Tag: opioids

Fentanyl Induces Autism-like Behaviours in Young Mice

Mouse
Photo by Kanasi on Unsplash

Fentanyl is one of the most commonly used analgesics in the hospital and, in rodents, may have lasting sensorimotor and behavioural impacts. A study published in the British Journal of Anaesthesia has shown that fentanyl can induce changes similar to autism-like behaviours in young mice.

Fentanyl, a mu-opioid receptor agonist, is a potent synthetic opioid, which, similar to morphine, produces analgesia but is 50 to 100 times more potent. A dose of only 100 micrograms can produce equivalent analgesia to approximately 10mg of morphine. However, fentanyl exhibits vastly different properties and pharmacokinetics. Clinically, its most common use is as a sedative in intubated patients and severe cases of pain in patients with renal failure due to its primarily hepatic elimination. Fentanyl’s side effects are similar to those of heroin.

However, whether the use of fentanyl is associated with the development of autism is not known. An animal study led by investigators at Massachusetts General Hospital (MGH), Shanghai 10th People’s Hospital, and the University of Pennsylvania e. The findings are

Research by other groups has shown that N-methyl-D-aspartate receptor dysfunction contributes to autism. Variations in Grin2a and Grin2b, the genes encoding GluN2A and GluN2B subunits of N-methyl-D-aspartate receptor, are associated with autism. In addition, the anterior cingulate cortex of the brain is affected in autism.

In this current study, the research team reported that fentanyl induces autism-like behaviors in young male and female mice via activating the mu-opioid receptor in the anterior cingulate cortex. Further, these fentanyl-induced autism-like behaviors appear partially due to the hypermethylation-mediated reduction of Grin2b expression in the anterior cingulate cortex of mice.

“Because the anterior cingulate cortex is a hub for mediating social information, we focused on the expression of Grin2b in that area,” says Yuan Shen, MD, PhD, the paper’s senior author and a professor of Psychiatry at Shanghai 10th People’s Hospital. “We found fentanyl decreased expression of Grin2b in the anterior cingulate cortex. The overexpression of Grin2b prevents fentanyl-induced autism-like behavior in the mice. These findings suggest a potential mechanism to prevent or treat the autism-like behavior,” says Shen.

The group used an open field test (in which a mouse can walk inside a box) and an elevated plus-maze (in which a mouse can walk on an elevated platform) to observe the anxiety and stereotyped behaviours of mice. Using a three-chamber social preference test (where a mouse can interact with another mouse), they also assessed potential social deficits. “We used these tests because impaired social interaction, stereotyped behaviours, and anxiety are the key feature of autism-like behaviours in mice,” said Zhihao Sheng, co-first author of the paper. Sheng is a graduate student at Shanghai 10th People’s Hospital.

“However, the changes of mice in these behavioral tests do not equal autism in humans. These behavioral tests are only used to study the autism-like behaviors in mice because they can demonstrate certain features of behavior changes similar to the manifestation of autism,” said co-first author Qidong Liu, PhD, assistant professor at Shanghai 10th People’s Hospital.

Co-senior author Zhongcong Xie, MD, PhD, added: “There is no current evidence that fentanyl is associated with a similar effect in humans and the outcome of the animal study is not an indication to avoid fentanyl in clinical anesthesia. However, the outcome will promote further research, including clinical investigations, to determine the potential neurobehavioral influence of opioids on brain development.” 

Opioid Misuse in Young Sarcoma Patients

Depression, young man
Source: Andrew Neel on Unsplash

Nearly a quarter of young patients prescribed opioids while being treated for sarcoma continue to use opioids after treatment is completed according to findings published in CANCER, highlighting the need for safe deprescribing.

Individuals with sarcoma, a type of cancer in the bones or soft tissues, often develop damaged and fractured bones and undergo major surgical operations, and physicians may prescribe opioids for pain management. It was not clear whether doing so raises the risk for opioid misuse and overdose in these young patients. 

Melissa Beauchemin, PhD, RN, CPNP-PC, CPON, of Columbia University School of Nursing, and her colleagues sought to determine the rate of new persistent opioid use among adolescents and young adults treated for sarcoma. Persistent opioid use was defined as at least two opioid prescriptions in the 12 months after treatment was completed.  

The team drew from a large insurance claims database to analyse information on patients aged 10–26 years old who had not received prior opioids and who were diagnosed with sarcoma between 2008 and 2016.  

