The present study was performed to determine whether acetaminophen (paracetamol) use after the measles-mumps-rubella vaccination could be associated with autistic disorder. This case-control study used the results of an online parental survey conducted from 16 July 2005 to 30 January 2006, consisting of 83 children with autistic disorder and 80 control children. Acetaminophen use after measles-mumps-rubella vaccination was significantly associated with autistic disorder when considering children 5 years of age or less (OR 6.11, 95% CI 1.42-26.3), after limiting cases to children with regression in development (OR 3.97, 95% CI 1.11-14.3), and when considering only children who had post-vaccination sequelae (OR 8.23, 95% CI 1.56-43.3), adjusting for age, gender, mother's ethnicity, and the presence of illness concurrent with measles-mumps-rubella vaccination. Ibuprofen use after measles-mumps-rubella vaccination was not associated with autistic disorder. This preliminary study found that acetaminophen use after measles-mumps-rubella vaccination was associated with autistic disorder.
Background: Acetaminophen is extensively used during pregnancy. But there is a lack of population-representative cohort studies evaluating its effects on a range of neuropsychological and behavioural endpoints. We aimed to assess whether prenatal exposure to acetaminophen is adversely associated with neurodevelopmental outcomes at 1 and 5 years of age.
Methods: This Spanish birth cohort study included 2644 mother-child pairs recruited during pregnancy. The proportion of liveborn participants evaluated at 1 and 5 years was 88.8% and 79.9%, respectively. Use of acetaminophen was evaluated prospectively in two structured interviews. Ever/never use and frequency of use (never, sporadic, persistent) were measured. Main neurodevelopment outcomes were assessed using Childhood Autism Spectrum Test (CAST), Conner’s Kiddie Continuous Performance Test (K-CPT) and ADHD-DSM-IV form list. Regression models were adjusted for social determinants and co-morbidities.
Results: Over 40% of mothers reported using acetaminophen. Ever-exposed offspring had higher risks of presenting more hyperactivity/impulsivity symptoms [incidence rate ratio (IRR) = 1.41, 95% confidence interval (CI) 1.01–1.98), K-CPT commission errors (IRR = 1.10, 1.03–1.17), and lower detectability scores (coefficient β = −0.75, −0.13–−0.02). CAST scores were increased in ever-exposed males (β = 0.63, 0.09–1.18). Increased effect sizes of risks by frequency of use were observed for hyperactivity/impulsivity symptoms (IRR = 2.01, 0.95–4.24) in all children, K-CPT commission errors (IRR = 1.32, 1.05–1.66) and detectability (β = −0.18, −0.36–0.00) in females, and CAST scores in males (β = 1.91, 0.44–3.38).
Conclusions: Prenatal acetaminophen exposure was associated with a greater number of autism spectrum symptoms in males and showed adverse effects on attention-related outcomes for both genders. These associations seem to be dependent on the frequency of exposure.
https://journals.sagepub.com/doi/pdf/10.1177/0300060517693423 The role of oxidative
stress, inflammation and
acetaminophen exposure
from birth to early childhood
in the induction of autism
William Parker1
, Chi Dang Hornik2
,
Staci Bilbo3
, Zoie E. Holzknecht1
,
Lauren Gentry1
, Rasika Rao1
, Shu S. Lin1
,
Martha R. Herbert4 and Cynthia D. Nevison5
Abstract: The wide range of factors associated with the induction of autism is invariably linked with either
inflammation or oxidative stress, and sometimes both. The use of acetaminophen in babies and
young children may be much more strongly associated with autism than its use during pregnancy,
perhaps because of well-known deficiencies in the metabolic breakdown of pharmaceuticals during
early development. Thus, one explanation for the increased prevalence of autism is that increased
exposure to acetaminophen, exacerbated by inflammation and oxidative stress, is neurotoxic in
babies and small children. This view mandates extreme urgency in probing the long-term effects of
acetaminophen use in babies and the possibility that many cases of infantile autism may actually be
induced by acetaminophen exposure shortly after birth. https://www.ncbi.nlm.nih.gov/pubmed/18445737
The present study was performed to determine whether acetaminophen (paracetamol) use after the measles-mumps-rubella vaccination could be associated with autistic disorder. This case-control study used the results of an online parental survey conducted from 16 July 2005 to 30 January 2006, consisting of 83 children with autistic disorder and 80 control children. Acetaminophen use after measles-mumps-rubella vaccination was significantly associated with autistic disorder when considering children 5 years of age or less (OR 6.11, 95% CI 1.42-26.3), after limiting cases to children with regression in development (OR 3.97, 95% CI 1.11-14.3), and when considering only children who had post-vaccination sequelae (OR 8.23, 95% CI 1.56-43.3), adjusting for age, gender, mother's ethnicity, and the presence of illness concurrent with measles-mumps-rubella vaccination. Ibuprofen use after measles-mumps-rubella vaccination was not associated with autistic disorder. This preliminary study found that acetaminophen use after measles-mumps-rubella vaccination was associated with autistic disorder.
ImportanceAcetaminophen (paracetamol) is the most commonly used medication for pain and fever during pregnancy in many countries. Research data suggest that acetaminophen is a hormone disruptor, and abnormal hormonal exposures in pregnancy may influence fetal brain development.
ObjectiveTo evaluate whether prenatal exposure to acetaminophen increases the risk for developing attention-deficit/hyperactivity disorder (ADHD)–like behavioral problems or hyperkinetic disorders (HKDs) in children.
Design, Setting, and ParticipantsWe studied 64 322 live-born children and mothers enrolled in the Danish National Birth Cohort during 1996-2002.
ExposuresAcetaminophen use during pregnancy was assessed prospectively via 3 computer-assisted telephone interviews during pregnancy and 6 months after child birth.
Main Outcomes and MeasuresTo ascertain outcome information we used (1) parental reports of behavioral problems in children 7 years of age using the Strengths and Difficulties Questionnaire; (2) retrieved HKD diagnoses from the Danish National Hospital Registry or the Danish Psychiatric Central Registry prior to 2011; and (3) identified ADHD prescriptions (mainly Ritalin) for children from the Danish Prescription Registry. We estimated hazard ratios for receiving an HKD diagnosis or using ADHD medications and risk ratios for behavioral problems in children after prenatal exposure to acetaminophen.
ResultsMore than half of all mothers reported acetaminophen use while pregnant. Children whose mothers used acetaminophen during pregnancy were at higher risk for receiving a hospital diagnosis of HKD (hazard ratio = 1.37; 95% CI, 1.19-1.59), use of ADHD medications (hazard ratio = 1.29; 95% CI, 1.15-1.44), or having ADHD-like behaviors at age 7 years (risk ratio = 1.13; 95% CI, 1.01-1.27). Stronger associations were observed with use in more than 1 trimester during pregnancy, and exposure response trends were found with increasing frequency of acetaminophen use during gestation for all outcomes (ie, HKD diagnosis, ADHD medication use, and ADHD-like behaviors; P trend < .001). Results did not appear to be confounded by maternal inflammation, infection during pregnancy, the mother’s mental health problems, or other potential confounders we evaluated.
Conclusions and RelevanceMaternal acetaminophen use during pregnancy is associated with a higher risk for HKDs and ADHD-like behaviors in children. Because the exposure and outcome are frequent, these results are of public health relevance but further investigations are needed.
Affiliations: Aurin Biotech Inc. Ltd., Vancouver, BC, Canada
Correspondence: [*] Correspondence to: Dr. Patrick L. McGeer, Aurin Biotech Inc Ltd., 4727 West Second Avenue, Vancouver, BC V6T 1C1, Canada. Tel.: +1 604 822 7377; Fax: +1 604 822 7086; E-mail: mcgeerpl@mail.ubc.ca.
