Death by Medicine, Revisited (part IV)
by Gary Null, PhD.; Martin Feldman, MD; Debora Rasio, MD; and Carolyn Dean, MD, ND; edited by Helen Buyniski
Problems with Drugs
Prescription drugs constitute the major treatment modality of scientific medicine. With the discovery of the “germ theory,” medical scientists convinced the public that infectious organisms were the cause of illness. Finding the “cure” for these infections proved much harder than anyone imagined. From the beginning, chemical drugs promised much more than they delivered. But far beyond not working, the drugs also caused incalculable side effects. The drugs themselves, even when properly prescribed, have side effects that can be fatal. But human error can make the situation much worse.
In December 2017, a nurse at Vanderbilt University Medical Center, intending to administer a mild sedative to a claustrophobic patient, instead injected them with a lethal dose of a paralyzing nerve blocker used to execute death row convicts. The patient had presented with a brain bleed and partial vision loss but was otherwise stable; doctors opted to do a full-body PET scan and sent the patient to the radiology department. When they expressed worry over being placed in the scanner, a doctor prescribed the sedative Versed. A nurse, instead, injected the patient with vecuronium, which blocks neuromuscular junctions and causes paralysis. During the scan, the patient suffered cardiac arrest and partial brain death. They died a day later.
The nurse explained the medication switch had occurred because they couldn’t find Versed in the medication cabinet. Typing in the first two letters of the drug name, they hit an “override” setting that allowed them to retrieve the first medication on the list: vecuronium. The drug is part of a cocktail used to execute prisoners; it is also used to keep patients still during surgery.1
A Vanderbilt doctor then attempted to conceal the mistake by telling the Davidson County Medical Examiner that the patient had died from “bleeding” – and that anything else was “hearsay.” The examiner, believing the patient had died of natural causes, did not investigate the death; the medication error had not been included in the patient’s chart, and there was no reason to suspect the doctor. When the malfeasance came to light, it nearly cost Vanderbilt its Medicare reimbursement status – but they were ultimately able to dodge the bullet by submitting a “corrective action plan.”2
Drug iatrogenesis may also include anesthesia. Major complications of spinals and epidurals include damage to nerves or the spinal cord by infection (meningitis and abscess), bleeding and blood clots (hematoma), direct damage to the nerves (needle injury or chemical injury) and poor blood supply to the spinal cord (ischemia). All can cause permanent nerve injury including paralysis. A further complication occurs when a “drug switch” or “route switch” occurs: either the wrong drug is delivered as an epidural or spinal (drug switch) or a drug that should have been administered intravenously is used in as an epidural or spinal, or vice versa (route switch). The sensitivity of the nervous system and the type of drugs used means these mistakes can be fatal.3
“Although anesthesia is considered very safe, it is not risk free. . . .Uncommon complications include chest infections and difficulty breathing, damage to teeth, lips or tongue, and awareness under general anesthesia The rare and very rare complications of anesthesia include damage to the eyes, serious allergic reactions to medications, nerve damage, equipment failure and death. . . .
Deaths caused solely by anesthesia are very rare, and are usually the result of several serious complications together [such as allergies], your previous medical conditions, your body size, your surgical procedure, and your habits like smoking, [all of which may] influence the risks of certain complications Risk cannot be completely avoided, but the combination of your anesthesia professional’s training, modern [sterilized] equipment used to deliver anesthesia and monitor your condition, and modern medications have made anesthesia a much safer procedure in recent years.”4
A 2002 study showed that 20% of hospital medications for patients had dosage errors. Nearly 40% of these errors were considered potentially harmful to the patient. In a typical 300-bed hospital, the number of errors per day was 40.5
Problems involving patients’ medications were even higher the following year. The error rate intercepted by pharmacists in a 2003 study was 24%, raising the potential minimum number of inpatients harmed by prescription drugs to 417,908.6
In 2014, the Institute of Medicine found that medication errors caused 1 of 131 outpatient deaths and 1 of 854 inpatient deaths.7
Adverse Drug Reactions
A study conducted by Lazarou et.al. analyzed records for prescribed medications for 33 million US hospital admissions in 1994. It discovered 2.2 million serious injuries due to prescribed drugs; 2.1% of inpatients experienced a serious adverse drug reaction, 4.7% of all hospital admissions were due to a serious adverse drug reaction, and fatal adverse drug reactions occurred in 0.19% of inpatients and 0.13% of admissions.8 The authors estimated that 106,000 deaths occur annually due to adverse drug reactions; using current figures for the number of hospital inpatients and calculating with the same formula yields 112,640 deaths.
A 2013 study of the clinical and economic burden of adverse drug reactions published in the Journal of Pharmacology and Pharmacotherapy found that ADRs may cost the US up to $30.1 billion per year.9
Studies of adverse drug reactions show that their frequency has increased sharply since Lazarou et.al.’s landmark publication. A 2012 meta-analysis published in Pharmacoepidemiology and Drug Safety found adverse drug reactions occurred in 16.88% of hospitalized patients.10 Given the 2018 figure of 35.2 million admissions across all US hospitals, that amounts to 5.9 million adverse drug reactions.
Serious adverse drug reactions commonly emerge after FDA approval of the drugs involved. The safety of new agents cannot be known with certainty until a drug has been on the market for many years. Not only are clinical trial populations too small to surface some rare adverse events, but most trials are too short for patients to manifest the effects of taking a drug long-term, and clinical trials do not take drug-drug interactions into account – a serious issue, given that the average American takes four prescription medications.11 A 2009 study of 133 reports on randomized clinical trials found nearly a third (32.3%) of published reports included limited data on adverse events, often describing only the most common events. Only 52% reported the number of patient drop-outs due to ADRs.12
In 2014, according to the CDC, almost 1.3 million people visited emergency rooms due to adverse drug events, and nearly 124,000 died because of those events.13 As many as 17 percent of hospitalized patients may suffer from an ADE while in the hospital.14 A 2006 study found one preventable error for every five doses of medication administered, with most errors occurring due to dose omission, wrong dose, wrong drug, wrong administration technique, or drug-drug interactions.15
Perhaps most worryingly, a study published in Clinical Toxicology in 2017 found a more than 100 percent increase in the number of serious medication errors per 100 US residents between 2000 and 2012 – from 1.09 to 2.28. The frequency and rate of medication error increased for all age groups except children under six, for whom it increased early in the study and then dropped off after 2005 – a decline possibly associated with a reduction in use of cough and cold medicines, which were subject to a Food and Drug Administration recommendation in 2007 that warned against giving them to children.16 The spike in medication error is no surprise – the total number of prescriptions filled by Americans increased by 85% from 1997 to 2016, while the total US population increased just 21%.17 According to a 2017 Consumer Reports survey, 55% of Americans take at least one prescription drug, with the average being four prescriptions, and fully 75% take at least one over-the-counter drug. More than a third of the drug-takers report their doctor has never stopped to review their chart to see if they can discontinue a medication. Instead, more drugs are prescribed to treat the side effects of previous drugs. It is a pharmacological house of cards.18
Children are especially vulnerable to medication errors, according to a 2014 study which found a child receives the wrong medication or the wrong dosage every eight minutes in the US. The younger a child was, the more likely they were to be the victim of a medication error.19
In a New England Journal of Medicine study, an alarming one in four patients suffered observable side effects from the more than 3.34 billion prescription drugs filled in 2002.20 One of the doctors who produced the study was interviewed by Reuters and commented, “With these 10-minute appointments, it’s hard for the doctor to get into whether the symptoms are bothering the patients.”21
William Tierney, who editorialized on the New England Journal study, wrote, “Given the increasing number of powerful drugs available to care for the aging population, the problem will only get worse.” Indeed, a 2018 study found preventable ADRs were responsible for hospital admissions in 19.5% of elderly patients with those taking multiple drugs at especially high risk.22 Another study found elderly patients admitted to the hospital for ADRs were more likely to die than their peers admitted for other reasons, and half the admissions were related to drug-drug interactions – a major risk in a population where 86% are taking more than one prescription drug.23
The drugs with the worst record of side effects were opioid pain relievers, nonsteroidal anti-inflammatory drugs (NSAIDs), anticoagulants, beta blockers, and diuretics.24 25
Reuters also reported that prior research has suggested that nearly 5% of hospital admissions (over 1 million per year) are the result of drug side effects, but that most of the cases are not documented as such. The study found that one of the reasons for this failure is that in nearly two thirds of the cases, doctors could not diagnose drug side effects or the side effects persisted because the doctor failed to heed the warning signs.
In 2017, the world pharmaceutical market did $1.143 trillion in sales; the US market accounted for 48.1 percent of that total.26 With just 4.3% of the world’s population, the US sells almost half of the world’s drugs.
Underreporting of Side Effects
Standard medical pharmacology texts admit that relatively few doctors ever report adverse drug reactions to the FDA.27 The reasons range from not knowing such a reporting system exists to fear of being sued. Yet the public depends on this tremendously flawed system of voluntary reporting by doctors to know whether a drug or a medical intervention is harmful.
Pharmacology texts also tell doctors how hard it is to separate drug side effects from disease symptoms. Treatment failure is most often attributed to the disease and not the drug or doctor. Doctors are warned, “Probably nowhere else in professional life are mis- takes so easily hidden, even from ourselves.” 28 It may be hard to accept, but it is not difficult to understand why only about 1 in 20 side effects is reported to either hospital administrators or the FDA.29
If hospitals admitted to the actual number of errors for which they are responsible, they would come under intense scrutiny.
