Tag Archives: painkiller

Medicinal plant extract used by Native Americans can treat both pain and diarrhea

California Coast Redwood Forest land from which plants were collected for this study. Credit: Geoffrey Abbott

Researchers at the University of California, Irvine (UCI) have identified a molecule in extracts from plants with a long history of use by Native Americans as topical analgesics also doubles as a gastrointestinal aid. The study “shines a light on the incredible ingenuity and medicinal wisdom of Californian Native American tribes,” said Geoffrey Abbott, lead author and a professor in the Department of Physiology and Biophysics at the UCI School of Medicine.

Stopping both pain and diarrhea

Before the advent of modern pharmacology, humans have had to rely on nature for ailments. Specifically, they would look for plants that could heal wounds, cure some diseases, and ease troubled minds. The oldest evidence of medicinal plants dates from 60,000 years ago, the age of a burial site of a Neanderthal man who had been buried alongside eight species of plants, some of which have medicinal properties. Even in today’s age of synthetic drugs, about 40% of the most common drugs found in a pharmacist’s counter are derived from plants that people have used for centuries.

Native Americans are one of the cultures renowned for their medicinal plant knowledge. According to one myth, the earliest use of medicinal plants among the Native American tribes started after they watched animals eat certain plants when they were sick. Some of their favorite medicinal herbs include red clover (treats inflammation and respiratory conditions), black gum bark (relieves chest pains), hummingbird blossom (treats mouth and throat conditions), wild ginger (treats earache and ear infections), slippery elm (treats skin conditions, sore throats, and even spider bites), and lavender (a remedy for insomnia, anxiety, and depression).

Such plants were so important and cherished that medicine men would take steps to protect them from over-harvesting. For instance, they would only pick every third plant they found.

In a new study, researchers analyzed the molecular makeup of an extract of plants collected in Muir Woods National Monument, a region in California known for its coastal redwood forests. These plants have a long history of use in Native American traditional medicine as topical analgesics for insect bites, stings, sores, and burns. Overall, the researchers analyzed 40 plants from Californian coastal redwood forest plants.

Traditional medicinal usage of KCNQ2/3-activating plants. Geographical and tribal traditional medicinal usage of 8 native plant extract “hits” from KCNQ2/3 screening, categorized by plant genus. Muir Woods location indicated by green rectangle. Credit: Abbott et al.

The scientists found that the plants activated the KCNQ2/3 potassium channel, which passes electrical impulses between the brain and other tissues. KCNQ2/3 is present in nerve cells that sense pain, and its activation soothes pain by lowering the strength of the pain signal.  The team found that extracts from 9 of the 40 plant species increased KCNQ2/3 current significantly — and all 9 were used as traditional medicine by Native Americans.

But the same plant extracts that activate KCNQ2/3 have the opposite effect on KCNQ1-KCNE3, an intestinal potassium channel. The inhibiting effects on the ion protein channel KCNQ1-KCNE3 can prevent diarrhea, the researchers found. Diarrhea is no joke — it is responsible for 1 in 9 child deaths worldwide, more than AIDS, malaria, and measles combined. The fact that we could have a drug that doubles as both a painkiller and diarrhea inhibitor may prove mighty useful in the future.

“Done in collaboration with the US National Parks Service, this study illustrates how much there is still to learn from the medicinal practices of Native Americans, and how, by applying molecular mechanistic approaches we can highlight their ingenuity, provide molecular rationalizations for their specific uses of plants, and potentially uncover new medicines from plants,” Abbott said.

Inspired by these findings, Abbott and colleagues are now undertaking a broader screen of plants native to North America, on the lookout for new molecules that could be used to treat a range of conditions. They’ve already found that quercetin, tannic, and gallic acids present in several of the plants studied are responsible for the medicinal properties of these plants.

Of particular interest are potentially novel non-opioid painkillers. According to 2018 data, up to 30% of patients prescribed opioids for chronic pain misuse them and 10% develop an opioid use disorder.

The findings appeared in the journal Frontiers in Physiology.

Credit: Pixabay.

Researchers reveal how marijuana develops pain-relief molecules 30 times stronger than Aspirin

Credit: Pixabay.

Credit: Pixabay.

Canadian researchers at the University of Guelph have discovered how the Cannabis sativa plant generates pain-relieving molecules. In the future, the authors of the new study hope that biochemistry could enable a new class of painkillers based on Cannabis which doesn’t share the dangers of opiates.

“There’s clearly a need to develop alternatives for relief of acute and chronic pain that go beyond opioids,” said Prof. Tariq Akhtar, Department of Molecular and Cellular Biology, co-author of the new study published in the journal  Phytochemistry. “These molecules are non-psychoactive and they target the inflammation at the source, making them ideal painkillers.”

Prof. Akhtar and colleagues used biochemistry and genomics to investigate how the cannabis plant produces cannflavin A and cannflavin B, two flavonoids — one of the largest nutrient families known to scientists. Flavonoids include over 6,000 polyphenolic plant compounds and are one of the reasons why fruits and veggies are good for you. Previously, researchers established that flavonoids exhibit anti-inflammatory, anti-thrombogenic, antidiabetic, anticancer, and neuroprotective activities through different mechanisms of action in vitro and in animal models.

Cannaflavins A and B were first identified in 1985 by studies that found that the compounds’ anti-inflammatory effects are 30 times stronger, gram-for-gram, than acetylsalicylic acid, or Aspirin.

Unfortunately, these promising molecules haven’t been closely investigated ever since because cannabis research used to be highly regulated. But, today, cannabis is legal in Canada and researchers like Prof. Akhtar are free to study the plant as they please.

What’s more, huge leaps in genomics research means that there is now a trove of potential applications for cannabis waiting to be discovered.