Alzheimer’s disease (AD) is characterized by deposits of amyloid-β protein (Aβ) in brain which become foci of inflammation. Neurons are destroyed by this inflammatory process, leading to the cognitive deficits which define AD clinical onset. Epidemiological studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) can ameliorate this destructive process if they are started well before clinical signs develop. Biomarker studies indicate that the disease process starts at least a decade before cognitive deficits appear. This pre-clinical onset explains the NSAID effect. It also opens a window of opportunity for preventive treatment that can be met with a simple diagnostic test. Salivary levels of Aβ42may fulfill that need. They can be measured by a simple ELISA test we have developed using commercially available reagents. By this ELISA test, normal controls, who are not at risk for AD, have levels of Aβ42 close to 20 pg/ml. AD cases, as well as high level controls, secrete levels in the range of 40–85 pg/ml. Widespread application of this test to detect high level controls, followed by NSAID consumption, could substantially reduce the prevalence of AD.
You may have taken ibuprofen today, be it to ease a headache or alleviate back pain. But there might be more to this common medication than pain relief; a new paper suggests that a daily dose of ibuprofen could prevent Alzheimer's disease.
Researchers say that ibuprofen could ward off Alzheimer's if taken every day.
Led by Dr. Patrick McGeer, who is the CEO of Aurin Biotech in Canada, the study describes how ibuprofen could reduce inflammationcaused by an Alzheimer's-related peptide.
The paper was recently published in the Journal of Alzheimer's Disease.
This number is predicted to rise to almost 14 million by 2050.
The search continues for the exact causes of Alzheimer's, but a sticky protein called beta-amyloidis believed to play a role in the disease.
Beta-amyloid can clump together and form "plaques" in the brain. These plaques will interfere with brain cell communication, which can lead to memory loss, behavioral changes, and many other symptoms characteristic of Alzheimer's disease.
In a study published last year, Dr. McGeer and colleagues revealed that a beta-amyloid peptide — known as amyloid-beta 42 (Abeta 42) — is present in saliva, as well as the brain, and that levels of this peptide are higher in adults who are at greater risk of Alzheimer's.
Based on those results, the team suggests that a saliva test could be used to predict the risk of Alzheimer's disease years before symptoms arise.
"What we've learned through our research," reports Dr. McGeer, "is that people who are at risk of developing Alzheimer's exhibit the same elevated Abeta 42 levels as people who already have it; moreover, they exhibit those elevated levels throughout their lifetime so, theoretically, they could get tested anytime."
A 'true breakthrough'?
In their paper, the researchers claim that ibuprofen — a widely used nonsteroidal anti-inflammatory drug (NSAID) — could prevent the development of Alzheimer's in people with high levels of Abeta 42.
Dr. McGeer and team point to previous research that they conducted, in which they suggested that Abeta 42 triggers an inflammatory response.
This response could be reduced by ibuprofen and other NSAIDs, say the researchers, which could stop Alzheimer's in its tracks.
The team says that identifying the risk of Alzheimer's through a saliva test would offer people the opportunity to prevent Alzheimer's development through a daily dose of ibuprofen.
"Knowing that the prevalence of clinical Alzheimer's disease commences at age 65," explains Dr. McGeer, "we recommend that people get tested 10 years before, at age 55, when the onset of Alzheimer's would typically begin."
"If they exhibit elevated Abeta 42 levels then, that is the time to begin taking daily ibuprofen to ward off the disease."
Dr. Patrick McGeer
He hails the saliva test as a "true breakthrough" because it "points in a direction where [Alzheimer's disease] can eventually be eliminated." However, Dr. McGeer's claims have been met with some criticism.
Daily ibuprofen recommendation 'premature'
Dr. Doug Brown, chief policy and research officer at the Alzheimer's Society in the United Kingdom, believes that it is far too soon to be recommending daily ibuprofen for Alzheimer's prevention.
"Population studies," he says, "which gather large amounts of information from medical records from thousands of people, have thrown up an idea that taking ibuprofen and other over-the-counter anti-inflammatories might be linked to a lower risk of dementia."
"But results of clinical trials with these drugs have been disappointing so far."
"The researchers' suggestion in this paper that taking a daily anti-inflammatory drug as soon as a positive result for dementia risk is shown by a saliva test is premature," adds Dr. Brown, "based on the evidence at the moment."
He also notes the risks of long-term NSAID use, including intestinal bleeding and stomach ulcers. NSAIDs may also interact with other medications, such as warfarin, and produce harmful effects.
"We always recommend talking to your doctor before changing your medication," Dr. Brown says.
Noncancer pain and cognitive impairment affect many older adults and each is associated with functional disability, but their combined impact has yet to be rigorously studied.
Methods.
This is a cross-sectional analysis of the Canadian Study of Health and Aging. Pain was collapsed from a 5-point to a dichotomous scale (no and very mild vs moderate and greater). Cognitive status was dichotomized from the Modified Mini-Mental State Examination (0–100) to no (>77) or mild-moderate (77–50) impairment. Five Instrumental Activities of Daily Living (IADL) and seven Activities of Daily Living (ADL) were self-rated as “accomplished without any help” (0), “with some help” (1), or “completely unable to do oneself” (2) and then summed to create a composite score of 0–10 and 0–14, respectively. Multivariate linear regression analysis was conducted to determine the associations between self-reported functional status with moderate or greater pain, cognitive impairment, and the interaction of the two.
Results.
A total of 5,143 (90.2%) participants were eligible, 1,813 (35.6%) reported pain at a moderate intensity or greater and 727 (14.3%) were cognitively impaired. The median IADL and ADL summary scores increased among the pain and cognition categories in the following order: no pain and cognitively intact (0.63 SD 1.24, 0.23 SD 0.80), pain and cognitively intact (1.18 SD 1.69, 0.57 SD 1.27), no pain and cognitively impaired (1.64 SD 2.22, 0.75 SD 1.57), and pain and cognitively impaired (2.27 SD 2.47, 1.35 SD 2.09), respectively. Multivariate linear regression found IADL summary scores were associated with pain, coefficient .17 (95% confidence interval [CI] 0.07–0.26), p < .01; cognitive impairment, coefficient .67 (95% CI 0.51–0.83), p< .01; and an interaction effect of pain with cognitive impairment, coefficient .24 (95% CI 0.01–0.49), p = .05. ADL summary scores were associated with pain coefficient .10 (95% CI 0.04–0.17), p < .01 and cognitive impairment, coefficient .29 (95% CI 0.19–0.39), p < .01, but had a nonsignificant interaction term, coefficient .12 (95% CI −0.03 to 0.29), p = .12.
Conclusions.
Noncancer pain and cognitive impairment are independently associated with IADL and ADL impairment and IADL impairment is even greater when both conditions are present.
Researchers at UC San Francisco have found that older people with persistent pain show quicker declines in memory as they age and are more likely to have dementia years later, an indication that chronic pain could somehow be related to changes in the brain that contribute to dementia.
The study, published June 5 in JAMA Internal Medicine, appears to be the first to make this association.
The researchers analyzed data from 10,000 participants aged 60 and up over a 12-year period. Those participants who said they were persistently troubled by moderate or severe pain in both 1998 and 2000 declined 9.2 percent faster in tests of memory function over the next 10 years than those who said they were not troubled by pain. The patients who complained about persistent pain also had a small but significantly increased likelihood of developing dementia overall.
Researchers found that the additional amount of memory decline in those who reported persistent pain suggested that these patients would likely have had a harder time with tasks of daily living, such as independently managing their medications and finances.
Elizabeth Whitlock, MD, MSc, a postdoctoral fellow in the UCSF Department of Anesthesia and Perioperative Care and the first author of the study, said the findings point toward new ways of thinking about how to protect older people from the cognitive insults of aging.
“Elderly people need to maintain their cognition to stay independent,” she said. “Up to one in three older people suffer from chronic pain, so understanding the relationship between pain and cognitive decline is an important first step toward finding ways to help this population.”