Jerry Phillips, associate director of the FDA’s Office of Post Marketing Drug Risk Assessment, confirmed the numbers. “In the broader area of adverse drug reaction data, the 250,000 reports received annually probably represent only 5% of the actual reactions that occur.”30 Dr. Jay Cohen, who has extensively researched adverse drug reactions, noted in 2001 that because only 5% of adverse drug reactions are reported, there were in fact 5 million medication reactions each year.31 In 2018, with 1.6 million reports of adverse events in the FDA’s database, the real number may be closer to 32.6 million.32
Looking at the FDA’s Adverse Event Reporting database, MedPage Today found a fivefold increase in reported adverse events from 2004 to 2015. Requirements adopted by the FDA in 2015 that mandate electronic reporting of adverse events by drug companies led to the single largest jump in the number of reported events in the FAERS database’s 20-year history that year.33 Some drug companies actually outsourced their adverse event reporting to Indian call centers to cut costs, sacrificing expert oversight to the almighty bottom line.34
An increase in consumer-reported events has also contributed to the spike in adverse event reporting, but enough of the increase is organic to be extremely worrying. From the 1.2 million adverse events reported under the new rules in 2015, the number has continued climbing, reaching a peak of 1.8 million in 2017 before dropping back to 1.6 million the following year. The Government Accountability Office continues to estimate that only 1 to 10 percent of all adverse reactions are reported.35
While the FDA still discourages use of the FAERS for research purposes, it has been beneficial in identifying problems with drugs after they are on the market – and highlighting flaws within the FDA’s own approval processes. In 2015, a transdermal sumatriptan patch called Zecuity was approved by the FDA after testing on just 58 people, none of whom reported problems even though a previous iteration of the patch had caused burns and skin lesions. After nine months on the market, with hundreds of reports of adverse events from scarring to burns, blisters and pain, the drug’s manufacturer, Teva, pulled it from the market.
The FDA has begun to embrace the FAERS as a stand-in for more rigorous clinical testing. FDA spokesperson Lyndsay Meyer explained, “It’s not always necessary to wait and go through a traditional development program before making a drug available to patients,” adding that the agency encourages healthcare providers and the public to report adverse drug events electronically.36
Medicating Our Feelings
Patients seeking a more joyful existence and relief from worry, stress, and anxiety are frequently swayed by the messages endlessly displayed on TV and billboards. Often, instead of gaining relief, they fall victim to the myriad iatrogenic side effects of antidepressant medication.
Moreover, a whole generation of antidepressant users has been created from young people growing up on Ritalin®. Medicating young people and modifying their emotions must have some impact on how they learn to deal with their feelings. They learn to equate coping with drugs rather than with their inner resources. As adults, these medicated youth reach for alcohol, drugs, or even street drugs to cope.
According to JAMA, “Ritalin® acts much like cocaine.”37 Today’s marketing of mood-modifying drugs such as Prozac® and Zoloft® makes them not only socially acceptable, but almost a necessity in today’s stressful world.
You cannot turn on TV without hearing a pitch for drugs for social anxiety, depression, or lethargy. Note that when they tell you the side effects, they often show a pastoral scene of beauty, or a joyful activity, at the same time, so you will equate the obligatory warning of danger with a pleasant memory.
Doctors (not just consumers) are bombarded with psychoactive pharmaceutical propaganda, so they will prescribe certain drug products:
“In 2006 money from the pharmaceutical industry accounted for about 30 percent of the [American Psychiatric] Association’s $62.5 million in financing. About half of that money went to drug advertisements in psychiatric journals and exhibits at the annual meeting, and the other half to sponsor fellowships, conferences and industry symposiums at the annual meeting.”38
While the APA promised in March 2009 it would end pharmaceutical funding of continuing medical education seminars and convention lunches, two months later, the group accepted $1.7 million from pharmaceutical companies to fund its annual conference in San Francisco. Still, in 2015, it received just $5.6 million from the pharmaceutical industry, of a budget of $42.6 million.39
A 2017 study published in Social Science & Medicine analyzed the relationship between pharmaceutical company perks and psychotropic drug prescriptions. The researchers found that in states that banned gifts from pharmaceutical companies to doctors, uptake of costly new psychotropic drugs was reduced by up to 83 percent. Such a drastic reduction in prescribing is not difficult to understand. In 2011, pharmaceutical companies spent $15.7 billion on “detailing” – sending sales representatives to doctors to provide them with information, meals, gifts, and – of course – free samples to give to their patients.40
A study published in the American Journal of Medicine found that while 61% of doctors deny that pharmaceutical gift-giving influences their practices, only 16% believe their colleagues are similarly incorruptible.41 Most doctors may think they are immune to such bribes, but a 2016 ProPublica study confirmed that doctors who received more than $5,000 from drug companies were significantly more likely to prescribe brand-name medications than their peers.42
The 2010 Physician Payment Sunshine Act, a rare example of legislative pushback against the abuses of Big Pharma, created the Open Payments program, which collects and publishes data on relationships between pharmaceutical and medical device companies and healthcare providers. The public now has access to a searchable online database that tracks payments, gifts, meals, speaking fees, and other pharmaceutical company largesse bestowed upon doctors and teaching hospitals. It is not unreasonable to think that the passage of this law has contributed to more and more states banning pharmaceutical “detailing.”
To reach the widest audience possible, drug companies no longer simply target medical doctors with their marketing of antidepressants.
By 1995, drug companies had tripled the amount of money allotted to direct advertising of prescription drugs to consumers. The majority of this money is spent on seductive television ads. From 1996 to 2000, spending rose from $791 million to nearly $2.5 billion.43 By 2017, it had more than doubled again to $6.1 billion, which actually represented a slight drop from the previous year’s high of $6.5 billion and a quarter of the total pharmaceutical advertising budget for the US.44
While the drug companies maintain that direct-to-consumer advertising is educational, Dr. Sidney M. Wolfe of the Public Citizen Health Research Group in Washington, DC, argues that the public often is misinformed about these ads.45 People want what they see on television and are told to go to their doctors for a prescription. Doctors in private practice either acquiesce to their patients’ demands for these drugs or spend valuable time trying to talk patients out of unnecessary drugs. A 2006 study found that nearly three-quarters of drugs patients requested based on seeing an advertisement were medically unnecessary.46
Dr. Wolfe remarks that one important study found that people mistakenly believe that the “FDA reviews all ads before they are released and allows only the safest and most effective drugs to be promoted directly to the public.”47
A finding of a national survey of 643 physicians by Harvard’s Dr. Joel Weissman, et al., also found that “direct-to-consumer advertising (DTCA) led patients to seek unnecessary treatments.”48
In 2017, Americans spent $333.4 billion on prescription medications,49 which was more than 2½ times the $121 billion spent in 2000.50
Dr. David Graham of the FDA’s Center for Drug Evaluation and Research warns:
“Direct-to-consumer advertising in general is a great disservice to the American people. We see wonderful ads of people demonstrating their health, whether they’re skating across the ice or doing their Tai Chi. Madison Avenue knows that a picture is worth a thousand words, so they convey an image, a message, and it makes an impression on patients and on physicians. It creates needs or desires where there really isn’t a need or a desire.
There was a recent study in the Journal of The American Medical Association that showed that if patients mentioned a drug that they’ve seen on television to their physician they were much more likely to be prescribed that drug by the doctor. Drug companies know this. That’s why they do it. Clearly, direct-to-consumer advertising does not serve the American people well.”51
How Do We Know Drugs Are Safe?
Another aspect of scientific medicine that the public takes for granted is the testing of new drugs. Drugs generally are tested on individuals who are fairly healthy and not on other medications that could interfere with findings. But when these new drugs are declared “safe” and enter the drug prescription books, they are naturally going to be used by people who are on a variety of other medications and have a lot of other health problems. Then a new phase of drug testing called “post-approval” comes into play, which is the documentation of side effects once drugs hit the market.
A 2017 Yale School of Medicine study found that 32% of the drugs approved in the first decade of the 21st century were withdrawn or required a “black box” or safety warning to be added to their label – after the drugs were already on the market. It took an average of 4.2 years for the drugs’ safety issues to be noticed. The worst offenders were psychiatric drugs, biologics (drugs manufactured in living cells), drugs granted “accelerated approval,” and drugs approved shortly before the regulatory deadline.52
The same researchers also found that the majority of 21st century drug trials leading to the approval of new therapeutic agents include fewer than 1,000 patients and last less than six months, leaving scant time for long-term side effects to emerge. Because of the limited time window and the chronic nature of many diseases, the bulk of the trials also de-emphasize “curing” anything in favor of so-called “surrogate endpoints” – indications like lowered blood cholesterol or tumor size that point to an improvement in the patient’s condition.53
In a year-long investigation, NBC News’s Dateline found that because doctors can legally prescribe any drug to any patient for any condition, drug companies heavily promote “off-label”—that is, frequently inappropriate and untested—uses of these medications, even though these drugs are approved only for the specific indications for which they have been tested.54 Such promotion is illegal and has resulted in some of the largest settlements ever reached in lawsuits against drug companies.
The leading causes of adverse drug reactions among adults are antibiotics, immunosuppressive and antineoplastic drugs, non-steroidal anti-inflammatory drugs (NSAIDs), cardiovascular drugs, opioid painkillers, and anticoagulants.55 56 A 2012 study of adverse drug reactions in the elderly found that warfarin was responsible for 33% of emergency hospitalizations, with insulin coming in second at 14% and antiplatelet drugs (including aspirin) third at 13%.57 Among children, anti-infectives, anti-epileptics, and NSAIDs were the most common causes of ADRs.58
Drugs Pollute Our Water Supply
We have reached the point of saturation with prescription drugs. Every body of water tested contains measurable drug residues. The tons of antibiotics used in animal farming, which run off into the water table and surrounding bodies of water, are conferring antibiotic resistance to germs in sewage, and these germs also are found in our water supply. Flushed down our toilets are tons of drugs and drug metabolites that also find their way into our water supply. We have no way to know the long-term health consequences of ingesting a mixture of drugs and drug-breakdown products. These drugs represent another level of iatrogenic disease that we are unable to completely measure.