Among the 938 patients in the analysis, 64% received opioid prescriptions during treatment. After completing cancer therapy, 14% of patients overall and 23% of those who used opioids during treatment continued to use opioids and met the criteria for new persistent use. Being covered by Medicaid versus commercial insurance, having bone tumours versus soft tissue tumours, and receiving concurrent lorazepam (often prescribe to treat anxiety and sleeping problems) were associated with persistent opioid use. 

“Adolescents and young adults are a vulnerable population because they have benefitted less than younger and older cancer patients from recent advances. These results highlight the need to monitor young patients with sarcoma for posttreatment opioid use, given the potential negative impacts of long-term opioid use, including misuse and overdose,” said Dr Beauchemin. “Age- and developmentally appropriate strategies to effectively manage pain while minimising opioid exposure are urgently needed.” 

Dr Beauchemin stressed that for young people needing opioids for effective pain management, early and safe discontinuation of opioids should be prioritised. “Further, there is a critical need for clinical practice guidelines to support clinical decision making to safely and effectively manage pain specifically for adolescents and young adults with cancer,” she said. 

Source: Wiley

Carrying Naloxone in EDs Could Save Lives

Source: Mat Napo on Unsplash

In a study published in JAMA Network Open, researchers found that after a visit to the ED, many opioid overdose patients carried naloxone, which helps reverse opioid overdoses, which could save their lives in the event of a future overdose.

About 70% of current overdose deaths in the US involve opioids, which means that many of them could be prevented with naloxone. Naloxone is an opioid antagonist, blocking the effect of opioids in overdoses and able to save lives when used in time. It is easy to carry and use, and studies have demonstrated that laypeople can administer it safely and effectively to reverse overdoses.

However the people most likely to witness an overdose, including opioid users and their friends and relatives, may not be able to easily obtain naloxone. Strategies are needed to increase uptake, carrying, and administration of naloxone, especially among at-risk individuals in the community who may not be engaged in routine health care or with community naloxone distribution efforts.

Many at-risk individuals find themselves in the emergency departments (ED), either because of an overdose or other complications of substance use. The Perelman School of Medicine’s Anish Agarwal, an assistant professor of emergency medicine, and Margaret Lowenstein, an assistant professor of medicine, recently examined the potential for ED visits as a critical, reachable moment to engage high-risk individuals in overdose prevention. The team reached out to at-risk patients prescribed naloxone in the ED to understand whether they had obtained their naloxone during or after their ED visit, whether they were carrying it, and their plans to carry it in the future.

The survey asked patients about their experiences and perceptions following the ED encounter related to accessing, using, and carrying naloxone. Most of the patients did not carry naloxone prior to their ED, yet over a third reported having a personal history of an overdose requiring naloxone, and more than a quarter had used naloxone to reverse an overdose for another person in the past. Approximately half of the patients said that they were carrying naloxone after their ED visit, and two-thirds planned to continue carrying. And of patients not carrying naloxone prior to their ED visit, 54% reported a plan to continue carrying it in the future.

Source: University of Pennsylvania

Fall in Paediatric Post-surgical Opioid Prescriptions

Children
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A large study has shown that opioid prescriptions for children who underwent one of eight common outpatient surgeries declined over a period of five years. These findings, reported in the journal Pediatrics, suggest that clinicians are using more discretion when considering which paediatric patients require an opioid prescription after their procedures.

Opioids are routinely prescribed after a surgery to help paediatric patients manage mild or moderate pain. However, recent studies have suggested that recovery is similar with limited or no opioid use. Additionally, opioids prescribed to children can result in respiratory depression, which causes carbon dioxide to not be expelled from the lungs properly, and the continued use of those opioids, after acute pain has resolved. Despite these findings, no prior studies had looked at recent data on national opioid trends for surgery in children in the context of whether there has been any shift away from prescribing opioids more broadly.

“Children grow throughout their childhood, and because opioids are often prescribed based on weight, we cannot assume that what is appropriate for a 5-year-old could also apply to an adolescent,” said the study’s lead author Tori N. Sutherland, MD, MPH. “In our study, we wanted to be responsible with our data and consider surgical distribution by age group.”

In this study, the researchers used data from a private insurance database to study opioid-naïve patients under the age of 18 who underwent one of eight surgical procedures between 2014 and 2019. The procedures ranged from tonsillectomies to knee surgery. The primary outcome of the study was whether a prescription for opioids was filled within 7 days of surgery, and the secondary outcome was the total amount of opioid dispensed. A total of 124 249 patients were included in the study. Patients were separated by age into adolescents, school-aged children and preschool-aged children.