3 Potential Causes
The research, conducted in collaboration with members of UCSF’s Division of Geriatrics, suggests three potentially overlapping reasons for the association between chronic pain and dementia. An increased dementia risk could be caused by painkillers, such as opioids, which people are taking in greater numbers. It could also be that the experience of pain somehow compromises the brain’s ability to encode memories and other cognitive functions. Finally, it could be due to some other factor that was not measured in the study, and therefore could not be analyzed. But even if this is the case, Whitlock said, the findings remain clinically relevant, because pain could be used as a marker for increased risk of future cognitive decline even if the biological basis of the association is still unclear.
The data that the researchers analyzed – an ongoing national study of older Americans called the Health and Retirement Study – did not include information about opioid use, so they could not tell which of their participants were taking the drugs. While opioid use could be the cause of the cognitive changes they observed, Whitlock said, so could the pain itself. For example, a recent study of chronic pain sufferers found that those who took nonsteroidal anti-inflammatory drugs, such as ibuprofen, had nearly the same increased dementia risk as those taking opioids.
“This means we have to consider the potential direct effects of chronic pain on cognition,” she said.
People who suffer from chronic pain tend to have diminished attentional capacity and impaired memory, and Whitlock said that particularly when pain is severe or causes patients to ruminate, it could divert enough attention to interfere with the consolidation of memory. Another possibility, she said, is that the emotional stress of being in pain activates stress-hormone pathways in the body that have been implicated in cognitive decline. If either is the case, she said, then effectively treating the pain could protect cognition.
Better Managing Impact of Chronic Pain
Doctors often struggle to manage their patients’ pain, since current therapies, in addition to being addictive, do not always work. But Whitlock said that even those patients who continue to suffer, and may be experiencing a more rapid cognitive decline as a result, can still be helped with assistive devices, physical and occupational therapy, or strategies, such as mindfulness techniques, that are aimed at increasing self-efficacy and curbing the emotional impact of chronic pain.
“This is something I really feel we can do something about as clinicians,” Whitlock said. “It’s part of taking care of the whole patient.”
Other authors of the study include Grisell Diaz-Ramirez, MS; W. John Boscardin, PhD; Kenneth E. Covinsky, MD; and Alexander K. Smith, MD, MPH, all of the Division of Geriatrics in the UCSF Department of Medicine; and Maria Glymour, ScD, MS, of the UCSF Department of Epidemiology and Biostatistics.
UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises three top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospitals in San Francisco and Oakland, and other partner and affiliated hospitals and healthcare providers throughout the Bay Area.
QuestionIs persistent pain associated with accelerated cognitive decline in the elderly?
FindingsIn this longitudinal, population-based cohort study, reporting pain in 2 successive interviews 2 years apart was associated with a statistically significant increase in the rate of memory decline and the probability of dementia over the subsequent 12 years, compared with controls who did not report persistent pain.
MeaningPersistent pain, which may reflect chronic pain, may help identify elders at risk of accelerated cognitive decline.
Abstract
ImportanceChronic pain is common among the elderly and is associated with cognitive deficits in cross-sectional studies; the population-level association between chronic pain and longitudinal cognition is unknown.
ObjectiveTo determine the population-level association between persistent pain, which may reflect chronic pain, and subsequent cognitive decline.
Design, Setting, and ParticipantsCohort study with biennial interviews of 10 065 community-dwelling older adults in the nationally representative Health and Retirement Study who were 62 years or older in 2000 and answered pain and cognition questions in both 1998 and 2000. Data analysis was conducted between June 24 and October 31, 2016.
Exposures“Persistent pain,” defined as a participant reporting that he or she was often troubled with moderate or severe pain in both the 1998 and 2000 interviews.
Main Outcomes and MeasuresCoprimary outcomes were composite memory score and dementia probability, estimated by combining neuropsychological test results and informant and proxy interviews, which were tracked from 2000 through 2012. Linear mixed-effects models, with random slope and intercept for each participant, were used to estimate the association of persistent pain with slope of the subsequent cognitive trajectory, adjusting for demographic characteristics and comorbidities measures in 2000 and applying sampling weights to represent the 2000 US population. We hypothesized that persistent pain would predict accelerated memory decline and increased probability of dementia. To quantify the impact of persistent pain on functional independence, we combined our primary results with information on the association between memory and ability to manage medications and finances independently.
ResultsOf the 10 065 eligible HRS sample members, 60% were female, and median baseline age was 73 years (interquartile range, 67-78 years). At baseline, persistent pain affected 10.9% of participants and was associated with worse depressive symptoms and more limitations in activities of daily living. After covariate adjustment, persistent pain was associated with 9.2% (95% CI, 2.8%-15.0%) more rapid memory decline compared with those without persistent pain. After 10 years, this accelerated memory decline implied a 15.9% higher relative risk of inability to manage medications and an 11.8% higher relative risk of inability to manage finances independently. Adjusted dementia probability increased 7.7% faster (95% CI, 0.55%-14.2%); after 10 years, this translates to an absolute 2.2% increase in dementia probability for those with persistent pain.
Conclusions and RelevancePersistent pain was associated with accelerated memory decline and increased probability of dementia.
A little known, but potentially life-saving fact is that common medications deplete your body of a host of vital nutrients essential to your health. In this practical guide I’ll show you how to avoid drug-induced nutrient depletion and discuss options for replacing nutrient-robbing medications with natural supplements.
America has been called a pill-popping society, and the statistics bear this out. Nearly 50 percent of all American adults regularly take at least one prescription drug, and 20 percent take three or more.(1) Our increasing reliance on prescription medications has contributed to the growing problem with nutrient depletion. The truth is that every medication, including over-the-counter drugs, depletes your body of specific, vital nutrients. This is especially concerning when you consider that most Americans are already suffering from nutrient depletion.
Additionally, many of the conditions physicians see in their everyday practice may actually be related to nutrient depletion. The good news is that, armed with information and the right supplements, you can avoid the side effects of nutrient depletion, and even better, you may be able to control and prevent chronic diseases, such as diabetes, cardiovascular disease and osteoporosis.
Drug-induced nutrient depletion is an important topic, but most consumers know very little about it. More than 400 prescription and over-the-counter medications are known to cause multiple nutritional deficiencies. Over the last four decades, in excess of 600 scientific studies have documented the evidence.1 2 Unfortunately, this potentially life-saving information has not been made widely available.
The side effects from these nutrient losses can affect energy, mood, libido, the immune system, the ability to ward off degenerative diseases, and can even shorten life. Pharmaceutical drugs rob vital nutrients by interfering with the ability to properly digest, absorb, transport, metabolize, synthesize, utilize, or excrete vital nutrients.
If it is necessary to take medication, it is recommended to cover the bases nutritionally through the addition of superfoods and natural supplements along with a healthy diet containing an abundance of local and organic fruits and vegetables. Commercially grown produce and packaged foods will not provide the kind of nutrition needed. Many reliable studies now indicate that modern intensive agricultural methods have stripped increasing amounts of nutrients from the soil.3
The following is an easy-to-follow path through some of the most common drug categories that affect health by depleting valuable vitamins, minerals, and antioxidants. I have also included the foods and supplements recommended to replenish the body and meet its optimal needs.
Acid-Blocking Drugs e.g. Losec, Nexium, Pepcid, Tagamet, Zantac
These drugs deplete vitamins B1, B12, and D, folic acid, iron, calcium, iron, magnesium, selenium, and zinc. A high-quality multi-vitamin/mineral plus a liquid solution form of calcium, magnesium, and iron are suggested to replenish these nutrients. Acid-blocking drugs substantially decrease production of stomach acid, causing potential bacterial overgrowth of the small intestine. When using these drugs, it is important to take probiotics (acidophilus/bifidus) and consume fermented vegetables (sauerkraut) and beverages (kombucha, kefir). Acid-blocking drugs also interfere with proper protein digestion and the production of adequate digestive juices. A potent digestive enzyme that also breaks down the hard-to-digest proteins (e.g., gluten and casein) can help gut issues. Kiwi fruit contain protein-digesting enzymes that can relieve constipation, gas, and bloating caused by improper digestion.
