help their patients, and to customers purchasing directly from NBI, is uncompromising quality.

NBI is a name you can trust. But don’t take our word for it. Spend some time on our website [6], learn about our products, and educate yourself on the hundreds of research citations and studies that they’re based on.

Transcript

Karolyn Gazella: Hello. I’m Karolyn Gazella, publisher of the Natural Medicine Journal. Thank you so much for joining me. Today, our topic is the integrative approach to insomnia. During this interview, we will learn that insomnia is a significant problem for many patients that can have far reaching physical, mental and emotional health ramifications. We will also learn how to successfully treat this condition by using a combination of diet, lifestyle recommendations, and dietary supplements.

My expert guest today is Dr. John Neustadt. Dr. Neustadt received his naturopathic doctorate from Bastyr University and he was the founder and medical director of Montana Integrative Health.

Before we begin, I’d like to thank the sponsor of this topic who is Nutritional Biochemistry Incorporated, or NBI, manufacturers of high-quality dietary supplements for health care professionals.

Dr. Neustadt, thank you so much for joining me today.

John Neustadt, ND: Thank you for having me on.

Gazella: Well, so the Centers of Disease Control and Prevention calls lack of sleep a public health epidemic. Now, that seems pretty significant so today we’re going to talk specifically about insomnia. How common is insomnia in particular?

Neustadt: Well, the CDC is absolutely correct. It is a public health epidemic. Up to 80% of people struggle at some point with what’s considered transient insomnia, less than two weeks of duration and insomnia effects 10 to 15 percent of the general population.

In primary care settings, it’s estimated that up to almost 70 percent of primary care patients have insomnia so it is incredibly common.

Gazella: Oh, yeah that is. So how does lack of sleep impact a patient’s overall health from like a physical, mental, emotional standpoint?

Neustadt: It has devastating impacts. There are two ways to think of it. One is short-term impacts and the other are the long-term impacts. So, short term it can impact decreased job performance, impact social and family life by creating greater fatigue. I mean, just you’re more tired during the day. Decreased mood and depression, increases in anxiety and stress. Decreased vigor and just not being able to cope with the demands of daily life and be able to complete tasks. That’s only short term. Devastating just in the short term.

But in the long term, it can be a killer. There, if people are sleeping an average of less than six hours per night, it can increase the … or decrease the quality of life at the same magnitude of a similar condition such as congestive heart failure and major depressive disorder. It’s an early symptom for Alzheimer’s Disease and Parkinson’s Disease and Huntington’s Disease and there’s a sweet spot for sleeping of about eight hours. That research shows is the healthiest, and if you’re sleeping less than six, or longer than nine hours, it increases your risk for diabetes, metabolic syndrome, and death and, in fact, for metabolic syndrome, there’s a 45 percent increase in risk compared to people who are sleeping seven to eight hours a night.

Gazella: Wow, so yeah, so this is a very important topic for clinicians to have on their radar. So, when you’re evaluating a patient with a sleep disorder such as insomnia, how do you approach the work up?

Neustadt: Well, insomnia’s really a qualitative diagnosis. It’s how are they … how do they feel that they’re sleeping? How do they feel that it’s impacting their health? Now the DSM official diagnosis, there is a quantitative or a couple of quantitative aspects to that and that is it’s occurring at least three nights per week, and present for at least three months. So understand the difference between transient insomnia, less than two weeks, versus the diagnosis, official diagnosis, needs to be going on for greater than three months.

So there’s a huge discrepancy there and in time periods and clinically it’s important to be aware of that because these detrimental and dangerous effects of insomnia and sleep deprivation definitely are occurring in shorter than three months period of time. They’re happening pretty quickly if someone’s not getting enough sleep and even over a few days the short term consequences.

And so what I ask people about is how many hours, on average, do they think they’re sleeping a night? Do they have any difficulty with falling asleep or staying asleep called sleep phase delay or sleep phase advance? Are they waking refreshed in the morning? What’s going on with them psychosocially? Are there any stresses going on at work or in relationships or financially that’s increasing their anxiety and could be impacting their sleep? Are they are risk for any hormonal abnormalities or imbalances because the research is clear that low estrogen, low or high testosterone, elevated TSH, those are all things that can create insomnia. Abnormal progesterone, as well.

And then looking at medications because there are some medications that can impact sleep, as well.

Gazella: Yeah, let’s talk about the medications that can impact sleep. What are some of those medications that can impact sleep?

Neustadt: Well, prednisone, that can cause hyper-arousal, or can cause somebody to not sleep, not be able to fall asleep, or have fragmented sleep. Beta-blockers, very common heart medications, can decrease melatonin production. So we know what the mechanism of action … their interaction of sleep is they decrease melatonin and can cause poor sleep.

Some antidepressants, actually, can cause poor sleep. Antidepressants can, depending on the antidepressants, can either cause somebody to not be able to sleep enough or can cause hypersomnolence, somebody to be sleeping too much. So looking at those, looking up … it’s very easy to look up whatever medication they’re taking quickly and see, besides the ones that I mentioned, could it be potentially interfering and impacting with their sleep.

Gazella: So I’ve been hearing about hyperarousal, or the hyperarousal hypothesis, which I find quite fascinating. What is the hyperarousal hypothesis and how can it affect what is recommended to patients?

Neustadt: Great question. So the hyperarousal hypothesis I like to refer to as “wired-but-tired.” And it occurs to people typically who are under a lot of stress, they have elevated cortisol, and when they end up trying to fall asleep they just can’t turn their mind off, or even if their mind isn’t racing, they just can’t calm down. Their body can’t relax and settle into sleep. They’re staring at the ceiling, it can cause fragmented sleep. And that wired-but-tired, again, typically occurs in people who are under chronic stress.

Gazella: Yeah. And you know the other day when you and I were talking as it related to the hyperarousal hypothesis, you were telling me about something else that was new to me and it was called social jet lag. Talk a little bit about social jet lag and the research associated with social jet lag.

Neustadt: I’m so happy you brought this up because I love this as well. Fitbit, that maker of the wearable tracking devices, and tracking people’s sleep as well, they had access, because of their users, to over six billion data points of sleep. And they looked at those. And they looked at the data and determined that the biggest predictor of healthy sleep, restful sleep, is going to bed at about the same time every night. Basically training our body that it’s bedtime, getting that routine.

Social jet lag occurs when people are going to bed at about the same time every night during the week but then the weekend comes. Friday night they go out, hang out with friends, stay out late. Saturday night maybe do the same thing, and then Sunday comes around and they try to go to bed again at their weekday, or their work week time, and they can’t fall asleep. And essentially what they’ve done is it’s as if they’ve flown to another time zone and their body thinks that it’s not time to go to sleep yet. And they’ve induced their own jet lag called social jet lag.

And so one of the things that Fitbit found, and I think one of the most impactful things, is showing that getting that regular bedtime, being in that routine, going to bed at about the same time every night is one of the best things people can do for improving their sleep.

Gazella: And even on the weekend, and I’ll tell, you, when you put this on my radar I, of course, had to do a little research and there’s a lot of studies on this that actually show that the physical effects that you talked about with sleep deprivation earlier also occur with this social jet lag. So I think it’s really important for clinicians to be aware of that. So thank you for bringing this to my attention.

So now doctors often prescribe benzodiazepine or benzodiazepine-like drugs to help patients sleep. What are some of the potential risks of these particular medications?

Neustadt: Well, the potential risks are very well documented and they increase risk for falling, dizziness, light-headedness, those risks are increased in people who are 60 years or older because their ability to metabolize the drug tends to decrease. And so because it increases the risk for falls and dizziness and light-headedness, it then increases the risk for fall-related injuries, such as osteoporotic fractures, such as concussions, such as death, even. But even beyond those risks associated with increased risks for falling, the research has shown that cancer risk is actually increased in people who take over about 132 doses of benzodiazepine a year. So that’s even … that’s less than half of a year worth.

And in fact some of these risks are increased with very small and limited exposure. So you know from half a dose to 18 doses per year, the hazard risk for death is increased 3.6 times. 18 to 132 doses, the hazard risk for death increased 4.43 times in a study that looked at this. And for greater than 132 doses, it increases 5.32 times. That’s 532 percent greater than somebody not taking these medications for death. And the research has shown to actually get one benefit, the number needed to treat, to have one patient benefit is 13 patients. But the number to treat to create harm is only 6 patients.

Gazella: Yeah, that’s problematic. So what about the newer class of medications, like the orexin receptor antagonist Belsomra?

Neustadt: Belsomra came on the market in 2015, it’s a schedule 4 drug and it’s a CNS depressant. So, like other CNS depressants, like benzodiazepine, it can have similar adverse effects. Some of the benzodiazepine drugs like Lunesta or Ambien can also cause, like Belsomra, can cause daytime impairment including impaired driving skills, risk of falling asleep while driving, abnormal thinking and behavioral changes are part of the adverse events spectrum, including amnesia, anxiety, hallucinations, other neuropsychiatric symptoms, even complex behaviors like sleep-driving. I mean, you’re driving while not fully awake, after taking the hypnotic. Or other complex behaviors have been documented, like preparing and eating food, making phone calls, or even having sex, without remembering it.

And so the drug has some serious risks, including worsening of depression and suicidal ideation, and the benefits of that, it can increase … or the benefits of the medication, because all medication, it’s a risk-reward calculation … it can decrease sleep latency, that is, the amount of time to fall asleep by about eight to 10 minutes and increase sleep duration by 17 to 20 minutes.

So at the most beneficial end of that, maybe it’s 30 extra minutes of sleep. But you get all of those risks associated with it.

Gazella: And are patients getting good sleep when they’re on these prescription and over-counter medications? Are they getting good quality sleep?

Neustadt: Well, you raise a great point. That’s one of the problems with all of these medications is they tend to increase sleep duration, sleep quantity, but they’re not increasing sleep quality. They’re not getting patients into that deep, restorative phrases of sleep, the slow-wave sleep, phase 3 and into phase 4, to get that good, restorative sleep.

So the quantity of the sleep may be increased but the quality has not been shown to be increased.

Gazella: So you’ve made a pretty compelling case that a more integrated, holistic approach is needed. And integrative practitioners often recommend melatonin for insomnia with their patients. Can you talk a little bit about melatonin and why for some patients, many even many patients, it may not be enough?

Neustadt: Melatonin is one of the first things I find that people with whom I speak, they’ve tried. They’ve reached for that. If they’re going to try a natural product, they’ve reached for the melatonin, you know, first, almost universally.

The challenge with melatonin is that it’s got a very short half life, 40 to 50 minutes. And so while melatonin is considered a circadian modulator, meaning it helps the body recognize day from night, and it is a natural hormone, a natural product that our body uses to help us fall asleep, it’s not really used for sleep maintenance. And so when somebody takes melatonin to help them fall asleep, because it’s got such a short half life, well 50 percent of the melatonin is eliminated from the body in less than an hour, so let’s just be generous and say an hour for easy calculations. So common doses out there is a 3 mg dose. So in an hour, they’ve got a one and a half milligrams left. An hour later they’ve got .75 milligrams left. And on down.

And so 3, 4 hours later, essentially most of that melatonin is out of their body and they wake up again. I hear so often people who take melatonin, they end up waking up in the middle of the night, still. And so what do they do? Well, they might need more melatonin. And so they keep taking higher and higher doses until they’re sleeping through the night and then they wake up feeling drugged in the morning. Groggy, hungover and it takes them hours to actually feel fully awake.

So the natural rhythm of melatonin in our body is that the rise in melatonin occurs around 10 PM and then it peaks at about 2 AM in the morning, and it declines at approximately 6 AM, it’s declined back to baseline. And that makes sense because that’s sort of the rhythm of when we start to fall asleep and when our body then starts to wake up. Of course melatonin is balanced with other hormones as well that the body is producing during sleep, but the immediate release of melatonin that people are taking is not mimicking the body’s cycle of melatonin production during the night. And it’s also not a complete solution because it’s not dealing with the other phases of sleep, we’re looking at the other hormones in sleep, GABA for example. Or the other variables that can impact sleep such as poor blood sugar. When blood sugar can drop, hormones are secreted like cortisol and epinephrine to increase the body’s blood sugar and we wake up.

And so that’s why melatonin for a lot of people doesn’t work, because it’s just not a complete enough solution.

Gazella: I think that’s a really good point, that it’s not a complete solution for many people and that’s why you use such an integrative approach. So I’d like to really dig into your integrative approach, I’d like to talk about dietary supplements, diet, and other lifestyle factors. So as long as we’re talking about melatonin, let’s keep on that subject and talk about dietary supplements. Are there specific dietary supplements that you use in your clinical practice specifically for insomnia?

Neustadt: There are and it depends typically on the clinical picture. So for example if somebody has muscle aches or tight muscles that’s keeping them from sleeping, magnesium can help, that can be a gentle muscle relaxant. If there’s some anxiety that may keep them from sleep, well, glycine is an amino acid that’s also an inhibitory neurotransmitter, that can be helpful. GABA also an inhibitory neurotransmitter used in the body available as a dietary supplement. That can be helpful. Botanical extracts such as alphianine increases alpha-wave production in the brain which is associated with calming, alert calmness. Then there are some sedative botanicals that can be helpful such as hops or skullcap, also called Scutellaria. And others.

So that’s part of it and for potential, looking at decreasing the response to stress, I like using, if they’re under a lot of stress, some adaptogenic herbs like ashwagandha, or jujube, magnolia bark extract. If there is vaso … if there’s an issue with hot flashes and perimenopause, pine back extract. There’s a clinical trial on that showing that it improved sleep quality and sleep quantity.

And so I typically, you know, this monotherapy approach of one symptom, 1 pill, it really doesn’t work when we’re looking at complex pathologies like insomnia or many other chronic issues. And so I tend to like products that combine those different nutrients shown in clinical trials to work that target the underlying pathology, the underlying biochemical pathways at work and sleep and affected by insomnia in a time release or a biphasic time release delivery system because it more closely mimics the body’s natural rhythm of the 2 major categories of your sleep. One is helping somebody fall asleep, you know how do we do that, and the other, over … you know, the subsequent 6, 7 hours later after they’ve fallen asleep, how do we help them stay asleep?

And so that’s how I conceptualize it and that’s the overall approach with dietary supplements when they’re indicated.

Gazella: So before I move on to diet, I know that you helped formulate and create a specific sleep supplement. I want you to tell me the name of that supplement but I also want you to tell me why you created it, because let’s face it, there are a lot of sleep supplements in the market. So why did you want to create the supplement that you created?

Neustadt: So the name of the product is NBI’s, my company, NBI’s Sleep Relief is the name of the product. And I created it for a couple reasons.

One, just like all the products that I’ve created in NBI and formulated, I couldn’t find the combination of nutrients or the dose and form of nutrients in a product shown in clinical trials to actually work. And I personally suffered from insomnia for years and years. And I tried a lot of different things. It wasn’t helping me. I’d work with a lot of my patients trying to different things, having to dispense different bottles of products, in addition of course to working with diet and lifestyle and other psychosocial factors involved. And I couldn’t find something that worked consistently.

And so I started digging into the sleep research, the pathophysiology of sleep, the clinical trials, what are the underlying mechanisms affecting sleep. And after over a year of research and formulating and working, trying over a dozen different combinations and doses, that’s when I created Sleep Relief.

Gazella: Okay perfect, Sleep Relief. So now let’s talk a little bit about diet. What are some of the things that you recommend to your patients when it comes to sleep, associated with diet that may not be on the radar of some practitioners?

Neustadt: So one of the big things that I see over and over is a lot of people have, may have acid reflux and they don’t know about it. And because maybe it’s not … maybe they have a cough when they lay down, maybe they are just not aware that that’s going on. And so evaluating for that because that can wake people up.

The other thing that I find with diet that’s very important, and with acid reflux, you know, that can be diet related. There are 5 most common foods that can contribute to that and interrupt sleep, that’s raw garlic and onion, chocolate, coffee, and citrus. Although other things can do it for other people. An infection can do that, H. Pylori can cause that as well. And then if they have a hernia, a hiatal hernia, that can cause it as well. So looking at that, looking at those underlying potential causes if that is involved.

The other thing is poor blood sugar control which I already mentioned. And one of the things I like to ask that can indicate if they might have poor blood sugar control is if they get that afternoon, postprandial tiredness. You know, about 3, 4 o’clock in the afternoon, a couple hours after lunch do they just get that energy slump. And that can be an indication that they’re having a little bit of blood sugar control issues. Or are they waking up at the same time every night. Both of those questions can give clues.

And if that does seem to be involved, one thing that I love to try with patients … it doesn’t work very often but when it does, it’s really a home run, and that is ask them to eat 8 to 10 grams of protein before bed. Protein’s one of the best ways to regulate blood sugar. And so if they do that and it stabilizes their blood sugar and they then are sleeping through the night, well, again, it’s a home run. I mean, there are no pills, no powders, it’s just natural doing it with food and it also opens the door for even more discussions with helping them understand how they can improve their diet during the day to help, to eat, to promote … to help them understand how they can eat, changes they can make to eat, the promote their health for the rest of their life.

Gazella: Yeah, those are some great suggestions when it comes to diet. Now let’s talk a little bit about lifestyle. What are some things that may not be on the radar of some practitioners when it comes to lifestyle aspects?

Neustadt: So we talked about going to sleep at about the same time every night, that’s really important. The other thing is … and most practitioners, or hopefully all of them have heard of sleep hygiene. The research shows that about the 69 to 70 degrees for most people is the ideal temperature for sleep. Some people who, if they’re in a relationship with their partner, they may like different temperatures may be most comfortable for them.

So there are wonderful things out there now, it’s call the ChiliPad, that you can get, it’s a pad you can put on your bed, where you can control the temperature on each side of the bed. So that can be really helpful.

Stress of course is a big issue in our society, a lot of people are under chronic stress, so anything that we can do to help people decrease their stress or better deal with stress is really important. And a fantastic study came out recently that showed that a lot of the impact of stress is not the actual event happening to us, it’s how we view it. So if people view stress as a good thing, meaning “I gotta learn something from it and what can I take from this,” the health impacts from stress are mitigated. If somebody sees a stressful event and they’re internalizing it and they’re not seeing it as a growth opportunity, then it magnifies the negative stress impacts.

So, A) getting them to just understand that mindset is really important, just when it comes to stress happening, and then what can they do to have more control over those events that may be causing them stress to decrease that stress. And that could mean creating healthy boundaries for themselves. That could mean doing any yoga or mind-body techniques. You know there’s lots of things that we can offer to patients that can be incredibly, incredibly helpful.

Gazella: Yeah, I would agree. And now your approach focuses on diet, lifestyle, and dietary supplements. How important is it to focus on all 3? So some practitioners might be really focused on the person’s diet, or some might be looking at their stress level, and some might be focused on just melatonin. Why is it so important to look at this from an integrative standpoint?

Neustadt: Well I think if we want to do the best job we possibly can for our patients and give them the best results, looking at it through a more integrative approach is important. And I like the approach of trying dietary supplements to give people benefit quickly. So if somebody is sleep deprived, it’s gonna increase their tendency to reach for those comfort foods. I think we’ve probably all experienced that. And especially because what happens with insomnia and sleep deprivation, it decreases mood. It can cause depression. And sugary foods, for example, when we reach for those, it can increase our serotonin production and temporarily lift mood. But it causes this rollercoaster of insulin and blood sugar that’s hard to get off of.

So just getting people sleep can help improve their mood. So I like the dietary supplement approach for triage to get them feeling better so they can make healthier decisions, have a more present mindset, be more proactive instead of reactive, while I’m working with them also on improving their diet. Transitioning to a healthier way of eating, which, the research has shown, unambiguously is the Mediterranean pattern of eating. And also stress reduction and exercise and those things as well.

Gazella: Yeah, I mean that all makes a lot of sense. And this is a very important topic and I want to thank you, Dr. Neustadt for a very interesting conversation and once again, I’d also thank today’s sponsor, Nutritional Biochemistry Incorporated, or NBI. Thanks again, Dr. Neustadt, for joining me.

Neustadt: Thank you for the opportunity.

The above was from: https://www.naturalmedicinejournal.com/journal/2019-02/insomnia-integrative-approach

Naltrexone could alleviate depression symptoms in patients who relapsed while taking antidepressants

The drug naltrexone is approved for use in the treatment of opioid use disorders and alcohol use disorders, but preliminary research suggests it could also aid the treatment of depression.

The double-blind, randomized study found that low dose naltrexone reduced depression severity in 12 depressed subjects who had relapsed on dopamine-enhancing antidepressants. The study will be published in the January 2017 issue of the Journal of Affective Disorders.

Mischoulon: Our group studies a wide variety of treatments for depression. We are especially interested in the underlying biology of antidepressants and mechanisms by which depression develops. This study of low dose naltrexone (LDN) was based on a model proposed by Bear and Kessler, originally for restless leg syndrome for which it was patented. During treatment of patients with RLS, they observed anecdotally that LDN seemed to benefit depression as well.

Because one of the apparent mechanisms of low dose naltrexone is through dopamine, which is a neurotransmitter associated with mood regulation, Dr Bear’s company, PharmoRx, was interested in funding a pilot study on this agent for people with depression who had relapsed on dopaminergic antidepressants. They spoke with us about running such a study at MGH, and we agreed to do it.

What should the average person take away from your study?

The main finding is that if you have depression and relapsed while taking a previously effective antidepressant that works primarily by dopaminergic mechanisms, addition of LDN could potentially alleviate the depression in combination with the original antidepressant.

PsyPost interviewed the study’s corresponding author, David Mischoulon of Massachusetts General Hospital/Harvard Medical School. Read his explanation of the research below:

he main limitation of this work is the small patient sample. We only treated 12 patients and this is too few to draw firm conclusions. We need to replicate this work in a larger group of patients. The study included only antidepressants that work by dopaminergic mechanisms, and so we don’t know how well it would work with other types of antidepressants, such as those that are primarily serotonergic (e.g. SSRIs) or noradrenergic (e.g. tricyclic antidepressants).