“Our objective was to better understand how these molecules are made, which is a relatively straightforward exercise these days,” said Akhtar. “There are many sequenced genomes that are publicly available, including the genome of Cannabis sativa, which can be mined for information. If you know what you’re looking for, one can bring genes to life, so to speak, and piece together how molecules like cannflavins A and B are assembled.”

The team of researchers at the University of Guelph uncovered the genes responsible for creating cannflavins A and B. However, since the cannabis plant produces these molecules at such low levels, the scientists plan on developing a biological system that creates the flavonoids in large quantities.

Most people suffering from chronic pain use opioid painkillers to manage their condition. These drugs work by blocking the brain’s pain receptors but, in doing so, also carry significant side effects and the potential for addiction, and can even cause death. In 2018, tens of thousands of Americans were killed by overdosing on prescription opioid painkillers.

Cannflavins do not carry the same risks as opioids because they can block pain by reducing inflammation — a totally different approach.  In the future, the researchers hope that cannabis-based flavonoids will become widely accessible through a variety of medical products such as pills, creams, patches, and other options.

Jo Cameron (left) feels no physical pain and heals quickly. Her abilities are caused by two genetic mutations which may one-day be targetted in novel pain-relief treatments. Credit: Jo Cameron.

Scottish woman who feels no pain and heals without scars might help create novel painkillers

Jo Cameron (left) feels no physical pain and heals quickly. Her abilities are caused by two genetic mutations which may one-day be targetted in novel pain-relief treatments. Credit: Jo Cameron.

Jo Cameron (left) feels no physical pain and heals quickly. Her abilities are caused by two genetic mutations which may one-day be targeted in novel pain-relief treatments. Credit: Jo Cameron.

Jo Cameron, a 71-year-old Scottish woman, has lived all her life without the sensation of physical pain. Although what you might think at first glance, living without feeling pain comes with its own challenges and problems. For instance, the woman has suffered numerous burns and cuts, which often inflicted more damage than they should have. Sometimes, Cameron would realize her skin was burning only after she smelled fumes coming out of her flesh. But luckily Cameron possesses another superman trait: she heals quickly and often with very little or no scarring at all. In a new study, scientists have found that these traits are due to a newly identified genetic mutation — one that could pave the way for new treatments.

‘X-woman’

Cameron’s extraordinary abilities first came to doctors’ attention when, only a few years ago, she sought treatment for a hip injury. Her hip proved to have severe arthritis and required replacing. Immediately doctors knew something was off since Cameron’s disease should have caused her immense discomfort, which wasn’t the case. After two painless surgeries, doctors decided they should investigate more closely this unique patient.

“We had banter before theatre when I guaranteed I wouldn’t need painkillers,” the woman told BBC News, recounting the moment her doctors couldn’t believe she wouldn’t need painkillers after her surgery.

“When he found I hadn’t had any, he checked my medical history and found I had never asked for painkillers.”

Doctors at Raigmore Hospital, Inverness, ran some tests on her finding that the woman had almost no pain response. She could even eat Scotch bonnet chillis, which are famous for being extremely hot, without so much as flinching.

Cameron was then referred to experts in pain genetics at the University College London and the University of Oxford who identified two mutations that may be linked to her pain sensitivity and healing ability. One is a mutation that affects a gene called FAAH (Fatty Acid Amide Hydrolase), which plays a major role in regulating the body’s endocannabinoid system — a family of endogenous ligands, receptors, and enzymes that are important in pain, memory, and mood. The endocannabinoid system is also the target of compounds in cannabis which provoke a ‘high’ or ‘buzz’ once they are ingested.

The second mutation targets a gene which previously had no apparent useful purpose. The new research, however, shows that this mutation switches the FAAH gene on or off. In the case of Cameron, the gene’s activity is switched off, the authors reported in the British Journal of Anaesthesia.

These mutations may explain why Cameron doesn’t feel physical pain or heals so quickly. What’s more, there may also be some psychological effects. For instance, Cameron scored zero on clinical tests for anxiety and depression. She says she never panics or loses her cool — not even when she was in a recent car accident.

But despite her rare condition, Cameron says that she would have preferred to feel pain.

“Pain is there for a reason, it warns you – you hear alarm bells.”

“It would be nice to have warning when something’s wrong – I didn’t know my hip was gone until it was really gone, I physically couldn’t walk with my arthritis.”

Scientists hope to translate the findings into novel drugs that annihilate the pain response. Right now, half of the patients recovering from surgery still experience pain despite taking strong painkillers. In the future, researchers hope to study other people with the same kind of mutations. In 2013, ZME Science wrote about a similar case — that of Ashlyn Blocker, a normal looking American teenager from a small town called Patterson, GA.

 “People with rare insensitivity to pain can be valuable to medical research as we learn how their genetic mutations impact how they experience pain, so we would encourage anyone who does not experience pain to come forward,” Dr. James Cox, of UCL, told the BBC.

“We hope that with time, our findings might contribute to clinical research for post-operative pain and anxiety, and potentially chronic pain, PTSD and wound healing.”

Credit: Recovery Bootcamp.

Fentanyl is now the deadliest drug in America

Credit: Recovery Bootcamp.

Credit: Recovery Bootcamp.

An opioid that’s several times stronger than heroin is now officially the deadliest drug in the United States, say researchers at the Centers for Disease Control and Prevention (CDC). The same report shows that drug overdoses climbed again last year, contributing to a growing drug epidemic in the country that shows no sign of slowing down in the near future.

Fentanyl is a very powerful synthetic opioid that’s 50 to 100 times more concentrated than morphine. For a user with little tolerance to the drug, even less than a milligram of fentanyl can trigger an overdose. Imagine a few grains of sand — that’s enough to kill you if it’s fentanyl. This makes it incredibly easy for people to overestimate their dosage, getting themselves killed in the process. In most cases, however, people are not aware that they are taking fentanyl as the drug is often cut into other substances to make them stronger.