Antibiotics
Deplete folic acid, biotin, vitamin B complex, and vitamin K2. They also immediately wipe out certain strains of friendly bacteria flora that colonize the intestinal tract and support healthy digestion and immune function. Unfortunately, antibiotics can create a massive gut bacteria imbalance, encouraging the presence of obesity-promoting bacteria. Researchers speculate antibiotic usage is a major contributor to both obesity and diabetes. The healthy bacteria can be replaced with a probiotic supplement and fermented foods during and following use of this type of medication. Also, look to replenish with 30 to 100 mcg daily of vitamin K2-M7, normally made by friendly intestinal bacteria. Note: mineral supplements (magnesium, calcium, zinc, iron, selenium, iodine) need to be taken at least two hours away from many types of antibiotics, as they can bind to antibiotics and reduce absorption of both.
As of 2015, approximately 80% of the antibiotics consumed in Canada are destined for livestock either for preventing illness or promoting growth. What are the effects on the human body?
Anti-anxiety & Anti-depression Meds e.g. Xanax, Valium, Ativan, Prozac
These drugs deplete melatonin, a very important anti-cancer hormone that plays a pivotal role in sleep and immune function. Melatonin also plays a key role as the biological “time keeper” of hormone secretions. Ideally, melatonin supplementation is started at a low dose, between 1.5 and 3 mg per night, to ensure the melatonin is not causing side effects.
Female Hormones
e.g. oral contraceptives, bio-identical hormones containing estrogen, or synthetic estrogens
These drugs deplete the body of vitamin B6, magnesium, zinc, and friendly gut bacteria, regardless of the form of estrogen. As well, oral contraceptives deplete vitamins C, B12, B1, B2, B6, folic acid, magnesium, and selenium. Increasing dietary intake of cruciferous vegetables (broccoli, cauliflower, cabbage, brussel sprouts, kale, mustard greens, turnip, arugula) can increase the safety of this medication by promoting favourable metabolism of estrogens instead of producing carcinogenic metabolites. Including a multi-vitamin/mineral in your routine is highly recommended when taking female hormones.
Anti-inflammatory Drugs, NSAIDS e.g. Ibuprofen, Naproxen, Indomethacin, Diclofenac
These drugs deplete folic acid, iron, and vitamin C. NSAIDs also deplete melatonin.
Aspirin e.g. Bufferin, Bayer, Baby ASA
These drugs deplete all of the above as well as pantothenic acid (Vit. B5), calcium, potassium, and sodium. Folic acid or folate is a water-soluble vitamin eliminated from the urine like most B vitamins, and is destroyed by many different drugs. A three times per day multi-vitamin/mineral supplement that provides at least 300 mcg of folic acid per capsule is ideal. The highest food sources of folate are dark leafy greens, asparagus, broccoli, and legumes.
Statin Drugs
e.g. Mevacor, Pravachol, Zocor, Lipitor
These drugs deplete Omega-3 fatty acids, Vitamin K2, and CoQ10-each an important nutrient for the health of the cardiovascular system. In a March 2015 PubMed journal article, the authors state: “the epidemic of heart failure and atherosclerosis that plagues the modern world may paradoxically be aggravated by the pervasive use of statin drugs.” In order to protect oneself from the adverse effects of these drugs, it is advisable to supplement with the following: vitamin K2-M7, a fish oil Omega-3 blend, and at least 100 mg of a high-quality CoQ10.
There is a growing realization in the medical community that long-term drug treatments of many of the most common drugs can deplete a number of vitamins and minerals and may be harming patients. As a consumer, check for possible drug-nutrient depletions and take the necessary steps to replenish the body’s nutrient levels.
MedicalXpress Breaking News-and-Events | June 07, 2019
People who use common heartburn drugs for months to years may face heightened risks of dying from heart disease, kidney failure or stomach cancer, a new study suggests.
The study included more than 200,000 US veterans. It's the latest to raise concerns over drugs called proton pump inhibitors (PPIs). They include prescription and over-the-counter drugs like Prilosec (omeprazole), Prevacid (lansoprazole) and Nexium (esomeprazole). And they rank among the top-selling medications in the US.
Research in recent years has linked prolonged PPI use to increased risks of various diseases and premature death.
These latest findings point to the specific causes of death tied to the drugs, said lead researcher Dr. Ziyad Al-Aly.
He stressed that the excess risks were relatively small. For example, over 10 years, 13% of PPI users died of a cardiovascular condition, including heart disease or stroke. That compared with just over 11% of people who used H2 blockers, another class of heartburn drug.
When the researchers weighed other factors—such as patients' age and chronic health conditions—PPI use was tied to a roughly 18% higher risk of cardiovascular death.
However, based on patients' medical records, many of those with PPI prescriptions had no documented need for one.
"That's unsettling," said Al-Aly, an assistant professor at Washington University School of Medicine in St. Louis.
"It suggests a lot of people were using a PPI without actually needing one," he said. "They could be taking a risk without deriving any benefit."
But an expert not involved in the study said it's unclear whether PPIs, themselves, are responsible for the higher death rates.
Dr. Lawrence Kim is a member of the American Gastroenterological Association's governing board. He said the current study, like others before it, is "observational"—that is, it used medical records to track patients' outcomes.
Those types of studies cannot prove cause and effect, Kim said. There may be other explanations for the higher risks seen among PPI users.
In 2017, Kim said, the gastroenterological association published a review of the research into the issue.
"The report concluded that the evidence supporting all of these risks was low- to very-low quality," he said. "Therefore, there's insufficient evidence to conclude that these adverse outcomes are likely to be an effect of the PPI therapy."
PPIs work by blocking the enzyme system that creates stomach acid. They are commonly prescribed for gastroesophageal reflux disease (GERD), where stomach acid chronically escapes into the esophagus (the tube connecting the mouth and stomach).
Many people with GERD can take a PPI for just a short time, Al-Aly said. That allows damaged tissue in the esophagus to heal. Then patients can switch to a different treatment, like an H2 blocker. Those medications include drugs such as Tagamet (cimetidine), Pepcid (famotidine) and Zantac (ranitidine).
"Most people don't need to be on a PPI for months or years," Al-Aly said.
In this study, the risks linked to PPIs rose with prolonged use. The odds of death over 10 years were 63% to 71% higher among patients who'd used the drugs for at least a year, vs those who'd used them for a few months.
However, some GERD patients do need long-term PPI treatment, Al-Aly and Kim said. That includes people with recurrent stomach ulcers or Barrett's esophagus—serious damage to the esophageal lining that can raise the risk of cancer.
Before you start a PPI, Al-Aly said, be sure you actually need one. The drugs are available over the counter, but they should not be used for more than a couple weeks without talking to a doctor, he said.
If you've used a PPI for a long time, Kim said, talk to your doctor about whether you need to continue.
According to the study, more than 15 million Americans have PPI prescriptions. And millions more buy them over the counter without a doctor's knowledge.
The findings were published recently in the journal BMJ. The veterans in the study—mostly older men—started on a PPI or H2 blocker between 2002 and 2004.
Over the next 10 years, 38% of PPI users died, as did nearly 36% of those on H2 blockers.
If PPIs contribute to deaths, it's unclear why. According to Al-Aly, lab research has hinted the drugs may cause dysfunction in the lining of the blood vessels, or disrupt the gut's immune function and normal bacterial makeup.
Impaired generation and signaling of nitric oxide (NO) contribute substantially to cardiovascular (CV) risk (CVR) associated with hypertension, hyperlipidemia, and diabetes mellitus. In our rapidly aging society, advanced age is, in itself, a consistent and independent CVR factor. Many processes involved in aging are modulated by NO. We therefore postulated that aging might be independently associated with impaired NO signaling.