Also, LDN may involve a range of different doses that are defined as “low,” and so a dose-finding study to determine the optimal “low” dose would also be valuable to do. Clinicians who wish to prescribe LDN for depressive relapse should realize that this is considered an experimental therapy, and should inform their patients about the risks of trying a relatively unproven therapy.

Is there anything else you would like to add?

While LDN is obtainable by prescription from a licensed physician, it cannot be bought in most drugstores, because commercially available forms of naltrexone come in much higher doses. To obtain LDN you will need to take your prescription to a compounding pharmacy where they can prepare it for you in the appropriate dosage form. Most insurance plans will cover it, however, so LDN should be accessible to most people.

In addition to Mischoulon, the study “Randomized, proof-of-concept trial of low dose naltrexone for patients with breakthrough symptoms of major depressive disorder on antidepressants” was co-authored by Lindsay Hylek, Albert S. Yeung, Alisabet J. Clain, Lee Baer, Cristina Cusin, Dawn Flosnik Ionescu, Jonathan E. Alpert, David P. Soskin and Maurizio Fava.

Kresser Institute

Clinicians are increasingly using low-dose naltrexone to treat challenging illnesses such as autoimmune conditions and neurodegenerative disease. LDN is extremely safe and well tolerated, especially compared to the drugs typically used to treat these conditions, making LDN a valuable tool for clinicians and an important focus for ongoing research.


naltrexone
istock.com/baona

As a practitioner, you may be familiar with the drug naltrexone, which was approved by the FDA in 1984 for treating addiction patients. In doses of 50 to 100 milligrams, naltrexone completely blocks opioid receptors in the brain, preventing patients from experiencing a high when they take opioid drugs.

Soon after the drug’s initial approval, Dr. Bernard Bihari discovered a potential alternate application for naltrexone. He noticed that in AIDS and cancer patients, a much lower dose of naltrexone (about 3 milligrams) had beneficial immune-modulating effects. This discovery gave rise to a grassroots movement of patients and practitioners who had seen LDN work and were calling for additional research and mainstream attention.

Despite the promise of this new treatment, formal research on LDN has been slow to happen, likely because LDN is off patent and therefore not as profitable to drug companies. Even so, our understanding of the mechanisms behind LDN’s effectiveness in various conditions continues to progress, and results from preliminary clinical trials are slowly being published.

In this article, I’ll describe our current understanding of LDN’s mechanisms and review the clinical trials that have been conducted thus far. I’ll also give you a more practical take on LDN from my perspective as a clinician and cover concerns that might be relevant for other clinicians who want to prescribe LDN to their patients.

How Does LDN Work?

As research on LDN progresses, it appears more and more likely that it functions through a variety of different mechanisms and that the most relevant mechanism might differ depending on the disease that is being treated. But at this point, the two most well-characterized functions of LDN are as an opioid antagonist and an anti-inflammatory.

Increasing Endogenous Opioid Activity

Like its full-dose counterpart, low-dose naltrexone blocks opioid receptors in the brain, the major difference being that LDN is cleared from the system after only a few hours. Most researchers believe that this temporary opioid receptor blockade creates a “rebound effect,” resulting in up-regulated production of the endogenous opioids beta-endorphin and met-enkephalin, as well as increased expression of opioid receptors (1).

How these adaptive changes affect the disease processes that LDN influences is less established. However, several mechanisms have been proposed. First, endogenous opioids are known to have analgesic and stress-relieving effects, which alone could account for some of the symptom relief seen with LDN.

What the latest research says about low-dose naltrexone

Second, we know that immune cells possess opioid receptors, and both endogenous and exogenous opioids have long been considered important immune modulators (2, 3). The exact effects of endogenous opioids on the immune system, however, remain unclear; both increases and decreases in immune cell activity and proliferation have been observed in response to LDN, as well as beta-endorphin and met-enkephalin (4, 5, 6).

These endogenous opioids may also exert therapeutic benefits based on their regulation of cellular proliferation. Met-enkephalin, also known as opioid growth factor (OGF), has been found to regulate the cell cycle by suppressing DNA synthesis via its action on the OGF receptor (7, 8). This so-called “OGF–OGFr axis” is the focus of research on LDN for treating cancer and may also be another mechanism by which LDN modulates immune function.

Reducing Inflammation in the CNS

LDN appears to have a second mechanism of action that is independent from the opiate-antagonist pathway described above: suppression of microglial activity. Microglia are the primary immune cells in the central nervous system and are responsible for creating inflammation in response to pathogens or injury. When activated, microglia secrete factors such as pro-inflammatory cytokines, prostaglandins, nitric oxide, and excitatory amino acids (9).

The activation of the microglia and the subsequent release of cytokines—though essential to protecting the brain and CNS—cause symptoms such as fatigue, reduced pain tolerance, sleep and mood disturbances, cognitive disruption, and general malaise, all classically referred to as “sickness behaviors” (10). While these adaptive symptoms may make sense in the short term for promoting rest and recovery, ongoing CNS inflammation is maladaptive and can contribute to a wide range of diseases and syndromes.

Evidence indicates that LDN can suppress microglial activation, likely via its antagonistic effect on toll-like receptor 4 (TLR4), a non-opioid receptor that is found on macrophages such as microglia (11). This mechanism may explain LDN’s effectiveness for conditions like fibromyalgia and other chronic pain disorders, which involve chronic activation of microglial cells.

LDN in the Scientific Literature

Unfortunately, research on LDN as a treatment for human disease is still extremely sparse. Most of the trials that have been conducted thus far were primarily intended to test the tolerability and safety of LDN, rather than the efficacy, so keep that in mind, but the initial research does show promise. I’ve summarized the existing studies below, and hopefully additional research won’t be far behind.

Crohn’s Disease

A small open-label pilot study from 2007 had remarkable results, reporting that 89 percent of participants responded to LDN, and a whopping 67 percent achieved remission (12). This was the first published LDN trial in humans.

Results from two subsequent randomized controlled trials were less dramatic, but still extremely promising. One study from 2011 reported significant improvement in 88 percent of the participants in the LDN group, compared to 40 percent in the placebo group (13). And 33 percent of participants in the LDN group achieved remission, compared to 8 percent in the placebo group, although this difference was not statistically significant.

The second RCT was published in 2013 and looked at the effectiveness of LDN in children with Crohn’s disease (14). They found that of those treated with LDN, 67 percent exhibited improvement, and 25 percent went into remission. In all of these studies, LDN was very well tolerated with no significant difference in side effects compared to placebo.

Fibromyalgia and Other Conditions

In 2009, a pilot study involving 10 fibromyalgia patients reported a greater than 30 percent reduction in symptoms over placebo in those taking LDN (15). Interestingly, they found that patients with a higher erythrocyte sedimentation rate (ESR) at baseline had greater symptom reduction in response to LDN treatment. ESR is a marker for inflammation, so this observation lends credence to the theory that LDN works by reducing inflammation in the central nervous system.

The second study, a randomized controlled trial involving 31 fibromyalgia patients, was published in 2013. They reported significant improvements in pain, mood, and general satisfaction with life in the LDN group compared to placebo (16). And again, LDN was well tolerated in these studies.

LDN has also been studied in and shown potential efficacy for autism (17), pain (18, 19), depression (20), multiple sclerosis (21, 22, 23), systemic sclerosis (24), and complex regional pain syndrome (25). Additionally, preliminary evidence in vitro and in animal models indicates that LDN may be an effective treatment for cancer, including ovarian cancer and pancreatic cancer (26, 27).

Clinical Success Using LDN for Autoimmune and Neurodegenerative Diseases

As I mentioned at the beginning of this article, LDN is unusual in that its use has spread as a result of grassroots efforts by patients themselves, rather than the typical top-down marketing of new drugs by pharmaceutical companies. Because of this, clinical and anecdotal evidence for the drug’s effectiveness in a wide variety of conditions still vastly outpaces the scientific literature.

This is initially a cause for concern because we obviously want any treatment we use on patients to be as evidence based and extensively studied as possible. But we do have ample safety data from the approval process of full-dose naltrexone, and all of the evidence we have so far on LDN shows that it is extremely safe and well tolerated. It’s still a judgment call, but the fact that existing treatments for many of these illnesses are demonstrably toxic with significant side effects certainly makes LDN an attractive option.

Conditions that have clinically responded well to LDN but have not been formally studied include autoimmune diseases such as Hashimoto’s thyroiditis, Graves’ disease, rheumatoid arthritis, lupus, psoriasis, and ulcerative colitis, as well as neurodegenerative diseases like Parkinson’s and Alzheimer’s, and other conditions like chronic fatigue syndrome and even infertility. Because these conditions share the same underlying disease processes of immune dysregulation and inflammation, it’s not a huge surprise that LDN can be an effective treatment, despite the differences in disease presentation.

Practical Concerns for Prescribing LDN

LDN is generally very well tolerated, but patients may experience insomnia, headaches, or unusually vivid dreams when first starting the medication. These side effects are usually minor and dissipate after a week or two of taking LDN.  

Because naltrexone is only produced in 50-milligram tablets, prescriptions for LDN do need to be filled at a compounding pharmacy. And, because LDN is off label, it’s unlikely that insurance companies will cover it, but the out-of-pocket cost of LDN is only about $40 per month, making it more affordable than many drugs on the market.

One downside of LDN is that there’s not a standardized dose, and the most effective dose for a given patient may be anywhere from 1.25 to 4.5 milligrams. We typically start patients on 1 to 1.5 milligrams, then gradually increase to 4.5 milligrams and see how they do. From my experience, I’ve seen most people end up around 2.5 to 3 milligrams.

Note that in patients with Hashimoto’s or Graves’, their previous dose of thyroid medication could suddenly be too high as their thyroid function improves on LDN. It may be necessary to reduce their normal thyroid medication to prevent them from becoming hypo- or hyperthyroid.

Finally, be aware that while LDN can be miraculous for some patients, others may see no benefits at all. Unfortunately we don’t know enough yet to determine if there’s a subset of patients that LDN is most likely to help, so the best we can do is try and hope for the best. It can sometimes take a little while for patients to notice improvement on LDN, so we typically allow about three months as a trial period before deciding whether to continue treatment.

Ketamine – Psycom

8 herbs and supplements for depression

Depression is a serious mood disorder with symptoms that range from mild to debilitating and potentially life-threatening. Some people look to manage depression with herbal remedies, rather than with medication a doctor prescribes.

The most recent data from the National Institute of Mental Health suggest that in the United States, 6.7 percent of people experienced a major depressive episode in 2016.

Medications and counseling are conventional ways to alleviate the symptoms of depression. However, some herbs and supplements may also help.

In this article, we look at the common herbs and supplements with links to the treatment of depression and discuss their safety and effectiveness.

Herbs and supplements

herbs for depression

Some herbs, essential oils, and supplements have shown promising effects for people with depression.

The use of complementary therapies continues to gain popularity, as people look for more natural methods of managing their health.

However, herbal does not always mean safe or effective, and knowing which products to choose can save a lot of time and money.

In the United States, the Food and Drug Administration (FDA) do not monitor herbs in the same way as food and drugs. As a result, manufacturers are not always 100 percent clear about the quality or purity of their product.

Research suggests promise for some supplements in treating mild-to-moderate depression. These are some of the supplements that people most widely use:

1. St. John’s wort

St. John’s wort is also known as Hypericum perforatum. This plant has been a common herbal mental health treatment for hundreds of years. However, people must use caution if they chose to try it as a potential treatment for depression.

2016 systematic review found that St. John’s wort was more effective than a placebo for treating mild to moderate depression and worked almost as well as antidepressant medications.

However, this review of eligible studies did not find research on the long-term effects of St. John’s wort on severe depression.

The authors also advised caution against accepting the results wholesale, as the herb has adverse effects that many of the studies did not consider.

St John’s wort can also interfere with the effects of antidepressant medication, meaning that it may make symptoms worse or reduce the effectiveness of conventional treatment.

While St. John’s wort might help some people, it does not show consistently beneficial effects.

For these reasons, people should not use St. John’s wort instead of conventional treatment. Neither should they try St. John’s wort to treat moderate to severe depression.St. John’s Wort: Should I use it?Should I take St. John’s wort? Click here to find out more.READ NOW

2. Ginseng

This supplement comes from the gnarled root of the American or Asian ginseng plant. Siberian, Asian, and Eleuthero ginseng are different plants with different active ingredients.

Practitioners of Chinese medicine have used ginseng for thousands of years to help people improve mental clarity and energy and reduce the effects of stress.

Some people associate these properties of ginseng with potential solutions for the low energy and motivation that can occur with depression.

However, the National Center for Complementary and Integrative Health (NCCIH) advise that none of the many studies that people have conducted on ginseng have been of sufficient quality to form health recommendations.

3. Chamomile

study in 2012 reviewed data about chamomile, which comes from the Matricaria recutita plant, and its role in helping to manage depression and anxiety.

The results show that chamomile produced more significant relief from depressive symptoms than a placebo. However, further studies are necessary to confirm the health benefits of chamomile in treating depressive symptoms.

4. Lavender

Lavender oil is a popular essential oil. People typically use lavender oil for relaxation and reducing anxiety and mood disturbances.

2013 review of various studies suggested that lavender might have significant potential in reducing anxiety and improving sleep.

Lavender has mixed results in studies that assess its impact on anxiety. However, its effectiveness as a treatment for ongoing depression has little high-quality evidence in support at the current time.

5. Saffron

Some studies cite using saffron as a safe and effective measure for controlling the symptoms of depression, such as this non-systematic review from 2018.

However, more research would help confirm the possible benefits of saffron for people with depression. Scientists also need to understand any possible adverse effects better.

6. SAMe

man looks at drugs

Some supplements have shown promising effects on depression symptoms. However, many investigations confirming their benefits are low quality.

SAMe is short for S-adenosyl methionine. It is a synthetic form of a chemical that occurs naturally in the body.

In 2016, researchers reviewed all the randomized controlled trials on record for the use of SAMe to treat depression in adults. They found no significant difference between the effects of SAMe on depression symptoms and those of a placebo.

However, they also found that SAMe had about the same effectiveness as the common antidepressants imipramine or escitalopram. Furthermore, it was better than a placebo when the researchers mixed SAMe with selective serotonin reuptake inhibitor medications.

As with many other studies into herbs and supplements, the investigations into the safety and efficacy of SAMe are of low quality. More research is necessary to determine its exact effect.

People use the supplement in Europe as a prescription antidepressant. However, the FDA have not yet approved this for use in the U.S.

7. Omega-3 fatty acids

In a 2015 systematic review, researchers concluded that omega-3 fatty acid supplements are not useful across the board as a depression treatment.

While the study authors reported no serious side effects from the supplement, they also advised that it would only be an effective measure in treatment for depression that was due to omega-3 deficiency.

8. 5-HTP

Also known as 5-hydroxytryptophan, this supplement may be useful in regulating and improving levels of serotonin in the brain. Serotonin is the neurotransmitter that affects a person’s mood.

5-HTP has undergone a number of animal studies, and some, such as this review from 2016, cite its potential as an antidepressant therapy. However, evidence of its effects in human subjects is limited.

5-HTP is available as an over-the-counter (OTC) supplement in the U.S. but may require a prescription in other countries.

More research is necessary, especially regarding concerns that it may cause serotonin syndrome, a serious neurological complication if a person takes 5-HTP in excess.

Supplement manufacturers do not have to prove that their product is consistent. The dose on the bottle may also be inaccurate.

People should ensure they purchase herbs and supplements from a trusted manufacturer.

FOODS for Depression:

https://www.medicalnewstoday.com/articles/318428.php

Important foods and nutrients

The following foods and nutrients may play a role in reducing the symptoms of depression.

Selenium

Selenium can be a part of reducing symptoms of depression in many people. Low selenium levels have been linked to poor moods.

Selenium can be found in supplement form or a variety of foods, including whole grains, Brazil nuts, and some seafood. Organ meats, such as liver, are also high in selenium.

Vitamin D

Vitamin D deficiency is associated with many mood disorders, including depression. It is important to get enough vitamin D to help in the fight against depression.

This vitamin is obtained easily through full body exposure to the sun, and there are also many high-quality supplements on the market that contain vitamin D.

Food sources of vitamin D include fatty fish such as salmon, tuna, and mackerel.

Omega-3 fatty acids

Nuts and seeds are a source of omega fats

Nuts and seeds are sources of omega fats, which can help treat mood disorders and improve cognitive function.

In a study posted to the Indian Journal of Psychiatry, researchers observed that populations that do not eat enough omega-3fatty acids might have higher rates of depressive disorders.

Good sources of omega-3s may include:

  • cold water fish, such as salmon, sardines, tuna, and mackerel
  • flaxseed, flaxseed oil, and chia seeds
  • nuts, such as walnuts and almonds

The quality of these foods can affect the levels of omega-3s they contain.

Eating omega-3 fatty acids may increase the level of healthful fats available to the brain, preserve the myelin sheath that protects nerve cells, and keep the brain working at the highest level. In turn, this can reduce the risk of mood disorders and brain diseases occurring.

Antioxidants

Antioxidants have become popular as they fight free radicals. Free radicals are damaged molecules that can build up in different cells in the body and cause problems, such as inflammation, premature aging, and cell death.

The brain may be more prone to this type of damage than other areas of the body. As a result, it needs a good way to get rid of these free radicals and avoid problems. Foods rich in antioxidants are believed to help reduce or reverse the damage caused by free radicals.

Everyday antioxidants found in a variety of whole foods include:

These nutrients may help reduce stress-related symptoms of psychiatric disorders.

B vitamins

Some B vitamins are also key in mood disorders such as depression. Vitamin B12 and folate, or vitamin B9, have both been linked to a reduced risk of mood disorders.

Sources of B vitamins include:

  • eggs
  • meat
  • poultry
  • fish
  • oysters
  • milk
  • whole grains

Fortified cereals may also contain vitamins B12 and folate. Other foods that have folate in them include:

  • dark leafy vegetables
  • fruit and fruit juices
  • nuts
  • beans
  • whole grains
  • dairy products
  • meat and poultry
  • seafood
  • eggs

Eating a varied diet is an easy way to ensure there is enough folate in the diet.

Zinc

Zinc helps the body perceive taste, boosts the immune system, and may also influence depression. Zinc levels may be lower in people with clinical depression, and zinc supplementation may also improve the effectiveness of antidepressants.

Zinc is found in supplements. Foods, including whole grains, oysters, beans, and nuts, are also good sources of zinc.

Protein-rich foods

High-quality proteins are the building blocks of life. Getting adequate protein is essential for everyone, but some forms of protein, in particular, may be more helpful for people with depression.

Foods such as tuna, turkey, and chickpeas have good levels of tryptophan, which is needed to form serotonin.

Serotonin deficiency was once thought to be a major cause of depression. We now know that the link between serotonin and depression is very complex, but it does seem to influence depression in many people. Including foods rich in tryptophan in a diet may help relieve symptoms.

Foods to avoid

Just as certain foods and nutrients may be of benefit to people with depression, there are also some that should be avoided.

Caffeine

For people with depression that is linked to anxiety, it may be important to avoid caffeine. Caffeine can make it difficult to sleep and may trigger symptoms of anxiety in many people.

Caffeine also affects the system for hours after it is consumed. It is best for people with depression to avoid caffeine if possible, or reduce consumption and stop consuming it after noon.

Alcohol

Though occasional alcohol drinking is seen as an acceptable distraction, it may make depression symptoms worse.

Excessive alcohol consumption may increase the risk of panic attacks or depressed episodes. Alcohol also alters a person’s mood and may turn into a habit, which could influence depression symptoms.

Refined foods

High-calorie foods with few nutrients in them may also influence depression symptoms. Foods high in sugar and refined carbs can promote a crash, as the energy from them is depleted. This can make a person feel mood swings or energy swings.

Nutrient-dense whole foods are a much better approach to balancing mood and energy levels.

Processed oils

Highly processed or refined oils, such as safflower and corn oil, are very high in omega-6 fatty acids. Having too many omega-6s in the diet can cause an imbalance in the body that may promote inflammation in the brain and influence depression symptoms.

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Other factors in depression

Woman walking.

Regular physical activity and spending time outdoors are proven ways to help improve the symptoms of depression.

There are other factors that link to both diet and depression and play a role in this mental healthillness.

Emerging research has shown gut bacteria to play an integral role in major mood disorders, including depression and bipolar disease. A 2016 meta-analysis reported that probiotics, in both supplement form and in fermented foods such as yogurt and kefir, resulted in significant reductions in depression.

More research is needed to identify the therapeutic value of specific strains, but so far Lactobacillus and Bifidobacterium show potential.

Obese people may be more likely to be depressed, and depressed people are more likely to become obese. This may be due to hormone changes and immune system imbalances that come with depression.

Spending time outdoors and at least 150 minutes of physical activity weekly have been shown to improve mood and depressive symptoms.

Some people with depression also have substance abuse problems. Alcohol or other drugs can interfere with sleep patterns, decrease motivation, and alter a person’s mood.

Sleep may also play a role in depression. The body’s natural sleep cycle creates mood-altering chemicals to match the time of day. Altering this natural cycle may affect how well the body can use these chemicals.

Most adults respond well when they get 7 to 8 hours of sleep, though the number varies from person to person. It may also help to reduce exposure to blue light, during the hours leading up to sleep. Blue light is emitted by electronic devices and low-energy light bulbs.

LDN for psychiatric disorders:

LDn Information

When I have to describe my patient population, I often say that “my patients are normal people with some problems.” A significant number of my patients also have a chronic medical illness, such as an autoimmune disorder. Since I added it to my prescribing armamentarium many years ago, LDN has become a frequently used tool that I offer to my patients along with the other therapeutic strategies.

…LDN has become a frequently used tool that I offer to my patients along with the other therapeutic strategies.

For what kinds of conditions do you prescribe LDN?