“It’s very difficult for people to know just how much they are extracting from the patch and injecting. It is already a very powerful opioid and people are injecting it without being able to control how much,” said NDARC’s Director Michael Farrell.

“Like all opioids including heroin, fentanyl is a respiratory depressant – it interferes with the user’s ability to breathe. Because it is so concentrated people can misjudge the dose for themselves to dangerous degree.”

In 2015, more than 52,000 people died of drug overdoses. In 2016, the total rose to more than 63,000 — a jump that was largely driven by fentanyl. According to the latest CDC report on drug use, fentanyl was involved in nearly 29% of those cases, while heroin came in second with 25% and methamphetamine was third at a rate of over 10%. What’s staggering is that in 2011, fentanyl was responsible for only 4% of overdoses. Between 2013 and 2016, overdoses from fentanyl rose 113% a year.

Credit: CDC.

Credit: CDC.

The drug has been around for decades in the form of medicine meant to relieve pain. The main reason why it’s become so popular can be traced down to the rise in opioid painkillers that have been sweeping the nation. As people looked for stronger, cheaper alternatives, fentanyl naturally became popular. This is a drug that’s relatively easy to produce, which provides a cheaper high per dose than heroin.

And as if fentanyl wasn’t scary enough, an analog called carfentanil is also creeping up in the illicit drug market. Carfentanil is normally used as a sedative for large animals such as elephants and can be very dangerous if it enters the body of humans. It’s so dangerous that some countries, the U.S. included, have described it as a ‘chemical weapon’ and have prepared contingency plans in the face of its potential use in war.  

Law enforcement officials believe that most of this fentanyl comes from labs in China, from where it is shipped to South America before making its way to US markets. One of the things that make these drugs so deadly is the fact that very often drug users don’t seek them out, instead buying heroin that turns out to be laced with potent fentanyl or one of its analogs. A user might take a hit of their usual dose, only to end up overdosing because of the added fentanyl. Of course, many times users deliberately take these drugs. Prince, for example, overdosed on fentanyl he was taking as medication.

There’s no clear-cut solution to the rise of fentanyl or synthetic opioids in general. Even cracking down on the supply is not a particularly good solution. If opioid painkiller would magically disappear overnight, people would turn to heroin. If there was no heroin, they’d go for fentanyl, and then to carfentanil, and then to the hundreds of other analogs. Perhaps a solution to the crisis involves tackling demand, not supply, through extensive drug prevention and treatment measures.  

Dog and owner.

FDA says seriously, stop stealing your pets’ opioids

Veterinarians, beware — the Food and Drug Administration (FDA) wants you to keep an eye out for owners taking opioids prescribed to their pets.

Dog and owner.

Image via Pixabay.

The US opioid crisis has been frequently making headlines in recent years, and for good reason: mortality rates associated with opioid abuse are at an alarming high and continue to climb. The half-century-long War on Drugs, despite draining over a trillion dollars, doesn’t seem capable of curbing these deaths.

Over-prescription of opioid medication, caused by misleading advice offered by pharmaceutical companies, has taken most of the blame for the crisis. Government health services responded by issuing a five-point strategy for ‘front line’ members of the medical community, providing support for addiction treatment, advising alternatives to opioids, and promoting research partnerships.

However, the FDA fears it left the back door unwatched. Despite their efforts to mediate legal access to opioid medication, overdose-induced tragedy still takes place; the agency believes that pet prescriptions may be part of the reason why.

Pet addiction

An online statement published last week by the FDA draws attention to a rarely considered access point for illicit opioid medications. FDA Commissioner Scott Gottlieb reminded veterinarians that some pet owners are taking the opioids prescribed for their companions.

“One such important care group is veterinarians who may prescribe them to manage pain in animals,” he says. “That’s why we have developed a new resource containing information and recommendations specifically for veterinarians who stock and administer opioids.”

Gottlieb admits that veterinarians have been left out in the cold on this one. Very little effort has been made to inform them of the risks posed by prescriptions for pets. He also recognizes the role opioids and associated pain medications play in treating both animal and human patients — so they won’t be going anywhere soon.

“But just like the opioid medications used in humans, these drugs have potentially serious risks, not just for the animal patients, but also because of their potential to lead to addiction, abuse and overdose in humans who may divert them for their own use,” Gottlieb adds.

The FDA’s new resource, titled The Opioid Epidemic: What Veterinarians Need to Know, reminds practitioners to follow state and federal regulations when prescribing opioid medication, seek alternatives where possible, educate pet owners, and be vigilant of signs of abuse.

While this is the largest single measure the FDA has taken to combat opioid abuse sourced from veterinarians, it’s not the first such measure in the US. Last year, Maine and Colorado passed legislation requiring veterinarians to check the prescription history of a pet’s owner before prescribing opioids for the animal. Alaska, Connecticut, and Virginia instead chose to set strict prescription limits.

The FDA further hopes that their resource will help put the worries of vets at ease. Speaking to the Washington Post on the topic last year, Kevin Lazarcheff, president of the California Veterinary Medical Association, said that he’s a “veterinarian, not a physician,” so he “shouldn’t have access to a human’s medical history.” The new recommendations don’t require the vets to dig into an owner’s medical history.

“We know that licensed veterinarians share our concerns and are committed to doing their part to ensure the appropriate use of prescription opioids,” says Gottlieb.

“We hope the resources we’re providing today, coupled with the existing guidelines from AVMA, will assist the veterinary medical community about steps they can take when prescription opioids are part of their care plan for their animal patients.”

