In a bid to tackle the global opioid crisis, researchers have found that a Chinese medicinal plant extract can prevent morphine tolerance and dependence while also reversing opiate addiction. The researchers published their results in Pharmaceuticals.
For over two decades, opioid analgesic overprescription has driven a wave of misuse and consequent drive overdose deaths around the world, with the number of drug overdose deaths tripling in the US from 1997 to 2017. The COVID pandemic has only worsened the opioid epidemic. Fortunately, the documented effects of YHS, the extract of the plant Corydalis yanhusuo, could help curb the opioid epidemic.
“It is critical that we decrease the use and abuse of opiates,” said Olivier Civelli, PhD, professor of pharmaceutical sciences at the UCI School of Pharmacy & Pharmaceutical Sciences and corresponding author. “To help achieve this goal, we are proposing the use of this therapeutic plant. When used in animals, the Corydalis extract prevents pain and the negative effects of opiate use. The next step would be to test it with humans.”
The overprescription of opioid analgesics stemmed from treatment of chronic pain requiring repeated opioid administrations. This ultimately leads to tolerance, physical dependence, and addiction.
One possible solution involves a co-medication that maintains the analgesic benefits of opioids while preventing their adverse liabilities. The study showed that YHS, when co-administered with morphine, inhibits morphine tolerance, dependence and addiction.
In Chinese traditional medicine, YHS has been used as an analgesic for centuries. It is considered safe and readily available for purchase. “Opiate tolerance is of utmost importance to opiate users,” ProfvCivelli said. “They need to constantly increase the need of opiates to reach the same analgesic response. This is what leads to opiate overdose. YHS prevents opiate tolerance, so there is less need to increase opiate consumption.”
More than a fifth of ‘opioid-naïve’ patients continue to use opioids three months after having a procedure, underscoring the often-overlooked role surgery plays in the opioid epidemic.
In research presented at the ANESTHESIOLOGY® 2021 annual meeting, smokers and people with bipolar disorder, depression or pulmonary hypertension were found to be at highest risk.
Persistent opioid use was much higher than expected among opioid-naïve patients (those who did not have an opioid prescription filled in the previous year). Surgery is the first time many patients have used opioids, often prescribed for post-surgical pain management.
The study examined data on 13 970 opioid-naïve adults from 2013-2019. In the study, opioid-naïve patients were those who had not filled an opioid prescription 31 days to one year before surgery (patients often are prescribed opioids in advance so they are available immediately after the surgery). Researchers found that 21.2% of patients refilled their opioid prescription three months to one year after the procedure. Unless they have cancer or had chronic pain before surgery, very few patients should still need opioids three months after surgery, the researchers note.
Analysing 46 potential risk factors, researchers found many patients were still using opioids after three months. The top four risk-factors identified, which were modifiable, were: smoking, bipolar disorder, depression and pulmonary hypertension. They also found that procedures with cardiac and podiatry surgical providers and patients who had cataract surgery were at an increased risk of persistent opioid use.
“To reduce the likelihood of ongoing opioid use, physician anesthesiologists should use the preoperative assessment to identify patients at highest risk for persistent use,” said lead author Gia Pittet, AuD, PhD, visiting graduate researcher for anesthesiology and perioperative medicine at the University of California, Los Angeles. “Before they have surgery, patients who smoke should be encouraged to quit, those with pulmonary hypertension should see a doctor to help them get the condition under control and patients with bipolar disorder or depression may require a preoperative adjustment of their medications.”
Patients should also receive counseling about the safe use of opioids and be offered alternative pain management, such as limited or non-opioid multimodal treatment and be monitored frequently and closely while they are taking opioids.
Vitamin D deficiency enhances the craving for and effects of opioids, potentially worsening addiction risk, according to a new study.
These findings by researchers at Massachusetts General Hospital (MGH), published in Science Advances, suggest that the opioid crisis could partly be addressed by treating the common problem of vitamin D deficiency with inexpensive supplements.