In my practice, I use LDN for these conditions because I see it work:

  • Some subtypes of depression (subtypes that seem to be triggered by inflammation, seasonal type, postpartum, or related to deficiency of dopamine or endorphins);
  • Some subtypes of anxiety (for example, that come with obsessive ruminations or intrusive thoughts);
  • Obsessive-compulsive disorder and OCD-spectrum disorders;
  • Post Traumatic Stress Disorder (PTSD);
  • Modulation of sleep architecture;
  • A variety of sexual problems, including problems of desire, performance and satisfaction;
  • What I call “LDN assisted psychotherapy”. (I think I found how to use it to help extinguish unwanted behaviors and reinforce wanted alternative behaviors. This work is done with therapists I teach and then collaborate with);
  • Appetite control;
  • Addiction to internet, sex, gambling;
  • Alcohol and drug dependence. (While we probably need a “traditional dose” of naltrexone for treatment of alcohol dependence, some other types are doing great on LDN);
  • Helping patients stop opioids and then recover quicker from the prolonged post-opioid use problems, or just decreasing the amount of pain pills they are taking.

You mention prescribing LDN for certain subtypes of depression/anxiety. What subtypes are you referring to?

In my opinion, depression is not a single disorder. It is rather a generic name that was chosen to describe a number of diverse conditions, just because they share a few common symptoms. There were many attempts in academic psychiatry to separate the clearly heterogeneous group of disorders collectively called “depression” into subtypes. Unfortunately, for a long time, this work had no impetus, as most of the medications that came to market during the last 20-30 years were inspired by the same theory – that depression is related to the imbalance in one or more principal neurotransmitters in the brain – serotonin, norepinephrine and dopamine. In my view, in the nearest future, we will see that new medications will seek approval to treat specific symptoms of depression, such as sadness, racing thoughts, obsessive ruminations and changes in energy, rather than for the generic indication “depression”.Which subtypes of depression are more responsive to LDN?

Although not always, patients whose depression comes with tiredness, inability to feel any excitement, no motivation, no enthusiasm, slowed movements and thinking, decreased appetite, etc. are more likely to respond to LDN. This is compared to patients who describe their depression as “painful”, who feel discontent, antsy, and/or pessimistic. There are no strict rules; some of the depression types can overlap in their symptoms. I also want to add that it is very uncommon for LDN to worsen depression.

Although not always, patients whose depression comes with tiredness, inability to feel any excitement, no motivation, no enthusiasm, slowed movements and thinking, decreased appetite, etc. are more likely to respond to LDN.

What effects did you see LDN providing?

Since the majority of my patients are already taking at least a few, if not more, medications, I do not have a luxury to stop all their medications suddenly and switch them only to LDN. I usually start by adding LDN, along with making some other changes to the cocktail of their medications. I can only say that the result of adding LDN is sometimes spectacular and sometimes there is no obvious change.In your experience, who can benefit from LDN?

LDN works on opioid receptors. Everybody who has opioid receptors can benefit from LDN. Although at this point there are no recommendations to take LDN prophylactically, knowing how much LDN can do, and how many autoimmune conditions remain undetected for long time, a trial of LDN is probably warranted for most of the cases of “vague symptoms”, for the cases of incomplete resolution of an illness, etc.What do you advise your patients about the timing of taking their LDN?

In psychiatry, we frequently adjust dosages and schedules. Of course, I am aware of the traditional way to take low dose naltrexone before bed and I always recommend that patients start taking it this way. If, however, we do not get a desirable result – and, in the case of psychiatry, the patient, not the lab value is the best judge of the result – the dosage can be changed or the timing can be changed. I have patients who take LDN once a day and others who sip an LDN solution throughout the day. In some cases of addiction, or if my goal is to modify an unwanted behavior, I might instruct the patient to take naltrexone every time they think they might find themselves engaged in the behavior they want to extinguish.Have you observed long-term effects of LDN yet?

As far as I understand, there is no official information related to the long term use of LDN. A lot of patients feel that they “returned back to step one” when they stopped taking LDN. Because of this, especially taking in consideration practically negligible side effects, the risk-benefit ratio of LDN is clearly supporting long-term use. Even when I treat illnesses with episodic courses, such as depression, I still recommend that patients continue taking LDN because of the high risk of recurrence. On the other hand, I had patients who felt strongly about stopping all medications as soon as they improved; it made no sense, but they had strong philosophical disagreement with taking any medications in general. In their cases, I just made sure that they have a strategic supply of LDN which can be started when the next episode begins. Unfortunately, this kind of patient is not always able to catch the first signs of the illness and start the treatment before it becomes severe.

…especially taking in consideration practically negligible side effects, the risk-benefit ratio of LDN is clearly supporting long-term use.

Do you think there is a risk of receptors becoming adjusted to LDN and creating the potential for either tolerance or addiction to it?

Some of my patients who say, “If I forget to take my LDN, I feel it” wonder the same. They feel they are “missing something”, and they might become more irritable, tired, have difficulty concentrating, and complain of “brain fog”. This makes sense because LDN works on the opioid receptors, after all. At the same time, I do not know a case when a patient could not stop LDN or had unbearable withdrawal, even after a prolonged use. Based on what I understand now, this “dependence” on LDN does not look like dependence to opioids or benzodiazepines (Xanax®, Ativan®, Valium®, etc.). It looks more like dependence to coffee. Some people who drink coffee every day and stop abruptly also complain of withdrawals – they have no energy, no concentration, they start having headaches, etc. These symptoms, however, are more of a nuisance than a tragedy. As a rule, they subside in a few days. Based on what I know now and what I read, I would not stop LDN because of the fear of dependence.

…I do not know a case when a patient could not stop LDN or had unbearable withdrawal, even after a prolonged use.

Have you seen any side effects from LDN?

The patients I treat are probably more vulnerable to vivid dreams and their dreams might become unpleasant. Additionally, after a couple of surprises, I do not forget to tell my female patients to be more careful about pregnancy precautions, because they might become unexpectedly more fertile.What kind of research on LDN for sexual dysfunction are you interested in?

There is a tight connection between autoimmune conditions and hormone imbalance; there is even an opinion that autoimmune conditions are caused by hormone imbalance. Sexual dysfunctions (not only disorders of performance, but also disorders of desire and satisfaction) are only a small part of the consequences of the hormone imbalance. My most recent project is focusing on post-coital dysphoria or “post-sex blues”. Basically, it describes a phenomenon when people become dysphoric (tearful, depressed, or, possibly, argumentative) after they have an orgasm, even though they had satisfying sex with a person they loved. The phenomenon is most likely related to the skyrocketing and then sudden dropping of the dopamine level. The mechanism is somewhat similar to the crash following cocaine use. A few years ago, I came up with the idea of using LDN prior to sex to normalize this dopamine/endorphin response. In essence, taking LDN prior to sex can fix the problem, and the only question left is the timing and the amount of LDN.

In essence, taking LDN prior to sex can fix the problem, and the only question left is the timing and the amount of LDN.

What dose and timing do you recommend for this kind of sexual dysfunction condition?

In practice, I recommend LDN as a part of a stimulant-vitamin-drug combination. At this point, I need a little more data to announce the magic combination, dose and timing. I would like to invite the readers, whether you are on LDN currently or not, openly or anonymously, to share your experience about using LDN for this condition.

LDN can → ↑ BDNF as well as: exercise caloric restriction glutamate, cucurmin

To boost endorphins, use LDN with: ● high-protein food ● vitamins: B, C, Omega-3 with vit D, E, Zink; ● avoiding sugar, flour, coffee – (“exorphins”) ● exercise, massage, acupuncture, sunlight ● guided imagery, music, romance, nature

BDNF – norbuprenorphine, kratom, cannabidiol (Epidiolex), THC (Marinol) – inhibited by trazodone, buprenorphine

Naltrexone Alcoholism Medication

Naltrexone is a medication that can be used for the treatment of opioid violations and alcohol addiction. The research that was conducted in order to study the action of this drug showed that naltrexone can also be taken within the patients suffering from severe depression.

As a result of the research, it was found that taking the drug naltrexone can help to reduce depression. The patients participating in the research were people, who had depression and took antidepressants. It was set up that the severity of depression was reduced within the patients taking naltrexone. The results of the research were published in the Journal of Affective Disorders in January 2017.

The author of this study was David Mischoulon, a medical specialist of the Massachusetts Hospital and one of the specialists of the Harvard Medical School. He was the leader of the group that studied a variety of ways to treat severe depression. The group studied the action mechanism and the effect of antidepressant medications, as well as the mechanisms that contribute to the development of depression. Initially, the LDN drug was patented as the drug indicated for the treatment of restless legs syndrome (RLS), but during the treatment of patients with RLS taking LDN, it was found that LDN also positively affects suppression of depression.

One of the mechanisms of the low dose naltrexone medication is dopamine. It is a neurotransmitter, which is associated with the regulation of human mood and helps to reduce depression.

The studies, connected with LDN, have also shown that if a patient suffers from depression and takes antidepressants that work with dopaminergic mechanisms, the additional use of LDN in combination with the antidepressant drugs can help to cope with depression in a shorter period of time.

There was also a disadvantage of the research. It is connected with the fact that there were just 12 patients who participated in the study. This number of the participants is too small to make exact conclusions, concerning the LDN action mechanisms and taking it in order to treat depression. To be sure about the action of this drug during treating depression, more studies should be done, involving larger groups of participants. In the study described above, the patients used just the antidepressants, acting through dopaminergic mechanisms. This fact does not give any confidence that LDN will act positively in combination with other antidepressants, for example, with serotonergic and noradrenergic antidepressants.

Moreover, it would be useful to conduct an optimal LDN study, as the LDN medication includes a number of different dosages and they are all defined as low doses. Such a study has not previously been conducted. Therefore, some medical specialists who prescribe LDN should inform their patients about this drug and warn the patients that the therapy associated with LDN while treating depression is experimental. The patients should be aware of the potential risks before taking this medication, as the drug is not accepted in medicine, regarding the treatment of depression.

LDN can’t be bought at most pharmacies, although it can be obtained by prescription from a licensed doctor. The commercially available forms of naltrexone come in much higher doses. To get LDN, you need to bring a prescription from your doctor to the pharmacy and there the appropriate dosage form will be prepared for you. In general, LDN is available for the majority of people.

Ketamine has rapid and robust antidepressant effects. However, there are concerns about the abuse liability of ketamine.1This concern was heightened recently owing to a preliminary report suggesting that antidepressant effects of ketamine might be dependent on opiate receptor stimulation.2 Below, we present pilot data that indicate that the antidepressant effects of ketamine are not attenuated by naltrexone pretreatment. As a result, the combination of opiate receptor antagonism with ketamine might be a strategy to reduce addiction risk among patients with depression at risk for substance abuse.Methods

We recruited and obtained written informed consent from 5 patients with current major depressive disorder and alcohol use disorder. In this 8-week open-label pilot study, which recieved institutional review board approval by the VA Connecticut Healthcare System Human Subjects Subcommittee, patients received injectable naltrexone (380 mg once 2-6 days prior to the first ketamine infusion) and repeated intravenous ketamine treatment (0.5 mg/kg once a week for 4 weeks; a total of 4 ketamine infusions). The study had 2 phases: (1) a 4-week ketamine treatment phase and (2) a 4-week follow-up phase. All patients were abstinent from alcohol for 5 days or longer prior to the first ketamine infusion. The primary outcome measure was clinical response defined as a 50% or higher improvement from baseline in the Montgomery-Åsberg Depression Rating Scale scores at 4 hours postinfusion.Results

The combination of naltrexone and ketamine was associated with reduced depressive symptoms. The Figure shows that 60% (3 of 5) of patients met response criteria after their initial ketamine dose and 100% (5 of 5) met response criteria by their fourth dose, although 1 patient left the trial after receiving 2 ketamine infusions. The Table shows that depressive symptoms improved about 57% to 92%. Also, 80% (4 of 5) of patients reported improvement in alcohol craving and consumption as measured by the Obsessive Compulsive Drinking Scale. The combination treatment was safe and well tolerated in all participants. No serious adverse effects were reported in the trial.Discussion

Our pilot data suggest that naltrexone pretreatment did not interfere with the antidepressant effects of ketamine and might enhance the treatment of comorbid alcohol use disorder. This result conflicts with that reported by Williams et al2 in which pretreatment with 50 mg of naltrexone reduced the rate of clinical response to ketamine from 71% (5 of 7 individuals) to 0% (0 of 7 individuals). Their data and an editorial by George,3 although preliminary, make a case for a central role for opiate agonism in the antidepressant effects of ketamine. Although our pilot data were collected under somewhat different conditions than those of Williams et al2 (eg, different primary outcome time of 4 hours vs 1 day postinfusion, presence vs absence of alcohol use disorder, injectable vs oral naltrexone), they do not support the hypothesis that opiate receptor stimulation mediates the antidepressant effects of ketamine. Since Williams et al2 did not provide depression ratings over a 4-hour period postinfusion, we cannot examine whether 50 mg of oral naltrexone blunted ketamine response in this early 4-hour period. Our findings are consistent with an earlier study in healthy individuals showing that the behavioral effects of an antidepressant dose of ketamine were not altered by pretreatment with 25 mg of naltrexone,4 and some preclinical evidence that ketamine isomers may be weak partial agonists at μ opiate receptors.5

The initial report by Williams et al2 and our preliminary data should be interpreted with great caution. Larger randomized clinical trials are needed to better understand whether opiate receptor stimulation contributes to the antidepressant effects of ketamine. If so, then preclinical research will be needed to help us to understand this role for opiates and its implications for future rapid-acting antidepressant treatments.

Unique Drug Combo Promising for Severe, Intractable Pain

 Low doses of the hormone oxytocin along with the anestheticketamine may provide a unique and effective therapeutic approach to some patients with severe, intractable pain

This therapeutic approach is “incredibly unique” and is safe and effective in some patients with intractable pain. “If you put these two together, you could replace any short-acting opiate,” Caron Pedersen, FNP-C, DC, BSN, BS-PT, a nurse practitioner, chiropractor, and physical therapist specializing in patients with spinal pain, told Medscape Medical News.

Dr Caron Pedersen

Dr Pedersen has been working with pain management expert, Forest Tennant, MD, DPH, Veract Intractable Pain Clinic, West Covina, California, to find better ways to treat patients with very severe pain.

Such patients, said Dr Pedersen, “are pretty much opioid-dependent and have been for long time, and are not getting relief.”

Dr Pedersen presented some of her research here at the Academy of Integrative Pain Management (AIPM) 28th Annual Meeting.

Alternative to Opioids?

A variety of antiseizure, antidepressant, and anti-inflammatory agents, as well as muscle relaxants and adrenergic blocking agents, provide mild to moderate pain relief. But these approaches are not always a substitute for opioids in patients with severe pain.

Both oxytocin and ketamine provide analgesia by mechanisms other than stimulating opioid receptors.

Produced in the hypothalamus, oxytocin is a potent natural pain reliever. The hormone is released in pregnant women during labor and also in other painful conditions or stressful events.

It has been reported to relieve pain in patients with headache, chronic back pain, and fibromyalgia, and there is “a mountain of research” on oxytocin’s complex production, release, and receptor system, said Dr Pedersen.

Dr Tennant explained that some of the hormone is released into the peripheral circulation via the posterior pituitary and some into the central nervous system, including the spinal fluid.

Oxytocin receptors are found at multiple sites in the brain and throughout the spinal cord, said Dr Tennant. In addition to activating its own receptors and decreasing pain signals, oxytocin binds to opioid receptors and stimulates endogenous opioid release in the brain.

In addition to relieving pain, oxytocin lowers serum cortisol and can produce a calming effect and improve mood.

“It has the effect of making people happy, making them feel a little less anxious,” said Dr Pedersen. “It changes the central nervous system; it makes the hypothalamus pump out chemicals that are telling the body it’s okay, calm down.”

Oxytocin can block “anticipatory pain,” added Dr Pedersen. Patients with intractable pain are constantly waiting for “the next burse of pain” so are “in constant stress,” she said.

However, when they take oxytocin, “they may actually get a lot of relief based on the fact that they are no longer having that anticipation.”

Pain Free, No Side Effects

The investigators are working to determine optimal doses and routes of administration for oxytocin. They have experimented with combining oxytocin with low-dose naltrexone, benzodiazepines, neuropathic agents, opioids, and now ketamine, an N-methyl-D-aspartic acid receptor antagonist.

There has been a resurgence of interest in ketamine as a possible therapy for chronic pain conditions, including neuropathic pain, complex regional pain syndrome, fibromyalgia, postherpetic neuralgia, migraines, and spinal cord injury

At relatively high doses, ketamine has significant psychomimetic and euphoric properties that have led to abuse. Oral ketamine, sometimes called Special K, has become a popular nightclub drug.

Dr Tennant and Dr Pedersen have been experimenting with low-dose ketamine added to oxytocin in patients with the most severe intractable pain.

The study they presented at the AIPM meeting included five such patients (mean age, about 40 years) who had used oxycodonemorphinehydrocodone, or hydromorphone for over a year.

Patients had not taken their short-acting opiate for several hours when they received 0.5 mL (2 mg — half of a syringe, or 20 units) of liquid oxytocin sublingually. Within 10 minutes, all five patients reported varying degrees of pain relief.

About 15 minutes after receiving the oxytocin, patients then received 0.25 to 0.50 mL (12.5 to 25 mg) of liquid ketamine, also sublingually.

The ketamine enhanced the pain relief. With the combination, two patients became completely pain free. These patients would “positively not” have been pain free with opioids, said Dr Pedersen.

The pain relief lasted about 4 hours with no side effects.

The Worst of the Worst

Dr Pedersen said the study patients were “the very worst” of pain patients. In her clinic, many patients suffer intractable pain — pain that never completely goes away with surgery or with drugs. “Some have had, say, seven or eight back surgeries and they have so much inflammation in their spine.”

Some are battling an autoimmune disease, such as lupus. Others have arachnoiditis, an incurable inflammatory condition of the arachnoid mater, the middle layer of the meninges.

Because oxytocin is a hormone, its pain-relieving ability varies from patient to patient and its effectiveness is related, among other things, to blood levels, pain severity, and sex. 

In her experience, Dr Pedersen has found that men tend to have a better response to the combination of oxytocin and ketamine than women.

But women also respond “fabulously,” she said. She described one 38-year-old female patient in her practice with a disc herniation who had been taking opioids, which were not helping her much. “She stopped taking them when she started using this combination therapy.”

Other patients have been able to cut back on opioids “significantly enough that if they had to stop taking them, they would be okay,” said Dr Pedersen.

The combination therapy may also address the issue of addiction, said Dr Pedersen. Some of her patients had become addicted to opioids, but after using the oxytocin-ketamine regimen, they’re not craving or abusing opioids.

The liquid form taken sublingually provides “the best delivery system” and is much more effective than pills, said Dr Pedersen.

Although liquid oxytocin typically has a shelf life of only about 10 days, Dr Pedersen has found pharmacies that put the hormone in a suspension that lasts for 3 months.

Intriguing Results

Commenting on the research for Medscape Medical News, Charles E. Argoff, MD, professor of neurology, and director, Comprehensive Pain Center, Albany Medical College, New York, said it “provides intriguing results.”

However, he said, a single-center open-label study of only five patients “is insufficient to draw any conclusions.”

While the use of oxytocin as an analgesic is supported by basic science, “this study does not add significantly to the human studies already completed, given its size and design,” said Dr Argoff.

Adding ketamine “dampens enthusiasm” for this therapeutic approach because of concerns about dependency and side effects, said Dr Argoff.

Adverse effects of ketamine can include nausea, headaches, fatigue, and dysphoria.

The authors have disclosed no relevant financial relationships.

Academy of Integrative Pain Management (AIPM) 28th Annual Meeting. Abstract 24. Presented October 21, 2017. 

Pain Sand Diego

Web Blog Pain management Link


Metformin & Pain

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A diabetes drug used for many who have no diabetes. Recent discussion on metformin here and here.

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Metformin “can lead to a long-lasting reversal of pain hypersensitivity even long after treatment cessation, indicative of disease modification.” [ref below]

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References:

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A successful case of pain management using metformin in a patient with adiposis dolorosa.

International Journal of Clinical Pharmacology and Therapeutics [2013], from Medical University of Silesia, Katowice, Poland

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This is a very rare condition that has no known treatment.

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Abstract:

In this case report, we describe a patient with Dercum’s disease who was successfully managed with metformin. The administration of metformin reduced pain intensity from 9/10 to 3/10 and favorably affected the profile of inflammatory cytokines (i.e., TNF a, IL-1β, IL-6, and IL-10), adipokines (i.e., adiponectin, leptin, and resistin), and β-endorphin. Because each variable was affected moderately by the drug, in the range of 20 – 30%, it follows that these effects are additive, i.e., they act independently of each other. However, taking into account advances in the pharmacology of metformin, it seems that other phenomena, such as modulation of synaptic plasticity, activation of microglia, and autophagy of the afferents supplying painful lipomas should be taken into consideration. Nonetheless, metformin deserves further exploration in the biology of pain.

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The use of metformin is associated with decreased lumbar radiculopathy pain

Journal of pain [2013], from University of Arizona Tucson, Ted Price’s lab, and USC

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Abstract:

Lumbar radiculopathy pain represents a major public health problem, with few effective long-term treatments. Preclinical neuropathic and postsurgical pain studies implicate the kinase adenosine monophosphate activated kinase (AMPK) as a potential pharmacological target for the treatment of chronic pain conditions. Metformin, which acts via AMPK, is a safe and clinically available drug used in the treatment of diabetes. Despite the strong preclinical rationale, the utility of metformin as a potential pain therapeutic has not yet been studied in humans. Our objective was to assess whether metformin is associated with decreased lumbar radiculopathy pain, in a retrospective chart review. We completed a retrospective chart review of patients who sought care from a university pain specialist for lumbar radiculopathy between 2008 and 2011. Patients on metformin at the time of visit to a university pain specialist were compared with patients who were not on metformin. We compared the pain outcomes in 46 patients on metformin and 94 patients not taking metformin therapy. The major finding was that metformin use was associated with a decrease in the mean of “pain now,” by −1.85 (confidence interval: −3.6 to −0.08) on a 0–10 visual analog scale, using a matched propensity scoring analysis and confirmed using a Bayesian analysis, with a significant mean decrease of −1.36 (credible interval: −2.6 to −0.03). Additionally, patients on metformin showed a non-statistically significant trend toward decreased pain on a variety of other pain descriptors. Our proof-of-concept findings suggest that metformin use is associated with a decrease in lumbar radiculopathy pain, providing a rational for larger retrospective trials in different pain populations and for prospective trials, to test the effectiveness of metformin in reducing neuropathic pain.