Marijuana legalization helps decrease opioid consumption, research shows

Every day, 90 Americans die from opioid overdoses, according to existing research. Two new studies published in the journal JAMA Internal Medicine now show that in states where marijuana is legal, opioid prescriptions decreased significantly.

Image credits Flickr / Jeffrey Beall.

Researchers have analyzed prescription data from Medicare Part D and Medicaid from the past five years and discovered that opioid prescriptions and the average daily dose of opioids patients took were significantly lower in areas where marijuana is legal.

“In this time when we are so concerned — rightly so — about opiate misuse and abuse and the mortality that’s occurring, we need to be clear-eyed and use evidence to drive our policies,” said W. David Bradford, an economist at the University of Georgia and an author of one of the studies.

“If you’re interested in giving people options for pain management that don’t bring the particular risks that opiates do, states should contemplate turning on dispensary-based cannabis policies.”

Previous research suggests the same. A 2014 paper discovered that in states where cannabis use is legal for medical purposes, nearly 25 percent fewer deaths from opioid overdoses occurred.

One of the studies revealed that Medicare patients filled 14% fewer opioid prescriptions after medical cannabis use became legal. The other study, which monitored Medicaid opioid prescriptions, found that participants filled nearly 40 fewer opioid prescriptions per 1,000 people (4%) each year after their state passed laws that made cannabis accessible — states that legalized both medical and recreational marijuana showed greater falls in opioid prescriptions.

With the arrival of fentanyl on the black market, doctors fear we’ll see even more cases opioid overdose. This powerful opioid is up to 100 times more potent than morphine. Due to its powerful effect, fentanyl doses are very small, which is actually a problem. Overdoses usually occur when miscalculating the amount of drug administered, and it’s easier to go wrong with smaller doses. When fentanyl became a go-to drug for dealers, opioid deaths immediately spiked due to its high potency at low doses. Basically, people did not know that surpassing the dosage with only a few micrograms might be fatal.

So, the findings seem positive from a public health point of view. Marijuana is generally perceived as ‘safe’, and according to The National Center for Biotechnology Information, there is insufficient evidence to support or refute a statistical association between cannabis use and death due to cannabis overdose — in other words, there’s not enough data to say that cannabis use can or cannot be fatal, which, relative to fentanyl, makes it super-duper safe.

One recent paper even suggested that opioids didn’t provide any more relief for chronic arthritis pain than over-the-counter painkillers.

The studies also discovered differences in decline in opioid prescription between the states that legalized medical marijuana: states with dispensaries open for business saw the greatest decrease in opioid prescriptions, while states without active dispensaries saw a far less dramatic decline — about 14% and 7%, respectively

Bradford said that this made sense. The difference between picking up ready-to-use marijuana and growing your own plant with little support from the authorities is huge.

One impediment in substituting opioids with marijuana is that neither Medicaid nor Medicare will reimburse people for the money they spend on marijuana.

“I did a back-of-the-envelope calculation that suggested that a daily pain management dose of hydrocodone would be about $10 out of pocket in the U.S,” Bradford said, although Medicare Part D plans cover much of that.

Last year, a daily dose of marijuana cost around $6 — and that sum should be smaller by now, Bradford said. “It’s becoming relatively comparable in cost.”

“I know policymakers are often skeptical of cannabis. But we need to be terrified of things like fentanyl, and we need to be willing to use evidence-based approaches to help address that,” Bradford added. “Cannabis looks like it could be one,” he concluded.

Microglia activity makes morphine less effective as a painkiller for women

More active ‘brain immune cells’ in regions involved in pain processing might explain why women aren’t as responsive to painkillers as men, a new paper concludes.

Image credits Wolfgang Claussen

Microglia — the brain’s resident macrophage cells — are tasked with keeping our intelligence-wielding soft bits safe and sound. But they may also make painkillers less efficient in the female brain, a new study has found. The paper shows that when microglia were blocked, female response to opioid pain medication raised to the level of pain relief seen in males.

Statistically speaking, women have a higher incidence of chronic and inflammatory pain conditions such as osteoarthritis. And it doesn’t help that pain medication just seems to work to a less degree for them. Severe chronic pain requires powerful drugs, the most powerful in use being morphine — but it is often reported to be less effective in females, who require larger doses for the same effect.

“Indeed, both clinical and preclinical studies report that females require almost twice as much morphine as males to produce comparable pain relief,” said Hillary Doyle, graduate student in the Murphy Laboratory in the Neuroscience Institute of Georgia State. “Our research team examined a potential explanation for this phenomenon, the sex differences in brain microglia.”

Microglia are the resident brain immune cells. They keep watch in the brain for signs of pathogens or infections to gobble up and keep neurons in pristine working condition. But in female brains, these cells seem to treat morphine molecules as pathogens — since they interfere with normal body function — causing the release of inflammatory chemicals such as cytokines.

Previous studies have linked them with differences in perceived pain levels between the male and female brain, but the full scope of their effect remains unknown. To test their interaction with morphine, the team gave male and female rats a drug that inhibits microglia activation then treated them with the painkiller. Inhibiting the microglia “potentiated morphine antinociception in females such that no sex differences in [resistance] were observed,” the team reports.

“The results of the study have important implications for the treatment of pain, and suggests that microglia may be an important drug target to improve opioid pain relief in women,” said Dr. Anne Murphy, co-author on the study and associate professor in the Neuroscience Institute at Georgia State.

The full paper “Sex Differences in Microglia Activity within the Periaqueductal Gray of the Rat: A Potential Mechanism Driving the Dimorphic Effects of Morphine” has been published in The Journal of Neuroscience.

 

A sea-snail’s venom could rival opioids in pain relief capability

University of Utah researchers have identified a compound that could offer an alternative to opioids. Sourced from the venom of a small marine snail Conus regius, it blocks pain by targeting a non-opioid pathway in the brain.