However, the EPA found in 2013 that half of drinking water samples obtained from wastewater treatment plants around the US tested positive for at least 25 of the 56 most common drugs, with blood pressure medications appearing most frequently and in the highest concentrations.
Pharmaceutical companies applying for drug approval are actually required to submit estimates to the FDA of how much of the drug will persist in the environment. The model takes into account the number of patients taking the drug, its passage through the body, and its water solubility. If their estimate exceeds 1 part per billion, the FDA is supposed to require a detailed explanation of how the drug will affect the aquatic ecosystem.
While the 2013 EPA study found eight of the drugs present at maximum levels above 1 ppb, the FDA apparently felt inconveniencing drug companies was a greater crime than polluting the nation’s waterways, because officials said “it would be a challenge to go back and ask the pharmaceutical companies to re-evaluate.”59
None of this information is really new – even in 2000, the US Geological Survey found pharmaceuticals – including steroids, hormonal contraceptives, and antibiotics – in 80% of rivers and streams sampled. Yet wastewater treatment plants are still not required to filter or remove pharmaceuticals. Citizens Campaign for the Environment warns that constant low-level exposure to this pharmacopeia can cause hormone disruption and antibiotic resistance, while antidepressants in particular have been shown to alter the reproductive behavior of fish and mollusks. Flounder in Jamaica Bay, New York are actually turning female because of the pharmaceutical soup they must swim through.60
Wastewater treatment plants barely make a dent in the pharmaceutical pollution, according to a 2013 study that found a low rate of removal for multiple antibiotic and antibacterial drugs, as well as anti-inflammatory and anti-seizure compounds, and only 12 pharmaceuticals are even under consideration by the EPA for regulation under drinking water standards. Currently, there are no laws regulating the presence of pharmaceuticals in drinking water or wastewater.61
Drug Companies Fined
Periodically, the FDA fines a drug manufacturer when its abuses are too glaring and impossible to cover up. In May 2002, the Washington Post reported that Schering–Plough Corp., the maker of Claritin®, was to pay a $500 million fine to the FDA for quality-control problems at four of its factories.62 The indictment came after the Public Citizen Health Research Group, led by Dr. Sidney Wolfe, called for a criminal investigation of Schering–Plough, charging that the company distributed albuterol asthma inhalers even though it knew the units were missing the active ingredient.
The FDA tabulated infractions involving 125 products, or 90% of the drugs made by Schering-Plough since 1998. Besides paying the fine, the company was forced to halt the manufacture of 73 drugs or suffer another $175 million fine. Schering–Plough’s news releases told another story, assuring consumers that they should still feel confident in the company’s products.
This large settlement was supposed to serve as a warning to the drug industry, but it has long since been dwarfed by much larger fines. In 2009, Pfizer was slapped with what was then the largest healthcare fraud settlement in history, forced to pay $1.3 billion in criminal penalties for illegally promoting its anti-inflammatory drug Bextra for off-label uses in dangerously high doses and another $1 billion in civil penalties for false claims and further off-label promotion of other drugs, as well as kickbacks to doctors in exchange for prescribing the drugs. Pfizer was forced to enter into a “corporate integrity agreement” with the Inspector General of the Department of Health and Human Services, essentially to force them to follow the law in the future.63
In 2016, a federal appeals court revived a class action lawsuit against Pfizer, accusing the company of misleading shareholders about the safety of Bextra and Celebrex and causing tens of billions of dollars in losses when the company’s stock price plummeted after the drugs’ risks became public knowledge. The suit was finally settled for $486 million. Other shareholder suits and personal injury suits have nibbled away at Pfizer’s profits over the years – a $400 million settlement in 2015,65 a $164 million settlement in 2012 – but next to the drugmaker’s yearly revenues of $55 billion, such suits are merely a rounding error.66
Pfizer’s record-setting 2009 fine was quickly eclipsed. In 2012, GlaxoSmithKline was hit with a $1 billion fine after pleading guilty to a three-count criminal indictment for introducing “misbranded” drugs (the antidepressants Paxil and Wellbutrin) into interstate commerce and concealing safety data about the diabetes drug Avandia from the FDA. The company also had to pay $2 billion in civil penalties under the False Claims Act.
The criminal charges centered on GSK’s off-label promotion of all three drugs. Despite a lack of FDA approval for that purpose, the company pushed Paxil for treatment of pediatric patients, suppressing and manipulating study data to show efficacy where none existed and seducing doctors with sponsored dinners, spa days, and other perks. This marketing campaign continued even after Paxil was forced to add a “black box” warning of suicide risk in under-18s to its label. Wellbutrin, too, was promoted off-label for everything from weight loss and ADHD to addiction and sexual dysfunction, despite the fact that the FDA had only approved it for treatment of depression; doctors were again wined and dined to convince them to prescribe, sometimes receiving millions of dollars to speak at medical conferences.
The violations concerning Avandia were more sinister. GSK was found to have covered up increased risk of congestive heart failure and heart attack in patients taking the drug, adverse effects that emerged after the drug was approved but which were hidden from regulators.
The company’s civil liabilities included off-label promotion of Advair, Lamictal and Zofran in addition to Paxil and Wellbutrin; paying kickbacks to doctors to prescribe those and other drugs in its stable; ripping off Medicare; and making false claims about Avandia’s safety and effectiveness.
On top of the $3 billion settlement, GSK was also required to submit to a five-year “Corporate Integrity Agreement” with the DHHS’ Inspector General. Under their version of the agreement, executives caught in “significant misconduct” could have their bonuses clawed back, and the company was required to increase transparency surrounding its research and publication policies.67
Surely this was no mere slap on the wrist. Yet just three years later, GlaxoSmithKline was hit with the largest corporate fine in Chinese history – 3 billion yuan – for bribing health officials. What American regulators could not do, Chinese regulators may have: the company announced following the settlement that they would end the practice of paying doctors for speaking engagements and do away with individual prescription sales targets.68
Indeed, GSK’s experience so frightened western pharmaceutical companies that many executives wondered if the Chinese market was worth the risk. According to Reuters, “China’s crackdown on corruption in the pharmaceutical sector has frightened foreign executives so much that some fear they could be jailed and have asked their lawyers if they should leave the country for six months. Others are thinking of going for good.”69
Mark Reilly, the British GSK executive caught up in the bribery scandal, was ultimately deported from China and handed a three-year suspended prison sentence – less than the 20 years he initially faced, but enough to keep him and his company on the straight-and-narrow. It’s hard to imagine a similar scenario playing out in the US.
Problems with Specific Classes of Drugs
According to statistics from the FDA and Pew Charitable Trusts, the United States consumed about 42 million pounds of antibiotics in 2015. A full 34.3 million pounds of these were sold by veterinary pharmaceutical manufacturers for use in livestock.70 And less than 17% of those were given to animals who were sick.71
Low concentrations of antibiotics are measurable in many of our foods and in various waterways around the world, much of it seeping in from animal farms, and scientists have long warned that the overuse of antibiotics results in food-borne infections that are resistant to antibiotics. Salmonella, which infects about 1.2 million people annually in the US, is found in 22% of retail poultry and is heavily present in cattle and pigs as well. In a sampling of salmonella strains found on retail chickens, more than 82% were resistant to at least one antibiotic. Another study found that more than two thirds of some strains of salmonella found in chickens are resistant to five or more antibiotics.72
The conventional approach to countering this epidemic is to irradiate food to try to kill all organisms while continuing to use the antibiotics that created the problem in the first place. In a 2014 study by Sapkota et.al., when a conventional farm was converted to an organic farm, antibiotic-resistant salmonella prevalence dropped significantly.73
The National Antimicrobial Resistance Monitoring System (NARMS) found 47% of chicken breasts were contaminated with Campylobacter jejuni, an organism that causes 1.3 million cases of illness in the US annually.74 And these infections don’t just spread through food, either – a Campylobacter outbreak in 2018 which sickened over 100 people with a multi-drug-resistant strain of the illness was traced to puppies from the Petland chain of stores. Samples taken from infected individuals found bacteria that were resistant to as many as nine (!) antibiotics, and it was later found that the puppies had received at least one course of antibiotic treatment before they were purchased.75 76 At least 27% of C. jejuni organisms are resistant to ciproflaxin, and a growing number are resistant to more than one antimicrobial agent.77
When growth-promoting antibiotics were banned across Europe in 2006, drug producers in the Netherlands at first merely relabeled their drugs as disease-preventive. Antibiotic consumption did not start to decline until 2009, when two outbreaks of drug-resistant bacterial infections – both bearing resistance signatures indicating they’d developed through overmedication of livestock – terrified Dutch farmers into cooperating with a nationwide antibiotic prescribing database and strict goals to reduce antibiotic use by 20% one year, 50% in three. The Dutch agriculture ministry announced in 2013 that antibiotic sales had dropped by 56% since the ban was first imposed. “This was done without any big consequences in efficiency, or financial returns,” microbiology professor Jan Kluytmans boasts. But farmers have also had to clean up their act, reducing crowding and implementing sanitation measures.78
After over 40 years of controversy regarding their use, the FDA introduced a voluntary three-year phase-out of growth-promoting antibiotics in 2013. It was mostly a disaster: consumption of the drugs continued to increase, particularly in “medically-important antimicrobials” – the kind used in humans – and just 17% of those were used to treat infections.79 A 2016 paper sounded the alarm, revealing that antibiotic sales were up 20 percent over the preceding five years – growing faster than the meat industry itself.80
In 2017, the FDA implemented a ban on growth-promoting antibiotics, which included a mandate that a veterinarian administer all drugs (97% of antibiotics were previously doled out over the counter). So far, it appears American drug companies are following the Dutch’s bad example, merely relabeling their growth-promoting drugs as preventives.