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The anti-diabetic drug metformin protects against chemotherapy-induced peripheral neuropathy in a mouse model.

PLoS One [2014] from MD Anderson Cancer Center

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Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) characterized by loss of sensory sensitivity and pain in hands and feet is the major dose-limiting toxicity of many chemotherapeutics. At present, there are no FDA-approved treatments for CIPN. The anti-diabetic drug metformin is the most widely used prescription drug in the world and improves glycemic control in diabetes patients. There is some evidence that metformin enhances the efficacy of cancer treatment. The aim of this study was to test the hypothesis that metforminprotects against chemotherapy-induced neuropathic pain and sensory deficits. Mice were treated with cisplatin together with metformin or saline. Cisplatin induced increased sensitivity to mechanical stimulation (mechanical allodynia) as measured using the von Frey test. Co-administration of metformin almost completely prevented the cisplatin-induced mechanical allodynia. Co-administration of metformin also prevented paclitaxel-induced mechanical allodynia. The capacity of the mice to detect an adhesive patch on their hind paw was used as a novel indicator of chemotherapy-induced sensory deficits. Co-administration of metformin prevented the cisplatin-induced increase in latency to detect the adhesive patch indicating that metformin prevents sensory deficits as well. Moreover, metformin prevented the reduction in density of intra-epidermal nerve fibers (IENFs) in the paw that develops as a result of cisplatin treatment. We conclude that metformin protects against pain and loss of tactile function in a mouse model of CIPN. The finding that metformin reduces loss of peripheral nerve endings indicates that mechanism underlying the beneficial effects of metformin includes a neuroprotective activity. Because metformin is widely used for treatment of type II diabetes, has a broad safety profile, and is currently being tested as an adjuvant drug in cancer treatment, clinical translation of these findings could be rapidly achieved.

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Proteomic and functional annotation analysis of injured peripheral nerves reveals ApoE as a protein upregulated by injury that is modulated by metformin treatment

from Mol Pain [2013], from University of Arizona

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Abstract

BACKGROUND:

Peripheral nerve injury (PNI) results in a fundamental reorganization of the translational machinery in the injured peripheral nerve such that protein synthesis is increased in a manner linked to enhanced mTOR and ERK activity. We have shown that metformin treatment, which activates adenosine monophosphate-activated protein kinase (AMPK), reverses tactile allodynia and enhanced translation following PNI. To gain a better understanding of how PNI changes the proteome of the sciatic nerve and ascertain how metformin treatment may cause further change, we conducted a range of unbiased proteomic studies followed by biochemical experiments to confirm key results.

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CONCLUSIONS:

These proteomic findings support the hypothesis that PNI leads to a fundamental reorganization of gene expression within the injured nerve. Our data identify a key association of ApoE with PNI that is regulated by metformin treatment. We conclude from the known functions of ApoE in the nervous system that ApoE may be an intrinsic factor linked to nerve regeneration after PNI, an effect that is further enhanced by metformin treatment.

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Targeting AMPK for the Alleviation of Pathological Pain

Volume 107 of the series Experientia Supplementum [2016] from University of Texas Dallas

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Abstract:

Chronic pain is a major clinical problem that is poorly treated with available therapeutics. Adenosine monophosphate-activated protein kinase (AMPK) has recently emerged as a novel target for the treatment of pain with the exciting potential for disease modification. AMPK activators inhibit signaling pathways that are known to promote changes in the function and phenotype of peripheral nociceptive neurons and promote chronic pain. AMPK activators also reduce the excitability of these cells suggesting that AMPK activators may be efficacious for the treatment of chronic pain disorders, like neuropathic pain, where changes in the excitability of nociceptors is thought to be an underlying cause. In agreement with this, AMPK activators have now been shown to alleviate pain in a broad variety of preclinical pain models indicating that this mechanism might be engaged for the treatment of many types of pain in the clinic. A key feature of the effect of AMPK activators in these models is that they can lead to a long-lasting reversal of pain hypersensitivity even long after treatment cessation, indicative of disease modification. Here, we review the evidence supporting AMPK as a novel pain target pointing out opportunities for further discovery that are likely to have an impact on drug discovery efforts centered around potent and specific allosteric activators of AMPK for chronic pain treatment.

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Targeting adenosine monophosphate-activated protein kinase (AMPK) in preclinical models reveals a potential mechanism for the treatment of neuropathic pain.

Mol Pain [2011] from University of Arizona

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Abstract

Neuropathic pain is a debilitating clinical condition with few efficacious treatments, warranting development of novel therapeutics. We hypothesized that dysregulated translation regulation pathways may underlie neuropathic pain. Peripheral nerve injury induced reorganization of translation machinery in the peripheral nervous system of rats and mice, including enhanced mTOR and ERK activity, increased phosphorylation of mTOR and ERK downstream targets, augmented eIF4F complex formation and enhanced nascent protein synthesis. The AMP activated protein kinase (AMPK) activators, metformin and A769662, inhibited translation regulation signaling pathways, eIF4F complex formation, nascent protein synthesis in injured nerves and sodium channel-dependent excitability of sensory neurons resulting in a resolution of neuropathic allodynia. Therefore, injury-induced dysregulation of translation control underlies pathology leading to neuropathic pain and reveals AMPK as a novel therapeutic target for the potential treatment of neuropathic pain.

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Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice.

Age [20124, from University of Arizona

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Abstract:

The chronic and systemic administration of rapamycin extends life span in mammals. Rapamycin is a pharmacological inhibitor of mTOR. Metformin also inhibits mTOR signaling but by activating the upstream kinase AMPK. Here we report the effects of chronic and systemic administration of the two mTOR inhibitors, rapamycin and metformin, on adult neural stem cells of the subventricular region and the dendate gyrus of the mouse hippocampus. While rapamycin decreased the number of neural progenitors, metformin-mediated inhibition of mTOR had no such effect. Adult-born neurons are considered important for cognitive and behavioral health, and may contribute to improved health span. Our results demonstrate that distinct approaches of inhibiting mTOR signaling can have significantly different effects on organ function. These results underscore the importance of screening individual mTOR inhibitors on different organs and physiological processes for potential adverse effects that may compromise health span.

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Two Weeks of Metformin Treatment Enhances Mitochondrial Respiration in Skeletal Muscle of AMPK Kinase Dead but Not Wild Type Mice

.PLoS One from University of Copenhagen [2013].

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Abstract:

Metformin is used as an anti-diabetic drug. Metformin ameliorates insulin resistance by improving insulin sensitivity in liver and skeletal muscle. Reduced mitochondrial content has been reported in type 2 diabetic muscles and it may contribute to decreased insulin sensitivity characteristic for diabetic muscles. The molecular mechanism behind the effect of metformin is not fully clarified but inhibition of complex I in the mitochondria and also activation of the 5′AMP activated protein kinase (AMPK) has been reported in muscle. Furthermore, both AMPK activation and metformin treatment have been associated with stimulation of mitochondrial function and biogenesis. However, a causal relationship in skeletal muscle has not been investigated. We hypothesized that potential effects of in vivo metformin treatment on mitochondrial function and protein expressions in skeletal muscle are dependent upon AMPK signaling. We investigated this by two weeks of oral metformin treatment of muscle specific kinase dead α2 (KD) AMPK mice and wild type (WT) littermates. We measured mitochondrial respiration and protein activity and expressions of key enzymes involved in mitochondrial carbohydrate and fat metabolism and oxidative phosphorylation. Mitochondrial respiration, HAD and CS activity, PDH and complex I-V and cytochrome c protein expression were all reduced in AMPK KD compared to WT tibialis anterior muscles. Surprisingly, metformin treatment only enhanced respiration in AMPK KD mice and thereby rescued the respiration defect compared to the WT mice. Metformin did not influence protein activities or expressions in either WT or AMPK KD mice.

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We conclude that two weeks of in vivo metformin treatment enhances mitochondrial respiration in the mitochondrial deficient AMPK KD but not WT mice. The improvement seems to be unrelated to AMPK, and does not involve changes in key mitochondrial proteins.

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Effects of metformin on microvascular function and exercise tolerance in women with angina and normal coronary arteries

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Journal of the American College of Cardiology [2006], from University of Glasgow Cardiovascular Research Centre
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Abstract:

We conducted an 8-week double-blind, randomized, placebo-controlled study of metformin 500 mg twice a day in 33 women with a prior history of normal coronary angiography but 2 consecutive positive (ST-segment depression ≥1 mm) exercise tolerance tests.Women randomized to metformin (n = 16) showed significant improvements in endothelium-dependent microvascular function (p < 0.0001) and maximal ST-segment depression (p = 0.013), and a trend (p = 0.056) toward reductions in chest pain incidence relative to placebo recipients. Hence, metformin may improve vascular function and decrease myocardial ischemia in nondiabetic women with chest pain and angiographically normal coronary arteries. Larger controlled trials of longer duration are warranted.

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The material on this site is for informational purposes only.

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It is not legal for me to provide medical advice without an examination.

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It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.

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This site is not for email and not for appointments.