Methods and Results
In a prospective cohort study of 204 subjects (mean age 63±6 at study entry), we evaluated the effects of 4 years of aging on parameters of NO generation and effect, including platelet aggregability and responsiveness to NO, and plasma concentrations of the NO synthase inhibitor, asymmetric dimethylarginine (ADMA). Clinical history, lipid profile, high‐sensitivity C‐reactive protein, routine biochemistry, and 25‐hydroxyvitamin D levels were obtained at study entry and after 4 years of follow‐up. Aging was associated with marked deterioration of responsiveness of platelets to NO (P<0.0001) and increases in plasma ADMA concentrations (P<0.0001). There was a significant correlation between changes in these parameters over time (r=0.2;P=0.013). On multivariable analyses, the independent correlates of deterioration of responsiveness of platelets to NO were female gender (β=0.17;P=0.034) and low vitamin D concentrations (β=0.16;P=0.04), whereas increases in ADMA were associated with presence of diabetes (β=0.16;P=0.03) and impaired renal function (β=0.2;P=0.004).
Impaired generation and signaling of nitric oxide (NO) contribute substantially to cardiovascular (CV) risk (CVR) associated with hypertension, hyperlipidemia, and diabetes mellitus. In our rapidly aging society, advanced age is, in itself, a consistent and independent CVR factor. Many processes involved in aging are modulated by NO. We therefore postulated that aging might be independently associated with impaired NO signaling.
Methods and Results
In a prospective cohort study of 204 subjects (mean age 63±6 at study entry), we evaluated the effects of 4 years of aging on parameters of NO generation and effect, including platelet aggregability and responsiveness to NO, and plasma concentrations of the NO synthase inhibitor, asymmetric dimethylarginine (ADMA). Clinical history, lipid profile, high‐sensitivity C‐reactive protein, routine biochemistry, and 25‐hydroxyvitamin D levels were obtained at study entry and after 4 years of follow‐up. Aging was associated with marked deterioration of responsiveness of platelets to NO (P<0.0001) and increases in plasma ADMA concentrations (P<0.0001). There was a significant correlation between changes in these parameters over time (r=0.2; P=0.013). On multivariable analyses, the independent correlates of deterioration of responsiveness of platelets to NO were female gender (β=0.17; P=0.034) and low vitamin D concentrations (β=0.16; P=0.04), whereas increases in ADMA were associated with presence of diabetes (β=0.16; P=0.03) and impaired renal function (β=0.2; P=0.004).
Conclusions
Aging is associated with marked impairment of determinants of NO generation and effect, to an extent which is commensurate with adverse impact on CV outcomes. This deterioration represents a potential target for therapeutic interventions.
FDA Drug Safety Communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes [ 7-9-2015 ] Safety Announcement The U.S. Food and Drug Administration (FDA) is strengthening an existing label warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) increase the chance of a heart attack or stroke. Based on our comprehensive review of new safety information, we are requiring updates to the drug labels of all prescription NSAIDs. As is the case with current prescription NSAID labels, the Drug Facts labels of over-the-counter (OTC) non-aspirin NSAIDs already contain information on heart attack and stroke risk. We will also request updates to the OTC non-aspirin NSAID Drug Facts labels. Patients taking NSAIDs should seek medical attention immediately if they experience symptoms such as chest pain, shortness of breath or trouble breathing, weakness in one part or side of their body, or slurred speech. NSAIDs are widely used to treat pain and fever from many different long- and short-term medical conditions such as arthritis, menstrual cramps, headaches, colds, and the flu. NSAIDs are available by prescription and OTC. Examples of NSAIDs include ibuprofen, naproxen, diclofenac, and celecoxib (see Table 1 for a list of NSAIDs). The risk of heart attack and stroke with NSAIDs, either of which can lead to death, was first described in 2005 in the Boxed Warning and Warnings and Precautions sections of the prescription drug labels. Since then, we have reviewed a variety of new safety information on prescription and OTC NSAIDs, including observational studies,1 a large combined analysis of clinical trials,2 and other scientific publications.1 These studies were also discussed at a joint meeting of the Arthritis Advisory Committee and Drug Safety and Risk Management Advisory Committee held on February 10-11, 2014 External Link Disclaimer. Based on our review and the advisory committees’ recommendations, the prescription NSAID labels will be revised to reflect the following information: The risk of heart attack or stroke can occur as early as the first weeks of using an NSAID. The risk may increase with longer use of the NSAID. The risk appears greater at higher doses. It was previously thought that all NSAIDs may have a similar risk. Newer information makes it less clear that the risk for heart attack or stroke is similar for all NSAIDs; however, this newer information is not sufficient for us to determine that the risk of any particular NSAID is definitely higher or lower than that of any other particular NSAID. NSAIDs can increase the risk of heart attack or stroke in patients with or without heart disease or risk factors for heart disease. A large number of studies support this finding, with varying estimates of how much the risk is increased, depending on the drugs and the doses studied. In general, patients with heart disease or risk factors for it have a greater likelihood of heart attack or stroke following NSAID use than patients without these risk factors because they have a higher risk at baseline. Patients treated with NSAIDs following a first heart attack were more likely to die in the first year after the heart attack compared to patients who were not treated with NSAIDs after their first heart attack. There is an increased risk of heart failure with NSAID use. We will request similar updates to the existing heart attack and stroke risk information in the Drug Facts labels of OTC non-aspirin NSAIDs. In addition, the format and language contained throughout the labels of prescription NSAIDs will be updated to reflect the newest information available about the NSAID class.
Next time you reach into the medicine cabinet seeking relief for a headache, backache or arthritis, be aware of important safety information for non-steroidal anti-inflammatory drugs.
FDA is strengthening an existing warning in prescription drug labels and over-the-counter (OTC) Drug Facts labels to indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) can increase the chance of a heart attack or stroke, either of which can lead to death. Those serious side effects can occur as early as the first few weeks of using an NSAID, and the risk might rise the longer people take NSAIDs. (Although aspirin is also an NSAID, this revised warning doesn’t apply to aspirin.)
The OTC drugs in this group are used for the temporary relief of pain and fever. The prescription drugs in this group are used to treat several kinds of arthritis and other painful conditions. Because many prescription and OTC medicines contain NSAIDs, consumers should avoid taking multiple remedies with the same active ingredient.
The Risks and What’s New
Prescription NSAIDs are an important treatment for the symptoms of many debilitating conditions, including osteoarthritis, rheumatoid arthritis, gout and other rheumatological and painful conditions. OTC NSAIDs are used to temporarily reduce fever and to treat minor aches and pains such as headaches, toothaches, backaches, muscular aches, tendonitis, strains, sprains and menstrual cramps. Common OTC NSAIDs include ibuprofen (Motrin, Advil) and naproxen (Aleve). In addition, some combination medicines that relieve various symptoms, such as multi-symptom cold products, contain NSAIDs.
“Be careful not to take more than one product that contains an NSAID at a time,” says Karen M. Mahoney, M.D., deputy director of FDA’s Division of Nonprescription Drug Products. How will you know? Check the list of active ingredients in the Drug Facts label.
The labels for both prescription NSAIDs and OTC NSAIDs already have information on heart attack and stroke risk. In the coming months, FDA will require manufacturers of prescription NSAIDs to update their labels with more specific information about heart attack and stroke risks. FDA will also request that the manufacturers of OTC NSAIDs update the heart attack and stroke risk information in Drug Facts labels.
FDA added a boxed warning to prescription drug labels for this risk in 2005. More recent data and information are prompting FDA to update NSAID labeling. Today we know that the risk of heart attack and stroke may occur early in treatment, even in the first weeks.
“There is no period of use shown to be without risk,” says Judy Racoosin, M.D., M.P.H., deputy director of FDA’s Division of Anesthesia, Analgesia, and Addiction Products.
People who have cardiovascular disease, particularly those who recently had a heart attack or cardiac bypass surgery, are at the greatest risk for cardiovascular adverse events associated with NSAIDs.
FDA is adding information in the drug label for people who already have had a heart attack. This vulnerable population is at an increased risk of having another heart attack or dying of heart attack-related causes if they’re treated with NSAIDs, according to studies.
But the risk is also present in people without cardiovascular disease. “Everyone may be at risk – even people without an underlying risk for cardiovascular disease,” Racoosin adds.