Indeed, a September 2018 analysis found that 13 antibiotics classified as “critically important” to human medicine by the World Health Organization are still present in the same amounts throughout the US meat supply chain as they were before the ban. Nine of these, the WHO warns, are “the last line, or one of limited treatments available to treat serious bacterial infections in humans.” The year after the FDA’s recommendations became mandatory, the number of residues of those nine antibiotics actually increased – from 363 in 2016 to 461 in 2017, according to the Bureau of Investigative Journalism. By overusing these drugs, meat producers are not only ensuring bacteria will develop resistance to them, but that there will be no stronger drugs left to treat individuals infected with the new superbugs.81
Antibiotic-resistant bacteria kill 700,000 people around the world every year, and by 2050 that number is expected to exceed 10 million per year – more deaths than cancer.82 The CDC estimates that in the US alone, 23,000 people a year die from antibiotic-resistant infections, and other estimates place that number at four times higher. Such infections cost the country over $20 billion per year.83
The current crowded, unsanitary methods of animal farming in the US support constant stress and infection, and are geared toward high antibiotic use; like the Dutch, American farmers will have to change their habits if they want to make meaningful changes to reduce superbug-producing antibiotic abuse.84
In the US, over 7.5 million pounds of antibiotics are used every year on humans.85 With a population of 328 million Americans, this amount is enough to give every man, woman, and child two teaspoons of pure antibiotics per year. Exposure to a steady stream of antibiotics has altered pathogens such as Streptococcus pneumoniae, Staphylococcus aureus, and various Enterococci, to name a few.
About half of patients with upper respiratory tract infections in the US still receive antibiotics from their doctors, which is inappropriate in most cases. These antibiotics are increasingly of the broad-spectrum variety, increasing the likelihood they will contribute to the development of antibiotic-resistant pathogens.86
Data obtained from three US health plans on antibiotic use in children from 2000 to 2010 found that rates of antibiotic use decreased across the board, with babies aged 3 to 24 months experiencing the greatest overall decline (down to 1.41 prescriptions per patient per year from 1.97), but the declines tended to plateau or even creep back up slightly toward the end of the period studied.87
From 2011 to 2014, antibiotic prescription in the overall US population decreased 5%, with the most significant decline found in children under the age of 19, who received 11 million fewer prescriptions than they had three years previously.88 Still, a 2014 study found 11.4 million unnecessary antibiotic prescriptions are written for children and teens every year.89
Antibiotics are the most frequently implicated drug in pediatric adverse drug reactions, causing up to 150,000 unplanned medical visits every year, and there is a mounting body of evidence that antibiotic exposure early in life can disrupt the gut microbiome in ways that contribute to later development of chronic health conditions such as obesity, inflammatory bowel syndrome, eczema, and asthma.90
In 2015, about 269 million antibiotic prescriptions were dispensed from outpatient pharmacies, enough for five out of six Americans to receive a prescription every year – and at least 30% of those are still unnecessary. Overprescription is worst for acute respiratory conditions in 20-64 year olds – 70% of antibiotics prescribed to treat these conditions are unnecessary, according to the CDC.91 Up to 50% of in-hospital prescriptions are unnecessary,92 and hospital use of high-powered carbapenem antibiotics actually increased 40% from 2006 to 2012.93
Group A beta-hemolytic streptococci is the only common cause of sore throat that requires antibiotics, with penicillin and erythromycin the only recommended treatment. More than 90% of sore throat cases in adults, however, are viral. A 2013 survey found that doctors prescribed antibiotics for 60% of sore throat visits and 73% of acute bronchitis visits – when the appropriate prescribing rate should be about 10% and zero, respectively. While this represents an improvement from a 2001 study that found antibiotics prescribed 73% of the time for sore throats, the increasing trend toward treating patients with non-recommended broad-spectrum antibiotics instead of the recommended antibiotics penicillin and erythromycin bodes ill for the growth of antibiotic-resistant infections.94
The rise of antibiotic-resistant bacteria alarmed President Barack Obama’s administration sufficiently to launch a National Action Plan for Combating Antibiotic-Resistant Bacteria (CARB) in 2015, setting the goal of halving the inappropriate outpatient use of antibiotics. The following year, Congress appropriated $160 million in new funding to put this plan into action. The CDC pledged to do its part by stepping up tracking of antibiotic use and resistance, funding research, improving outbreak detection, and keeping the public informed.95 In a press release accompanying the announcement, they warn that one of every three antibiotic prescriptions is unnecessary, that the vast majority of respiratory conditions for which antibiotics are prescribed are caused by viruses, and that the 47 million excess prescriptions written every year place patients at risk for drug-resistant infections and Clostridium difficile, an iatrogenic infection causing diarrhea which can be fatal.
Most people involved with alternative medicine have known about the dangers of antibiotic overuse for decades. Finally, the government is focusing on the problem, yet it is spending only a miniscule amount of money on an iatrogenic epidemic that is costing billions of dollars and thousands of lives.
The CDC, however, seems to be blaming patients for misusing antibiotics even though they are available only by prescription from physicians. According to Dr. Richard Besser, then head of the “Get Smart” program to educate patients about proper antibiotic use, “Programs that have just targeted physicians have not worked. Direct-to-consumer advertising of drugs is to blame in some cases.” Besser says the program “teaches patients and the general public that antibiotics are precious resources that must be used correctly if we want to have them around when we need them. Hopefully, as a result of this campaign, patients will feel more comfortable asking their doctors for the best care for their illnesses, rather than asking for antibiotics.”96
What constitutes the “best care”? The CDC does not elaborate and ignores the latest research on the dozens of nutraceuticals that have been scientifically proven to treat viral infections and boost immune-system function. Will doctors recommend garlic, vitamin C, lactoferrin, elderberry, vitamin A, zinc, or DHEA? Probably not. The CDC’s commonsense recommendations that most people follow anyway include getting proper rest, drinking plenty of fluids, and using a humidifier.
The CDC also is involved in trying to minimize antibiotic resistance, but nowhere in its publications is there any reference to the role of nutraceuticals in boosting the immune system, or to the thousands of journal articles that support this approach. This tunnel vision and refusal to recommend the available non-drug alternatives is unfortunate when the CDC is desperately trying to curb the overuse of antibiotics.
The AHRQ reports that C. difficile infections are on the rise, now accounting for more than 12% of all healthcare-associated infections,97 and the CDC’s 2013 Antibiotic Resistance Threat Report classifies C. difficile as an “urgent threat.” A 2015 study found 500,000 C. difficile infections every year, causing 15,000 deaths. Less dire, but still a “serious threat,” is methicillin-resistant Staphylococcus Aureus, which AHRQ reveals is the most common HAI [healthcare-associated infection] agent.98
NSAIDs rank first among commonly prescribed drugs for serious adverse reactions, though studies have shown that many patients are not aware of the side effect profile of these drugs and often don’t connect their symptoms with the drugs they are taking. A 2004 study found NSAID patients were frequently uninformed as to the possibility of gastrointestinal side effects, and when they were informed, it was not because their doctor had told them.99
In 2003, J.S. Hochman, MD, Executive Director of the National Foundation for the Treatment of Pain, referring to NSAID-related deaths as a “silent epidemic,” wrote:
“It has been estimated conservatively that 16,500 NSAID-related deaths occur among patients with rheumatoid arthritis or osteoarthritis every year in the United States. This figure is similar to the number of deaths from the acquired immunodeficiency syndrome and considerably greater than the number of deaths from multiple myeloma, asthma, cervical cancer, or Hodgkin’s disease.”100
Deaths from NSAIDs’ gastrointestinal adverse effects alone outnumber those from cervical cancer, asthma, or malignant melanoma, according to a 2011 paper by R.J. Adams et.al. The researchers warned that deaths from cardiovascular adverse effects may be even more frequent, citing a Danish population study that found increased cardiovascular mortality among frequent NSAID users without a prior history of heart disease.101
Additionally, use of NSAIDs in conjunction with other drugs can have dire consequences. The use of NSAIDs and SSRIs together greatly increases the chance of gastrointestinal side effects, which are already present in up to half those taking NSAIDs.102
Over 66,000 people were killed over a 10-year period during the Vietnam War. More people are killed by NSAIDs in one year (16,500 deaths) than were killed in any two years of the Vietnam War.
In 2003, the British Medical Journal warned that women who took NSAIDs—“painkillers like Advil®, Motrin®, and Naprosyn®—had an 80 percent higher risk of miscarriage than women who avoided these medications.” The risk increased if such painkillers were taken shortly before or after conception, or for longer than one week.103
On September 30, 2004, Merck announced “a voluntary worldwide withdrawal of Vioxx® (Rofecoxib), its arthritis and acute pain medication…due to safety concerns of an increased risk of cardiovascular events (including heart attack and stroke) in patients on rofecoxib. Rofecoxib is a prescription COX-2 selective, non-steroidal anti-inflammatory drug (NSAID) that was approved by the FDA in May 1999.”104 The drug was later approved for treating the symptoms of rheumatoid arthritis in adults and children – meaning an unknown number of children were exposed to this dangerous drug.