Image credits James St. John / Flickr.

Opioids are very good at blocking pain, making them invaluable for medical applications. But they’re also very good at being addictive, which is a big problem. The CDC reports that some 91 people die from opioid overdose every day in the US alone and they always come back for more.

An alternative to opioids

So an alternative painkiller, one that doesn’t rely on the same brain structures as opioids but has the same punch, is needed. An alternative that the Conus regius, a small cone snail native to the Caribbean Sea, is poised to offer — this predatory critter’s venom, used to paralyze and kill prey, shows promise as a powerful painkiller.

“Nature has evolved molecules that are extremely sophisticated and can have unexpected applications,” begins Baldomera Olivera, Ph.D., professor in biology at the University of Utah.

“We were interested in using venoms to understand different pathways in the nervous system.”

The paper describes a compound isolated from the snail’s venom, called RglA, which acts through a different pathway than that targeted by opioid drugs. Rat studies have shown that its analog RglA4 can block α9α10 nicotinic acetylcholine pain receptors, effectively shutting down this pain pathway. Not only that, but the effect lasts for a long time, even after the substance has been cleared from the rat’s system (which took about 4 hours.) This would suggest that RglA4 has effects that go beyond numbing the sensation of pain — such as a regenerative effect on the nervous system.

“We found that the compound was still working 72 hours after the injection, still preventing pain,” said J. Michael McIntosh, M.D., professor of psychiatry at the University of Utah Health Sciences.

“What is particularly exciting about these results is the aspect of prevention,” he added. “Once chronic pain has developed, it is difficult to treat. This compound offers a potential new pathway to prevent pain from developing in the first place and offer a new therapy to patients who have run out of options.”

Rodent trials

To check if the substance would work on humans, the team took RglA and created 20 analogs of the compound. In essence, they took the bit that fits into the receptors, and put together slightly different configurations of it to see which one worked best. The analog RgIA4 was the one who bound the strongest to the human receptors.

To see how effective it would be as a painkiller, the team administered RglA4 to rodents who had previously been treated with a chemotherapy drug that induces extreme cold sensitivity and touch hypersensitivity. The team also set up two control groups — one which group was treated but didn’t receive RglA4, and one who was genetically modified to lack α9α10 receptors.

“Interactions that are not normally painful, like sheets rubbing against the body or pants against the leg, becomes painful,” said McIntosh.

The rodents who received RglA4 and the genetically altered control group didn’t show any signs of pain, but the other control group did.

“RgIA4 works by an entirely new pathway, which opens the door for new opportunities to treat pain,” McIntosh added.

“We feel that drugs that work by this pathway may reduce burden of opioid use.”

The full paper “Inhibition of α9α10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain” has been published online in the journal PNAS.

Scientists make new opioid painkiller, without the nasty side effects

Using brute computational power, researchers have developed a new drug that blocks out pain without sharing many of the unwanted side effects painkillers often bring.

Photo by sfxeric, via Flickr.

They started from scratch, using computational techniques to explore more than four trillion different chemical interactions. In the end, the drug seemed to do as good as morphine in terms of killing pain (on mice), while not causing addiction and not impairing breath in any way. More work is needed to confirm that these effects will carry on in humans, but if they do, then it could very well be a game changer.

Morphine itself was a game changer back in the day – and it still is. It allowed us to develop medicine in a way which would have otherwise been impossible, but there’s also a price to pay. Even in small amounts, morphine can be addictive, and especially in large doses it can be life threatening.

“Morphine transformed medicine,” said Brian Shoichet, PhD, a professor of pharmaceutical chemistry in UCSF’s School of Pharmacy and co-senior author on the new paper. “There are so many medical procedures we can do now because we know we can control the pain afterwards. But it’s obviously dangerous too. People have been searching for a safer replacement for standard opioids for decades.”

Several research groups have attempted to develop viable alternatives to morphine. The general approach is to take morphine and try to eliminate the parts of it which have the unwanted effects. This time however, the team went for a much more radical approach – they started everything from scratch.

“We didn’t want to just optimize chemistry that already existed,” Shoichet said. “We wanted to get new chemistry that would confer completely new biology.”

They did this because the very structure of morphine (your starting block) can limit the path you go on. Basically, they wanted to think outside the morphine box:

“With traditional forms of drug discovery, you’re locked into a little chemical box,” Shoichet said. “But when you start with the structure of the receptor you want to target, you can throw all those constraints away. You’re empowered to imagine all sorts of things that you couldn’t even think about before.”

There is still a lot of work that still needs to be carried out, especially on the non-addictive claims. Basically, they haven’t chemically shown that the drug doesn’t cause addiction, even though they did show that mice don’t actively seek out the drug, which would imply a lack of addiction.

As it so often happens in recent times, the work is a result of an intensive cross-disciplinary collaboration.

“This promising drug candidate was identified through an intensively cross-disciplinary, cross-continental combination of computer-based drug screening, medicinal chemistry, intuition and extensive preclinical testing,” said co-senior author and 2012 Nobel laureate Brian Kobilka, MD, a professor of molecular and cellular physiology at the Stanford University School of Medicine.

“If you took away any one of these collaborators it simply wouldn’t have worked,” Shoichet added.

Journal Reference: Structure-based discovery of opioid analgesics with reduced side effects. Nature, 2016; 1 DOI:10.1038/nature19112

ibuprofen patch

This is an ibuprofen patch that relieves pain 12 hours straight

Researchers at the University of Warwick in the UK, in collaboration with drug delivery research firm Medherant, devised the first ever ibuprofen patch.

ibuprofen patch

Its made out of a polymer matrix which allows the painkiller to be steadily diffused in the body of the patient over the course of 12 hours. During whole time the seemingly flimsy patch can prevent pain since its made out of 30% ibuprofen by weight.