What Consumers Should Do
NSAIDs are effective treatments for pain, inflammation and fever. Consumers can still take them but should be aware of this increased risk of heart attack or stroke, especially at higher doses.
“As always, consumers must carefully read the Drug Facts label for all nonprescription drugs. Consumers should carefully consider whether the drug is right for them, and use the medicine only as directed. Take the lowest effective dose for the shortest amount of time possible,” Mahoney says.
When using prescription NSAIDs, read the consumer-friendly Medication Guide attached to your filled prescription, which provides important safety information.
If you have heart disease or high blood pressure, consult a health care provider before using an NSAID. Balance the benefits of NSAIDs with the possible risks and weigh your options. If you take low-dose aspirin for protection against heart attack and stroke, you should know that some NSAIDs, including ibuprofen and naproxen, can interfere with that protective effect.
Stop taking NSAIDs and seek medical help if you experience symptoms that might signal heart problems or stroke, such as chest pain, trouble breathing, sudden weakness in one part or side of the body, or sudden slurred speech.
Reduce your risk factors for heart disease and stroke. “Smoking, high blood pressure, high cholesterol and diabetes are significant risk factors for these conditions,” Mahoney says. “If you smoke, work on quitting. See your doctor regularly to find out if you have these other strong risk factors, and commit yourself to taking care of them and of your health.”
Background—The frequency with which non-steroidal anti-inflammatory drugs (NSAIDs) increase small intestinal permeability and cause inflammation is uncertain.
Aims—To examine small intestinal permeability and inflammation in a large number of patients on long term NSAIDs.
Methods—Sixty eight patients receiving six different NSAIDs for over six months underwent combined absorption-permeability tests at three different test dose osmolarities (iso-, hypo-, and hyperosmolar). Two hundred and eighty six patients on 12 different NSAIDs underwent indium-111 white cell faecal excretion studies to assess the prevalence and severity of intestinal inflammation.
Results—The iso- and hyperosmolar tests showed significant malabsorption of 3–0-methyl-D-glucose, D-xylose, andL-rhamnose. Intestinal permeability changes were significantly more pronounced and frequent with the hypo- and hyperosmolar as opposed to the iso-osmolar test. Sequential studies showed that four and nine patients (of 13) developed inflammation after three and six months treatment with NSAIDs, respectively. There was no significant difference (p>0.1) in the prevalence (54–72%) or severity of intestinal inflammation in the 286 patients taking the various NSAIDs apart from those on aspirin and nabumetone, these having no evidence of intestinal inflammation. There was no significant correlation between the inflammatory changes and age, sex, dose of NSAID, length of disease, or NSAID ingestion.
Conclusions—Intestinal permeability test dose composition is an important factor when assessing the effects of NSAIDs on intestinal integrity. All the conventional NSAIDs studied were equally associated with small intestinal inflammation apart from aspirin and nabumetone which seem to spare the small bowel.
NSAID-Induced Acute Phase Response is Due to Increased Intestinal Permeability and Characterized by Early and Consistent Alterations in Hepatic Gene Expression
Toxicogenomics using a reference database can provide a better understanding and prediction of toxicity, largely by creating biomarkers that tie gene expression to actual pathology events. During the course of building a toxicogenomic database, an observation was made that a number of non-steroidal anti-inflammatory compounds (NSAIDs) at supra-pharmacologic doses induced an acute phase response (APR) and displayed hepatic gene expression patterns similar to that of intravenous lipopolysaccharide (LPS). Since NSAIDs are known to cause injury along the gastrointestinal tract, it has been suggested that NSAIDs increase intestinal permeability, allowing LPS and/or bacteria into the systemic circulation and stimulating an APR detectable in the liver. A short term study was subsequently conducted examining the effects of aspirin, indomethacin, ibuprofen, and rofecoxib to rats and a variety of endpoints were examined that included serum levels of inflammatory cytokines, histologic evaluation, and hepatic gene expression. Both indomethacin and ibuprofen injured the gastrointestinal tract, induced an APR, and increased serum levels of LPS, while rofecoxib and aspirin did not affect the GI tract or induce an APR. In treatments that eventually showed a systemic inflammatory response, hepatic expression of many inflammatory genes was noted as early as 6 hours after treatment well before alterations in traditional clinical pathology markers were detected. This finding led to the creation of a hepatic gene expression biomarker of APR that was effectively shown to be an early identifier of imminent inflammatory injury. In terms of the relative gastrointestinal safety and the NSAIDs studied, an important safety distinction can be made between the presumptive efficacious dose and the APR-inducing dose for indomethacin (1—2-fold), ibuprofen (5-fold), and rofecoxib (~250-fold). Our data support the notion that NSAID-induced intestinal injury results in leakage of commensural bacteria and/or LPS into the circulation, provoking a systemic inflammatory response and that hepatic gene expression-based biomarkers can be used as early and sensitive biomarkers of APR onset.
The suggestion that the intestinal mucosa may be abnormally permeable and thus a site of antigen absorption in rheumatoid arthritis was tested by a 51Cr EDTA intestinal permeability test. Twelve patients with rheumatoid arthritis untreated by non-steroidal anti-inflammatory drugs (NSAIDs) had normal test results, while 12 NSAID-treated patients had increased intestinal permeability. Ten volunteers ingested aspirin, ibuprofen and indomethacin 8 and 1 hours before the study. The increased intestinal permeability was proportional to drug potency to inhibit cyclo-oxygenase. Intestinal permeability also increased following an indomethacin suppository, which suggests that the effect is systemically mediated. 111Indium leucocyte scintigrams and faecal collection showed no evidence of intestinal inflammation in 9 patients untreated by NSAIDs. Twenty-nine of 53 NSAID-treated patients showed abnormal localisation of 111indium in the right iliac fossa at 20 hours, and 32 of 49 patients had increased faecal excretion of 111indium. A 99mTc-porphyrin scan suggested that the main site of NSAID-induced intestinal inflammation was the small bowel. NSAIDs are thus shown to disrupt intestinal integrity and long term treatment leads to inflammation of the small intestine.
BMJ Case Rep. 2013 Aug 28;2013. pii: bcr2013200097. doi: 10.1136/bcr-2013-200097.
Clinical and histological resolution of collagenous sprue following gluten-free diet and discontinuation of non-steroidal anti-inflammatory drugs (NSAIDs).
Collagenous sprue is a rare small bowel enteropathy that has overlapping clinical features with coeliac disease; it is commonly associated with arthritic autoimmune conditions, which often require non-steroidal anti-inflammatory drugs (NSAIDs). In the limited published literature available, there are putative suggestions of a link between NSAID use and collagen deposition in intestinal subepithelia in such patients. The authors present a case of a 43-year-old woman with long-standing NSAID use for autoimmune polyarthropathy and positive coeliac antibodies. However, distal duodenal biopsies revealed a thickened band of subepithelial collagen with villous atrophic appearances consistent with collagenous sprue. The patient was treated with a gluten-free diet and her NSAIDs were discontinued. After 6 months, her gastrointestinal symptoms had resolved with complete histological resolution of the collagenous subepithelial bands and villous atrophy on duodenal biopsy.