The Lancet carried an article in its first issue of December 2004 titled, “Risk of cardiovascular events and rofecoxib: cumulative meta-analysis,” which found that “rofecoxib should have been withdrawn several years earlier. The reasons why manufacturer and drug licensing authorities did not continuously monitor and summarize the accumulating evidence need to be clarified.”105
The NSAID “Vioxx® was withdrawn after evidence came to light that it almost doubled the risk of heart attacks and stroke in people who had been taking it for 18 months.”106
FDA researcher Dr. David Graham, testifying before the US Senate, estimated 88,000 to 138,000 Americans had heart attacks or strokes as a side effect from Vioxx®. “Of these,” Graham said, “30–40% probably died.”107 That works out to an estimated 27,000 to 55,000 preventable deaths that can be attributed to Vioxx®.108
Dr. Graham continues his Senate testimony, “If there were an average of 150 to 200 people on an aircraft, this range of 88,000 to 138,000 would be the rough equivalent of 500 to 900 aircraft dropping from the sky. This translates to 2–4 aircraft every week, week in and week out, for the past 5 years.”109
Approximately 30 billion NSAIDs are sold over the counter in the US annually. While opioid drugs are (perhaps justifiably) receiving the lion’s share of regulatory scrutiny as far as pain pills are concerned, doctors’ increasing aversion to prescribing opioids should not lead them to replace those drugs with NSAIDs without evaluating the risk-benefit profile of those drugs as well.110
More than 70,000 Americans died of drug overdoses in 2017 alone, and most of those deaths involved an opioid painkiller. Claiming more than 350,000 lives between 1999 and 2016, the opioid epidemic has outstripped all other pharmaceutical disasters in sheer body count.111
This epidemic can be traced back to a skillful marketing and manipulation campaign by OxyContin manufacturer Purdue Pharma and has since metastasized into a multi-headed hydra of addiction – to legal prescription pain pills, illegal heroin, and legal “substitute” opioids like methadone and buprenorphine.
In 2012 alone, 259 million prescriptions for opioids were filled in the US, enough to medicate every adult for a month.112 In 2015, more than one in three Americans was prescribed opioids. While the rate of opioid prescription for pain is finally starting to fall from that peak, “medication-assisted treatment” – opioids to treat opioid addiction – is growing by leaps and bounds, with nearly twice as many patients starting such treatment in 2017 as in 2015.113
Purdue Pharma finally reformulated OxyContin in 2010 to make it impossible to crush, snort, or inject. By then, however, the damage was done, and millions of people were hooked. Other opioids had stepped in to fill the void: Vicodin, Roxicodone, Lortab, Opana. But more popular than these was heroin. Economists William Evans and Ethan Lieber have suggested that OxyContin’s reformulation actually kicked the heroin epidemic into high gear, as desperate addicts were driven to the streets in search of stronger and cheaper highs. In a paper published in the National Bureau of Economic Research in April 2018, Evans and Lieber found that oxycodone deaths dropped off after August 2010, just as heroin deaths began climbing.114 According to a 2014 JAMA Psychiatry study, a full 75 percent of heroin users began their addictions with prescription pain pills.115 Other studies have placed the number as high as 86 percent for young users,116 and the number of heroin users under 25 doubled during the last decade as the prescription opioid wave began to recede.
A 2010 paper published in the Archives of Internal Medicine compared seniors using opioids, NSAIDs, and another type of non-narcotic pain reliever, finding:
- opioid users were over four times more likely to experience a fracture than NSAID users
- all-cause mortality was 87% higher among opioid users
- opioid users were 77% more likely to experience cardiovascular events than NSAID users (even though NSAIDs have their own cardiovascular side effect profile)
These unsettling revelations came just a year after the American Geriatrics Society recommended more opioid use for seniors. Five of the 10 experts on the panel that made these recommendations had ties to opioid companies. The pain treatment guide they endorsed claimed older adults with chronic pain could get back to work, even become physically active again, if they sought relief in opioids – even though a study published in 2008 in Spine revealed back injury patients were twice as likely to be disabled and out of work a year after their injury if they took opioids for more than a week during the first six weeks following injury.117
The American Geriatrics Society was only following the lead of the American Academy of Pain Medicine, the Joint Commission, and the American Pain Society, which – guided by Purdue Pharma – issued their infamous joint statement in 1995 declaring pain was the “fifth vital sign” and endorsing the use of opioid painkillers in treating it. Purdue was able to hoodwink doctors by proclaiming this new opioid had somehow transcended the addictive pitfalls of past formulations (including Purdue’s own morphine-based formula MS Contin) even though decades of scientific study had clearly shown that as many as half of patients taking opioids became addicted.
Aside from addiction, long-term opioid use can result in increased pain sensitivity – the brain ceases to produce its own endorphins, instead relying on the drug. Immunosuppression and hormonal changes are not infrequent. Constipation is so common that laxative co-prescription is not unusual.
While prescribing guidelines have changed – the CDC no longer recommends opioids for most chronic pain conditions, and the American Medical Association dropped pain as a “vital sign” in June 2016 – the damage is done.118 Those 70,000 overdoses actually brought down the American life expectancy in 2017.119
In 1989, German biostatistician Ulrich Abel, PhD, wrote a monograph entitled “Chemotherapy of Advanced Epithelial Cancer.” It was later published in shorter form in a peer-reviewed medical journal. Abel presented a comprehensive analysis of clinical trials and publications representing over 3,000 articles examining the value of cytotoxic chemotherapy on advanced epithelial cancer.
Epithelial cancer is the type of cancer with which we are most familiar, arising from epithelium found in the lining of body organs such as the breast, prostate, lung, stomach, and bowel. From these sites, cancer usually infiltrates adjacent tissue and spreads to the bone, liver, lung, or brain. With his exhaustive review, Abel concluded there is no direct evidence that chemotherapy prolongs survival in most patients with advanced carcinoma.
According to Abel, “Many oncologists take it for granted that response to therapy prolongs survival, an opinion which is based on a fallacy and which is not supported by clinical studies.”119 Over a decade after Abel’s exhaustive review of chemotherapy, there seems no decrease in its use for advanced carcinoma. For example, when conventional chemotherapy and radiation have not worked to prevent metastases in breast cancer, high-dose chemotherapy (HDC) along with stem-cell transplant (SCT) is the treatment of choice. In March 2000, however, results from the largest multi-center randomized controlled trial conducted thus far showed that, compared to a prolonged course of monthly conventional-dose chemotherapy, HDC and SCT were of no benefit, with even a slightly lower survival rate for the HDC/SCT group.120
Serious adverse effects occurred more often in the HDC group than in the standard-dose group. One treatment-related death (within 100 days of therapy) was recorded in the HDC group, but none was recorded in the conventional chemotherapy group. The women in this trial were highly selected as having the best chance to respond.
Unfortunately, no all-encompassing follow-up study such as Dr. Abel’s exists to indicate whether there has been any improvement in cancer-survival statistics since 1989. In fact, research should be conducted to determine whether chemotherapy itself is responsible for secondary cancers instead of progression of the original disease. We continue to question why well-researched alternative cancer treatments are not used.
Until now, the extent to which chemotherapy tortures young patients, formerly thought to be strong enough to withstand the toxicity, was unknown. On August 16, 2006, Harvard Medical School- affiliated Drs. Michael J. Hassett, A. James O’Malley, Juliana R. Pakes, Joseph P. Newhouse, and Craig C. Earle published, “Frequency and Cost of Chemotherapy-Related Serious Adverse Effects in a Population Sample of Women With Breast Cancer” in the Journal of the National Cancer Institute. The authors acknowledge that “breast cancer is the most common indication for chemotherapy among women in the United States, and chemotherapy drugs are the leading cause of serious drug-related adverse effects among women with breast cancer,” but the authors suggest that studies in older women cannot be extrapolated to the general population. This, therefore, is the first study of chemotherapy-related serious adverse effects in a population-based sample of younger women with breast cancer. 12,239 women 63 years of age or younger with newly diagnosed breast cancer participated in the study.
For the purposes of the study, “a drug-related serious adverse effect has been defined as any untoward medical occurrence that is related to drug use and results in death or significant disability/incapacity, requires hospital admission or prolongation of existing hospital stay, or is life threatening.” Several of the adverse effects are:
■ dehydration or electrolyte disorders (potentially fatal)
■ bronchitis (potentially fatal)
■ pneumonia (potentially fatal)
■ flu (potentially fatal)
■ kidney infection (potentially fatal)
■ other infections (potentially fatal)
■ shock (potentially fatal)
■ anemia (potentially fatal)
■ deep-vein thrombosis or pulmonary embolism (potentially fatal)
■ fractures and dislocations
■ emphysema (potentially fatal)
■ asthma (potentially fatal)
■ renal failure (potentially fatal)
■ thyroid disorders, including goiter (potentially fatal)
■ headaches, including migraines
Prior to this study, it was believed that women over age 65 could be expected to have comorbid conditions that would make them more susceptible to adverse side effects of chemotherapy, but that the younger population could survive the toxicity. The authors conclude that “breast cancer chemotherapy may cause more patient suffering and higher healthcare costs than previously estimated.”121
They emphasize that clinical trials of new drugs are often inadequate to accurately show experiences of the general population, warning:
“Although clinical trials of new drug therapies provide some information regarding the number and nature of serious adverse effects, reports of these complications are frequently inadequate and may not accurately reflect the experiences of the general population. Indeed, recent and widely publicized cases have demonstrated that serious adverse effects that are not fully appreciated during early clinical trials can appear after a drug is approved by the US Food and Drug Administration (FDA) and used by the public. In fact, one study of serious adverse effects identified after FDA approval found that 22 cancer drugs had been linked with 25 serious adverse effects between 2000 and 2002.”