The researchers found that the percentage of children who had an opioid prescription filled after their surgery fell across all three age categories. For adolescents, prescriptions dropped from 78.2% to 48%; for school-aged children, from 53.9% to 25.5%; and for preschool-aged children, from 30.4% to 11.5%. Additionally, the average morphine milligram equivalent dispensed declined by approximately 50% across all three age groups.

The researchers also found that there was a steeper decline in opioid prescriptions beginning in late 2017, first in the adolescent group and then followed by school- and preschool-aged children. This trend appeared to represent a ‘trickle down’ effect, but more research is needed to explore the difference in trends by age group.

“Our findings demonstrate that pain treatment for children and adolescents undergoing surgery has changed dramatically over the past 5 years,” said Mark Neuman, MD, senior author. “Understanding what these trends mean for patient experiences and health outcomes is a key next step.”

Source: EurekAlert!

A Small Risk of Increased Congenital Abnormalities from Opioids in Pregnancy

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In a new study in the Canadian Medical Association Journal, researchers drawing on a provincial database report a small increased risk of congenital abnormalities in infants exposed to opioid medications in the first trimester of pregnancy.

Prescribed opioid pain medications are capable of crossing the placenta and have the potential to cause harm. In a study comparing placental crossing rates for various opioids, oxycodone, a commonly prescribed opioid for pain relief, was the fastest. About 2%–4% of foetuses are exposed to these drugs. To determine the association between opioid pain medications in early pregnancy and congenital abnormalities in infants, investigators analysed administrative health data from Ontario on almost 600 000 birth parent–infant pairs. 

Among the infants included in the study, 2% (11 903) were exposed in utero to opioid analgesics, such as codeine, oxycodone, hydromorphone, tramadol, and morphine. Analysis showed a small increased risk of major anomalies with exposure to tramadol and morphine, and of minor anomalies with exposure to codeine, hydromorphone and oxycodone. Specific congenital anomalies observed included gastrointestinal and genital anomalies, neoplasms and tumours, and ankyloglossia.

This study adds to the evidence from previous studies in Sweden and Norway and also from a recent study of pregnant US Medicaid beneficiaries that suggested a small increased risk of congenital anomalies, an important finding for a pregnant person who may be prescribed opioids for pain relief.

“Both the potential for harm or distress to the pregnant person as a consequence of foregoing treatment and the subsequent risk to the infant must be considered for effective treatment,” the authors concluded. “These findings further quantify harms associated with prenatal exposure to opioid analgesics to inform treatment choices for pain in pregnancy.”

Source: EurekAlert!

Electroacupuncture Spares Opioids for Knee Replacement Pain Relief

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Patients who have electroacupuncture during total knee replacement surgery report less pain and need far fewer opioids to manage their discomfort. In the study, 65% of patients who received acupuncture during surgery were able to have a low-dose or opioid-free postoperative experience, compared to 9% of patients outside of the study.

The results of the study were presented at the ANESTHESIOLOGY® 2021 annual meeting

“Total knee replacements are one of the most common operative procedures in the United States and often very painful, so there’s a great need to explore non-opioid pain relief techniques for this type of surgery,” said lead author Stephanie Cheng, MD, DABMA, assistant attending anaesthesiologist at the Hospital for Special Surgery and assistant professor of clinical anaesthesiology at Weill Cornell Medicine. “Acupuncture is extremely safe and can help reduce pain with few unwanted side effects, but it has not been well researched as part of surgical anesthesia.”

The study enrolled 41 patients who had primary total knee replacement, all of whom received the institution’s standard opioid-sparing multimodal analgesic protocol, with the addition of electroacupuncture, which is a modified form of traditional acupuncture that applies a small electric current to thin needles that are inserted at known acupuncture points on the body. The acupuncture was administered during surgery by Dr Cheng, who is board-certified in medical acupuncture, to eight specific points in the ear to provide targeted pain relief in the knee.

With the addition of acupuncture, the majority of patients had reduced postoperative opioid use, compared to historical controls, while 65% of patients either maintained a low-dose opioid regimen of 15 oxycodone pills or less (57.5%) or remained completely opioid-free (7.5%) from induction of anaesthesia to 30 days post-surgery. Historically, only 9% of patients outside of the study were able to maintain a low-dose or opioid-free regimen post-surgery. Thirty days after surgery, all patients discontinued opioid use.