“Many commercial patches surprisingly don’t contain any pain relief agents at all, they simply soothe the body by a warming effect. Our technology now means that we can for the first time produce patches that contain effective doses of active ingredients such as ibuprofen for which no patches currently exist. Also, we can improve the drug loading and stickiness of patches containing other active ingredients to improve patient comfort and outcome,” said University of Warwick research chemist Professor David Haddleton.

“Our success in developing this breakthrough patch design isn’t limited to ibuprofen; we have also had great results testing the patch with methyl salicylate (used in liniments, gels and some leading commercial patches). We believe that many other over the counter and prescription drugs can exploit our technology and we are seeking opportunities to test a much wider range of drugs and treatments within our patch.”

Centipede venom could hold the secret of the perfect painkiller

Chinese researchers discovered a chemical compound that works just as well as morphine — without any of the negative side effects. The substance is derived from the venom of a centipede native to China. The discovery has huge medical applications, and could potentially reduce the country’s military reliance on morphine for battlefield use.

Wrong kind of painkiller.
Image via lparchive

It’s a bit funny to be looking for painkillers in venom, isn’t it? The centipede’s secretions usually cause burning pain and swelling in the bite area without being life-threatening — but one particular chemical compound found in the venom explains Lai’s efforts. His team isolated the compound called RhTx from a complex toxin in the Chinese red-headed centipede’s chemical weapon, which has the handy ability to switch the sensation of pain on and, more usefully, off. Lai hopes to develop a painkiller based on RhTx that can be used for long-term treatments and does not compromise the user’s health.

“It is completely different from morphine,” said Professor Lai Ren who works with the Chinese Academy of Sciences’ Kunming Institute of Zoology in southern Yunnan province, and lead scientist of the study. “Morphine is only intended for emergency use. It has many side effects and can lead to addiction over the longer-term.”

Morphine has been in use by armed forces since the start of World War one, and is still the most powerful pain-relieving drug that field medics can turn to, but it’s not a miracle drug. Morphine works by depressing the central nervous system — that’s why it’s named after Morpheus, the Greek god of dreams, as it tends to cause sleepiness — and can wreak havoc on patients’ breathing and blood pressure, often to lethal effect. Another issue the drug has is that it’s addictive, big time: Being an opium derivative, it induces feelings of calm and euphoria as it interacts with our central nervous system, and most countries label it as a dangerous drug and impose drastic measures for its usage, even in medicine.

One of the early bottles in which morphine was sold in pharmacies.
Image via pinterest

However, for all its faults, its importance as a painkiller cannot be overstated. From cancer patients to combat veterans, morphine was the only thing making life livable — some veterans with combat injuries that lead to chronic pain even resorted to taking their own lives, reports show. Lai’s team search for an alternative to painkillers such as morphine or codeine lead them to the centipede’s venom, on the logic that if a chemical can activate pain receptors, we could learn to reverse the process and get the opposite effect.

Their work lead them to centipedes. Some of the earliest known fossils date back to nearly 460 million years ago, twice as old as some dinosaurs. Pretty impressive for such small critters, and Lai suspected that the venom some species of centipede produce helped them survive through the eons. So they looked for the most aggressive, most venomous centipede they knew of, the Chinese red head, averaging in at 20 centimeters when fully grown.

“[Their bite causes] extremely sharp pain … has an instant onset and lasts from half an hour up to two to three days,” reported the research team in their paper, which was published recently in the journal Nature Communications.

It took them years of research to sift through the list of exotic chemical compounds in the critter’s venom and identify the pain related compound, RhTx. Using several observational methods, such as n-MRI and fluorescence imaging, Lai’s team found that RhTx causes a false pain alert on the victim’s central nervous system by binding to TRPV1, a heat-sensing proteins common in animals and humans.

The RhTx was able to dupe the so-called sentry protein into believing that the external temperature had suddenly shot up above its true reading, thus causing feelings of pain similar to being scalded in boiling water. But if the same compound was programmed to work in the opposite direction, the test animal could be persuaded to swim in boiling water without realizing the damage it was subjecting itself to, the team said.

The Chinese researchers said their study “opens the door for the molecular modification” of the centipede venom to reverse its effect from pain generator to painkiller.

“But there are still long roads ahead,” said Lai. “Pain is a very complex scientific issue, with lots of questions remaining about its underlying mechanisms,” he said.

“It is still too early to say whether the centipede toxin will replace morphine and become the ultimate painkiller,” Lai concluded.

Painkiller abuse

Prescription painkillers cause 67.8% of opioid overdoses. Heroin a distant second at 16.1%

An American national study that looked at hospital emergency department visits for opioid overdoses found that 67.8% of the cases involved overdosing on prescription opioid drugs, including methadone. Next in line were heroin, other unspecified opioids and multiple opioids. It’s estimated that the treatment costs for the hospitalized overdosed patients in 2010 alone was $2.3 billion.

Prescription drugs cause four times more opioid overdoses than heroin

Painkiller abuse

Credit: Corner Stone Recovery Center

Recreational use of prescription drugs is a serious problem with teens and young adults. National studies show that a teen is more likely to have abused a prescription drug than an illegal street drug. Actually, according to the  National Institute on Drug Abuse an estimated 48 million people (aged 12 and older) have used prescription drugs for nonmedical reasons in their lifetime or roughly 20% of the US population. The three most commonly abused prescription drug classes are:

  • Opioids used to treat pain
  • Central nervous system (CNS) depressants, such as benzodiazepines (Xanax, Valium, Ativan, Klonopin), used to treat anxiety and sleep disorders
  • Stimulants, such as Adderall or Ritalin, used to treat attention deficit disorder and narcolepsy (a sleep disorder)

illicitdruguse12th_0

A recent study made by researchers at Stanford University School of Medicine yet again highlights these disheartening statistics after it found an overwhelming majority of patients hospitalized for opioid overdoses used legally prescribed drugs. The researchers crunched the numbers from the 2010 Nationwide Emergency Department Sample and identified 135,971 weighted ED visits that were coded for opioid overdose. Of these 67.8 percent involved prescription opioids, followed by 16.1 percent heroin overdoses, while  unspecified opioids and and multiple opioid types accounted for 13.4 percent and 2.7 percent of overdoses, respectively. The greatest proportion of prescription opioid overdoses happened in urban areas (84.1 percent), in the South (40.2 percent) and among women (53 percent).