The authors conclude that their findings “have important implications for quality of life and could affect decisions regarding [risks of] therapy.”122
A 2004 pioneer overview study, “The Contribution of Cytotoxic Chemotherapy to 5-year Survival in Adult Malignancies,” by Drs. Graeme Morgan, Robyn Ward, and Michael Barton in Clinical Oncology, reports that “The overall contribution of curative and adjuvant cytotoxic chemotherapy to 5-year survival in adults was estimated to be 2.1% in the USA.”123 That is, patients receiving cytotoxic chemotherapy are only 2.1% more likely to survive 5 years post-treatment than those who received no therapy at all. They note that their estimate of benefit is statistically generous, using the “upper limit of effectiveness,” and “the benefit of cytotoxic chemotherapy may have been overestimated for cancers of esophagus, stomach, rectum, and brain.” The authors refer to “the minimal impact of cytotoxic chemotherapy on 5-year survival, and the lack of any major progress over the last 20 years.” They point to the yawning gap between the perception of chemotherapy and the reality in treating breast cancer, where new and more expensive drugs demonstrate no improvements over those used in the 1970s and no survival benefit in recurrent or metastatic breast cancer is apparent at all.
It is clear that despite the American medical system’s deliberate projection of infallibility, the flaws in our current profit-oriented “care” paradigm are inflicting an indefensible level of harm on patients. A complete reimagining of our current medical model is necessary to even begin to address the systemic problems at hand, beginning with the Hippocratic oath itself: first, do no harm.
1 Kelman, Brett. “At Vanderbilt, a nurse’s error killed a patient and threw Medicare into jeopardy.” Tennessean. 29 Nov 2018. https://www.tennessean.com/story/money/2018/11/29/vanderbilt-nurse-killed-patient-drug-death-medicare/2148545002/
2 Form CMS-2567(02-99). Centers for Medicare and Medicaid Services, Department of Health and Human Services. 8 Nov 2018. https://www.documentcloud.org/documents/5346023-CMS-Report.html?fbclid=IwAR2xQsxlfKxis4mecgrCSt6XvKnSmKDeN7Sb_20is2oBbFICt_9xUDkyvQ#document/p6
3 “Largest Ever Prospective Medical Study Shows Epidurals And Spinal Anesthetics Are Safer Than Previously Reported [in Britain].” ScienceDaily. 16 Jan 2009. http://www.sciencedaily.com/releases/2009/01/090113074445.htm
4 FAQ’s: Anesthesia and Brain Monitoring: What are the risks of anesthesia? Aspect Medical Systems, 2009. http://www.aspectmedical.com/patients/ anesthesia-risks.mspx (accessed February 1, 2009).
5 Barker, K. N., E. A. Flynn, G. A. Pepper, D. W. Bates, and R. L. Mikeal. “Medication errors observed in 36 health care facilities.” Arch Intern Med. 2002. 162 (16):1897–903.
6 LaPointe, N. M., and J. G. Jollis. Medication errors in hospitalized cardiovascular patients. Arch Intern Med. 2003; 163 (12):1461–6.
7 Wittich, CM et.al. “Medication errors: an overview for clinicians.” Mayo Clinic Proceedings. 2014 Aug;89(8):1116-25. https://www.ncbi.nlm.nih.gov/pubmed/24981217
8 Lazarou, J., B. H. Pomeranz, and P. N. Corey. 1998. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 279 (15):1200–5.
9 Sultana, Janet et.al. “Clinical and economic burden of adverse drug reactions.” Journal of Pharmacology and Pharmacotherapeutics. 2013 Dec;4(Suppl1):S73-S77. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3853675/
10 Miguel, A et.al. “Frequency of adverse drug reactions in hospitalized patients: a systematic review and meta-analysis.” Pharmacoepidemiology and Drug Safety. Nov 2012;21(11):1139-1154. https://www.ncbi.nlm.nih.gov/pubmed/22761169/
11 Carr, Teresa. “Too Many Meds? America’s Love Affair With Prescription Medication.” Consumer Reports. 3 Aug 2017. https://www.consumerreports.org/prescription-drugs/too-many-meds-americas-love-affair-with-prescription-medication/
12 Pitrou, I. et.al. “Reporting of safety results in published reports of randomized controlled trials.” Archives of Internal Medicine. 2009 Oct 26;169(19):1756-61. https://www.ncbi.nlm.nih.gov/pubmed/19858432/
13 Carr, op.cit
14 Miguel, op.cit
15 Kopp, BJ et.al. “Medication errors and adverse drug events in an intensive care unit: direct observation approach for detection.” Critical Care Medicine. 2006 Feb;34(2):415-25. https://www.ncbi.nlm.nih.gov/pubmed/16424723/
16 “Rate of medication errors resulting in serious medical outcomes rising, study finds.” Science Daily. 10 Jul 2017. https://www.sciencedaily.com/releases/2017/07/170710091716.htm
17 Carr, op.cit
19 Smith, M.D. et.al. “Out-of-Hospital Medication Errors Among Young Children in the United States, 2002–2012.” Pediatrics. Nov 2014;134(5). http://pediatrics.aappublications.org/content/134/5/867
20 Gandhi, T. K., S. N. Weingart, J. Borus, A. C. Seger, J. Peterson, E. Burdick, D. L. Seger, K. Shu, F. Federico, L. L. Leape, and D. W. Bates. 2003. Adverse drug events in ambulatory care. N Engl J Med 348 (16):1556–64.
21 “Medication side effects strike 1 in 4.” Reuters. 17 April 2003.
22 Schmiedl, S. et.al. “Preventable ADRs leading to hospitalization – results of a long-term prospective safety study with 6,427 ADR cases focusing on elderly patients.” Expert Opinions on Drug Safety. 2018 Feb;17(2):125-137. https://www.ncbi.nlm.nih.gov/pubmed/29258401
23 Pedros, C. et.al. “Adverse drug reactions leading to urgent hospital admission in an elderly population: prevalence and main features.” European Journal of Clinical Pharmacology. 2016 Feb;72(2):219-26. https://www.ncbi.nlm.nih.gov/pubmed/26546335
24 Sultana, J.et.al. “Clinical and economic burden of adverse drug reactions.” Journal of Pharmacology and Pharmacotherapeutics. 2013 Dec;4(Suppl1):S73-S77. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3853675/
25 Davies, E.C. “Adverse Drug Reactions in Hospital In-Patients: A Prospective Analysis of 3695 Patient-Episodes.” PLoS One. 2009;4(2):e4439. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2635959/
26 “Global Pharmaceutical Industry – Statistics & Facts.” Statista. https://www.statista.com/topics/1764/global-pharmaceutical-industry/ Retrieved 25 Jan 2019.
27 Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor. Goodman and Gilman’s The Pharma-cological Basis of Therapeutics. New York: Pergamon Press, 1996.
28 Melmon, K.L., H.F. Morrelli, B.B. Hoffman and D.W. Nierenberg, eds. Melmon and Morrelli’s Clinical Pharmacology: Basic Principles in Therapeutics. 3rd ed. (New York: McGraw- Hill, Inc., 1992).
29 Hazell, Lorna and Saad A.W. Shakir. “Under-Reporting of Adverse Drug Reactions.” Drug Safety. 2006;29(5):385-396. https://people.eecs.berkeley.edu/~daw/teaching/c79-s13/readings/AdverseDrugReactions.pdf
30 Dickinson, JG. “FDA seeks to double effort on confusing drug names.” Dickinson’s FDA Review. 2000 Mar;7(3):13–4.
31 Cohen, J.S. Overdose: The Case Against the Drug Companies. New York: Tarcher-Putnum, 2001.
32 FDA Adverse Events Reporting System (FAERS) Public Dashboard. Food and Drug Administration. https://fis.fda.gov/sense/app/d10be6bb-494e-4cd2-82e4-0135608ddc13/sheet/7a47a261-d58b-4203-a8aa-6d3021737452/state/analysis Retrieved 25 Jan 2019.
33 “FDA Adverse Events Database: Time to Worry?” MedPage Today. 17 Mar 2017. https://www.medpagetoday.com/publichealthpolicy/fdageneral/63903
34 McLain, Sean. “New Outsourcing Frontier in India: Monitoring Drug Safety.” Wall Street Journal. 1 Feb 2015. https://www.wsj.com/articles/new-outsourcing-frontier-in-india-monitoring-drug-safety-1422814766
35 MedPage Today, op.cit
37 Vastag, B. 2001. Pay attention: Ritalin acts much like cocaine. JAMA 286 (8):905–6.
38 Bailey Esq, B. “Bad medicine.” Texas Injury Law. July 27, 2008. http://www.txinjurylawblog.com/tags/drugs-accolate-accutane-arava-1/ (accessed January 30, 2009).