“Our study shows that if a trained medical acupuncturist is available to perform acupuncture in the operating room, it can help patients with postoperative pain recovery,” said Dr Cheng. “Most studies fail to incorporate nontraditional techniques, such as acupuncture, to help decrease the dependence on opioid medications for postoperative pain control.”

Low-dose perioperative opioid consumption is key to mitigating the opioid epidemic and opioid misuse by patients. Dr Cheng pointed out that with acupuncture being commonly used outside of the hospital as an effective therapy for pain management and treatment for a range of health issues and symptoms, it’s time to consider its benefits inside the hospital as well. “Additional research is needed to further define acupuncture’s effects and encourage its use in all aspects of disease treatment.”

Source: American Society of Anesthesiologists

Breakthrough Could Lead to New Opioid Alternatives

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Monash University researchers have made a breakthrough discovery that might lead to new non-opioid analgesics to treat neuropathic pain safely and effectively, without the risk of opioid addictions.

Neuropathic pain occurs when nerves are damaged or dysfunctional, and can be caused by injury, virus infection or cancer treatment, or it can be a symptom or complication of conditions such as multiple sclerosis and diabetes.

The new study, published in Nature, has shown a new mode of targeting the adenosine A1 receptor protein, which had long been a promising therapeutic target for non-opioid painkillers to treat neuropathic pain. However, development of analgesics using it had failed due to a lack of sufficient on-target selectivity, as well as undesirable adverse effects.

In the study, Monash researchers used electrophysiology and preclinical pain models to show that a particular class of molecule, called a ‘positive allosteric modulator’ (PAM), can enhance the targeting of the A1 receptor by binding to a different region of the protein.

Another breakthrough in the study was observing the high-resolution structure of the A1 receptor bound to both its natural activator, adenosine, and an analgesic PAM, which was facilitated by the application of cryo electron microscopy (cryoEM), providing the first atomic level snapshot of the drug binding location.

Chronic pain remains a widespread global health burden. A lack of treatment options has led to over-reliance on opioid painkillers, which provide only limited relief in patients with chronic (particularly neuropathic) pain, while having severe adverse effects, such as respiratory depression and addiction. In 2016, 42 000 deaths related to opioid misuse were recorded in the US, while 25 million Americans suffer from chronic pain.

This new discovery opens the door to the development of non-opioid drugs that lack such side effects.

Co-corresponding author of the study and Dean of the Faculty of Pharmacy and Pharmaceutical Sciences, Professor Arthur Christopoulos said: “The world is in the grip of a global opioid crisis and there is an urgent need for non-opioid drugs that are both safe and effective.”

Source: Monash University

High-dose Buprenorphine in ED Could Improve Opioid Abuse Outcomes

Photo by Mat Napo on Unsplash
Photo by Mat Napo on Unsplash

High-dose buprenorphine therapy, provided under emergency department care, is safe and well tolerated in people with opioid use disorder experiencing opioid withdrawal symptoms, according to a study supported by the National Institutes of Health’s National Institute on Drug Abuse (NIDA).

Lower doses of buprenorphine, a medication approved by the US Food and Drug Administration to treat opioid use disorder, are the current standard of care. Higher doses, however, could extend the period of withdrawal relief for people after being discharged from the emergency department that could help them better seek care. 

“Emergency departments are at the front lines of treating people with opioid use disorder and helping them overcome barriers to recovery such as withdrawal,” said Nora D Volkow, MD, director of NIDA. “Providing buprenorphine in emergency departments presents an opportunity to expand access to treatment, especially for underserved populations, by supplementing urgent care with a bridge to outpatient services that may ultimately improve long-term outcomes.”

Presently, some emergency departments already administer higher buprenorphine doses to treat withdrawal and opioid use disorder. They do this as a response to the growing potency in illicit opioid drug supplies and delays in access to follow-up care, but this practice has not been evaluated previously.

Researchers used a retrospective chart review to analyse data from electronic health records documenting 579 emergency department visits at the Alameda Health System Highland Hospital in California, made by 391 adults with opioid use disorder in 2018. Many patients were from vulnerable populations, with 23% experiencing homelessness and 41% having a psychiatric disorder.

In 63% of cases, clinicians administered more than the standard upper limit of 12 mg of sublingual buprenorphine during emergency department induction, and in 23% of cases, patients were given 28 mg or more. Higher doses of buprenorphine were seen to be safe and tolerable, and there were no reports of respiratory problems or drowsiness among those given the higher doses. The few serious adverse events that occurred were determined to be unrelated to high-dose buprenorphine therapy.