In 2007, David E. Fisher, MD, PhD, director of the Mass General Cancer Center’s Melanoma Program and director of MGH’s Cutaneous Biology Research Center (CBRC) and his team found something unexpected: UVB ray exposure causes the skin to produce endorphin, which is chemically related to morphine, heroin and other opioids, which all activate the same receptors in the brain. Further research found that UV exposure raises endorphin levels in mice, which then display behaviour consistent with opioid addiction.
Endorphin induces a sense of mild euphoria. Research has suggested that some people develop urges to sunbathe and visit tanning salons that mirror the behaviours of opioid addicts. Dr Fisher and colleagues speculated that people may seek out UVB for the endorphin rush. But that suggests a major contradiction. “Why would we evolve to be behaviourally drawn towards the most common carcinogen that exists?” asked Dr Fisher.
Dr Fisher believes that the only explanation for why humans and other animals seek out the sun is that UV radiation exposure is necessary for production of vitamin D. One of vitamin D’s functions is promoting the uptake of calcium, essential for building bone. As humans migrated north during prehistoric times, they must have developed some kind of compulsion to venture outside of caves and on dark days, otherwise the vitamin D level would have debilitated them, especially the children.
This theory led Fisher and colleagues to hypothesise that sun seeking is driven by counteracting vitamin D deficiency for survival, and that vitamin D deficiency might also make the body more sensitive to the effects of opioids, potentially contributing to addiction. “Our goal in this study was to understand the relationship between vitamin D signaling in the body and UV-seeking and opioid-seeking behaviors,” says lead author Lajos V. Kemény, MD, PhD, a postdoctoral research fellow in Dermatology at MGH.
The researchers addressed the question from dual perspectives. One study arm compared normal laboratory mice with mice that were deficient in vitamin D (either through special breeding or by removing vitamin D from their diets). “We found that modulating vitamin D levels changes multiple addictive behaviours to both UV and opioids,” said Kemény. Importantly, when the mice were conditioned with modest doses of morphine, the vitamin D deficient mice continued seeking out the drug, more than the normal mice. Mice with low vitamin D levels were far more likely to develop morphine withdrawal symptoms.
The study also found that morphine relieved pain more effectively in mice with vitamin D deficiency – an exaggerated opioid response in these mice, and possibly concerning if it’s also true in humans, said Dr Fisher. For example, a surgery patient receiving morphine for pain control after the operation, and if they are deficient in vitamin D, the euphoric effects of morphine could be exaggerated, said Dr Fisher, “and that person is more likely to become addicted.”
This data suggesting vitamin D deficiency increases addictive behaviour was bolstered by analyses of human health records. One showed that, compared to those with normal levels, patients with modestly low vitamin D levels were 50 per cent more likely to use opioids, while patients who had severe vitamin D deficiency were 90 percent more likely. Another analysis found that patients with opioid use disorder (OUD) were more likely to be deficient in vitamin D.
Back in the lab, one of the study’s other critical findings could have significant implications, said Dr Fisher. “When we corrected vitamin D levels in the deficient mice, their opioid responses reversed and returned to normal,” he says. In humans, vitamin D deficiency is widespread, but is safely and easily treated with low-cost dietary supplements, notes Fisher. While more research is needed, he believes that treating vitamin D deficiency may be a new way to reduce the risk for OUD and bolster existing treatments for the disorder. “Our results suggest that we may have an opportunity in the public health arena to influence the opioid epidemic,” says Fisher.
For Kevin Lamb, MD, the opioid crisis became real to him in 2009.
Once, he said, he had spoken at a leadership forum on opioid abuse, about the role of hospital systems in addressing it. Thinking over what to say, he “realized there was very little I could add. The crisis is epidemic, and hospitals are ill-prepared to do anything proactive. It is that overwhelming.” But leading medical missions made him realise that the rest of the world has overwhelming needs too, which only become real once they are experienced firsthand.
Since transparency is so important, he decided to share his own story.
“This is my story of how close I came to going down that perilous path that is opioid addiction (or any addiction for that matter). I was fortunate that I stopped before I went too far down that path. Unfortunately, too many are unable to stop and continue the downward spiral toward that deep, dark pit called despair and its brother hopelessness. If this could happen to me, it could happen to anyone. If my story prevents even one of you from experiencing this, then the trepidation I feel sharing this will be worth it.”