Source: Karolinska Institutet Summary: The long-term use of over-the-counter (OTC) anti-inflammatory drugs can inhibit muscle growth in young, healthy individuals engaging in weight training, according to a new study. Share: FULL STORY The long-term use of over-the-counter (OTC) anti-inflammatory drugs can inhibit muscle growth in young, healthy individuals engaging in weight training, according to a new study from Karolinska Institutet, reporting on the effects of ibuprofen on the skeletal muscles and published in Acta Physiologica. Most mild analgesic and antipyretic OTC drugs, apart from paracetamol, are of the NSAID (non steroidal anti-inflammatory drugs) kind. These drugs are some of the most widely consumed in the world, and they all inhibit the so-called COX enzymes. In the present study, healthy 18 to 35-year-old men and women were randomly assigned to two groups, one that took a relatively high dose of NSAID (1,200 mg ibuprofen, which is a normal 24-hour dose) and one a relatively low dose (75 mg acetylsalicylic acid) every day for eight weeks. During the same period, the participants also engaged in supervised weight-training exercises for the thigh muscles two to three times a week. The researchers then measured certain variables, such as muscle growth, muscle strength and anti-inflammatory markers in the muscles. It was found that after eight weeks, the increase in muscle volume, as measured by MR imaging, was twice as large in the low-dose aspirin group as in the high-dose ibuprofen group. "The results are extremely interesting since the use of anti-inflammatory drugs is so globally widespread, not least amongst elite athletes and recreationally active individuals," says principal investigator Tommy Lundberg, researcher at Karolinska Institutet's Department of Laboratory Medicine. "We chose to look at the effect of ibuprofen as it is the most well-studied anti-inflammatory drug on the market, but we believe that high doses of all types of OTC NSAIDs have similar effects." Muscle strength was also impaired with high doses of anti-inflammatory drugs, but not to such a pronounced extent. Analyses of muscle biopsies showed that classical markers for inflammation were inhibited in the muscles of the ibuprofen group. "This suggests that muscular inflammation processes when combined with weight training are beneficial to the long-term development of new muscle mass, at least in the young," says Dr Lundberg. "Our results suggest that young people who do weight training to increase their muscle mass should avoid regular high doses of anti-inflammatory drugs." The results partly contradict studies in older populations, which have indicated that anti-inflammatory drugs can protect against age-related muscle-mass loss. The researchers think, therefore, that the mechanism regulating muscle mass differs between the old and the young. https://www.ncbi.nlm.nih.gov/pubmed/10660873?dopt=Abstract
Abdominal cramping, nausea, diarrhea, and GI bleeding are often reported in long-distance runners. This study set out to determine the effects of prolonged (2-4 hrs) exercise and NSAID ingestion on gastric and intestinal permeability during the first 5 hrs following the 1996 Chicago Marathon. Thirty-four healthy volunteers (20 M, 14 F; ages 30-50) completed the race and ingested the test solution (5 g sucrose, 5 g lactulose, 2 g rhamnose, in 40 ml water) within 10-15 min. The urinary excretion ratio of lactulose/rhamnose was used to assess small intestine permeability; sucrose excretion was used to evaluate gastric impairment. There were no significant differences for mean training mileage, postrace rectal temperature, and percent dehydration between runners who ingested NSAIDs and those who did not. In all, 75% of subjects reported aspirin or ibuprofen ingestion before or during the race. Runners who ingested ibuprofen had significant elevations in urinary lactulose excretion and lactulose/rhamnose ratio, whereas those who ingested aspirin or who did not ingest either NSAID had no significant differences in urinary excretion of lactulose, rhamnose, sucrose, or lactulose/rhamnose ratio compared to resting controls. Thirteen of the 26 NSAID users and 4 of the 8 non-users reported GI symptoms. It is concluded that (a) ibuprofen but not aspirin ingestion during prolonged exercise may increase gastrointestinal permeability and lead to GI symptoms, and (b) prolonged exercise alone can produce GI symptoms.
Nonsteroidal anti-inflammatory drugs are commonly used by athletes to prevent anticipated exercise-induced pain, thereby putatively improving physical performance. However, these drugs may have potentially hazardous effects on the gastrointestinal (GI) mucosa during strenuous physical exercise. The aim of the current study was to determine the effect of oral ibuprofen administration before exercise on GI integrity and barrier function in healthy individuals.
METHODS:
Nine healthy, trained men were studied on four different occasions: 1) 400 mg ibuprofen twice before cycling, 2) cycling without ibuprofen, 3) 400 mg ibuprofen twice at rest, and 4) rest without ibuprofen intake. To assess small intestinal injury, plasma intestinal fatty acid binding protein (I-FABP) levels were determined, whereas urinary excretion of orally ingested multisugar test probes was measured using liquid chromatography and mass spectrometry to assess GI permeability.
RESULTS:
Both ibuprofen consumption and cycling resulted in increased I-FABP levels, reflecting small intestinal injury. Levels were higher after cycling with ibuprofen than after cycling without ibuprofen, rest with ibuprofen, or rest without ibuprofen (peak I-FABP, 875 ± 137, 474 ± 74, 507 ± 103, and 352 ± 44 pg·mL, respectively, P < 0.002). In line, small intestinal permeability increased, especially after cycling with ibuprofen (0-2 h urinary lactulose/rhamnose ratio, 0.08 (0.04-0.56) compared with 0.04 (0.00-0.20), 0.05 (0.01-0.07), and 0.01 (0.01-0.03), respectively), reflecting loss of gut barrier integrity. Interestingly, the extent of intestinal injury and barrier dysfunction correlated significantly (RS = 0.56, P < 0.001).
CONCLUSION:
This is the first study to reveal that ibuprofen aggravates exercise-induced small intestinal injury and induces gut barrier dysfunction in healthy individuals. We conclude that nonsteroidal anti-inflammatory drugs consumption by athletes is not harmless and should be discouraged.
This article has been cited by other articles in PMC.
There are theoretical reasons for believing that selective serotonin reuptake inhibitors (SSRIs), widely used to treat depression, might increase the risk of gastrointestinal bleeding. Gastroprotective drugs are advocated for high risk patients taking non-steroidal anti-inflammatory drugs, another class of drug that causes gastrointestinal bleeding. What is the evidence that this advice should be extended to patients receiving SSRIs?
Serotonin is released from platelets in response to vascular injury and promotes vasoconstriction and a change in the shape of the platelets that leads to aggregation.1 Platelets cannot themselves synthesise serotonin. SSRIs inhibit the serotonin transporter, which is responsible for the uptake of serotonin into platelets. It could thus be predicted that SSRIs would deplete platelet serotonin, leading to a reduced ability to form clots and a subsequent increase in the risk of bleeding.
We have reviewed the published database studies on the relation between SSRI use and gastrointestinal bleeding. Four of these studies compared the risk of an upper gastrointestinal bleed in those prescribed SSRIs with those who were not. The odds ratios of a bleed in an SSRI-treated patient ranged from 1.38 to 3.6: 3.0 (95% confidence interval 2.1 to 4.4),2 3.6 (2.7 to 4.7),3 2.1 (0.6 to 8.3),4 and 1.38 (0.82 to 2.34).5This roughly threefold increase in risk may also hold for other types of bleeding. Movig et al reported that patients taking SSRIs were 3.71 (1.35 to 10.18) times more likely to require a blood transfusion during orthopaedic surgery than patients not taking them.6 Meijer el al reported that women taking SSRIs with a high affinity for the serotonin transporter were 3.0 (0.8 to 4.9) times more likely to experience abnormal uterine bleeding than women who took antidepressants with low affinity for this transporter.4
An association between the risk of bleeding and increasing affinity for the serotonin transporter has been noted in several studies,2,4,7 although the confidence intervals around the quoted odds ratios overlap considerably. Clomipramine, fluoxetine, sertraline, and paroxetine have a high affinity for the serotonin transporter while citalopram, fluvoxamine, and venlafaxine have intermediate affinity. Low affinity drugs include doxepin, mirtazepine, moclobemide, and nortriptyline.
Risk decreases to the same level as controls in past users of SSRIs, indicating that bleeding is likely to be associated with the drug rather than the illness it was prescribed for.3 The association also holds when age, gender, and the effects of other drugs such as aspirin and non-steroidal anti-inflammatory drugs are controlled for.