If you wish an appointment, please telephone the office to schedule.

~~~~~

For My Home Page, click here:  Welcome to my Weblog on Pain Management!

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Posted in AMPK agonistAngina in WomenAnti-iinflammatoryChemotherapy induced neuropathyChronic PainMetforminMicrovascularMitochondrial respirationmTORNeuropathySciaticaUncategorized. Tags: AMPK agonistAngina in WomenAnti-inflammatoryChemotherapy induced neuropathyChronic PainMetforminMicrovascularMitochondrial respirationmTORPeripheral NeuropathySciaticaLeave a Comment »

Metformin Targets Aging – no lactic acidosis, no significant hypoglycemia in 18,000 patients-years of follow-up

03/15/2017 — Nancy Sajben MD      Rate This

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Metformin targets multiple pathways affected by aging (pdf)

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Authors Nir Barzilai, Jill P. Crandall, Stephen B. Kritchevsky, and Mark A. Espeland from aging research centers at Albert Einstein Medical School and Wake Forest Medical School, Cell Metabolism June 2016

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….in 2012, when over 18,000 patients-years of follow-up had accrued, and by which time 20% of the cohort was age 70 or older (mean age 64). There were no cases of lactic acidosis or significant hypoglycemia (Diabetes Prevention Pro- gram Research Group, 2012). Mild anemia occurred in 12% of metformin-treated participants versus 8% in the placebo group (p = 0.04). Vitamin B12 deficiency occurred in 7% of metformin group versus 5% in placebo group after 13 years; risk of B12 deficiency increases with duration of use but was not greater in older compared with younger subjects in DPPOS (Lalau et al., 1990). Further, the risk of lactic acidosis appears to be related to renal function, not age per se, and is currently considered to be very low (Aroda et al., 2016).

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B12 deficiency is related to MTHFR. I prescribe the doses of B vitamins to take daily, as published by University of Oxford for seniors. Their work shows it prevents 90% of brain atrophy in those areas that are known to involve Alzheimers Disease [avoid toxic B6 doses that damage brain].

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When time permits, I will be adding more on metformin.

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If low blood sugar (hypoglycemia) occurs, juice works quickly but rapidly disappears and then blood sugar is low again in minutes. Use good diet practices, and use plenty of small protein snacks if needed. Protein lasts longer and does not trigger sugar spikes like juice.

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Common side effects, if present at all, are mostly GI such as diarrhea, nausea, gas, distension of the belly with discomfort, indigestion, anorexia, headache, asthenia. If present, stop the drug, wait till all resolve, and very slowly, increase only as tolerated. This is not a speed test.

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Lactic Acidosis potential rare side effect

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The potentially serious side effect of concern is lactic acidosis. I advise patients to review its list of potential side effects.

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http://www.medsafe.govt.nz/profs/PUarticles/5.htm

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https://www.healthgrades.com/conditions/lactic-acidosis–symptoms

Introduction

Symptoms

Causes

Treatments

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What are the symptoms of lactic acidosis?

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Symptoms of lactic acidosis may include nausea and vomiting, abdominal pain, weakness, rapid breathing, rapid heart rate or irregular heart rhythm, and mental status changes.

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Common symptoms of lactic acidosis

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If you experience lactic acidosis, it may be accompanied by symptoms that include:

Abdominal pain

Anxiety

Fatigue

Irregular heart rate (arrhythmia)

Lethargy

Nausea with or without vomiting

Rapid breathing (tachypnea)

Rapid heart rate (tachycardia)

Shortness of breath

Weakness

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Serious symptoms that might indicate a life-threatening condition

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In some cases, lactic acidosis can be life threatening.

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Seek immediate medical care (call 911) if you, or someone you are with, have any of these life-threatening symptoms including:

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Bluish coloration of the lips or fingernails

Change in level of consciousness or alertness, such as passing out or unresponsiveness

Chest pain, chest tightness, chest pressure, palpitations

High fever (higher than 101 degrees Fahrenheit)

Not producing any urine, or an infant who does not produce the usual amount of wet diapers

Rapid heart rate (tachycardia)

Respiratory or breathing problems, such as shortness of breath, difficulty breathing, labored breathing, rapid breathing, or not breathing

Severe abdominal pain

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…….

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The material on this site is for informational purposes only.

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It is not legal for me to provide medical advice without an examination.

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It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.

~~

This site is not for email and not for appointments.

If you wish an appointment, please telephone the office to schedule.

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For My Home Page, click here:  Welcome to my Weblog on Pain Management!

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Posted in AgingAnti-iinflammatoryMetabolomeMetforminSide Effects. Tags: AgingAlzheimer’sAnti-inflammatoryMetforminSide EffectsLeave a Comment »

METFORMIN for Nerve Pain

03/06/2017 — Nancy Sajben MD      2 Votes

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Is metformin the new wonder pill or snake oil? Based on one man’s response to metformin and recent exciting research on the drug, I am looking forward to finding out how it works clinically for my patients with intractable pain (and possibly treatment resistant depression). Hopefully most will confirm it is well tolerated. I am just beginning to trial it after learning this one man’s amazing story:

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50% relief of nerve pain &

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musculoskeletal pain

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after 2nd week on metformin

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One Man’s Story

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A few days ago I spoke with a man, not my patient, who had 50% relief of pain after the second week on metformin. He’s taken it for 3 months now, but the big change came dramatically after the second week when he had been on the 2,000 mg dose a full week. In 2013, he was on the side of the freeway median lane, and had crawled into the engine of his disabled Ford F350 reaching in with his left hand when his vehicle was hit by a Lexus SUV going 70 mph and he was thrown. He doesn’t talk about his pain. Ever. He needs total knee replacement in the next few weeks, and has had four surgeries on his left wrist, mangled in that engine, now with a long steel plate in the wrist. He broke the titanium plate and it wasn’t healing. Since metformin, the skin and surgical scar is healing. He’s one of these quiet guys who don’t ever talk about pain. His wife simply said these days he’s sleeping since on metformin.

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But no one had asked him about pain since on metformin or for years either. It took 30 minutes to get one little bit of information from him on pain, like pulling teeth: Since metformin, he’s had 50% relief including the nerve pain at his wrist.

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She said he used to sit up all night in pain for years and was very irritable. Irritability is what happens with no sleep; pain is worse with no sleep. I could not get him to rate his pain. Stoic. Bright man, stoic. Devilish sense of humor. Severe pain for so many years he would never talk about. His surgeon had him stop the Vicodin 5/325 weeks before his last surgery “to help it heal.”

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Some of his relief may have also been influenced by blood sugar dropping from 170 to 90, no more excessive thirst and urination keeping him awake, but the neuropathic pain at his wrist had been nasty a few years. Pain had kept him up for months. He had no side effects.

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Metformin

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Metformin is a medication approved in Canada in 1972 and in the United States by the FDA in 1994 for type 2 diabetes. It is well tolerated when prescribed for people who do not have diabetes but who have other conditions such as PCOS (polycystic ovary syndrome), infertility; and it is the focus of intense activity being studied for its

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(1) anti-aging (PDF from Wake Forest University or the Albert Einstein Medical School Longevity study clinicaltrials.gov), 

(2) anti-cancer (it “has become the focus of intense research as a potential anticancer agent” per Cancer Treat. Res. publication 2014) and now recently being studied for

(3) anti-inflammatory analgesic effects.

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“Metformin increases the number of oxygen molecules released into a cell, which appears to boost robustness and longevity. It works by suppressing glucose production in the liver and increasing insulin sensitivity, therefore benefiting patients with type 2 diabetes.”

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I am very interested by all the new research being done on an old drug, metformin, that has suddenly turned heads in just the last few months as we learn its mechanisms involving the pain matrix. Is this metformin some miracle drug, another hot trendy bandwagon people jump on in medicine? It’s an old drug already FDA approved, now repurposed, with excellent safety, and four months ago a publication shows it to be a glial modulator and anti-inflammatory, centrally active. Best of all, it was dramatically potent in the setting of this man’s intractable nerve and musculoskeletal pain.

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But how do we get from 1994 to 2017, through the Decade of Pain, seeing patients who have astonishing pain relief without asking a single patient, millions of patients if it helped pain? A recent past president of the American Endocrine Society said: “No good data on metformin to treat pain. Everything else, but not pain.” He also said, “Safe. We do it all the time for people with PCOS, infertility, cancer, etc. The anti-aging people use it all the time. No risk of hypoglycemia. Just be sure their GFR is above 40.” So ask your doctor who may not know it’s hot research right now.

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When was it first mentioned for pain?

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Less than one year ago, a report on metformin’s use for pain was a 2016 poster presentation at the annual meeting of the American Pain Society from Ted Price’s lab at University Texas Dallas. “The AMPK activator metformin has been shown by our lab to reverse the effects of chronic neuropathic pain in various short term studies….The treatment successfully decreased the hypersensitivity and cold allodynia associated with neuropathic pain, and showed persistent relief for several weeks post-injection. Metformin also decreased the activation of microglia in the spinal cord.”

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I have cautiously held back prescribing it for pain until I heard this man’s story a few days ago, and days later I am still astonished at the relief he had. I immediately suspected metformin must be a strong glial modulator and that mechanism was confirmed in a publication four months ago, in animal (discussed at end).

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O

 SIDE EFFECTS

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If some develop side effects, stop the medication until all side effects are zero. Then at your own body’s rate, as slowly as needed, increase if needed to 1000 mg twice daily.

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If you again have side effects, again stop til all are zero. Maybe your top dose with no side effects is less than 2,000 mg/day.

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More information on potential side effects  are on the next metformin post – almost none in 18,000 patient years, and not a single case of lactic acidosis.

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STUDIES NEEDED

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It would be extremely helpful to see a study on metformin’s use for pain in a major cancer center, including the range of all underlying diagnoses of those patients who may not be in best of health.  What are % of side effects?

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INFLAMMATION

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Metformin helps inflammation. Inflammation is the cause of 90% mortality. Almost all disease in the body begins with inflammation including atherosclerosis that leads to plaque, heart attacks, stroke. And the same risk factors for heart disease are same for Alzheimers. Inflammation manifests differently in each of us, but to relieve pain, major depression, bipolar disease, PTSD, it can be very dynamic to see response in a few hours once you have the right dose and combination of glial modulators. If this one can relieve 50% of severe chronic pain in two weeks, with few or no side effects, then millions can benefit now. It is an old generic drug repurposed for pain, that is anti-inflammatory. Best of all anti-inflammatory up there in the brain where the inflammatory cytokines produced by glia make you feel like you have the flu:  difficulty thinking, fatigue, drowsy, achey, irritable, needing sleep. That is inflammation. The innate immune system going into gear to attack a virus or…..damage.

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Studies reported about 2001, NIMH showed brain atrophy and memory loss in chronic depression, and about 2009 others showed the same in chronic low back pain.

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My focus for years has been on inflammation in the CNS (brain, spinal cord) because NSAIDs like ibuprofen, Aleve, do not reach the CNS and do not interact on the cells of interest: glia, the cells of the innate immune system that produce a balance of anti-inflammatory and pro-inflammatory chemicals called cytokines. BALANCE.

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Tolerance is a big issue in treating pain or major depression. I strongly recommend reading yesterday’s post on tolerance, i.e. when the body stops responding to ketamine or morphine or an antidepressant after several days or weeks or years. Inflammation may be one cause.

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A publication four months ago shows metformin has both immune and glial suppressive effects that can relieve tolerance to morphine.  It’s a centrally acting analgesic because that’s where chronic pain or major depression is, in the CNS.

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MECHANISM of PAIN RELIEF

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It has both immune and glial suppressive effects: J Neuroinflammation. 2016 Nov 17;13(1):294.

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Metformin reduces morphine tolerance by inhibiting microglial-mediated neuroinflammation.

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ABSTRACT

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BACKGROUND:

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Tolerance [see post on this subject yesterday] seriously impedes the application of morphine in clinical medicine. Thus, it is necessary to investigate the exact mechanisms and efficient treatment. Microglial activation and neuroinflammation in the spinal cord are thought to play pivotal roles on the genesis and maintaining of morphine tolerance. Activation of adenosine monophosphate-activated kinase (AMPK) has been associated with the inhibition of inflammatory nociception. Metformin, a biguanide class of antidiabetic drugs and activator of AMPK, has a potential anti-inflammatory effect. The present study evaluated the effects and potential mechanisms of metformin in inhibiting microglial activation and alleviating the antinociceptive tolerance of morphine.

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RESULTS:

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We found that morphine-activated BV-2 cells, including the upregulation of p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation, pro-inflammatory cytokines, and Toll-like receptor-4 (TLR-4) mRNA expression, which was inhibited by metformin.Metformin suppressed morphine-induced BV-2 cells activation through increasing AMPK phosphorylation, which was reversed by the AMPK inhibitor compound C. Additionally, in BV-2 cells, morphine did not affect the cell viability and the mRNA expression of anti-inflammatory cytokines. In bEnd3 cells, morphine did not affect the mRNA expression of interleukin-1β (IL-1β), but increased IL-6 and tumor necrosis factor-α (TNF-α) mRNA expression; the effect was inhibited by metformin. Morphine also did not affect the mRNA expression of TLR-4 and chemokine ligand 2 (CCL2). Furthermore,systemic administration of metformin significantly blocked morphine-induced microglial activation in the spinal cord and then attenuated the development of chronic morphine tolerance in mice.

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CONCLUSIONS:

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Metformin significantly attenuated morphine antinociceptive tolerance by suppressing morphine-induced microglial activation through increasing AMPK phosphorylation.

BACKGROUND:

Tolerance seriously impedes the application of morphine in clinical medicine. Thus, it is necessary to investigate the exact mechanisms and efficient treatment. Microglial activation and neuroinflammation in the spinal cord are thought to play pivotal roles on the genesis and maintaining of morphine tolerance. Activation of adenosine monophosphate-activated kinase (AMPK) has been associated with the inhibition of inflammatory nociception. Metformin, a biguanide class of antidiabetic drugs and activator of AMPK, has a potential anti-inflammatory effect. The present study evaluated the effects and potential mechanisms of metformin in inhibiting microglial activation and alleviating the antinociceptive tolerance of morphine.

METHODS:

The microglial cell line BV-2 cells and mouse brain-derived endothelial cell line bEnd3 cells were used. Cytokine expression was measured using quantitative polymerase chain reaction. Cell signaling was assayed by western blot and immunohistochemistry. The antinociception and morphine tolerance were assessed in CD-1 mice using tail-flick tests.

RESULTS:

We found that morphine-activated BV-2 cells, including the upregulation of p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation, pro-inflammatory cytokines, and Toll-like receptor-4 (TLR-4) mRNA expression, which was inhibited by metformin. Metformin suppressed morphine-induced BV-2 cells activation through increasing AMPK phosphorylation, which was reversed by the AMPK inhibitor compound C. Additionally, in BV-2 cells, morphine did not affect the cell viability and the mRNA expression of anti-inflammatory cytokines. In bEnd3 cells, morphine did not affect the mRNA expression of interleukin-1β (IL-1β), but increased IL-6 and tumor necrosis factor-α (TNF-α) mRNA expression; the effect was inhibited by metformin. Morphine also did not affect the mRNA expression of TLR-4 and chemokine ligand 2 (CCL2). Furthermore, systemic administration of metformin significantly blocked morphine-induced microglial activation in the spinal cord and then attenuated the development of chronic morphine tolerance in mice.

CONCLUSIONS:

Metformin significantly attenuated morphine antinociceptive tolerance by suppressing morphine-induced microglial activation through increasing AMPK phosphorylation.

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Ketamine Infusion Combined With Magnesium as a Therapy for Intractable Chronic Cluster Headache: Report of Two Cases

Chronic cluster headache (CH) is a rare, highly disabling primary headache condition. As NMDA receptors are possibly overactive in CH, NMDA receptor antagonists, such as ketamine, could be of interest in patients with intractable CH.

Ketamine Infusion Combined With Magnesium as a Therapy for Intractable Chronic Cluster Headache: Report of Two Cases

September 1, 2017 by CHSG Admin

Authors: Xavier Moisset MD, PhD, Pierre Clavelou MD, PhD, Michel Lauxerois MD, Radhouane Dallel DDS, PhD, Pascale Picard MD
Source: Headache, Vol. 57, Issue 8, September 2017: 1261–1264. 

Abstract

Background

Chronic cluster headache (CH) is a rare, highly disabling primary headache condition. As NMDA receptors are possibly overactive in CH, NMDA receptor antagonists, such as ketamine, could be of interest in patients with intractable CH.

Case reports

Two Caucasian males, 28 and 45 years-old, with chronic intractable CH, received a single ketamine infusion (0.5 mg/kg over 2 h) combined with magnesium sulfate (3000 mg over 30 min) in an outpatient setting. This treatment led to a complete relief from symptoms (attack frequency and pain intensity) for one patient and partial relief (50%) for the other patient, for 6 weeks in both cases.

Conclusion

The NMDA receptor is a potential target for the treatment of chronic CH. Randomized, placebo-controlled studies are warranted to establish both safety and efficacy of such treatment.

Ketamine Infusions for Treatment Refractory Headache

December 27, 2016

Management of chronic migraine (CM) or new daily persistent headache (NDPH) in those who require aggressive outpatient and inpatient treatment is challenging. Ketamine has been suggested as a new treatment for this intractable population.

Ketamine Infusions for Treatment Refractory Headache

December 27, 2016 by CHSG Admin

Authors: Jared L. Pomeroy MD, MPH, Michael J. Marmura MD, Stephanie J. Nahas MD, MSEd, Eugene R. Viscusi MD
Source: Headache, Dec. 27, 2016

Abstract

Background

Management of chronic migraine (CM) or new daily persistent headache (NDPH) in those who require aggressive outpatient and inpatient treatment is challenging. Ketamine has been suggested as a new treatment for this intractablepopulation.

Methods

This is a retrospective review of 77 patients who underwent administration of intravenous, subanesthetic ketamine for CM or NDPH. All patients had previously failed aggressive outpatient and inpatient treatments. Records were reviewed for patients treated between January 2006 and December 2014.

Results

The mean headache pain rating using a 0-10 pain scale was an average of 7.1 at admission and 3.8 on discharge (P < .0001). The majority (55/77, 71.4%) of patients were classified as acute responders defined as at least 2-point improvement in headache pain at discharge. Some (15/77, 27.3%) acute responders maintained this benefit at their follow-up office visit but sustained response did not achieve statistical significance. The mean length of infusion was 4.8 days. Most patients tolerated ketamine well. A number of adverse events were observed, but very few were serious.

Conclusions

Subanesthetic ketamine infusions may be beneficial in individuals with CM or NDPH who have failed other aggressive treatments. Controlled trials may confirm this, and further studies may be useful in elucidating more robust benefit in a less refractory patient population.

Ketamine i. v. for the treatment of cluster headaches: An observational study

April 11, 2016

Cluster headaches have an incidence of 1–3 per 10,000 with a 2.5:1 male-to-female gender ratio. Although not life threatening, the impact of the attacks on the individual patient can result in tremendous pain and disability. The pathophysiology of the disease is unclear, but it is known that the hypothalamus, the brainstem, and genetic factors, such as the G1246A polymorphism, play a role. A distinction is made between episodic and chronic cluster headaches. In a controlled setting, we treated 29 patients with cluster headaches (13 with chronic cluster and 16 with the episodic form), who had been refractory to conventional treatments, with a low dose of ketamine (an NMDA receptor antagonist) i.v. over 40 min to one hour every 2 weeks or sooner for up to four times. It was observed that the attacks were completely aborted in 100 % of patients with episodic headaches and in 54 % of patients with chronic cluster headaches for a period of 3–18 months. We postulated neuroplastic brain repair and remodulation as possible mechanisms.

Safety and Efficacy of Prolonged Outpatient Ketamine Infusions for Neuropathic Pain

July 1, 2006

Ketamine has demonstrated usefulness as an analgesic to treat nonresponsive neuropathic pain; however, it is not widely administered to outpatients due to fear of such side effects as hallucinations and other cognitive disturbances. This retrospective chart review is the first research to study the safety and efficacy of prolonged low-dose, continuous intravenous (IV) or subcutaneous ketamine infusions in noncancer outpatients.

Ketamine has demonstrated usefulness as an analgesic to treat nonresponsive neuropathic pain; however, it is not widely administered to outpatients due to fear of such side effects as hallucinations and other cognitive disturbances. This retrospective chart review is the first research to study the safety and efficacy of prolonged low-dose, continuous intravenous (IV) or subcutaneous ketamine infusions in noncancer outpatients. Thirteen outpatients with neuropathic pain were administered low-dose IV or subcutaneous ketamine infusions for up to 8 weeks under close supervision by home health care personnel. Using the 10-point verbal analog score (VAS), 11 of 13 patients (85%) reported a decrease in pain from the start of infusion treatment to the end. Side effects were minimal and not severe enough to deter treatment. Prolonged analgesic doses of ketamine infusions were safe for the small sample studied. The results demonstrate that ketamine may provide a reasonable alternative treatment for nonresponsive neuropathic pain in ambulatory outpatients.

Intranasal Ketamine for the Relief of Cluster Headache

Ketamine’s Mechanism of Action

Ketamine (2-chlorophenyl)-2-(methylamino)-cyclohexanone hydrochloride), a human and veterinary anesthetic agent, has an extremely varied set of pharmacologic actions depending on the dosage used.1 A selective uncompetitive N-Methyl-D-aspartic acid (NMDA) glutamate receptor antagonist, the drug has been in legitimate clinical use since 1963.

When administered as an appropriate pharmacologic agent, ketamine has been shown to serve as a safe anesthetic agent. At sub-anesthetic doses, ketamine acts as an uncompetitive antagonist at ionotropic NMDA-type glutamate receptors, binding to a site on the receptor while it is open. Ionotropic glutamate receptors (iGluRs) mediate the majority of excitatory neurotransmission throughout the mammalian brain. Based on their pharmacology, there are three main classes of glutamate-activated channels:

  • α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs)
  • kainate receptors
  • N-methyl-d-aspartate receptors (NMDAR).

Among ion-gated receptor subtypes (iGluRs), NMDAR are exceptional in their high unitary conductance, high Ca2+ permeability, and remarkably slow gating kinetics.

Ketamine has relatively specific effects on other glutamate subtypes. Several families of these receptors also include AMPA-type and kainate receptors, and the metabotropic family of receptors, of which many exist. NMDARs, in particular, are glutamate-gated ion channels primarily for calcium ions and are crucial for neuronal communication. NMDARs form tetrameric complexes that consist of several subunits. The subunit composition of NMDARs is subject to many changes, resulting in large numbers of receptor subtypes. Each subtype has distinct pharmacological and signaling properties.1 Interest and research is growing and abounds in defining specific functions of subtypes of the glutamate receptor system in both normal and pathological conditions in the central nervous system.

Clinical use of ketamine has led to reports of psychedelic side effects, such as hallucinations, memory defects, panic attacks, as well as nausea/vomiting, somnolence, cardiovascular stimulation and, in a minority of patients, hepatoxicity.In the author’s clinical experience, patients may feel a temporary sense of calm or fogginess after ketamine infusion.

Use in Migraine, Cluster Headache, and Neuropathic Pain Disorders

In more recent years, a very small number of clinicians, including the author, have used ketamine intravenously (IV), and in some cases, via intramuscular injection, to treat migraine, cluster headache, and various other chronic pain disorders, including mixed headache and neuropathic pain clinical syndromes.3-21 In the author’s clinic specifically, ketamine has been used via IV administration for more than 20 years to treat nearly 1,000 patients with various headache and pain disorders. These include: migraine and cluster headache flare-ups; headaches associated with orofacial pain disorders, such as trigeminal neuralgia (TN); atypical face pain; temporomandibular joint disorder (TMD); and neck pain.

Clinical use of ketamine has led to reports of psychedelic side effects, such as hallucinations, memory defects, panic attacks, as well as nausea/vomiting, somnolence, cardiovascular stimulation and, in a minority of patients, hepatoxicity. In the author’s clinical experience, patients may feel a temporary sense of calm or fogginess after a ketamine infusion.