His story began following his first back surgery in 2009 for an acutely herniated disc that occurred while leading a medical mission in Eastern Europe, which he said was the worst pain he had ever experienced, leaving him with a weak, numb right leg. Having to be carried to bed, living in very basic conditions, with no running water and power interruptions, he feared his condition would force him to be evacuated, although he was able to regain neurologic function for a short while, finishing the mission.
He went in for surgery two days after getting home. He received Oxycontin with a refill, which at the time was common practice, and it eased the pain and had a calming effect, he said. Before the trip, he had experienced a lot of stress, and now being on medical leave he enjoyed the feeling of relief that it gave.
However, as the pills started to run out, he felt embarrassed at the thought of having to request a refill, at being thought of as an addict. But after he used the last pill, withdrawal symptoms kicked in — restlessness, abdominal cramping, diarrhea. “Though relatively mild, it frightened me. I never imagined I could become physically and mentally dependent. I thought this only happened to people who were ‘weak’ or lacked ‘self-discipline’. I was wrong,” he recalled.
He said that besides “scary and humbling”, it was also “surreal… “If it could happen to me, it could happen to anyone!” he warned. The reality is that many in the medical profession are at risk, the pressures of the profession can mean that substance abuse is an easy escape with devastating consequences.
He concluded, hoping that by sharing his story he could make a difference. “My fervent desire is that it will make this crisis more personal and thus more real to you. Only then can you better know the enemy you face and how best to defeat it.”
In order to improve transparency about the opioid crisis, the University of California San Francisco and Johns Hopkins University launched a digital public archive of documents from lawsuits against drug manufacturers.
The digital repository of publicly disclosed legal documents related to the crisis allows free, public access to anyone interested in the continuing litigation and uncovered evidence.
“All too often, the public never gets the benefit of seeing and learning from litigation that generally takes place behind closed doors,” said Caleb Alexander, MD, a professor of epidemiology and medicine at Johns Hopkins and the founding co-director of the Center for Drug Safety and Effectiveness, which will assist in maintaining the archive.
“Our focus is to be sure that the millions of pages of documents arising from opioid litigation ultimately see the light of day,” Alexander told MedPage Today. “We owe it to all those who have been impacted — especially patients and their loved ones — to see to it that these materials are placed in the public domain.”
The goal of the archive is to provide transparency into the methods used by drug companies to increase opioid sales, which led to the opioid epidemic in which, according to the CDC, over the past two decades, nearly 500 000 Americans died of overdoses involving an opioid. Additionally, the economic cost of the crisis in 2015-2018 was put at $2.5 trillion by the White House Council of Economic Advisers.
Most of the archive’s documents were released thanks to efforts by the Washington Post and the Charleston Gazette. Records include company emails, memos, presentations, sales reports, audit reports, budgets, Drug Enforcement Administration briefings, expert witness reports, and depositions of drug company executives.
The archive is located on a website called Drug Industry Archives, a UCSF project that houses documents illustrating how the pharmaceutical industry, academic institutions, continuing medical education organizers and regulatory agencies impact public health. (UCSF also maintains similar archives related to tobacco, food, chemicals, and fossil fuel industries.)
The Opioid Industry Documents Archive presently holds over 3300 legal documents, much of it coming from litigation in Kentucky and Oklahoma, as well as documents from the Insys investigation, which sold an oral fentanyl spray called Subsys. This archive’s launch coincides with the university hosting over 250 000 documents produced during Insys’ bankruptcy proceedings that resulted from successful lawsuits and criminal prosecutions.
“We don’t really know what’s in these documents yet, but there is a wealth of information,” said Kate Tasker, an associate librarian at UCSF who helps manage the archive. “Our number one goal is to make this information accessible and useful.”
Alexander said the opioid crisis was “an epidemic of catastrophic public health proportions.” He said that placing legal documents in the public domain is a crucial step to ensure that lessons are learned from the crisis.
“The primary goal is to ensure that history never repeats itself,” Alexander said. “And we can’t learn from past mistakes without understanding what those mistakes have been.”