39 Whitaker, Robert and Lisa Cosgrove. Psychiatry Under the Influence. Springer, 2015. https://books.google.com/books?id=VBHACQAAQBAJ
40 King, Marissa and Peter S. Bearman. “Gifts and influence: Conflict of interest policies and prescribing of psychotropic medications in the United States.” Social Science and Medicine. Jan 2017;172:153-162. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5154797/
41 Steinman, MA et.al. “Of principles and pens: attitudes and practices of medicine housestaff toward pharmaceutical industry promotions.” American Journal of Medicine. 2001 May;110(7):551-7. https://www.ncbi.nlm.nih.gov/pubmed/11347622
42 Ornstein, Charles. “Drug Company Payments Mirror Doctors’ Brand-Name Prescribing.” NPR. 17 Mar 2016. https://www.npr.org/sections/health-shots/2016/03/17/470679452/drug-company-payments-mirror-doctors-brand-name-prescribing
43 Rosenthal, M. B., E. R. Berndt, J. M. Donohue, R.G. Frank, and A. M. Epstein. 2002. Promotion of prescription drugs to consumers. N Engl J Med 346 (7):498–505.
44 “Advertising spending in the pharmaceutical preparations industry in the United States from 2010 to 2019 (in million US dollars).” Statista. https://www.statista.com/statistics/470460/pharmaceutical-preparations-industry-ad-spend-usa/ Retrieved 25 Jan 2019.
45 Wolfe, S. M. 2002. Direct-to-consumer advertising—education or emotion promotion? N Engl J Med 346 (7):524–6.
46 Abel, G.A. et.al. “Direct-to-Consumer Advertising in Oncology.” The Oncologist. 2006;11:217-226. http://theoncologist.alphamedpress.org/content/11/2/217.full.pdf
47 Wolfe, op.cit.
48 Weissman, J. S., D. Blumenthal, A. J. Silk, M. Newman, K. Zapert, R. Leitman, and S. Feibelmann. “Physicians report on patient encounters involving direct-to-consumer advertising. Health Aff (Millwood) Suppl Web Exclusives. 2004:W4-219-33. http://content.healthaffairs.org/cgi/content/abstract/hlthaff.w4.219v1 (accessed January 29, 2009).
49 “National Health Expenditures 2017 Highlights.” US Centers for Medicare and Medicaid Services. https://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/NationalHealthExpendData/Downloads/highlights.pdf
50 “Prescription drug expenditure in the United States from 1960 to 2018 (in billion U.S. dollars).” Statista. https://www.statista.com/statistics/184914/prescription-drug-expenditures-in-the-us-since-1960/ Retrieved 25 Jan 2019.
51 Loudon, Manette. “The FDA Exposed: An Interview With Dr. David Graham, the Vioxx Whistleblower.” Natural News. 30 Aug 2005. http://www.naturalnews.com/011401.html
52 Downing, N.S. et.al. “Postmarket Safety Events Among Novel Therapeutics Approved by the US Food and Drug Administration Between 2001 and 2010.” JAMA. 2017;317(18):1854-1863. https://jamanetwork.com/journals/jama/fullarticle/2625319
53 Downing, N.S. et.al. “Clinical Trial Evidence Supporting FDA Approval of Novel Therapeutic Agents, 2005-2012.” JAMA 2014;311(4):368-377. https://jamanetwork.com/journals/jama/fullarticle/1817794
54 “Dateline.” NBC. www.msnbc.com/news/937302. asp?cp1=1. (accessed May 22, 2006).
55 Davies, EC et.al. “Adverse drug reactions in hospital in-patients: a prospective analysis of 3695 patient-episodes.” PLoS One. 2009;4(2):e4439. https://www.ncbi.nlm.nih.gov/pubmed/19209224/
56 Schatz, Stephanie N. and Robert J. Weber. “Adverse Drug Reactions.” PSAP 2015. American College of Clinical Pharmacy. https://www.accp.com/docs/bookstore/psap/2015B2.SampleChapter.pdf
57 Budnitz, DS et.al. “Emergency Hospitalizations for Adverse Drug Events in Older Americans. NEJM. 2011;365:2002-12. https://www.nejm.org/doi/pdf/10.1056/NEJMsa1103053
58 Smyth, RMD et.al. “Adverse Drug Reactions in Children-A Systematic Review.” PLoS One. 2012; 7(3):e24061. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3293884/
59 Fallik, Dawn. “This New Study Found More Drugs in Our Drinking Water Than Anybody Knew.” New Republic. 11 Dec 2013. https://newrepublic.com/article/115883/drugs-drinking-water-new-epa-study-finds-more-we-knew
60 Scheer, Roddy and Doug Moss. “External Medicine: Discarded Drugs May Contaminate 40 Million Americans’ Drinking Water.” Scientific American. https://www.scientificamerican.com/article/pharmaceuticals-in-the-water/ Retrieved 25 Jan 2019.
61 Bienkowski, Brian. “Only Half of Drugs Removed by Sewage Treatment.” Environmental Health News. 22 Nov 2013. https://www.scientificamerican.com/article/only-half-of-drugs-removed-by-sewage-treatment/
62 Kaufman, M. “Drugmaker to pay FDA $500 million. Manufacturing problems found at Schering-Plough.” Washington Post. 18 May 2002:A01.
63 Loucks, Michael L. “Justice Department Announces Largest Health Care Fraud Settlement in Its History.” US Department of Justice. https://www.justice.gov/sites/default/files/usao-ma/legacy/2012/10/09/Pfizer – PR (Final).pdf
64 Palmer, Eric. “Pfizer extricates itself from investor suit with $400M settlement.” Fierce Pharma. 27 Jan 2015. https://www.fiercepharma.com/pharma/pfizer-extricates-itself-from-investor-suit-400m-settlement
65 Staton, Tracy. “Pfizer wraps up Celebrex suit in $164M settlement.” Fierce Pharma. 10 Oct 2012. https://www.fiercepharma.com/regulatory/pfizer-wraps-up-celebrex-suit-164m-settlement
66 “Pfizer beats profit estimates but lowers its 2018 revenue forecast.” CNBC. 31 Jul 2018. https://www.cnbc.com/2018/07/31/pfizer-beats-profit-estimates-on-higher-sales-of-prevnar-xeljanz.html
67 Office of Public Affairs. “GlaxoSmithKline to Plead Guilty and Pay $3 Billion to Resolve Fraud Allegations and Failure to Report Safety Data.” US Department of Justice. 2 Jul 2012. https://www.justice.gov/opa/pr/glaxosmithkline-plead-guilty-and-pay-3-billion-resolve-fraud-allegations-and-failure-report
68 Sullivan, Thomas. “GSK Chinese Bribery Scandal Ends in $489 Million Fine, Executive Sentenced.” Policy & Medicine. 6 May 2018. https://www.policymed.com/2014/09/gsk-chinese-bribery-scandal-ends-in-489-million-fine-executive-sentenced.html
69 Jourdan, Adam. “Spooked by probes, pharma executives ask: should I leave China?” Reuters. 12 Jun 2014. https://www.reuters.com/article/us-china-pharmaceuticals/spooked-by-probes-pharma-executives-ask-should-i-leave-china-idUSKBN0EO00V20140613
70 McKenna, Maryn. “After Years of Debate, the FDA Finally Curtails Antibiotic Use in Livestock.” Newsweek. 13 Jan 2017. https://www.newsweek.com/after-years-debate-fda-curtails-antibiotic-use-livestock-542428
71 McKenna, Maryn. “Despite Attempted Curbs, Animal Antibiotic Use in US Still Increasing.” National Geographic. 15 Apr 2015. https://www.nationalgeographic.com/science/phenomena/2015/04/15/fda-adufa2013/
72 Nair, DVT et.al. “Antibiotic-Resistant Salmonella in the Food Supply and the Potential Role of Antibiotic Alternatives for Control.” Foods. 2018 Oct;7(10):167. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6210005/
73 Sapkota, A.R. et.al. “Lower prevalence of antibiotic-resistant Salmonella on large-scale U.S. conventional poultry farms that transitioned to organic practices.” The Science of the Total Environment. 2014 Apr 1;476-477:387-92. https://www.ncbi.nlm.nih.gov/pubmed/24486494
74 Marler Clark. “Antimicrobial Resistance in Campylobacter Bacteria.” About Campylobacter. https://about-campylobacter.com/campylobacter-antimicrobial-resistance Retrieved 25 Jan 2019.
75 “Multistate Outbreak of Multidrug-Resistant Campylobacter Infections Linked to Contact with Pet Store Puppies.” US Centers for Disease Control and Prevention. 30 Jan 2018. https://www.cdc.gov/campylobacter/outbreaks/puppies-9-17/index.html
76 Fleming, Michaela. “Multidrug-Resistant Campylobacter Outbreak Emphasizes Need for Antibiotic Stewardship Practices in Pets.” Contagion Live. 20 Sep 2018. https://www.contagionlive.com/news/multidrug-resistant-campylobacter-outbreak-emphasizes-need-for-antibiotic-stewardship-practices-in-pets
77 “Antibiotic Resistance.” Campylobacter (Campylobacteriosis). US Centers for Disease Control and Prevention. https://www.cdc.gov/campylobacter/campy-antibiotic-resistance.html Retrieved 25 Jan 2019.