The focus of this paper is to provide a summary of specific retrospective cases in which intranasal ketamine was used for the rescue of cluster headache in patients who had previously experienced a positive outcome from IV ketamine in the author’s outpatient clinic. Cluster headache was successfully eradicated in several patients [n = 17], prompting a mini anecdotal-based trial of rescue intranasal ketamine for continuing or new cluster headache flare-ups to be used by these patients at their home. Table I outlines the outpatient clinic’s treatment of various migraine and headache types. As shown, cluster headache was successfully eradicated in several patients [n = 17], prompting a mini anecdotal-based trial of rescue intranasal ketamine for continuing or new cluster headache flare-ups to be used by these patients at their home.

Retrospective Case Summaries

The dose of intranasal ketamine prescribed to patients ranged between 7.5 mg and 15 mg per 0.1 cc nasal spray (75 and 150 mg of ketamine per cc compounded in normal saline by a pharmacy). Patients were instructed to use one spray in the nostril of the affected side and wait 10 to 15 minutes to feel any effects, including side effects. They were to use the spray when they felt a cluster attack coming on. Patients were asked to use another spray of ketamine in the same nostril at 10- to 15-minute intervals until a sufficient degree of relief (at least 60 to 75%) was obtained for that cluster attack. If the attack still came on after about one hour, the instructions were for the patient to repeat the procedure. All patients were instructed not to drive after taking the medication and signed off on this agreement. Patients were also instructed to keep the nasal spray refrigerated when not in use; no efficacy loss was reported. Of the 17 patients who trialed the nasal spray, 11 elected not to have the intranasal ketamine compounded, or were lost to follow-up, leaving six case scenarios which are summarized herein.

Case 1

A 38-year-old male, with a 16-year history of cluster headache, including a family history of the same, had tried a number of acute and prophylactic agents with, at best, a shortening of the cluster episode. His attacks tended to flare in the spring and lasted up to three months at a time with 4 to 6 episodes per day. The attacks prevented him from working and he came to the outpatient clinic for IV treatment with ketamine, which resulted in a complete cessation after three days, with resolution of allodynia on the right side as well. He elected to try intranasal ketamine (15 mg) at the first onset of his next cluster episode. He reported pain relief and a feeling of calm after 2 to 3 sprays, with no adverse effects. Sometimes, he had to repeat the dosing regimen the next day.

Case 2

A 25-year-old woman was thrown from a horse during a competition and fractured her cervical spine, requiring surgery. The injury included syringomyelia between C3 and C7-T1 and left her with left-sided dystonia of the upper and lower body, abdomen, and chest wall, together with left-sided migraines, which she reported as new. Several times a year, she would awaken every night with left-sided cluster headache episodes, with facial allodynia, tearing, eyelid drooping, and increased dystonia and neck spasm; these occurred primarily in the winter season, with several up to six episodes in per night for a period of three to six weeks.

IV ketamine relieved most of her dystonic, cluster headache, and migraine symptoms, when complemented by IV and oral baclofen and tizanidine, as well as rescue opioids. Nasal spray ketamine was compounded, as well as buccal troches; both allowed her to continue working full-time in her hair salon. She reported no side effects while using the nasal spray ketamine. Liver function tests conducted every three to six months were unremarkable.

Cluster headache is characterized by excruciating, debilitating pain lasting from 15 to 180 minutes, or occasionally longer. The pain is typically located around or through one eye or on the temple. (Source: 123RF)

Case 3

A 55-year-old woman with episodic cluster headache and migraine (3 to 4 attacks per week) also experienced chronic neck pain and had diagnosed TN on the right side. Her cluster headache attacks started at age 27, with tearing, allodynia, and facial numbness. On occasion, her migraine would evolve into a cluster episode that came on during sleep and was seasonal as well, lasting about 2 months on average. She was not a smoker and had no family history of cluster headache but did have a family history of migraine.

She was treated successfully for migraine, right TN, and neck pain with botulinum toxin-A injections (Botox) every 3 to 5 months, supplemented by prophylactic neuropathically active medications, but no opioids. The Botox did not affect her cluster headache, except when they evolved from a migraine, and only to a slight extent (15 to 20%). Multiple acute and prophylactic therapies were attempted to resolve the cluster headache episodes to no significant avail.

IV ketamine was tried on one occasion over a period of 4 days during a cluster headache episode. As a result, the attacks were reduced from 5 per day to 1 per day, and only 1 cluster attack the following week, which was resolved with additional oral oxcarbazepine (600 mg).

The patient agreed to trial nasal spray ketamine which was compounded at 10 mg per 0.1 cc spray with the suggestion that she spray the right nostril every 10 to 15 minutes upon attack to give the medicine time to absorb from the nasal mucosa and to repeat the process until at least 75% relief was obtained. She reported being happy with this approach as it gave her control of her hardest-to-treat symptom. She also reported that her cluster episodes became less frequent over about 1 year and that her migraine and TN also improved; her Botox injection intervals grew longer over time.

Case 4

A 70-old-male, with a 40-plus year history of right-sided cluster attacks with eyelid drooping, tearing, allodynia, neck pain, and other symptoms was treated for these symptoms for many years. Opioids provided him with partial relief, at best. He had a chronic cluster headache that typically awoke him from a sound sleep at 1 or 2 am. These episodes were especially bad in the winter and during weather changes. He had a history of facial and other traumas before the headaches started, including a car accident, but no family history of cluster headache. He also had occasional migraine, about three per month, as well as chronic neck and back pain. He was treated with IV medications, including ketamine, up to 200 mg over 5 hours, with relief of his symptoms in the clinic.

He agreed to trial a compounded nasal spray of ketamine [12.5 mg per 0.1 cc] to use at each bedtime. Two sprays were indicated before each bedtime and at the first onset of any cluster headache at night. Sprays were repeated every 10 minutes until 50 to 65% relief was achieved. He took tizanidine before bedtime for neck spasm and sleep. The patient would, on occasion, repeat one or two ketamine sprays in the morning or during the day if he felt the next cluster attack coming on. As he was on frequent IV and nasal spray ketamine, his liver functions tests were routinely monitored over the course of several years; there was no observed impact.

Case 5

A 34-year-old male who worked in construction began having episodic cluster headache episodes at age 22. He had a family history of migraine and cluster headache. His attacks were season-specific, occurring mostly in the early summer of each or every other year. He described the attacks as very disabling and often awoke from a sound sleep for several weeks at a time as a result of them. He had tried several oral medications, including opioids, for suppression of symptoms without any real benefit and many side effects. When he first presented to the clinic, he trialed IV lidocaine, IV valproate sodium, and IV magnesium sulfate with only partial success in shutting down the episode.

IV ketamine was also offered at the beginning of one of his episodes, and it proved to work more effectively than other treatments. Specifically, the patient’s cluster episode duration was reduced by more than two-thirds (6 to 7 weeks to 7 to 10 days). Based on this result, he was prescribed compounded nasal spray ketamine (7.5 mg per 0.1cc spray) and instructed to use the spray once at bedtime, with additional sprays in one nostril (the affected side of the cluster headache) every 10 minutes until relief was obtained to at least 75%. The patient was also instructed to use the same approach during the day if the cluster headache returned. He used nasal spray ketamine for several years and his overall pattern became easier to treat successfully. His episodes grew further apart and he has reported only one short cluster headache episode in the past four years.

She got extinction of the cluster episode or at least 75% reductions in the cluster headache severity with up to 4-5 nasal sprays of ketamine at the dose described above, and has also noticed a shortening and diminution of the cluster headache episodes as time has gone by.

Case 6

A 51-year-old male, with a family history of cluster headache began having episodic attacks at age 18 with strong occurrences in the spring. He was a smoker. He had tried a calcium channel blocker, lithium, and other medications to little or no avail over the years. He found that triptans taken early in the course of a cluster attack, at several doses, would sometimes abort or lighten the burden of that particular cluster series.

A 3-day course of IV ketamine at the onset of one of his episodes nearly eradicated the episode, and since he lived a great distance (6 hours each way) from the clinic, he wanted to try the nasal spray form of ketamine for at-home application. He reported that a daily dose of 1500 mg of Depakote-ER often softened the arrival of his next cluster headache episode, as did prescribed triptans. However, he did not experience an end to the attack until IV ketamine had been administered.

15 mg per 0.1cc of nasal spray ketamine were compounded for this patient. He reported some nasal burning with the nasal ketamine formulation, so was advised by his pharmacist to use one drop of 2% lidocaine and orange oil as part of the prescription. This addition alleviated the side effect. The patient has successfully used this approach for many years to date. He requires 5 to 6 nasal sprays of ketamine per day, and his episodic cluster headache pattern has markedly softened and shortened in the past few years. He has reduced his dosage of Depakote-ER to 1 or 2 per day as well and attempted to stop smoking several times.

Discussion and Recommendation

The specificity of the ketamine speaks to a unique mechanism of action primarily through the blockade of the NMDA-glutamate and other close-related receptors. This treatment approach may provide insight into the distinctive involvement of this receptor family in the generation and maintenance of this and perhaps other, more rare trigeminal autonomic cephalalgias, or TACs.21

Based on this anecdotal evidence, observed retrospectively in the author’s outpatient clinic over a period of 20 years, intranasal ketamine seems to offer a legitimate, safe pharmacologic treatment for cluster headache rescue. The medication adds a new dimension to managing out-of-control cluster headache and mixed headache/pain disorders in an outpatient setting with no monitoring. Double-blind, placebo-controlled studies are needed to confirm these primarily open-label observations. It should be noted that a small number of patients (5) were given sham nasal treatment and their cluster headache did not respond.

The author found sub-anesthetic doses of intranasal ketamine to be very useful in the control of episodic and chronic cluster headache attacks, as well as in managing certain trigeminal neuralgia symptoms. On a 0 to 10 visual analog scale, pain scores were below 60 to 65% from initial baseline pain score after the use of the intranasal ketamine spray. Efficacy, as well as safety, and tolerability, of low dose IV ketamine were seen consistently in the outpatient clinic, without significant adverse effects. In the author’s opinion, therefore, ketamine may be considered when treating this clinically disabling condition. When used under controlled conditions, ketamine in a nasal spray form may offer a safe and more effective option to patients than emergency room visits and may also serve as a substitute for more standard IV-based rescue cluster headache medications.

About Cluster Headache:Cluster headache is characterized by excruciating, debilitating pain lasting from 15 to 180 minutes, or occasionally longer. The pain is typically located around or through one eye or on the temple. A series of cluster headaches can take place over several weeks to months, and may occur once or twice per year. Several of the following related symptoms may occur: lacrimation, nasal congestion, rhinorrhea, conjunctival injection, ptosis, miosis of the pupil, or forehead and facial sweating. Nausea, bradycardia and general perspiration may present as well. Attacks usually recur on the same side of the head. Cluster headaches afflict males more than females by a 2.5 to 1 ratio and have an overall prevalence of 0.4%. Onset of clusters is usually between ages 20 and 45. There is often no family history of cluster headache.

  1. Robert K, Simon C. Pharmacology and Physiology in Anesthetic Practice. 4th ed. Baltimore, MD: Lippincott, Williams & Wilkins; 2005
  2. Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. Br J Clin Phamacol. 2014;77(2):357–367.
  3. Virginia Scott-Krusz, Jeanne Belanger, RN, Jane Cagle, LVN, Krusz, JC, Effectiveness of IV therapy in the headache clinic for refractory migraine, poster at 9th EFNS meeting Athens, Greece. 2005.
  4. Krusz, JC. Intravenous treatment of chronic daily headaches in the outpatient headache clinic. Curr Pain Headache Rep. 2006;10(1):47-53.
  5. Krusz JC, Cagle J, Belanger J, Scott-Krusz, V. Effectiveness of IV therapy for pain in the clinic, Poster P183 presented at 2nd International Congress on Neuropathic Pain Berlin, Germany. 2007
  6. Krusz JC, Cagle J, Hall S. Efficacy of IV ketamine to treat pain disorders in the pain clinic, (poster 216). J Pain. 27th Annual Scientific. American Pain Society, 2008.
  7. Krusz JC, Cagle J, Hall S. Efficacy of IV ketamine in treating refractory migraines in the clinic (poster 218). J Pain. 27th Annual Scientific. American Pain Society, 2008.
  8. Krusz JC, Cagle J, Hall S. Intramuscular (IM) ketamine for treating headache and pain flare-ups in the clinic (poster 219). J Pain. 27th Annual Scientific. American Pain Society, 2008.
  9. Krusz JC. IV ketamine in the clinic to treat Cluster Headache (poster abstract). American Academy of Neurology. Neurol. 2009;72(11):A89-90.
  10. Krusz JC, Cagle J, Scott-Krusz VB. Ketamine for treating multiple types of headaches (poster). 14th Congress International Headache Society. Cephalalgia. 2009;29(Suppl 1)163.
  11. Krusz JC. Difficult Migraine Patient. Pract Pain Manage. 2011;11(4):16.
  12. Krusz JC, Cagle J. IV Ketamine: Rapid Treatment for All TAC Subtypes in the Clinic, Abstract Poster #72, 15th Congress of the International Headache Society, Berlin, Germany, 2011.
  13. Krusz JC, Cagle J. IM ketamine for intractable headaches and migraines (poster abstract). American Headache Society Annual Meeting, Los Angeles, CA, 2012.
  14. Krusz JC. Traumatic Brain Injury: Treatment of Post-traumatic Headaches. Pract Pain Manage. 2013;13(5):57-68.
  15. Krusz JC, Cagle J, Belanger J, Scott-Krusz V. Effectiveness of IV therapy for pain in the clinic, Poster P183. European J Pain:11, Suppl 1, pS80, presented at 2nd Int’l Congress on Neuropathic Pain, Berlin, Germany. 2007.
  16. Krusz JC, Cagle J, Hall S. Efficacy of IV ketamine to treat pain disorders in the pain clinic, (poster 216). J Pain, 9: Suppl 2, P30, 27th Annual Scientific. American Pain Society. 2008.
  17. Krusz JC. Ketamine IV in an outpatient setting: effective treatment for neuropathic pain syndromes (poster #378). 32nd Annual Scientific Meeting, American Pain Society, New Orleans, 2013.
  18. Krusz JC. Ketamine IV – for CRPS, TN/TMD and other neuropathic pain in the outpatient clinic (poster #524). 4th International Congress on Neuropathic Pain, Toronto, Ontario, 2013.
  19. Krusz JC. The IV ketamine experience: treatment of migraines, headaches and TAC. JAMA Neurol. 2018
  20. Matharu MS, Goadsby PJ. Trigeminal Autonomic Cephalalgias: Diagnosis and Management. In: Silberstein SD, Lipton RB, Dodick DW, eds. Wolff’s Headache and Other Head Pain. 8th ed. New York, NY: Oxford Univ Press; 2008:379-430.
  21. Johnson JW, Glasgow NG, Povysheva NV. Recent insights into the mode of action of memantine and ketamine. Curr Opin Pharmacol. 2015 ;20:54-63. 

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Cluster Headache Support Group

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Ketamine could be first of new generation of rapid acting antidepressants, say experts

Ketamine is the first truly new pharmacological approach to treating depression in the past 50 years and could herald a new generation of rapid acting antidepressants, researchers have predicted.

“We haven’t had anything really new for about 50 or 60 years,” said Allan Young, professor of mood disorders at the Institute of Psychiatry, Psychology and Neuroscience at King’s College, London, at a briefing on 12 July at London’s Science Media Centre.

Most of the new launches have been “tinkering with drugs which were really discovered in the ’50s and ’60s,” he explained. “Even the famous Prozac, which came in in the late ’80s, is really just a refinement of the tricyclic antidepressants that came in the ’50s. People say we are still in the age of steam, and we need to go to the next technological advance.”

Slow onset

In the past few years the focus has fallen on ketamine, which is used for pain relief and anaesthesia but is better known for being a horse sedative and a “club drug” that can induce hallucinations and calmness. It has been found to have rapid antidepressant effects and to be effective in many patients with treatment resistant depression.

US clinics increasingly offer IV infusions of ketamine off label, and in March esketamine, a nasal ketamine based drug, was approved by the US Food and Drug Administration for treatment resistant depression,1 at a cost of £32 400 (€36 060; $40 615) per patient per year.

Carlos Zarate, chief of the Experimental Therapeutics and Pathophysiology Branch at the US National Institute of Mental Health, who has been a key figure in the discovery and evaluation of ketamine as an antidepressant, said that one of the main problems with current antidepressants was their speed of onset in terms of antidepressant and anti-suicidal effects.

He explained that it took 10-14 weeks to see significant improvement with monoaminergic based antidepressants. “In my mind that is too slow,” he said. “We are focusing on treatments that can produce results within hours. That is where we are heading with the next generation of antidepressant, and ketamine is now the prototype for future generation antidepressants which will have rapid, robust antidepressant effects—rapid within a few hours.”

Efficacy and tolerability

Zarate said that, besides correcting chemical imbalances of serotonin and norepinephrine, the new generation of ketamine based antidepressants had other effects such as enhancing plasticity and restoring the synapses and dendrite circuits that shrivel in depression.

When ketamine is given to patients it binds to the N-methyl-D-aspartate (NMDA) receptor, causing a series of transient side effects including decreased awareness of the environment, vivid dreams, and problems in communicating. But the half life of ketamine is only two to three hours, so these side effects quickly subside, whereas the therapeutic effects of the drug last seven days or longer.

Zarate’s team is now focusing on the 24 metabolites of ketamine to hone the drug’s efficacy and tolerability. One of these, hydroxynorketamine, has already been shown to have similar antidepressive effects to ketamine in animals, without the side effects, and it is due to be tested in patients this autumn.

“Ketamine may actually be a prodrug for hydroxynorketamine,” said Zarate.

High cost

A few dozen patients with treatment resistant depression have been treated with ketamine in UK trials, and the European Medicines Agency and the Medicines and Healthcare Products Regulatory Agency are due to reach a decision on authorising esketamine for marketing in October. If the drug is approved private clinics will be able to provide it. But it would be unlikely to be available through the NHS until at least 2020, if at all, as the National Institute for Health and Care Excellence would need to deem it cost effective.

Rupert McShane, consultant psychiatrist and associate professor at the University of Oxford, said that, as well as the likely high cost of esketamine, patients treated with it must be observed in a clinic for two hours after each administration. This would require substantial clinical time, as esketamine is given twice a week for the first month, once a week for the second month, and once a week or once a fortnight from then on.

McShane also recommended that, if approved, a multidrug registry should be set up to monitor the long term safety and effectiveness of ketamine based drugs. Patients would be asked to input their use of any prescribed ketamine, esketamine, or any other future ketamine based product, as well as any self medication with illicit ketamine.

References


    1. Silberner J
    . Ketamine should be available for treatment resistant depression, says FDA panel. BMJ2019;364:l858.doi:10.1136/bmj.l858 pmid:30796014FREE Full TextGoogle Scholar

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Intranasal Ketamine for the Relief of Cluster Headache

Ketamine’s Mechanism of Action

Ketamine (2-chlorophenyl)-2-(methylamino)-cyclohexanone hydrochloride), a human and veterinary anesthetic agent, has an extremely varied set of pharmacologic actions depending on the dosage used.1 A selective uncompetitive N-Methyl-D-aspartic acid (NMDA) glutamate receptor antagonist, the drug has been in legitimate clinical use since 1963.

When administered as an appropriate pharmacologic agent, ketamine has been shown to serve as a safe anesthetic agent. At sub-anesthetic doses, ketamine acts as an uncompetitive antagonist at ionotropic NMDA-type glutamate receptors, binding to a site on the receptor while it is open. Ionotropic glutamate receptors (iGluRs) mediate the majority of excitatory neurotransmission throughout the mammalian brain. Based on their pharmacology, there are three main classes of glutamate-activated channels:

  • α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs)
  • kainate receptors
  • N-methyl-d-aspartate receptors (NMDAR).

Among ion-gated receptor subtypes (iGluRs), NMDAR are exceptional in their high unitary conductance, high Ca2+ permeability, and remarkably slow gating kinetics.

Ketamine has relatively specific effects on other glutamate subtypes. Several families of these receptors also include AMPA-type and kainate receptors, and the metabotropic family of receptors, of which many exist. NMDARs, in particular, are glutamate-gated ion channels primarily for calcium ions and are crucial for neuronal communication. NMDARs form tetrameric complexes that consist of several subunits. The subunit composition of NMDARs is subject to many changes, resulting in large numbers of receptor subtypes. Each subtype has distinct pharmacological and signaling properties.1 Interest and research is growing and abounds in defining specific functions of subtypes of the glutamate receptor system in both normal and pathological conditions in the central nervous system.

Clinical use of ketamine has led to reports of psychedelic side effects, such as hallucinations, memory defects, panic attacks, as well as nausea/vomiting, somnolence, cardiovascular stimulation and, in a minority of patients, hepatoxicity.In the author’s clinical experience, patients may feel a temporary sense of calm or fogginess after ketamine infusion.

Use in Migraine, Cluster Headache, and Neuropathic Pain Disorders

In more recent years, a very small number of clinicians, including the author, have used ketamine intravenously (IV), and in some cases, via intramuscular injection, to treat migraine, cluster headache, and various other chronic pain disorders, including mixed headache and neuropathic pain clinical syndromes.3-21 In the author’s clinic specifically, ketamine has been used via IV administration for more than 20 years to treat nearly 1,000 patients with various headache and pain disorders. These include: migraine and cluster headache flare-ups; headaches associated with orofacial pain disorders, such as trigeminal neuralgia (TN); atypical face pain; temporomandibular joint disorder (TMD); and neck pain.

Clinical use of ketamine has led to reports of psychedelic side effects, such as hallucinations, memory defects, panic attacks, as well as nausea/vomiting, somnolence, cardiovascular stimulation and, in a minority of patients, hepatoxicity. In the author’s clinical experience, patients may feel a temporary sense of calm or fogginess after a ketamine infusion.

The focus of this paper is to provide a summary of specific retrospective cases in which intranasal ketamine was used for the rescue of cluster headache in patients who had previously experienced a positive outcome from IV ketamine in the author’s outpatient clinic. Cluster headache was successfully eradicated in several patients [n = 17], prompting a mini anecdotal-based trial of rescue intranasal ketamine for continuing or new cluster headache flare-ups to be used by these patients at their home. Table I outlines the outpatient clinic’s treatment of various migraine and headache types. As shown, cluster headache was successfully eradicated in several patients [n = 17], prompting a mini anecdotal-based trial of rescue intranasal ketamine for continuing or new cluster headache flare-ups to be used by these patients at their home.

Retrospective Case Summaries

The dose of intranasal ketamine prescribed to patients ranged between 7.5 mg and 15 mg per 0.1 cc nasal spray (75 and 150 mg of ketamine per cc compounded in normal saline by a pharmacy). Patients were instructed to use one spray in the nostril of the affected side and wait 10 to 15 minutes to feel any effects, including side effects. They were to use the spray when they felt a cluster attack coming on. Patients were asked to use another spray of ketamine in the same nostril at 10- to 15-minute intervals until a sufficient degree of relief (at least 60 to 75%) was obtained for that cluster attack. If the attack still came on after about one hour, the instructions were for the patient to repeat the procedure. All patients were instructed not to drive after taking the medication and signed off on this agreement. Patients were also instructed to keep the nasal spray refrigerated when not in use; no efficacy loss was reported. Of the 17 patients who trialed the nasal spray, 11 elected not to have the intranasal ketamine compounded, or were lost to follow-up, leaving six case scenarios which are summarized herein.

Case 1

A 38-year-old male, with a 16-year history of cluster headache, including a family history of the same, had tried a number of acute and prophylactic agents with, at best, a shortening of the cluster episode. His attacks tended to flare in the spring and lasted up to three months at a time with 4 to 6 episodes per day. The attacks prevented him from working and he came to the outpatient clinic for IV treatment with ketamine, which resulted in a complete cessation after three days, with resolution of allodynia on the right side as well. He elected to try intranasal ketamine (15 mg) at the first onset of his next cluster episode. He reported pain relief and a feeling of calm after 2 to 3 sprays, with no adverse effects. Sometimes, he had to repeat the dosing regimen the next day.

Case 2

A 25-year-old woman was thrown from a horse during a competition and fractured her cervical spine, requiring surgery. The injury included syringomyelia between C3 and C7-T1 and left her with left-sided dystonia of the upper and lower body, abdomen, and chest wall, together with left-sided migraines, which she reported as new. Several times a year, she would awaken every night with left-sided cluster headache episodes, with facial allodynia, tearing, eyelid drooping, and increased dystonia and neck spasm; these occurred primarily in the winter season, with several up to six episodes in per night for a period of three to six weeks.

IV ketamine relieved most of her dystonic, cluster headache, and migraine symptoms, when complemented by IV and oral baclofen and tizanidine, as well as rescue opioids. Nasal spray ketamine was compounded, as well as buccal troches; both allowed her to continue working full-time in her hair salon. She reported no side effects while using the nasal spray ketamine. Liver function tests conducted every three to six months were unremarkable.

Cluster headache is characterized by excruciating, debilitating pain lasting from 15 to 180 minutes, or occasionally longer. The pain is typically located around or through one eye or on the temple. (Source: 123RF)

Case 3

A 55-year-old woman with episodic cluster headache and migraine (3 to 4 attacks per week) also experienced chronic neck pain and had diagnosed TN on the right side. Her cluster headache attacks started at age 27, with tearing, allodynia, and facial numbness. On occasion, her migraine would evolve into a cluster episode that came on during sleep and was seasonal as well, lasting about 2 months on average. She was not a smoker and had no family history of cluster headache but did have a family history of migraine.

She was treated successfully for migraine, right TN, and neck pain with botulinum toxin-A injections (Botox) every 3 to 5 months, supplemented by prophylactic neuropathically active medications, but no opioids. The Botox did not affect her cluster headache, except when they evolved from a migraine, and only to a slight extent (15 to 20%). Multiple acute and prophylactic therapies were attempted to resolve the cluster headache episodes to no significant avail.