Studies have shown that initiating buprenorphine in emergency departments improves engagement in treatment and is cost effective, but barriers to the medication’s use in the US persist, with restrictions on what training is required, how much can be administered and for how long. Recent changes to prescribing guidelines by the US Department of Health and Human Services now let some clinicians treating up to 30 patients to prescribe buprenorphine without the previous training and services criteria.

“Once discharged, many people have difficulty linking to follow-up medical care,” explained study leader Andrew A Herring, MD, of Highland Hospital Department of Emergency Medicine. “Adjusting the timing and dosage of buprenorphine in the emergency department, along with resources and counseling aimed at facilitating the transition to outpatient services, may provide the momentum needed to access continuing care.”

“This study enhances the evidence we know about emergency-department buprenorphine induction, and could be a gamechanger, particularly for vulnerable populations who would likely benefit from a rapid induction at the time of the visit,” said study author Gail D’Onofrio, MD, of Yale University. Dr D’Onofrio published the original studies on emergency department-initiated buprenorphine, as well as recent consensus recommendations on the emergency department treatment of opioid use disorder.
The researchers noted that their findings need confirmation in other emergency departments. Nevertheless, this study suggests that with proper support and training, emergency medicine providers may safely and effectively initiate high-dose buprenorphine therapy.

Source: NIH

Journal information: JAMA Network Open (2021). DOI: 10.1001/jamanetworkopen.2021.17128

Physician’s Personal Brush with Opioid Addiction

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.”

Source: KevinMD

Unique Genetic Basis for Chronic Pain in Women Discovered

A meta-analysis of UK genetic data has found a different genetic basis for chronic pain in women compared to men.

While the results are still preliminary, this is one of the largest genetic studies on chronic pain analysing by sexes.

“Our study highlights the importance of considering sex as a biological variable and showed subtle but interesting sex differences in the genetics of chronic pain,” said population geneticist Keira Johnston of the University of Glasgow in Scotland.

Chronic pain conditions are among the most prevalent, disabling, and expensive conditions in public health, and are frequently overlooked for research funding. With 100 million people in chronic pain in the US in 2016, overprescription of opioids for chronic pain has resulted in an epidemic of opioid misuse, with 66% of overdose cases being for opioids. Even very moderate opioid use carries the risk of addiction and abuse.

Even when studies are done, they often overlook underlying sex differences, and that’s a huge and detrimental oversight. Compared to men, women are far more likely to develop multiple chronic pain disorders, and yet historically, 80 percent of all pain studies have been conducted on male mice or male humans. This means we know very little about how and why females are suffering more and what treatments can help them best.

While there are probably multiple biological and psychosocial processes in this sex discrepancy, the current genome-wide study suggests there’s a genetic factor in the mix, too.

The researchers compared gene variants associated with chronic pain in 209 093 women and 178 556 men from the UK Biobank, and found 31 genes associated with chronic pain in women and 37 genes associated with chronic pain in men with barely any overlap. This might be due to the slightly smaller sample size of men but the results are nonetheless intriguing, the researchers maintained.

The vast majority of these genes were active in a cluster of nerves within the spinal cord, known as the dorsal root ganglion, which transmits messages from the body to the brain.
While several genes in the male-only or female-only list were linked with psychiatric disorders or immune function, only one, called DCC, was found in both lists.
DCC encodes for a receptor that binds with a protein crucial for the development of the nervous system, especially the dopaminergic system. The dopaminergic system is the ‘reward centre’ but also has been linked to pain.

DCC is also linked to depression, and DCC mutations appear in those with congenital mirror movement disorder, which results in movements on one side of the body being replicated on the other side.

It’s not how DCC is linked to chronic pain, but the researchers believe their results support several theories “of strong nervous system and immune involvement in chronic pain in both sexes”, which will, they hope, result in the development of better treatments.

Should chronic pain be more closely linked to immune function in women, immune-targeting drugs may have very different side-effects than in men. Opioids negatively impact immune function, indicating that they could in fact worsen the situation for women suffering chronic pain. However, more research is needed to strengthen these findings and understand their impacts.

“All of these lines of evidence, together, suggest putative central and peripheral neuronal roles for some of these genes, many of which have not been historically well studied in the field of chronic pain,” the authors concluded.

Source: Science Alert

Journal information: Johnston KJA, Ward J, Ray PR, Adams MJ, McIntosh AM, Smith BH, et al. (2021) Sex-stratified genome-wide association study of multisite chronic pain in UK Biobank. PLoS Genet 17(3): e1009428. doi.org/10.1371/journal.pgen.1009428