78 McKenna, Maryn. “The Abstinence Method.” Modern Farmer. 17 Jun 2014. https://modernfarmer.com/2014/06/abstinence-method/
79 McKenna, Maryn. “Despite Attempted Curbs, Animal Antibiotic Use in US Still Increasing.” National Geographic. 15 Apr 2015. https://www.nationalgeographic.com/science/phenomena/2015/04/15/fda-adufa2013/
80 Spellberg, Brad et.al. “Antibiotic Resistance in Humans and Animals.” National Academy of Medicine. 22 Jun 2016. https://nam.edu/antibiotic-resistance-in-humans-and-animals/
81 Wasley, Andrew et.al. “Critical Antibiotics Still Used on US Farm Animals Despite Superbug Crisis.” Bureau of Investigative Journalism. 19 Sep 2018. https://www.thebureauinvestigates.com/stories/2018-09-19/critical-antibiotics-still-used-us-farms
82 Expert Commission on Addressing the Contribution of Livestock to the Antibiotic Resistance Crisis. “Combating Antibiotic Resistance.” Antibiotic Resistance Action Center. 2 Jan 2018. http://battlesuperbugs.com/sites/battlesuperbugs.com/files/Expert%20Commission%20Report%2001.02.18.pdf#page=9
83 Spellberg, op.cit.
84 Dall, Chris. “Nearly a fourth of outpatient antibiotics unneeded, study finds.” Center for Infectious Disease Research and Policy. 17 Jan 2019. http://www.cidrap.umn.edu/news-perspective/2019/01/nearly-fourth-outpatient-antibiotics-unneeded-study-finds
85 “10 Facts About Antibiotics, Resistance, and Food Animal Production.” PEW Charitable Trusts. 5 May 2014. https://www.pewtrusts.org/en/research-and-analysis/fact-sheets/2014/05/05/10-facts-about-antibiotics-resistance-and-food-animal-production
86 Ebell, Mark H. and Taylor Radke. “Antibiotic Use for Viral Acute Respiratory Tract Infections Remains Common.” American Journal of Managed Care. 10 Nov 2015. https://www.ajmc.com/journals/issue/2015/2015-vol21-n10/antibiotic-use-for-viral-acute-respiratory-tract-infections-remains-common
87 Vaz, L.E. et.al. “Recent Trends in Outpatient Antibiotic Use in Children.” Pediatrics. 2014 Mar;133(3):375-385. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3934343/
88 “Antibiotic Use in the United States, 2017: Progress and Opportunities.” US Centers for Disease Control and Prevention. https://www.cdc.gov/antibiotic-use/stewardship-report/outpatient.html Retrieved 25 Jan 2019.
89 Kronman, MP et.al. “Bacterial Prevalence and Antimicrobial Prescribing Trends for Acute Respiratory Tract Infections.” Pediatrics. 2014 Oct;134(4). http://pediatrics.aappublications.org/content/134/4/e956.abstract
90 Hersh, AL et.al. “Principles of Judicious Antibiotic Prescribing for Upper Respiratory Tract Infections in Pediatrics.” Pediatrics. 2013 Dec;132(6). http://pediatrics.aappublications.org/content/132/6/1146
91 “Antibiotic Use in the United States: Progress and Opportunities.” US Centers for Disease Control and Prevention. 2017. https://www.cdc.gov/antibiotic-use/stewardship-report/pdf/stewardship-report.pdf Retrieved 25 Jan 2019.
92 “Core Elements of Hospital Antibiotic Stewardship Programs.” US Centers for Disease Control and Prevention. https://www.cdc.gov/antibiotic-use/healthcare/implementation/core-elements.html Retrieved 25 Jan 2019.
93 “Antibiotic Prescribing and Use in the US.” US Centers for Disease Control and Prevention. https://www.cdc.gov/antibiotic-use/stewardship-report/index.html Retrieved 25 Jan 2019.
94 Barnett, Michael L. and Jeffrey A. Linder. “Antibiotic Prescribing to Adults With Sore Throat in the United States, 1997-2010.” JAMA Internal Medicine. 2014;174(1):138-140. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/1745694
95 “CDC: 1 in 3 antibiotic prescriptions unnecessary” (press release). US Centers for Disease Control and Prevention. 3 May 2016. https://www.cdc.gov/media/releases/2016/p0503-unnecessary-prescriptions.html
96 “Get Smart: Know When Antibiotics Work.” Oklahoma State Department of Health. http://www.health.state.ok.us/program/cdd/ar/. (accessed May 22, 2006).
97 “Health Care-Associated Infections.” Patient Safety Primer. Agency for Healthcare Research and Quality. https://psnet.ahrq.gov/primers/primer/7 Retrieved 25 Jan 2019.
98 “Biggest Threats and Data.” US Centers for Disease Control and Prevention. https://www.cdc.gov/drugresistance/biggest_threats.html Retrieved 25 Jan 2019.
99 Gibson, Jeremy C. “Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients.” BMJ. 2004;329:15. https://www.bmj.com/rapid-response/2011/10/30/survey-patients-knowledge-nsaid-side-effects
100 Hochman, JS. “NSAID deaths. NSAIDs in the news.” Our Chronic Pain Mission. 2003. http:// www.cpmission.com/main/NSAIDSs2.html (accessed January 29, 2009).
101 Meschino, James P. “In the News: Dangers of Anti-Inflammatory Meds.” To Your Health. 2012 Jan;6(1). https://www.toyourhealth.com/mpacms/tyh/article.php?id=1508
102 De Jong, JCF et.al. “Combined use of SSRIs and NSAIDs increases the risk of gastrointestinal adverse effects.” British Journal of Clinical Pharmacology. 2003 Jun;55(6):591-595. https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1046/j.0306-5251.2002.01770.x
103 Li, D. K., L. Liu, and R. Odouli. “Exposure to non-steroidal anti-inflammatory drugs during pregnancy and risk of miscarriage: population based cohort study.” BMJ. 2003; 327 (7411):368. http:// www.bmj.com/cgi/content/full/327/7411/368
104 Merck. “Merck Announces Voluntary Worldwide Withdrawal of VIOXX.” (press release). September 30, 2004. http://www.merck.com/newsroom/vioxx_withdrawal/pdf/vioxx_press_release_final.pdf
105 Juni, P., L. Nartey, S. Reichenbach, R. Sterchi, P.A. Dieppe, and M. Egger. “Risk of cardiovascular events and rofecoxib: cumulative meta-analysis.” Lancet. 2004; 364 (9450):2021–9. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(04)17514-4/fulltext
106 Laurance, J. and S. Foley. “Safety review ordered into popular painkillers.” The Independent. 22 October 2004. http://www.independent.co.uk/life-style/health-and-wellbeing/health-news/safety-review-ordered-into-popular-painkillers-544615.html
107 US Senate Finance Committee. Testimony of David J. Graham, MD, MPH. November 18, 2004. http://finance.senate.gov/hearings/testimony/2004test/111804dgtest.pdf
108 Sardi, Bill. “Just How Many Americans Did Vioxx Kill?” Lew Rockwell (blog). April 21, 2006. http://www.lewrockwell.com/sardi/sardi53.html (accessed January 29, 2009).
109 Graham, op.cit.
110 “The Overuse of NSAIDs.” Physician’s Weekly. 18 Jul 2017. https://www.physiciansweekly.com/the-overuse-of-nsaids/
111 Wells, Nick and Meg Tirrell. “How doctors in the US prescribe opioids – four charts.” CNBC. 19 Apr 2018. https://www.cnbc.com/2018/04/19/how-doctors-in-the-us-prescribe-opioids–four-charts.html
112 “Opioid Addiction 2016 Facts & Figures.” American Society of Addiction Medicine. https://www.asam.org/docs/default-source/advocacy/opioid-addiction-disease-facts-figures.pdf Retrieved 25 Jan 2019.
113 Wells, op.cit.
114 Evans, W.N. et.al. How the Reformulation of OxyContin Ignited the Heroin Epidemic. National Bureau of Economic Research. April 2018. https://www.nber.org/papers/w24475
115 Cicero, T.J. et.al. The Changing Face of Heroin Use in the United States. JAMA Psychiatry. 2014;71(7):821-826. https://jamanetwork.com/journals/jamapsychiatry/fullarticle/1874575
116 Compton, W.M. et.al. Relationship between Nonmedical Prescription-Opioid Use and Heroin Use. New England Journal of Medicine. 14 Jan 2016; 374:154-163. https://www.nejm.org/doi/full/10.1056/NEJMra1508490
117 Fauber, John and Ellen Gabler. “Narcotics use for chronic pain soars among seniors.” Milwaukee-Wisconsin Journal Sentinel. 29 May 2012. http://archive.jsonline.com/watchdog/watchdogreports/narcotics-use-for-chronic-pain-soars-among-seniors-kg56kih-155555495.html/
118 Garrett, Linda. Pain Management in the Era of Opioid Addiction. California Hospital Association. https://www.calhospital.org/sites/main/files/file-attachments/garrett-3_up-painmanagementslides.pdf
119 Lopez, German. “Drug overdose deaths were so bad in 2017, they reduced overall life expectancy.” Vox. 29 Nov 2018. https://www.vox.com/science-and-health/2018/11/29/18117906/opioid-epidemic-drug-overdose-deaths-2017-life-expectancy
120 Schulman, K. A., E. A. Stadtmauer, S. D. Reed, H.A. Glick, L. J. Goldstein, J. M. Pines, J. A. Jack- man, S. Suzuki, M. J. Styler, P. A. Crilley, T. R. Klumpp, K. F. Mangan, and J. H. Glick. “Economic analysis of conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer.” Bone Marrow Transplant. 2003; 31 (3):205–10.
121 Hassett, M. J., A. J. O’Malley, J. R. Pakes, J. P. Newhouse, and C. C. Earle. “Frequency and cost of chemotherapy-related serious adverse effects in a population sample of women with breast cancer.” J Natl Cancer Inst. 2006; 98 (16):1108–17.
123 Morgan, G., R. Ward, and M. Barton. “The contribution of cytotoxic chemotherapy to 5-year survival in adult malignancies.” Clin Oncol (R Coll Radiol) 2004; 16 (8):549–60.