IV ketamine was tried on one occasion over a period of 4 days during a cluster headache episode. As a result, the attacks were reduced from 5 per day to 1 per day, and only 1 cluster attack the following week, which was resolved with additional oral oxcarbazepine (600 mg).

The patient agreed to trial nasal spray ketamine which was compounded at 10 mg per 0.1 cc spray with the suggestion that she spray the right nostril every 10 to 15 minutes upon attack to give the medicine time to absorb from the nasal mucosa and to repeat the process until at least 75% relief was obtained. She reported being happy with this approach as it gave her control of her hardest-to-treat symptom. She also reported that her cluster episodes became less frequent over about 1 year and that her migraine and TN also improved; her Botox injection intervals grew longer over time.

Case 4

A 70-old-male, with a 40-plus year history of right-sided cluster attacks with eyelid drooping, tearing, allodynia, neck pain, and other symptoms was treated for these symptoms for many years. Opioids provided him with partial relief, at best. He had a chronic cluster headache that typically awoke him from a sound sleep at 1 or 2 am. These episodes were especially bad in the winter and during weather changes. He had a history of facial and other traumas before the headaches started, including a car accident, but no family history of cluster headache. He also had occasional migraine, about three per month, as well as chronic neck and back pain. He was treated with IV medications, including ketamine, up to 200 mg over 5 hours, with relief of his symptoms in the clinic.

He agreed to trial a compounded nasal spray of ketamine [12.5 mg per 0.1 cc] to use at each bedtime. Two sprays were indicated before each bedtime and at the first onset of any cluster headache at night. Sprays were repeated every 10 minutes until 50 to 65% relief was achieved. He took tizanidine before bedtime for neck spasm and sleep. The patient would, on occasion, repeat one or two ketamine sprays in the morning or during the day if he felt the next cluster attack coming on. As he was on frequent IV and nasal spray ketamine, his liver functions tests were routinely monitored over the course of several years; there was no observed impact.

Case 5

A 34-year-old male who worked in construction began having episodic cluster headache episodes at age 22. He had a family history of migraine and cluster headache. His attacks were season-specific, occurring mostly in the early summer of each or every other year. He described the attacks as very disabling and often awoke from a sound sleep for several weeks at a time as a result of them. He had tried several oral medications, including opioids, for suppression of symptoms without any real benefit and many side effects. When he first presented to the clinic, he trialed IV lidocaine, IV valproate sodium, and IV magnesium sulfate with only partial success in shutting down the episode.

IV ketamine was also offered at the beginning of one of his episodes, and it proved to work more effectively than other treatments. Specifically, the patient’s cluster episode duration was reduced by more than two-thirds (6 to 7 weeks to 7 to 10 days). Based on this result, he was prescribed compounded nasal spray ketamine (7.5 mg per 0.1cc spray) and instructed to use the spray once at bedtime, with additional sprays in one nostril (the affected side of the cluster headache) every 10 minutes until relief was obtained to at least 75%. The patient was also instructed to use the same approach during the day if the cluster headache returned. He used nasal spray ketamine for several years and his overall pattern became easier to treat successfully. His episodes grew further apart and he has reported only one short cluster headache episode in the past four years.

She got extinction of the cluster episode or at least 75% reductions in the cluster headache severity with up to 4-5 nasal sprays of ketamine at the dose described above, and has also noticed a shortening and diminution of the cluster headache episodes as time has gone by.

Case 6

A 51-year-old male, with a family history of cluster headache began having episodic attacks at age 18 with strong occurrences in the spring. He was a smoker. He had tried a calcium channel blocker, lithium, and other medications to little or no avail over the years. He found that triptans taken early in the course of a cluster attack, at several doses, would sometimes abort or lighten the burden of that particular cluster series.

A 3-day course of IV ketamine at the onset of one of his episodes nearly eradicated the episode, and since he lived a great distance (6 hours each way) from the clinic, he wanted to try the nasal spray form of ketamine for at-home application. He reported that a daily dose of 1500 mg of Depakote-ER often softened the arrival of his next cluster headache episode, as did prescribed triptans. However, he did not experience an end to the attack until IV ketamine had been administered.

15 mg per 0.1cc of nasal spray ketamine were compounded for this patient. He reported some nasal burning with the nasal ketamine formulation, so was advised by his pharmacist to use one drop of 2% lidocaine and orange oil as part of the prescription. This addition alleviated the side effect. The patient has successfully used this approach for many years to date. He requires 5 to 6 nasal sprays of ketamine per day, and his episodic cluster headache pattern has markedly softened and shortened in the past few years. He has reduced his dosage of Depakote-ER to 1 or 2 per day as well and attempted to stop smoking several times.

Discussion and Recommendation

The specificity of the ketamine speaks to a unique mechanism of action primarily through the blockade of the NMDA-glutamate and other close-related receptors. This treatment approach may provide insight into the distinctive involvement of this receptor family in the generation and maintenance of this and perhaps other, more rare trigeminal autonomic cephalalgias, or TACs.21

Based on this anecdotal evidence, observed retrospectively in the author’s outpatient clinic over a period of 20 years, intranasal ketamine seems to offer a legitimate, safe pharmacologic treatment for cluster headache rescue. The medication adds a new dimension to managing out-of-control cluster headache and mixed headache/pain disorders in an outpatient setting with no monitoring. Double-blind, placebo-controlled studies are needed to confirm these primarily open-label observations. It should be noted that a small number of patients (5) were given sham nasal treatment and their cluster headache did not respond.

The author found sub-anesthetic doses of intranasal ketamine to be very useful in the control of episodic and chronic cluster headache attacks, as well as in managing certain trigeminal neuralgia symptoms. On a 0 to 10 visual analog scale, pain scores were below 60 to 65% from initial baseline pain score after the use of the intranasal ketamine spray. Efficacy, as well as safety, and tolerability, of low dose IV ketamine were seen consistently in the outpatient clinic, without significant adverse effects. In the author’s opinion, therefore, ketamine may be considered when treating this clinically disabling condition. When used under controlled conditions, ketamine in a nasal spray form may offer a safe and more effective option to patients than emergency room visits and may also serve as a substitute for more standard IV-based rescue cluster headache medications.

About Cluster Headache:Cluster headache is characterized by excruciating, debilitating pain lasting from 15 to 180 minutes, or occasionally longer. The pain is typically located around or through one eye or on the temple. A series of cluster headaches can take place over several weeks to months, and may occur once or twice per year. Several of the following related symptoms may occur: lacrimation, nasal congestion, rhinorrhea, conjunctival injection, ptosis, miosis of the pupil, or forehead and facial sweating. Nausea, bradycardia and general perspiration may present as well. Attacks usually recur on the same side of the head. Cluster headaches afflict males more than females by a 2.5 to 1 ratio and have an overall prevalence of 0.4%. Onset of clusters is usually between ages 20 and 45. There is often no family history of cluster headache.

  1. Robert K, Simon C. Pharmacology and Physiology in Anesthetic Practice. 4th ed. Baltimore, MD: Lippincott, Williams & Wilkins; 2005
  2. Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. Br J Clin Phamacol. 2014;77(2):357–367.
  3. Virginia Scott-Krusz, Jeanne Belanger, RN, Jane Cagle, LVN, Krusz, JC, Effectiveness of IV therapy in the headache clinic for refractory migraine, poster at 9th EFNS meeting Athens, Greece. 2005.
  4. Krusz, JC. Intravenous treatment of chronic daily headaches in the outpatient headache clinic. Curr Pain Headache Rep. 2006;10(1):47-53.
  5. Krusz JC, Cagle J, Belanger J, Scott-Krusz, V. Effectiveness of IV therapy for pain in the clinic, Poster P183 presented at 2nd International Congress on Neuropathic Pain Berlin, Germany. 2007
  6. Krusz JC, Cagle J, Hall S. Efficacy of IV ketamine to treat pain disorders in the pain clinic, (poster 216). J Pain. 27th Annual Scientific. American Pain Society, 2008.
  7. Krusz JC, Cagle J, Hall S. Efficacy of IV ketamine in treating refractory migraines in the clinic (poster 218). J Pain. 27th Annual Scientific. American Pain Society, 2008.
  8. Krusz JC, Cagle J, Hall S. Intramuscular (IM) ketamine for treating headache and pain flare-ups in the clinic (poster 219). J Pain. 27th Annual Scientific. American Pain Society, 2008.
  9. Krusz JC. IV ketamine in the clinic to treat Cluster Headache (poster abstract). American Academy of Neurology. Neurol. 2009;72(11):A89-90.
  10. Krusz JC, Cagle J, Scott-Krusz VB. Ketamine for treating multiple types of headaches (poster). 14th Congress International Headache Society. Cephalalgia. 2009;29(Suppl 1)163.
  11. Krusz JC. Difficult Migraine Patient. Pract Pain Manage. 2011;11(4):16.
  12. Krusz JC, Cagle J. IV Ketamine: Rapid Treatment for All TAC Subtypes in the Clinic, Abstract Poster #72, 15th Congress of the International Headache Society, Berlin, Germany, 2011.
  13. Krusz JC, Cagle J. IM ketamine for intractable headaches and migraines (poster abstract). American Headache Society Annual Meeting, Los Angeles, CA, 2012.
  14. Krusz JC. Traumatic Brain Injury: Treatment of Post-traumatic Headaches. Pract Pain Manage. 2013;13(5):57-68.
  15. Krusz JC, Cagle J, Belanger J, Scott-Krusz V. Effectiveness of IV therapy for pain in the clinic, Poster P183. European J Pain:11, Suppl 1, pS80, presented at 2nd Int’l Congress on Neuropathic Pain, Berlin, Germany. 2007.
  16. Krusz JC, Cagle J, Hall S. Efficacy of IV ketamine to treat pain disorders in the pain clinic, (poster 216). J Pain, 9: Suppl 2, P30, 27th Annual Scientific. American Pain Society. 2008.
  17. Krusz JC. Ketamine IV in an outpatient setting: effective treatment for neuropathic pain syndromes (poster #378). 32nd Annual Scientific Meeting, American Pain Society, New Orleans, 2013.
  18. Krusz JC. Ketamine IV – for CRPS, TN/TMD and other neuropathic pain in the outpatient clinic (poster #524). 4th International Congress on Neuropathic Pain, Toronto, Ontario, 2013.
  19. Krusz JC. The IV ketamine experience: treatment of migraines, headaches and TAC. JAMA Neurol. 2018
  20. Matharu MS, Goadsby PJ. Trigeminal Autonomic Cephalalgias: Diagnosis and Management. In: Silberstein SD, Lipton RB, Dodick DW, eds. Wolff’s Headache and Other Head Pain. 8th ed. New York, NY: Oxford Univ Press; 2008:379-430.
  21. Johnson JW, Glasgow NG, Povysheva NV. Recent insights into the mode of action of memantine and ketamine. Curr Opin Pharmacol. 2015 ;20:54-63. 

The Path from Episodic to Chronic Migraine

Although episodic migraine and chronic migraine are common, they represent distinct types of headaches on the migraine pain spectrum.1 Factors involved in the transformation from episodic to chronic migraine include frequency of episodes, failure to optimize acute treatment, overuse of acute migraine medication, lower socioeconomic status, obesity, and being female.1,2 The most common technique for managing these headache conditions is pharmacologic, however, medication overuse is also the most common reason that episodic migraine may evolve into chronic migraine, often resulting in medicine overuse headache (MOH).

According to Lipton, et al,3 patients have reported that their acute treatment of episodic migraine was poorly managed as measured by the Migraine Treatment Optimization Questionnaire, with 6.8% of patients developing chronic migraine within one year compared to 1.9% of patients reporting optimized acute treatment. These results suggested the need for more effective acute treatment strategies to manage symptoms associated with episodic and chronic type migraine. In response, several studies have since shown a potential alternative treatment involving the sphenopalatine ganglion (SPG) to be effective in reducing episodes of chronic migraine (see Figure 1).

Figure 1. The sphenopalatine ganglion (SPG). (Image courtesy of authors).

The SPG is the largest neurological ganglion outside the brain, located within the pterygopalatine fossa at the posterior attachment of the middle turbinate. This ganglion has sensory, parasympathetic, and sympathetic components that house the trigeminal nerve, branches of the palatine nerves, and various sympathetic and parasympathetic automatic branches all of which innervate the cranial cavities (eg, nose, mouth) as well as facial areas, and the nasal and pharyngeal glands.4 Based on the SPG’s anatomy and physiology, it has become evident that many associated symptoms of chronic migraine may be managed by targeting the SPG using alternative methods that aim to decrease activity in this region.

Migraine may be related, at least in part, to a hyper-excited SPG. Stimulation of the SPG has been shown to induce a pathophysiological response seen in migraine attacks, including vasodilation of intra- and extra-cranial arteries, release of substance P and neurokinin A, as well as activation of meningeal nociceptors, which may be contributing to the pain.4

Treatment Alternatives
Neurological Blockage of the SPG

Alternative treatments targeting the SPG have been developed as a means of lessening the symptoms associated with migraine. One trialed approach is a neurological blockade at the SPG with bupivacaine using a nasal applicator5,6 and topical lidocaine applied with a deep nasal anesthetic applicator (DNAA).7 Cady, et al, published two studies utilizing the device to deliver bupivacaine to the mucosa of the SPG. The first, primarily a safety study, was designed to determine acute effects. The researchers reported the bupivacaine treatment group (n = 26) decreased from pre-treatment 3.18 ± 2.79 to post-treatment at 15 minutes 2.53 ± 2.61, 30 minutes 2.41 ± 2.61, and 24 hours 2.85 ± 2.74.5

The second study was designed to determine the long-term effects of bupivacaine by delivering a set of 12 treatments over a period of six weeks. Results demonstrated that the bupivacaine treatment group (n = 25) had a significant decrease in the number of headaches in a month from 23.15 ± 5.12 to 17.44 ± 9.08 compared to 24.75 ± 4.35 to 22.82 ± 5.36 in a sham group, which was administered saline. Additionally, the average pain scores reported by the subjects in the prior 24 hours decreased from pre-treatment of 4.92 ± 2.2 to 2.86 ± 2.62 at six months after the last bupivacaine treatment.6

Lee, et al, reported 59 out of 66 cases treated with 26% lidocaine applied with DNAA had an average decrease of 4.9 pain points and 4.2 points at 15 minutes and 60 minutes post-application, respectively.7 The treatment provided rapid relief of the headache pain and decreased activity of the SPG, thereby reducing the pain associated with the migraine.5-7

Similarly, an inhibitory dose of photobiomodulation (PBM) appears to have a similar efficacy in decreasing SPG activity and may reduce migraine pain and frequency by inhibiting nerve conduction of type C pain fibers.8,9

Moving away from pharmacologic methods to treating migraine. (Source: 123RF)

Photobiomodulation

Adopted by the North American Association of Photobiomodulation Therapy, photobiomodulation refers to light therapy treatments that utilize non-ionizing light sources in the visible and infrared spectrum.8 PBM is a non-thermal process that involves endogenous chromophores which elicit photophysical and photochemical events. These events theoretically lead to beneficial therapeutic outcomes, including the alleviation of pain or inflammation and immunomodulation, as well as the promotion of wound healing and tissue regeneration.8 More specifically, PBM emits photons of light that penetrate the skin and stimulate endogenous light receptors, which result in a physiological response. Low doses of PBM stimulate tissue healing and increase blood flow9 while higher doses tend to have an inhibitory effect, which may be used therapeutically to decrease pain.9

For example, low doses of light that are delivered to the tissue stimulate the cytochrome C oxidase (CCO) within the mitochondria, resulting in an increase in adenosine triphosphate (ATP) and a release of nitric oxide (NO) and reactive oxygen species (ROS).9 The ATP provides an increase in energy availability within the cells. When NO is released from CCO and from blood vessels, the result is an increase in ATP production and vasodilation. When ROS is in low concentrations, it activates the transcription factors, which lead to cell proliferation and growth.9

The authors trialed PBM on three patients (ages 42, 53, and 72) with a history of chronic migraine. Each patient had suffered from two to five migraine attacks per week for at least the prior 10 years (see Table I). Each was successfully treated using a PBM protocol to the SPG.

Initial reported pain levels ranged from 8 to 10 out of a 10-point pain scale. All three patients completed daily activities with difficulties due to frequent and painful symptoms. All patients had previously attempted pharmacological methods of treatment with little to no relief, or with additional side effects from MOH that hindered daily functioning.

Each PBM treatment consisted of applying a laser puncture utility probe attached to a PBM-transducer (Multi Radiance Medical) that delivered the photons to the SPG. The probe was placed just inside each nostril pointing toward the posterior nasal cavity where the SPG is located (see Figure 2). The treatment frequency and number of overall treatments were tailored to each patient’s responsiveness.

Figure 2. Inhibitory photobiomodulation treatment to the sphenopalatine ganglion with probe (image courtesy of authors).

Each treatment lasted 180 seconds per nostril (23.9 joules, 0.0382 watts, 6.87J/chronic). The device characteristics were as follows: wavelength super pulsed laser 905 nm; infrared 875 nm; Red 670 nm; total power, 25W, SPL variable frequency: 1000 Hz and beam spot size 0.4. The patients were evaluated for migraine frequency and intensity both pre- and post-treatment, and throughout the duration of the treatment.

Patient 1: This 42-year old male developed a chronic migraine condition following a traumatic head injury, resulting in a skull fracture. His regimen encompassed three PBM treatments over a 4-week period. After the first treatment, the patient experienced no migraine for 2 weeks. His reported migraine pain decreased from 8 out of 10 to a 0 out of 10 after each treatment. After the full course, the patient reported no migraine for another 2 weeks and self-discharged from our care (follow-up was not possible).

Patient 2: A 53-year-old female was scheduled to receive a course of six PBM treatments over 21 days. The patient reported reduced frequency and intensity of migraine with aura after the first six treatments. This patient did not miss any work during the treatment period. It is worth noting that prior to starting the PBM treatments, Patient 2 had missed work due to pain intensity of her migraine and what she reported as mental dullness as a result of the medication used to control her migraine symptoms. Due to the decrease in frequency and intensity of her migraine attacks, PBM treatments were reduced to one per week for 4 weeks. Patient 2 was migraine-free at discharge after 8 weeks of total treatment. At 90-day follow-up, the patient reported that she had not experienced a post-treatment migraine.

Patient 3: A 72-year-old female underwent a course of eight PBM treatments over 4 weeks (two applications per week). Patient 3 reported that she was migraine free for 10 days after the month-long treatment was completed. She was prescribed a second round of treatments, which were then reduced to weekly for another 4 weeks. The patient reported being migraine-free during the continued treatment period. There was no 90-day follow-up for this patient.

Discussion and Steps Forward

Two of the main factors that may cause episodic migraine attacks to become chronic are medication overuse and improper care for acute attacks.1-3 As demonstrated in the three cases herein, PBM treatments to the SPG were shown to be effective in decreasing pain ratings from 8 out of 10 to 0 out of 10 after each treatment. If PBM could be used effectively to treat episodic migraine, patients may not overuse medications, which may ultimately prevent the transition of episodic to chronic migraine.

Overall, the PBM treatments described herein were deemed successful in treating chronic migraine (see Table I for details). Patient 1 started with two migraine attacks per week and decreased his episodes to zero attacks per week after a course of three treatments over 4 weeks. Patient 2 reduced her migraine frequency from two to three per week to zero after 10 treatments over 12 weeks. Patient 3, who had previously experienced three to five migraine attacks per week for 59 years, reduced her attack frequency to zero migraine attacks per week after 12 treatments over 8 weeks. None of the patients reported any side effects and tolerated the treatments well.

Similar to neurologic blocks of the sphenopalatine ganglion, the response to PBM is bi-phasic, stimulatory or inhibitory, and dose dependent.9 There has been strong evidence supporting PBM inhibition of acute, chronic, and neurological pain.10 As noted, light may reduce the formation of inflammatory proteins associated with pain including prostaglandin, cox 2 mRNA, and TNF α.10 Additionally, PBM works to inhibit nerve conduction along the AΔ and C nerve fibers, which are the main nerve fiber types that conduct pain.10

It appears that the SPG and associated nerves are hyperactive during migraine attacks, as suggested by Khan, et al.4 An inhibitory dose of PBM seems to restore the SPG and associated nerves back to their normal physiological levels. A similar occurrence was reported by Cady, et al,5-6 and Lee, et al,7 after treating migraine (with bupivacaine and lidocaine, respectively) applied to the posterior nasal cavity directed at the SPG. There is some evidence that the SPG may also be associated with refractory chronic post-traumatic headaches.10 For example, Sussman, et al, successfully treated a post-concussion headache utilizing intranasal lidocaine application to the SPG.11

In this case presentation, use of PBM treatment reduced migraine frequency to zero episodes per week in patients with a 10-year or greater history of migraine for whom medication failed to manage symptoms effectively. Due to a decrease in pain and episode occurrence, all three patients were able to improve their daily function following completion of individualized PBM treatment regimen to block the SPG. With a growing demand for non-pharmacological treatments for migraine pain, photobiomodulation may be a noninvasive therapeutic option for chronic migraine. To demonstrate the efficacy of this treatment protocol, large randomized control trials should be completed to confirm validity and long-term effects.

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The Brain on Fire: Depression and Inflammation

According to the World Health Organization, depression is the leading cause of disability. Unfortunately, 30 to 60 percent of patients are not responsive to available antidepressant treatments (Krishnan & Nestler, 2008). In other words, 40 to 70 percent of patients are not helped by existing treatments. One area of research might shed some light on why a sizable portion of patients are not helped by current antidepressants.

There is growing evidence that inflammation can exacerbate or even give rise to depressive symptoms. The inflammatory response is a key component of our immune system. When our bodies are invaded by bacteria, viruses, toxins, or parasites, the immune system recruits cells, proteins, and tissues, including the brain, to attack these invaders. The main strategy is to mark the injured body parts, so we can pay more attention to them. Local inflammation makes the injured parts red, swollen, and hot. When the injury is not localized, then the system becomes inflamed. These pro-inflammatory factors give rise to “sickness behaviors.” These include physical, cognitive and behavioral changes. Typically, the sick person experiences sleepiness, fatigue, slow reaction time, cognitive impairments, and loss of appetite. This constellation of changes that take place when we are sick is adaptive. It compels us to get more sleep to heal and remain isolated so as not to spread infections.

However, a prolonged inflammatory response can wreak havoc in our bodies and can put us at risk of depression and other illnesses. There is plenty of evidence solidifying the link between inflammation and depression. For example, markers of inflammation are elevated in people who suffer from depression compared to non-depressed ones (Happakoski et al., 2015). Also, indicators of inflammation can predict the severity of depressive symptoms. A study that examined twins who share 100 percent of the same genes found that the twin who had a higher CRP concentration (a measure of inflammation) was more likely to develop depression five years later.  

Doctors noticed that their cancer and Hepatitis C patients treated with IFN-alpha therapy (increases inflammatory response) also suffered from depression. This treatment increased the release of pro-inflammatory cytokines, which gave rise to a loss of appetite, sleep disturbance, anhedonia (loss of pleasure), cognitive impairment, and suicidal ideation (Lotrich et al., 2007). The prevalence of depression in these patients was high. These results add credence to the inflammation story of depression.

Subsequent careful studies showed that the increase in the prevalence of depression in patients treated with IFN-alpha was not only because they were sick. Using a simple method of injecting healthy subjects with immune system invaders, researchers found higher rates of depressive symptoms in the ones who were exposed compared to the placebo group. The subjects who were induced to have an inflammatory response complained of symptoms such as negative mood, anhedonia, sleep disturbances, social withdrawal, and cognitive impairments.

The link between inflammation and depression is even more solid for patients who don’t respond to current antidepressants. Studies have shown that treatment-resistant patients tend to have elevated inflammatory factors circulating at baseline than the responsive ones. This is clinically important; a clinician can utilize a measure like CRP levels, which are part of a routine physical, to predict the therapeutic response to antidepressants. In one study, they found that increased levels of an inflammation molecule prior to treatment predicted poor response to antidepressants (O’Brien et al., 2007).

There are environmental factors that cause inflammation and therefore elevate risk for depression: stress, low socioeconomic status, or a troubled childhood. Also, an elevated inflammatory response leads to increased sensitivity to stress. The effect has been reported in multiple studies in mice. For example, mice that have gone under chronic unpredictable stress have higher levels of inflammation markers (Tianzhu et al., 2014). Interestingly, there are individual differences that make some mice more resistant to stress, therefore initiating a calmer immune response (Hodes et al., 2014).

Depression is a heterogeneous disorder. Each patient’s struggle is unique given their childhood, genetics, the sensitivity of their immune system, other existing bodily illnesses, and their current status in society. Being on the disadvantageous end of these dimensions irritates our immune system and causes chronic inflammation. The brain is very responsive to these circulating inflammatory markers and initiates “sickness behavior.” When the inflammation is prolonged by stressors or other vulnerabilities, the sickness behavior becomes depression.

If you are a professional working with patients suffering from depression, I urge you to consider the health of your patients’ immune systems. If you are a patient suffering from an exaggerated immune disorder (e.g., arthritis), do not ignore the depressive symptoms that you might be experiencing. If you are suffering from depression, avoid anything that might exacerbate your immune response. This is another example of the beautiful dance between mind and body!

References

Haapakoski,R.,Mathieu,J.,Ebmeier,K.P.,Alenius,H.,Kivimäki,M., 2015. Cumulative meta-analysisofinterleukins6 and 1β,tumournecrosisfactorα and C-reactive protein in patients with major depressive disorder. Brain Behav.Immun. 49,206.

Hodes GE, Pfau ML, Leboeuf M, Golden SA, Christoffel DJ, Bregman D et al (2014). Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc Natl Acad Sci USA 111: 16136–16141.

Krishnan V, Nestler EJ (2008). The molecular neurobiology of depression. Nature 455: 894–902.

Lotrich,F.E.,Rabinovitz,M.,Gironda,P.,Pollock,B.G., 2007. Depression following pe-gylated interferon-alpha:characteristics and vulnerability.J.Psychosom.Res.63, 131–135.https://doi.org/10.1016/j.jpsychores.2007.05.013.

O’Brien, S.M., Scully, P., Fitzgerald, P., Scott, L.V., Dinan, T.G., 2007a. Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy. J. Psychiatr. Res. 41, 326e331.