[NOW READ] Painkiller addiction is the worst drug epidemic in US history

About 1.4 percent of patients who arrived in the ED eventually died of overdose and the authors suggest hospitals should ramp up their overdose emergency services. About half of the patients in the study sample who went to the ED for opioid overdoses were admitted to the hospital and costs for both inpatient and ED care totaled nearly $2.3 billion, according to the study published in JAMA Internal Medicine.

[INTERESTING] How a girl that doesn’t feel any pain might help create the painkillers of tomorrow

I think it’s important to get one thing straight, though. Some readers might get the impression after reading this article that prescription drugs are more dangerous than heroin, which is true in absolute numbers, but far from being true when accounting proportions. It’s estimated 0.2% of Americans use heroin, so  heroin’s contribution to ER visits heavily outweighs painkillers.

“Opioid overdose exacts a significant financial and health care utilization burden on the U.S. health care system. Most patients in our sample overdosed on prescription opioids, suggesting that further efforts to stem the prescription opioid overdose epidemic are urgently needed,” the study concludes.

 

An analgesic molecule discovered in its natural state in Africa

Nauclea latifolia (also know as the pin cushion tree) is a small shrub, relatively common, used in traditional medicine throughout the sub-Saharan regions. Of course, African traditional medicine is not often your first choice when it comes to a treatment, but what if I told you that this plant produces large quantities of molecules – identical to those found in one of the most popular analgesics – Tramadol ?

Fotolia_50050157_S-466x657

A team of researchers led by Michel De Waard, Inserm Research Director at the Grenoble Institute of Neurosciences studied the plant and showed that the molecules are identical to Tramadol, a wholly synthetic medication that is used world-wide as a painkiller. This is the first time ever that a synthetic drug chemically produced by the pharmaceutical industry has been found in significant concentrations in nature. Tramadol is used to treat different disorders, including epilepsy, fevers, malaria, insomnia, or simply pain.

The plant was used more or less for the same things in the area, especially in Cameroon. Without even suspecting what they would find, researchers set out to isolate the analgesic compounds in the plant’s bark, and much to their surprise, they found that this component was already commercially available.

Credit: The structure of Tramadol, compared to morphine.

Credit: The structure of Tramadol, compared to morphine.

“It was identical to Tramadol, a synthetic medication developed in the seventies and often used to treat pain”, explained Michel De Waard, Inserm research director. “This medication is used world-wide, because although it is a derivative of morphine, it has less side effects than morphine, in particular addiction problems.”

In order to confirm their results and eliminate any possible error, scientists then set out to test it in a lab environment – their results were confirmed by 3 independent laboratories.

“All results converge and confirm the presence of Tramadol in the root bark of Nauclea latifolia. On the other hand, no trace of this molecule was detected in the aerial part of the shrub (leaves, trunk or branches)“, explained the researcher.

Finally, to eliminate any other risk of possible outside contamination with the drug, they also analyzed the plant’s roots, thus confirming what was already clear. Dried bark extracts contain between 0.4% and 3.9% Tramadol – extremely high levels of the substance.

This research opens up a big door for potentially cheap (or even free) treatment, while also validating the concepts of traditional medicines (as decoctions made from barks and roots).

 

Via Inserm.

Ashlyn Blocker, the teenager that can't feel pain. (c) Justin Heckert

How a girl that doesn’t feel pain at all might help create the painkillers of tomorrow

Some people are born with the innate ability, or better said disability, of not feeling pain – whatsoever. It’s not that they can’t feel anything, quite on the contrary – they still have a sense of texture, they feel pressure, they can feel a hug or handshake just like anyone, they experience warmth or coldness and so on – it’s just that any sensation that passes a certain threshold, effectively becoming pain, isn’t registered with these people.

That’s really weird, right? For a bit of insight into what’s it like living without physical pain, I’d recommend you read this NY Times piece on Ashlyn Blocker, a normal looking teenager from a small town called Patterson, GA  who at first glace isn’t significantly different from any other kid her age. In the article, however, you’ll find out how she never cried as a baby, how she first burned her hand when she was only two years old or how later on in her teens she constantly bruised herself and had broken bones.

“The girl who feels no pain was in the kitchen, stirring ramen noodles, when the spoon slipped from her hand and dropped into the pot of boiling water. It was a school night; the TV was on in the living room, and her mother was folding clothes on the couch. Without thinking, Ashlyn Blocker reached her right hand in to retrieve the spoon, then took her hand out of the water and stood looking at it under the oven light. She walked a few steps to the sink and ran cold water over all her faded white scars, then called to her mother, “I just put my fingers in!” Her mother, Tara Blocker, dropped the clothes and rushed to her daughter’s side. “Oh, my lord!” she said — after 13 years, that same old fear — and then she got some ice and gently pressed it against her daughter’s hand, relieved that the burn wasn’t worse.” excerpt from the NY Times article.