The mechanisms by which non-steroidal antiinflammatory drugs and SSRIs are associated with gastrointestinal bleeding are different. Non-steroidal anti-inflammatory drugs directly damage the gastrointestinal mucosa, while SSRIs reduce the effectiveness of the normal clotting mechanism. Aspirin does both. The absolute additional risk of an upper gastrointestinal bleed (requiring admission to hospital) with an SSRI prescribed alone is about 1 in 300 patient years, but co-prescription of SSRIs with aspirin increases the risk to 1 in 200 and with non-steroidal anti-inflammatory drugs to 1 in 80.3 The risk with a non-steroidal drug alone is 1 in 200.8
The well established association between nonsteroidal anti-inflammatory drugs and upper gastrointestinal bleeding is estimated to result in 700-2000 deaths/year in the UK.8,9 This has led to the recommendation that patients in high risk groups should receive gastroprotection in the form of an H2 antagonist, proton pump inhibitor, or misoprostil.10 High risk groups are defined as patients older than 65 years, those with a history of peptic ulcer or gastrointestinal bleed, those who are debilitated, and those receiving other drugs that are associated with an increased risk of bleeding such as warfarin and corticosteroids. Yet only misoprostol has been proved to reduce the risk of serious bleeds. Proton pump inhibitors have been shown to reduce endoscopically diagnosed mucosal damage and heal ulcers induced by non-steroidal anti-inflammatory drugs but not to reduce the incidence of severe gastrointestinal bleeds.10
SSRIs are widely prescribed in the general population and for elderly people. Almost 14 million prescriptions were dispensed in community pharmacies in England in 2003.11 They are recommended by the National Institute for Health and Clinical Excellence as first line treatments in patients with at least moderate depression.12
Gastroprotection is unlikely to be justified in patients who receive SSRIs alone, but those who are also taking non-steroidal anti-inflammatory drugs or aspirin are clearly at increased risk. This increased risk may also apply to those who are very old or have a history of gastrointestinal bleeding. The use of antide-pressants with low affinity for the serotonin transporter should be considered in these patients. Gastroprotective agents have not been shown to reduce the risk of bleeds associated with SSRIs alone or in combination with non-steroidal drugs, but until such studies are conducted we recommend that SSRIs are added to the list of drugs that increase the risk of bleeding induced by non-steroidal anti-inflammatory drugs and suggest that gastroprotection should be considered in patients who are prescribed both SSRIs and non-steroidal anti-inflammatory drugs or aspirin, including those under the age of 65.
All drugs that affect serotonin reuptake were associated with some increased risk of ICH.
Risk of intracranial hemorrhage (ICH) associated with selective serotonin reuptake inhibitors (SSRIs) increases with the strength of the agent used (ICH), according to results from a large-scale population-based study published in JAMA Neurology.1
Depression has been linked to an increased risk for hemorrhagic stroke, independent of therapy type.2 Approximately two-thirds of SSRI prescriptions are for depression.3 Previous observational studies of the incidence of ICH with SSRI use have demonstrated conflicting results,4 which may have been due to a potential indication bias to the diagnosis of depression.
The current study was designed to specifically reduce this bias. “Separating the effect of depression from the effect of antidepressants on the risk of intracranial bleeding is difficult,” explained lead author Christel Renoux, MD, PhD, Assistant Professor of neurology and neurosurgery at McGill University in Montreal, Quebec, Canada and a researcher at the Lady Davis Research Institute. “This is why we chose to use a comparator group of patients also treated with antidepressants instead of a comparator group of patients not treated with antidepressants,” she told Neurology Advisor.
Dr Renoux and colleagues examined data from a population-based cohort of 1,363,990 people prescribed antidepressants. SSRIs are among the most commonly prescribed medictions.13,14 Among the participants, 773,364 (56.7%) were new users of SSRIs, compared with 534,587 (39.2%) new users of TCAs and 56,039 (4.1%) new users of other antidepressants. Mean age was 47.9 years, and gender distribution was 63.2% female to 36.8% male. The incidence rate for ICH over a mean follow-up period of 5.8 years was quite low at 3.8 (95% CI, 3.7-3.9) per 10,000, indicating a rare occurrence.
The investigators found that the use of all drugs that affect serotonin reuptake were associated with some increased risk of ICH compared to those using tricyclic antidepressants (relative risk (RR)= 1.17; 95% CI, 1.02-1.35), but these risks were increased by 25% among the participants taking the strongest SSRIs (RR= 1.25; 95% CI, 1.01-1.54) compared to those taking the weakest. Incremental increases between the strengths of different agents were associated with more modest increases in risk, which the authors noted accounted for the addition of relatively few new ICH events.
Concomitant use of oral anticoagulants among people taking SSRIs contributed to a significantly higher increased risk for ICH (RR=1.73; 95% CI, 0.89-3.39). The RR across all groups (high, medium, and low-strength SSRIs, with and without anticoagulants) was highest during the first 30 days of use, decreasing thereafter.
Although ICH was a relatively rare occurrence, the serious consequences of stroke warrant concern. The results of this large-scale study support a cautious approach to prescribing high-strength SSRIs, particularly in combination with anticoagulant therapies. “We showed that spontaneous ICH is slightly increased with antidepressants with strong serotonin reuptake inhibition properties. Although this event is quite rare, this potential risk must be kept in mind in patients at higher risk of intracranial bleeding,” Dr. Renoux said.
QuestionWhat is the risk for intracranial hemorrhage associated with selective serotonin reuptake inhibitors and with antidepressants according to the strength of the inhibition of serotonin reuptake?
FindingsIn this population-based cohort study, the use of selective serotonin reuptake inhibitors and more generally of antidepressants that are strong inhibitors of serotonin reuptake were associated with an increased risk for intracranial hemorrhage compared with tricyclic antidepressants, particularly in the first 30 days of use. Concomitant use of oral anticoagulants further increased this risk.
MeaningAntidepressants with strong serotonin reuptake inhibition properties increase the risk for intracranial hemorrhage, and caution must be exerted with concomitant use of anticoagulants.
Abstract
ImportanceSelective serotonin reuptake inhibitors (SSRIs) may increase the risk for spontaneous intracranial hemorrhage (ICH), an effect that is in theory linked to the strength of inhibition of serotonin reuptake of an antidepressant. However, whether antidepressants that are strong inhibitors of serotonin reuptake actually increase the risk for ICH and the effect of concomitant use of antithrombotics are unknown.
ObjectivesTo assess the risk for ICH associated with the use of SSRIs compared with tricyclic antidepressants (TCAs) among new users of antidepressants and according to the relative affinity of the antidepressant for the serotonin transporter and to assess whether concomitant use of antithrombotics modifies this risk.
Design, Setting, and ParticipantsThis population-based cohort study included new users of antidepressants 18 years or older from January 1, 1995, to June 30, 2014. More than 650 general practices in the United Kingdom contributing to the Clinical Practice Research Datalink enrolled patients. with use of a nested case-control approach, each case of a first ICH identified during follow-up was matched with as many as 30 control individuals by age, sex, calendar time, and duration of follow-up. Follow-up was completed on October 31, 2014.
InterventionsCurrent use of SSRIs compared with TCAs and strong compared with weak serotonin reuptake inhibitors.
Main Outcomes and MeasuresIncidence rate ratios (RRs) of ICH.
ResultsAmong a cohort of 1 363 990 incident users of antidepressants (36.8% male; 63.2% female; mean [SD] age, 47.9 [18.5] years), 3036 cases of ICH were identified during follow-up and matched to 89 702 controls. Current SSRI use was associated with an increased risk for ICH (RR, 1.17; 95% CI, 1.02-1.35) relative to TCAs, highest during the first 30 days of use (RR, 1.44; 95% CI, 1.04-1.99), and translating in very few additional events. Similarly, the risk was increased by 25% with strong inhibitors (RR, 1.25; 95% CI, 1.01-1.54) and highest during the first 30 days of use (RR, 1.68; 95% CI, 0.90-3.12). Concomitant use of anticoagulants may increase the risk substantially (RR, 1.73; 95% CI, 0.89-3.39).
Conclusions and RelevanceThe use of SSRIs and more generally of antidepressants with strong inhibition of serotonin reuptake are associated with an increased risk for ICH, particularly in the first 30 days of use and when used concomitantly with oral anticoagulants.
Researchers at UC San Francisco have found that older people with persistent pain show quicker declines in memory as they age and are more likely to have dementia years later, an indication that chronic pain could somehow be related to changes in the brain that contribute to dementia.
https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2629448