Tianzhu, Z., Shihai, Y., Juan, D., 2014. Antidepressant-like effects of cordycepin in a mice model of chronic unpredictable mild stress. Evid. Based Complement. Altern. Med. 2014, 438506.

The Serotonin Transporter Gene and Depression

A new large-scale study casts doubt on a widely reported association.

Why some people develop major depressive disorder and others do not is a complex and not well-understood process. Several factors have been discussed to contribute to depression, among them:

Genetic variation: Individuals carrying one or two copies of a specific risk allele on one or more “depression gene/s” have a higher risk of developing depression.

Environmental influences: Negative life events such as trauma, negligence, or abuse increase the risk of developing depression.

Gene-by-environment interactions: Negative life events only lead to depression in individuals with a specific genetic set-up that makes them risk-prone to develop depression.

The gene most commonly associated with depression is the serotonin transporter gene SLC6A4 (Bleys et al., 2018). Serotonin is a neurotransmitter affecting multiple physiological processes and cognitivebrain functions, among them mood and emotions, which is why it has been linked to mood disorders such as depression. Indeed, low serotonin levels have been associated with depressed mood (Jenkins et al., 2016), and selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants. SSRIs block the reuptake of serotonin during cellular communication in the brain, making more serotonin available, and thus in theory helping to reduce depression.

Along these lines, the idea that the serotonin transporter gene could affect depression risk or severity intuitively made sense. Specifically, many scientists focused on the so-called 5-HTTLPR polymorphism in the promoter region of the serotonin transporter gene to research the effects of this gene on depression. Genetic polymorphism means that at a specific location in the genome, different people might have slight variations in their DNA which could affect how well the protein that the gene produces could do its job. In the case of the 5-HTTLPR polymorphism, there is a short allele (s) and a long allele (l). Already back in the 1990s, researchers showed that people with two or one short alleles have a higher chance of developing depression than those with two long alleles, as the short allele leads to reduced expression of the serotonin transporter (Collier et al., 1996).

This initial study sparked interest in the 5-HTTLPR polymorphism, but not all empirical works could find a clear association. In 2003, a surprising finding seemingly resolved this controversy. In a widely cited study, Caspi and colleagues were able to show that the effects of 5-HTTLPR polymorphism genotype on depression were moderated by a so-called gene-by-environment interaction (Caspi et al., 2003). This means that the genotype would only have an effect if individuals were also subjected to specific environmental conditions. Specifically, the scientists found that individuals reacted differently to highly stressful life events, depending on the 5-HTTLPR genotype. People with at least one short allele on the 5-HTTLPR polymorphism developed more depressive symptoms if they experienced a highly stressful life event than people with two long alleles. However, without a stressful life event, the genotype did not have an effect on the probability to develop depression.

This study further increased the interest in the 5-HTTLPR polymorphism and its relation to depression, leading to more studies on this topic. However, a problem of many of these studies was that their sample sizes were comparably small for genetic studies, potentially leading to erroneous results and overblown effects.

Almost a decade ago, Risch and co-workers (Risch et al., 2009) conducted a so-called meta-analysis, a statistical integration of empirical studies. They analyzed 14 studies on the 5-HTTLPR polymorphism and its relation to depression and on whether this relation was influenced by stressful life events as had been suggested by Caspi et al. (2003). Their result was clear: While more stressful life events led to a higher risk of depression, there was no effect of the 5-HTTLPR genotype on depression and no gene-by-environment interaction effect between genotype and stressful life events.

Despite this finding, hundreds of studies on the 5-HTTLPR polymorphism and depression have been published since 2009 (the scientific search engine PubMed lists more than 800 hits for the search term “5-HTTLPR depression” as of early May 2019). A new study recently published by Richard Border and colleagues in The American Journal of Psychiatry(Border et al., 2019) aimed to resolve the controversy about whether or not the 5-HTTLPR genotype affects depression and whether there is a gene-by-environment interaction between this genotype and stressful life events once and for all. To avoid the statistical problems of previous studies, they obtained data from several large genetic datasets available to researchers, leading to a sample size of several hundred thousand individuals. The results of the analysis were clear as well: There was no statistical evidence for a relation between the 5-HTTLPR polymorphism and depression, and there was also no evidence that traumatic life events or adverse socioeconomic conditions might show a gene-by-environment interaction with this genotype.

This, of course, does not mean that there is no relationship between serotonin and depression (there clearly is, as shown by the treatment success of SSRIs), but it lends further support to an emerging insight in psychiatry genetics: Mental illness is a highly complex process that is likely influenced by a large number of genetic and non-genetic effects. As such, it is unlikely that single genetic variations such as the 5-HTTLPR polymorphism have a huge impact on whether or not an individual develops depression or any other form of mental illness. Future psychiatry genetic studies will need to take this complexity into account by analyzing genetic variation across the whole genome and epigenome and relating it to mental illness (Meier & Deckert, 2019).

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Traumatic Brain Injury: Definition, Classification, and Management

We hear a lot about traumatic brain injury (TBI) nowadays: among NFL players (as in the movie ‘Concussion’), and as a signature diagnosis among recent combat veterans. What doesn’t get as much press coverage is the impact of TBI on those suffering from addiction. Having an alcohol or other substance use disorder greatly increases the risk of TBI. But what is TBI? How do I diagnose it? How does it manifest? How do I manage it?

Defining TBI
Although there is no universally accepted definition for TBI, recently updated guidelines from the Department of Veterans Affairs (VA/DoD Clinical Practice Guideline for the Management of Concussion-mild Traumatic Brain Injury, 2016; https://tinyurl.com/y8e6owdx) state that a TBI is an injury to the brain caused by an external force accompanied by one of several clinical signs following the event). These signs can be an intracranial lesion, loss of consciousness, amnesia, confusion, slowed thinking, muscle weakness, sensory loss, or another neurological deficit. The severity of a TBI (mild, moderate, or severe) is determined by the symptoms immediately following the injury (see the VA TBI severity table below). If the patient meets different ratings for the different criteria, go with the more severe rating. The lay term “concussion” equates to a mild TBI. In addition to the neurological symptoms, patients may experience cognitive problems affecting their attention, memory, processing speed, and executive function. Mental health effects include irritability, impulsivity, depression, and anxiety. However, these symptoms can be an effect of the TBI or part of a comorbid, major depressive disorder, posttraumatic stress disorder (PTSD), or substance use disorder.

Table: Classification of TBI Severity

Table: Classification of TBI Severity

(Click to view full-size PDF.)

Assessment and treatment
But what symptoms should I really be concerned about? For any TBI that is associated with progressively declining neurological function or worsening headache, pupil asymmetry, seizures, intractable vomiting, ongoing disorientation or neurological deficit, slurred speech, or new bizarre behavior, you should immediately refer for emergency evaluation.

The good news is that the vast majority of mild TBI cases resolve without any intervention. It’s important for the physician to provide education and reassurance to the patient and family. Any interventions should be tailored to the specific symptoms while reinforcing good sleep hygiene, relaxation techniques, and limiting use of caffeine, tobacco, and alcohol. Return to normal functioning at work or school should be encouraged in a gradual, monitored fashion. Patients with a TBI who report ongoing symptoms need appropriate referral and a comprehensive treatment plan (Silver JM et al, Textbook of Traumatic Brain Injury, American Psychiatric Publishing, Inc; 2nd ed;2011).

Cognitive rehabilitation therapy (CRT) 
You may have heard of cognitive rehabilitation therapy (CRT) as a treatment for TBI. But what exactly does it involve? And does it work? After a TBI there may be functional deficits that are both physical and mental in nature. CRT is a therapeutic process structured to improve the patient’s functioning in their daily lives. Patients are first guided through recognizing their strengths, weaknesses, and what deficits they want to improve. Then techniques are relearned when possible (solve the problem), or compensatory strategies are identified (work around the problem). The last step is to incorporate these relearned or new skills into daily life. This process can be applied to both physical and cognitive deficits that arise from a TBI.

CRT sessions should be tailored to the individual but most incorporate memory compensation techniques. Such techniques include having the patient write down at each session what was important to them, then reviewing their notes and memory of what was said during the next session. This method not only increases their participation in the therapy sessions but teaches them how to use the memory compensation techniques in their daily lives.

The evidence for CRT after stroke and moderate to severe TBI has long been established, showing improvement in the domains of memory, attention, and communication (Cicerone KD et al, Arch Phys Med Rehabil 2005;86(8):1681-1692). However, for mild TBI, CRT remains more controversial as there isn’t strong evidence for improved functional outcomes. The 2016 VA clinical guidelines recommend short-term CRT for moderate to severe TBI and discourages prolonged treatment courses without measurable improvements.

Sometimes the most concerning symptoms the patient will come to us for are the cognitive deficits and they may press for neuropsychological (NP) testing early. However, NP testing should not be done in the first 30 days. Most cognitive deficits of mild TBI will improve within this time period. And if the problems last longer than 30 days, NP testing may be helpful. Whenever referring for NP testing, be specific in why you are making the request. A targeted referral allows the NP examiner to choose the right tests to provide the most useful information.

Pharmacologic treatment 
When considering medication treatment for symptoms following a TBI, there are several general guidelines to follow (Silver JM et al, Neurology 2006;67(5):748-755.2011). Again, most symptoms of a mild TBI will abate within a month, so watchful waiting and reassurance are important. Symptom improvement may continue throughout the first year as the brain continues to heal, so be sure to reassess the need for the medication intervention. Many times, the neuropsychiatric symptoms after a TBI can be complicated by concurrent major depressive disorder, PTSD, or a substance use disorder. Untreated depression can be the root cause of cognitive problems, irritability, sleep disturbance, fatigue, and headache. Be sure to perform a thorough psychiatric assessment so that you can tailor the treatment plan accordingly. Target specific symptoms or concurrent conditions with your medication choices. After a TBI the brain can be more susceptible to side effects of medications, underscoring the importance of “starting low, and going slow.”

Here are a few specific medication recommendations to target neuropsychiatric symptoms (Silver JM et al, 2011). For improving processing speed, methylphenidate has the most evidence. Donepezil and rivastigmine also may have some utility for treating memory impairment. When targeting depression and anxiety, SSRIs are first-line and choose a specific SSRI based on side effect profile and limiting medication interactions (sertraline, citalopram, and escitalopram are favorable choices) (Salter DL et al, J Head Trauma Rehabil 2016;31(4):E21-32). Be cautious with bupropion due to increased seizure risk. Caution is also advised with typical antipsychotics as they may inhibit neuronal recovery, and also benzodiazepines due to the memory impairment effects. For controlling mania or irritability, valproate is preferred due to its anti-seizure effect as well as having less cognitive side effects in long term treatment than other mood stabilizers (carbamazepine or lithium). Atypical antipsychotics may also be helpful in controlling irritability especially when combined with psychosis, and are preferred over typical antipsychotics. More recent research shows beneficial effects of amantadine in treating aggression from TBI even 6 months post-injury and more studies are evaluating its use in the acute phase after a severe TBI (Hammond FM et al, J Head Trauma Rehabil. 2017;32(5):308-318).

CATR Verdict: When treating patients with TBI, always remember that the brain has a great capacity for plasticity and recovery. Encourage patients to see their treatment as a process and journey. Take care to evaluate for comorbid mental health disorders, and handle accordingly. Those with substance use disorders, whether existing pre-TBI or newly occurring, should be encouraged to enter into treatment promptly. With the right combination of cognitive rehabilitation, pharmacotherapy, and a good therapeutic alliance, your patients can make great strides in recovery after a TBI.

Ohio State TBI

Alcohol use and TBI are closely related. Up to two-thirds of people with TBI have a history of alcohol abuse or risky drinking. Between 30-50% of people with TBI were injured while they were drunk and about one-third were under the influence of other drugs. Around half of those who have a TBI cut down on their drinking or stop altogether after injury, but some people with TBI continue to drink heavily, which increases their risk of having negative outcomes.

After TBI, many people notice their brains are more sensitive to alcohol. Drinking increases your chances of getting injured again, makes cognitive (thinking) problems worse, and increases your chances of having emotional problems such as depression. In addition, drinking can reduce brain injury recovery. For these reasons, staying away from alcohol is strongly recommended to avoid further injury to the brain and to promote as much healing as possible.

Facts about TBI and alcohol

Alcohol and brain injury recovery

  • Recovery from brain injury continues for much longer than we used to think possible. Many people notice improvements for many years after injury.
  • Alcohol slows down or stops brain injury recovery.
  • Not drinking is one way to give the brain the best chance to heal.
  • People’s lives often continue to improve many years after brain injury. Not drinking will increase the chance of improvement.

Alcohol, brain injury and seizures

  • Traumatic brain injury puts survivors at risk for developing seizures (epilepsy).
  • Alcohol lowers the seizure threshold and may trigger seizures.
  • Not drinking can reduce the risk of developing seizures.

Alcohol and the risk of having another brain injury

  • After a brain injury, survivors are at higher risk (3 to 8 times higher) of having another brain injury.
  • Drinking alcohol puts survivors at an even higher risk of having a second brain injury. This may be because both brain injury and alcohol can affect coordination and balance.
  • Not drinking can reduce the risk of having another brain injury.

Alcohol and mental functioning

  • Alcohol and brain injury have similar negative effects on mental abilities like memory and thinking flexibility.
  • Alcohol magnifies some of the cognitive problems caused by brain injury.
  • Alcohol may affect brain injury survivors more than it did before their injury.
  • The negative mental effects of alcohol can last from days to weeks after drinking stops.
  • Not drinking is one way to keep your mental abilities at their best and stay sharp and focused.

Alcohol and mood

  • Depression is about 8 times more common in the first year after TBI than in the general population.
  • Alcohol is a “depressant” drug, and using alcohol can cause or worsen depression.
  • Alcohol can reduce the effectiveness of anti-depressant medications. People who are taking antidepressants should not drink alcohol.
  • One way to improve problems with sadness or depression after TBI is to stop or cut down on the use of alcohol.

Alcohol and sexuality

  • Lowered desire is the most common effect of TBI on sexuality.
  • Alcohol reduces testosterone production in males.
  • Alcohol reduces sexual performance (erection and ejaculation) in men.
  • Alcohol reduces sexual satisfaction in men and women.
  • Avoiding alcohol improves sexual ability and activity in men and women.

How much alcohol is “safe” after TBI?

After TBI the brain is more sensitive to alcohol. This means that even one or two drinks may not be safe, especially when you need to do things that require balance, coordination and quick reactions, such as walking on uneven surfaces, riding a bicycle or driving a car. The fact is, there is no safe level of alcohol use after TBI.

Alcohol and medications

Alcohol is especially dangerous after TBI if you are taking certain prescription medications. Alcohol can make some medicines less effective and can greatly increase the effects of others, potentially leading to overdose and death. Using alcohol along with anti-anxiety medications or pain medications can be highly dangerous because of the possible multiplying effect.

What about using other drugs?

Alcohol is a drug. Almost everything mentioned above about alcohol applies equally to other drugs. If your drug of choice is something other than alcohol-such as marijuana, cocaine, methamphetamine or prescription drugs, anti-anxiety medications (benzodiazepines such as Ativan, Valium, or Xanax), or pain medication (opioids like Percocet, Oxycodone or Oxycontin)-many of the same principles apply. In addition, use of illegal drugs or misuse of prescription drugs can lead to legal problems.

If you use multiple drugs like alcohol and marijuana, or alcohol and pain pills, there is a higher risk of addiction and overdose. Using alcohol and pain medications together, or alcohol and anti-anxiety medications, has killed many people. Contact your doctor if you are drinking and using prescription drugs.

What should you do?

The stakes are higher when people choose to use alcohol after having a TBI. Some people continue drinking after a TBI and don’t have any desire to change that behavior. Others know they probably should stop or reduce alcohol use, but don’t know how or have tried in the past and not been successful.

There are many ways to stop using alcohol or other drugs and many ways to reduce the potential for harm. The great majority of people who have stopped having alcohol problems did it on their own. They got no professional help or counseling and did not use Alcoholics Anonymous (AA). Don’t underestimate your ability to change if you want to.

There are many ways to change, cut down or stop drinking

The key ingredients to changing your drinking are: (1) find people who will support your efforts to change your drinking; (2) set a specific goal; (3) make clear how you will meet your goal; (4) identify situations or emotions that can trigger drinking, and figure out ways to cope with those triggers ahead of time; and (5) find ways to reward yourself for sticking to your plan and meeting your goals.

If you have questions or concerns about your drinking, there are many ways to get information or help:

  • Take a confidential on-line drinking assessment: http://www.alcoholscreening.org/.
  • Talk to your physician about your concerns, and ask about medications that can help you resist relapse or reduce cravings for alcohol, such as naltrexone (Revia).
  • Psychologists or other counselors in your brain injury rehabilitation program can help you get started on a treatment program that is right for you.
  • Alcoholics Anonymous (AA) has helped millions of people. There are meetings in most towns and cities (http://www.aa.org/).
  • Moderation Management (http://www.moderation.org/) and Smart Recovery (http://www.smartrecovery.org/) are alternatives to AA that do not use the 12-step model.
  • Substance Abuse and Mental Health Services Administration (SAMHSA) is a federal program that can help you find a treatment facility wherever you live (http://findtreatment.samhsa.gov/; 800-662-4357).
  • Private treatment: look in the Yellow Pages under substance abuse, chemical dependency counselor, or addiction treatment.

Reduce the harm from drinking

For those who don’t want to stop drinking, it is still possible to reduce some harm from drinking:

  • Eat food and drink water before you drink alcohol. This will help reduce the sharp spike in blood alcohol level that can cause nausea, vomiting, falls, blackouts and alcohol poisoning.
  • Plan your transportation so you don’t drink and drive: have a non-drinking designated driver; plan to spend the night where you are doing your drinking; or drink only at home.
  • To avoid dangerous peaks in blood alcohol concentrations, drink beer rather than hard liquor, or mix hard liquor with water instead of with sweet, carbonated beverages.
  • Sip your drinks slowly (no more than one per hour). Drinking too fast can make the pleasant feelings of alcohol go away.
  • Drinking in bars slows some people down because of the expense. However, be sure you do not drive after drinking.
  • Take vitamins B1 (thiamine), B12 and folate to reduce the chances of alcohol-related brain damage.
  • Keep your drinking to no more than two drinks per day. Or cut back on certain days of the week, such as weeknights.
  • Take a drinking “holiday” (days or weeks when you decide not to drink at all). This can remind you of some of the benefits of being sober.

How family members can help

No one can force another person to stop using alcohol or drugs, but you can have an influence. Attending Al Anon meetings can be a good source of support for a friend or family member of someone who abuses alcohol or drugs, and it can help promote change. Planning an “intervention” where family and friends confront the person may help.

A program called Community Reinforcement and Family Training (CRAFT) has been found to work best. CRAFT takes a more positive, motivational approach that helps loved ones make not drinking more rewarding for the person with the alcohol problem. Research has shown that alcoholics are more likely to go into treatment if their loved ones follow the CRAFT method. To learn about CRAFT, see the book Get Your Loved One Sober in the Resources section below, or find a counselor familiar with this approach.

Reference

Bombardier, C.H. & Turner, A. (2009). Alcohol and traumatic disability. In R. Frank & T. Elliott (Eds.), The Handbook of Rehabilitation Psychology, Second Edition (pp. 241-258). Washington, DC: American Psychological Association Press.

Resources

  • Brown, J., Corrigan, J., & Hammer, P. (2010). “Substance Abuse and TBI.” Brainline Webcast #4, Defense and Veterans Brain Injury Center. (http://www.brainline.org/webcasts/4-TBI_and_Substance_Abuse/index.html)
  • Corrigan, J., & Lamb-Hart, G. (2004). Alcohol, Other Drugs, and Brain Injury. Columbus, Ohio: Ohio Valley Center for Brain Injury Prevention and Rehabilitation, Ohio State University Dept. of Physical Medicine and Rehabilitation. (Available from the Brain Injury Association, http://www.biausa.org/LiteratureRetrieve.aspx?ID=43235. )
  • Meyers, R.J., & Wolfe, B.L. (2004). Get Your Loved One Sober: Alternatives to Nagging, Pleading, and Threatening. Center City, MN: Hazelden Publications.
  • Substance Abuse Resources and Disability Issues (SARDI); http://www.med.wright.edu/citar/sardi/index. html.

Disclaimer

This information is not meant to replace the advice from a medical professional. You should consult your health care provider regarding specific medical concerns or treatment.

Source

Our health information content is based on research evidence whenever available and represents the consensus of expert opinion of the TBI Model System directors.

Authorship

Alcohol Use After Traumatic Brain Injury was developed by Charles Bombardier, PhD, in collaboration with the University of Washington Model Systems Knowledge Translation Center.

https://msktc.org/tbi/factsheets/Alcohol-Use-After-Traumatic-Brain-Injury

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NOVA Health Recovery | Alexandria, Va 22306 | Call for esketamine and nasal ketamine as well as IV Ketamine for depression, PTSD, anxiety  703-844-0184 < Link

Ketamine Virginia Link

Long known as a party drug, ketamine now used for depression, but concerns remain

What Makes the Ketamine-Based Drug for Depression So Different?

On Tuesday (March 5), the U.S. Food and Drug Administration (FDA) approved a ketamine-like nasal spray for patients with depression who haven’t responded to other treatments.

But what makes this newly approved treatment so different?

The drug, called Spravato and made by Janssen Pharmaceuticals, contains the active ingredient esketamine. This substance has the same molecular formula as ketamine but a different chemical structure. (In other words, it contains the same type and number of elements but in a different configuration.) Ketamine is typically used as an anesthetic, but it’s also been used as an illicit party drug.

One reason experts are excited about the nasal spray is that its effects can be seen within several hours to days. Other antidepressants, meanwhile, can take weeks to start working

Antidepressants work by regrowing brain cells and the connections between them, and ketamine appears to have the same effects, said David Olson, an assistant professor of chemistry, biochemistry and molecular medicine at the University of California, Davis. But, these effects likely start much sooner than with other antidepressants, he said.

Still, it’s not entirely clear how the drug works.

Ketamine-like drugs are “dirty”, meaning they likely hit a variety of targets in the brain, Olson told Live Science. “There are a lot of very interesting hypotheses out there, [and] many of them are probably partially valid.”

One idea is that ketamine treats depression by blocking a neurotransmitter called glutamate from binding to the NMDA receptor, and stopping signals from cascading across the brain, Dr. Alan Schatzberg, a professor of psychiatry and behavioral sciences at the Stanford University School of Medicine, told Live Science.

Glutamate is a chemical that brain cells use to send signals to other brain cells. But high levels of it can cause over-excitement in the brain, which can, in turn, damage brain cells.

A more controversial idea is that ketamine binds to opioid receptors, causing a release of naturally occurring opioids in the body. Schatzberg and his team published a small study on this last summer in which they gave patients with depression ketamine twice — once after receiving an opioid-blocking drug, and once after receiving a placebo in place of the opioid blocker. The two treatments took place about a month apart, and neither the participants nor the researchers knew whether patients received the opioid blocker or the placebo. The study found that the patients responded well to the ketamine treatment if they didn’t receive the opioid-blocking drug, but ketamine had no effect on those that did, suggesting an opioid-like role.

This hypothesis has some experts concerned about ketamine-based drugs as a depression treatment.

“My concern about this compound is that it is a disguised form of opiates,” said Dr. Mark George, a distinguished professor of psychiatry, radiology and neurosciences at the Medical University of South Carolina. While George said he is “overjoyed” for the prospect of a new treatment option, “I’m alarmed that there is pretty clear evidence [that] the way ketamine works is through the opioid system.”

If this is the mechanism that ketamine acts through to treat depression, its effects won’t last and people might develop a tolerance to the drug, possibly even becoming addicted, George told Live Science. But if its antidepressant effects come from other mechanisms, such as blocking the NMDA receptor, then “that’s good,” he said.

Olson, however, said that he is less convinced by the opioid hypothesis and thinks more work needs to be done before ringing the alarm bells.

What’s more, the new drug will see limited use. The medication comes with a risk of sedation and dissociation, such as difficulty with judgment, attention and thinking. Because of that, the nasal spray was approved to be used only under a “restricted distribution system,” according to a statement from the FDA.

This means that only patients with severe depression who haven’t responded to at least two antidepressant treatments can receive the drug. In addition, the treatment is administered only in doctor’s offices, and patients must stay in the office and be monitored for several hours after receiving the treatment.

Ultimately, despite some potential problems with the newly approved drug, experts are hopeful it will come through strong.

“I think that the FDA approval of ketamine is a huge landmark in the history of treating neuropsychiatric diseases,” Olson said. “Ketamine really represents a leap forward in terms of new ideas for attacking depression and related neuropsychiatric diseases.”



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