Pain, like all sensations we experience, is there for a purpose. It’s there to  protect us, to warn us if we’ve strayed too far, it lets us know that we’re in danger and we need help, and best of all it tells us that we need to stop whatever it is we’re doing that causes the pain. Some people, however, are on the other side of fence. There are millions of people in the world suffering from diseases that induce chronic, unbearable pain. Some of these people need to live with an acute sensation of pain for the rest of their lives, and most of the time painkillers don’t cut it or induce side effects that turns the patient into an emotional train wreck (see painkiller epidemic in America).

X-men – Subject 1 – mutation: “can feel no pain”

A team of European researchers recently analyzed the genome of an anonymous girl or woman from Germany, dubbed “Index Subject 1”, that in most respect is just like Ashlyn – she can’t feel any pain. Photos published in a paper about her show severe injuries to her head, face and knee, the latter of which she has fractured multiple times. After comparing her genome with several human genome databases, such as “1,000 Genomes,” which includes all the genes of 1,092 people from 14 populations, the researchers identified a specific gene mutation in Index Subject 1 that couldn’t be found in  in any of the human genome databases they scoured.

This almost unique mutation (the researchers have since found a male also carrying it Index Subject 2 – to no surprise, the man can’t also feel pain)  affected a gene called SCN11A  that  makes a protein that controls how much sodium goes in and out of cells in the human body. Sodium channels are indispensable for relaying information back and forth nerve endings in the body, and apparently the  particular type of sodium channel that was mutated in Index Subject 1 is abundant in nociceptors, the types of nerves that sense pain. The pieces of puzzles seem to fit nicely, however intuitive how this may all seem, the scientists still had to test this assumption.

They introduced the mutated gene into 101 lab mice. Of these, 11  gave themselves self-inflicting wounds suggesting that they couldn’t feel the pain. Also, to be sure, the researchers injected the mice with a chemical that caused their paws to swell up. The mice which underwent the successful mutation didn’t try to protect the swollen paw like the other, normal mice did. When subjected to high temperature, the mutated mice showed no sign of discomfort, again compared to normal mice. Also, as another important indicator, mutated mice bowels didn’t move as well as normal mice – digestive issues, sometimes severe, are common among people who can’t experience pain.

The findings published in Nature are nothing short of remarkable, hinting that indeed this single gene mutation is what causes some people, like Ashlyn, to live in world without physical pain. By better understanding the sodium channel mechanics, it’s foreseeable that one day researchers might be able to craft painkillers that exploit the symptoms of Index Subject 1, but with temporary effects. Remember, pain is good.

Painkiller addictions are the worst drug epidemic in US history

Fatal overdoses due to painkillers have reached epidemic levels, greatly exceeding those from heroin and cocaine combined, becoming the worst drug epidemic in US history.

Painkiller_1475416c

Prescriptions for painkillers in the United States have nearly tripled in the past two decades, and the results are dreadful. In 2012, enough painkillers were prescribed to keep every single citizen medicated around the clock for a month – or once every 12 days for an entire year.

Dr. Andrew Kolodny, president of Physicians for Responsible Opioid Prescribing talked of a painkiller addiction epidemic:

“According to the CDC, this is the worst drug epidemic in U.S. history,” he said. “CDC has data demonstrating that around the same time doctors began aggressively prescribing these medications in the late 1990s, there have been parallel increases in rates of addiction.”

Even worse, he adds, the Food and Drug Administration (FDA), Kolodny said, is “failing miserably” at fighting against the epidemic:

“The way to turn this epidemic around is for doctors to prescribe painkillers more cautiously,” he said. But that can only happen, Kolodny said, when the FDA changes labeling requirements for painkillers, “making it easier for medical schools and the larger medical community to prescribe these meds more cautiously.”

Meanwhile, the US is loading its guns and going harder and harder against “illegal drugs” – again, even while mortality associated with painkillers alone tops that of heroin and cocaine combined, authorities seem to ignore this issue. The so-called “war on drugs” stigmatizes psychological addiction, but at the same time, it encourages the consumption of “prescription drugs”. The study, which was published in The Lancet examined four categories of illegal drugs – opioids (which include painkillers and heroin), cocaine, amphetamines and cannabis (on which interestingly enough, you can’t overdose, even though it’s illegal).

Research paper here.

Powerful new painkiller with no side effects could be just one year away

Unfortunately, pretty much every human being with access to medical care has taken some sort of painkillers at some point – unfortunately because of the reason; but painkillers don’t make the pain signal go away. What happens is the signal still goes to the brain, but the opiates such as morphine alter the way the brain “understands” it, and as a side effect, also alter the patient’s judgement, and also can lead to addiction. However, this new type of painkiller that is being developed by researchers from the Stony Brook University works in a totally different way, and so far, it showed absolutely no side effects or addictive qualities.

This offers a major paradigm shift in the control of pain,” declares Dr. Simon Halegoua, Professor of Neurobiology & Behavior at Stony Brook

During the 1990s, the professor teamed up with Dr. Gail Mandel and Dr. Paul Brehm to identify a novel sodium ion channel involved in the transmission of pain. Basically, they were trying to find the “wire” that transmits the pain signal to the brain and find a way to “cut” it.

“When a patient is given an opiate like morphine, pain signals are still transmitted from sensory nerves to the central nervous system. Morphine action throughout the brain reduces and alters pain perception, but it also impairs judgement and results in drug dependence,” explains Halegoua, also director of the Center for Nervous System Disorders at Stony Brook University. “With drugs targeting the PN1/Nav1.7 sodium ion channel, the pain signals would not be transmitted, even by the sensory nerves. And since the central nervous system is taken out of the equation, there would be no side effects and no addictive qualities.”

Of course the benefits for such a painkiller would be absolutely huge, bringing the elimination of pain to people suffering from a number of diseases, from cancer or arthritis, to migraines or burns. It is still yet in clinical trials, but the odds are in just a year or two, it will hit the market – it will be interesting to see what pharmaceutical companies will do with other painkillers when this one comes out.
Picture source